Diagnosis A Symptom-based Approach in Internal Medicine

Diagnosis A Symptom-based Approach in Internal Medicine

CS Madgaonkar MBBS FCGP Consultant Family Physician Hubli, Karnataka, India Honorary National Professor Indian Medical Association College of General Practitioners Chennai (HQ), Tamil Nadu, India

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First Edition : 2011 ISBN 978-93-80704-75-3 Typeset at JPBMP typesetting unit Printed in India Dedicated to The memory of my dear brothers Ramakant and Vasant

PREFACE

The best physician is the one who is able to differentiate the possible and the impossible. Herophilus of Alexandria Diagnosis: A Symptom-based Approach in Internal Medicine was conceived during my practice in general internal medicine. I wrote this book because I wished it had been written for me. Although there are many textbooks and excellent manuals devoted to symptom-oriented diagnosis, I personally felt the need for a book that provides the essential information necessary in a concise and practical method, and thus relieve one from time and labor in searching through voluminous medical textbooks on the diagnostic process of symptoms presented by patients in today’s arduous ambulatory health care delivery system. A symptom is commonly defined as,”Any affection which accompanies disease; a perceptible change in the body or its functions, which indicates disease, or the kind or phases of disease”. The importance of symptoms, therefore, cannot be overemphasized because symptoms are why patients visit physicians; and based on their analysis, a physician attempts to make as accurate a clinical diagnosis as possible. Many symptoms encountered in everyday practice may suggest undifferentiated problems and many may suggest problems that are self-limited, while many symptoms are characteristic of early disease. New or serious symptoms often drive patients to overcrowded office or emergency departments. However, physicians need medical resource that can deliver timely and effective diagnostic information which, besides providing diagnosis on an established or common disease, does not ignore other possibilities. Besides, relevant diagnostic investigations and clinical aspects of related disorders are essential to support the diagnosis of any disease and treatment accordingly. Thus, in a busy ambulatory care, diagnosis has to be made without it being unrecognized until advance disease is present, treatment options are limited, and prognosis may be unfavorable. It is in this context, I have made an attempt to first project common symptoms encountered in internal medicine, especially as applicable to the epidemiological incidence to the adult patient population, and then create a framework in which a physician can arrive at a tentative diagnosis. The main features which remain constant for each symptom are: • Synopsis: A symptom introduction in brief; • of the symptom: Classified in three main groups, namely—common, occasional and rare; • Investigations: In two sections, namely—general and specific; • Clinical notes: In short paragraphs, helpful in the diagnosis of most of the diseases; • Red flags: Key points highlighted to alert serious disorders not to be missed; • Tables: To simplify and comprehensively illustrate text, wherever needed; • Selective glossary: Brief summary of assorted, common and uncommon diseases, denoted by the sign “vide infra ↓↓”; and • References: From various journals, textbooks, etc. where applicable. viii

Thus, the contents of this book are focused on commonly encountered symptoms, with their differential diagnosis in a concise form, which will lead to a working diagnosis and investigations. The emphasis is on the axiom, ‘common diseases present commonly, and its converse, uncommon diseases present uncommonly’. However, pointers to ‘red flags’, i.e. uncommon manifestations of common diseases should alert the physician of serious diseases not to be missed. No attempt has been made to discuss etiology or pathology of illness, or the complexities of practice management. The frequency with which a disease is encountered by physician will depend upon its prevalence in the region from which their patients are drawn and also their specialty; therefore, regional variations in the incidence of diseases or methodology, or guidelines for investigations and diagnosis are not discussed, which can be accessed from other relevant sources. The book assumes much basic knowledge and the information it contains must be supplemented by further reading. However, my endeavor has been to cover a spectrum of symptoms, with emphasis on practical features of diagnosis, based on recent evidence-based guidelines. The contents of the book are intended for medical students, internists, and house-officers during their daily office or hospital practice, and also to physicians to boost their diagnostic skills during busy practice day, and preparation for ‘rounds’ and clinical teaching. I also anticipate that physicians of other specialties will also value this book as an easy-to-use ready-reference guide beyond their everyday experience and in various practice settings. There is no substitute for knowledge, and this book, I believe, will make symptom-based diagnostic process more accessible to many physicians, and if it prompts others to delve further and achieve sophistication in this clinical expertise, then this book has accomplished its purpose. Finally, I would welcome feedback, which can be posted to me via my website: www.drcsm.com, or email: [email protected], or to the publishers.

CS Madgaonkar ACKNOWLEDGMENTS

My work in writing this book has been shared among many individuals. First of all, I would like to appreciate the comments and advice of the following eminent specialists who reviewed appropriate chapters of this book: • Dr Vidya C Madgaonkar MD DA, Professor of Anesthesiology, Bangalore Medical College and Research Institute, Bengaluru, Karnataka, India. • Dr AS Guruprasad MS, Fellow Sankara Nethralaya, Head of Vitreoretinal Services, MM Joshi Eye Institute, Hubli, Karnataka, India. • Dr Shailesh E Gokavi MD, Infertility Consultant and Gynecological Endoscopic Surgeon, Hubli, Karnataka, India. • Dr Neminath R Patil MS DLO, Consulting ENT Surgeon, Shravan ENT Neuro-Otology Clinic, Hearing Aid Center, Hubli, Karnataka, India. I have received most generous assistance from the former Dean Dr YS Rai FRCS (Ed), SDM College of Medical Sciences and Hospital, Manjushree Nagar, Sattur, Dharwad, Karnataka for extending Central Library facilities, and also to the library staff, who took immense care and pains to provide innumerable references in the compilation of this book. I would also like to sincerely thank the library staff of my alma mater, Kasturba Medical College, Manipal, Karnataka, India who have been a consistent resource. My sincere thanks are extended to Shri Jitendar P Vij (Chairman and Managing Director), and Mr Tarun Duneja, (Director-Publishing), M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India who have helped me throughout and displayed patience, understanding and professionalism in publishing this book. I would also like to record my appreciation from Mr Venu Gopal V, (Bengaluru branch) for extending his cooperation at every step. I owe a debt of gratitude to my dear mother, Smt Sumitra S Madgaonkar, for her unstinted support, encouragement, and forbearance. Thanks, as ever, also goes to my other family members and friends, for their constant support, guidance and encouragement. The true kudos, however, belong to my wife, Dr Vidya, and my son, Varun, for their eternal patience and incredible support throughout, which ultimately made this book a realty.

CONTENTS

1. ...... 1 Common 1; CBC 2; ESR 2; Urinalysis 2; Stools 2; LFTs 2; AXR 2; US Abdomen/Pelvis 2; Tuberculin or PPD and Casino’s Test 3; Serum Lipase 3; CT/MRI Scan 3; MRI Angiography 3; Diagnostic Paracentesis 3; Laparoscopy with Biopsy 3; Exploratory Laparotomy 3; Functional GI Disorders (FGIDs) 4; Meigs Syndrome 5; Proctalgia Fugax 5; Rumination Syndrome 5; Spontaneous Bacterial Peritonitis (SBP) 6 2. ...... 7 Common 10; Occasional 10; Rare 10; CBC 10; ESR 10; Urinalysis 10; 10; Blood Glucose 10; LFTs, Amylase, Lipase 11; Urea, Creatinine, Electrolytes 11; ECG 11; Pregnancy Test 11; US Abdomen 11; HRCT Scan 11; MRI 11; Endoscopy 11; CXR—Upright View 12; AXR 12; Magnetic Resonance Cholangiopancreatography (MRCP) 12; Endoscopic Ultrasound (EUS) 12; Radionuclide Scans 12; Angiography 12; Other Imaging 12; FNAC and Biopsy 13; Paracentesis 13; Laparoscopy 13; Surgical Exploration 13 3. Amenorrhea...... 18 Primary Amenorrhea 19; Occasional 19; Rare 19; Secondary Amenorrhea 19; Pregnancy Test 19; US of Pelvis 21; TFTs 21; ESR 21; Blood Glucose 21; Urea, Creatinine, Electrolytes, LFTs 21; RF, ANA 21; Physical Examination 21; Endocrine Hormone Assays 21; Serum Prolactin (PRL — Normal Reference- <25 ng/ml) 21; Serum LH, FSH 21; DEHA-S 21; Free Testosterone 21; Progestin Challenge (Withdrawal) Test 21; Estrogen-progestin Challenge (Withdrawal) Test 22; Dexamethasone Suppression Test 22; MRI/CT Scan—Brain 22; Karyotyping 22; Laparoscopy 22; Hysteroscopy 22 4. Anxiety ...... 25 Common 26; Occasional 26; Rare 26; Blood Glucose 27; Thyroid Profile 27; ECG 27; 24-hour Urine for Catecholamines 27; Serum Insulin/C Peptide 27; 24-hour Holter Monitor 27; CT Scan/MRI Pancreas 27; EEG 27 5. Arthralgia and Arthritis ...... 29 Common 29; Occasional 30; Rare 30; CBC 31; ESR, CRP 31; RF 31; Serum Uric Acid 31; X-rays 31; ASO Titer 31; Blood Culture 31; ANA 31; Anti-double-stranded DNA (anti-dsDNA); Antibody 32; Anti-Smith (anti-Sm) Antibody 32; Cytoplasmic Antineutrophilic Cytoplasmic (C-ANCA) Antibody 32; Cyclic Citrullinated Peptide (CCP) Antibody 32; Human Leukocyte Antigen (HLA - B27) Typing 32; HLA DR4/ DR1 Typing 32; Serology 32; TFTs 32; US with Duplex Scanning 32; CT/MRI 32; Synovial Fluid Analysis 32; Synovial Biopsy (Diagnostic Arthroscopy) 32 6. Back Pain ...... 36 Common 37; Occasional 37; Rare 37; CBC, ESR, CRP 38; Urinalysis 38; Spine X-ray 38; Sr Calcium, Phosphorus, Alk Phosphatase, Acid Phosphate 38; Sr Uric Acid 38; PSA 38; xii Diagnosis: A Symptom-based Approach in Internal Medicine

Plasmoprotein Electrophoresis 38; Bence Jones Protein 38; CXR 38; US Abdomen 38; CT Spine 39; HRCT Abdomen 39; MRI Spine 39; Bone Scans (Technetium) 39; Upper GI Endoscopy 39; CSF Analysis 39; Electrodiagnosis 39; Histocompatibility Antigen Test (HLA-B 27) 39; Myelography, Discography, Diagnostic Selective Nerve Blockade 39; Bone Marrow Biopsy/Aspiration 39 7. Breast Lump ...... 42 Common 42; Occasional 43; Rare 43; CBC 43; ESR 43; LFTs 43; Serum Calcium 43; CXR 43; Mammography 43; Digital Mammography 43; FNAC or FNA Biopsy (FNAB)†† 44; US Breast 44; US Abdomen 44; MRI 44; Core-needle Biopsy 44; Excision Biopsy 44; Triple Diagnosis Test 44; Genetic Testing for Breast Cancer 44 8. ...... 48 Common 49; Occasional 49; Rare 49; CBC 50; Blood Glucose/Lipid Profile 50; ECG 50; CXR 50; Cardiac Enzymes 50; Exercise ECG 51; Echocardiography – 2-D and Doppler 51; HRCT/ MRI 51; Ventilation-perfusion (V/Q) Scans 51; Myocardial Perfusion Imaging 51; Coronary Angiography 51; Intravascular Ultrasound (IVUS) 51; Multislice Computed Tomography (MSCT)/ 64-Slice Spiral Computed Tomography 52; GI Studies 52; PFTs 52; TFTs 52 9. ...... 57 Common 58; Occasional 58; Rare 58; CBC 58; ESR 58; FOBT 58; Proctoscopy (Anoscopy) 58; Urea, Creatinine, Electrolytes 58; Endocrine Panel 58; Serum Calcium 59; AXR 59; US Abdomen 59; Colonoscopy 59; Sigmoidoscopy/Barium Enema 59; MRI—Brain, Spine 59; Expanded Physiological Studies 59; Rectal Biopsy 59 10. Convulsions ...... 63 Common 64; Occasional 64; Rare 64; CBC 64; Blood Glucose 65; Serum Electrolytes 65; ECG 65; Neuroimaging 65; Biochemistry Panel 65; CSF 65; EEG 65; Ambulatory EEG (aEEG) 65; Video-EEG Monitoring2, 3 65; Toxicology (Serum and Urine) Screen 65 11. ...... 68 Common 69; Occasional 69; Rare 69; CBC 69; 69; CXR 70; Peak Expiratory Flow Rate (PEFR) 70; PFTs 70; Pulse Oximetry 70; pH Studies 70; CT Chest /MRI 70; CT Sinus 70; Esophagogastroduodenoscopy (EGD) 71; Bronchoscopy 71; Purified Protein Derivative (PPD) Skin Test 71; HIV Serology 71; Culture of Nasopharyngeal Secretions/PCR 71; Sputum Cytology 71 12. Dementia ...... 73 Common 74; Occasional 75; Rare 75; CBC 75; ESR 75; Urea, Creatinine, LFTs 75; Electrolytes— Sodium, Potassium, Calcium, Glucose 75; TFTs 75; Neuroimaging—CT/MRI 76; Infection Screen 76; Vitamin B12 Assay 76; VDRL/Fluorescein Treponema Antibody (FTA-ABS) 76; HIV Serology 76; ANA, Anti-ds DNA 76; CSF 76; CXR/ECG 76; EEG 76; SPECT/PET 76; MR Angiography (MRA) 77; Brain and Meningeal Biopsy 77; Genetic Test 77; Neuropsychologic evaluation 77 13. ...... 83 Common 84; Occasional 84; Rare 84; CBC 84; ESR 84; Blood Glucose 84; Metabolic Panel 84; HIV 84; Fecal Leukocytes 84; Rectal Swab for c/s 85; FOBT 85; Stool for Protozoa 85; Stools for Contents xiii

Clostridium Difficile Titer 85; Stool pH 85; Stool for ZN Stain (Modified) 85; Stool Chemical Analysis 85; Stool Fat (Sudan Stain) 85; TFTs 85; LFTs 85; Sigmoidoscopy with Biopsy and Culture 85; Colonoscopy or Barium Enema 85; US or CT Abdomen 85; Upper GI Barium Series 86; Laxative Abuse Detection 86; Urine 24-hr Collection for 5-HIAA Excretion 86; Serum Gastrin 86; Serum Calcitonin 86 14. Dyspepsia...... 90 Common 90; Occasional 91; Rare 91; CBC 91; ESR 91; FOBT and Parasites 91; ECG 91; Metabolic Panel 91; TFTs 91; LFTs, Amylase, Lipase 91; EGD with or without Biopsy for H. pylori (HP) 92; Tests for HP 92; US Abdomen or CT 92; Esophagography and upper GI Barium Meal Series 92; Esophageal Manometry 92; 24-hour esophageal pH Manometry 93; Fasting Serum Gastrin 93 15. ...... 97 Oropharyngeal Causes 98; Esophageal Causes 99; CBC, ESR 99; CXR 99; X-ray Neck—lateral view 99; Barium Swallow (Barium Esophagography, or Modified Barium Swallow (MBS) 99; EGD 100; Esophageal Manometry (Stationary and Ambulatory) 100; Esophageal 24-hours pH Reflux Study 100; Videofluoroscopic Swallowing Function Study (VSFS) 101; Radionucleotide Study (Tc-99m Sulfur Colloid Bolus) 101; CT Scan/MRI 101; Muscle Enzymes 101; TFTs 101; RF, ANA 101; Antiacetylcholine Antibodies 101; Genetic Analysis 101; Common 108 16. Dyspnea—Acute ...... 108 Occasional 109; Rare 109; CBC 109; Blood Glucose, Electrolytes, Urinalysis 109; Peak Expiratory Flow Rate (PEFR) 109; ECG 109; CXR 109; X-ray Neck—Lateral View 109; Pulse Oximetry 109; Sr Cardiac Markers 110; Sputum and Blood Culture 110; Pulmonary Function Tests 110; Arterial Blood Gases (ABG) 110; Bronchoscopy 110; D-dimer 110; HRCT of Thorax 110; V/Q scan 110; BNP (Brain or B-type Natriuretic Peptide) 110; Echocardiography 110; Drug Screen 110 17. Dyspnea—Chronic ...... 114 Common 114; Occasional 115; Rare 115; CBC 115; Sputum 115; CXR 115; Pulse Oximetry 115; ECG 115; Metabolic Panel 115; Blood Chemistry 116; PFT/Spirometry 116; Methacholine Challenge Test 116; Echocardiography 116; B-type Natriuretic Peptide (BNP) 116; HRCT 116; HRCT Angiography 117; V/Q Scan 117; 24-hour Esophageal pH Monitoring 117; EMG and NCS 117; Noninvasive Cardiovascular Testing 117; Cardiopulmonary Exercise (CPEx) Testing 117; Bronchoscopy / Biopsy 117 18. Facial Asymmetry and Weakness ...... 120 Common 121; Occasional 121; Rare 121; CBC 121; Blood Glucose 121; VDRL 121; CXR 121; CT Skull 121; MRI with Gadolinium 121; CSF 121; EMG/NCS 122; Lyme titer 122; Serum Calcium and Angiotensin-converting Enzyme Levels 122 19. Facial Swelling ...... 127 Common 127; Occasional 127; Rare 128; CBC 128; ESR 128; Urinalysis 128; Plasma Protein 128; Urea, Creatinine 128; Blood Glucose 128; CXR 128; X-ray PNS 128; TFTs 128; ANA 128; Parotid Sialography 128; CT/MRI Brain 128; CT/MRI , Abdomen 128; CT/MRI PNS 128; Plasma/urinary Cortisol 129; Muscle Biopsy (Bx) 129 xiv Diagnosis: A Symptom-based Approach in Internal Medicine

20. Fever of Unknown Origin ...... 131 Common 132; Occasional 132; Rare 132; CBC, PS. 132; ESR 132; Culture 132; Urinalysis 133; PPD or Mantoux Test 133; CXR 133; Plain X-ray of Bones 133; US Abdomen, Pelvis 133; LFT 133; Sputum 133; Stool Microscopy and Culture 133; Blood Glucose 133; CSF 133; HRCT Abdomen/Pelvis 133; Nuclear Imaging 134; FNAC and Directed Biopsies 134; Leg Doppler Imaging 134; Echocardiography 134; Serological Tests 134; HRCT Chest 134; Endoscopic Procedures 134 21. Gait Disorders ...... 138 Common 139; Occasional 139; Rare 139; CBC 139; ESR 139; X-ray 139; ECG 139; MRI Brain/spinal cord 139; CT Brain 140; CSF 140; Serum Electrolytes 140; Muscle Enzymes 140; TFTs 140; RA factor and ANA 140; Serum B12 and Folate Levels 140; EMG/NCS 140; Genetic Testing 140; Drug Screen 140; Muscle Biopsy 140 22. Gastrointestinal Bleeding ...... 146 Common 147; Occasional 147; Rare 147; CBC 148; Coagulation/clotting screen 148; Serum Chemistry/Serology 148; LFTs 148; ECG 148; EGD 148; Sigmoidoscopy 149; Colonoscopy 149; Angiography (Mesenteric) 149; Multidetector Computed Tomographic (MDCT) Angiography 149; 99mTc RBC Scanning 149; Abdomen US/HRCT 149; Double-contrast Barium Enema 149; Small Bowel Imaging 149; Capsule Endoscopy 149; Echocardiography 150; Laparotomy with Intraoperative Enteroscopy 150 23. Headache ...... 155 Common 156; Occasional 156; Rare 156; CBC 156; ESR 156; Skull X-ray 156; X-ray PNS 156; Blood Culture 156; Biochemistry 156; CXR/spine X-ray 157; CT 157; CSF 157; MRI 157; Temporal Artery Biopsy 157; PET/SPECT Imaging 157; MR Angiography (MRA) 157; IOP 158 24. Hearing Loss ...... 163 Common 164; Occasional 165; Rare 165; CBC 165; ESR 165; Blood Glucose 165; Serology for Syphilis 165; TFTs 165; Pure tone Audiometry 165; Speech Audiometry 165; Tympanometry 166; CT Scan of the Temporal Bones (without contrast) 166; MRI of the Head (Gadolinium-enhanced) 166; Brainstem Auditory Evoked Responses (BAERs) 166; Electrocochleography 166 25. Hematuria ...... 170 Common 171; Occasional 171; Rare 171; CBC 171; ESR 171; Urine Dipstick 171; Urine Microscopy/culture 172; US 172; X-ray KUB 172; Multichemistry profile 172; Hb electrophoresis 172; HRCT—KUB 172; IVP/IVU 172; Cystoscopy 172; Urine for Schistosomiasis 173; Urine Cytology 173; Biopsy: Renal / bladder/ prostate 173 26. ...... 176 Common 177; Occasional 177; Rare 177; CXR 177; Bronchoscopy 177; Sputum Gram Stain, AFB Smear, Culture, and Cytology 178; CBC 178; ESR 178; Coagulation Screen 178; Mantoux Test 178; ECG 178; Pulse Oximetry 178; HRCT Scan 178; Multidetector CT (MDCT) 178; D-dimer 179; Echocardiography 179; V/Q lung scan 179; c-ANCA (Classical or Cytoplasmic Antineutrophil Cytoplasmic Antibodies) 179; HIV 179; Lung Biopsy—(Bronchoscopic or Video-assisted Thorascopic Surgery, i.e. VATS) 179 Contents xv

27. ...... 184 Common 185; Occasional 185; Rare 186; CBC, Blood Film 186; ESR 186; Urea/creatinine 186; Electrolytes—Na, K, Ca 186; LFT 186; Fluoroscopy of Diaphragmatic Movement 186; CXR 186; ECG7 186; EGD 186; US Abdomen 186; CT Scan Chest 186; MRI Brain 186; Bronchoscopy 187; Echocardiography 187; CSF 187 28. Insomnia ...... 189 Common 190; Occasional 190; Rare 190; CBC 190; TFTs 190; ECG 190; Pulse Oximetry 190; Sleep Diary 191; Polysomnography (Sleep Study) 191; Actigraphy 191; CT/MRI Brain 191; Mini-Mental State Examination (MMSE) and Geriatric Depression Scale 191; Drug Toxicology Screen 191 29. ...... 195 Common 196; Occasional 196; Rare 196; CBC 197; ESR 197; Urinalysis 197; Serum Bilirubin 197; Serum Albumin 197; Prothrombin Time (PT) 197; Hepatic transaminase enzymes 198; Serum Alkaline Phosphatase (SAP) 198; Acute Viral Hepatitis Serology Markers (A, B, C and D) 198; Ultrasound (US) 198; Serum Amylase 200; HIV Serology 200; CT Scanning 200; Endoscopic Retrograde cholangiopancreatography (ERCP) 200; Magnetic Resonance Cholangiopancreatography (MRCP) 200; X-ray 200; Antimitochondrial antibodies 200; Autoantibody Tests 200; Serum Copper/ceruloplasmin 200; Serum Iron 200; Leptospirosis 200; Coombs’ Test 200; Biopsy 200 30. Myalgia ...... 205 Common 206; Occasional 206; Rare 206; CBC 206; ESR 206; Urine 206; CPR 206; CK (with isoenzymes) 206; FBG, PPBG 207; Calcium 207; Electrolytes 207; Sr Alkaline Phosphate 207; TFTs 207; ANA, RF 207; X-rays 207; EMG 207; NCS 207; MRI 207; Endocrine/metabolic panel 207; Muscle biopsy/genetic analysis 207 31. and ...... 211 Common 212; Occasional 212; Rare 212; CBC 212; ESR 212; Urea, Creatinine, Electrolytes 212; LFTs, Amylase, Lipase 213; CXR 213; AXR 213; ECG 213; Blood Glucose 213; Serum Calcium 213; Urine 213; Pregnancy Test 213; US Abdomen and Pelvis 213; HRCT Abdomen 213; CT scan/MRI—Head 213; Upper GI/Barium Enema X-rays 213; Nuclear Scintigraphy 213; Audiometry 213; Toxicology Screen 213 32. Pain—Chronic ...... 218 Common 219; Occasional 220; Rare 220; CBC 220; ESR or CRP 220; Blood Glucose 220; Serum Calcium/Alkaline Phosphatase 220; Urea, Creatinine, Electrolytes 220; CPK 221; X-ray/CT scan 221; MRI 221; Bone Scan 221; NCS/EMG 221; Cancer Screen/Tumor Markers 221 33. Palpitation ...... 225 Common 226; Occasional 226; Rare 226; ECG 226; CBC 226; Blood Glucose 226; Ambulatory ECG (AECG) Recording/Holter Monitoring 226; Electrophysiological Studies (EPS) 227; Continuous —Loop Event Recorder 227; Continuous Mobile Cardiac Outpatient Telemetry (MCOT) 228; Pacemaker Evaluation 228; Exercise ECG/TMT 228; Echocardiography 228; TFTs 228; Urea, Creatinine, Electrolytes 228; Urine 228; Drug Levels 228 xvi Diagnosis: A Symptom-based Approach in Internal Medicine

34. Polyuria ...... 234 Common 235; Occasional 235; Rare 236; Urinalysis 236; CBC 236; Blood Glucose 236; 24-hour urine specimen 236; Serum Urea, Creatinine, Electrolytes 236; Serum Calcium 236; Ultrasound 236; 24-hour Urinalysis 236; Water deprivation test 236; Plasma vasopressin (ADH) 237; US of Neck 237; CT/ MRI 237; Renal Biopsy 237 35. Pruritus ...... 241 Common 241; Occasional 242; Rare 242; CBC 242; Urinalysis 242; Stool Examination 242; Microscopy of Skin Scrapings 242; Potassium Hydroxide (KOH) 10-20% mounts 242; Blood Glucose 243; Serum Calcium 243; LFTs 243; Blood Urea, Creatinine, Electrolytes 243; TFTs 243; CXR 243; Serum ferritin 243; Serology 243; Serum Protein Electrophoresis 243; Urine for 5-hydroxyindoleacetic Acid (5-HIAA) 243; Antimitochondrial Antibody 243; US Abdomen 243; HRCT—Chest and Abdomen 243; ERCP (Endoscopic Retrograde Cholangiopancreatography) 243; Lymph Node Biopsy 244; Bone Marrow Aspirate and Biopsy 244; Skin Biopsy for Direct Immunofluorescence with Special Stains 244; Radioallergosorbent Tests (RASTs) or Patch Test 244; Tumor Markers 244 36. Red Eye ...... 249 Common 249; Occasional 249; Rare 250; ESR 250; Blood Glucose 250; Gram’s Stain of Conjunctival Exudates 250; Culture of Exudate 250; Immunofluorescent PCR Tests 250; Orbital US 250; Orbital CT Scan 250; RF, ANA 250; HLA-B27 250; Syphilis Serology 250 37. Sexual Dysfunction ...... 254 Common 255; Occasional 256; Rare 256; Blood Glucose 256; Lipid Profile 256; TFTs 256; Chemistry Panel 256; Serum Testosterone-free (AM Sample) 256; Microscopy/Culture 256; Serum Prolactin (PRL) 256; LH and FSH 256; Nocturnal Penile Tumescence (NPT) 257; Intracavernosal Injection and Sexual Stimulation 257; Penile Duplex US 257; Perineal and Clitoral Electromyography 257; Pelvic Arteriography 257; US Testis and Pelvis 257; CT/MRI Scan 257 38. Sweating Abnormalities ...... 263 Hyperhidrosis 264; Common 264; Occasional 264; Rare 264; Hypohidrosis and anhidrosis 264; Common 264; Occasional 264; Rare 265; CBC 265; ESR 265; TFTs 265; Blood Glucose 265; Urea, Electrolytes 265; Purified Protein Derivative (PPD) 265; HIV 265; CXR 265; Blood Culture 265; Iodine Starch Test 265; Urinary Catecholamines 265; Urinary 5-hydroxyindoleacetic Acid (5-HIAA) 265; Biopsy 265; Sudomotor Testing 266 39. Swelling of the Legs...... 269 Common 269; Occasional 270; Rare 270; CBC 270; Urinalysis 270; Serum Protein (total) 270; Lipid Profile 270; LFT 270; TFTs 270; ECG 270; Duplex US (Compression US) with Doppler 270; D-dimer Test 271; Brain Natriuretic Peptide (BNP) 271; Magnetic Resonance Venography (MRV) 271; US/CT Abdomen/Pelvis 271; Echocardiogram 271; Serology for Hypercoagulability State 271; Biopsy 271; Acquired 273; Inherited 273; Risk Factors 273 40. Syncope ...... 276 Common 277; Occasional 277; Rare 277; ECG 277; Blood Glucose 277; CBC 277; Urea, Creatinine, Electrolytes 277; CXR 277; Cardiac Enzymes 278; Stress ECG 278; Contents xvii

Echocardiography 278; Holter Monitor 278; Carotid Doppler US 278; CT/MRI brain 278; Head-up Tilt-Testing 278; Electrophysiology study (EPS) 278; Implantable Loop Recorder (ILR) 278; Electroencephalography (EEG) 278; Psychiatric Evaluation 279 41. Tingling and Numbness ...... 284 Common 285; Occasional 285; Rare 285; Transient 286; Upper Limbs 286; Lower Limbs 286; CBC 286; ESR 286; Blood Glucose, Urea, Creatinine, Electrolytes 286; CXR 287; X-ray 287; TSH 287; Rheumatology Screen 287; Angiotensin-Converting Enzyme Level 287; Urine for Porphobilinogen 287; Nerve Conduction Study (NCS) 287; CT/MRI 287; Nerve Biopsy 287; Lyme Titer 287; HIV 287; Serum B12 and Folate Levels 287; CSF Analysis 287; Serum Protein Electrophoresis and Immuno-fixation 287; Toxic Screen 287; Genetic Test 287 42. Tinnitus ...... 291 Common 292; Otologic 292; Nonotologic 292; Physiological 292; Occasional 292; Rare 292; CBC, ESR 292; FBG, PPBG 293; Audiogram 293; Tympanogram 293; Biochemistry 293; TFTs 293; CT Scan 293; MRI Scan 293; MRI Cerebral Angiography 293; X-ray 293; CSF 293; Brainstem Evoked Potentials 293 43. Tiredness ...... 296 Common 296; Occasional 297; Rare 297; CBC 297; ESR 297; Blood Glucose 297; LFTs 297; Urea, Electrolytes and Creatinine 297; TFTs 297; Pregnancy Test 297; CXR 297; Chronic Infection Screening 297; HIV and VDRL Serology 298; RF and ANA 298; Plasma Cortisol (8 AM-10 AM specimen) 298; Muscle Enzymes CK, CK-MB 298; Tensilon (edrophonium) Test 298; EMG 298; Muscle / Tissue Biopsy 298; Bone Marrow Biopsy/Aspirate 298; MRI Brain 298; Polysomnography (Sleep Study) 298; Cancer Screening 298 44. Urinary Frequency ...... 302 Common 303; Occasional 303; Rare 303; Urinalysis 304; Quantitative Culture for Bacteriuria 304; Suprapubic Aspiration/ Catheterization 304; CBC 304; Blood Glucose 304; Urea, Creatinine 304; Electrolytes 304; Pregnancy Test 304; Urine Culture 304; US of Kidneys, Ureter, and Bladder (KUB) 304; CT scan of KUB 304; Intravenous pyelography (IVP) or Intravenous Urography (IVU) 305; MRI Brain/Spine 305; Cystoscopy 305 45. Urticaria and Angioedema ...... 308 Occasional 309; Rare 309; CBC 309; ESR 309; Urinalysis 309; Stools 309; Challenge Testing for Physical Urticaria 310; Throat and Urine Culture 310; Multichemistry Screening Panel 310; TFTs 310; Serology 310; Skin Prick Test or Patch Test 310; Serum Immunoglobulin Analysis 310; Autologous Serum Skin Test (ASST) 310; Serum Complement 310; Cold Agglutinins and Cryoproteins 311; ANA 311; Skin Biopsy 311 46. Vaginal Bleeding—Abnormal ...... 315 Common 316; Occasional 316; Rare 316; Pregnancy Test 316; CBC 316; Coagulation Profile 317; Blood Sugar 317; Pap Smear 317; Cervical Culture 317; Thyroid Function Test 317; Pelvic US 317; Transvaginal Ultrasound (TVUS) 317; Saline Infusion Sonography (SIS): Conventional and 3D-SIS 317; Hysteroscopy 318; Coagulation Profile 318; Serum Progesterone 318; LH, FSH 318; Prolactin (PRL) 318; Serum Testosterone, Free Testosterone, 17-Hydroxyprogesterone 318; Urinary Gonadotropins 318; Abdominal CT xviii Diagnosis: A Symptom-based Approach in Internal Medicine

Scan 318; MRI of Pituitary 318; Endometrial Biopsy (EMB) 318; Pelvic Examination 321; Digital Rectal Examination (DRE) and Proctoscopy 321 47. Vertigo ...... 323 Common 324; Occasional 324; Rare 325; CBC 325; ESR 325; Audiometry 325; CT Head 325; MRI and Angiography 325; Brainstem Evoked Response (BSER) 325; Carotid Doppler Ultrasound 325; ECG/Holter Monitor 325; EEG 325; X-ray Cervical Spine 325 48. Vision Loss—Gradual...... 330 Common 331; Occasional 331; Rare 331; CBC 331; ESR 331; Blood Glucose/HbA1C 331; Lipid Profile 331; Coagulation Screen 331; TFTs 331; IOP (Tonometry) 331; Visual Field (Perimetry) 332; Fluorescein Angiography 332; US of Eye and Orbits 332; CT Scan Skull, Orbits/MRI Brain 332; Carotid Doppler Scan 332; Echocardiogram 332; Visual evoked response (VER) 332; Temporal Artery Biopsy 332 49. Vision Loss—Sudden ...... 335 Common 335; Occasional 336; Rare 336 50. Weakness in the Arms and Legs ...... 339 Occasional 340; Rare 340; CBC 340; ESR 340; Blood Glucose 340; Biochemistry and Metabolic Panel 341; Thyroid Function Tests 341; CT Scan Brain 341; X-ray Skull, Cervical and Lumbosacral Spine 341; CXR 341; Blood Culture 341; Creatine Kinase (total)—(CK) 341; Serum Acetylcholine Receptor Antibody Titer 341; ANA 341; Tensilon (Edrophonium Chloride) Test 341; Urine 341; CT—Thorax 341; MRI—Cervical and Lumbosacral Spine 341; Magnetic Resonance Angiography (MRA) 342; US (Duplex Scanning) of Carotid and Vertebral Arteries in the Neck 342; CSF Analysis 342; Nerve Conduction Study (NCS) 342; Electromyography (EMG) 342; Muscle Biopsy 342 51. Weight Loss...... 346 Common 347; Occasional 347; Rare 347; CBC 347; ESR 347; Urinalysis 347; Blood Glucose 347; HIV 347; Urea, Creatinine, Electrolytes 347; Tuberculin or PPD Test 347; LFTs 348; TFTs 348; Serum Calcium 348; CXR 348; Stool 348; US Abdomen / Pelvis 348; Endoscopy 348; CT / MRI abdomen 348; Fecal Fat 348; Antigliadin Antibodies 348; Other Screening Procedures 348

Index ...... 351 CHAPTER 1 Abdominal Distension

SYNOPSIS mnemonic device the causes can be remembered as five ‘fs’: fat (obesity), fluid (), flatus Abdominal distension* may be defined as an (gastrointestinal), fetus (pregnancy), and feces increase in the girth of the abdomen. It is noticed (constipation). However, abdominal distension/ by the patient because of the increase in belt or may be contributed to by several clothing size, recent weight gain, or ankle edema. simultaneous conditions, and the diagnosis may Its onset may be sudden or gradual, persistent be particularly challenging, especially in a or intermittent. It may be entirely asympto- subset of patients with functional GI disorders matic. More often the patient may describe 3-6 distension as bloating,1,2 fullness, hardness, (FGIDs). A careful history and physical tightness or pressure. These symptoms are examination are necessary to develop an ade- usually exacerbated by meals, fluctuate in quate differential and investigations, including intensity, and are worse in the day and settle psychosocial evaluation, that will help in the overnight. Other symptoms such as belching, cost-effective approach to the diagnosis and care postprandial discomfort, nausea, vomiting, of these patients, who are otherwise susceptible , localized pain, and consti- to receiving unnecessary, costly, and sometimes 7 pation, if present, may provide clues for risky studies and treatments. the etiology of abdominal distension. As a DIFFERENTIAL DIAGNOSIS *The terms ‘distension’ and ‘bloating’ are largely used Common synonymously; however, it has been suggested that the term ‘bloating’ should be reserved exclusively for the • FGIDs (vide infra ↓↓): (; IBS, globus; subjective symptom of abdominal enlargement, with the ↓↓ term ‘distension’ being used only when there is an actual rumination syndrome: vide infra ; dysmoti- change in girth. lity-like dyspepsia; gallbladder dysfunction; Bloating appears to be more frequently associated proctalgia fugax: vide infra ↓↓) with visceral hypersensitivity, whereas distension is more often related to hyposensitivity and delayed transit. The • Infestations diarrhea (giardiasis) two phenomenons may not be precisely the same. • Obesity (metabolic syndrome) 2

• Pregnancy Urinalysis • Distended bladder • Ascites • Albuminuria in renal disorders • Intra-abdominal lump (, • Urobilinogenuria may be present in hepatic tumor, cyst, neoplasm). disorders, absent in complete biliary obs- truction OCCASIONAL • In women, hCG to rule out pregnancy.

• Peritonitis (bacterial, tubercular, perforated Stools viscus) • Intestinal obstruction (strangulated , • Ova, cysts, and parasites; rule out giardiasis adhesions, fecal impaction) • Occult blood in carcinoma • Paralytic ileus (intra-abdominal inflamma- • Steatorrhea in malabsorption syndromes. tion, metabolic, drug induced). LFTs RARE • Bilirubin (mostly conjugated) often elevated • Ascites (constrictive pericarditis, portal • Aminotransferases like ALT (i.e. SGPT), AST hypertension, Meigs syndrome: vide infra ↓↓). (i.e. SGOT) markedly elevated in cirrhosis of • Peritonitis (spontaneous bacterial peritoni- the liver ↓↓ tis, i.e. SBP: vide infra , malignancy) • Alkaline phosphatase (ALP) elevated in any • Toxic megacolon (pseudomembranous biliary obstruction. colitis, ulcerative colitis) • (traumatic rupture or AXR perforation of viscus) • Malabsorption syndromes (secondary • Dilated loops of intestine with multiple air- lactase deficiency) fluid levels in intestinal obstruction. • Hypoalbuminemia (malnutrition, liver failure). US Abdomen/Pelvis

INVESTIGATIONS—GENERAL • Can confirm the presence of ascites suspected at physical examination CBC • Can detect as little as few milliliters of fluid • Leukocytosis in bacterial infection, inflam- located in obscure area, such as subdia- mation (e.g. infestations diarrhea, peri- phragmatic region tonitis); eosinophilia in parasitic infection • Can help determine the cause of ascites such • Microcytic or megaloblastic anemia in as cirrhosis, portal hypertension, portal and malabsorption syndrome. hepatic vein thrombosis • Can guide paracentesis; particularly useful ESR in the presence of small amount of ascitic • Elevated in infection, inflammation and fluid or when the fluid is compartmen- malignancy. talized 3

• To assess organomegaly, hepatobiliary because the estimation of the serum ascites obstruction, and presence of a mass albumin gradient (SAAG: Table 1.1) and ascitic • In women—to evaluate pregnancy, uterine, fluid cholesterol is found to be a better or ovarian lesion. marker in the diagnosis of ascites due to:  Portal hypertension (a high gradient INVESTIGATIONS—SPECIFIC > 1.1 g/dl indicates that the ascites is due to portal hypertension; and a low gra- Tuberculin or PPD and Casino’s Test dient <1.1 g/dl indicates ascites of • In TB and hydatid cyst. nonportal hypertensive etiology)8,9  To distinguish malignant from non- Serum Lipase malignant causes of ascites.10

• May be elevated with pancreatic carcinoma, Table 1.1: Causes of ascites by the serum pancreatitis or perforated viscus. ascites albumin gradient (SAAG) High gradient (>1.1 g/dl) CT/MRI Scan • Cirrhosis* • Alcoholic hepatitis • Often has a complimentary role with US in • Fulminant hepatic failure • Massive liver metastasis the evaluation of patients with ascites, • Congestive cardiac failure, constrictive pericarditis especially in patients with obscure source (cardiac ascites) of ascites • Myxoedema, Budd-Chiari syndrome (hepatic vein thrombosis), or Veno-occlusive disease. • Can evaluate and confirm intra-abdominal or retroperitoneal mass lesion Low gradient (<1.1 g/dl) • Valuable in the diagnosis of acute distension • Peritoneal tuberculosis • Nephrotic syndrome of abdomen suspected to be due to trauma, • Peritoneal carcinomatosis ruptured viscus, hemorrhage, obstruction, • Pancreatic ascites bowel ischemia, or leaking abdominal • Biliary ascites • Bowel obstruction/infarction aneurysm. *Patients with high SAAG most often have portal hypertension. MRI Angiography

• In patients with hepatic or portal vein Laparoscopy with Biopsy thrombosis or obstruction by tumor. • Direct visualization of abdominal and pelvic Diagnostic Paracentesis organs to detect extra-, peritoneal deposits of tumor, TB, or meta- • Ascitic fluid analysis for Gram’s stain, AFB, static disease of the liver. Biopsies are taken culture and cytology under direct vision to enhance diagnostic • Estimation of amylase, lipase, and trigly- accuracy. cerides to rule out pancreatitis and chylous ascites Exploratory Laparotomy • Recent statistical data indicate that the exudate-transudate concept should be • In undetermined etiology with adequate discarded in the classification of ascites investigations. 4

CLINICAL NOTES • Mixed ascites, i.e. ascites from two different causes may coexist in few patients with • Acute abdominal distension may signal life- ascites, e.g. cirrhosis of the liver with CHF/ threatening peritonitis or acute intestinal pancreatitis/tuberculosis/malignancy. obstruction. A rapid check for signs of , such as pallor, thready pulse, RED FLAGS diaphoresis, hypotension, altered mentation and focussed physical examination is • Aerophagia is not always ‘neurotic’; swallo- indicated for urgent diagnosis and manage- wing air may be a response to abdominal ment discomfort from organic disease • While dealing with patients with FGIDs, • Patients with FGIDs with psychological developing an effective patient-physician difficulties such as depression, panic, relationship through empathy, reassurance, somatization, and personality disorders and education is most rewarding may need psychologist or psychiatric • History—Includes onset, duration; weight referral gain (BMI >30 kg/m2); weight loss (tubercular • Swallowed air (aerophagia) that is not abdomen, diabetic gastroparesis, anorexia eructed may get trapped in the splenic nervosa, malignancy); bowel movements— flexure (colon makes a 90 degree turn at this constipation, diarrhea or altered bowel habits location) causing distension with gas of that (IBS, malignancy); diet (excess fiber, milk or part of the large intestine in the region of the its products); medications (diphenoxylate, spleen. Since this location is just beneath the cisapride); substance use or abuse (laxatives, diaphragm, the location of the pain appears ecstasy); personal/social stress factors (food to be coming from the lower left chest, habits, smoking, alcohol); and family history causing discomfort or pain which may be (diverticulosis, polyposis) referred to left side of chest, shoulder or arm. • Physical examination—Febrile episodes; This splenic flexure syndrome (SFS) may be abdominal tenderness, dilated veins, bowel mistaken for a coronary event. However, it sounds or mass; inguinal and femoral hernia; may be distinguished from cardiac pain by measuring the abdominal girth for a its intermittent, colicky behavior and baseline value; and pelvic examination in fluctuations in intensity of the pain. Also women are important relief of pain of SFS is characteristically • Physical tests for ascites such as flank obtained by . dullness, , and the are not helpful when a small volume SELECTIVE GLOSSARY (less than 1 liter) of ascites exists Functional GI Disorders (FGIDs)7, 11, 12 • Ascites is rarely the sole physical finding. Once identified, investigations should follow FGIDs is defined as a variable combination of to determine its cause chronic or recurrent GI symptoms not explained • Development of symptoms of fever, by structural or biochemical abnormalities. It abdominal pain, or mental status changes cannot be diagnosed through endoscopic, (encephalopathy) in a patient with ascites radiologic, or laboratory studies. Furthermore, indicates complication such as SBP which even though these disorders share certain has poor prognosis physiologic characteristics (such as abnormal 5 motility and visceral hypersensitivity) that are systemic lupus erythematosus and enlarged associated with symptom generation, the ovaries. findings are not specific for diagnosis, and the clinician has limited ability to evaluate them in Proctalgia Fugax practice. In the absence of any objective marker, Proctalgia fugax is a diagnosis of exclusion, and the identification and classification of FGIDs are defined as sudden, severe pain in the anorectal based on symptoms, and consist of a wide region lasting several seconds or minutes, and spectrum of syndromes which cross over and in then disappearing completely. It is common but some cases overlap various anatomic areas of largely underreported. The etiology is not well- the luminal gut. Although IBS has traditionally defined. Attacks are infrequent, left-sided, and been the most studied and written about, FGIDs short-lived. Patients are asymptomatic between constitute a number of unique disorders, episodes. The discomfort is usually triggered by including functional esophageal disorders stressful event; can occur during the day or (noncardiac chest pain, functional dysphagia, night; although it is not typically associated and globus sensation); functional dyspepsia with bowel movements, it may be relieved by (pain, discomfort, nausea, and other symptoms heat, anal dilatation, or relaxation techniques. above the navel in persons who do not meet the diagnostic criteria for IBS); functional abdominal Rumination Syndrome pain syndrome; functional abdominal bloating; functional diarrhea; functional disorders of the Rumination means repeated regurgitation biliary tract, including Oddi sphincter; functional (backflow of food from the stomach into the disorders of the anorectal area, such as pelvic mouth) and rechewing of food, i.e. voluntary or floor ; and proctalgia fugax. The involuntary regurgitation and rechewing diagnosis of FGIDs relies heavily on the clinical of partially digested food that is either re history, a limited diagnostic evaluation and early swallowed or expelled. This regurgitation symptomatic treatment that include symptom appears effortless, may be preceded by a monitoring and reassessment. There is increasing belching sensation, and typically does not evidence that psychopharmacologic and psycho- involve retching or nausea. In rumination, the therapeutic management of FGIDs are highly regurgitant does not taste sour or bitter. The effective and, in many instances, surpass the behavior must exist for at least 1 month, with efficacy of standard medical treatment. evidence of normal functioning prior to onset. Rumination occurs within a few minutes Meigs Syndrome postprandial and may last 1-2 hours. Though Meigs syndrome is defined as the triad of benign frequency may vary, rumination typically ovarian tumor with ascites and pleural effusion occurs daily and may persist for many months that resolves after resection of the tumor. The or years. Although the etiology of rumination is ovarian tumor in Meigs syndrome is a fibroma. unknown, multiple theories have been advan- Pseudo-Meigs syndrome consists of pleural ced to explain the disorder. These theories range effusion, ascites, and benign tumors of the from psychosocial factors to organic origins. ovary other than fibromas. Pseudo-pseudo Cultural, socioeconomic, organic, and psycho- Meigs syndrome includes patients with dynamic factors have been implicated. 6

Spontaneous Bacterial Peritonitis (SBP) user-assets/Documents/08_Publications/ 06_GIHep_Annual_Review/Articles/Crowell. SBP is a bacterial infection of ascitic fluid in pdf. Accessed on 27-08-08. 4. Jiang X, et al. Prevalence and risk factors for patients with decompensated cirrhosis. The abdominal bloating and visible distention: A term ‘spontaneous’ distinguishes this from population-based study Gut. 2008; 57(6):756-63. [PMID: 18477677: Free full text]. surgical peritonitis. Enteric organisms are 5. Azpiroz F, et al. The pathogenesis of bloating isolated from more than 90% of infected ascites and visible distension in irritable bowel fluid in SBP, suggesting that the GI tract is the syndrome. Gastroenterol Clin Nortn Am 2005; 34(2):257-69. [PMID: 15862934: Abstract]. source of bacterial contamination. Symptoms 6. Azpiroz F, et al. Abdominal bloating. Gastro- of infection occur in most patients with SBP, enterology. 2005; 129(3):1060-78. [PMID:16143143: Abstract]. including fever, abdominal pain, mental status 7. Drossman DA. Diagnosing and Treating Patients changes, and ileus. A high index of suspicion with Refractory Functional Gastrointestinal Dis- should exist for SBP in patients with cirrhosis orders. Ann Intern Med 1995; 688-97. [PMID: 7574225: Abstract]. and ascites, especially in those who do not 8. Runyon BA, et al. The serum-ascites albumin improve follow-ing administration of diuretic gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites. medication. Ann Intern Med 1992; 117(3):215-20. [PMID: 1616215: Abstract]. REFERENCES 9. Wong CL, et al. Does this patient have bacterial peritonitis or portal hypertension? How do I 1. Lea Richard, et al. Expert Commentary-Bloating, perform a paracentesis and analyze the results? Distension, and IBS. Medscape General Med. JAMA 2008; 299(10):1166-78. [PMID: 18334692: Abstract]. 2005; 7(1):18).web site: http://www.med-scape. 10. Rana SV, et al. Usefulness of ascitic fluid chole- com/viewarticle/483079_print. Accessed on sterol as a marker for malignant ascites. Med Sci 28-08-08. Monit 2005; 11(3):CR136-42. [PMID: 15735567: 2. Agrawal A, et al. Review article: Abdominal Abstract]. bloating and distension in functional gastro- 11. Coraazziari E, et al. Definition and epidemiology intestinal disorders—epidemiology and explo- of functional gastrointestinal disorders. Best Pract ration of possible mechanisms. Aliment Pharmacol Res Cli Gastroentrol 2004; 18(4):613-31. [PMID: 15324703: Abstract]. ther. 2008;27(1):2-10. Epub 2007 Oct 11. [PMID: 12. Jones MP, et al. Functional Gastrointestinal Dis- 17931344: Abstract]. orders: An Update for the Psychiatrist. Psycho- 3. Crowell MD. Future treatment approaches for somatics 2007; 48:93-102 [PMID: 17329601: Free Functional GI Disorders. http://www.gastro.org/ full text]. CHAPTER 2 Abdominal Pain

SYNOPSIS early ischemia or by direct involvement of sensory nerves, e.g. malignant infiltration. Abdominal pain is a subjective sensation of a Visceral pain is most often felt in the midline noxious internal stimulus. Classic teaching because of the bilateral sensory supply to the separates abdominal pain into three categories spinal cord, and produce associated nausea, based on underlying pathophysiology, namely vomiting, diaphoresis and tachycardia. visceral, parietal, and referred. Parietal pain, also referred as somatic pain, Visceral pain (originating via autonomic usually signifies peritoneal lining irritation by fibers within the organ itself, hence the name blood, fluid or other organ contents. Peritoneum visceral, referring to viscera organs) occurs when has a larger number of highly sensitive nerve the solid or hollow viscous organs such as endings (mediated by fast transmitting both kidney, liver, spleen, bowel, gallbladder, and urinary bladder are involved. Most organs do myelinated afferent C, and A delta nerve fibers), not have many nerve endings (mediated so pain is more acute, better localized—the primarily by bilateral unmyelinated afferent C patient will typically be able to point to the pain fibers which are slow transmitters), so the pain with one finger—and more intense, usually is generally slow in onset; may be mild, diffuse, described as sharp and constant. The pain is and poorly localized, meaning the patient will localized to the dermatome above the site of have difficulty pointing to the pain with one stimulus. Initially, parietal pain is perceived as finger. Most often the patient will wave his or unilateral because the parietal peritoneum is her hand over the area indicating a general or innervated only from one side of the nervous more diffuse pain; usually described as dull, system. Patients with peritoneal irritation aching, or crampy, may be intermittent or usually lie very still with the legs drawn up constant. It arises from distension or of a towards the chest in what appears to be a fetal hollow organ, e.g. the discomfort experienced position, which helps to relax the parietal early in intestinal obstruction, or inflammation peritoneum and thus reduces pain. Also, the in . Less commonly it is caused by patient will breathe shallow and fast to reduce 8 movement of the diaphragm and subsequent Table 2.1: Embryogenic location of abdominal pain aggravation of the peritoneum. When visceral Origin Organs Spinal Pain pain is replaced by parietal pain, it is typically levels locations an indication that the condition has progressed, Foregut Distal esophagus, T5-T6 to Between and is potentially worsening, e.g. the pain of stomach, proximal (first T8-T9 xiphoid two parts) duodenum, and acute appendicitis—felt initially around the liver, biliary tree, umbilicus, i.e. umbilicus as visceral pain, and then becomes pancreas epigastrium localized to the right iliac fossa as parietal or Midgut Duodenum (3rd T8-T11 to Periumb- somatic pain when the peritoneum becomes and 4th parts) L 1 -ilical Small intestine, involved. appendix, ascending Referred pain is a type of visceral or organ pain colon, proximal 2/3 that is felt away from the actual affected organ of transverse colon site, even though the patient is complaining of Hindgut Distal 1/3 of transverse T11- L1 Between discomfort or pain in that particular area. colon, descending umbilicus colon, rectosigmoid and pubis, Because of fewer nerve endings in the organs, the Reproductive organs i.e. supra- brain may misinterpret (i.e. cortical misper- (ovaries, fallopian pubic ception of either visceral or parietal afferent tubes, uterus, seminal vesicles, prostate), stimuli; viscerosomatic convergence) where the bladder pain is coming from. For example, cholecystitis pain is commonly referred to the right shoulder Table 2.2: Extraintestinal and extra-abdominal area; renal pain is commonly felt in the testis on causes of acute abdominal pain: what not to miss the same side; and appendicitis may also Diagnosis Investigations/remarks manifest by pain in the right testis. Cardiac: Acute MI; Usually elderly patient; Patterns of referred pain are also based on especially inferior wall cardiac risk factors present; embryologic sharing of dermatomes. (Table 2.1). obtain ECG/cardiac enzymes A pair of sites may share development from the Vascular: Ruptured Request abdominal US; same embryologic tissue, and may share abdominal aneurysm HRCT/MRI Mesenteric infarction Abdominal duplex US; MR innervation to some extent. Therefore, pain at mesenteric angiography one site may be referred to the other site, even Pulmonary: Pulmonary Subdiaphragmatic referred though the pathologic site is not painful initially. embolism; lower pain; CXR; HRCT pneumonia For example, epigastric pain may be the initial Metabolic: Diabetic Blood glucose; ketones; symptom of appendicitis; acute cholecystitis ketoacidosis; electrolytes; ABG may cause shoulder pain; acute inferior wall Hypercalcemia (hyperth- ‘Stones, bones, abdominal myocardial infarction may cause abdominal yroidism or malignancy) moans, and psychic groans’; pain. Just as abdominal conditions may cause serum calcium; PTH Hematological: Porphyr- Typical urine referred pain outside of the abdominal cavity, ia-acute intermittent discoloration; urine the same is true for some extraintestinal and Sickle-cell disease porphobilinogen abdominal conditions (Table 2.2). Hemolytic anemia; sickled erythrocytes; hemoglobin Although each type of pain is thought to have electrophoresis a different neuropathophysiology, the categories Gynecological: Ectopic Missed if pregnancy is not are not entirely discrete because of variability in pregnancy-ruptured confirmed in women of innervation between patients, and due to the child-bearing age complex dual visceral and parietal sensory Contd... Abdominal Pain 9

Contd... threatening etiologies of * such as a Abdomen: Pancreatitis; History of alcohol abuse; dissecting aneurysm, perforation, or obs- pancreatic carcinoma hyperlipidemia; serum truction, than to make a specific diagnosis. Once lipase; US abdomen or CT scan these have been reasonably excluded, a Spine: Vertebral Pain in relation to nerve systematic approach should be employed to compression; herpes- root involvement obtain a thorough history and physical exami- zoster Psychogenic: Somatization Bizarre ; nation with pertinent laboratory, radiologic, disorders; FGID repeated negative work-up and endoscopic procedures. The choice of the most appropriate test is determined by a host network innervating the abdominal area, e.g. of factors; however, any shotgun approach to visceral pain often blends with parietal pain as a abdominal pain, although tempting and pathologic process evolves. The parietal pleura frequently reassuring, should be avoided. may be involved in cases of pneumonia and the Table 2.3: Common causes of acute abdominal pain is predominantly felt in the central abdomen. pain in hospitalized patients The pain of myocardial infarction may also be felt All age groups • NSAP predominantly in the central abdomen instead of • Appendicitis in the precordial region. Further, classical • Renal colic • Acute urinary retention descriptions of abdominal pain have limitations • Acute cholecystitis because individuals react to pain differently. An • Acute pancreatitis • Perforated peptic ulcer elderly or a diabetic may not be much aware of • Intestinal obstruction abdominal pain or discomfort due to mesenteric • Diverticular disease ischemia. Moreover, abdominal pain is often a Elderly • Medical causes (MI, pneumonia, DKA) nonspecific complaint that presents with other • Vascular (MI, mesenteric ischemia, AAA) organ disorders, e.g. severe headache in a patient • Cancer (colorectal) with abdominal migraine, altered sensorium in a Children • Upper respiratory tract infection patient with diabetic ketoacidosis, weight loss in • Urinary tract infection anorexia nervosa, and neoplastic disease. Thus, • Hernia • Intussusception the overall sensitivity and specificity of the Women—obstetric history and physical examination in diagnosing • Ectopic pregnancy the different causes of abdominal pain is poor, • Abortion problems (septic abortion) 1,2 • Acute hydramnios particularly for benign conditions. • Concealed accidental hemorrhage The causes of abdominal pain are legion, • Perforating mole • Rupture uterus embracing all age groups and specialities (Table • Imminent eclampsia 2.3). The spectrum of diseases ranges from life- Women—gynecologic • Misplaced IUCD threatening to benign. Often the diagnosis • Fibroid cannot be established in a single encounter. • Ovarian tumor (Torsion) Though newer imaging modalities have *The term acute abdomen is defined as severe abdominal succeeded in solving many challenging pro- pain of unclear etiology lasting for several hours, which blems, an odd case continues to be a daunting might indicate a progressive intra-abdominal condition that is threatening to life or capable of causing severe task—being extremely difficult to pinpoint its morbidity; hospital admission is usually necessary and source of distress—a situation often meta- operative surgery is the most likely outcome. However, not all patients turn out to have such a threatening phorized as Pandora’s Box. Therefore, it’s condition but they need to be considered as being in probably more important to first exclude life- danger until surgical evaluation has been completed. 10 Diagnosis: A Symptom-based Approach in Internal Medicine

DIFFERENTIAL DIAGNOSIS Rare Common • Cardiorespiratory (MI, aortic dissection, pneumonia) + • Nonspecific abdominal pain (NSAP Table 2.4). • Malignancy (gastric, pancreatic, metastasis) Table 2.4 : Nonspecific abdominal pain (NSAP) • Metabolic (DKA, uremia, hypercalcemia, • Clinical presentation and causes Addison’s disease) • Viral infections: Mesenteric adenitis • Hematologic (hemolytic crisis, porphyria) • Bacterial infection: Acute bacterial gastroenteritis • Ischemic (mesenteric thrombosis, i.e. abdo- • Worm infestation: Roundworm, hookworm, thread- worm minal angina) • Parasitic infestation: Amebiasis, giardiasis • Allergy (lactose intolerance, gluten sensitivity) • Abdominal wall pain: Hematoma, hernia, herpes- • Psychogenic (Manchansen’s syndrome – vide zoster, nerve entrapment, ‘rib-tip’ syndrome ↓↓ • Functional: IBS infra , somatization disorder). • Gynecological: PID, Mittelschmerz pain (vide infra ↓↓), ovarian cyst INVESTIGATIONS—GENERAL • Others: Food allergy, abdominal epilepsy, abdominal ↓↓ migraine, myofascial pain syndrome (vide infra ), CBC spinal referred pain • Psychogenic: Conversion disorder • Anemia with chronic blood loss, e.g. PUD, malignancy • Systemic disease (gastroenteritis, viral • Chronic hemolytic anemia and abnormal RBCs hepatitis A, UTI) in peripheral blood smear in sickle cell disease • Appendicitis • Leukocytosis may be seen in infective process; • Peptic ulcer disease (PUD) however, a normal WBC count does not • Biliary colic (cholecystitis, cholelithiasis) exclude a serious cause of abdominal pain. • Renal colic (calculus) • Gynecological (dysmenorrhea, PID). ESR Occasional • Elevated with infection, malignancy. • Abdominal wall pain (postoperative scars, Urinalysis herpes zoster, abdominal hernia, trauma) • Hematuria in infection, calculi, malignancy; • Intraperitoneal lesion (infections—abscess, pus cells in infection tuberculosis, pancreatis; mass lesion) • Increased urobilinogen in viral hepatitis, • Perforation (appendix, typhoid ulcer, duo- absent in complete biliary obstruction denal ulcer) • Ketones in DKA • Obstruction (intestinal, volvulus, strangu- • Porphobilinogen in porphyria. lated hernia, ileus) Fecal Occult Blood • Internal hemorrhage (ruptured ectopic pregnancy/ovarian cyst/Graafian follicle) • May be positive in PUD, mesenteric ische- • Torsion (ovarian cyst, pedunculated fibroid, mia, carcinoma of colon, Crohn’s disease, and diverticulitis. testis). Blood Glucose +NSAP is defined as an acute, self-limiting pain of short duration and indeterminate cause, which requires no • To monitor glycemic control in diabetes surgical treatment. complicated by DKA. 11

LFTs, Amylase, Lipase INVESTIGATIONS—SPECIFIC

• ALT and AST markedly elevated in acute HRCT Scan hepatitis • Sustained elevation of serum alkaline • In general, nonenhanced HRCT scanning of the phosphatase and presence of HBsAg or anti- entire abdomen and pelvis is proved to be the HCV in hepatocellular carcinoma may be seen single most accurate factor for identifying need • Serum amylase and lipase elevated significantly for urgent intervention in patients with acute (three times normal) in acute pancreatitis, nontraumatic abdominal pain, including those perforated ulcer, and mesenteric thrombosis. associated with retroperitoneal structures. Urea, Creatinine, Electrolytes Many inflammatory, ischemic, and mass lesions such as appendicitis, cholecystitis, • To assess the state of hydration, and to rule diverticulitis, hernia, obstructed or perforated out renal disease. bowel, pancreatitis, renal colic, and acute ECG bowel ischemia can be evaluated with high • To rule out MI, atrial . degree (>90%) of sensitivity and specificity • A contrast enhanced CT scan is invaluable Pregnancy Test in the work-up of patients with hepatic, • Indicated in all women of childbearing age pancreatic, and renal disorders to exclude normal (before imaging proce- • HRCT can be considered a better alternative dures) or ectopic pregnancy. than IVU because it has a higher diagnostic accuracy, faster, less expensive and less risky US Abdomen than IVU. In addition, it also has the capa- • Preferred in pregnant women to minimize bility of detecting various additional renal radiation and extrarenal pathologies5 • In general right upper quadrant pain is best • CT scan is also helpful to guide biopsies and evaluated initially by US, such as due to other minimally invasive procedures. hepatobiliary diseases • It is also helpful in evaluating appendicitis, MRI gynecological disease, intra-abdominal fluid, abscesses, and pregnancy—both normal • Provides diagnostic information in the work and ectopic up of patients with hepatic, adrenal, pan- • Transvaginal Doppler US may be indicated creatic disease, and lesions associated with to further confirm or exclude ectopic mesenteric circulation. pregnancy • Although US remains the primary modality Endoscopy by which complaints specific to the in women are evaluated, in many • EGD may be indicated in the diagnosis of instances, CT and MRI imaging, due to their upper GI bleeding (PUD, esophageal varices) improved technology have become equal to • Sigmoidoscopy or colonoscopy for rectal, that of ultrasound in diagnosing causes of sigmoidal, or colonic obstruction pelvic pain in women.3,4 • Cystoscopy for lower renal disease. 12 Diagnosis: A Symptom-based Approach in Internal Medicine

CXR—Upright View psoas shadows (retroperitoneal inflam- mation or hemorrhage) may be seen. • In patients with visceral perforation, free intraperitoneal air can be seen as a crescent Magnetic Resonance Cholangiopancreato- of lucency under the right diaphragm (as this graphy (MRCP) is at a higher level). The amount of air as little as 1 to 2 ml is detectable • This has largely replaced the invasive • Parenchymal consolidation, CHF, or pleural diagnostic ERCP in delineating the cause of lesion that may be the cause of referred pain obstructive jaundice. to the abdomen can also be confirmed Endoscopic Ultrasound (EUS) • Those who cannot maintain upright position, lateral decubitus view, and across the table • This is a recent innovation in the world of view may be helpful. In lateral decubitus endoscopy. Its advantage over conventional view, free air can be viewed between the right endoscopy is its ability to provide trans- edge of the liver and the lateral right mural details. Also, it is extremely useful diaphragm. In across the table view, air may in small tumors that cannot be properly be viewed just behind the parities assessed by CT scan. The option of EUS- • US of abdomen is shown to be superior to guided fine needle aspiration cytology the erect CXR for the detection of free intra- (FNAC) and brush cytology is an added asset peritoneal gas.6,7 in selected situations.

AXR Radionuclide Scans • Liver-spleen scans, HIDA scans, and gallium • Supine plus erect or decubitus views to scans may be useful in localizing intra- primarily evaluate GI gas pattern, i.e. air abdominal abscesses (now replaced by CT under diaphragm or multiple air-fluid levels, scans) indicative of perforated ulcer or viscus, or • 51Crlabelled erythrocyte scans may be useful # bowel obstruction to identify the source of intermittent or slow • Other lesions such as renal calculi; gallstones, GI bleeding gas in biliary tree in gallstone ileus; aortic • 99mTechnetium pertechnetate scans are calcification (aneurysm); and obliteration of helpful in the diagnosis of Meckel’s diverti- culum.

#Numerous signs are described for pneumoperitoneum Angiography on plain radiographs. The Rigler sign, or the double-wall or bas-relief sign, is a visualization of the outer surface of • Percutaneous invasive angiography or a bowel loop wall as a result of free air in the peritoneal magnetic resonance angiography (MRA) is cavity. The intraluminal gas provides negative contrast and outlines the internal wall. The , typically indicated if intra-abdominal intestinal ische- seen on supine radiographs, is an inverted cup-shaped mia or ongoing hemorrhage is suspected. arcuate lucency overlying the lower thoracic spine and Selective visceral angiography is a reliable projecting caudally to the heart. This sign is formed as air method of diagnosing mesenteric infarction. accumulates anteriorly in the median subphrenic space under the central leaf of the diaphragm. The football sign, typically seen in pediatric patients, is a visualization of Other Imaging the entire peritoneal cavity as an oval gas shadow, with the vertically oriented falciform ligament representing • Upper GI barium series or enema with the seam of an American football. double contrast media, and IVP are rarely Abdominal Pain 13

indicated (time consuming and excess obstruction, perforation; acute biliary disease, radiation exposure). However, where CT ectopic pregnancy, etc. particularly if there is scan facility is lacking, a barium enema will preoperative diagnostic uncertainty. Biopsy confirm the diagnosis of volvulus of sigmoid of the pathological organ may be performed. colon (‘beaked’ appearance). IVP may be needed occasionally when it is difficult to CLINICAL NOTES differentiate right sided ureteric colic and acute appendicitis. In such cases a single film • Perhaps in no other situation is the history IVP is found to be useful. In ureteric colic and physical examination more important there may not be secretion of dye on the in arriving at a rapid diagnosis than in the affected side, or there may be hold up in the acute abdomen.$ Decisions have to be made line of ureter. Intravenous cholangiography quickly with minimum investigations. is now replaced by US and HIDA scans in Therapeutic efforts have to be instituted often the diagnosis of jaundiced patients and those within minutes. A structured date sheet** is suspected with cholangitis. now widely used in many health services as aide-memoire to minimize diagnostic errors FNAC and Biopsy • Special points to note in the general examination • Histopathological or exfoliative cytology of in a patient with an acute abdomen include: superficial lesion, e.g. in patients suspected general appearance (well looking, or ill, thin, with lymph node tuberculosis, or metastasis; emaciated); alertness or state of consciousness; or ultrasound/CT guided biopsies of abdo- hydration; temperature-pulse-respiration; and minal organs; or endoscopically obtained blood pressure. Life-threatening causes (Table specimen in inflammatory or malignant 2.5) should always be ruled out before focussing disease, e.g. abdominal TB, hepatocellular on less serious diagnosis. Periodic examination carcinoma, metastatic liver disease, adeno- and critical assessment of the changes in the carcinomas, lymphomas, and neoplastic condition of the patient, including vital signs lesions of retroperitoneal organs like kidneys and appearance are clues to risk stratification and adrenals. and appropriate diagnosis • A careful examination of hernial sites, Paracentesis scrotum, pelvis, and rectal examination is • In patients with SBP, TB peritonitis, chylous mandatory in every patient with abdominal ascites, and for peritoneal cytology. pain—especially in acute cases to rule out intestinal obstruction. Laparoscopy

• A less invasive procedure for the diagnosis $Dr Zachary Cope in the classical text Cope’s Early Diagnosis of extraluminal, intra-abdominal solid of the acute Abdomen, reminds us that, “the general rule can lesions which cannot be visualized by be laid down that the majority of severe abdominal pains endoscopic procedures. that ensue in patients who have been previously fairly well, and that last for as long as six hours, are caused by conditions of surgical import”. Surgical Exploration **For a typical example refer to—Michael M Henry et al. Clinical Surgery, 2nd International edn.; Publisher: WB • May be required in a few complicated or Saunders Company; Chapter 22—Acute Abdominal undiagnosed cases, e.g. intestinal adhesions, Conditions—p. 367. 14 Diagnosis: A Symptom-based Approach in Internal Medicine

Table 2.5: Physical findings in various acute • In a woman with abdominal pain a detailed abdominal conditions gynecological history, including the timing of Condition Helpful symptoms and signs LMP, pregnancy history, and vaginal discharge Hemorrhage Increasing restlessness; air- or dysmenorrhea should be obtained (Internal) hunger; pallor; shock; • Pregnant women with abdominal pain, in increasing distension; pulsatile addition to all other causes of abdominal (aneurysm) or tender (ectopic pregnancy) mass; rectal pain, may present with atypical locations of 8,9 bleeding (occasionally) abdominal conditions. Also, prior to Obstruction Patient anxious, restless; examination of the abdomen, the patient (Intestinal) vomiting (in high obstruction); constipation (in low should empty the bladder obstruction); Distension; • History of collapse or fainting in a patient hyperperistalsis (early); visible with abdominal pain is suggestive of an acute peristalsis (late); ‘silent vascular catastrophe such as internal abdomen’ (late); diffuse pain without rebound hemorrhage, ruptured ectopic pregnancy, tenderness acute pancreatitis, torsion, strangulation, or Torsion (sigmoid Sudden, severe pain; rapid mesenteric vascular thrombosis or embolism colon/ovary) distension; palpable • Past history of abdominal surgery makes sigmoid colon (like a pneumatic tyre) in left lower abdomen; or intestinal obstruction from adhesions more likely in a female palpable, freely • In elderly patients with history of CAD or mobile, cystic swelling in the presence of cardiac risk factors with abdominal lower abdomen pain, especially upper abdominal pain of acute Vascular (ischemia) Patient elderly; atherosclerosis or valvular heart disease; post- onset, obtain an ECG to rule out MI prandial acute pain but little • In elderly patients with abdominal pain tenderness; not distended (till associated with skin xanthomas and late); rectal bleeding (occasionally) generalized atherosclerosis, the possibility of Inflammation (mass Fever; Tender MI, AAA, and mesenteric ischemia must be or abscess) mass (abdominal, Rectal, or excluded by obtaining ECG, US, or CT scan pelvic); special signs (Murphy’s • Drug history should include prescription and psoss, Obturator) Peritonitis Patient motionless; fever; illicit drug use as well as alcohol. NSAIDs, tachycardia; cough and steroids and immunosuppressants facilitate rebound tenderness; board-like perforation or peritonitis. Anticoagulants rigidity (late); absent bowel sounds enhance bleeding and hematoma formation. Perforation (viscus) Patient pale, anxious, lies still in Alcohol predisposes to pancreatitis. Purgatives bed; vomiting; rising pulse; may ease perforation in a case of acute hypotension; tenderness, rigidity (early); increasing appendicitis. Sulpha, steroids, barbiturates, distension; diffuse tenderness estrogen, beta-blockers are known to (late); loss of liver dullness; precipitate porphyria. Megadoses of vitamin A absent bowel sounds and D, diuretics, lithium, oral calcium intake Note: mnemonic “HOT—VIP (double) P” lead to hypercalcemia which may present with acute abdominal pain • Biliary diseases such as cholecystitis, • There are specific signs associated with cholelithiasis occur commonly in a fatty, certain specific diagnosis (Table 2.6); these flatulent, fertile, and female of forty should be elicited where applicable. 15

Table 2.6: Significance of named signs in abdominal pain conditions Sign Description Significance Carnett’s sign Contract the abdominal To differentiate abdominal musculature by raising the head wall pain from intra- or straightened legs off the table abdominal pain Cullen sign Periumbilical ecchymosis Intraperitoneal hemorrhage (due to hemorr- hagic pancreatitis, ruptured ectopic pregnancy); retro- peritoneal hemorrhage Turner sign Bruising of flanks Acute pancreatitis; ruptured AAA; severe abdominal injury Rovsing sign More RLQ pain with palpation Acute appendicitis of LLQ RLQ pain with internal rotation Acute appendicitis of the fixed right hip RLQ pain with hyperextension Acute appendicitis of the right hip Murphy sign ‘Catch’ in the breath on finger Acute cholecystitis pressure in RUQ McBurney’s sign Tenderness located 2/3 distance Acute appendicitis from anterior iliac spine to umbilicus on right side Kehr’s sign Severe left shoulder pain Splenic rupture, Ectopic pregnancy rupture

RED FLAGS with perforated appendix or peptic ulcer with peritonitis; it could be misleading • Catastrophic abdominal emergencies such as • Screen any women in the reproductive age perforated peptic ulcer or internal hemorr- with history of missed period and presenting hage may be associated with minimal or no with abdominal pain, vaginal bleeding, or detectable pain or muscle spasm in frail elderly, spotting for pregnancy—normal or other- seriously ill patients, and in patients with HIV wise. An ectopic pregnancy can present even infection, or those taking immunosup- before a missed period pressants. A thorough work up and ad- • In a patient with recurrent abdominal pain mission is usually warranted with repeated negative work up—rule out • Intrathoracic diseases that most often three Ps, i.e. pancreatitis, porphyria, and masquerade as abdominal emergencies (MI, psychiatric disorder. PE, pneumonia, pericarditis, and esophageal disease) must be considered in every patient SELECTIVE GLOSSARY with abdominal pain, especially if the pain Mittelschmerz pain (pronounced mitel- is in the upper part of the abdomen schma-rts). It is the ovulation pain or midcycle • Whenever the cause of abdominal pain is pain—pain associated with ovulation. The obscure, a metabolic or vascular origin (diabetes pain may occur just before, during, or after mellitus, Addison’s disease, mesenteric ischemia, ovulation. Symptoms include lower- and porphyria) must always be considered abdominal pain that is: • Beware of silent abdomen—the temporary • One-sided improvement (easing of pain) in a patient • Recurrent or with similar pain in past 16 Diagnosis: A Symptom-based Approach in Internal Medicine

• Typically lasting minutes to a few hours, but Myofascial pain syndrome (MPS)— Myofascial may extend as long as 24-48 hours pain is a chronic, painful condition that affects • Usually sharp, cramping, distinctive pain. the fascia, i.e. the connective tissue that covers • Severe (rare) the muscles-either a single muscle or a muscle • May switch sides from month to month or group. Myofascial pain symptoms usually from one episode to another involve muscle pain with specific “trigger” or • Begins midway through the menstrual cycle. “tender” points. Trigger points can be identified by pain that results when pressure is applied Signs and tests: A pelvic examination shows no to an area of the patient’s body. The pain can be abnormalities. Other diagnostic procedures (such as an US abdomen) may be performed to made worse with activity or stress. In addition to the local or regional pain associated with MPS, rule out other causes of ovarian pain if ovulatory people with this disorder also can suffer from pain is prolonged. depression, fatigue, and behavioral distur- Munchausen syndrome (pronunciation: Mun- bances. No specific lab tests confirm the chau-zen) was named after the Baron Karl diagnosis of MPS, but lab tests can be helpful in Friedrich Hieronymus Freiherr von Munchau- looking for predisposing conditions, such as sen, who was a German cavalry officer and hypothyroidism, hypoglycemia, and vitamin known as a tremendous liar. Patients with deficiencies. Chronic infections and sleep Munchausen syndrome go from physician to deprivation have been cited as causative factors, physician dramatically presenting very as have radiculopathy, visceral diseases, and plausible symptoms and histories and receiving depression. The pathogenesis likely has a central care, up to and including surgery. They fake mechanism with peripheral clinical mani- physical signs of illness and abnormal festations. laboratory findings. The person may: • Claim that he or she has symptoms, when REFERENCES none exist. 1. Dietrich CF, et al. Acute abdomen, gastroentero- • Produce false test results, such as by sticking logists view. Praxis (Bern 1994), 2007; 96(16):645- a thermometer in hot water to mimic a fever 59. [PMID: 17474291: Abstract]. or by putting bacteria or something else in 2. Heikkinen M, et al. GPs’ ability to diagnose dyspepsia based only on physical examination laboratory test samples. and patient history. Scand J Prim Health • Self-inflict injuries, such as cutting the skin. Care 2000;18(2):99-104. [PMID: 10944064: Abstract]. • Create symptoms, such as causing vomiting 3. Kalish GM, et al. Computed tomographic and by taking medication. magnetic resonance features of gynecologic • Say that symptoms are worse than they abnormalities in women presenting with acute or chronic abdominal pain. Ultrasound Q. 2007; really are, such as claiming to have severe 23(3):167-75. [PMID: 17805165: Abstract]. pain or bleeding when a milder condition is 4. Patel MD, et al. Reimaging the female pelvis with actually present. ultrasound after CT: General principles. Ultrasound Q. 2007;23(3):177-87. [PMID: • Request surgical procedures. 17805166: Abstract]. Approximately 50% of those with Munchau- 5. Pfister SA, et al. Unenhanced helical computed sen syndrome are subject to drug abuse, and tomography vs intravenous urography in patients with acute flank pain: Accuracy and economic many have borderline personality disorder. The impact in a randomized prospective trial. Eur disorder generally starts during early adult- Radiol 2003;13(11):2513-20. Epub 2003 Jul 24. hood, but may begin during childhood. [PMID: 12898174: Abstract]. Abdominal Pain 17

6. Yen HP, et al. Ultrasonography is superior to 8. Cappell MS, et al. Abdominal pain during pregnancy. plain radiography in the diagnosis of Gastroenterol Clin North Am 2003;32(1):1-58. pneumoperito-neum. British J of Sur 2002;89(3) [PMID: 12635413: Abstract]. :351-4. [Abstract]. 9. Gray J, et al. Abdominal pain, abdominal pain in 7. Okkes Ibrahim Karahan, et al. New method for the detection of intraperitoneal free air by sono- women, complications of pregnancy and labour. graphy: Scissors maneuver. J of Clinical Ultra- Emerg Med J 2004;21(5):606-13. [PMID: 15333547: sound 2004;32(8):381-5. [Abstract]. Free full text]. CHAPTER 3 Amenorrhea

SYNOPSIS sexual characteristics.* Secondary amenorrhea refers to absence of menstruation for 3 consecutive months Normal menstruation depends on the integrated in women who have previously menstruated.@,1 hypothalamic-pituitary-ovarian (HPO) axis and Amenorrhea may be physiological such as endometrial function, and a patent lower genital during pregnancy, lactation, and after meno- outflow tract. Briefly, the pulsatile hypothalamic pause. Pathological amenorrhea results from gonadotropin releasing hormone (GnRH) disorders of the HPO—uterine axis, endo- stimulates release of pituitary gonadotropins crinopathies, psychological factors, drug usage, luteinizing hormone (LH) and follicle-stimulating and other rare causes such as anatomic abnor- hormone (FSH), which stimulate ovarian pro- malities, and genetic factors. duction of estrogen (17-β estradiol) and pro- In clinical practice, it is helpful to consider gesterone. Sequential endometrial stimulation by amenorrhea as an abnormality in one of the four estrogen initially, followed by progesterone, cause areas based on the underlying anatomic or uterine endometrial proliferation (in preparation endocrine dysfunction; viz. the hypothalamic, for possible nidation of fertilized ovum). Cyclical the anterior pituitary, the ovaries, and the withdrawal of these hormones (in the absence of outflow tract, including the uterus, cervix, and nidation) results in sloughing of the endometrium vagina. Investigating and treating the cause for and menstrual bleeding. amenorrhea can prove challenging because In normal healthy women, the cyclical men- disorders at any of the above several hormonal struation is mostly constant with an average levels can disturb the normal function and alter rhythm of 28 ± 7 days, inclusive of 4 to 6 days of the pattern of menstruation or prevent it bleeding which persists throughout the entirely. However, in the majority, diagnosis and management is usually straightforward, reproductive period of life. Amenorrhea indicates the absence of men- * For the purpose of evaluation, absence of any menses struation; its onset may be primary or secondary. and secondary sexual characteristics by age 14 is defined Primary amenorrhea is arbitrarily defined as failure of as primary amenorrhea. @ Menopause is defined as the terminal episode of naturally onset of menstruation beyond the age of occurring menses; it’s a retrospective diagnosis, usually 16 years regardless of development of secondary made after 6 months of amenorrhea. 19 and a few need detail investigations, especially • Systemic disorders (autoimmune disease, if fertility is desired but impaired. adrenal tumor) • Radiation, chemotherapy. DIFFERENTIAL DIAGNOSIS B—Secondary Amenorrhea (Table 3.1) The causes for amenorrhea are grouped into Common primary and secondary, but these are shared • Physiological (pregnancy, lactation, menopause) between the two categories • Functional hypothalamic amenorrhea (due to A—Primary Amenorrhea emotional, physical, social stress; depression) Common • Drug-induced hyperprolactinemia (Table 3.2) • Post-pill amenorrhea • Constitutional (i.e. physiological: delayed • Infection (mumps, tuberculosis of the genital menarche and puberty) tract) • Severe psychogenic stress, depression • Rapid weight loss (10-15%) or extreme obesity • Chronic illness • Anorexia nervosa, bulimia • Weight loss / lean body weight2,3 • Surgery (hysterectomy) • Anorexia nervosa • Endometrial ablation • Heavy exercise. • Progestogen IUD Occasional • Polycystic ovarian syndrome (PCOS) ↓↓ • Imperforate hymen# • Female athlete triad (vide infra ). • Vaginal septum • Primary hypothyroidism, hyperthyroi-dism Occasional • Diabetes mellitus (Type 1) • Premature ovarian failure (POF) • Systemic disease (endometrial TB, malnutrition) • Prolactin secreting adenoma • Drugs (hormones, antiemetics, antihy- • Primary hypothyroidism pertensives, antipsychotics). • Surgery, chemotherapy, radiotherapy. Rare Rare • Pregnancy before menarche4 • Disorders of cerebral cortex (trauma, tumor) • Disorders of pituitary (Sheehan’s syndrome) • Disorders of hypothalamus (Kallmann’s • Disorders of ovary (virilizing ovarian syndrome) tumors, resistant ovarian syndrome) • Disorders of anterior pituitary (prolacti- • Disorders of genital outflow tract (Asherman’s noma, Cushing’s disease, Fröhlich syndrome, syndrome, Rokitansky-Küster-Hauser Laurence-Moon-Biedl syndrome, empty syndrome) sella syndrome) • Systemic disorders (autoimmune disease, • Disorders of ovary (Turner’s syndrome, adrenal tumors). polycystic ovarian syndrome, i.e. PCOS) • Müllerian dysgenesis (uterovaginal agenesis) INVESTIGATIONS—GENERAL • Chromosomal abnormalities (intersex, Turner’s Pregnancy Test syndrome, testicular feminizing syndrome) • All patients require an initial pregnancy test #Causes ‘false’ or ‘cryptomenorrhea’ — menstruation is taking place but the patient is unaware of it as the outflow (serum or urine hCG). Any woman with is obstructed. amenorrhea is considered pregnant until proven 20

Table 3.1: Differential diagnosis of secondary amenorrhea Clinical scenario Investigations Comments • Pregnancy possible Serum, urine hCG elevated Pregnant; no further testing • Galactorrhea, visual defect Prolactin elevated >100 ng/ml MRI – positive – Prolactinoma; MRI – Negative – other causes ≤ 100 ng/ml Drug-induced/other causes for prolactinemia (Table 3.2) • Symptoms of hypo- THS, FT4 abnormal; prolactin normal Evaluate as indicated for thyroid hyperthyroidism dysfunction • Menopausal symptoms FSH elevated Primary ovarian failure; karyotyping if never menstruated (i.e. primary amenorrhea) • Hyperandrogenic state Pelvic ultrasound–bilateral enlarged PCOS ovaries, subcapsular cysts; altered FH:FSH ratio >3:1; Testosterone >200 ng/ml DHEA-S and/or 17-alpha-OHP Evaluate for adrenal tumor; congenital elevated adrenal hyperplasia • None of the above Normal screening for hCG, prolactin, FH, FSH. a. Progestin challenge test Positive Chronic anovulation Negative Evaluation further for other causes of secondary amenorrhea b. Estrogen–Progestin challenge test Positive Hypogonadotropic hypogonadism (constitutional delay, stress, weight loss, systemic disease, hypothalamic/ pituitary disorder, etc.) Negative Anatomical or endometrial abnormality

Table 3.2: Causes of hyperprolactinemia# Contd... Physiological • Hormones • Pregnancy • Glucocorticoid excess • Breastfeeding • Opiates, cocaine • Breast stimulation Altered Metabolism • Sexual intercourse • Liver failure • Exercise • Renal failure • Stress (e.g. venesection, trauma, surgery, myocardial • Seizures infarction) Ectopic production Pathological (serum prolactin ≥ 100 ng/ml) • Bronchogenic (e.g. carcinoma) • Pituitary disease (e.g. Prolactinoma, nonsecreting • Gonadoblastoma adenoma, meningioma, metastasis) • Hypopharynx • Hypothalamic and pituitary stalk disease (e.g. TB, • Ovarian dermoid cyst , craniopharyngioma, empty sella, meta- • Renal cell carcinoma stasis, cranial irradiation) • Teratoma Medications Others • Oral contraceptive pills • Hypothyroidism • Antipsychotics • PCOS • Antidepressants • Addison’s disease • Antihypertensives • Antiemetics #Normal serum prolactin reference range – ≤25 ng/ ≥ • Histamine H2 receptor blockers ml; Hyperprolactinemia = serum prolactin 40 ng /ml Contd... (40 mcg/l) 21

otherwise; false-positive testing may occur vary Endocrine Hormone Assays rarely with ectopic hCG secretion (e.g. chorio- • May include serum LH, FSH, serum prolactin, carcinoma or bronchogenic carcinoma). estradiol, free testosterone, 17-hydroxy- progesteron, and dehydroepian-drosterone US of Pelvis sulfate (DEHA-S). • Anatomic abnormalities should be excluded Serum Prolactin (PRL — Normal Reference- before performing an endocrine evaluation. <25 ng/ml) Pelvic ultrasound will evaluate for the • Level up to 100 ng/ml suggests hyperpro- presence or absence of pregnancy, ovarian lactinemia; more than 100 ng/ml occurs in cysts (PCOS), ovarian tumor, uterine lesions the presence of a tumor. PRL levels fluctuate such as hematometra, Asherman’s synd- periodically, therefore, several measure- rome, and uterovaginal disorders. ments may be necessary to confirm hyper- prolactinemia. TFTs • Hypothyroidism, including subclinical Serum LH, FSH hypothyroidism, may affect menstruation, • Elevated LH and FSH (>40 ml IU/ml) are leading to amenorrhea. Besides, abnormal suggestive of ovarian failure, e.g. POF, thyroid hormone levels can affect prolactin resistant ovary syndrome, or autoimmune ovarian failure. If FSH and LH levels are levels; therefore, measuring TSH, FT4 levels elevated, POF is the most likely cause is indicated in patients with amenorrhea. • An increased ratio of LH: FSH exceeding 3:1 ESR suggests PCOS, and helps differentiating patients of PCOS from hypothalamic • Elevated in autoimmune disorders; may be of dysfunction significance in patients associated with POF. • Low LH and FSH values (<20 ml IU / ml) suggest physiological hypothalamic ame- Blood Glucose norrhea (stress, anxiety, diet, exercise) or • Diabetes mellitus type 1 is associated with a pituitary disease (GnRH deficiency). higher incidence of hypogonadotrophic DEHA-S amenorrhea, secondary to chronic systemic illness, possibly due to derangement in HPO axis. • Elevated DEHA-S suggests adrenal insuffi- ciency or tumor. Urea, Creatinine, Electrolytes, LFTs Free Testosterone • For assessing renal and hepatic disease, including alcoholism. • Elevated values are seen in PCOS, ovarian tumor, adrenal tumor, and Cushing’s syndrome. RF, ANA Progestin Challenge (Withdrawal) Test • For evidence of autoimmune disease • This test is performed to confirm the presence associated with resistant ovarian syndrome. of adequate endogenous estrogen (>50 pg / INVESTIGATIONS—SPECIFIC ml). Medroxyprogesterone acetate 10 mg is given orally once daily for 5-7 days or Physical Examination injection progesterone in oil 100 mg • For evidence of structural abnormality of the intramuscularly. Any withdrawal bleeding genital tract, it should be performed earlier occurring within 2 days to 2 weeks in investigation of primary amenorrhea. following the final dose indicates that the 22 Diagnosis: A Symptom-based Approach in Internal Medicine

patient has sufficient estrogen, suggesting Karyotyping that the major components of the • If LH and FSH levels are high, POF is the most hypothalamic, pituitary, ovarian, and likely explanation. In patients <30 years age or uterine pathways are at least minimally stigmata of Turner’s syndrome, karyotyping functioning. The amenorrhea is likely caused is indicated to determine the chromosomal sex. by anovulation. The common underlying If a Y chromosome is found, the chance of a causes are hypothalamic dysfunction and gonadal malignancy is greatly increased. PCOS. Absence of with-drawal bleeding during the week following after the final dose Laparoscopy indicates estrogen deficiency or possibly • In PCOS, laparoscopy reveals bilateral en- outflow tract abnormality. larged ovaries with thickened tunica albu- Estrogen-progestin Challenge ginea and multiple cystic follicles. (Withdrawal) Test Hysteroscopy • This test helps to differentiate outflow • Helps to establish the diagnosis of Asher- abnormalities from estrogen deficiency. man’s syndrome. Estrogen is given for 21-25 days and a progestational agent for the final 5-7 days of CLINICAL NOTES estrogen therapy to stimulate withdrawal • The clinical evaluation of the patient should bleeding. If no bleeding occurs, an outflow include careful history, and should always tract abnormality (uterine agenesis, imper- include the following: forate hymen) is present. If bleeding occurs, • Menstrual history, including dates of last estrogen deficiency (due to hypothalamic, menstrual period—Age of menarche is pituitary cause) is present and further important and separates primary amenorr- testing is necessary. hea from secondary amenorrhea. A history of Dexamethasone Suppression Test cyclical abdominal colicky pain, retention of • To screen for Cushing’s syndrome and to urine suggests cryptomenorrhea presenting as primary amenorrhea. Sudden missed differentiate disorders causing hypercorti- menses preceded by regular menses suggests solism without Cushing’s syndrome (i.e. pregnancy in reproductive-age woman. pseudo-Cushing’s syndrome) such as in Oligomenorrhea progressing gradually to alcoholism, depression, anorexia nervosa, amenorrhea characterizes PCOS and antiseizure drugs. • Additional history may include symptoms of; MRI/CT Scan — Brain Pregnancy (nausea, breast tenderness, weight gain); menopause or premature ovarian failure • Hyperprolactinemia (i.e. serum prolactin (hot flushes, vaginal dryness, mood changes); > 100 ng/ml) warrants MRI of the brain. headache, visual disturbances, galactorrhea Various tumors such as craniopharyn- (prolactinoma); seborrhea, acne, excessive giomas and meningiomas may cause coarse hair growth, voice change hyperprolactinemia, but pituitary adeno- (hyperandrogenism, mostly caused by PCOS); mas are the most common. anosmia (Kallmann’s syndrome) Amenorrhea 23

• Medications (Table 3.2) may induce hyper Table 3.3: Tanner staging for female secondary prolactinemia. Post-pill amenorrhea may sexual characteristics persist for several months Stages of breast (B) Stages of pubic hair (PH) • Vigorous exercise—A history of excessive development development activity level suggests the female athlete triad • B1 preadolescent, • PH 1 preadolescent, no (i.e. amenorrhea, eating disorder, and elevated papilla, small pubic hair, fine vellus hair osteoporosis: vide infra ↓↓) flat areola covers genital area • Social history includes—Dietary habits, • B2 (age 11, range 8-13) • PH 2 (age 11) sparse ‘crash’ dieting, nutritional status, weight breast bud, papilla and distribution of long slightly areola elevate, increased pigmented straight hair loss, emotional and physical stress, and areolar diameter bilaterally along medial sexual activity border of labia majora • Family history includes—Family pattern of • B3 (age 12) continued • PH3 (age 12) pubic hair sexual development (menarche of mother enlargement of breast increases in pigmentation, bud, no separation of begins to curl and spread and sisters), genetic anomalies, and endo- breast contours sparsely over mons pubis crinopathies (diabetes, thyroid dysfunction) • B4 (age 13) areola and • PH4 (age 13) pubic hair • Past history includes—Trauma, surgery papilla separate from continues to curl and (hysterectomy), endometrial curettage, contour of breast to form becomes coarse, increase infection (TB), chemotherapy, and irradiation secondary mound in number • B5 (age 15, 13-18) • PH 5 (age 14) mature, • Physical examination—This is guided by mature, areolar mound pubic hair attains triangular history and should address the following: recedes into general pattern, spread to surface of  Psychologic status (stress, depression) contour of breast, papilla medial thigh  BMI,§§ nutritional status, height (short continues to project stature in Turner’s syndrome)  Secondary sexual characteristics (Tanner • Pelvic examination—Physical findings may staging: Table 3.3) be grouped as below:  • The type and stage of development of secon- In primary amenorrhea: dary sexual characteristics such as breast — External genitalia (male or female) and areola development, axillary and pubic — Clitoromegaly*** — Imperforate hymen hair growth, provide most important guide — Absent or blind ending vagina to diagnostic work-up in patients with — Uterus and cervix (present or primary amenorrhea absent) • Associated symptoms and signs as clues to  In secondary amenorrhea: the diagnosis include: — Clitoromegaly  Signs of hirsutism (acne, excessive facial — Atrophy of vulva and vaginal skin and body hair), virilization (voice change, — Uterine size temporal baldness) are suggestive of — Ovarian tumor PCOS and ovarian or adrenal tumor. • Systemic examination—For evidence of Tur-  Expressive galactorrhea suggests hyper- ner’s syndrome, hypo- and hyperthyroi- prolactinemia. dism, Cushing’s disease, panhypopitui-  Anosmia with hypogonadism suggests tarism, chronic hepatic or renal disease. Kallmann’s syndrome. Evidence of autoimmune disorder (RA, SLE,  Visual field defects on confrontation and myasthenia gravis) is suggestive of indicate pituitary adenoma. autoimmune ovarian failure  Features of Turner’s syndrome may be present. • Primary amenorrhea with normal secon- dary sexual characteristics is commonly due

§§Menstruation fails to occur regularly if BMI falls below *** 18-19 kg/m2 and it is estimated that 22% of female body Clitorimegaly defined as a length times width product 2 weight should be fat to ensure ovulatory cycle. of greater than 40 mm . 24

to anatomical defects and rarely due to secondary amenorrhea and shortened luteal androgen insensitivity syndrome, i.e. patient phases is much higher among women partaking phenotypically female but genetically male in athletics, specifically in sports requiring low with undescended testes. A karyotype body weight for per-formance and aesthetics. The analysis is needed to determine proper hormone pattern seen in these amenorrheic treatment. If testes are present, they should athletes includes a decrease in GnRH pulses from be removed because of the high risk of the hypo-thalamus, which results in decreased malignant transformation after puberty pulsatile secretion of LH and FSH and shuts down • Primary amenorrhea with hypoplastic stimulation of the ovary. The recently dis-covered secondary sexual characteristics is com-monly hormone leptin may also play a large role as a due to HPO axis disorders; Turner’s syndrome significant mediator of reproductive function. The is the commonest type of dysgenetic gonad. prevalence of eating disorders is high among female athletes who practice sports which emphasize RED FLAGS leanness. Consequently, the cause of menstrual • Although primary pregnancy before men- irregularities is not due to the exercise alone, but arche is extremely rare, it’s not impossible. to chronic inadequate or restrictive caloric intake “Although the first few menstrual cycles that does not com-pensate for the energy after menarche are often anovulatory, this expenditure. The most dangerous risk associated is not always the case. Because it is no longer with amenorrhea for the female athlete is the uncommon for girls to be sexually active in impact on the skeleton. Complications associated their early to mid teens, a sensitive dis- with amenorrhea include compromised bone cussion of this subject and a pregnancy test density, failure to attain peak bone mass in are necessary in the initial investigation of adolescence and increased risk of stress fractures. amenorrhea in women of almost any age”5 The diagnosis of exercise-associated menstrual • Although ‘constitutional delay of menarche dysfunctions is one of exclusion. The most effective and puberty’ is a common cause for primary treatment is to decrease the intensity of the amenorrhea, it should not be assumed to exercise and increase the nutritional intake. account for amenorrhea; periodic follow up Hormone replacement has also been under 6 to evaluate other pathological causes for investigation as a possible treatment”. delayed puberty (e.g. growth velocity for skeletal age) is indicated REFERENCES • In patients with secondary amenorrhea, 1. Tierney Lawrence M Jr, et al. Current Med Diag physical and pelvic examinations must rule out and Treat 2006; 45th ed. 1184. pregnancy before diagnostic testing begins 2. Kaplowitz PB. Link between body fat and the • Oral contraceptives do not cause amenorrhea timing of puberty. Pediatrics 2008; 121 Suppl 3:S208-17. [PMID: 18245513: Abstract]. after discontinuation. Amenorrhea occurring 3. Baker ER. Body weight and the initiation of after discontinuation of oral contraceptive puberty. Clin Obstet gynecol 1985;28(3): 573-9. therefore needs the same investigations as [PMID: 4053451: Abstract]. amenorrhea temporarily unrelated to 4. Child Marriage: Girls 14 and Younger At Risk. previous use of an oral contraceptive. Web site - http://www.iwhc.org/resources/ youngadolescents/childmarriage.cfm. Accessed on 11-09-08. SELECTIVE GLOSSARY 5. Bryan M, et al. Evaluation and Management of Amenorrhea, Mayo Clin Proc 1997;72:1161-9. Female athlete triad—Includes “amenorrhea, 6. Warren MP, et al. Exercise-induced endocrine osteoporosis and eating disorders. The inci-dence pathologies. J Endocrinol Invest 2003 Sep; of menstrual irregularities including primary and 26(9):873-8. [PMID: 14964440: Abstract]. CHAPTER 4 Anxiety

SYNOPSIS Anxiety is always accompanied by distur- bances of autonomic functions, and because the In clinical practice, a significant number of patients patients are not aware of the relation between presenting with psychiatric symptoms seek an their anxiety and other symptoms, the latter acceptable explanation and relief from symptoms usually dominate the clinical picture. Patients or illness. These symptoms are either quantit- may present with any of the complaints (Table atively excessive (compared with normal reaction 4.1), but particularly common are headache, to stress), or qualitatively abnormal (they do not dizziness, chest pain, palpitation, abdominal usually occur as understandable reaction to stress). , diarrhea, , fatigue, and emotional For many patients such episodes of illness represent upset. There is often an increase in tone in major disruption to life; they may even express voluntary muscles, so that the patient has a fears for their own mortality. All these are sense of tension and complains of feeling tense, essentially normal and understandable responses keyed-up, on edge, unable to relax, lack of to the illness and the context in which they occur, concentration, irritable, and insomnia. When and a normal individual deals with such fears or anxiety becomes intense, chaotic motor apprehensions effectively by utilizing his inherent behavior may occur, which is usually called defence mechanisms that produce a natural ‘fight- panic; the patient may experience chocking or or-flight’ adaptive response. However, in some the smothering, feeling of dead or threat, which may defensive mechanism is inadequate, leading to a lead the patient to associated comorbid maladaptive response, resulting in overt emotional, disorders.† behavioral and physical manifestations, which can The evaluation and management of anxiety vary enormously from feeling tense or tired to panic attack. Thus, the experience of an unpleasant and * Anxiety is sometimes differentiated from fear, as anxiety inappropriate affective state (i.e. fear or apprehension is a feeling of unease or dread in response to an internal out of harmony with the idea, thought, or object stimulus, in contrast to fear, which is based on an external accompanying it) with the expectation of, but not threat. the certainty of something untoward happening is †In certain individuals anxiety may extend beyond the single issue of their worry and may lead to phobias, defined as anxiety*. A definition which is briefer and obsessive compulsive disorder, panic disorders, hypo- 1 to the point is: ‘a fear for no adequate reason. chondriasis, and somatization. 26

Table 4.1: Clinical features of anxiety: Table 4.2: Anxiety and anxiety-like state emotional/psychological symptoms A-Medical conditions which can mimic or cause anxiety • Apprehension/fearful • Behavioral problems • Hypertyroidism • Adrenal disorders anticipation (especially in children and • Hypoglycemia • Temporal lobe epilepsy adolescents) • • Cardiac—acute coronary • Irritability • Nervousness and jumpiness syndrome syndrome, MVP • Impaired concentration/ • Exaggerated startle • • Psychiatric illnesses— ‘mind going blank’/ response • Sleep disorders depression impatience • Trauma • Feeling restless/on • Fear that you are dying/ B-Medications and substances which can induce anxiety edge ‘going crazy’ • Stimulant drugs • Bronchodilators and • Confusion (Caffeine and respiratory inhalers • Insomnia other stimulants) • Abuse drugs (heroin, • Herbal remedies (ephedra) can be challenging because patients present with cocaine, amphetamine) distress and concern about disease in the absence • Over-the-counter • Hypertensive medication medications (decon- • Withdrawal from alcohol of objective evidence. However, “...central to the gestants) • ADHD medications whole issue of diagnosing anxiety disorders, it is • Steroids (amphetamine) usually not the illness that is masked but the • Hormones (oral • Withdrawal from contraceptives, benzodiazepines doctor who is blind. By confining enquiries to thyroid medication) (Diazepam) physical systems, the correct questions are not asked, and consequently the correct diagnosis is • Substance abuse (alcohol, benzodiazepines, missed...”.2 Also, anxiety and anxiety-like caffeine) symptoms may be consequent to a variety of • Menopause. medical aliments and their treatment (Table Occasional 4.2).3 Therefore, a comprehensive, emphatic understanding, and time to listen to the patient • Medications (bronchodilators, antipsycho- permits a reasoned and often a therapeutically tics, amphetamine, insulin) effective approach to the difficult problem. • Drug withdrawal (anxiolytics, sedatives, hypnotics) DIFFERENTIAL DIAGNOSIS • Chronic systemic disease (diabetes mellitus, Common cardiac arrhythmia, hyperthyroidism, rheumatoid arthritis, hepatitis B and C, post- • Acute stress reaction (death; accident; herpetic neuralgia) traumatic diagnosis: HIV, ESRD, end-stage • Psychiatric disorders (panic, phobia, obs- COPD; cancer; assault; rape) essive compulsive disorder, post traumatic • Adjustment reaction with anxiety (inter- stress disorder, hysteria, psychosis, demen- personal conflict) tia). • Psychiatric disorder (generalized or chronic anxiety state, depression, hyperventilation Rare syndrome) • Acute systemic illness (acute coronary • Systemic disorders (mitral valve prolapse, syndrome, bronchial asthma, stroke, pheochromocytoma, Cushing’s disease) seizure, migraine) • Secreting tumors (carcinoid, insulinoma) Anxiety 27

• Metabolic (electrolyte disorders, porphyria). EEG • Anaphylaxis. • Patients with intermittent anxiety with period of remission in between the episode INVESTIGATIONS—GENERAL should have a wake-and-sleep EEG (and Blood Glucose possibly a CT) to rule out cerebral tumor.

• In diabetic patients on insulin and/or CLINICAL NOTES sulfonylureas, plasma glucose <50 mg/dl causes hypoglycemic episodes leading to • Anxiety is a normal human emotion. Dis- adrenergic symptoms such as anxiety, tinguishing normal anxiety from pathologic ‡ palpitations, and tremor anxiety and anxiety disorders often requi- • Asymptomatic fasting hypoglycemia may res systematic evaluation and a thorough indicate primary pancreatic β cell dysfunction, understanding of the individual patient’s typically a β cell tumor—insulinoma. physical and psychological status • Also, it cannot be assumed that physical Thyroid Profile symptoms are simply secondary to an • Decreased levels of TSH with increased anxiety disorder because anxiety may be the levels of FT4 suggest thyrotoxicosis. consequence of a physical illness such as in the cardiac or hyperthyroid patient. Anxiety ECG may also coexist with other psychiatric • Useful to evaluate possible tachyarrhy- disorders as in bipolar depression. Hence it thmias, coronary syndromes, and to screen is important to be certain about the diagnosis of anxiety per se for drug-induced QT prolongation. • Typical features of pathological anxiety include INVESTIGATIONS—SPECIFIC excessive, unrealistic, and persistence of its somatic and physical symptoms (Table 4.3) 24-hour Urine for Catecholamines for more days than not, for at least six months, in the absence of an objective stimulus. The focus of • Increased levels of VMA and HMMA in urine, anxiety may be everyday trifle activities (e.g. or increased levels of free metadrenaline in urine appointment, communication) or life events and blood (soon after episode of anxiety symp- (e.g. job performance, marriage relationship, toms) is suggestive of pheochromocytoma. financial stability, and retirement) Serum Insulin/C Peptide • Diagnosis of anxiety is based on the history— It is vital to listen carefully to what patients’ • May be indicated if insulinoma is strongly say; it helps to determine whether their suspected.

‡ 24-hour Holter Monitor As outlined in the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV), anxiety • To exclude paroxysmal cardiac arrhythmia. disorders include generalized anxiety disorder (GAD), social anxiety disorder (SAD, also known as social CT Scan/MRI Pancreas phobia), specific phobia and panic disorder (PD), with β and without agoraphobia, obsessive-compulsive disorder • May be useful to detect pancreatic cell (OCD), somatization and post-traumatic stress disorder tumor, e.g. insulinoma. (PTSD). 28 Diagnosis: A Symptom-based Approach in Internal Medicine

Table 4.3: Pathological anxiety: signs and symptoms critical to diagnose depressive disorders Motor tension Autonomic overactivity because they are common, treatable, carry a high risk of morbidity and mortality, and Muscle tension or ache Dry mouth Tension headaches Palpitation/tachycardia frequently coexist with anxiety. In addition , twitches, Sweating/cold clammy skin DSM IV criteria may be used to determine and jitters Tiredness/fatigue Flushes/chills specific psychiatric disorder. ‘Lump in throat’/difficult swallowing RED FLAGS Diarrhea/abdominal distress Frequent urination Anxiety and depression frequently occur together, Difficulty /suffocating Dizziness/light headedness which can complicate the clinical picture, including suicidal attempts or self-medication with alcohol or other illicit drugs.4-7 anxiety is dysfunctional, i.e. whether it is Cardiac arrhythmias, endocrinopathies excessive and sustained and interferes with (insulinoma), and medication reactions consti- daily living. History also helps to ascertain if tute significant number of undiagnosed psy- medications, substance abuse, a medical chiatric referrals for ‘anxiety’. illness, or associated psychiatric disorder is aggravating patient’s anxiety. Historical data REFERENCES from family members may indicate the cause of acute anxiety 1. Hamilton M. Fish’s Clinical Psychopathology— Signs and Symptoms in Psychiatry; 2nd ed. • History of intermittent anxiety—Suggests (Indian), p. 72. cardiac arrhythmia such as PSVT or AF, 2. Hodgkiss A. Anxiety; French’s Index of Diff. Diag. psychomotor epilepsy, insulinoma, and 14th ed. P. 38. pheochromocytoma 3. Härter MC, et al. Associations between anxiety • Age—The young and the middle-aged patient disorders and physical illness. Eur Arch Psychiatry Clin Neurosci 2003; 253(6):313-20. is more likely to suffer from a psychiatric [PMID: 14714121: Abstract]. disorder, while older patient may be suffering 4. Katon W, et al. The association of depression and from vascular or some other form of dementia anxiety with medical symptom burden in patients • Physical examination—Patient with anxiety with chronic medical illness. Gen Hosp Psychiatry 2007; 29(2):147-55. [PMID: 17336664: is restless, agitated; vital signs reveal tachy- Abstract]. cardia and increased blood pressure and 5. Sareen J, et al. Anxiety disorders and risk for sui- respiration; neurologic examination usually cidal ideation and suicide attempts: A population- shows brisk tendon reflexes and tremors. based longitudinal study of adults.Arch Gen Sustained tachycardia with weight loss makes Psychiatry 2005; 62(11):1249-57. [PMID: 16275812: Abstract]. hyperthyroidism a very likely possibility. 6. Hawgood J, et al. Anxiety disorders and suicidal Presence of a thyroid bruit, auscultatory behaviour: An update. Curr Opin Psychiatry 2008; systolic click indicates hyperthyroidism and 21(1):51-64. Review. [PMID: 18281841: Abstract]. mitral valve prolapse respectively 7. Petry NM, et al. Comorbidity of DSM-IV patho- • Exclusion of other psychiatric disorders, logical gambling and other psychiatric disorders: Results from the National Epidemiologic Survey especially depression—The Mini Mental on Alcohol and Related Conditions. J Clin Psychia- State Examination (MMSE) protocol is useful try 2005; 66(5):564-74. [PMID: 15889941: to screen patients for this purpose. It is Abstract]. CHAPTER Arthralgia and 5 Arthritis

SYNOPSIS alternative diagnostic possibilities. Similarly, an elderly woman, diagnosed initially as RA, may Arthralgia is pain or discomfort in one or more later develop a molar rash and oral ulcer which joints. Apart from tenderness, abnormalities of would change the diagnosis to SLE. the joint cannot be identified. Arthritis is painful joint with associated signs A careful history and physical examination of inflammation such as erythema, swelling, are essential which will help guide appropriate tenderness, effusion, and limitation of move- investigations and management. The most ments of the joint. Often, both arthralgia and relevant aspects to decide are threefold: arthritis coexist in the same joint;* arthralgia 1. Whether the underlying disorder is infla- being an early symptom whose clinical signs is mmatory or not (Table 5.1). not yet apparent or too subtle for detection. 2. Establish the type of onset (acute or other- Joint pain can be a manifestation of disorders wise), and its subsequent evolution (i.e. confined to the joint and also of a number of self-limiting, monoarticular, polyarticular systemic disorders. Identifying the cause of joint symmetrical, or polyarticular nonsymme- pain, therefore, can be difficult because of trical: Table 5.2). extensive differential diagnosis. In some cases 3. The presence of associated extra-articular and the diagnosis may be hindered by atypical systemic manifestations (e.g. fever, rash, eye presentation (as in the elderly or immunocom- involvement, bowel symptoms, Raynaud’s, etc.) promised), or masked in those with multiple The majority of conditions are benign and self- comorbidities and / or symptoms. Consequently, limiting, but a minority (trauma, sepsis, gout) may it is prudent to keep the diagnosis open in require an urgent assessment and treatment. patients who present with pain in multiple joints. For instance, what may begin as a DIFFERENTIAL DIAGNOSIS monoarthritis may in course of time become polyarthritis, thereby necessitating a review of Common

*The term arthrosis is sometimes used to describe a • Infection (viral: adenovirus, parvovirus— degenerative lesion of a joint. especially B19, alphavirus1, 2 For example: 30

Table 5.1: Differentiating inflammatory arthritis from Table 5.2: Pattern of joint involvement and noninflammatory (usually degenerative) arthritis differential diagnosis Features Inflammatory Noninflammatory • Monoarticular—Acute arthritis arthritis – Septic arthritis (gonococcal, nongonococcal, Synovial WBC >2000/μl <2000/μl or viral) count – Gout (due to uric crystal deposition) -ESR, CRP - Elevated - Usually normal -Early morning - Prolonged; >1 hr - ‘Gel phenomenon’ – Pseudogout (due to calcium pyrophosphate stiffness observed, i.e. pain and cry-stal deposition) stiffness lasting few – Hemarthrosis minutes after a period of – Acute presentation of seronegative spondylo- joint immobility, and improves with mild to arthropathies, e.g. Reactive arthritis moderate activity. • Monoarthritis—Subacute or chronic Nights worse than Yes No – Tuberculosis days – Postinfective arthropathies (mostly viral) Constitutional Yes, in certain No – Osteoarthritis features (e.g. conditions – Trauma fever, fatigue, weight loss) – Rheumatoid arthritis (i.e. palindromic onset) Spontaneous Common Uncommon – Juvenile chronic arthritis disease flares – Malignancy • Polyarticular—Asymmetrical chikungunya, dengue; bacterial—gonoco- – Seronegative spondyloarthropathies: ccal, nongonococcal, e.g. staphylococcal, – Ankylosing spondylosis streptococcal; tubercular) – Reiter’s disease • Osteoarthritis – Psoriatic arthritis • Rheumatoid arthritis – Enteropathic arthritis (associated with IBD) • Trauma. • Polyarticular—Symmetrical – Rheumatoid arthritis Occasional – Osteoarthritis – Arthritis associated with autoimmune rheumatic • Infection (Brucellosis; viral: HBV, HCV, HIV; disease: Lyme disease) – Systemic lupus erythematosus • Gout, pseudogout – Scleroderma • Reactive arthritis (i.e. Reiter’s syndrome ^) – Vasculitis • Prosthetic joint arthritis (bacterial, – Sjögren’s syndrome (primary) – Antiphospholipid syndrome tubercular, fungal) – Dermatomyositis/polymyositis • Adult onset Still’s disease (Juvenile rheuma- – Polyarticular septic arthritis toid arthritis). – Poncet’s disease (vide infra ↓↓) – Polyarticular gout– Rare – Arthritis associated with malignancy • Rheumatic fever with arthritis – Miscellaneous—sarcoidosis, amyloidosis • Spondyloarthropathies (ankylosing spon- dylitis, i.e. AS; Reiter’s syndrome; Psoriatic • Collagen disease (SLE, PAN, PMR, sclero- arthritis, IBD) derma) ^ • Immune-mediated (serum sickness, lepra Of historical interest is the fact that this diagnosis shares its name with the man who first described it, Hans Reiter, a reaction) Nazi physician who tested unapproved vaccines and • Hematologic (hemophilia, sickle cell disease, performed experimental procedures on victims in leukemia) concentration camps. The infamous legacy of Reiter’s name has led to the proposal that the syndrome be referred to by • Malignancy (hypertrophic pulmonary another, more descriptive name such as Reactive arthritis. osteoarthropathy, i.e. HPOA; metastasis). 31

INVESTIGATIONS—GENERAL Table 5.3: Radiographic findings in common arthritis CBC Disease Findings in target joints Acute Initially normal; localized soft-tissue • Hb reduced in inflammatory arthritis; osteomyelitis swelling, bone destruction, involu- leukocytosis in osteomyelitis, reactive crum, sequestrum, cloaca formation arthritis, and acute gout; and eosinophilia seen as disease advances Osteoarthritis Joint space narrowing; subchondral in collagen arthropathies, e.g. SLE, PAN. sclerosis, osteophytes, cysts; effusion; varus or valgus deformities in weight- ESR, CRP bearing joints. Growth of osteophy- tes is one of the best indicators of • Most useful in the assessment of patients disease progression. with RA, PMR, and giant cell arthritis; Rheumatoid Target areas include all five MCP, PIP arthritis joints, and all wrist compartments however, their values are elevated in a wide and feet. Joint space widening is the variety of disorders, including infections, earliest and very transient finding (due trauma, inflammatory arthritides and to effusion). Other early features include peri- various neoplasms. articular swelling, regional osteo- porosis, and erosion near joint capsule. RF Late signs are joint space narrowing, periarticular erosion, extensive des- • IgM RF may be positive in the majority of truction of bone ends, bony fusion, patients with RA. and cyst formation. Psoriatic arthritis Almost always accompanies skin dis- Serum Uric Acid ease, especially nail changes; mostly involves DIP joints of hand, classical • Values are elevated at some point during deformity is called “cup-and-pencil acute attack, though a single estimation is deformity”. normal in up to 25% of acute gouty patients. Involvement of MTP and interphalan- geal joints of feet may cause “ivory X-rays phalanx” Gout Often unremarkable early in disease. • Bone and/or joint X-rays are indicated in all Later “punched-out” lytic bone cases of major trauma to exclude fracture; to lesion with sclerosis, interosseous diagnose pathological fracture such as in tophi, and calcium deposits in soft tissues. osteomalacia, bone metastasis, and to Pseudogout Most frequent in the knees; calcifi- diagnose stress fracture. Other radiological (CPPD) cation in the hyaline and fibroc-artilage features of common arthritic disorders are (chondrocalcinosis) is present. given in Table 5.3. Ankylosing Sacroiliac joint involvement. Sacroi- spondylosis liitis occurs early with “saw-teeth” appearance. Initially the joint may INVESTIGATIONS—SPECIFIC look widened; squaring of the lumbar vertebral bodies is charac-teristic; ASO Titer followed by “bamboo-spine” appearance. • In patients with rheumatic fever the ASO titer is useful to document evidence of a ANA preceding streptococcal infection. • A positive ANA does not confirm diagnosis Blood Culture of SLE; a negative value virtually excludes • In septic arthritis. the diagnosis of SLE and drug induced lupus. 32 Diagnosis: A Symptom-based Approach in Internal Medicine

Anti-double-stranded DNA (Anti-dsDNA) cartilage lesions. High-resolution ultrasono- Antibody graphy (HRUS) allows detailed ‘real time’ imaging of joint and tendon morphology, • Almost diagnostic of SLE; occasionally found and structural changes involving the hand in other conditions, e.g. RA, drug-induced in patients with several rheumatic diseases, lupus, autoimmune hepatitis and lupus including RA, SLE, and gout, even in clini- nephritis. cally silent joints.3-5 Anti-Smith (Anti-Sm) Antibody CT/MRI • Diagnostic of SLE. • CT to diagnose fractures, infection, neoplasm, and vascular necrosis; MRI is best for assessing Cytoplasmic Antineutrophilic Cytoplasmic soft-tissue and spinal-cord elements. (C-ANCA) Antibody

• Positive in vasculitis, e.g. Wegener’s granu- Synovial Fluid Analysis lomatosis. • Provides valuable information, especially in patients with monoarthritis and joint effusion. Cyclic Citrullinated Peptide (CCP) Antibody Gouty arthritis is definitely diagnosed in the • Positive in RA. presence of urate crystals. Other parameters such as cell count and culture studies help to Human Leukocyte Antigen (HLA - B27) Typing differentiate inflammatory arthritis from non- inflammatory and septic arthritis. • Positive in spondyloarthropathies, espe- cially AS. Synovial Biopsy (Diagnostic Arthroscopy) • May be essential in the diagnosis of granulo- HLA DR4/ DR1 Typing matous arthritis such as tuberculosis, • In the initial diagnosis of RA; its presence is sarcoidosis, amyloidosis, synovial tumors, or associated with poor prognosis. mycotic infections.

Serology CLINICAL NOTES

• For evidence of HBV, HCV, HIV, and Lyme • When an individual presents with com- disease. plaints of musculoskeletal aches and pains, it is prudent to ascertain that the symptoms TFTs confirm to ‘arthritis’, because what may apparently look like an arthritic condition • For evidence of hyperthyroidism or may actually be a manifestation of ‘soft tissue hypothyroidism. rheumatism (STR)‡, also known as ‘non- articular rheumatic pain syndrome’. For US with Duplex Scanning

‡ • Helpful in imaging small structures or subtle STR is a collection of nonarticular pain generators that abnormalities such as partial ligament result from pathology of extra-articular and extraosseous periarticular structures. These soft tissue structures or tendon tears; synovial inflammation, include bursae, tendons and their synovial sheaths, hypertrophy, or effusions; and articular entheses, muscles and fasciae. Arthralgia and Arthritis 33

example, ‘pain in the knee’ as the patient may episode may be a harbinger of a chronic complain, may actually be due to pain polyarticular disease, and a chronic condi- because of bursitis over the knee; ‘pain in tion can present as an acute episode. There- the shoulder’ may be due to adhesive fore, chronic conditions such as RA, SLE, and capsulitis as against arthritis in the shoulder gout should be considered, at least initially, joint. The main features that differentiate in patients who present with acute poly- arthritis and STR are explained in Table 5.4. articular or monoarticular joint pain • The most useful information in evaluating • Inflammatory or degenerative etiology— joint pain comes from history and physical Inflammatory features include the presence examination. The relevant aspects are age; of all or some of the cardinal signs of whether the underlying condition is inflammation (i.e. erythema, warmth, pain, inflammatory or degenerative; type of onset swelling, and morning stiffness), and generally (i.e. acute or otherwise); subsequent evolution associated with systemic symptoms (e.g. fever, (i.e. self-limiting, monoarticular, polyarti- fatigue, weight loss). Common examples are cular symmetrical, or polyarticular non- infections, RA, gout, and reactive arthritis. symmetrical); and presence of associated or Degenerative (i.e. noninflammatory) features complicating extra-articular features. include pain without swelling or warmth, activity-related pain, minimal or absent Table 5.4: Difference between arthritis and STR morning stiffness, and absence of systemic Clinical features Arthritis STR symptoms. Common examples are OA, Pain Deep, diffuse, around Superficial and localized area of affected joint around affected bursa, fibromyalgia, and neoplasms tendon, muscle, etc. • Affected joints—Early OA can present in one Tenderness Circumferential Localized to the site of around the joint affected structure joint, most commonly the knee. Podagra, or where capsule is pain in the first metatarsophalangeal joint, accessible to surface Effusion Develops with more Usually superficial is the classic presentation of gout, appearing advanced disease swelling; effusion rare suddenly at night. Gout most commonly Pain on active Present Absent range of motion affects joints in the feet, ankles, hands, wrists, (ROM) elbows, and knees; less commonly affected Pain on passive Present Absent ROM areas include the sacroiliac, sternoclavicular, Instability/ Often present Absent and shoulder joints. Gout rarely affects the deformity hip and spine. Symmetrical involvement of • Age—Infectious causes as well as trauma have metacarpal phalangeal, proximal interpha- no particular age association. SLE presents langeal joints, wrist, and feet is more between second and forth decades of life; RA is common in RA; involvement of knees and more common between fourth and sixth decades; hips is unusual. OA favors knees, ankles, feet, and OA peaks in the seventh and eighth decades and spinal column, but involvement is not • Duration—Joint disorders are acute or chro- necessarily symmetrical. Depending upon nic, i.e. either less or more than six weeks the underlying cause, the pattern of arthritis respectively. Acute disorders are often may change overtime traumatic, infectious, metabolic (gout), or • Lifestyle factors—Diet rich in purine foods reactive; chronic disorders often include (liver, kidney, red meat) and alcoholism can noninflammatory and immunologic dis- precipitate an attack of gout in susceptible orders such as OA and RA. However, an acute individuals. High-risk behaviors, intravenous 34 Diagnosis: A Symptom-based Approach in Internal Medicine

drug use, past history of STD are risk factors Table 5.5: Clinical signs associated with for infectious arthritis, including viral arthritis and systemic disease hepatitis and HIV Signs Disease association • Medications—Diuretics, chemotherapeutic Eyes Conjunctivitis Gonococcal/Reactive arthritis agents, niacin, and aspirin can precipitate gout. Episcleritis/scleritis RA, vasculitis Hydralazine, isoniazid, methyldopa, procaina- Uvulitis/iritis Spondyloarthropathies Keratitis sicca Sjögren syndrome mide, chlorpromazine, and quinidine are Skin, Nails, Mucous membrane Butterfly rash on face SLE known to cause a lupus-like syndrome Hypopigmented anesthetic Leprosy, acute lepra reaction • Family history—RA, SLE, OA, ankylosing patch Plaques Psoriasis spondylosis, and (primary) gout have a familial Nodules / tophi RA, Gout component. SLE is also found in families with Thickened skin Scleroderma Photosensitivity SLE other autoimmune disorders such as hemolytic Petechiae, purpura Henoch-Schönlein purpura anemia, thyroiditis, idiopathic thrombocyto- Transient, superficial SLE, Behçet’s disease Oral ulcer penic purpura, vitiligo, and antiphospholipid Jaundice Hepatitis antibody syndrome Nails pitting, dystrophy Psoriatic arthritis Clubbing Metastatic lung cancer, • Extra-articular symptoms and systemic endocarditis manifestations are often helpful in narrowing Head, ENT Hair thinning, alopecia Hypothyroidism, SLE the differential diagnosis (Table 5.5). Scalp tenderness Giant cell arteritis Parotid enlargement Sjögren’s syndrome RED FLAGS Sinusitis, epistaxis Wegener’s granulomatosis Macroglossia Amyloidosis Heart, lungs • Arthritis caused by alpha viruses, especially Pericarditis, endocarditis RF, RA Ross River, Chikungunya and Pogosta Pleuritis TB, SLE, RA disease is increasing, and these should be Parenchymal lung RA, PAN, SLE, sarcoidosis Infiltration kept in mind as a possibility, especially in Hilar lymphadenopathy Sarcoidosis, SLE those cases where the disease starts with Abdomen, genitourinary Enteritis, colitis IBD flu-like symptoms, and rash is involved RA, SLE, Felty’s syndrome • Beware of the red-hot joint (Table 5.6), i.e. a Nephropathy SLE Calculi Gout single acutely inflamed, swollen joint that Proteinuria, hematuria SLE, vasculitis, infective may present a diagnostic problem. For endocarditis Urethritis, cervicitis Gonococcal, reactive arthritis example, acute gout is often confused with Neurologic cellulitis; joint aspiration and bacteriological Loss of pain and deep Neurogenic arthropathy, Tabes, Sensation Hansen’s disease, diabetes studies are indicated for precise diagnosis Seizures SLE • Pain in wrists and ankles in a middle-aged Facial palsy Lyme disease or elderly smoker with new onset of digital clubbing strongly suggests HPOA caused by • Presence of HIV infection should be ruled out underlying bronchogenic carcinoma in a patient with Reiter’s syndrome, (i.e. • Persistent underlying bone or skeletal pain, Reactive arthritis—a clinical tetrad of nocturnal pain, swelling, and spontaneous urethritis, conjunctivitis or uveitis, muco- fracture warrants prompt evaluation to cutaneous lesions, and aseptic arthritis), exclude malignancy (usually secondaries) who belong to high risk group for HIV and leukemic arthritis. infection. Arthralgia and Arthritis 35

Table 5.6: The red-hot joint disease remains a diagnosis of exclusion. Poncet’s • Infectious disease is postulated to be an immunologic – Bacterial reactive form of polyarthritis, and associated – Gonococcal with an excellent prognosis with rapid resolution – Mycobacterial – Virus on commencing antituberculous therapy and no – Lyme disease sequelae. Therefore, recognition of Poncet’s • Crystal-induced – Gout disease can be important. – Pseudogout (CPPD) – Hydroxyapatite (acute calcific periarthritis) REFERENCES • Hemarthrosis (hemophilia) • Traumatic 1. Toivanen A. Alphaviruses: An emerging cause • Septic bursitis (i.e. prepatellar bursitis) of arthritis? Curr Opin Rheumatol 2008; 20(4):486- • Flare of rheumatoid joint (existing RA) 90. [PMID: 18525365: Abstract]. • Psoriatic arthritis 2. McGill PE. Viral infections: Alpha-viral arthro- • Reactive arthritis pathy. Baillieres Clin Rheumatol 1995;9(1):145- • Osteomyelitis secondary to septic arthritis 55. [PMID: 7728877: Abstract]. 3. Szkudlarek M, et al. Ultrasonography of the meta- tarsophalangeal joints in rheumatoid arthritis: SELECTIVE GLOSSARY Comparison with magnetic resonance imaging, conventional radiography, and clinical exami- Poncet’s disease—In 1897, Poncet described nation. Arthritis Rheum 2004;50(7):2103-12. polyarthritis in patients suffering from tuber- [PMID: 15248207: Abstract]. culosis which was not caused by tuberculosis 4. Wright SA, et al. High-resolution ultrasonography infection of the joints. It is characterized by of the first metatarsal phalangeal joint in gout: A controlled study. Ann Rheum Dis 2007; polyarthritis that occurs during acute tuber- 66(7):859-64. Epub 2006;21. [PMID: 17185326: culosis infection that affects persons with visceral Abstract]. or disseminated tuberculosis. No mycobacterial 5. Wright S, et al. Hand arthritis in systemic lupus erythematosus: An ultrasound pictorial essay. involvement can be found or other known cause Lupus 2006; 15(8):501-6. [PMID: 16942002: of polyarthritis detected. Therefore Poncet’s Abstract]. CHAPTER 6 Back Pain

SYNOPSIS findings of many extensive studies that, “uncomplicated acute LBP is a benign, self- Back pain is one of the most common complaints limited condition that does not warrant any and cause of disability in people seen in practice. imaging studies. The vast majority of these More than 80% of the adults have had at least patients are back to their usual activities within one episode of back pain, and many have had 30 days. The challenge for the clinician, therefore, recurrent episodes since adolescence. Despite is to distinguish that small segment within this the frequency of low back syndrome, it is poorly large patient population that should be understood and physical examination is often evaluated further because of suspicion of a more unrewarding in locating the etiopathogenesis serious problem”.2, 3 The history and of backache because low back pain may examination will identify both the majority of originate from many spinal structures, patients with self-limiting disease and also the including ligaments, facet joints, the vertebral minority who have a potentially serious periosteum, the paravertebral musculature conditions that may present as back pain and fascia, blood vessels, the anulus fibrosus, needing further evaluation (Table 6.1). and spinal nerve roots. Although advanced Diagnostic testing should not be a routine part imaging tools such as CT, MRI, and nuclear of the initial evaluation, but used selectively scans have made it possible to distinguish wide based upon the history, examination, and initial variety of spinal aliments, their association treatment response.4 between symptoms and imaging results is weak.1 Anatomically backache can be grouped as: Because of the high prevalence and high cost  Upper back Pain (i.e. UBP or Thoracic or of dealing with this problem, and also because Dorsal Pain) related to the thoracic (T 1 to T many experts believe the problem has been 12) segments, and ‘overmedicalized’, resulting in rapidly rising  Low back pain (i.e. LBP or Lumbosacral Pain) workers’ compensation claim burden being related to the lumbosacral region (L 1-L5 + imposed on state budgets by low back pain S1-S5), which may be associated with lower (LBP) management, it is now clear, from the extremity symptoms. Back Pain 37

Table 6.1: Potentially serious conditions that may Table 6.2: Psychosocial barriers to back pain recovery present as back pain • Fear, financial problems, anger, or stress Possible condition Findings from the medical history • Depressed or negative moods, social withdrawal Fracture • Serious accident or injury • Overprotective family or lack of support • History of even a minor trauma or strenuous • Problems at work, e.g. heavy work, unsociable lifting in an older or osteoporotic patient hours, low job satisfaction • Chronic oral steroid use • Belief that pain and activity are harmful Tumor or infection • Age >50 years or <20 years • “Sickness behaviors” such as extended rest • History of cancer • Problems with claim and compensation • Constitutional symptoms (fever, chills, unexplained weight loss) • Bacterial infection – TB, UTI • Trauma/accident • Intravenous drug use • Infective (TB, i.e. Pott’s disease, epidural • Immunosuppression (corticosteroid use, transplant recipient, HIV infection) abscess, brucellosis) • Pain worse at night or ‘rest pain’ • Lumbar spondylosis (degenerative OA) • Failure to improve after 4 to 6 weeks of conservative low back pain therapy • Spinal dysfunction (intervertebral disk Cauda equina • Saddle anesthesia syndrome • Recent onset of bladder/bowel dysfunction prolapse, i.e. IVDP) • Abnormal gait/severe or progressive • Psychosocial (depression, anxiety, drug neurologic deficit in lower extremity Referred pain • Cardiac – Angina, MI seeking behavior) • Vascular–Pneumothorax, pulmonary • Referred (lower cervical segments, renal embolism, dissecting aneurysm calculi, pyelonephritis) Clinically backache is usually classified into: • Pelvis (in women—dysmenorrhea, pelvic  Acute backache—Usually lasting <4 weeks of inflammatory disease). duration; mostly due to injury, strain, or faulty posture; symptoms such as pain, and Occasional restricted movements often confined to lower • Infective (osteomyelitis) back, which are aggravated on coughing, • Spinal abnormalities (kyphosis, scoliosis, straining, or bending. The main task is to secondary to poliomyelitis, Scheuermann’s watch on events, e.g. any neurological deficit, disease) and address them as indicated. • Vertebral collapse (osteoporosis, osteom-  Chronic backache—Lasting >4 to 8 weeks of alacia) duration. At this point it is appropriate to • Referred pain (cardiac—angina, MI; GI— reassess the patient’s symptoms and physical findings; perform selective investigations, duodenal ulcer, pancreas) evaluate psychosocial barriers (Table 6.2), and a • Spondyloarthropathies (ankylosing spon- surgical referral should be considered. dylitis, Reiter’s syndrome) Since there is overlapping in the etiopatho- • Malignancies (usually secondaries: from genesis and management between the UBP, LBP, lungs, breast, prostate, thyroid). acute, and chronic disorders, their causes are Rare considered together for the purpose of practical clinical approach. • Congenital (spina bifida, spondylolisthesis*) • Malignancies (primary: myeloma, Hodg- DIFFERENTIAL DIAGNOSIS kin’s) Common • Referred pain (aorta, ) • Faulty posture * Spondylolisthesis, i.e. anteroposterior movement of • Mechanical pain (muscle/ligamentous strain, one vertebral body upon another body or the sacrum, sprain) commonly L4 on L5, occasionally L5 on S1. 38 Diagnosis: A Symptom-based Approach in Internal Medicine

• Compensatory neurosis (legal issues, INVESTIGATIONS—SPECIFIC workers’ compensation) Sr Calcium, Phosphorus, Alk Phosphatase, • Spinal canal stenosis Acid Phosphate • Cauda equina syndrome • Paget’s disease • Elevated in malignancy, myeloma, and bony • Coccydynia metastasis • Malingering. • Serum acid phosphate is commonly elevated in prostate carcinoma with bone secondaries. INVESTIGATIONS—GENERAL Sr Uric Acid CBC, ESR, CRP • Elevated in gout and lymphoma • Required when back pain is likely to be due • Tophaceous gout may mimic epidural/extra to infection, inflammation, or malignancy. epidural infection, abscess, or may coexist with other rheumatological disorders. Urinalysis PSA • Including c/s may be indicated to rule out • Backache may be an uncommon presenta- UTI and pyelonephritis as referred causes tion of metastasized carcinoma of the pro- complicating low back pain. state • Prostate carcinomas with established malig- Spine X-ray nant potential are more likely to be identified with PSA threshold >4.0 ng/ml. • Not useful in mechanical pain. Required if pain is associated with red flags (Table 6.3) Plasmoprotein Electrophoresis indicating more serious problems. • Useful in the diagnosis of plasma cell neo- Table 6.3: Lumbar spine X-rays should be plasms, e.g. multiple myeloma, and lym- limited to red flag indications phoma. • Unrelenting night pain or pain at rest • Fever above 38°C (100.4°F) for more than 48 hours Bence Jones Protein • Progressive neuromotor deficit • May be raised in serum and/or urine in • Pain with distal numbness or leg weakness • Loss of bowel or bladder control (retention or myeloma. incontinence) • Clinical suspicion of ankylosing spondylitis CXR • Significant trauma • A solitary pulmonary nodule or metastatic • History of or suspicion of cancer • Osteoporosis deposits, usually from thyroid, or breast • Chronic oral steroids may be an associated lesion in elderly with • Immunosuppressed or on immunosuppression chronic back pain. medication • Drug or alcohol abuse US Abdomen Note: Generally AP and LAT X-rays are adequate; Oblique • Intra-abdominal disorders such as aortic X-rays are not recommended; they add only minimal information in a small percentage of cases, and more aneurysm, renal, and uterine disease are an than double the exposure to radiation (Ref. Table 6.4). occasional cause of referred pain to thoracic Back Pain 39

or lumbar region which can be demon- Table 6.4: Limitations of X-rays in low back pain***

strated on US of abdomen and pelvis. • The radiation dose of one lumbar spine is equivalent to 150 chest X- rays and potential of gonadal irradiation. CT Spine • X-rays will not reveal a slipped disk. • Even in well-established metastatic disease, the tumor must erode • CT scanning is considered the imaging more than half of the vertebra before it is visible on plain X-ray. • There is a high false-positive rate in lumbar spine. modality of choice to evaluate patients for • Several X-ray findings are of questionable clinical significance spinal trauma and vertebral fractures. and may be unrelated to back pain. These findings include: – Disk calcification – Mild to moderate scoliosis HRCT Abdomen – Single disk space narrowing – Spondylolysis • To confirm abdominal US findings, and /or for – Lumbarization – Sacralization evidence of pancreatic, aortic, or pelvic lesions. – Schmorl nodes – Spina bifida occulta MRI Spine *** Diagnostic imaging practice guidelines for musculoskeletal complaints in adults - an evidence-based approach. Part 3: spinal • MRI is noninvasive, does not involve radia- disorders. Web site: tion, covers a large area of the spine, and can http://www.guideline.gov/content.aspx?id=13009&search= adult+ show changes within the disk and vertebral low+back+pain#Section405 body. It has become the imaging modality of Histocompatibility Antigen Test (HLA-B 27) choice in the diagnosis of radiculopathy, spinal cord abscesses, spinal cord tumors, spinal • In suspected spondyloarthropathies, e.g. stenosis, and nontraumatic vascular lesions. ankylosing spondylitis.

Bone Scans (Technetium) Myelography, Discography, Diagnostic Selective Nerve Blockade • In bone secondaries, and bone infection. • Myelography has been largely replaced by Upper GI Endoscopy CT myelography or MRI. • Discography and/or nerve blockade are • In patients suspected with GI causes, e.g. indicated in selective chronic back pain gastric or duodenal ulcer. patients in an attempt to either locate or abolish the exact source of back pain. CSF Analysis • To confirm CNS infections—bacterial, Bone Marrow Biopsy/Aspiration tubercular, fungal, or viral. • In conditions undetectable by conventional methods, e.g. granulomatous bone disease, Electrodiagnosis lymphomas, myelomas, and metastatic disease. • Such as NCS, needle EMG evoke potential studies are usually not necessary in a clear- CLINICAL NOTES cut radiculopathy or in patients with isolated • A careful history taking and physical mechanical low back symptoms. These studies examination should address the following are helpful in the evaluation of patients with three aspects of back pain, which are mostly limb pain in whom the diagnosis remains sufficient to arrive at a working diagnosis: unclear, e.g. peroneal neuropathy vs. radi-  Is the back pain due to any systemic culopathy and motor neuron disease. disease? 40 Diagnosis: A Symptom-based Approach in Internal Medicine

 Is there a neurological deficit that may the interscapular region of the thoracic spine. entail surgical evaluation? A clinical rule is to consider the cause of  Is there a psychosocial distress that is thoracic pain as cardiac until the examination aggravating or prolonging the pain (see and investigations prove otherwise below)? • Beware of herpes zoster in the thoracic • The vast majority of LBP are mechanical, i.e. segments especially in old and immunocom- muscular and ligamentous strains. They are promised persons self-limiting and not severe • Beware of spinal canal stenosis, especially • Diagnostic testing should not be a part of in middle-aged or elderly patient, with their initial evaluation. However, a patient’s history of neurogenic claudication‡ such as back failure to improve with conservative pain referred to hips, paresthesias worsened treatment (within 4–6 weeks) is an by back extension, walking and relieved by indication for further evaluation sitting, or lying with the trunk flexed (finds • Absence of history of trauma does not exclude hills easier to climb than to descend) mechanical causes, IVDP, or vertebral • In chronic cases, exclude significant pathology. fractures. A seemingly insignificant episode, Focus on counseling; discussing preventive such as a minor fall, may be a red flag for measures and patient education for self- fracture in an elderly management of future episodes improves • Examine the spine after its adequate prognosis. Avoid unnecessary, costly investi- exposure and in good light. Sometimes an gations unexpected finding such as midline mole, tuft • Suspect malingering, especially in patients of hair, dimpling, or hemangioma will spot with legal, or mediclaim issues. False-positive the diagnosis of spina bifida occulta physical findings such as positive SLR tests • Palpation is an important component of may be seen, yet the person may not have examination. Unlike the lumbar spine, the any problem while walking, sitting, or thoracic vertebrae are superficial and it is climbing. However, when the diagnosis of relatively easy to locate affected (painful) malingering is doubtful, it is safest to assume segment a person is not, unless a contradictory sym- • Sciatica usually involves L4 - L5, L5- S1 nerve ptom or sign is witnessed (Table 6.6)5 roots, either alone or together (Table 6.5) • Although any one episode of back pain may be • IVDP is very uncommon in the thoracic spine started by a physical problem in the back, its • Thoracic spine pain is frequently associated prognosis is vastly influenced by psychosocial with the lower cervical spine lesions factors. The added morbidity of depression and • The thoracic spine is the commonest site in anxiety with chronic pain is strongly associated the vertebral column for metastatic deposits with more severe pain, greater disability, and • Back pain that is unilateral may have a poorer health-related quality of life.6 urologic etiology such as pyelonephritis, or obstructive nephropathy RED FLAGS • Only congenital abnormalities which may cause back pain are spina bifida and spon- • Back pain associated with severe or pro- dylolisthesis. Sacralization† of L5 is gene- gressive neurological deficit is a medical rally asymptomatic emergency; suspect IVDP, cord compression, • The pain of myocardial ischemia, from angina, ‡ or myocardial infarction can be referred to Neurogenic claudication, i.e. presence of neurological symptoms/deficit in lower extremities while walking with † Sacralization—fusion of the sacrum and L5 vertebra. normal peripheral pulses. Back Pain 41

Table 6.5: Sciatica — Nerve root • Cauda equina syndrome—Back pain with compression and symptoms bladder or bowel incontinence, saddle area Level/ Nerve Pain Neurological Sciatica perineal numbness, disturbed gait is an disk root radiation deficit emergent condition. location involved • Beware of patients, especially elderly, with L3 – L4 L4 Lateral Patellar Uncommon weight loss, pain at rest, or constant pain at thigh jerk(reflex); and dorsiflexion night; significant pathology, especially inner of foot malignancy, must be ruled out. aspect (motor) • In elderly men, especially over age 50 with of leg L4 – L5 L5 Anterola Extensor of Common back pain, per rectal examination is man- -teral leg great toe datory; associated PSA estimation may be and great (motor) toe indicated to rule out prostate malignancy. L5 – L6 S1 Posterior Ankle Common • Chronic back pain before the age of 20 years leg and jerk (reflex); lateral plantar flexion is an indication to rule our primary spinal toes (motor) tumors, e.g. osteosarcoma. Midline Cauda Bilateral Saddle Uncommon disk equina leg anesthesia hernia weakness urinary REFERENCES -tion retention 1. Mulconrey DS, et al. Interobserver reliability in Table 6.6: What physical exam techniques are the interpretation of diagnostic lumbar MRI and useful to detect malingering? nuclear imaging. Spine J 2006;6(2):177-84. [PMID: 16517390: Abstract]. The Diagnostic and Statistical Manual of Mental 2. National Clearing House. Clinical Practice Guide- Disorders (DSM-IV) defines malingering as: line. Web site - http://www. guideline. gov/ “The intentional production of false or grossly exaggerated summary/summary.aspx? doc_id=8599 and nbr = physical or psychological symptoms motivated by external 004786 and string = low + and + back + and + pain. incentives such as avoiding military duty, avoiding work, Accessed on 03.10.08. obtaining financial compensation, evading criminal 3. Carragee E, et al. Are first-time episodes of prosecution, or obtaining drugs.” serious LBP associated with new MRI findings? Malingering is not considered a mental disorder Spine J. 2006;6(6):624-35. [PMID: 17088193: because symptoms are intentionally produced for Abstract]. external incentives. 4. Chou R, et al. Clinical Guidelines: Diagnosis and Several exam tests are commonly thought to detect treatment of low back pain: A joint clinical practice nonorganic causes of low back pain such as Waddell’s guideline from the American College of Physi- signs, Mankopf’s test, Hoover’s test, Arm Drop test, cians and the American Pain Society. Ann Midline Split test, etc. which have low diagnostic yield. Intern Med. 2007;147(7):478-91. [PMID: Since no examination technique objectively proves 17909209: Abstract]. malingering, the DSM-IV recommends suspicion of Web site: http://www.annals.org/cgi/content/ malingering for patients who present with 2 or more of abstract/147/7/478? maxtoshow = and hits = 10 the following: and hits = 10 and Resultformat = and fulltext = Diagnosis + and + Treatment + of + Low + Back + • Medicolegal issues Pain% 3A + Recommendations + from + the + • Disagreement between objective and subjective American + College + of + Physicians% 2F stress or disability American + Pain + Society and searchid Back = 1 • Noncompliance with evaluation or treatment, or and first index = 0 and resource type = HWCIT. • Antisocial personality disorder. Accessed on 04.10.08. 5. American Psychiatric Association. Diagnostic and vertebral fracture, and viral myelitis (her- Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Washington pes, polio, HIV). Hospitalization is indicated. DC: American Psychiatric Press Inc; 2000:683. • In a patient with acute back pain, who is 6. Bair MJ, et al. Association of Depression and withering with pain and clinically unstable, Anxiety Alone and in Combination with Chronic Musculoskeletal Pain in Primary Care Patients. suspect intra-abdominal or vascular Psychosom Med. 2008. [Epub ahead of print]. process. Hospitalization is indicated. [PMID: 18799425: Abstract]. CHAPTER 7 Breast Lump

SYNOPSIS In either case, however, the importance of correctly diagnosing a breast lump early can A breast lump* is a swelling or a protuberance in not be understated irrespective of woman’s age, the breast which feel different from surroun- clinical status, and risk factors. Goodson WH et ding breast tissue. Although breast lumps may appear at all al states, “The leading cause of physician delay ages—infants, young girls, and teenage boys— in diagnosis of breast cancer continues to be they are transitory and disappear on their own inappropriate reassurance that a mass is benign over a period of months. It is the breast lump in without biopsy. Reducing delay in diagnosis an adult woman that raises concern for breast will require less willingness to rely on clinical cancer, even though most lumps turn out to be examination to decide that a mass is benign, benign breast lesions. less reliance on benign mammography reports Frequently, it is the patient who has noticed to decide not to biopsy a mass, and a require- the ‘lump’ herself and expects reassurance or ment that fine-needle aspiration biopsy be done early evaluation. Not infrequently, a lump may by persons with demonstrated competence for have been detected on routine mammographic the procedure”.1 screening† called as a ‘mammographic lesion’‡. As most women who present with breast lump are emotionally distressed, the goal of the *The terms breast ‘lump’ and breast ‘mass’ are used interchangeably; however, since the term ‘mass’ is also evaluation is not only differentiating a benign used in the context of breast imaging modalities , the term breast disease from cancer, but also addressing ‘lump’ may be preferred to avoid confusion. the patient’s symptoms and alleviating the † ‘Screening’ is performed in the absence of symptoms; anxiety about breast cancer. when symptoms exist, the evaluation may dictate going beyond screening procedures. ‡ DIFFERENTIAL DIAGNOSIS Screening mammographic ‘lesion’ could be a lump, architectural distortion, asymmetric parenchyma, calci- Common fication, or skin changes. These findings are further defined by diagnostic mammographic imaging modalities as benign or malignant as per the Breast Imaging–Reporting • Benign breast disorders (fibrocystic condi- and Data System protocol. tion, fibroadenoma) 43

• Breast abscess (mastitis —acute or chronic) INVESTIGATIONS—SPECIFIC • Breast cancer. Mammography Occasional • Indicated as an initial screening procedure to § • Lipoma, pseudolipoma evaluate a breast lump in women aged 30 • Cysts (galactocele, solitary cyst, multiple years and more. The purpose is to evaluate a cysts, sebaceous cyst) palpable or dominant** mass, or to define the • Drug induced (aldactone, aldomet, and presence or absence and extent of nonpalpable digitalis). lesion associated with the mass; and also to identify additional abnormalities in the Rare ipsilateral or contralateral breast that may • Injuries of the breast (traumatic fat necrosis, influence further management. The purpose hematoma) of the mammogram is not to diagnose the • Tuberculous abscess palpable findings, and normal mammogram • Retromammary abscess (cold abscess) does not ensure absence of malignancy • Phyllodes tumor • Because the breasts are relatively radiodense • Metastasis (carcinoma of bronchus, thyroid, in women under 30 years of age, mammo- opposite breast). graphy is rarely of value in this age group. In older women some amount of fatty dis- INVESTIGATIONS—GENERAL placement of breast tissue makes mammo- CBC graphic evaluation more informative • Mammographic findings that suggest • Anemia in chronic infection and malignancy; malignancy include increased density, leukocytosis in breast abscess. irregular margin, speculation, and clustered ESR irregular microcalcifications. • Elevated in infection, tuberculosis and Digital Mammography malignancy. • This procedure greatly facilitates the use of LFTs computer-aided-detection (CAD), which • Elevated liver enzymes with secondary allows further evaluation of an abnormal deposits in liver. mass or some breast lesion that may have missed on initial evaluation. CAD is used Serum Calcium selectively especially in women with a • Elevated in secondary deposits in bones. genetic predisposition for breast cancer, where intensified early detection programs CXR may have to start from 25 to 30 years of age.2 • To detect underlying lung disease, e.g. TB, secondary deposits in lungs and ribs. **Dominant mass is a palpable mass which persist through- § out the menstrual cycle. These masses may be discrete ‘Pseudolipoma’ is a bunching of fat between retracted or poorly defined, but they differ in character from the suspensory ligaments of the breast and is associated with surrounding breast tissue and the corresponding area in an underlying carcinoma. the contralateral breast. 44

FNAC or FNA Biopsy (FNAB)†† Screening MRI may be helpful for women for whom mammography is not optimal, such • The material aspirated, either fluid from the as young women at substantially increased cyst or samples of solid lesions, are subjected risk for breast cancer because of known to cytological examination. Any finding that BRCA1 or BRCA2 mutations.3 is suspicious for malignancy on FNA is subjected to surgical excision for definitive Core-needle Biopsy diagnosis • This procedure can be combined with US, • Mostly used to evaluate small or difficult- i.e. US guided FNAC, to further assess poorly to-palpate lesions, or nonpalpable breast defined palpable masses masses identified on mammogram with • If FNA is done before mammography, the ultrasound guidance. A minimum of four diagnostic mammography should be de- core samples are taken to achieve greater layed for 2 weeks after needle aspiration so histologic accuracy. as to avoid false-positive results due to trauma and possible hematoma formation. Excision Biopsy • Indicated if FNAC or core Biopsy is US Breast inconclusive and there is clinical suspicion • Indicated as an initial procedure to evaluate of malignancy; the other possible indications palpable masses in women under 30 and are: a discrete lump which is increasing in lactating or pregnant women size, and when the patient is not willing to • Helps to differentiate a benign simple cyst, a ‘wait-on-events’ and anxious to have a rapid complex cyst, or any suspicious mammo- diagnosis. graphic solid density • Useful for guidance of interventional pro- Triple Diagnosis Test cedures • It’s a combination of clinical breast exami- • Not indicated as a screening study for occult nation (CBE), imaging studies, and FNAC, masses. used as an alternative to surgical excision to establish that the breast mass is benign. US Abdomen • If the above three parameters indicate a • To detect metastasis, especially to liver. benign process, the breast mass is considered as benign. If biopsy is deferred after triple MRI diagnosis, careful follow-up is warranted. If any of these three modalities suggests • It has high sensitivity for breast cancer besides aiding in its (TNM) staging and malignancy, excisional biopsy is mandatory. management. MRI is also found to be an Genetic Testing for Breast Cancer4 optimum method of imaging breast implants and detecting implant leakage and rupture. • Woman with personal history of breast cancer

^^ at young age; family history of breast cancer Some distinction is made between FNAC and FNAB; in two or more close relatives, such as FNAC refers to aspiration of fluid for cytology, and FNAB refers to obtaining tissue from solid lesion for cytological parents, siblings and children; a family evaluation. history of breast cancer in more than one Breast Lump 45

generation; a family member who has both Table 7.2: Risk factors for breast cancer breast and ovarian cancers; a male relative • Early menarche, before age 12 with breast cancer; or a positive BRCA1 or • Age greater than 50 years BRCA2 genetic test in a relative; may • Late menopause, after age 50 • Age greater than 30 at first birth undertake genetic testing after proper genetic • Nulliparity counselling to see if she actually do have a • Ionizing radiation exposure mutated gene. If a woman has mutations in • Family history in first degree relative (i.e. mother, sister, daughter) either of two breast cancer susceptibility • Previous history of breast cancer, breast biopsy genes (BRCA1 and BRCA2), her risk of breast showing atypical hyperplasia • Minor risk factors include: alcohol intake, obesity or ovarian cancer is significantly higher than (BMI >= 30 kg per m2), high economic status, ## that of a woman without such a mutation. HRT, and use of oral contraceptive pills

CLINICAL NOTES • Breast pain (mastalgia), breast lump, and nipple-discharge are the most common • History—Important components of the symptoms history are listed in the Table 7.1. • The most common causes of breast pain are Table 7.1: Breast lump—medical history fibrocystic disease, i.e. cyclical mastalgia (pain increases before the menstrual period • Age of menarche • Details of menstrual history and settles afterwards), and mastitis • Breast changes or symptoms noted with menstrual • A breast lump in a woman in the ages of 15 and period 25 years suggests fibrocystic condition, or • Age at first pregnancy • Number of pregnancies and deliveries fibroadenoma; cysts tend to occur commonly • Nipple discharge (frequency, color, unilateral, or and frequently around the fourth decade of life bilateral discharge) and in the perimenopausal period. In any • Age of menopause woman with breast lump, no matter what her • Any exposure to hormone therapy or oral contraceptive pills (age when began, duration, age, the probability of developing breast cancer dosage) increases throughout life • Previous breast biopsies and their corresponding • Nipple discharge—Important features to be diagnosis evaluated by history and physical exami- • Family history of breast cancer (including in relat- ives), and other carcinomas, e.g. ovarian nation include:  Nature of discharge • Breast lump—Duration of the mass; how and  Association with a mass when it was first noticed; change in its size,  Unilateral or bilateral shape, and consistency; its relation to  Spontaneous or manually expressed menses; changes in surrounding skin; and  Relation to menses trauma should be questioned.  Premenopausal or postmenopausal • Presence of risk factors (Table 7.2) indicates  Any exposure to hormones or contra- highest risk for breast carcinoma. ceptive pills. • Characteristics of discharge—May be ## FDA has approved the TOP2A FISH pharmDx device to physiological (pregnancy or lactation, i.e. test for the TOP2A (topoisomerase 2 alpha) gene in cancer patients. Web site - http://www.fda.gov/bbs/topics/ galactorrhea). Purulent discharge may be NEWS/2008/NEW01774.html caused by mastitis, breast abscess, or duct 46 Diagnosis: A Symptom-based Approach in Internal Medicine

ectasia; unilateral blood stained discharge as pain, tenderness, and consistency is a increases the concern for malignancy; critical component of the examination spontaneous persistent discharge may • Any breast lump must be evaluated to indicate hyper-prolactinemia and warrants determine whether it is cystic or solid; endocrine work-up neither the CBE nor mammography can • Skin changes overlying the lump such as make this distinction orange peel appearance, retraction, inver- • Although benign masses are often mobile, sion, and ulceration of the nipple strongly soft, or cystic, these features are not specific indicate breast cancer enough to exclude malignancy • CBE of the breast lump is done in at least two • Malignant breast lump—Common symp- positions: Sitting (i.e. upright) and supine with toms include: the woman’s arms behind her head.  Often painless, possibly increasing dis- Although CBE can detect a variety of abnor- comfort, especially prior to menstruation. malities, by far the most common are those  Changes in the breast that include dis- detected by palpation. The entire breast tortion, puckering of the skin and nipple tissue, i.e. the four quadrants, is palpated retraction. gently, systematically and individually,  Lump that may be firm or hard with including the tail of Spence, by applying varying degree of fixity to surrounding varying pressure. This is clinically significant tissues, overlying skin, or underlying because abnormalities can arise in the ‘tail’ pectoral muscles. region (e.g. axillary extension of ipsilateral  Malignant ulcer may be present, and the breast cancer) just as they can in other areas nipple discharge is usually bloody. of the breast • Symptoms suggestive of metastasis disease • Normal breast tissue is dense, firm, and elastic. are—bone pain, back pain, cough, dyspnea, Generalized nodularity and tenderness is headache, personality changes, seizures, and common during the menstrual cycle. It is abdominal symptoms and jaundice important to differentiate between a dominant • If the CBE yields findings suspicious of lump and areas of nodularity which can occur carcinoma, the American Joint Committee at any age 5 on Cancer (AJCC) clinical staging should be • A dominant mass or lump is distinct from included in the medical records. surrounding tissues, asymmetrical relative to the other breast, and persist throughout RED FLAGS a menstrual cycle • In a premenopausal woman, CBE is ideally • Never ignore a women’s insistence that an performed 3 to 10 days after the onset of area of her breast is different or has changed menstruation (when ovarian hormones • An asymptomatic breast mass is the most exert least influences; breast engorgement common presentation of the breast cancer and nodular structure of breast tissue is • Any eczematous rash appearing on the usually decreased) nipple or areola indicates underlying breast • Examination of the regional lymph nodes, malignancy i.e. axillary, cervical, and supraclavicular, for • A negative mammogram does not replace the their site, size, and associated features such need for biopsy of the palpable mass Breast Lump 47

• Tuberculosis of the breast, though an 17(8):1931-42. Epub 2007 Feb 14. [PMID: uncommon disease, is still present and is also 17429645: Abstract]. misdiagnosed with carcinoma or bacterial 3. Joann G, et al. Screening for Breast Cancer. JAMA 2005;293:1245-56. abscesses. Moreover, simultaneous occurrence 4. http://www.nci.nih.gov/cancertopics/ Genetic- of these two major illnesses in the breast, i.e. Testing-for-Breast-and-Ovarian-Cancer-Risk/ tuberculosis and carcinoma has been reported print?page=&keyword= (accessed on 08-07-08). in the literature which can lead to many 5. Singletary SE, et al. Revision of the American 6,7 Joint Committee on Cancer staging system problems regarding diagnosis and treatment. for breast cancer. J Clin Oncol 2002;20(17): 3628-36. [PMID: 12202663: Free full text]. REFERENCES Web site - http://jco.ascopubs.org/cgi/content/ full/20/17/3628 (accesses on 09-07-2008). 1. Goodson WH, et al. Causes of physician delay in 6. Fadeei-Araqqhi M, et al. Breast tuberculosis: the diagnosis of breast cancer. Arch Intern Med. Report of eight cases. Arch Iran Med 2008; 2002;162(12):1343-8. [PMID: 12076232: Free full 11(4):463-5.[PMID: 18588382: Free full text]. text]. 7. Alzaraa A, et al. Coexistence of carcinoma and 2. Bick U, et al. Digital mammography: What we do tuberculosis in one breast. World J Surg Oncol and what we don’t know? Eur Radio 2007; 2008;6:29. [PMID: 18318914: Free full text]. CHAPTER 8 Chest Pain

SYNOPSIS When a person complains of chest pain as ‘crushing, retrosternal pain, or substernal Chest pain—broadly defined as any discomfort pressure’, it usually suggests a cardiac source in the anterior thorax occurring above the of chest pain. However, only 50% of patients epigastrium and below the mandible—can be with acute coronary syndrome (ACS) describe one of the most challenging problem managed their pain in classic terms such as crushing or by the physicians. The typical patients’ concern pressure-like; it is often experienced more as a with the first bout of chest pain is their ‘nonspecific’ sensation of discomfort than actual apprehension of the onset of cardiac pathology, pain. Many other descriptive terms are also such as CAD. However, of the patients’ referred used to convey chest pain, such as dull, aching, to the Rapid Access Chest Pain Clinic, 52% did tightness, squeezing, soreness, burning, or ‘gas’. 1 not have cardiac chest pain. In another study Diabetic and elderly people who may have statistics show that more than 50% of patients cardiac pain are more likely not to experience referred to cardiologists for chest pain are chest pain, or to have nonspecific symptoms ultimately found to have noncardiac chest pain; such as dyspnea, nausea and vomiting, unusual that is, their chest pain isnot shown to be caused fatigue, or syncopal attacks. Moreover, in 2 by cardiac ischemia. Further, patients with women, the presentation of chest pain of cardiac chest pain who present for the first time to origin is frequently atypical than in men. ambulatory care or to the emergency room, only Therefore, the physician has to be aware of both 11 to 39% are ultimately diagnosed with the typical and atypical presentations of chest coronary artery disease.3 The balance of patients pain, especially of cardiovascular origin. (approx. 50–60%) experience noncardiac chest pain.4 The differential diagnosis of chest pain Thus, although for the patient with chest pain, the includes conditions affecting organs throughout possible underlying (notably cardiac) cause is the the thorax, neck, jaw, shoulder, arm, forearm, chief concern, for the physician, the cause, cardiac and upper abdominal viscera (i.e. the area or otherwise, is often unrelated to the complaint of covered by six dermatome — T1 to T6 – sensory chest pain. nerves), with prognostic implications that vary 49 from benign to life-threatening, including death. Gastrointestinal Nora Goldschlager, MD, Professor of Medicine, • GERD University of California, San Francisco states, • Functional GI disease “evaluation of chest pain is really all about not • Peptic ulcer disease missing CAD*, and in particular not missing • Gallstones things that could be ACS†, and calling • Pancreatitis. them something else and sending the patient home”.5-8 Musculoskeletal The extent of evaluation of the chest pain is chiefly determined by the patient’s age, family • Chest wall syndrome (painful rib syndrome, history, cardiac risk factors’ estimation, total slipping rib syndrome) ischemic burden, and cost-effective analysis of • Chest wall bruising or trauma noninvasive and invasive procedures, so that • Costochondritis (Tietze’s syndrome) unnecessary tests, procedures, anxiety, and • Cervical/thoracic radiculopathy. hospitalization are minimized or avoided. However, chest pain is not always of cardiac Pulmonary origin. In some patients, further workup may • reveal a noncardiac cause of chest pain, while • Pneumonia in others, the results may be inconclusive. It is • Pleural effusion(due to CHF, TB, malignancy). in this latter population that diagnosis can be particularly challenging. Despite test results Emotional/Psychiatric that are negative for CAD, they may still have cardiac or systemic diseases.9 • Panic/anxiety • Depression DIFFERENTIAL DIAGNOSIS • Somatization • DaCosta syndrome Common • Fibromyalgia.

Cardiac Occasional • Stable effort angina • Pericarditis (due to rheumatic fever, TB) • Unstable angina pectoris • Pulmonary embolism(PE) • Coronary spasm (Prinzmetal’s angina) • Aortic stenosis • MI (ST-elevation, and non ST-elevation MI) • Intercostals neuritis (herpes zoster: prior to • Cardiac arrhythmias. the eruption; diabetes mellitus).

*Coronary artery disease (CAD) may manifest as: stable Rare angina; unstable angina, non-Q wave MI (NQMI), non- ST segment elevation MI (NSTEMI); ST segment • Diffuse esophageal spasm elevation MI (STEMI); heart failure; sudden death; and as • Cardiac syndrome X (CSX — microvascular an incidental finding (asymptomatic). ↓↓ † angina: vide infra ) The term acute coronary syndrome (ACS) refers to a • Cardiac causalgia# range of acute myocardial ischemic states. It encompasses unstable angina, non-ST segment elevation myocardial • Hypertrophic cardiomyopathy infarction (ST segment elevation generally absent), and # ST segment elevation infarction (persistent ST segment Pain with tenderness of anterior thoracic wall, burning elevation usually present). — BMJ 2003; 326:1259-61. in nature, observed mostly in post CABG patients. 50

• Aortic dissection • Dilatation of individual cardiac chambers • Mitral valve prolapse (MVP) and cardiomegaly is seen in hypertension, • Pulmonary hypertension(PH) valvular heart disease and chronic CHF. • Pneumothorax. Cardiac Enzymes INVESTIGATIONS—GENERAL • Levels of creatine kinase MB isoenzyme (CK- CBC MB) usually rise above the normal range within 4 hours after the onset of myocardial • Anemia — aggravates cardiac ischemia. infarction, and serial sampling of CK-MB over • Leukocytosis in lung infection, infarction, a period of 12 to 24 hours permits the detection and bacterial pericarditis. of virtually all acute myocardial infarctions. Blood Glucose/Lipid Profile However, CK-MB elevations can result from causes other than myocardial injury • To assess risk factors for CAD. • The cardiac troponin T and I markers are ECG more specific than CK-MB for myocardial • When obvious ST-segment elevation is present injury. After myocardial injury, the levels of

in patients with acute chest pain, the diagnosis cardiac troponins rise after approximately

of myocardial injury is straight forward. the same amount of time as CK-MB levels However, significantly more than 50% of and remain elevated for up to 2 week; patients with AMI have nondiagnostic ECG therefore, they are not useful in detecting changes. The ECG becomes even less sensitive episodes of reinfarction. However, the assay with increasing age and in those with a previous for CK-MB permits the detection of MI. Also, many ECG patterns interfere with the reinfarction diagnosis of AMI. These include left bundle- • The most appropriate strategy followed at branch block, WPW syndrome, early many hospitals is the combined use of the repolarization ST changes, left ventricular CK-MB and Troponin I and T hypertrophy, hyperkalemia, digoxin effect, etc • Although troponin has greater specificity • Further, ST-T changes in patients with chest than myoglobin and CPK-MB for myocardial pain due to MI, PE, and pericarditis can be damage, elevated levels may be present in similar; therefore, the clinical history and patients with nonischemic heart disease or physical examination, as well as ECG clues, noncardiac disease. Cardiac causes, such as must be considered before making a diagnosis heart failure, myocarditis, and the use of • As patients with initially normal ECG are cardiotoxic drugs, such as doxorubicin, still at risk for life-threatening complications 5-fluorouracil, and trastuzumab can produce and death, it is important to obtain serial nonischemic troponin elevations. Non- ECGs for any evaluation. cardiac causes, such as pulmonary embolism, sepsis, high-dose chemotherapy, stroke, CXR subarachnoid hemorrhage, pre-eclampsia, • PA projection provides valuable information and renal failure can also produce such about pneumonia, pneumothorax, media- elevations. Therefore, elevated troponin levels stinal disease, pulmonary hypertension, do not invariably signify myocardial aortic dissection, spine disease and trauma damage. 51

INVESTIGATIONS—SPECIFIC and in recent years, HRCT has been accepted both as the preferred primary diagnostic Exercise ECG modality, and also as the criterion standard • The overall sensitivity and specificity is for making or excluding the diagnosis of about 50–70% in patients with CAD. The pulmonary embolism. ECG is monitored for ST-depression and any ventricular arrhythmias. The patient is also Ventilation-perfusion (V/Q) Scans monitored for any fall in blood pressure, or • V/Q scan remains an important part of complaints of chest discomfort, or dyspnea. the evaluation for detecting pulmonary The test is performed if diagnosis is in doubt, thromboembolism when HRCT angio- for prognostic reasons, or to aid in the graphy is not available. timing of additional investigations, e.g. Coronary angiography. A normal stress ECG Myocardial Perfusion Imaging does not rule out CAD; both false-positive and false- negative results are common. • Intravenous administration of a radioiso- tope (e.g. 201thallium or tetrafosmin) at rest Echocardiography – 2-D and Doppler10 and during stress provides additional information about myocardial perfusion. • In patients with acute chest pain due to MI, Areas of decreased uptake during exercise, this technique can be performed at the followed by normal uptake at rest suggest bedside, and is very useful for assessing right ischemia; whereas areas of persistent defect and left ventricular function, wall motion indicate infarction. abnormalities, identification of vegetations in endocarditis, and for detecting important Coronary Angiography complications such as mitral regurgitation, • This technique, which delineates coronary ventricular septal defects, pericardial artery anatomy, is the gold standard and effusion, and cardiac rupture. indicated in those patients who are at high • In aortic dissection, Doppler echo may show risk for CAD by noninvasive tests, and for aortic regurgitation, a dilated aortic root those with persistent symptoms despite and, occasionally, the flap of the dissection. medical therapy, i.e. medical vs. surgical • In patients presenting with atypical chest management, including stenting and CABG. pain, suspected to be due to MVP, 2-D cardiac echo findings of > 2 mm superior displacement Intravascular Ultrasound (IVUS) of the mitral leaflets into the left atrium during • Coronary angiography, although generally systole, with a leaflet thickness of at least accepted to be the gold standard of diagnosis, 5 mm can be diagnostic. is not 100% sensitive for exclusion of coronary HRCT/MRI artery disease. Coronary angiography detects the later stage of atherosclerosis (negative • Particularly useful in imaging the aorta in remodeling stage), when larger plaques suspected aortic dissection significantly impinge on the coronary lumen. • HRCT with contrast has been shown to have Angiography may fail to detect the early stage sensitivity and specificity comparable to of atherosclerosis (positive remodeling stage), that of contrast pulmonary angiography, when smaller plaques cause minimal or no 52

luminal impingement. This stage is detectable TFTs only by intravascular coronary ultrasono- • Both hyper- and hypothyroidism can graphy.11 precipitate CAD. Low or undetectable TSH Multislice Computed Tomography (MSCT)/ in hyperthyroidism may contribute to 64-Slice Spiral Computed Tomography anxiety associated chest pain. • Multislice computed tomography coronary CLINICAL NOTES angiography (MSCT-CA) has emerged as a powerful noninvasive diagnostic modality • Regardless of where care is given – primary to visualize the coronary arteries and to or emergency department—the critical first detect significant coronary stenoses. The step in managing patients with chest pain is latest generation 64-slice computed tomo- to explore the possibility of potentially life- graphy (CT) scanners are a robust technique threatening causes of the symptoms, which allows high-resolution, isotropic, including ACS, aortic dissection, and PE nearly motion-free coronary imaging. • A focussed, expeditiously performed phy- Coronary stenoses are detected with high sical examination should include: heart sensitivity and a normal scan accurately rate, palpation of peripheral pulses, BP rules out the presence of a coronary stenosis. measure-ment in both arms, and With the introduction of further novel estimation of oxygen saturation. Other concepts in CT-technology one may expect salient features are listed in Table 8.1. that MSCT-CA will become a clinically used Besides coronary risk factors’ stratific- diagnostic tool.12 ation, few key investigations to search for evidence of CAD (a 12-lead ECG, CXR, and GI Studies serial measurements of cardiac enzymes) • Common GI causes of acute noncardiac chest may be indicated in patients with acute pain include esophageal spasm, reflux eso- undifferentiated chest pain phagitis, peptic ulcer, pancreatitis, cholecystitis, • Physical examination usually does not reveal and esophageal perforation. According to one any abnormality in the diagnosis of aortic study, GI disease is the most common cause for dissection and PE; thus clinical suspicion which patients are admitted to a coronary care must be heightened in order to diagnose these unit to have MI ruled out, accounting for 42% conditions of all cases of chest pain.13 • If acute CAD seems unlikely to be the cause • Esophagogastroduodenoscopy, 3 hours of the chest pain, the possibility of pul- monitoring of esophageal pH, esophageal monary, GI, and musculoskeletal conditions, mano-metry, Bernstein test, and ultrasonic as well as pericarditis and other cardio- examination of the abdomen may be indi- vascular causes (e.g. cardiomyopathy, CSX) cated where symptoms are atypical, or should be investigated cardiac evaluation is normal. • For clinical evaluation, patients with chest pain can be classified into three broad PFTs groups, namely: acute pain of recent onset; • Can be helpful in patients with pulmonary recurrent pain – lasting for minutes; and chest pain, in differentiating obstructive vs. persistent pain – lasting for hours or even restrictive disease and its severity. days (Table 8.2). 53

Table 8.1: Physical findings in acute chest pain  Location (diffuse, anterior retrosternal Features Cause pain, chest pain, interscapular pain) Altered mental state; cold Low cardiac output: MI; LVF  Radiation (to the neck, jaw, shoulders or extremities; pulsus alternans; arms) tachycardia; hypotension; S4 Dyspnea; tachycardia; hypoxia; Acute : MI;  Aggravating factors (exertion, meals, cold elevated JVP; rales; S gallop LVF 3 weather, and stress) Pulse deficit; hypertension; Aortic dissection BP difference between two arms;  Duration (brief pain lasting few seconds murmur of aortic insufficiency; neurological deficit to few minutes) ; hypotension; Pulmonary embolism  Relieving factors (rest) elevated JVP; right ventricular  Associated symptoms (dyspnea, cough, lift; accentuated P2; pulmonary rales, consolidation, effusion diaphoresis, presyncope, syncope). Dyspnea, dysphagia, hypoxia; Cardiac tamponade elevated JVP; hypotension; • Common features of atypical chest pain are tachycardia; pulses paradoxus; listed in Table 8.3 muffled heart sounds; pericardial rub • Coronary risk factors include—Age, family Dyspnea; hypoxia; tachycardia; Pneumothorax history of heart problems, diabetes, ; hyperresonance; absent/diminished breath sounds; hypercholesterolemia, smoking, hyper- subcutaneous emphysema tension, obesity, sedentary lifestyle, and Hamman’s sign (crunching, Pneumomediastinum; rasping sound, synchronous Pneumopericardium; stress or competitive occupation with heartbeat) esophageal rupture • Although cardiac risk factors are common

Table 8.2: Classification and examples of in patients with ACS, they are not a pre- chest pain based on duration requisite; absence of such risk factors does 14 Duration Examples not lower the risk of ACS Acute chest pain–lasting Cardiac: ACS; HCM; aortic stenosis; • The key distinctive point in the clinical for few seconds to few pericarditis Vascular: Aortic diagnosis of chest pain caused by CAD is in minutes dissection; PE; PH Pulmonary: pneumonia; tracheobronchitis; its relation to physical exertion. If the chest pleuritis; pneumothorax; mass lesion discomfort is not precipitated by physical GI: GERD; PUD; biliary disease; pancreatitis exertion, it is highly unlikely that coronary Musculoskeletal: costochondritis; cervical disk artery disease of any significant degree is Lesion; trauma present (Table 8.4) Others: breast disorders; herpes zoster; anxiety; emotional • Occasionally, effort-induced ischemic pain Recurrent chest pain – Cardiac: (same as in above) disappears while the activity continues; this lasting for minutes vascular: PE; PH pulmonary: (same as in above, except is known as walkthrough or second wind angina pneumothorax) • Occasionally, diagnosis based solely on GI / musculoskeletal, and others: (same as in above) history may not be possible; e.g. descriptions Persistent – lasting for hours Cardiac: pericarditis of chest pain of cardiac, upper gastroin- and days together Pulmonary: ( same as in above, except pneumothorax) testinal, or gallbladder origin can be identical. GI / musculoskeletal, and others: Hence, although patient’s history is usually a (same as in above) valuable starting point, it may not provide a • Careful assessment of patient’s history and definite diagnosis because of their poor cardiac risk factors is often the most helpful specificity in diagnosis of chest pain15 starting point. Historical features generally useful • Symptoms of angina equivalents, i.e. cardiac in the diagnosis of cardiac origin of chest pain ischemia without chest pain, such as include: 54

Table 8.3: Symptoms of atypical chest pain • The pain of diffuse esophageal spasm may • Features suggesting atypical, also called as non- mimic that of angina pectoris, including that cardiac/ nonanginal pain includes: the relief in many cases is obtained with • Pain—dull ache, sharp, shooting,’ knife-like’, pleuritic, nitroglycerine pain brought on by respiratory movements or cough. • Location—pain localized with one finger, left sub- • Severe chest pain, retrosternal, accompanied mammary. by dyspnea, cough, and hemoptysis deve- • Aggravating factors – body movements, respiration, loping in a patient who has been immo- swallowing, palpation of chest. • Duration – brief episodes lasting a few seconds, or bilized or bedridden is suggestive of constant lasting for days. pulmonary embolism • Pulmonary hypertensive pain may resem- Table 8.4: Questions to differentiate patients with non- ble angina in that it is precipitated by effort. cardiac chest pain from those with coronary heart disease# Associated moderate or severe dyspnea and Response evidence of signs of pulmonary hypertension Question Typical Atypical suggest its diagnosis If you go up a hill (or other stressor) on 10/10 <10/10 • Chest discomfort due to pericarditis is typi- 10 separate occasions on how many cally retrosternal, aggravated by coughing, do you get the pain? Of 10 pains in a row, how many occur at rest? <2/10 ≥2/10 deep respiration, or change in position; worse How many minutes does the pain usually last? <5 ≥5 in supine, and relieved in sitting upright and

When answers to all three questions are “atypical” the chance of leaning forward coronary disease is only 2% in patients aged <55 years and 12% in • The acute onset of pleuritic pain and dyspnea those aged ≥55 in a patient with a history of asthma or #Christopher Bass et al. Clinical review ABC of psychological emphysema is suggestive of pneumothorax medicine chest pain. BMJ 2002; 325:588-91. • Psychogenic chest pain is often associated breathlessness; profound, unexplained, with hyperventilation and other somatic sudden-onset fatigue, especially in the symptoms such as chronic headache, diz- elderly and diabetic patients is common ziness, sweating, paresthesia, and a sense of • Pain that radiates to the left arm and ‘impending doom’. shoulder is often assumed to indicate coronary ischemia, whereas pain that RED FLAGS radiates to the right shoulder is thought to suggest a biliary source. However, chest pain • Lack of chest pain does not exclude IHD that radiates to the right shoulder is more • Over-reliance on tests with poor sensitivity, specific for pain of cardiac origin than pain such as ECG, or on the initial values of cardiac that radiates to the left shoulder. Radiation biomarkers will miss many patients with MI of chest discomfort to the right arm is also • In a patient with chest pain, the clinical consistent with the diagnosis of acute IHD16 response to GI cocktail (a mixture of liquid • Acute, sudden and severe chest pain described antacid, viscous lidocaine, and an as ripping or tearing that is maximal at onset anticholinergic), or sublingual nitroglycerin and radiates to interscapular area raises the (NTG), cannot reliably identify the source of possibility of aortic dissection. Important pain. Failure to respond to NTG should not 7,17 diagnostic feature is the inequality in the pulses, be used to exclude the possibility of CAD e.g. carotid, radial and femoral, and a blood • A history of a psychiatric diagnosis or pressure differential of greater than 20 mm Hg overwhelming anxiety in a patient with 55

acute chest pain does not preclude the therefore proposed as a pathogenic factor in possibility of an acute coronary event. female patients. Recently, techniques such as functional angiography, SPECT, and stress MRI SELECTIVE GLOSSARY have been used to diagnose CSX. However, the diagnosis remains one of exclusion. CSX has a Cardiac syndrome X (CSX)§— It is a condition low mortality rate and an excellent prognosis defined by the presence of angina-like chest pain despite variable symptomatic improvement. with angiographically normal coronary arteries which is observed in approximately 20–30% of REFERENCES angina patients undergoing coronary arterio- graphy. To establish the diagnosis, patients 1. Dumville JC, et al. Non-cardiac chest pain: A retrospective cohort study of patients who must have evidence of stress-induced myo- attended a Rapid Access Chest Pain Clinic Family cardial ischemia by exercise ECG, stress Practice Advance Access published on April 1, scintigraphy, or stress echocardiography, in 2007; DOI 10.1093/fampra/cmm002. Fam. Pract. 24: 152-7. conjunction with anginal chest discomfort. 2. Sheps DS, et al. Chest pain in patients with Coronary angiography reveals normal or near cardiac and noncardiac disease. Psychosom normal epicardial coronary arteries. Patients Med 2004;66(6):861-7. [PMID: 15564350: Free full text]. with CSX are usually younger (mean age 49 3. Kachintorn U. How do we define non-cardiac years) than patients with atherosclerotic CAD; chest pain? J Gastroenterol Hepatol 2005;20 more common in women (most of whom are Suppl:S2-5. [PMID: 16359344: Abstract]. 4. Eslick GD. Noncardiac chest pain: Epidemiology, perimenopausal) than men. Pain, which usually natural history, health care seeking, and quality occurs at rest, may have atypical features. The of life. Gastroenterol Clin North Am 2004; exact pathophysiologic factors and mechanisms 33(1):1-23. [PMID: 15062433: Abstract]. 5. Nora Goldschlager. Chest pain: Avoiding com- of pain in these patients are unclear. However, mon pitfalls. Internal Medicine World Report: Aug patients with chest pain and normal coronary 2007. arteries have abnormal vasodilatory coronary 6. Wilhelmsen L, et al. “Nonspecific” chest pain associated with high long-term mortality: Results blood flow responses and an increased from the primary prevention study in Göteborg, sensitivity of the coronary microcirculation to Sweden. Clin Cadiol 1998;(7):477-82. [PMID: vasoconstrictor stimuli (microvascular angina). 9669056: Abstract]. 7. Amany H Ahmed, et al. Silent myocardial ische- Microvascular endothelial dysfunction appears mia: Current perspectives and future directions. to be responsible for these coronary micro- Exp Clin Cardiol 2007;12(4):189-96. [PMID: circulation abnormalities. Risk factors such as 18651003: Free full text]. 8. Arslanian-Engoren C, et al. Symptoms of men hypertension, hypercholesterolemia, increased and women presenting with acute coronary plasma homocysteine levels, diabetes mellitus, syndromes. Am J Cardiol 2006;98(9):1177- abnormal blood rheology, H. pylori infection, 81.Epub2006Sep7. [PMID: 17056322: Abstract]. 9. Wilhelmsen L, et al. “Nonspecific” chest pain and smoking can contribute to its development. associated with high long-term mortality: Results Most patients with CSX are postmenopausal from the primary prevention study in Göteborg, women and estrogen deficiency has been Sweden. Clin Cardiol 1998;21(7):477-82. [PMID: 9669056: Abstract]. 10. Autore C, et al. Role of echocardiography in acute chest pain syndrome. Am J Cardiol 2000; § CSX must be distinguished from metabolic syndrome x 86(4A):41G-42G. [PMID: 10997353: Abstract]. of insulin resistance (glucose intolerance), hypertension, 11. Nissen SE, et al. Intravascular ultrasound: Novel hyperlipidemia, elevated BMI, and frequently associated pathophysiological Insights and current clinical with abnormal coronary angiography. applications. Circulation 103:604-16. 56 Diagnosis: A Symptom-based Approach in Internal Medicine

12. DeFevter PJ, et al. Spiral multislice computed 15. Swap CJ, et al. Value and limitations of chest pain tomography coronary angiography: A current history in the evaluation of patients with Suspected status report.Clin Cardiol 2007;30(9):437-42. acute coronary syndromes. JAMA 2005;294:2623- [PMID: 17803209: Abstract]. 29. 13. Fruergaard P, et al. The diagnosis of patients admit- 16. Berger JP, et al. Right arm and plain extension can ted with acute chest pain but without myocardial help to differentiate coronary diseases from chest infarction. Eur Heart J 1996;17(7):1028-34. [PMID: pain of other origin: A prospective emergency 8809520: Free full text]. 14. Body R, et al. Do risk factors for chronic coronary ward study of 278 consecutive patients admitted heart disease help diagnose acute myocardial for chest pain. J Inter Med 1990;227(3):165-72. infarction in the emergency department? Resus- [PMID: 2313224: Abstract]. citation. 2008 Aug6 [Epub ahead of print. PMID: 17. Gibbons RJ. Nitroglycerin: Should We Still Ask? 18691797: Abstract]. Ann Intern Med 2003;1036-37. CHAPTER 9 Constipation

SYNOPSIS bowel frequency, and is not associated with symptoms such as pain on defecation or The definition of constipation varies substantially distension. among patients, physicians, and researchers; and In clinical practice, constipation is generally includes expressions such as infrequent bowel defined as fewer than three bowel movements per movements (too infrequent), incomplete eva- week. An alternative (Rome III) definition for cuation with small feces (too little), difficult bowel functional chronic constipation in adults is two or more movement, inability to evacuate at will, straining of the following criteria^ for at least 12 weeks, not at stooling, or a need for digital manipulation to necessarily consecutive, in the preceding 12 months 1,2 enable defecation (too hard). (without use of laxative): The frequency, consistency, and quantity of • Fewer than three bowel movements per stools also vary depending on an individual’s week diet, fluid intake, physical activity, lifestyle, and • Excessive straining during at least 25% of social factors. 3 In many patients the complaint bowel movements of constipation reflects a mistaken perception • Sensation of incomplete evacuation after at of what constitutes normal bowel habits*.4 least 25% of bowel movements Because of the subjective nature of the condition, • Passage of hard or pallet-like stools in at least no consensus exists on the definition of 25% of bowel movements constipation. • Manual maneuvers (e.g. digital evacuation) However, a working definition of consti- to facilitate more than 25% of bowel move- pation may be described as decreased stool ments. frequency from the patient’s usual pattern, with The information acquired from the history and examination largely determines the investi- or without difficult passage of small, hard stools, gations required.5 Majority of chronic consti- provided it does not represent a recent change in pation patients can be managed depending on

^ * A common saying is,” One man’s constipation is another These criteria should not be applied to diagnose man’s diarrhea.” constipation caused by underlying organic disease. 58 clinical assessment; however, the recently pub- Rare lished evidence-based recommendations by the • Diverticulosis American College of Gastroenterology Task • Carcinoma of the colon Force on Chronic Constipation serve as a useful • Neurologic (Parkinson’s disease, multiple guide in patients with sinister features at the sclerosis) 6 outset. • Pelvic floor dysfunction (PFD : vide infra ↓↓) •· Developmental abnormality(Hirschsprung’s DIFFERENTIAL DIAGNOSIS disease : vide infra ↓↓). Common INVESTIGATIONS—GENERAL • Lifestyle CBC  Low calorie diet  Low fiber diet • Low Hb level due to occult blood loss in  Deficient fluid intake colonic malignancy.  Immobility  Repressed defecatory urge ESR • Laxative/enema abuse • Elevated in inflammatory or malignant • Painful anal lesion (Fissure, hemorrhoids, bowel lesion. abscess, rectal prolapse) • Irritable bowel syndrome with constipation FOBT (i.e. IBS-C) • In chronically constipated middle-aged or • Psychological (depression, anxiety) elderly adults, and in at-risk individuals • Medication (Opioids, antacids, iron supple- (family history of colonic cancer, change in ments, calcium channel blockers, anticholi- stooling pattern, weight loss, blood in stools, nergics, antiparkinsonian drugs, antide- abdominal mass), FOBT may be useful to pressants, antipsychotics). assess an obstructing neoplasm of the colon. Occasional Perianal lesions can give false-positive results.

• Eating disorder (anorexia nervosa, bulimia) Proctoscopy (Anoscopy) • Intestinal obstruction (volvulus, strangu- lated hernia, intussusception, or extrinsic • For presence of internal hemorrhoids, fissure, compression by any growth) ulcer, growth, polyp, or stricture; biopsy (Bx) • Inflammatory bowel disease (IBD) can be obtained to confirm the diagnosis. • Endocrine disease (Hypothyroidism, dia- Urea, Creatinine, Electrolytes betes mellitus) • Neurologic disease (stroke syndromes, • Elevated urea, hypokalemia with dehy- dementia, spinal cord disease—, dration and intestinal obstruction. cauda equina lesion, tumors) • Metabolic disorder (hypokalemia, hyper- INVESTIGATIONS—SPECIFIC calcemia, uremia) Endocrine Panel • Postsurgical (abdominal, pelvic, colonic, anorectal). • High TSH with low T4 in myxoedema. Constipation 59

• High blood glucose in uncontrolled chronic Table 9.1: Anorectal and pelvic floor function tests1 diabetes mellitus complicating autonomic • Ultrasonography neuropathy. • Anorectal manometry • Defecation proctography Serum Calcium • Balloon expulsion test • Rectal sensation – mechanical and electrical • Elevated in malignancy, and hyperparathy- • Pudendal nerve terminal motor latencies roidism. • Perineometry • Measurement of rectoanal angle AXR • Sphincter/puborectalis electromyogram • Spinal evoked potentials by rectal stimulation • Dilated bowel loops with multiple fluid • Cerebral evoked potentials by rectal stimulation • Scintigraphic expulsion of artificial stool levels in intestinal obstruction. • May provide evidence for an excessive  Anorectal manometry—Mainly to exclude amount of stool in the colon. adult-onset or short segment Hirschsprung US Abdomen disease.  Barium defecography—To evaluate evacu- • To assess extrinsic abdominal or pelvic atory disorders such as rectal prolapse, compression (e.g. pregnancy, fibroid, tumor). enterocele, and rectocele. Colonoscopy  Colonic transit studies (using radiopaque marker)—To study colonic motility dis- • Preferred procedure in patients at risk (i.e. orders. In normal persons, most of the with warning signs) for colon cancer or IBD. markers should pass by day 5; in a patient • Enables biopsy (Bx) of suspicious lesion, and with slow colonic transit, the markers will remove any high impaction. be scattered throughout the colon. If the Sigmoidoscopy/Barium Enema patient has pelvic outlet obstruction, more than 20% of the markers will be held up in • May be appropriate in younger patients the rectum. who are not at risk for colon cancer. Polyps,  Balloon expulsion studies—To demonstrate diverticula, strictures, and luminal wall impaired rectal evacuation. lesions can be demonstrated. Rectal Biopsy MRI—Brain, Spine • Helpful to diagnose Hirschsprung’s disease, • As indicated in , spinal ulcerative colitis, Crohn’s disease, and infil- trauma, spinal disease. trative diseases such as scleroderma, and Expanded Physiological Studies (Table 9.1)1 amyloidosis.

• In patients with chronic constipation with CLINICAL NOTES no identifiable cause following initial evaluation, and in whom initial treatment • The initial step is to define the nature of the has failed, or in those patients wherein patient’s bowel habit, and how the current subtypes of constipation are suspected, such problem differs from the normal pattern. as colonic motility dysfunction, or pelvic History should include: floor dysfunction, following studies may be  Detailed inquiry into the patient’s normal helpful:7 pattern of defecation 60 Diagnosis: A Symptom-based Approach in Internal Medicine

 Amount of time spent on the toilet while weight loss, change in bowel habits (Table waiting to defecate 9.2), nausea, vomiting, abdominal pain,  Whether the patient is c/o decreased distension, presence of blood in the stools, frequency of stools, or painful/incom- family history of colon cancer is important. plete evacuation Table 9.2: Differential diagnosis of change  Perceived hardness of the stools in bowel habit (constipation/diarrhea)  Whether the patient strains in order to Constipation dominant defecate • Low-fiber diet  What maneuvers (pharmacological or • Drug effect — For example codeine, iron, laxative abuse • IBS physical) are used to facilitate this • Diabetic neuropathy (autonomic neuropathy) process • Fecal impaction  Any other symptoms (pain, protruding • Carcinoma of colon, rectum, or anus • Neurologic disease such as spinal cord injury mass, bleeding) the patient may be experiencing Diarrhea dominant • Viral gastroenteritis • Is the constipation acute or chronic—Consti- • Food poisoning pation is generally considered to be acute or • Parasite infection (giardiasis) • Traveler’s diarrhea (usually Escherichia coli infection) occasional if it’s less than three months, and • Change in resident bacterial flora, e.g. antibiotic chronic if it lasts thee months or more associated diarrhea • In acute constipation there is abdominal pain • Antibiotic-related diarrhea (Clostridium difficile colitis) • Hyperthyroidism and vomiting, suggesting the possibility of • Diabetic neuropathy (autonomic neuropathy) intestinal obstruction. The most common • Drug effect cause of acute constipation in the elderly is • Lactose intolerance • Gluten sensitivity (celiac sprue) fecal impaction. The diagnosis is made by • Crohn’s disease DRE by the presence of firm, clay-like mass • Diverticulitis (infection of a diverticulum) indicating impaction • Food intolerance • IBS • The most common cause of chronic habitual • Ulcerative colitis constipation is usually a combination of poor • Whipple’s disease diet low in fiber (fast foods/eat on the run), • Malabsorption syndrome decreased fluid intake, physical inactivity, and failure to acknowledge “call to toilets”‡ • Depression—Constipation can be a significant • Diet—Inquiry about a typical day’s diet symptom in all types of depressive illness should include the type and quantities of and may be aggravated by treatment with fiber, fluid, fruits, vegetables, as well as any depression recent change in diet • IBS—With IBS the patient may c/o consti- • Medications—Reviewing medications and pation or diarrhea or both alternating. Asso- discontinuing any responsible drug will ciated somatic and psychological complaints relieve constipation such as anxiety, depression, chest pain, • Risk factors—In adults inquiry about risk headache, fatigue, myalgias, and gynecologic factors for colon cancer such as unintentional symptoms strongly favor the diagnosis of IBS ‡ ‘Dyschezia’ or lazy bowel is the term used to describe a • Systemic disease—Diabetic neuropathy may rectum that has become unresponsive to fecal content result in constipation due to chronic dys- and this usually follows repeated ignoring of calls to defecate. motility, and slow transit time. Symptoms 61

such as cold intolerance, hair and skin changes  Significant weight loss suggest myxoedema. Any cause of  Therapy resistant constipation hypercalcemia, e.g. hyperparathyroidism,  New onset constipation in elderly and malignancy may cause constipation. The without obvious cause patient may also c/o abdominal pain,  Family history of IBD vomiting, nocturia, and mental symptoms  Family history of colon cancer. associated with this condition. A neurolo- • Intermittent colicky abdominal pain with gical examination may detect signs of CVA, distension and progressive constipation or dementia, Parkinson’s disease, spinal cord obstipation is an urgent indication to disease, or multiple sclerosis evaluate the cause of intestinal obstruction • Past history—A long history of bowel • Sexual abuse is a known cause of chronic obsession§, abdominal surgery, radiation constipation and needs to be excluded in therapy, may suggest the cause of constipation. patients especially with psychosexual • Physical examination—For weight, nutritio- problems. nal status, thyroid, and abdomen (tender- ness, mass, distended bowel loops) SELECTIVE GLOSSARY • PR—It is an important procedure because Hirschsprung’s disease (Congenital Mega- about one-forth of cancers are within reach colon)—Abnormally large or dilated colon due of the examining finger. Lesions such as to congenital absence of myenteric ganglion cells hemorrhoids, fissure, ulcer, impaction, in a distal segment of the large bowel, and growth, fecal occult blood are obvious resultant loss of motor function in this segment • Anal wink— Sensation of the perianal area causes massive hypertrophic dilatation of the and the ‘anal wink’ (a reflex constriction normal proximal colon, appears soon after birth, upon pinprick sensation of the perianal area; mediated by S2, S3, S4) reflex should be tested is called “Hirschsprung’s disease”. Signs and in spinal cord disease or lumbosacral roots symptoms (abdominal distension, vomiting, • Constipation from infancy may be due to constipation, etc.), may vary with the severity Hirschsprung’s disease. Occasionally symp- of the condition. Sometimes they appear toms may present for the first time in adult after birth; other times they may not be life apparent until the child becomes a teenager or • Lifelong constipation (severe refractory adult. constipation) is sometimes due to megacolon. Pelvic floor dysfunction (PFD)—The pelvic floor muscles support the pelvic organs, bladder and RED FLAGS rectum, and their function is critical to activities • Alarm symptoms and signs in patients with such as urinating, having bowel movements, constipation include: and sexual intercourse. PFD has traditionally  Persistent anemia been described as resulting from laxity or poor  Positive FOBT tone of the pelvic floor musculature and/or  Hematochezia ligaments. Damage of this nature usually results from aging, straining, or trauma, resulting in § The older generation considers defecation every day a complaints such as poor urine stream, consti- sign of good health. pation, low back pain, pain with ejaculation or 62 Diagnosis: A Symptom-based Approach in Internal Medicine vaginal penetration, pelvic pain or pressure, or 4. Ashraf W, et al. An examination of the reliability urinary frequency and urgency. of reported stool frequency in the diagnosis of idiopathic constipation. Am J Gastroenterol 1996; 91(1):26-32. [PMID: 8561138: Abstract]. REFERENCES 5. Marshall JB. Chronic constipation in adults. How far should evaluation and treatment go? Postgrad 1. Camilleri M, et al. Clinical management of intrac- Med 1990;88(3):49-51,54,57-9,63. [PMID: table constipation. Ann Intern Med 1994; 121(7):520-8. Full Text [PMID: 8067650: Abstract]. 2169048: Abstract]. 2. Herz MJ, et al. Constipation: A different entity for 6. Locke GR, et al. American Gastroenterological patients and doctors. Fam Pract. 1996;13(2):156- Association Medical Position Statement: Guide- 9. [PMID: 8732327: Free full text]. lines on constipation. Gastroenterology 2000; 3. Chang L, et al. Gender, age, society, culture, and 119(6):1761-6[PMID: 11113098: Abstract]. the patient’s perspective in the functional gastro- 7. Rantis PC Jr, et al. Chronic constipation—is the intestinal disorders.Gastroenterology. 2006; work-up worth the cost? Dis Colon Rectum. 1997; 130(5):1435-46. [PMID: 16678557: Abstract]. 40(3):280-6. [PMID: 9118741: Abstract]. CHAPTER 10 Convulsions

SYNOPSIS The term ‘convulsion’* is often used interchangeably with seizure,^ although there are A convulsion is a violent spasm, or a series of many types of seizures. Seizures are attacks of involuntary contractions of the voluntary muscles, cerebral origin consisting of sudden and especially those affecting the face, trunk, or extremities. During convulsions, the person may transitory abnormal phenomena of a motor cry out, fall to the floor unconscious, his or her body (convulsive jerking), sensory (light flashes, shaking rapidly and uncontrollably, drool, or even buzzing), autonomic (sweating, enuresis), loose bladder control. Within minutes the attack is automatic (abnormal behavior, memory lapse), over, and the person regains consciousness, but is or psychic nature (hallucinations), resulting dazed, confused, and incoherent, or may be from transient abnormal neuronal discharge of exhausted and asleep. This is the image most people the brain, with or without loss of consciousness. have when they describe the symptoms of Thus, paroxysmal changes in consciousness, convulsions to physicians which is typical of tonic- sensation, emotion, or thought processes may clonic grand mal seizure (Table 10.1). all be the manifestations of a seizure disorder without its motor component of convulsions, Table 10.1: Convulsions: common symptoms and signs which are termed as nonepileptic seizures (i.e. NES: • Fits Table 10.2), especially those subclassified as • Body twitching • Body spasm psychogenic origin, i.e. psychogenic nonepileptic 1 • Head spasm seizure (PNES). • Facial spasm • Limbs jerking • Loss of consciousness *The special problems posed by children with convulsions • Limb are not addressed. • Bladder incontinence ^ • Bowel incontinence ‘Seizure’ is a sudden act, action, or attack of seizing • Tongue bite something (as of disease), especially the physical mani- • Abnormal behavior festations as convulsions; and the clinician should certainly • Sleeping after fits refrain from diagnosing a first seizure as epilepsy. 64

Table 10.2: Nonepileptic seizures (NES): Differentiation • CNS infection (bacterial, TB, viral-HIV, Two major types of NES are recognized; their differen- cerebral malaria, cysticercosis) tiating features being as follows: • Seizures (generalized tonic-clonic, partial- • Psychogenic NESs are symptoms of an underlying simple, status epilepticus) psychiatric disorder, without a physiologic basis, • Cerebrovascular accident (TIA, stroke) e.g. conversion disorder, anxiety disorder, PTSD, psy-chotic disorder, factitious disorder. • Head injury (early or late) • Physiologic NESs are caused by physiologic dys- • Hypoglycemia function, such as cardiac arrhythmias, hypotensive • Malignant hypertension (hypertensive episodes, cerebrovascular disease, complicated mig- raine, parasomnias, tics, and . Such conditions encephalopathy) may result in loss of consciousness, with or without • Toxemia of pregnancy. associated motor manifestations. A detailed history and appropriate investigations (e.g. Holter moni- Occasional toring, noninvasive carotid artery studies, or tilt-table testing) will usually reveal the true diagnosis. • Migraine (complicated) Note: Most of the discussion in this article pertains to • Alcoholism/withdrawal (rum fits) psychogenic NESs, i.e. PNES. • Metabolic (electrolyte imbalance, hypo- calcemic, DKA, uremia, hepatic encephalo- Epilepsy‡ is a symptom complex in which pathy, cardiac arrest) there is a tendency to have repeated (two or • Drug toxicity (aminophylline, theophylline, more), unprovoked seizures, requiring definitive ephedrine, terbutaline, bupropion, penicillin, diagnosis and treatment. Not everyone who has insulin, metronidazole, pentazocine, lidocaine) seizures has epilepsy, but everyone who has • Substance abuse (amphetamines, ‘ecstasy’, epilepsy has seizures. antidepressants, antipsychotics, cocaine). Neither convulsions, seizures, nor epilepsy are a final diagnosis, but are symptom complexes Rare requiring a search for underlying etiologic • Pseudoseizure§ (i.e. PNES) factors. Further, it is extremely important to • Infections (tetanus, rabies) differentiate epileptic seizures, including various • Brain tumors (primary/secondary) simple partial seizures, complex partial seizures, • Degenerative disorders (dementia, multiple typical and atypical absence seizures from NES, sclerosis) because misdiagnosis leads to inappropriate • Sleep disorders (parasomnias) treatment with antiepileptic drugs, leading to • Poisoning (organophosphate insecticides, toxic side effects, causing additional disability cyanide, strychnine). and frustration. INVESTIGATIONS—GENERAL DIFFERENTIAL DIAGNOSIS CBC Common • Leukocytosis may suggest CNS infections. • Syncope (vasovagal, orthostatic hypoten- • Erythrocytes may show sickled cells. sion, cardiac arrhythmia) • Polycythemia with elevated hematocrit in ‡The word ‘epilepsy’ is derived from the Greek word for hypercoagulable states. ‘attack’, (presently meaning seizure). People once thought § that those with epilepsy were being ‘attacked’ by demons The term nonepileptic seizure is preferred to pseudoseizure, or Gods. However, in 400 BC Hippocrates suggested because the former term is nonjudgemental, and describes that epilepsy was a disorder of brain. problem without implying causation. 65

Blood Glucose abnormalities are seen after several EEGs have been obtained. The yield of the test is • In diabetics and DKA. enhanced by using sleep deprivation Serum Electrolytes activating procedures (e.g. hyperventilation, photic stimulation), increasing the recording • Hyponatremia, hypokalemia, hypomagne- time, and capturing sleep during testing. semia, hypoglycemia, and hypocalcemia can precipitate seizures. Ambulatory EEG (aEEG) • In selected cases with recurrent events, and ECG nondiagnostic EEG findings, or lack of • To identify cardiac rhythm, detect possible response to treatment. cardiac ischemia, and measure QT-interval. • Also useful in separating true seizure from Prolonged QT syndrome often presents with pseudoseizure, or other paroxysmal abnormal simple or convulsive syncope. behavior, especially when the two coexist. Neuroimaging Video-EEG Monitoring2, 3 • CT head is indicated in an emergency, e.g. • May be essential in difficult cases to when seizures are due to head trauma, distinguish between epileptic and NES. decreased level of consciousness, or a new Video-EEG recordings of the actual event neurologic deficit is evident. Otherwise, provide a correlation of clinical and EEG waiting for a more definitive imaging with findings, and a means to assess their MRI (for mass lesion, vascular malformation, evolution and resolution. stroke, cysticercosis, and multiple sclerosis) Toxicology (Serum and Urine) Screen should be considered. • For drugs and alcohol, especially if an Biochemistry Panel adequate history cannot be obtained. • LFTs, urea, creatinine, and VDRL as indicated. CLINICAL NOTES

INVESTIGATIONS—SPECIFIC • Although in the majority of the patients with CSF convulsions attending their physicians are known to be suffering from some kind of • CSF evaluation in febrile and immunocom- seizure disorder, in others the physician promised patients suspected with bacterial, usually does not witness the seizures, and viral, and fungal infection. must rely on information provided by the • In patients with systemic malignancy, CSF patient, an outside observer, or both. However, cytology can identify meningeal carcinoma. every patient must be assessed in detail, for if they are not, the systemic disorder that may EEG have triggered the attack will be missed • Can help to establish the presence and type • Listen to the patient—Not all jerks, shakes, of seizure. Both interictal (between seizures) tics, tremors, spasms, and dystonia are and ictal findings (during a seizure) are used convulsions. Therefore, the initial task, when in evaluating seizure and epilepsy disorders. a patient presents with convulsions, is to • A normal EEG, however, does not exclude the determine whether the attack in question possibility of epilepsy or seizures. Often had indeed features of true seizure 66 Diagnosis: A Symptom-based Approach in Internal Medicine

• Listen to the eyewitness—An accurate record Table 10.3: Differentiation between syncope and seizure from an observer is invaluable, particularly Parameter Syncope Seizure if there is evidence that his/her attack was Onset Gradual Sudden the first one. This record should include: Attack Rapid, but never Loss of  Details of the circumstances of the attack absolutely consciousness sudden; may with absolute (anxiety, panic, pain, prolonged standing, be averted suddenness; physiological acts, e.g. micturition). by lying down cannot be  Any prodromal symptoms (aura, e.g. odd promptly averted Position at Usually erect or Any behavior, repetitive actions). onset on change to  Details of the sequence of events of the attack erect; rarely itself (e.g. a rhythmic flexion-extension recumbent Warning Light Unusual movement of the extremities, loss of symptoms headedness sensations, consciousness, incontinence, tongue biting). dizzy, giddy, sounds, smells,  nausea,vomiting blurred vision, The aftermath - whether the episode was hallucinations, followed by period of (postictal) con-fusion. tingling, • These observations, especially presence or twitching of muscles absence of aura, and postictal confusion are Convulsions Rare Common critical and help to differentiate seizures Accompani- Incoherence, Confusion, from syncopal and other common physiologic ments incontinence, enuresis, tongue bruising tongue NES, such as postural hypotension, TIA, rare bruising complicated migraine, sleep disorders, and common psychogenic NES (Table 10.3) Duration Variable—seconds About a to few minutes minute • What is the cause of seizure? Knowledge of Sequela No sequela Confusion, patient’s medical history, including family after recovery headache, history, aids in the understanding the cause of from attack drowsiness, often deep convulsion or seizure. A history of head trauma, sleep;postictal fever, infection, alcoholism, and systemic disease paralysis such as diabetes mellitus, hypertension, may be present EEG Normal Normal or cerebrovascular disease, and metabolic abnormal disturbances suggest the cause of seizure • Medications and substance abuse—A review possibility of pseudoseizure should be care- of patient’s medications is important. Bron- fully considered as prompt recognition can chodilators (aminophylline, theophylline, prevent subsequent intervention. terbutaline, ephedrine); antidepressants • Physical examination—A focused exami- (bupropion, amitriptyline, imipramine); nation should be done soon after a paroxys- antipsychotics (thioridazine, clozapine, mal event and should include: haloperidol); opioids (tramadol); anes-  Evidence for injuries, including head thetics (lidocaine, pentazocine, fentanyl); injury. antimicrobials (penicillin, metronidazole,  Check oxygen saturation. isoniazid); antineoplastics (vincristine,  Chest for possible aspiration. methotrexate), ‘ecstasy’, etc. are known to  Heart rate, rhythm, BP, ECG (hypertensive provoke seizure. encephalopathy), and orthostatic changes • Pseudoseizure, i.e. PNES (Table 10.4)—The (syncope, arrhythmias). Convulsions 67

Table 10.4: Difference between seizure and RED FLAGS PNES (Pseudoseizure) • New onset of seizures in the elderly may Parameter Seizure (tonic- PNES (Pseudoseizure) clonic/grand mal) indicate serious disorder such as CVA, tumor, including alcoholism, and drug abuse; detail Setting Anywhere, anytime, Often in public, never 6, 7 also during sleep during sleep investigations are indicated Attack Tonic-clonic spasms Bizarre nature • In obscure cases, consider unusual presen- Accompaniments Mostly due to Mostly moans and groans, tation of systemic disorder, e.g. sarcoidosis, laryngeal spasm vocalization 8 Sequelae Patient may fall, may Patient never falls, no porphyria be injured, or tongue injury, no tongue bruising, • Discovery of papilledema should lead to bruising, incontinence not incontinent of urine and faces urgent investigations and treatment Consciousness Brief period of loss of Consciousness is retained • Consider inadvertent or unrecognized drug consciousness common (but loss of consciousness or alcohol withdrawal or illicit drug use. may be stimulated) Plantars Extensor, bilaterally Remain flexor Obtain urine toxicology. An amphetamine Pupils Dilated Unchanged derivative, Ecstasy, (Methylenedioxy-metha- Eyelids Opens easily, passively Patient screws up eyelids mphetamine—MDMA) often cannot be when an attempt is made to open them detected by standard toxicology screens; Blood pressure, Increased Do not alter these substances can present a vexing pro- heart rate blem for clinicians faced with symptoms Serum prolactin Often increased Often normal 9 levels from a totally unknown cause. CPK Increases Often normal EEG Normal or abnormal Normal REFERENCES

 Carotid auscultation for bruits / murmur 1. Epilepsy Foundation. Non-epileptic seizure. Web site:http://www.epilepsyfoundation.org/answer (sources of embolic stroke). place/Life/adults/women/Professional/non-  Presence of postictal phenomenon, i.e. epilep. Accessed on 22-11-08. 2. Ozkara C, et al. Differential diagnosis in pseu- Todd’s paralysis. doepileptic seizures.Epilepsia. 1993;34(2):294-  Fundoscopy— For evidence of papilledema, 8[PMID: 8453940:Abstract]. indicating ICP caused by an intracerebral 3. Bode NM, et al. Psychogenic non-epileptic seizures-Diagnostic issues: A critical review.Clin hemorrhage, or space occupying lesion. Neurol Neurosurg 2008. [Epub ahead of print]  Neurologic deficit—Dysarthria, facial [PMID: 19019531: Abstract]. asymmetry, or right or left . 4. Web site: http://www.minddisorders.com/Kau- Nu/Minnesota-Multiphasic-Personality-Inven- Pupillary asymmetry may indicate tory.html. Accessed on 22-11-08. brainstem herniation. 5. Mirnics Z, et al. Adjustment and coping in • If the patient is drowsy, the Glasgow Coma epilepsy. Seizure. 2001;10(3):181-7.[PMID: 11437616: Abstract]. Scale should be used to provide an objective 6. De Toledo JC. Changing presentation of seizures measure to any subsequent change in the with aging: Clinical and etiological factors. Geron- level of consciousness. tology. 1999;45(6):329-35. [PMID: 10559651: Abstract]. • Psychologic testing—Psychologic testing 7. Collins NS, et al. Elders with epilepsy.Med Clin may help distinguish patients with NES North Am 2006;90(5):945-66. [PMID: 16962851: Abstract]. from those with epileptic seizures. The 8. Soundravally R, et al. Acute intermittent por- Minnesota Multiphasic Personality Inven- phyria: Diagnosis per chance. Indian J Pathol tory4 and other inventories, such as the Microbiol 2008;51(4):551-2. [PMID: 19008594: Abstract]. Washington Psychosocial Seizure Inventory 9. Tierney LMJr, et al. Current Med Dia and Treat 5 can have a role in this regard. ed. 2006. Psychiatric Disorders, 1090. CHAPTER 11 Cough

SYNOPSIS chronic/persistent—when more than 3 weeks. Acute cough, in the great majority of healthy Cough may be defined as a sudden and variable adults, is minor and self-limiting, although the expiratory thrust of air from the lungs and possibility of serious cause such as acute through the air passages, associated with pulmonary edema, asthma exacerbation, phonation, which momentarily interrupts the pulmonary embolus, and pneumonia should physiological pattern of breathing. always be kept in mind. It is the chronic/ The act of cough is an important physiologic persistent variety that usually prompts patients pulmonary defence mechanism which is beneficial to seek medical care. In many patients, chronic in most instances; it helps to keep the lower cough is either pathologic by itself, e.g. bronchial respiratory passage clear, protects against entry of asthma, TB, malignancy, or a manifestation of foreign materials from outside, and prevents systemic disease, e.g. mitral stenosis, GERD, and stagnation of secretions within the air passages. LVF that requires attention. In some instances, Nevertheless, in many patients cough may be chronic cough may manifest as an acute event, troublesome, sometimes distressing, due to such as an acute exacerbation of chronic associated symptoms such as exhaustion, insomnia, bronchitis. In recent times, whooping cough fever, hoarseness, body aches and pains, or its (pertussis), a preventable infectious disease in complications such as rib fracture, urinary pediatric age group, is being documented incontinence and syncope, which can lead to frequently in adults too as the cause of chronic decrease in a patient’s health-related quality of life. cough (Table 11.1).1, 2 However, it is observed that, Clinically, cough is generally divided into two in patients with uncontrolled and unexplained groups: productive cough that is accompanied persistent cough, with expensive work-up and by sputum, and nonproductive cough, which is medications, and frequent visits to the physician, dry and does not produce any sputum. Based on as well as the patient’s and family’s distress and its duration, cough is said to be acute—less concern about an underlying disease, may cause than some arbitrary duration of 3 weeks, and significant psychological stress, including 69 anxiety, frustration, anger, and irritability. •LVF Therefore, it is suggested that, in the diagnosis • Drugs (ACE inhibitors, beta blockers, aspirin). and management of chronic cough, along with clinical efficacy and cost-effective considerations, Occasional psychological issues related to patients • COPD satisfaction should also be taken into account in 3-5 • formulating guidelines. • Pleural effusion

Table 11.1: The return of whooping cough: why? • Lung abscess • Cardiac (mitral stenosis) • Failure of children to receive full immunization schedule as recommended; i.e. five shots by age 7. • Immunodeficiency (Pneumocystis carinii • Failure of full protection in spite of completing pneumonia, i.e. PCP) recommended immunization schedule. • Whooping cough. • Protection from vaccines given in early childhood diminishes over time, offering little or no protection five to 10 years after the final injection, so that Rare pertussis can occur in such subset of older vaccinated individuals, who may then infect • Inhaled foreign body susceptible infants and individuals. • Interstitial lung disease • Atypical presentation of pertussis in adolescents • Bronchogenic carcinoma/secondaries and adults; symptoms may be indistinguishable from those of other upper respiratory infections. • Lymphoma • Physicians often do not include whooping cough • Aspiration in the differential diagnosis of a persistent cough. • Eosinophilic pneumonia (Löffler’s syndrome, • Failure to comply with treatment regimen during pertussis outbreaks. Tropical eosinophilia, parasitic, fungal) • Medications – (nitrofurantoin, sulfonamide, hydralazine, methotrexate, cyclophospha- DIFFERENTIAL DIAGNOSIS mide) • Ear wax, hair, foreign body in ear canal Common (Amold’s reflex) • Psychogenic cough, habit cough, tic cough. • Irritants (cigarette smoke, pollutants, allergens) • URTIs INVESTIGATIONS—GENERAL • Postinfectious cough6 ( generally after URTI) • Sinusitis CBC * 7 • Upper airway cough syndrome (UACS) • WBC count raised in bacterial infection • Allergic rhinitis • Anemia characteristic of chronic disease • Asthma exacerbation common • Acute bronchitis • Eosinophilia in allergic conditions • Pneumonia • Marked lymphocytosis in pertussis. • Tuberculosis • GERD Sputum

• Gram stain, acid fast stain and culture for * Formerly called Postnasal drip (PND). specific organisms 70 Diagnosis: A Symptom-based Approach in Internal Medicine

• Sputum eosinophilia in asthma and non- Table 11.2: Causes of chronic cough among adults with asthmatic eosinophilic bronchitis (NAEB)† normal CXR Diagnosis Differential diagnosis with normal CXR CXR Environmental Tobacco exposure; industrial pollutants; occupational allergens • Helpful in evaluating for: Infections— Postinfectious cough; chronic  Pneumonia (consolidation) respiratory bronchitis; TB; bronchiectasis;  Bronchiectasis (dilated tubular or cystic tropical pulmonary eosinophilia; mucus filled bronchi) whooping cough  COPD (hyperinflation, flat diaphragm) Infections/ Cerumen; Otitis media with  disorders—ENT effusion; chronic sinusitis; nasal TB (upper lobe infiltrates, hilar lympha- polyp; vocal cord dysfunction/paralysis; denopathy, cavitary lesions, pleural aspiration effusion) Asthma Cough-variant asthma; postinfectious  Sarcoid (hilar lymphadenopathy) hyperactivity airways  CHF (pulmonary edema, vascular conges Cardiac CHF; mitral stenosis tion, Kerley B lines, peripheral infiltrates, GI disorders Gastroesophageal reflux pleural effusion, cardiomegaly) Neoplasia Bronchial adenoma; mediastinal mass  Bronchogenic carcinoma (hilar mass or a with tracheal compression; laryngeal papilloma, hemangioma single coin shadow). Iatrogenic Drug induced; Foreign body – nose; • A normal CXR in an immunocompetent patient ear; trachea; larynx; bronchus with chronic cough usually excludes tuber- Psychogenic Habit cough; tic cough; psychoge- culosis, bronchiectasis, persistent pneumonia, nic cough bronchogenic carcinoma, and sarcoidosis. However, chronic cough can be a cause of many Pulse Oximetry disorders in spite of a normal CXR; a few of such conditions are given in Table 11.2. • To monitor arterial O2 saturation in patients with asthma or COPD. Peak Expiratory Flow Rate (PEFR)

• Serial measurements of peak flow rates on pH Studies waking, i.e. early morning, during day, and • Ambulatory 24-hour esophageal pH monitoring before bed, demonstrating wide variations is the most reliable but invasive test for GERD. in airflow limitation is seen in asthma, and It should, therefore, be performed only after facilitates monitoring its treatment. failure of empiric GERD treatment, and a INVESTIGATIONS—SPECIFIC negative evaluation for asthma and sinusitis.

PFTs CT Chest /MRI • Can differentiate obstructive, e.g. asthma, • More sensitive for evaluating patients with COPD, from restrictive disease, e.g. sarcoidosis, equivocal or negative CXR findings. pneumoconiosis. • Assists in evaluating for mass lesions of †NAEB—a recently defined clinical entity with high neoplasms, sarcoid, ILDs, and bronchiectasis. eosinophilic count in induced sputum, that manifests similarly to, but is distinct from asthma in that there is neither reversible CT Sinus airway obstruction nor airway hypersensitivity as defined by a positive methacholine challenge. • For diagnosing chronic sinusitis, UACS. Cough 71

Esophagogastroduodenoscopy (EGD) CLINICAL NOTES

• To evaluate GEDR or its complications such • Important historical features to be elicited as esophagitis, ulceration, stricture, Barrett’s are: normal (as a part of local irritation due esophagus, and adenocarcinoma. to viral URTI) versus pathological cough; acute versus chronic cough that persists for Bronchoscopy 3 weeks or longer; and respiratory versus • Generally indicated in patients with: nonrespiratory causes  CT/MRI suggesting neoplasm and their • Generally, in patients with chronic cough, biopsy procedures neither the patient’s description of his or her  Foreign body aspiration cough in terms of its character or timing, nor  Chronic, persistent cough with negative the presence or absence of sputum production, clinical and lab work out is helpful to rule in or rule out a diagnosis or to  Cough with hemoptysis. determine the clinical approach • Does the patient smoke – its frequency and Purified Protein Derivative (PPD) Skin Test duration; are there any occupational and • Performed in patients with high risk of environmental exposures? Is there any clear pulmonary TB. Results are read within 48 triggering or reliving factor? – 72 hours of placement. Test is considered • Associated red flag symptoms, including positive if skin erythema measures ≥ 5 hemoptysis, weight loss, night sweats and mm for HIV-infected and other fever, and concomitant risk factors for immunocom-promised individuals; ≥ 10 malignancy, HIV, and drug abuse (cocaine mm for those at high risk; and ≥ 15 for all lung) are very significant in the evaluation others. of chronic cough • Some physical signs which may provide HIV Serology etiological clues are: sinus tenderness • In a HIV positive patient CD4+ lymphocyte (sinusitis); conjunctival injection, rhinitis count should be obtained; if it’s below 200 / (URTIs); consolidation (pneumonia); fine mm3, a more intensive evaluation for (pulmonary edema); localized opportunistic infection, such as PCP, TB is (obstructive lesion – tumor, foreign body); indicated. cardiac – (murmur in valvular disease, S3 in CHF); ear canal – wax, hair (Arnold’s reflex) ‡ Culture of Nasopharyngeal Secretions/PCR • Ask specifically about UACS, i.e. postnasal • For the diagnosis of B. pertussis (Whooping drip, as patients often do not volunteer this cough). information • Although some evidence suggests that UACS Sputum Cytology is a common cause of chronic cough, it is an entity without a clear definition and no • May be helpful if history or CT/MRI suggest pathognomonic findings. It is usually neoplasm. diagnosed in the presence of suggestive symptoms such as rhinorrhea, nasal congestion, a sensation of drainage or tickle ‡ PCR confirmation is not recommended as there is no in the oropharynx, and throat clearing, with universally accepted, validated technique for routine clinical testing. or without mucoid secretions visualized in 72 Diagnosis: A Symptom-based Approach in Internal Medicine

the posterior pharynx. Its role in chronic • In a patient with chronic bronchitis, any cough, though controversial, is supported change in the character of the cough or by response to therapy — usually an sputum may be the presenting feature of a antihistamine-decongestant combination superimposed bronchogenic carcinoma drug or nasal corticosteroid spray8 • Smoker’s cough should not be neglected; it may • Cough due to ACE inhibitors is a class effect be an early symptom of bronchogenic and has been documented with all ACE carcinoma. Conversely, bronchogenic inhibitors in use; changing to another agent carcinoma is known to occur in nonsmokers will not ameliorate the symptoms or in patients with other pulmonary • A past history of recurrent lung infections conditions, such as chronic bronchitis from childhood is suggestive of cystic fibrosis • When a patient has a cough lasting for >2 and bronchiectasis; a history of hay fever and weeks without another apparent cause and eczema suggests asthma; while tuberculosis, it is accompanied by paroxysms of coughing, emphysema (alpha1-antitrypsin deficiency) posttussive vomiting, and/or an inspiratory asthma, cystic fibrosis have a familial whooping sound, the diagnosis of a B. predisposition pertussis infection should be made unless • In a healthy individual, cough, following another diagnosis is proven URTI and persisting for at least 3 weeks, but • In patients with unexplained cough, evaluate no more than 8 weeks, consider the diagnosis the possibility of drug-induced cough. of postinfectious cough. In some patients, transient bronchial hyperreactivity may be REFERENCES demonstrated 1. Senzilet LD. Pertussis is a frequent cause of • In all patients with chronic cough, even in prolonged cough illness in adults and adolescents. the absence of clinical signs or symptoms, Clin Infect Dis. 2001;32(12):1691-7. Epub 2001 consider UACS, asthma, and GERD, as they May 21. [PMID: 11360208: Abstract]. 2. Birkebaek NH. Bordetella pertussis in the may present only as cough, and no other aetiology of chronic cough in adults. Diagnostic associated clinical findings, i.e. ‘silent’ UACS, methods and clinic.Dan Med Bull 2001;48(2):77- cough-variant-asthma, and ‘silent’ GERD 80. [PMID: 11414122: Abstract]. 3. Tomasz J, et al. Chronic Cough From the Patient’s respectively Perspective. Mayo Clin Proc 2007;82:56-60. • In a nonsmoking patient with a clear chest 4. Kalpaklioglu AF, et al. Evaluation and impact of radiograph who does not use ACE inhibitors, chronic cough: Comparison of specific vs generic quality-of-life questionnaires.Ann Allergy Asthma one or more of the following four causes of Immuno 2005;94(5):581-5.[PMID: 15945562: chronic cough account for the overwhelming Abstract]. majority of cases; namely, UACS, asthma, 5. Brignall K, et al. Quality of life and psychosocial aspects of cough. Lung. 2008; 186 Suppl 1:S55- NAEB, or GERD. 8. Epub 2007. [PMID: 17939003: Abstract]. 6. Braman SS. Postinfectious cough: ACCP evidence- RED FLAGS based clinical practice guidelines. Chest. 2006; 129(1 Suppl):138S-146S. [PMID: 16428703: Free • A normal lung examination does not exclude full text]. 7. Pratter MR, et al. Chronic upper airway cough asthma, bronchitis, COPD, GERD or lung syndrome secondary to rhinosinus diseases malignancy (previously referred to as postnasal drip • Failure to improve with appropriate manage syndrome): ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1 Suppl):63S-71S. ment over 4 weeks signals a need for detail [PMID: 16428694: Abstract]. work up to exclude TB, cough variant asthma, 8. O’Hara J, et al. “Postnasal drip syndrome”: Most resistant pulmonary infections, malignancy, patients with purulent nasal secretions do not complain of chronic cough.Rhinology. 2006; and immunosuppression 44(4):270-3. [PMID: 17216744: Abstract]. CHAPTER 12 Dementia

SYNOPSIS Table 12.1: DSM-IV-TR criteria for dementia Dementia is an acquired neurological syndrome, Development of multiple cognitive deficits manifested common in the elderly, characterized by decline in by both: • Memory impairment (impaired ability to learn new memory and cognitive impairment, occurring in a information or to recall previously learned information) state of clear consciousness (i.e. the patient is alert). • At least one of: Although memory is the most common  Aphasia (language disturbance) cognitive ability lost with dementia*, other  Apraxia (impaired ability to perform motor common findings include (Table 12.1):1 activities despite intact motor function)   Agnosia (failure to recognize or identify objects Aphasia (i.e. difficulty with language, despite intact sensory function) speech, comprehension, naming, reading,  Disturbance in executive functioning (e.g. and writing); planning, organizing, sequencing, abstracting)  Apraxia (i.e. difficulty with motor actions, Cognitive deficits significantly interfere with work inability to perform previously learned or social activities and represent major decline from tasks such as combing hair, dressing); previous level of functioning. Course characterized by gradual onset and  Agnosia (i.e. difficulty with reorganization continuing cognitive decline. or comprehension of specific auditory, Cognitive deficits not due to any of the following: visual, and tactile stimulus); and  Other CNS conditions that cause progressive  Impaired executive functioning (i.e. impaired deficits in memory and cognition (e.g. cerebro- planning, organization, and judgement). vascular disease, Parkinson’s disease, Huntington disease, subdural hematoma, normal-pressure Symptoms may also include changes in: hydrocephalus, brain tumor)  Systemic conditions known to cause dementia  Personality (e.g. social inhibition, disinterest, (e.g. hypothyroidism, vitamin B12 and folic acid explosive spells, mistrust of others, low deficiency, niacin deficiency, hypercalcemia, moral character); neurosyphilis, HIV infection)  Deficits do not occur only during course of * Three types of memory loss may exist in demented delirium individuals, either individually or in combination; namely:  Disturbance cannot be accounted for by any immediate memory, i.e. difficulty in learning new information; nonorganic mental disorder (e.g. major depressive recent memory, i.e. recalling recent events; and remote memory, disorder, schizophrenia) i.e. remembering past personal information. 74

 Mood (e.g. growing apathy, depression, Table 12.2: Potentially treatable/reversible dementias withdrawal, anxiety, hallucinations); and • Alcoholism: Chronic  Behavior (e.g. repetitive actions, or • Connective tissue disorders: Temporal arteritis, questioning; purposeless hyperactivity; vasculitis, SLE • Drug toxicity wandering, agitation). • Endocrine: Thyroid disease, hyperglycemia, hypo- These clusters of symptoms and disabilities glycemia, insulinoma, adrenal disease, pituitary compromise the successful performance of activities disease, parathyroid disease • Infections: Viral encephalitis, postencephalitis of daily living in a demented individual (e.g. syndrome, chronic meningitis, AIDS, neurosyphilis neglecting household chorus, neglecting self-care, • Mass lesion: Chronic subdural hematoma (bilateral), tumor mistakes at routine work, difficulty handling money, • Metabolic: Dehydration, electrolyte disturbance, uremia, hepatic encephalopathy, hypercalcemia, trouble with shopping, and difficulty in driving). hypoxia Dementia does not occur de novo, but probably • Normal-pressure hydrocephalus • Nutritional: Vit. B , folate, thiamine deficiency represents the end of a spectrum from normal aging 12 • Others: Blindness, chronic seizures, CHF, dialysis through an intermediate state called mild cognitive encephalopathy, hearing loss, obstructive sleep impairment (MCI - vide infra ↓↓). Early identification of , radiation-induced MCI is important because some of the disorders • Psychiatric: Depression that cause dementia might be treatable, reversible, NOTE: Dementia due to alcoholism, HIV, TB, drugs, nutritional deficiency, and head trauma are preventable; and preventable (Table 12.2). On the other hand, the rest are amicable to therapy. dementia tends to be progressive, cognitive functions tend to decline steadily, vegetative Table 12.3: Typical features differentiating mild cognitive impairment and dementia symptoms such as change in appetite, weight, Mild cognitive impairment sleep, and fatigue are often absent, and there is little • Insidious onset – always or no response to medications. The typical • Deficit involves memory differentiating features between MCI and • Cognition remains intact ✝ • No interference with social and occupational dementia are given in Table 12.3. functioning The task of a physician caring for a demented • May or may not eventually lead to dementia patient, therefore, is twofold: Dementia  Early identification of those dementias • Insidious onset – generally that are treatable, especially because more • Impaired memory and one or more of the features treatment options are now available, and of aphasia, apraxia, agnosia, and impaired executive functioning  Educate and support the family of the • Cognitive deficits significantly interfere with work patient with incurable dementia. Much or social activities can be achieved by careful analysis of the • Deficit represents major decline from previous level of functioning problems, defining what can be restored • Deficit cannot be explained exclusively by delirium, and what cannot, even if the condition is CNS disorders, or major psychiatric illness irreversible. DIFFERENTIAL DIAGNOSIS Common ✝ There are a variety of ‘dementias’ which most frequently are categorized as cortical or subcortical. AD is the most • Degenerative disorders (e.g. Alzheimer’s well-known example of a cortical dementia. Subcortical disease, i.e. AD; Parkinson’s disease, i.e. PD) dementias include Parkinson’s, Huntington’s, and AIDS dementia. The presentation of these two types of • Vascular dementia (i.e. VaD; e.g. multi-infarct dementias differs. dementia; single strategic infarct, lacunar state, 75

diffuse white matter disease, i.e. Binswanger’s • Endocrinopathies (hyperinsulism, hyper- disease, hypoxic ischemic encephalopathy). parathyroidism, Addison’s disease, Cushing’s • Mixed dementia‡ (i.e. AD with VaD)2-4 syndrome, hypopituitarism) • Infection (viral encephalitis, HIV-associated • Autoimmune disease (cranial arteritis, SLE, MS)

dementia complex/AIDS dementia complex, • Nutritional deficiency (e.g. thiamine, B1- meningitis — TB) Wernicke’s encephalopathy; B12, folate- • Substance abuse (alcoholism) pernicious anemia; nicotinic acid-pellagra) • Head trauma (chronic subdural hematoma, • Chronic infections (neurosyphilis) postconcussional syndrome) • Prion disease (Creutzfeldt-Jakob disease, i.e. • Intracranial causes (spaceoccupying lesions – CJD) tumors, abscesses). • Normal pressure hydrocephalus (NPH - vide infra ↓↓) Occasional • Hypoxic dementia (e.g. cardiac arrest, • Drug toxicity/polypharmacy/interactions anesthetic accidents). (e.g. anticonvulsants, anticholinergics, antihistamines, antiparkinsonian, narcotics, INVESTIGATIONS—GENERAL psychotropics)5, 6 CBC • End-organ failure (cardiac/respiratory/ hepatic/renal failure) • To exclude anemia, including macrocytic

• Endocrine disorders (hypothyroidism) anemia with B12 deficiency and infection. • Neoplastic disease (primary cerebral tumors) ESR • Metabolic disorders (chronic electrolyte imbalance—hypocalcemia, hypercalcemia, • May be elevated in infection, inflammation, hyponatremia, hypernatremia, hypokalemia, neoplasm. hepatic encephalopathy, uremia). Urea, Creatinine, LFTs Rare • Raised with renal failure. • Degenerative disease (e.g. dementia with Lewy • Increased bilirubin and transaminases with bodies§, i.e. DLB; Frontotemporal dementia**, liver failure. i.e. FTD; Pick’s disease; Huntington disease). Electrolytes—Sodium, Potassium, Calcium, Glucose

‡Mixed dementia is diagnosed when patients have evidence • May be useful to monitor serum sodium and of AD and cerebrovascular disease, either clinically or potassium in patients with dementia due to based on neuroimaging evidence of ischemic lesions. Growing evidence indicates that vascular dementia and metabolic disorders. AD often coexist, especially in older patients with • Hypercalcemia with hyperparathyroidism, dementia. and metastatic bone tumors. §A Lewy body, described by Fredrick H Lewy, is an intracytoplasmic concentrically laminated round to TFTs elongated eosinophilic inclusion which often has a dense central core surrounded by a paler peripheral rim. • An elevated TSH level with a low free T4 level **The term FTD covers both the temporal and frontal is characteristic of primary hypothyroidism. presentations of this condition: the frontal variant presents • A decreased TSH level with a high free T with insidious changes in personality and behavior, with 4 neuropsychological evidence of disproportionate frontal level is characteristic of primary hyperthy- dysfunction. roidism. 76

Neuroimaging — CT/MRI VDRL/ Fluorescein Treponema Antibody (FTA- ABS) • As a general rule, imaging should be performed in most patients with dementia. • Neurosyphilis—VDRL test produces false- However, it may not be warranted in positive result; it must be followed with a patients in whom the medical history sensitive FTA-ABS test. reveals no significant findings, the results of physical and neurologic examination are HIV Serology normal, and the onset and progression of • If the history indicates. cognitive decline are consistent with AD. • The choice of imaging method is determined ANA, Anti-ds DNA by either the patient’s condition and • Connective tissue disorders, such as vasculitis. suspected pathologic cause at presentation or the brain region to be examined. CSF • CT is useful for excluding large strokes, • May be indicated in those with following subdural hematomas, tumor, and features: hydrocephalus.  Acute febrile episodes with meningeal • MRI is particularly recommended in signs patients with an atypical presentation,  Atypical presentation (e.g. seizures; facial, rapid deterioration, incontinence, focal ophthalmic, trigeminal cranial neuropathies) neurologic signs, past history of head injury,  Clinical findings suggestive of normal- or systemic diseases that prominently affect pressure hydrocephalus the brain (e.g. HIV infection, MS, SLE).  Evidence of immunosuppression • New techniques including diffusion and perfusion  Positive serum fluorescent treponemal magnetic resonance imaging are helpful for the antibody absorption test differentiation between vascular dementia  Suspected CJD (detection of specific 14-3- and degenerative disorders. Magnetic Resonance 3 protein in CSF suggests CJD) spectroscopy evolves as a tool for the diagnosis  Imaging abnormalities (e.g. meningeal of different forms of degenerative dementia. enhancement) Multimodal magnetic resonance holds promise to  Cytology to exclude carcinomatous diagnose AD at early clinical stages and to meningitis. monitor the progression of the disease.7 CXR/ ECG INVESTIGATIONS—SPECIFIC • To investigate possible cardiac and pulmo- nary sources of cognitive dysfunction such Infection Screen as silent MI; consolidation due to pneumonia, • Blood and urine culture may be indicated in SOL, or neoplasm. immunocompromised patients with resistant EEG infection. • In CJD and nonconvulsive seizure disorder

Vitamin B12 Assay SPECT/PET • Vitamin B12 deficiency in megaloblastic anemia, and not infrequently found with • SPECT and PET techniques that visualize subacute combined degeneration of the cord. cerebral functions as glucose metabolism and 77

blood flow, may provide positive evidence CLINICAL NOTES supportive of the diagnosis of AD, and may • Before confirming dementia, rule out benign be helpful to differentiate AD, FTD, and CJD. forgetfulness of the elderly, also known as age- MR Angiography (MRA) associated memory impairment, or MCI, i.e. dementia not so progressive or serious that • MRA allows for examination of cerebral it impairs reasonably successful and arterial vasculature in patients with productive daily functioning suspected cerebrovascular disease, and • Dementia is diagnosed from the history and • Cerebral vasculitis is a possible cause of basic examination, especially cognitive dementia. testing (e.g. The Mini-Mental Scale Exami- 8 ‡‡ Brain and Meningeal Biopsy nation, i.e. MMSE ; St. Louis University Mental state examination, i.e. SLUMS)9 and • Biopsy (Bx) sampling may be helpful in the confirmed by psychometric testing (e.g. the diagnostic approach to rare cases of Wechsler test and/or the Stanford-Binet dementia for which a reliable diagnosis Intelligence Scales) cannot be established on the basis of clinical • The MMSE is commonly used as a screening symptoms, CSF parameters, EEG, and MRI tool to detect dementia. However, it performs results, e.g. CJD, CNS vasculitis, and poorly in identifying persons with mild potentially treatable neoplasms or sarcoid. neurocognitive disorder. The SLUMS examination is a 30-point screening questi- Genetic Test onnaire that tests for orientation, memory, • The genetic test for apolipoprotein E4 attention, and executive functions, and is (apoE4): In general apoE4 is associated with possibly better at detecting mild neurocog- increased risk of developing AD and other nitive disorder, which the MMSE failed to neurodegenerative disorders. detect10 • MMSE is also been found to be biased by age Neuropsychologic Evaluation and education level. Statistical data indicates • To diagnose early dementia and to rule out that its appropriate cut-off scores can pseudodementia††. Patients with pseudode- improve the sensitivity of culturally modified mentia often have a pervious history of versions of the MMSE. A 7 minute mental §§ depression or a family history of mood screening (7MS) tool , consistingof 4 brief tests disorder. (enhanced cued recall, temporal orientation, verbal fluency, and clock drawing) to

†† Pseudodementia is a term used to describe the reversible distinguish between patients with probable cognitive impairment associated with major depressive AD and healthy control subjects appears disorder in older adults. The use of this term has been disputed by some investigators who note that though severe depression can cause real cognitive impairment, the ‡‡ MMSE is only a formal screening procedure to quantify condition is treatable (unlike irreversible dementias such as cognitive impairment; it is not diagnostic, but can be used AD). When depression is treated, many experience over a period of time to follow progression of dysfunction. improvement in cognitive function, and some go on to Further cognitive assessment is indicated in specific develop dementia within 2 years; therefore, there is nothing patients to confirm dementia. pseudo about the disability resulting from severe depression. (Ref. McAllister TW. Overview: pseudodementia. Am J §§ Described by Solomon and colleagues, the 7 minutes Psychiatry. 1983 May; 140(5):528-33. [ PMID: 6342420]). screening battery takes approximately 7 to 11 minutes. 78 Diagnosis: A Symptom-based Approach in Internal Medicine

highly sensitive to AD, and may be useful in 1. Memory loss that is getting worse, e.g. helping to make initial distinctions between cannot remember recent information, patients experiencing cognitive changes forget names and appointments; related to the normal aging process, and those 2. Difficulties with familiar activities, e.g. experiencing cognitive deficits related to housewife to prepare a meal; dementing disorders such as AD. It has 3. Language problems, e.g. has trouble expressing reasonable inter-rater and test-retest thoughts, difficulty finding right words; reliability, can be administered in a brief 4. Problems with spatial and temporal period, and requires no clinical judgement orientation, e.g. get lost at familiar place; 11-13 and minimal training. 5. Impaired capacity of judgement, e.g. • Unless the patient has obvious and profound dress inappropriately; cognitive impairment, it is generally 6. Problems with abstract thinking, e.g. advisable to first interview him or her alone, financial mistakes, simple miscalculations; followed by an interview with a close family 7. Leaving things behind, losing things; 14 member or caregiver (Table 12.4). 8. Mood swings and behavioral changes, Table 12.4: Questions for relatives to detect possible e.g. sudden mood swing without early dementia discernible cause, explosive outbursts; • Have you noticed any change in personality? 9. Personality change, e.g. a friendly person • Have you noticed increased forgetfulness or anxiety about forgetting things (such as using lists more, etc)? becomes unexpectedly angry, jealous; and • Have any activities been given up (hobbies and 10. Loss of initiative, e.g. lose interest in hobbies, interests, shopping, dealing with finances) and why? excessive procrastination, failure to thrive. • Have you noticed nocturnal confusion or muddling when out of usual routine or environment, or • Some of the potentially reversible causes of unusual avoidance of new circumstances? dementia should be considered before a • Have you noticed surprising failure to recognize people (such as more distant relatives)? diagnosis of AD is made (Table 12.2). • Have you noticed undue difficulty in speech? • History should include drug list, head • Have changes been gradual or has there been trauma, alcoholism, gastric surgery, risk sudden worsening? factors for HIV, functional disabilities, degree • In an elderly with suspected dementia, of social support, and familial disorders. cognitive testing should be ideally performed • Family history— As many as 40-50% of patients after assessing their visual and hearing status. with FTD have an affected family member. Their visual and hearing deficit may add to • Drug therapy of dementia—Although some confusion and misinterpretation of end result, drugs have shown low risk for causing leading falsely being classified them as cognition disorders in research studies, risk demented. Patients with early or doubtful may be increased in frail older adults taking dementia should be screened periodically up to several medications, and each case should six months and possibly at intervals thereafter be reviewed carefully.15 • Ten early warning signs—Due to time constraint, • As cognitive decline is a feature of number of it is difficult to perform screening test on all elderly medical conditions, the physical and systemic patients coming to the office. Therefore, particular review must be thorough and detailed. Special attention to the presence of warning signs attention must be paid for signs of common suggestive of cognitive impairment is a useful problems at the patient’s age, including: adjunct to maximize the gain:  Nutritional status, anemia Dementia 79

 Audiovisual loss Table 12.5: Alzheimer’s disease and vascular dementia:  Hygiene – oral, feet, perineum the differential diagnosis  Physical abuse or neglect Type Alzheimer’s disease Vascular dementia  Issues of poor balance when standing up Onset Gradual May be sudden or walking or gait Progression Steady decline Stepwise decline  Localizing or lateralizing motor signs Motor system Normal Focal deficits typical  Signs of extrapyramidal lesion (parkinso- Neuroimaging Normal or May suggest nism) findings atrophy vascular disease  Gait Normal May be abnormal Other systemic disorder (metabolic Comorbid No causative role Hypertension, 16,17 syndrome hypertension, hypoten- illness diabetes, CHF, sion,18 hypothyroidism). atrial fibrillation, IHD as • Psychiatric assessment: precipitating  Depression in the elderly may mimic causes dementia, and may even coexist in a significant number of individuals (vide mellitus, hypertension, coronary heart supra: pseudodementia). disease, and peripheral artery disease).  Patients with mild HIV dementia The onset of cognitive decline is either commonly present with psychiatric subtle or abrupt, and there is psycho- symptoms of depression and anxiety. motor slowing, executive dysfunction, Therefore, screening all patients with HIV focal cognitive deficits and motor signs. infection who present with depression  DLB—Clinical features are fluctuating for early HIV dementia is imperative. cognitive impairment over weeks or months • Among a long list of the differential diagnosis affecting memory and higher cortical of dementia, four common diseases — AD, functions (language, visuospatial ability VaD, (Table 12.5), DLB, and FTD — should be such as clock drawing or copying of a complex considered, based on history, physical figure, or reasoning); mild spontaneous examination, and simple neuropsychological extrapyramidal symptoms; recurrent visual evaluation. Although depression, delirium, hallucinations, and parkinsonism, with psychosis, aphasia, and mild cognitive intervening episodic lucid interval. In terms impairment share some features with of making a diagnosis, the two most dementia, each is a distinct syndrome with confusing diseases are DLB and Parkinson’s its own differential diagnosis. It is important disease with dementia (PDD) because the to consider all of these syndromes when clinical features are similar. evaluating a patient with suspected dementia.  FTD—Personality and behavioral  AD—Memory decline is the hallmark of changes (apathy, withdrawal, mutism) cognitive change in AD. In the early stage, are predominant with less prominent memory impairment for recent events is memory loss early in the course; common whereas long-term memory frequently FTD is misdiagnosed as remains intact. As the disease progresses, personality disorders or late-onset individuals with AD are increasingly psychiatric disorders. unable to recall more distant memories. • Aging affects the clinical presentation of both  VaD—Typical cases are usually seen with hypothyroidism and hyperthyroidism. Some atherosclerotic comorbidities (diabetes of the classic clinical features seen in younger 80 Diagnosis: A Symptom-based Approach in Internal Medicine

patients (e.g. cold intolerance, weight gain in Table 12.6: Comparison of features of delirium hypothyroidism; and tremor, nervousness, and dementia polyphagia, increased sweating in hyperthy- Delirium Dementia roidism) are absent in elderly patients. Also, Acute onset Insidious onset apathetic hyperthyroidism (i.e. paradoxical Profound confusion, clouding Clear consciousness of or impaired consciousness, presentation of hyperthyroidism with fatigue, drowsy, anxiety, agitation, psychomotor slowing, depression, and weight bewilderment Perceptual abnormalities Global impairment of cerebral gain) may also occur in this population. (illusions, hallucinations, functions (e.g. recent memory, Moreover, the common clinical features of imaginary conversations intellectual impairment, personality, or activities) and behavior abnormalities) hypothyroidism (e.g. fatigue, constipation, Paranoid ideas/delusions; Progressive course cognitive loss) are often attributed to normal fluctuating course with aging. These factors, along with the fact that lucid intervals Reversible Irreversible hypothyroidism has an insidious onset and affects multiple organ systems, may cause • “Despite the reemergence of syphilis with considerable delay and difficulty in diagnosis. the AIDS epidemic, neurosyphilis is often Therefore, it is important to have a high index neglected in the differential diagnosis of of suspicion and a low threshold for screening patients with aseptic meningitis and mental for thyroid dysfunction in elderly patients who status changes who are negative for the HIV. present with vague, nonspecific symptoms The high mortality rate associated with associated with MCI. delay in recognition, diagnosis, and treatment of neurosyphilis obligates its RED FLAGS inclusion in the differential of young 19 • Dementia and delirium can appear in the patients with cognitive decline.” same patient; however, it is important to • The mere presence of cerebral atrophy on a distinguish dementia from delirium (acute scan should not be taken as evidence of metabolically induced state of fluctuating dementing process. Atrophy can occur in consciousness).Table 12.6 compares the individuals with no cognitive impairment. features of delirium with those of dementia • When dementia and delirium coexist, SELECTIVE GLOSSARY making it difficult to separate them Normal pressure hydrocephalus—NPH clinically, it is not appropriate to give a describes hydrocephalus in the absence of patient a new diagnosis of dementia during papilledema and with normal CSF opening a state of delirium. With serial observations as the delirium resolves, it becomes possible pressure on lumbar puncture. The clinical to differentiate them symptom complex is characterized by • HIV dementia may manifest with acute- abnormal gait, urinary incontinence, and onset psychotic symptoms including dementia. It is an important clinical diagnosis delusions and hallucinations, and these because it is a potentially reversible cause of patients are at a higher risk for suicidal and dementia. The features of raised intracranial homicidal ideation. The initial interview pressure are generally absent. The syndrome should include screening for possible suicidal mainly occurs in the seventh or eighth decades and homicidal ideation of life. Possible etiologic factors include head Dementia 81 injury, subarachnoid hemorrhage, meningitis, according to memory and nonmemory and CNS tumor. The most reliable marker of NPH involvement as amnestic, multiple domain and is the characteristic in which patient nonmemory single domain clinical subtypes. has great difficulty in lifting feet off the ground However, further studies are suggested to while upright. This gait disorder looks like a very arrive at a consensus on the diagnostic criteria severe shuffling gait of PD with marked difficulty for MCI, determining the subgroups and its taking the first step (start hesitation) or turning. treatment modalities. However, rigidity, tremor, and slowing of rapid, alternating movements that are common with REFERENCES PD are less commonly observed in NPH. 1. Web site- http://www.behavenet.com/capsules/ Incontinence is usually urinary but may be fecal. disorders/alzheimersTR.htm. Accessed on In earlier stages, patients may complain of 06.10.08. 2. Rockwood K, et al. The diagnosis of “mixed” urgency and frequency rather than true dementia in the Consortium for the Investigation of incontinence. Dementia is characterized by Vascular Impairment of Cognition (CIVIC). Ann N prominent memory loss and bradyphrenia, i.e. Y Acad Sci 2000;903:522-8. [PMID: 10818547]. 3. Kenneth M, et al. Mixed dementia: Emerging slowness of thought processes. MRI assessment concepts and therapeutic implications. JAMA of CSF flow is found to be a promising technique 2004;292(23):2901-08 [PMID: 15598922]. for evaluation of patients with suspected NPH. 4. Schreiter Gasser U, et al. Alzheimer disease versus mixed dementias: An EEG perspective. Mild cognitive impairment20-22— MCI is a Clin Neurophysiol 2008 Sep 1.[PMID: 18768349]. 5. Moor AR, et al. Drug-induced cognitive syndrome defined as cognitive decline greater impairment in the elderly. Drugs Aging 1999; than expected for an individual’s age (generally 15(1):15-28. [PMID: 10459729]. older than 65 years) and education level, but 6. Gray SL, et al. Drug-induced cognition disorders in the elderly: Incidence, prevention and that does not interfere notably with activities management. Drug Saf 1999 Aug; 21(2):101-22. of daily life. Several terms have been suggested [PMID: 10456379]. to identify cognitive disorders without 7. Felber SR. Magnetic resonance in the differential diagnosis of dementia. J Neural Transm 2002; dementia. Benign senescent forgetfulness, age- 109(7-8):1045-51[PMID: 12111442]. associated memory impairment and aging-associated 8. Available at web site: http://www.hospital medicine.org/geriresource/toolbox/pdfs/ cognitive decline are considered to fall within the folstein_mini-mental.pdf limits of normal aging. A recently proposed 9. Available at web site: http://medschool.slu.edu/ term, MCI, as opposed to the terms mentioned agingsuccessfully/pdfsurveys slumsexam_05.pdf. above, identifies a transitional state between 10. Tariq SH, et al. Comparison of the Saint Louis University mental status examination and the mini- normal aging and dementia. Some people with mental state examination for detecting dementia mild cognitive impairment seem to remain and mild neurocognitive disorder—a pilot study. stable or return to normal over time, but more Am J Geriatr Psychiatry 2006;14(11):900-10. [PMID: 17068312]. than half progress to dementia within 5 years. 11. Paul R. Solomon, et al. A 7 Minute Neurocognitive Mild cognitive impairment can thus be Screening Battery Highly Sensitive to Alzheimer’s regarded as a risk state for dementia, and its Disease. Arch Neurol 1998;55(3):349-55. 12. de Jager CA, et al. Utility of the Malayalam identification could lead to secondary translation of the 7- minute screen for Alzheimer’s prevention by controlling risk factors such as disease risk in an Indian community. Neurol India alcoholism, smoking, obesity, systolic [serial online] 2008 [cited 2008 Oct 11]; 56:161- 6. Available from: hypertension, etc. Recently, it has been http://www.neurologyindia.com/text.asp?2008/ proposed to classify mild cognitive impairment 56/2/161/41994 82 Diagnosis: A Symptom-based Approach in Internal Medicine

13. Mathew R, et al. Issues in evaluation of cognition Sacramento Area Latino Study of Aging study. J in the elderly in developing countries. Ann Indian Am Geriatr Soc 2007;55(5):758-62. [PMID: Acad Neurol [serial online] 2008 [cited 2008 Oct 1749319]. 11];11:82-88. 18. Moretti R, et al. Risk factors for vascular dementia: Available from: http://www.annalsofian.org/ Hypotension as a key point. Vasc Health Risk text.asp?2008/11/2/82/41874 Manag 2008;4(2):395-402. [PMID: 18561514]. 14. Macdonald AJD. ABC of mental health: Mental 19. Schiff E, et al. Neurosyphilis. South Med J 2002 health in old age. BMJ 1997;315:413-7. Sep;95(9):1083-7. [PMID: 12356119]. 15. Lenzer J. FDA warns about using antipsychotic 20. Gauthier S, et al. Mild cognitive impairment. Lancet drugs for dementia. BMJ 2005;330:922, doi: 2006 Apr 15;367(9518):1262-70. [PMID: 10.1136/bmj.330.7497.922-c 16631882]. 16. Ho RC, et al. Metabolic syndrome and cognitive decline in Chinese older adults: Results from the 21. Gimzal A, et al. Mild cognitive impairment. Turk Singapore longitudinal ageing studies. Am J Psikiyatri Derg 2004 Winter;15(4):309-16. [PMID: Geriatr Psychiatry. 2008;16(6):519-22. [PMID: 15622511]. 18515697]. 22. Portet F, et al. What is a mild cognitive 17. Yaffe K, et al. Metabolic syndrome and cognitive impairment? Rev Prat 2005;55(17):1891-4. [PMID: decline in elderly Latinos: Findings from the 16396229]. CHAPTER 13 Diarrhea

SYNOPSIS defined as diarrhea that lasts for more than 4 weeks, and that often persists unless therapy is The definition of diarrhea is somewhat contro- instituted (unlike acute diarrhea, which is versial. It depends on the patient’s as well as the usually self-limited). Diarrhea that lasts 14 days physician’s perspective. Scientifically, diarrhea and resolves within a month is generally exists if more than 200 g stool is passed daily, referred to as persistent acute diarrhea. Diarrhea is which is best determined by a 72-hour stool 1 also classified into groupings such as osmotic collection. versus secretory, infectious versus noninfec- Patients usually consider diarrhea as being tious, and inflammatory versus noninflamma- an increase in the daily frequency, liquidity, or tory. Although each of these etiological factors volume of the stool. Clinically, it may be defined is helpful for understanding the pathophysio- as more than 3 bowel movements in a day. logy of individual diarrheal disease, most However, there may be some exceptions to this diarrheas are complex, and are produced by a definition. Stool weight depends on dietary intake combination of mechanisms. (e.g. Indian diet has high fiber content, and hence Acute diarrhea is usually associated with they have increased stool weight >200 g/day); abdominal colicky pain, urgency, tenesmus, therefore, stool weight by itself is an imperfect nausea and vomiting, watery stools, with or criterion to define diarrhea. Moreover, patient’s without blood or mucus. Systemic symptoms understanding of ‘diarrhea’ varies considerably— such as fever and myalgia may be present. In many complain of diarrhea when their stool is severe cases of diarrhea, urgency of defecation loose in consistency, while others complain only and is a common event. when their stool frequency increases.2 Therefore, In chronic diarrhea, the history is often a more practical definition of diarrhea may be nonspecific and physical findings are lacking. taken as, ‘ too frequent passage of too fluid stools’, Many patients do not seek medical attention as compared to patient’s baseline pattern. unless their diarrhea is associated with other Diarrhea that lasts less than 14 days is symptoms, such as weight loss, fecal inconti- referred to as acute, while chronic diarrhea is nence, rectal bleeding, or abdominal pain. 84

The majority of cases of acute diarrhea are Rare benign and self-limiting; but in selected clinical • Inflammatory bowel disease (IBD) settings such as elderly, dehydrated, immuno- • Colon malignancy compromised, or patients on immunosuppressive • Mesenteric ischemia therapy, this aliment can be life-threatening. • Malabsorption (lactose intolerance, tropical Further, the diagnosis of functional disease in sprue) patients with chronic watery diarrhea should be • Post GI tract surgery. performed with caution, since in most cases there 3,4 is an organic cause that justifies diarrhea. INVESTIGATIONS—GENERAL The goal of the initial evaluation of an adult with diarrhea, therefore, is to differentiate benign CBC patients from more serious or chronic disorders • Leukocytosis in invasive diarrhea or needing thorough investigations because of the dysentery. possibility of more serious underlying disease. • Anemia may suggest blood loss, malabsorp- Although the evaluation can be taxing, making tion, infection, or malignancy. an accurate diagnosis is rewarding, because • Eosinophilia may suggest parasitic disease effective therapy is available for many of the or allergic reaction. 5 conditions that cause chronic diarrhea. • Megaloblastic anemia suggests malabsorp- tion of B or folic acid. DIFFERENTIAL DIAGNOSIS 12 ESR Common • May be elevated in infection, IBD or malignancy. • Infections  Acute (Viral: rotavirus) Blood Glucose  Bacterial (Salmonella, Shigella, S.aureus, • To diagnose and monitor blood glucose in Campylobacter, traveler’s diarrhea) diabetes mellitus.  Parasitic (Giardia, Entamoeba, Cryptos- poridium) Metabolic Panel  Helminthic (Ascariasis, Ancylostoma • Urea, creatinine elevated with hyponatremia duodenale, Trichuris trichiura). • Hypokalemia in dehydrated patients. • Chronic (Giardiasis, Amebiasis, TB enteritis, HIV/AIDS infection) HIV • Food poisoning • May be indicated in patients with chronic, • IBS persistent diarrhea. • Laxative abuse. INVESTIGATIONS—SPECIFIC Occasional Fecal Leukocytes • Diabetic autonomic neuropathy • Hyperthyroidism • The presence of fecal leukocytes > 10/ (or • Fecal impaction with spurious diarrhea lactoferrin) in stool suggests an inflamma- • Hemorrhagic colitis (E. coli O157:H7: vide infra ↓↓) tory diarrheal disease and may support • Pseudomembranous colitis (PMC: vide infra ↓↓) . obtaining stool culture. Diarrhea 85

Rectal Swab for c/s suspicion of fat malabsorption (part one of the test - stool fat greater than 5 to 7 g. / 24 hr.), and • Useful only if the patient has persistent fever, it has the added advantage of being able to bloody diarrhea, immunocompromised, or suggest maldigestion of dietary triglyceride occasionally in traveler’s diarrhea. Routine (part two of the test). If both part two and part cultures will detect Shigella, Salmonella, and one of the Sudan Test is positive, it indicates Campylobacter species. Special media and maldigestion of dietary triglyceride (pan- conditions are required for pathogens such creatic insufficiency, small bowel resection). A as E. coli-057: H, Vibrio cholerae, yersinia, etc. negative part two of the Sudan Test does not FOBT exclude pancreatic insufficiency. Mineral oil, • Positive fecal occult blood may indicate and the unabsorbable fat substitute, sucrose, inflammatory, neoplastic disease, or ischemic polyester could cause false-positive Sudan colitis. Tests (parts one and two). Stool for Protozoa TFTs • Fecal ELISA test for giardia-specific antigen, • Low TSH with elevated T4 in thyrotoxicosis. cysts of E. histolytica, and strongyloides may LFTs be helpful. • Raised alkaline phosphatase in metastasis; Stools for Clostridium Difficile Titer higher values of γ-glutamyl transferase • Helpful if the patient is taking or has received (γGT) in chronic alcoholics. antibiotics within the past one month and PMC is strongly suspected. Sigmoidoscopy with Biopsy and Culture

Stool pH • Flexible sigmoidoscopy may be useful in • pH <5.3 indicates carbohydrate malabsorp- patients with signs and symptoms of tion. proctitis (tenesmus, rectal pain, and ) or C. difficile colitis, or for Stool for ZN Stain (Modified) identifying noninfectious causes of bloody • For Cryptosporidium, Isospora belli, Cyclospora in diarrhea such as IBD or ischemic colitis. HIV infection. Colonoscopy or Barium Enema Stool Chemical Analysis • Colonoscopy is more sensitive than barium • Stool volume, pH, osmolality, and electro- enema in detecting PMC, ischemic colitis, lytes estimation is useful in evaluating diverticular disease, and tumors and allows obscure cases of chronic diarrhea of secretory procurement of mucosal biopsies. The and osmotic etiology. Osmotic gap < 50 mOsm terminal ilium may also be inspected in most is suggestive of secretory diarrhea, and >125 patients. mOsm is suggestive of osmotic diarrhea.

Stool Fat (Sudan Stain) US or CT Abdomen • If a patient is ingesting fat (>80 g per day), • For evidence of organomegaly, metastasis, or to Sudan Test is excellent for proving clinical know the site and extent of carcinoid syndrome. 86 Diagnosis: A Symptom-based Approach in Internal Medicine

Upper GI Barium Series further evaluation. A careful history and physical examination generally allow these • Most commonly used when evaluating for conditions to be discriminated from true Crohn’s disease. diarrhea • The duration of symptoms is important in Laxative Abuse Detection the assessment of diarrhea. While infection • Stool water that turns red after alkanization is the leading cause of acute diarrhea (viral confirms the presence of phenolphthalein, a or bacterial), most cases of chronic diarrhea stimulant laxative. Urine tests are available are noninfectious—IBS being the leading to demonstrate the presence of aloes, senna cause of chronic diarrhea alkaloids, and bisacodyl. Sigmoidoscopy • History should include recent consumption shows Melanosis coli (graphically reminiscent of unsanitary food or water (raw or poorly of tiger, crocodile, or toad skin: vide infra↓↓), i.e. cooked foods such as eggs, meat, shellfish, brown discoloration to the colonic mucosa. dairy products, fruits and vegetables, or foods that may have been improperly handled or Urine 24 hr Collection for 5-HIAA Excretion stored). Patients should be asked specifically about the use of public swimming pools, • In suspected carcinoid syndrome. recent travel (ETEC infection), antibiotic use within two months (PMC), domestic animal Serum Gastrin exposure (Campylobacter infection), previous • In Zollinger-Ellison syndrome. surgery (cholecystec-tomy, intestinal resection and surgery for peptic ulcer Serum Calcitonin disease), or radiation exposure • A careful medication history should • To rule out medullary carcinoma of the specifically screen for antibiotic use causing thyroid. PMC, illicit drugs, alcohol, antacids, and laxative abuse. In chronic diarrhea, associated CLINICAL NOTES medical disorders such as diabetes mellitus, • Two common conditions, usually associated dysmotility diarrhea, arthropathies in IBD with the passage of stool totaling < 200 g/d, must are helpful in the diagnosis be distinguished from true diarrhea. Pseudo • Sexual history is important, particularly if diarrhea, or the frequent passage of small volumes there has been oral-genital or oral-anal of stool with rectal urgency, and accompanies contact. Homosexuals (gay bowel syndrome) irritable bowel syndrome or anorectal and HIV individuals are at a higher risk for disorders like proctitis. Fecal incontinence is the exposure to infectious agents, and diarrhea involuntary discharge of rectal contents and may be the initial presenting manifestation most often caused by neuromuscular disorders • Past medical history should focus on any or structural anorectal problems. Diarrhea and prior history of diarrheal illness, and urgency, especially if severe, may aggravate or significant underlying medical problems (e.g. cause incontinence. Many patients are hesitant AIDS, diabetes, cirrhosis, sickle cell disease, to discuss it because of embarrassment. cancer, endocrine - thyroid, Z-E syndrome, However, it is important to ask about fecal or autoimmune disease), prior radiotherapy, incontinence because the condition requires and immunological status. Diarrhea 87

• Important features in the history which help Table 13.1: The Manning criteria to distinguish IBS from guiding the evaluation and management of organic disease patients with acute diarrhea are: 1. Onset of pain associated with more frequent  Stool characteristics-frequency, consis- bowel movements tency, quantity, bloody, mucus-filled, 2. Onset of pain associated with looser bowel movements purulent, or greasy; 3. Pain relieved by defecation  Presence of dysentery—fever, tenesmus, 4. Visible abdominal bloating 5. Subjective sensation of incomplete evacuation blood, mucus, or both; more than 25% of the time  Symptoms of dehydration—thirst, 6. Mucorrhea more than 25% of the time lethargy, postural giddiness, decreased Table 13.2: Physical signs in diarrhea urination; and  Presence of associated symptoms— Physical signs Significance nausea, vomiting, abdominal cramps, General exam—Fever, Infection, IBD weight loss, tachycardia, Alcohol abuse, and significant upper or lower gastro- tremor, lymphadenopathy hyperthyroidism intestinal bleeding (coffee ground emesis, TB, malignancy hematemesis, melena, hematochezia). Skin — Erythema nodosum, IBD dermatitis herpetiformis, Celiac sprue • Some typical features of diarrhea and stools flushing, Carcinoid syndrome associated with common diseases are: venous telangiectasis, Carcinoid syndrome  hyperpigmentation Addison’s disease,Peutz- Nocturnal diarrhea—autonomic neuro- Jeghers syndrome pathy, e.g. diabetes mellitus; Kaposi sarcoma AIDS  Diarrhea alternating with constipation - Punch’ purpura Amyloidosis TB abdomen, laxative abuse, diverticu- Eyes—Iritis,uveitis IBD losis, carcinoma of colon; Neck—Goiter Hyperthyroidism  Chronic bloody or melanotic stools with Lungs—Bronchospasm Carcinoid syndrome Abdomen—mass, Crohn’s disease weight loss - IBD, colonic malignancy; RLQ mass Colonic ischemia  Pale, bulky, greasy, frothy, foul-smelling Bruit stools, which float in toilet, and associated PR—Rectal fistula, Crohn’s disease painless fissure, with nutritional deficiency, weight loss - perianal abscess malabsorption syndrome; and  Diarrhea worsened by eating fatty foods - patient with new-onset bloody diarrhea.

steatorrhea. Development of the hemolytic uremic • The Manning criteria (Table 13.1) are helpful to syndrome (HUS) or thrombotic thrombocy- differentiate IBS from organic causes of diarrhea topenic purpura (TTP) should raise strong

• Table 13.2 illustrates common findings on suspicion of E. coli O157:H7 infection and physical examination and their significance should lead to prompt evaluation in patients with diarrhea. • Nocturnal diarrhea, unless occurring in a known diabetic patient, usually points to an RED FLAGS organic cause • Abdominal TB (intestinal or peritoneal) can • Infection with E. coli O157: H7 presents with mimic IBS and must be considered in chronic

many clinical manifestations and should be diarrheal disease, especially due to rising

included in the differential diagnosis for any HIV incidence 88

• In general, a patient with any of the following Melanosis coli—It is a pigmentation of the warrants thorough work up: rectal and colonic mucosa due to use (or abuse)  Symptoms of dehydration: Particularly of anthraquinone type laxatives, and occurs postural giddiness, diminished urine because of the deposition of a brown black output, and excessive thirst; pigment called lipofuscin in the lamina propria  Advanced age (> 70 years); of the colon. The initial event is mucosal cell  Clinically suspected neoplasm, carcinoid death or apoptosis resulting from anthraqui- syndrome, colonic ischemia; none laxative abuse. These cells are then  Compromised immune system; and phagocytosed by macrophages in lamina  Inflammatory diarrhea: fever, blood and propria producing lipofuscin, which gives a mucus in stools. dark color to the colonic mucosa. Its incidence is understandably higher in older population and SELECTIVE GLOSSARY people who suffer from conditions like IBS and chronic constipation, and is rising because of Hemorrhagic colitis (E. coli O157:H7)— Entero- the popularity of the herbal remedies containing hemorrhagic E. coli (EHEC) strain designated E. anthraquinone. Melanosis coli is a benign coli O157:H7 serotype, causing Hemorrhagic reversible condition with no malignant colitis, is a gram-negative rod-shaped bacterium, potential. The main importance of diagnosing capable of producing potent toxins [verotoxic Melanosis coli correctly lies in the fact that if it’s (VT), shiga-like toxin] that cause severe damage extensive, there may be difficulty in differentiating to the lining of the intestine. Undercooked or raw it from ischemic colitis. Withdrawal of the hamburger (ground beef) has been implicated in offending laxative, which nearly always can be many of the documented outbreaks, however, E. substituted with a bulk laxative, is sufficient coli O157:H7 outbreaks have implicated alfalfa treatment. sprouts, unpasteurized fruit juices, milk, dry-  cured salami, lettuce, game meat, and cheese Peutz-Jeghers Syndrome (Pronunciation: putz  curds. The illness is characte-rized by severe j a’ge rz)—It is a hereditary disease caused by cramping abdominal pain, and diarrhea which autosomal dominant mutations involving is initially watery but becomes grossly bloody. Chromosome 19. It is characterized by the Occasionally vomiting occurs. Fever is either presence of intestinal polyps, consistently in the low-grade or absent. The illness is usually self- jejunum, and mucocutaneous pigmentation limited and lasts for an average of 8 days. The with melanin spots (small, flat, brown or dark majority of infections resolve completely; some blue spots with an appearance of freckles) of the victims, particularly the very young, have lips, buccal mucosa, and digits. Isolated developed HUS, characterized by renal failure melanotic mucocutaneous pigmentation and hemolytic anemia. In the elderly, it may be without gastrointestinal polyps has also been complicated by TTP with high mortality rate. described because of the genetic variability of Because person-to-person transmission of E. coli the syndrome. History includes: O157:H7 is not uncommon, and infection with • Family history of Peutz-Jeghers syndrome this organism may cause severe disease, stool • Repeated bouts of abdominal pain in patients specimens from all patients with a history of younger than 25 years acute bloody diarrhea should be cultured for • Unexplained intestinal bleeding in a young E. coli O157:H7. patient Diarrhea 89

• Prolapse of tissue from the rectum antibiotic therapy, or can occur up to 6 weeks after • Menstrual irregularities in females (due to discontinuation. Other causative factors for PMC hyperestrogenism from sex cord tumors are abdominal surgery, colonic obstruction, with annular tubules) uremia, and prolonged hypotension causing • Gynecomastia in males (possible due to the hypoperfusion of the bowel. PMC also has been production of estrogens from Sertoli cell described with lymphoma, leukemias, and testicular tumors) advanced HIV infection. Diagnosis is primarily by • Precocious puberty the detection of C. difficile, or its toxins in stool by • Gastrointestinal intussusception with ELISA techniques, or direct culture of C. difficile from bowel obstruction. the stool. CT scanning of the abdomen can be helpful The risk of cancer remains elevated with by revealing the presence of bowel wall edema (>4 disregard to the presence or the absence, as well mm) and inflammation, particularly in cases as the number, of gastrointestinal polyps. involving the right colon. Although these findings Pseudomembranous colitis—PMC is a descriptive are nonspecific, imaging studies are helpful in term for colitides associated with pseudo- patients with severe disease in detecting membrane formation (or plaques) on the colonic or complications (e.g. toxic dilation, perforation). small intestinal mucosa. Although small intestine can be involved in PMC, most cases encountered in REFERENCES the modern era involve only the colon. Clostridium difficile infection is responsible for virtually all cases 1. Achkar E. What is a practical approach to outpatient of PMC; the basic mechanism in its pathogenesis evaluation of diarrhea in a previously healthy, middle-age patient? Cleve Clin J Med 2001;68:104. being overgrowth of C. difficile and toxin production 2. Talley NJ, et al. Self-reported diarrhea: What does it (toxin A is an enterotoxin, while toxin B is a mean?Am J Gastroenterol 1994;89(8):1160-4. cytotoxin) by the organism that causes a wide [PMID: 8053428: Abstract]. 3. Fernández-Bañares F, et al. Systematic evaluation spectrum of illnesses, ranging from mild diarrhea of the causes of chronic watery diarrhea with to life-threatening PMC. The anaerobes that are functional characteristics. Am J Gastroenterol 2007 normally present in the colon control colonization Nov; 102(11):2520-8. Epub 2006. [PMID: 17680846 : Abstract]. by C. difficile; therefore, antibiotics that are most 4. Bertomeu A, et al. Chronic diarrhea with normal active against anaerobic organisms are more stool and colonic examinations: organic or commonly associated with PMC. Although functional? J Clin Gastroenterol. 1991;13(5):531- clindamycin and lincomycin classically have been 6. [PMID: 1744388: Abstract]. 5. Fine KD, et al. AGA Technical Review on the linked to PMC, virtually all antibiotics can cause Evaluation and Management of Chronic Diarrhea. PMC; its onset being within days after initiation of Gastroenterology 1999;116:1464–86. CHAPTER 14 Dyspepsia

SYNOPSIS nausea or early satiety. Patients use this term variously to express a feeling of bloating, Dyspepsia has been said to be ill-defined, poorly , (pyrosis), regurgitation, defined, defying definition, and vague and early satiety, acidity, and indigestion or ‘upset misunderstood.1,2 The Rome III committee stomach’. It is often accompanied by anorexia, recommends the following pragmatic definition nausea, vomiting, or . Although these of dyspepsia: “dyspepsia is defined as the symptoms are imprecise and nonspecific, care presence of one or more dyspepsia symptoms in taking the clinical history will often facilitate that is considered to originate from the making a tentative diagnosis and limit gastroduodenal region, in the absence of any unnecessary investigations.7 organic, systemic, or metabolic disease that is The main concern of the physician is to allay likely to explain the symptoms”.3,4 patient’s fear of organic GI disease by standard It further states that the term functional dyspepsia work up, and emphasize ‘patient empowerment’, should preferably be replaced by more distinctively i.e. discuss and agree with the patient how best defined disorders: (1) meal-induced dyspeptic he/she can control their symptoms with symptoms (postprandial distress syndrome), and treatments available, and advise when symptoms (2) epigastric pain syndrome. However, the need further investigations to rule out a more committee recommends this definition particularly serious underlying cause. for research purposes.5, 6 A working definition of dyspepsia may be DIFFERENTIAL DIAGNOSIS considered as episodic or persistent upper abdominal symptoms believed to arise from the Common upper digestive tract (i.e. epigastrium; pain in • Indiscriminate eating behavior* (too much, the right or left hypochondrium is not too rich, too fast). considered to constitute dyspepsia), which may or may not be related to eating, and may include * A rare cause of indiscriminate eating (hyperoral) behavior epigastric pain, bloating, fullness, belching, is frontotemporal dementia – vide infra ↓↓. 91

• Functional dyspepsia (Nonulcer dyspepsia, • Pancreatic malignancy i.e. NUD†, aerophagy, IBS) • Intra-abdominal malignancy • Peptic ulcer disease (PUD‡ e.g. duodenal • Gastrinoma (Zollinger-Ellison syndrome, i.e. ulcer, gastric ulcer, stress ulcer) ZES: vide infra ↓↓) • GERD • Metabolic (hypercalcemia) • Medications (NSAIDs, iron supplements, • Carbohydrate malabsorption (lactose, fructose). oral antibiotics, corticosteroids, theo- phylline, digitalis, potassium chloride, INVESTIGATIONS—GENERAL bisphosphonates, metformin, acarbose, OTC agents/herbal-garlic, gingko, Saw palmetto) CBC • Substance use/abuse—(alcohol, tobacco, • Leukocytosis with infection (cholecystitis, caffeine) pancreatitis, MI) • Systemic disease—(IHD, viral hepatitis A • IDA due to chronic GI bleeding infection, tuberculosis, sepsis) • Megaloblastic anemia in malabsorption and • Parasites (intestinal amoebiasis, giardiasis, gastric carcinoma. strongyloides) • Psychogenic (anxiety, depression, somatization) ESR • Pregnancy. • Elevated in infection, malignancy. Occasional FOBT and Parasites • Coronary ischemia • Gastroparesis (diabetes mellitus, vagotomy) • To screen for GI carcinoma, adenoma, • Hepatobiliary disease (cholecystitis, choleli intestinal ischemia, and IBD thiasis) • Stool microscopy/ ELISA for parasites. • Pancreatitis (chronic) • Organ failure (cardiac, renal, hepatic) ECG • Upper GI malignancy (esophagus, gastric). • If coronary ischemia is likely. Rare Metabolic Panel • Ischemic bowel disease • Hepatobiliary neoplasms (primary, secondaries). • Electrolytes, urea, creatinine, glucose, and calcium. † The older synonym nonulcer dyspepsia, though still widely used, is not recommended because some of the patients TFTs have symptoms typical of ulcer disease while others have symptoms not at all like an ulcer. Furthermore, peptic ulcer is not the only organic disease to be excluded before • Performed to evaluate for hypothyroidism the diagnosis of functional dyspepsia is appropriate. (Ref. or hyperthyroidism. - Dyspepsia-A National Clinical Guidelines, Scottish Intercollegiate Guidelines Network; March 2003). LFTs, Amylase, Lipase ‡ PUD includes ulcer in the stomach, pylorus, duodenum, or a Meckel’s diverticulum, as well as ulcers at sites of GI anastomosis (stomal ulcer) and at the gastroesophageal • Performed to check for pancreatic or junction. obstructive biliary disease. 92 Diagnosis: A Symptom-based Approach in Internal Medicine

INVESTIGATIONS—SPECIFIC and confirming eradication following therapy. It is inexpensive and the test of EGD with or without Biopsy for H. Pylori (HP) choice, especially in children • Endoscopy is indicated in: • Histology: Mucosal biopsies (four—two  All patients with dyspepsia aged >45 antral, and two corpus) obtained during years; endoscopy can be stained (H&E, Giemsa, or  In younger patients with positive HP Genta stains) to identify HP serology, or urea breath test (UBT); • In rapid urease test, the tissue specimen (obtained  Presence of any ‘alarm ‘ features (see ‘red at the time of endoscopy) is placed in urea flags’ below); rich agar medium with a pH sensitive dye. A  History of ulcerogenic medications; and color change represents a positive test  To obtain biopsy (Bx) specimens, particu- • Culture of HP is not often considered as larly of gastric ulcer. diagnostic tool due to the difficulty in culturing this fastidious organism; it is Tests for HP mostly confined to research laboratories • Urine and saliva tests for HP have not yet • These can be either noninvasive (serology, been completely validated. UBT, or stool antigen test), or invasive (histology, and rapid urease test) US Abdomen or CT • IgG serology is easy and most suitable for • Used as indicated to identify lesions that may initial diagnosis of HP infection because of be responsible for dyspeptic symptoms. its easy availability and low cost; but a • Gallstones detected are usually not causative positive test only indicates an ongoing or of dyspepsia. previous exposure to HP, and not active infection. Therefore, this test is not useful for Esophagography and Upper GI Barium Meal confirming eradication of the organism, and Series documenting successful treatment • Indicated if endoscopy is difficult or impossible • With the UBT, if HP is present, the urease as in patients with altered esophagogastric produced by the organism breaks down anatomy. A good barium meal study will ingested carbon 14 labelled (14C) urea into identify motility disorders of the esophagus, ammonia and labeled carbon dioxide, which (esophageal dilatation, loss of esophageal can be detected in the patient’s breath. UBTs peristalsis, poor esophageal emptying, and are useful both for diagnosing active infection ‘birds beak’ tapering of the distal esophagus), and confirming eradication following which may be missed endoscopically. treatment with antibiotics, because once HP is eradicated, urease is no longer produced. Esophageal Manometry The UBT is more sensitive and specific than serology testing, but its disadvantage is that • Not routinely used for mild to moderate it requires 14C (or 13C) detection equipment symptoms because findings seldom influence and tends to be more expensive further medical management; may be • Stool antigen test (PCR for HP), like UBT, is essential for patients who are undergoing useful both for diagnosing active infection surgery for GERD. Dyspepsia 93

24-hour Esophageal pH Manometry • Categorizing NUD in the diagnostic subgroups such as ulcer-like, reflux-like, • Performed in patients who have unex- dysmotility-like, and nonspecific dyspepsia plained chest pain that does not respond to have not shown to be helpful in predicting medications. diagnosis or response to treatment. This is Fasting Serum Gastrin mainly due to large amount of overlap between types of dyspeptic symptoms for • In patients with gastrin secreting multiple patients with underlying gastric ulcer, ↓↓ neuroendocrine tumors (MNE: vide infra ) duodenal ulcer, GERD, or NUD, which makes such as Zollinger-Ellison syndrome. the clinical history of little use in directing therapy toward a specific disease state.13,14 CLINICAL NOTES However, careful history is important to: • Dyspepsia for which an underlying disease  Elicit classical symptoms of specific process is thought to be responsible for the disorders, e.g. PUD, cholecystitis, GERD; symptoms is described as organic dyspepsia, e.g.  Detect complicated ulcer disease, e.g. IDA PUD, esophagitis; when symptoms persist for due to chronic GI blood loss, vomiting more than 12 weeks, and for which no cause due to gastric or duodenal outlet (structural or biochemical) can be found after obstruction, sudden, severe abdominal investigation, is usually termed as functional pain due to peptic perforation; dyspepsia—this entity is synonymously  Elicit alarm symptoms (see below) that termed as NUD. The Rome III criteria for suggest a high probability of organic functional dyspepsia are stated in Table 14.1. disease, and need further testing rather However, according to the Rome III criteria, than empiric therapy; and frequent clinical overlap of functional  Detect atypical symptoms more sugges- dyspepsia with IBS and GERD is very tive of other disorders, e.g. MI, IBS. common; but this overlap does not exclude a 8-11 • History should also include a complete review diagnosis of functional dyspepsia. of medications and OTC agents (see above); Table 14.1: The Rome III diagnostic criteria for dosage reduction or discontinuation of the Functional dyspepsia offending agent may relieve patient’s symptoms At least 3 months (which need not be consecutive), and avoid further expensive work-up with onset at least 6 months previously, of 1 or more of • Patient’s habits (alcohol, smoking), lifestyle, past the following: history of surgical procedures (appendicectomy, • Bothersome postprandial fullness • Early satiation gastrectomy), etc. may suggest potential • Epigastric pain etiologies • Epigastric burning • Evaluation of psychosocial factors—The • No evidence of structural disease (including at upper endoscopy) that is likely to explain the symptoms. contribution of psychosocial factors to the illness, i.e. functional dyspepsia, and the • The investigation of choice to make the decision for psychological referral can be diagnosis of NUD (functional) is endoscopy evaluated through several questions during of the upper GI tract. As such NUD can be the first visit. For example: referred to as investigated dyspepsia, which  What is the patient’s understanding of the should be distinguished from uninvestigated illness? Simple questions such as, “what dyspepsia.12 do you think is causing your symptoms?”, 94

or “is there anything that you are worried  Any associated chest pain, dyspnea, or about regarding these symptoms?”, may sweating help elicit concerns, relieve worries, and  Pain radiation to arm, jaw, shoulder, back improve patient satisfaction.  Associated with dizziness, syncope, or  Does the patient accept stressful lifestyle transient mental status changes and/or stressful life events playing a  History of IHD or cardiac risk factors contributing role?  Pulse and blood pressure abnormality.  Is there a concurrent psychiatric diag- • Alarm symptoms and signs suggestive of nosis such as anxiety, depression, organic cause in dyspeptic patients, and in somatization, alcoholism, and drug whom endoscopy is indicated, irrespective dependency? of their age, include:  What is the family’s involvement in  Progressive unintentional weight loss > terms of emotional and moral support? 3 kg (malignancy) When healthy and supportive behaviors  Constant or severe abdominal pain,

are present, the family members can be nocturnal pain (malignancy) recruited to help the patient toward  Pain that radiates to the back (posteriorly

recovery; or else counseling may be located ulcer, pancreatitis) indicated.  Persistent heartburn, regurgitation,  Unless the clinical data (e.g. occult blood in vomiting (obstruction)

the stool, significant weight loss, or  Hematemesis, melena, anemia (chronic

abnormal physical findings) suggest the GI bleeding) possibility of other disorders, the diagnostic  Progressive difficulty in swallowing studies ordered on the first visit should be (esophageal lesion) limited. The choice depends on the nature  Jaundice (alcoholic liver disease, and severity of symptoms and associated metastasis) clinical factors (see below - alarm signs and  Epigastric mass or suspicious barium symptoms). However, in the majority of meal patients with functional dyspepsia,  Unresponsive to the sequential treat- wherein a variety of emerging therapies ments for H. pylori eradication are being developed, but unfortunately,  Previous peptic ulcer to date, all of these therapies have yielded  Family history of cancer. only marginal results. Therefore, the physician’s most effective approach is to SELECTIVE GLOSSARY maximize the physician-patient relationship to help them cope with their Frontotemporal dementia (FTD)— It is a group symptoms.15 of diseases in which parts of the brain (the frontal and temporal lobes) shrink, or atrophy, RED FLAGS causing changes in personality and behavior.

• It is prudent to consider any dyspeptic People with FTD may have: symptoms as IHD, especially under follo- • Loss of social component—Not express any wing circumstances: caring for others. Dyspepsia 95

• Loss of personal awareness—Not attend to include hyperparathyroidism, hypercalcemia, personal hygiene hyperprolactinemia, Cushing’s disease, gastri- • Disinhibition—Say rude things to others, noma, and Zollinger-Ellison syndrome. This expose themselves, or make sexually explicit disease is due to loss-of-function of the MEN1 comments, or exhibit other socially inappro- gene, a tumor suppressor gene on chromosome priate behavior 11 (Locus: 11q13). Diagnosis of MEN1 depends • Hyperorality—Excessive eating, be obsessed on having a high level of suspicion in patients with repetitive routines or develop unusual food who present with one of the features such as obsessions, such as eating the same kind of food recurrent ulcers at atypical sites (esophagus, or eating in the same restaurant repeatedly jejunum) with poor response to standard ulcer • Speech output change—Reduction of speech, therapy, hyperparathyroidism, or increased stereotype of speech, and echolalia, difficulty gastric acid secretion, and serum hyper- understanding words and naming objects. calcemia. Many people may also be diagnosed because of a proband in the family. The physical examination usually reveals Zollinger-Ellison syndrome—A syndrome that early prominent primitive or frontal reflexes. One- is characterized pathophysiologically by a half of patients have a family history of dementia significant hypergastrinemia derived from a in a first-degree relative. There are three principal gastrin-secreting neuroendocrine tumor with varieties of FTD: frontal variant FTD, semantic a primary location in the pancreas or dementia, and progressive nonfluent aphasia. duodenum, but also found at other anatomic Frequently, FTD is misdiagnosed as personality sites, (e.g. heart, ovary, gallbladder, liver, disorders or late-onset psychiatric disorders. kidney), including stomach and small intestine Multiple Endocrine Neoplasias (MENS)— MEN (gastrinoma), which sometimes occurs in syndromes are genetic neoplastic conditions in families with MEN-1. Chronic hypergastrinemia which two or more endocrine glands develop triggers gastric acid hypersecretion yielding in hyperplasia, adenoma, or carcinoma, concur- chronic or recurrent or refractory peptic ulcer rently or consecutively. Two of the types that disease and/or chronic diarrhea. One half of occur are well-documented: MEN 1 (Werner’s patients with ZES will have distant metastases syndrome) involves hyperplasia and adenoma- in the liver by the time the diagnosis is tosis of the pituitary and parathyroid glands, established and one half of all patients with ZES islet cells of the pancreas and, rarely, the thyroid will experience chronic diarrhea as chief and adrenal glands; MEN 2 (Sipple’s syndrome) complaint rather than peptic ulcer-related which has three variants, classified as MEN2A, symptoms and signs. Therefore, a high index of MEN2B and involves medullary carcinoma of clinical awareness is needed to make a diagnosis the thyroid, with hyperplasia and adenoma- of ZES. The combination of diarrhea and tosis of the adrenal medulla (pheochromocy- abdominal pain is present in more than half the toma) and parathyroid glands. MEN I is the patients, usually > 40 years age. Heartburn is most common form, characterized by the the third most common symptom, and this combined occurrence of tumors in the symptom mimics GERD. The other factors that parathyroid glands, the pituitary gland, and the alert one to the presence of underlying pancreatic islets. The resulting clinical signs gastrinomas are the following:16 96 Diagnosis: A Symptom-based Approach in Internal Medicine

 Ulcers that is refractory to standard therapy 5. Tally NJ, et al. The Rome III Classification of  Multiple ulcers dyspepsia: Will it help research? Dig Dis 2008; 26(3):203-9. Epub 2008. [PMID: 18463436:  Giant ulcers, larger than 2 cm Abstract].  Recurrent ulcers 6. Suzuki H, et al. Therapeutic strategies for  Ulcers with unexplained diarrhea functional dyspepsia and the introduction of the Rome III classification. J Gastroenterol 2006;  Strong family history of ulcers 41(6):513-23. [PMID: 16868798: Abstract].  Hypercalcemia 7. Malfertheiner P. Current concepts in dyspepsia:  Duodenal ulcer that is not related to A world perspective. Eur J Gastroenterol Hepatol 1999; 11 Suppl 1:S25-9. [PMID: 10443909: Helicobacter pylori infection or nonsteroidal Abstract]. anti-inflammatory drug use. 8. Wang A, et al. The clinical overlap between A family history of nephrolithiasis, hyper- functional dyspepsia and irritable bowel parathyroidism, and gastrinoma also may be syndrome based on Rome III criteria. BMC Gastroenterol 2008;8:43.[PMID: 18808723 : Free present. Fasting serum gastrin (serial measure- full text]. ments on different days) is the best single 9. Geeraerts B, et al. Functional dyspepsia: Past, screening test. To localize the gastrin-secreting present, and future. J Gastroenterol 2008;43(4):251-5. Epub 2008 May 6. [PMID: tumor, computer-assisted tomography, endos- 18458839: Abstract]. copic ultrasound, and somatostatin receptor 10. Van kerkhoven LA, et al. Functional dyspepsia: scintigraphy provide useful help; but most Not All Roads Seem to Lead to Rome. J Clin Gastroenterol 2008. [PMID: 18719513: Abstract]. recently endoscopic ultrasound with high 11. Lundquist P, et al. Symptom criteria do not resolution transducers appear to improve distinguish between functional and organic preoperative site localization. dyspepsia. Eur J Surg 1998;164(5):345-52. [PMID: 9667468: Abstract]. 12. Sander JO Veldhuyzen van Zanten. Treating non- REFERENCES ulcer dyspepsia and H. pylori. BMJ 2000;321:648- 9, doi: 10.1136/bmj.321.7262.648. 1. Bytzer P, et al. Dyspepsia. Ann Intern Med 2001; 13. Hansen JM, et al. Management of dyspeptic 815-22. patients in primary care. Value of the unaided 2. Heading RC. Definitions of dyspepsia. Scand J clinical diagnosis and of dyspepsia subgrouping. Gastroenterol Suppl. 1991;182:1-6. [PMID: Scand J Gastroenterol 1998;33(8):799-805. 1896823: Abstract]. 3. Drossman DA, moderator. AGA Clinical [PMID: 9754725: Abstract]. Symposium — Rome III: New Criteria for the 14. Tally NJ, et al. Lack of discriminant value of Functional GI Disorders. Program and abstracts dyspepsia subgroups in patients referred for upper of Digestive Disease Week; May 20-25,2006; Los endoscopy. Gastroenterology. 1993;105(5):1378- Angeles, California. [Sp461-469]. In: From Rome 86. [PMID: 8224642: Abstract]. to Los Angeles – The Rome III Criteria for the 15. Saad RJ, et al. Review article: Current and Functional GI disorders. Lin Chang. Web site: emerging therapies for functional dyspepsia. http://www.medscape.com/viewarticle/533460. Aliment Pharmacol Ther 2006;24(3):475-92. Accessed on 13-11-08. [PMID: 16886913: Abstract]. 4. Tack J, et al. Functional gastroduodenal disorders. 16. Jennifer Lynn Bonheur. Gastrinoma. Web site - Gastroenterology. 2006;130:1466-79. [PMID: http://www.emedicine.com/med/ TOPIC2678. 16678560: Abstract]. HTM. Accessed on 15-11-08. CHAPTER 15 Dysphagia

SYNOPSIS Table 15.1: Dysphagia—Classification and clinical features Dysphagia is defined as the nonpainful Oropharyngeal Esophageal subjective sensation of having difficulty in • Usually bolus sticking • Usually bolus sticking below above suprasternal suprasternal notch swallowing, involving any structures of the notch upper —from the lips to • Rapid onset (< 2 sec) • Slower onset ( > 2 sec) • Oral and/or • Oral/pharyngeal symptoms are the lower esophageal sphincter (LES). The term pharyngeal symptoms minimal or absent; esophageal is used to describe disorders associated with are common. or systemic symptoms may For example: include: voluntary swallowing mechanism, and also the – Difficulty initiating a – Sensation of food sticking sensation that swallowed bolus is delayed or swallow throat/chest – Slow eating completely obstructed in its passage to the – Nasopharyngeal – Anorexia stomach. Some of the ways patients commonly regurgitation – Drooling of saliva – Change in dietary habits describe these feelings are—food being stuck in (sialorrhea) – Change in voice or – Unexplained weight loss the throat, or retrosternally, and sometimes speech difficulty initiating a swallow itself. Associated – Coughing or chocking – Cough before, symptoms such as difficult mastication, lump, during, or after – Chest pain fullness, or pressure in the throat or neck swallowing – – Throat secretions, – Reflux of food/bile into the (globus), drooling, coughing while eating, change frequent mouth in the voice, heartburn (pyrosis), and weight throat irritation • Risk groups: • Risk groups: loss may be present. – Any age group – Elderly Dysphagia is usually divided into oropharyn- – Cerebral palsy, – Diabetes mellitus developmental delay – Immunosuppressed / geal and esophageal causes (Table 15.1). Dysphagia – Patients with immunodeficient patients of oropharyngeal disease occurs in disorders history of CVA – Immunosuppressed / – Patients with reflux disease proximal to the esophagus, most often of immunodeficient – Alcohol, tobacco abuse patients neurological or muscular origin. The patient finds – Ventilator-dependent – Myopathy, dermatomyositis difficulty in preparing and swallowing food bolus patients – Ventilator-dependent patients from the mouth to the proximal esophagus (transfer – Head and neck surgery – Cardiothoracic surgery 98 dysphagia). There may be instant regurgitation of A—Oropharyngeal Causes food through the nose, chocking, repetitive Common swallowing, or cough due to tracheal aspiration. • Oral ulcers (aphthous ulcer; viral ulcers, e.g. There may also be dysphonia, dysarthria, or other HSV, CMV, HIV) neurological symptoms. • Oral inflammatory lesions (glossitis, is difficulty in stomatitis, tonsillitis, ‘kissing’ tonsils, transporting food bolus down the esophagus (transit peritonsillar abscess, i.e. Quincy, epiglottitis, dysphagia), usually as a result of obstructive or pharyngitis, retropharyngeal abscess, motility disorders. Patients complain of food Vincent’s infection, thrush) sticking at some point in esophagus, usually lower • Stroke (hemispheric stroke, brainstem sternum or epigastrium. Patients find that they stroke, Wallenberg syndrome, i.e. lateral must chew their food thoroughly and that fluids medullary syndrome: vide infra ↓↓) may be required to ‘wash the food down’. The time • Advanced age-related oral disorders† (loose, taken to eat is frequently prolonged. Occasionally unhygienic, or structurally defective the patient may notice regurgitation of undigested dentures‡, denture-induced stomatitis) food occurring minutes to hours after a meal. • Functional GI disorders (FGIDs: associated Dysphagia should be distinguished from with IBS, anorexia nervosa) odynophagia, i.e. painful swallowing; however, it • Dementia. may be associated with dysphagia per se. In addition, dysphagia should not be confused Occasional with globus*,1 i.e. constant or intermittent • Medication side-effect ( due to sensation of a lump in the throat, although no antihistamines, anticholinergics, antihyper- organic defect is apparent. tensives) Complaints of dysphagia are common, • Hypopharyngeal diverticulum (Zenker’s especially in aging persons, but many do not diverticulum: vide infra ↓↓). necessarily disclose this symptom to their physician, and for other patients swallowing Rare impairment does not seem to be a worry.2 However, • Premalignant lesion (leukoplakia, lichen in such patients with dysphagia, additional testing planus) may be indicated to diagnose the problem and • Neurologic disorders (PD, MS, MG, brainstem prevent complications. Therefore, although tumors) patients’ concern and experience of frequency, • Degenerative motor neuron disease (bulbar duration, and life interference are critical variables palsy, pseudobulbar palsy, ALS, i.e amyo- in consulting their physician for complaints of trophic lateral sclerosis: vide infra ↓↓) swallowing impairment, it is prudent for the • Degenerative cervical spine disease (impinging physicians to remain alert to the presence of cervical osteophytes) dysphagia in their patients. • Oropharyngeal tumors • Autoimmune and rheumatologic disorders DIFFERENTIAL DIAGNOSIS (RA, scleroderma, SS, i.e. Sjögren’s syndrome: ↓↓ These may be grouped into the two broad vide infra , myopathies) categories as stated above: † Dysphagia as a result of healthy ageing is termed primary * Originally called ‘globus hystericus’; however, the term presbyphagia ‘globus’ is preferred since there is no evidence to support ‡ Portcullis signs, i.e. the top denture falling on to the bottom the occurrence of ‘hysteria’ with this condition. one when the mouth is opened. 99

• Tracheostomy • Extrinsic compression (mediastinal mass, • Psychiatric disorder (somatization) pericardial effusion, enlarged left atrium, • Infections (Polio, diphtheria, tetanus, rabies§). thyromegaly, aortic aneurysm, dysphagia lusoria vide infra ↓↓) B—Esophageal Causes • Neurologic disorders (CVD, PD, MS, Guillain- Common Barré syndrome) • Food-bolus obstruction • Autoimmune disorders (systemic sclerosis, ↓↓ • GERD or scleroderma: vide infra ) • Hiatal hernia • Malignant lesions (adenocarcinoma, squa- • Pill-induced esophagitis (NSAIDs, iron mous cell carcinoma, leiomyosarcoma) • Psychiatric disorder (somatization) supplements, alendronate, potassium 4 chloride, doxycycline, zidovudine) • Idiopathic (or primary) achalasia. • Functional GI disorders (FGIDs — associated INVESTIGATIONS—GENERAL with IBS, anorexia nervosa). CBC, ESR Occasional • Eosinophilic esophagitis3 (vide infra ↓↓) • Reduced Hb with chronic infections, and • Esophageal motility disorders, i.e. EMDs malignancy. Anemia may be associated with (achalasia cardia, diffuse esophageal spasm, P-V syndrome. i.e. DES, LES dysfunction, ‘Nutcracker** • Elevated ESR in malignancy and auto- esophagus, i.e. NE) immune disease. • Esophageal webs, rings (Schatzki ring: vide CXR infra ↓↓) • For evidence of aspiration pneumonia, hilar • Benign strictures (due to chronic acid-peptic lymphadenopathy, growth, aortic aneu- ulceration) rysm, cardiomegaly (enlarged left atrium, • Benign neoplasm (leiomyoma, squamous cell pericardial effusion), and for locating papilloma) swallowed radiopaque foreign body. • Infectious esophagitis (bacterial, TB, viral, fungal in immunosuppressed patient) X-ray Neck-lateral view • Premalignant lesion (Barrett’s esophagus, i.e. • For evidence of cervical osteophytes or any BE: vide infra ↓↓). soft tissue lesion of retropharyngeal or postcricoid space (e.g. bacterial/tubercular Rare abscess, metastatic lymphadenopathy) • Foreign body causing dysphagia. • Plummer-Vinson syndrome (i.e. P-V syndrome, or Paterson-Brown-Kelly syndrome) INVESTIGATIONS—SPECIFIC Barium Swallow (Barium Esophagography, or §In tetanus, rabies, and pharyngeal paralysis there is morbid fear of swallowing, and refusal to swallow due to fear of Modified Barium Swallow (MBS) aspiration; this is known as Phagophobia. **The term “nutcracker esophagus” comes from the finding • The initial investigation of choice in patients of increased pressures during contractions (when especially with disorders of motor or pressures exceed 180 mmHg) in the lower esophagus; a ‘transfer’ dysphagia. Diagnostic features are force so strong that some observers have described them to a mechanical device called nutcracker — a tool powerful seen in patients with esophageal webs and enough to crack open a walnut or similar hard substances. rings; pharyngeal pouch or diverticulum; 100

strictures — benign (smooth) or malignant function. However, patients with mass lesion (irregular and tortuous ‘rat-tail’ deformity); or other lesions identified by barium esophageal dysmotility or spasm (‘corkscrew’ swallow should undergo EGD with cytology deformity); achalasia cardia (‘bird’s beak’ and biopsy(Bx) to confirm the diagnosis deformity with dilated proximal esophagus, • EGD allows certain therapeutic interven-tions: and air-fluid level); hiatus hernia; and  To remove an impacted food bolus or dysphagia due to external compression such foreign body, as mediastinal growth or aortic aneurysm. It  To dilate strictures with balloons or also reduces the risk of endoscopic perforation dilators, in these disorders, especially in those having  To destroy a lesion by laser, cautery, or pouch or diverticulum. Different consistencies photodynamic therapy, and of barium (solid, semisolid, or liquid; barium  To assist placing of implants or stents for pill, or a standard marshmallow) further assess advanced esophageal malignancy. swallowing disorders, as delays in transport may not be apparent with simple liquid barium. Esophageal Manometry (Stationary and If the patient has noted a problem with a specific Ambulatory) solid food, a mixture barium paste plus the • Indicated to assess EMDs, especially if no offending food may provide definitive obstructing lesion is identified by EGD or information.5 The disadvantage of barium X- barium swallow. Esophageal peristaltic rays is that they are relatively insensitive in contractions—their amplitude, duration, detecting mucosal disease, even if air contrast velocity, and coordination, as well as upper technique is added. Fluoroscopy can detect and lower end sphincter pressure studies, GERD. and their temporal correlations between EGD symptoms and reflux can be evaluated. On • Fiberoptic endoscopy directly visualizes the some patients esophageal manometry is used esophageal mucosa as well as other areas of in combination with 24 hours pH monitoring the upper GI tract. Its direct view is superior to evaluate uncommon causes of dysphagia, to barium X-rays for assessing mucosal e.g. DES, NE, achalasia, unexplained chest disease of the esophagus, and the esophago- pain, and scleroderma. scope permits assessment of structural Esophageal 24-hours pH Reflux Study‡‡ 6 lesions that are identified. Furthermore, punch biopsies and/or brush cytology of • Accepted as the most accurate method for specific lesions are easily obtained through diagnosing reflux. It is, however, uncomfor- the endoscope. Microscopic evidence of table and expensive investigation. Therefore, esophagitis may be found even when the indicated especially: mucosa looks grossly normal  If barium swallow or EGD studies are • Endoscopy is the single most useful test in negative, the evaluation of patients with reflux  In patients being considered for antire- symptoms, as it permits one to establish the flux surgery, and presence or absence of esophagitis or Barrett’s esophagus. Endoscopy gives little ‡‡ This technique has been revolutionized by a catheter- reliable information regarding esophageal less, wireless pH system. 101

 In the evaluation of patients with chest transit time in the upper, middle and lower thirds pain of undetermined origin. of the esophagus. Scintigraphy also can be • An abnormal result is indicated by a pH of combined with 24-hour pH manometry to <4 for more than 3% of the time when the check the cause of chest pain between patients are supine, and for > 8% of the time esophageal and possible cardiac factors. when they are erect. CT Scan/MRI Videofluoroscopic Swallowing Function Study (VSFS)‡‡ • In suspected structural CNS abnormalities, e.g. primary or secondary tumors, MS; or, aortic • The VSFS—performed jointly by a physician vascular lesions, e.g. aneurysm, lusorian artery. (typically a radiologist) and a speech- language pathologist—is the gold standard Muscle Enzymes for evaluating the mechanism of swallo- • Elevated serum CK may be observed in wing. For this study, the patient is seated motor neuron diseases, e.g. polymyositis, comfortably and given foods mixed with dermatomyositis. barium to make them radiopaque. The patient eats and drinks these foods while TFTs radiographic images are observed on a video • To detect hypothyroid or hyperthyroid monitor and recorded on videotape. disorders causing dysphagia, e.g. Graves’ • VSFS permits close observation of all structures disease or thyroid carcinoma. involved in swallowing process, i.e. lips, tongue, palate, pharynx, larynx, and proximal RF, ANA esophagus; indicated especially in patients at • In patients with autoimmune disorders, e.g. risk for silent aspiration, e.g. patients with RA, SLE, scleroderma. stroke, or neurologic impairment such as cerebral palsy, MS, PD, MG, motor neuron Antiacetylcholine Antibodies disease, systemic sclerosis, and connective tissue disorders such as SLE, and RA. • Antiacetylcholine receptor antibody activity • VSFS not only allows estimation of risks of may be elevated in patients suspected with aspiration and respiratory complications, MG, and polymyositis. but also helps in determining dietary modifications and training in swallowing Genetic Analysis techniques and maneuvers. • For example, in familial forms of ALS, or muscular dystrophy. Radionucleotide Study7 (Tc-99m Sulfur Colloid Bolus) CLINICAL NOTES • These assess gastroesophageal reflux, esophageal motility disorders, or to identify silent aspiration. • It is important to ascertain that the patient In GERD, reflux is present if the isotope is seen to truly has dysphagia, because some may travel back up into the esophagus. In esophageal misinterpret ‘lump in the throat’ (globus) as motility disorders, computer programs measure dysphagia • The clinical features of ‘globus’ sensation may ‡‡ The VSFS is similar to the MBS, except that the protocol occur with organic disease in the neck, pharynx, for the MBS specifies quite small bolus volumes and does or cervical esophagus; hence this diagnosis not include drinking from a cup. In practice, the terms “VSFS” and “MBS” are often used interchangeably. should only be made after a complete evaluation 102 Diagnosis: A Symptom-based Approach in Internal Medicine

• By asking following specific questions, the Table 15.2: Types of bolus causing dysphagia cause of dysphagia can usually be identified: Bolus Cause of dysphagia  Do you have difficulty swallowing? In what Dysphagia with both Muscular or neural control way? liquids and solids from disorders of swallowing the outset (bulbar, pseudobulbar palsy);  Do you have this sensation without motility disorders swallowing food? Dysphagia initially for Esophageal obstructive solids lesions (rings, webs,stricture)  Can you localize dysphagia? Intermittent, non- Benign obstructive lesions  Do you have trouble with solids or liquids? progressive dysphagia, (rings, webs, stricture); more for solids than esophageal spasm  Is the swallowing difficulty greater for liquids solids or liquids? Progressive dysphagia Obstructive inflammatory first for solids, then for stricture; achalasia;  Is the dysphagia intermittent or progressive? semisolids and liquids malignancy (carcinoma  Do you have heartburn? esophagus); scleroderma  Cold food or beverages Esophageal dysmotility, Any eating habits adopted to relieve precipitating dysphagia especially spasm symptoms? or causing chest pain  Are there any associated problems, e.g. stress, Table 15.3: Signs and symptoms of causes for dysphagia cough, chest pain, dysphonia, collagen Signs and symptoms Diagnostic clues disease, immunosuppression, weight loss? Sudden dysphagia Obstructive dysphagia, • Generally, dysphagia at the very beginning esophagitis, brainstem stroke, acute thyroiditis, of swallowing characterizes oropharyngeal Intermittent symptoms Rings and webs, DES, NE dysphagia; whereas dysphagia a few seconds Progressive symptoms Obstructive lesions, carcinoma, scleroderma after starting to swallow indicates an esopha- Difficulty initiating swallow geal cause Food ‘sticks’ after swallow Esophageal dysphagia Pain with dysphagia Esophagitis—infection, pill- • Onset—Acute dysphagia is commonly due induced to oropharyngeal causes such as infection, Regurgitation of old food, Zenker’s diverticulum halitosis inflammation, food bolus impaction, or Ulcers on the tongue; Lesions obvious on stroke (see above). Intermittent dysphagia tonsillar infection/abscess; examination of the oral retropharyngeal abscess cavity suggests esophageal dysmotility syndrome, Tongue ALS webs, or rings. Progressive dysphagia Pallor, koilonychia, Plummer-Vinson syndrome indicates an organic cause such as achalasia, hypochromic microcytic anemia carcinoma, mediastinal expanding lesion, or Mask-like facies, saliva Parkinson’s disease other systemic disorder, e.g. PD, scleroderma drooling from the mouth, tremors, cog-wheel rigidity • The type of bolus that elicits symptoms of Drooping of eyelids, Myasthenia gravis dysphagia may indicate its cause (Table 15.2) diplopia, swallowing becomes more difficult • Odynophagia often accompanies dysphagia in as meal progresses, esophagitis, pharyngitis, opportunistic extreme weakness infections, pill esophagitis, diffuse esopha- Palpable mass medial to Pharyngeal pouch sternomastoid geal spasm, rheumatoid arthritis (inflam- Hoarseness of voice, Mediastinal syndrome, mation of cricoarytenoid joint), or malignant visible neck, goiter, recurrent laryngeal nerve tracheal compression palsy, retrosternal goiter process involving the mucosa Puckered and narrow • Associated signs and symptoms as impor- mouth, inability to open Scleroderma, progressive mouth, thickened-hard-and systemic sclerosis tant clues for possible cause of dysphagia tight skin, Raynaud’s are given in Table 15.3 Phenomenon Dysphagia 103

• The swallow test8—The patient is observed muscles involved in articulation and during the act of swallowing liquids (a few swallowing. Dysarthria, nasal speech, or ounces of water) and solids. Normally a person regurgitation of food into the nose may can drink/chew, mix, and propel a food bolus represent weakness of the soft palate or to the posterior pharynx without chocking or pharyngeal constrictors. The combination of coughing, and no significant amount of hoarseness, dysphonia (difficulty or pain in material is retained after a swallow. Drooling, speaking), and nasal speech accompanying delayed swallow initiation, coughing, throat dysphagia is associated with the muscular clearing, or a change in voice may indicate a dystrophies. Direct laryngoscopy also disorder. After the swallow, the patient is helps to differentiate dysphagia due to observed for a minute or more to see if there is laryngopharyngeal reflux disorder (LPRD)§§, delayed cough response indicating aspiration and GERD (Table 15.4). Laryngopharyngeal • Oropharyngeal examination for ulcers, tonsillar reflux (LPR) and GERD are different disorders. infection, patch on mucosa, movements of the The term LPR is used to describe the acid in tongue, epiglottis, and soft-pallet, as well as the stomach that comes up into the throat at examination of neck for masses, thyromegaly, the level of the laryngopharynx. LPR causes and lymphadenopathy is important. Tongue irritation and changes in the larynx. GERD is fasciculations suggest ALS caused by the backflow of gastric contents • Pharynx and Gag reflex— Does the uvula elevate into the esophagus, which leads to tissue symmetrically when the patient says, “Aah”? damage or esophagitis and heartburn. Does the patient gag when the posterior pharynx is brushed? Unilateral movement of Table 15.4: Difference between GERD and LPRD uvula or total absence of its upward movement, GERD LPRD or gagging indicates palatal muscle due Symptoms to IX and X cranial nerve or brainstem lesion. Mainly supine reflux Mostly daytime, upright Noting the patient’s speech and voice often reflux confirm the oropharyngeal causes of Heartburn and/or Heartburn and/or regurgitation common regurgitation unusual dysphagia. The gag reflex needs to be tested Hoarseness, cough, Hoarseness, cough, only in patients with suspected brainstem dysphagia, globus dysphagia, globus pathology, impaired consciousness, or normally present not usually present impaired swallowing Physical findings • A decreased gag reflex, though commonly Laryngeal inflammation Laryngeal inflammation uncommon common associated with an increased risk of Dysfunction of the lower Dysfunction of the upper aspiration, absence of a gag reflex does not Esophageal esophageal sphincter necessarily indicate that a patient is unable sphincter to swallow safely Test results • Laryngoscopy— Indirect laryngoscopy helps to Normal pharyngeal pH Abnormal pharyngeal pH monitoring monitoring confirm the diagnosis of lesions of Abnormal esophageal pH Usually normal oropharynx, larynx, and hypopharynx. monitoring monitoring esophageal pH Direct laryngoscopy may be indicated to Dysmotility Good gastrointestinal motility evaluate obstructive or neuromuscular Erosive or Barrett’s Erosive or Barrett’s causes of oropharyngeal dysphagia. Changes Esophagus H uncommon esophagus may be present in speech, hoarseness, or a weak cough may represent vocal cord paralysis. Slurred speech §§LPRD is also termed as extraesophageal, reflux disorders, may indicate weakness or incoordination of i.e. EERD. 104 Diagnosis: A Symptom-based Approach in Internal Medicine

• Neurologic examination includes testing of all immunocompromised patient, especially cranial nerves, especially those involved in with HIV infection swallowing (sensory components of cranial • Although patients with dysphagia usually nerves V, IX and X, and motor components of present with a variety of signs and symptoms, cranial nerves V, VII, X, XI and XII) these can be quite subtle or even absent, e.g. in • Associated central nervous system deficits may those with silent aspiration. suggest neuromuscular diagnosis, e.g. evidence of cogwheeling suggests Parkinson’s disease; SELECTIVE GLOSSARY impaired memory indicates Alzheimer’s Amyotrophic lateral sclerosis (ALS)—This is the disease or other dementia; , dementia or most common variety of degenerative motor dysarthria suggests central nervous system neuron disease, with a combination of UMN and disease. LMN signs, although one type may predominate. Virtually all patients with ALS have dysphagia RED FLAGS - the initial complaint is food sticking at the level

• Esophageal dysphagia, e.g. spasm, reflux of the cervical esophagus. Bulbar involvement esophagitis, may mimic angina pectoris in leads lip and tongue weakness, followed by jaw

every respect, including site (retrosternal); and suprahyoid weakness. This, in turn, leads

radiation (neck, jaw, shoulder, thoracic spine, to labial spillage, poor bolus propulsion, poor arm, epigastrium); nature (crushing or laryngeal elevation, depressed gag reflex, and burning); vasovagal symptoms (pallor, poor airway protection. This disorder is sweating, tachycardia); and promptly relieved sometimes associated with dementia or by nitroglycerine, or sublingual nifedipine, as Parkinsonism. in angina pectoris. The crucial historical Barrett’s esophagus—BE is a condition in which differentiating points are—esophageal pain is columnar cells replace the usual squamous cell generally much longer in duration (15-30 in the mucosa of the esophagus. The condition minutes), has no relation to exertion, and ECG is recognized as a complication of GERD or or cardiac enzymes are normal inflammatory disorders of the esophagus. It • In complicated cases, both esophageal and occurs more often in men than in women (3:1 CAD may coexist; hence it is prudent to ratio); with the average age at diagnosis being exclude CAD by more definitive tests such as 55 years. Barrett’s esophagus does not produce barium esophagography, esophageal pH symptoms distinct from GERD or esophageal monitoring, Holter ECG monitoring, or stress inflammation. Most patients complain of thallium myocardial perfusion scintigraphy heartburn pain, indigestion, blood in vomit or • Consider esophageal disease as a possible stool, difficulty in swallowing solid foods, or cause in a patient with recurrent pneumonia; nocturnal regurgitation. Its importance lies in symptoms are often nocturnal due to its predisposition to evolve into adenocar- tracheal aspiration or regurgitation of cinoma in the esophagus. EGD is the procedure esophageal contents of choice for the diagnosis of BE. The diagnosis • A new onset dysphagia may indicate requires biopsy confirmation (from 4 quadrants esophageal cancer, especially in the elderly at standard intervals within the esophagus). • Dysphagia due to recurrent oral/pharyn- Chromoendoscopy, i.e. vital staining with geal ulcers or thrush may indicate an Lugol’s solution performed at the time of upper Dysphagia 105 endoscopy to aid in cancer detection to identify furrows, adherent white plaques, or a friable abnormal mucosa, may be used as a means of (crepe paper) mucosa, prone to tearing with esophageal cancer screening. In patients who minimal contact; or even normal looking are at increased risk for squamous cell esophagus. Frank esophagitis is not part of the carcinoma, the dye stains the glycogen in macroscopic endoscopic picture of eosinophilic normal squamous epithelium a dark brown esophagitis. The most important element in the color. Areas that are unstained, particularly diagnosis of eosinophilic esophagitis is to know those that are larger than 5 mm in size, are its macro- and micromorphological character- likely to be dysplastic or malignant, and can be istics. Biopsies from the proximal to the distal readily targeted for endoscopic biopsy. esophagus demonstrating > 15-20 eosinophilic Dysphagia lusoria—This is caused by a rare granulocytes per high powered field favor the anomaly of the subclavian artery. This artery diagnosis. With increasing recognition, this arises from the aortic arch distal of the left entity is taking its place as an established cause subclavian artery, crossing the midline, behind of solid food dysphagia. the esophagus. This abnormality is generally Progressive systemic sclerosis—Patients with silent and often an incidental X-ray finding, but progressive systemic sclerosis usually present can result in dysphagia, which generally with heartburn, dysphagia, and regurgitation. The appears after the age of 40 years. The diagnosis oral, pharyngeal, and esophageal phages of can be overlooked at endoscopy, but barium swallowing can all be affected. Progressive contrast examination of the esophagus shows a atrophy and fibrosis of esophageal smooth muscle characteristic diagonal impression at the level is usually prominent. Gastroesophageal reflux is of the fourth thoracic vertebra. CT with contrast frequent. Esophageal manometry typically shows study or MR angiography confirm the diagnosis lower pressures and sometimes aperistalsis. Poor and exclude aneurysms. peristalsis, decreased lower esophageal sphincter

Eosinophilic esophagitis—This is an emerging pressures, and gastroesophageal reflux can result in a transition from a patulous dilated esophagus cause of dysphagia, typically seen in young adults. Often, the history of dysphagia dates to to one that is strictured and scarred. Barrett adolescence. In children it is responsible for esophagus may develop. The presence of feeding disorders, vomiting, reflux symptoms oropharyngeal disease is usually accompanied by and abdominal pain, and in adults it causes pulmonary disease. Patients with progressive intermittent solid food dysphagia or food systemic sclerosis may also have xerostomia impaction. The natural history of this disorder (which is frequently due to medications), dental problems (due to fibrosis of the ligamentous tooth has not been well-characterized, but appears to be marked by periods of spontaneous attachments), trigeminal nerve involvement remission and exacerbations that are not linked (decreased bolus sensation), and lingual atrophy to specific factors, although food allergies and that can also contribute to dysphagia. exposure have been implicated. Some have a Schwartz ring (pronounced - shats-ke or schatz·ki’s history of atopy. Endoscopy may reveal a ring)—This is narrowing in the lower part of the number of subtle features that include a esophagus, consisting of a membrane-like ‘corrugated’ esophagus with fine rings; a structure, lined by squamous epithelium on its diffusely narrowed esophagus that may have superior aspect and columnar epithelium proximal strictures; the presence of linear inferiorly. Such a ring is quite common, being 106 Diagnosis: A Symptom-based Approach in Internal Medicine detected in up to 10% of all upper GI barium X- stroke manifested by imbalance, vertigo, rays. Few produce sufficient luminal obstruction difficulty swallowing, hoarseness of voice, and to cause dysphagia. When the lumen is narrowed sensory disturbance. Brainstem stroke is to a diameter of 13 mm or less, the patient will associated with a higher frequency of dysphagia. experience intermittent solid-food dysphagia or This is because the swallowing response control even episodic food-bolus obstruction. center resides primarily in the medulla. These patients often exhibit dysphagia at 1–2 weeks Sjögren’s syndrome (pronounced — “SHOW- after stroke, but can make improvements up to grins”)— SS is a chronic disease, probably due to week 3. Common problems include delayed or auto- immunologic factors with genetic predis- absent swallow response, unilateral pharyngeal position. Viral infections such as Epstein-Barr paresis, and upper esophageal sphincter virus (EBV), human T-lymphotrophic virus 1 dysfunction. VSFS demonstrates a lack of upper (HTLV-1), human herpesvirus 6 (HHV-6), human esophageal sphincter (UES) opening during immunodeficiency virus 1 (HIV-1), hepatitis C swallow in patients with lateral medullary virus (HCV), and cytomegalovirus (CMV) could syndrome, leading to varying degrees of be involved in the induction of SS. Women are aspiration. affected more often than men — the female-to-male ratio is 9:1; usually occurring between 30-50 years. Zenker’s diverticulum—It is also called a pharyn- The hallmark symptoms are the “sicca complex”, goesophageal diverticulum—an outpouching of a combination of dry eyes (keratoconjunctivitis posterior hypopharyngeal wall at an area of sicca—KCS) and dry mouth (xerostomia). SS can potential weakness in the inferior pharyngeal affect the oral phase of swallowing when the constrictor muscle referred to as the Killian salivary glands are involved. The oral dryness of dehiscence (usually at the C5/6 level), seen most SS leads to difficulty swallowing dry food, unless commonly in the elderly, in the seventh or eighth they are washed down with liquids. Patients decade of life. The most common presenting feature with xerostomia have a delayed swallow; some is upper esophageal dysphagia; other common patients will have dysphagia for solids and some symptoms include halitosis, regurgitation of undigested food, noisy swallowing, and may take longer to complete a meal. Abnormal aspiration. Hoarseness can be present when the esophageal motility consists of absent or diverticulum is large enough to compress the decreased contractility in the upper third of the recurrent laryngeal nerve. Some patients also esophagus, while decreased esophageal report excessive salivation and the sensation of a peristalsis can be seen in the distal esophagus. mass within the throat. A very large diverticulum SS occurs in a primary (glandular) form not can produce an external neck mass, usually on associated with other diseases (i.e. KCS and the left side. Weight loss and recurrent pulmonary xerostomia only) and in a secondary infections occur in approximately one-third of (extraglandular) form (i.e. KCS, xerostomia, and patients. There is an association with hiatal an autoimmune disease). Most commonly, this hernia, gastroduodenal ulcer, midesophageal autoimmune disease is RA. The disease is usually diverticulum, esophageal spasm, and achalasia. benign; however, in a few with systemic Fluoroscopic barium esophagography is the involvement, there is increased incidence of non- mainstay of diagnosis of Zenker diverticulum. Hodgkin’s lymphoma. Care must be taken in performing endoscopy in Wallenberg or lateral medullary or posterior patients with known Zenker diverticulum, as inferior cerebellar artery (PICA) syndrome— It passage of the endoscope into the diverticulum is a type of brainstem (medulla and cerebellum) carries some risk of perforation. Dysphagia 107

REFERENCES 5. Boyce HW. Dysphagia and odynophagia. In: Weinstein WM, Hawkey CJ, Bosch J. Editors. 1. Deary, et al. Convert psychiatric disturbances in Clinical Gastroenterology and Hepatology, Part patients with globus pharyngis; Br J Med Psychol I, Chapter 3, p.12. Mosby Elsevier,2005. 1989;62 (Pt 4):381-9. [PMID: 2597654] 6. Karthik Ravi, et al. New technologies to evaluate 2. Wilkins, et al. The Prevalence of Dysphagia in esophageal function. Expert Review of Medical Primary Care Patients: A HamesNet Research Devices, Vol. 4, No.6, 2007;829-37(9). Network Study; J Am Board Fam Med 2007;20: 7. Mariani G, et al. Radionuclide gastroesophageal 144-50. [PMID: 17341750]. motor studies.J Nucl Med 2004;45(6):1004- 3. Yan BM, et al. Eosinophilic esophagitis: A newly 28.[PMID: 15181137]. established cause of dysphagia; World J of 8. Kaor N, et al. Identification of a simple Gastroenterology 2006;12(15):2328-34. [PMID: screening tool for dysphagia in patients with 16688820]. stroke using factor analysis of multiple 4. Farnoosh F, et al. Idiopathic (primary) achalasia. dysphagia variables. J of Rehabilitation Med Orphanet J Rare Dis 2007;2:38. [PMID: Vol.37, Issue 4 July 2005,247–51. [PMID: 17894899]. 16024482]. CHAPTER 16 Dyspnea—Acute

SYNOPSIS point of view), patient with acute dyspnea experiences abnormally uncomfortable aware- Literally the term dyspnea means difficult breathing. ness of breathing, which is accompanied by Clinically, dyspnea is a term applied to sensations objective findings such as tachypnea, increased experienced by individuals who complain of unpleasant or uncomfortable respiratory sensations. respiratory effort, distress, and even altered The sensation of dyspnea is subjective*, and mental status. The patient in such an attack of includes both the perception of labored breathing acute dyspnea is classified as belonging to class III by the patient and the reaction to that sensation,1,2 or class IV gradation based on New York Heart which varies in quality and intensity. A recent Association classification; i.e. dyspnea on minimal consensus statement from the American Thoracic exertion or dyspnea at rest respectively. † Society offered the following definition of dyspnea: Acute dyspnea is a cardinal symptom affecting “Dyspnea is a term used to characterize a subjective the cardiopulmonary system, and can be a sign of experience of breathing discomfort that is potentially fatal illness (e.g. MI and pulmonary comprised of qualitatively distinct sensations that embolism); hence all reasonable methods should be vary in intensity. The experience derives from used to distinguish between cardiac and pulmonary interactions among multiple physiological, causes of dyspnea as rapidly as possible, so as to psychological, social and environmental factors, improve outcomes and patient survival. and may induce secondary physiological and behavioral responses.3 DIFFERENTIAL DIAGNOSIS A person with dyspnea may describe this Common symptom in terms such as shortness of breath, breathlessness, chocking sensation, or tightness • Status asthmaticus in the chest. Subjectively (i.e. from the patient’s • Acute exacerbation of COPD

*Like pain, dyspnea is a sensory experience that is †Acute dyspnea may be considered as ‘sudden’, i.e. perceived, interpreted, and rated solely by the patient within seconds to minutes, and ‘acute’, i.e. within hours himself. to days. Dyspnea—Acute 109

• Pneumonia (especially in immunocom- Peak Expiratory Flow Rate (PEFR) promised or immunodeficiency patients • Reduced flow rate of < 150 l/mit (normal such as HIV disease and alcoholics) value 400-600 l/mit) indicates obstructive • Acute laryngotracheobronchitis (Croup) pulmonary disease that may require • Acute LVF (due to MI, pericarditis, cardiac hospitalization; its complete reversibility tamponade, fulminant myocarditis) is diagnostic of asthma. • Arrhythmias (VT, AF, VF) • Psychogenic (hyperventilation syndrome). ECG • Although in most dyspneic patients the ECG Occasional does not contribute much to diagnosis, it does indicate whether heart disease of any • Spontaneous or tension pneumothorax disorder is present, such as cardiac ischemia, • Massive pleural effusion (tubercular, malignant) arrhythmia, chamber hypertrophy, and • Massive lobar collapse (traumatic, post- heart block. These cardiac disorders can operative) contribute to acute dyspnea. Also, lung disease • Massive pulmonary embolism(PE) eventually affects right side of the heart, and • Metabolic acidosis (DKA, uremia, salicylate may cause changes suggesting lung disease overdose) such as right atrial or right ventricular • Anaphylaxis (angioneurotic edema) hypertrophy in pulmonary hypertension • Severe acute respiratory syndrome (SARS). • The complex of an S wave in lead I, a Q wave in Rare III, and an inverted T wave in lead III is specific • Foreign body aspiration for pulmonary embolism, but rarely seen. • Drug induced (NSAIDs, beta blockers) CXR • Acute respiratory distress syndrome (ARDS) • Can demonstrate consolidation, infiltrate, • Neurologic (CVA, Guillain-Barré syndrome, effusion, pneumothorax, bullae, pulmonary Bulbar polio) edema, tumor, and cardiomegaly • Pacemaker syndrome. • In pulmonary embolism, the CXR is usually normal, but abnormalities include focal INVESTIGATIONS—GENERAL oligemia (i.e. Westermark’s sign); a peripheral CBC wedge shaped density (i.e. Hampton’s hump); pleural effusions; elevated hemidiaphragm; • Anemia aggravates dyspnea of any etiology or an enlarged right descending pulmonary • WBC count may be increased in pulmonary artery (i.e. Palla’s sign). infection • Significant eosinophilia is commonly X-ray Neck — Lateral View reported in asthma • May be indicated in patients with stridor, • Thrombocytopenia may accompany ARDS. e.g. to exclude obstructive lesion or foreign body aspiration. Blood Glucose, Electrolytes, Urinalysis Pulse Oximetry • To exclude hyperglycemia, and DKA • Renal and electrolyte abnormalities can • Used as a rapid method for assessment of precipitate acute dyspnea. oxygenation; of <90% on pulse 110 Diagnosis: A Symptom-based Approach in Internal Medicine

oximetry indicates further ABG estimation D-dimer for precise evaluation of dyspnea. • This is useful in determining risk for DVT or PE. Sr Cardiac Markers

• Cardiac troponin and CK-MB is elevated HRCT of Thorax with MI in the setting of acute LVF. • Spiral CT scanning of the chest with iodinated contrast is gradually replacing INVESTIGATIONS—SPECIFIC ventilation-perfusion lung scanning as the Sputum and Blood Culture screening procedure of choice for the diagnosis of pulmonary embolic disease • They are of value when infective etiology such • V/Q scans are recommended only if spiral as pneumonia, lung abscess is suspected. In an CT is not available acutely dyspneic patient the value of sputum • MR angiograms are recommended as a first examination depends on the production of line investigation only if spiral CT is uncontaminated sputum sample. contraindicated.

Pulmonary Function Tests V/Q scan

• Spirometry—With increasing airflow • V/Q scan should be used in cases where results limitation, FEV1 falls proportionately more than of HRCT are inconclusive, which may the FVC, so that the FEV1 / FVC ratio is reduced. necessitate the use of pulmonary angiography.

Arterial Blood Gases (ABG) BNP (Brain or B-type Natriuretic Peptide)

• Useful in assessing the type, degree of • This test is useful to evaluate for the presence respiratory failure, and measuring the of CHF in patients with dyspnea. A low value overall acid-base status (<80 pg/ml) has a high (99%) negative

• An increased pH with decreased pCO2 predictive value that helps to rule out CHF; indicates acute respiratory alkalosis, whereas a high value (>100 pg/ml) is nonspecific, but both decreased pH and bicarbonates indicate is about 90% sensitive for CHF. metabolic acidosis, such as due to DKA. However, normal levels of oxygenation are Echocardiography not useful to exclude respiratory or cardiac • This procedure is indicated if CHF, valvular diseases causing acute dyspnea. heart disease, or pericardial effusion is suspected. It also helps to identify an Bronchoscopy embolus in suspected PE. Pulmonary artery • It should be performed if aspiration of pressure can also be estimated to rule out foreign body is suspected; the procedure can pulmonary hypertension causing dyspnea. be both diagnostic and therapeutic. Drug Screen • It also allows collection of bronchial secretions for bacteriological/cytological • Serum levels of salicylates and other drugs examination. (e.g. Amiodarone) suspected to be responsible. Dyspnea—Acute 111

CLINICAL NOTES the objective finding of a rapid respiratory rate and may or may not be associated with • In an acutely dyspneic patient it is important the feeling of not being able to breathe to ensure that the Airway, Breathing, properly; tachypnea may be necessary for a Circulation (ABC) are attended to before sufficient gas-exchange of the body, for continuing with the diagnostic process. Life- example after exercise, in which case it is threatening problems must be excluded during initial examination (Table 16.1). The following not hyperventilation. Hyperventilation (or checklist of questions is useful in practice: overbreathing) is an increase in the respiratory rate above normal — a state of breathing faster and/or deeper than Table 16.1: Life-threatening causes of dyspnea necessary, thereby reducing the carbon • Myocardial infarction • Ventricular tachycardia dioxide concentration of the blood below • Status asthmaticus normal. These conditions may not always • Pulmonary embolism be associated with dyspnea. is the • Tension pneumothorax • Anaphylactic laryngeal edema sensation of breathlessness in the recumbent • Airway obstruction position, relieved by sitting or standing. Two • Diabetic ketoacidosis • Guillain-Barré syndrome uncommon types of breathlessness are • Carbon monoxide poisoning and . Trepopnea is • Salicylate poisoning dyspnea that occurs in one lateral decubitus position as opposed to the other (e.g. in  Is it dyspnea or a condition stimulating patients with unilateral lobectomy, it? pneumonectomy). Platypnea refers to  Is it due to cardiac dysfunction? breathlessness that occurs in the upright  Is it due to pulmonary dysfunction? position and is relieved with recumbency  If cardiac, what is the grade of dyspnea? (e.g. hepatopulmonary syndrome, cardiac  Is there PND or orthopnea? shunt — Tetralogies of Fallot)  Is the patient receiving drugs; if so what is the response? • Although the diagnosis of hyperventilation  What are the associated symptoms? syndrome is suggested by associated • Once an emergent situation has been excluded, symptoms of panic and anxiety, or frequent reassess the patient’s airways, mental status, sighing, it is wise to exclude cardiopulmo- ability to speak, and breathing effort, and nary diagnosis before arriving at this question the patient (or a family member) diagnosis about duration of the dyspnea, any underlying • Differentiation between bronchial asthma cardiac or pulmonary disease, medication use, and cardiac asthma is critical (Table 16.2). cough, fever, chest pain, and trauma However, both cardiac and pulmonary • Dyspnea should be differentiated from disease and/or disorders of different systems tachypnea and hyperventilation which refer may coexist in the same patient; e.g. LVF and to respiratory variations regardless of the COPD, pneumonitis and ARDS, respiratory patient’s subjective sensations. Tachypnea is muscle paralysis and aspiration pneumonia 112 Diagnosis: A Symptom-based Approach in Internal Medicine

Table 16.2: Clinical differentiation between cardiac and especially in the evaluation of a new patient. bronchial asthma For example, use of an inhaler would point Points Cardiac asthma Bronchial to a possible history of asthma or COPD. If asthma patient is taking furosemide he may have a Age Usually elderly Any age history of CHF or older • Angioedema, characterized by facial, Past history CAD, hypertension Previous attacks valvular disease of asthma, atopy extremity, and airway edema, may cause Family history Usually non- Generally difficulty breathing, and is a possible adverse contributing positive effect seen in patients who begin taking an Precipitating Exertion, Exposure to factors infraction allergens ACE inhibitor such as captopril Symptoms Cough, frothy Cough, thick • Cardiac tamponade related to trauma or HIV expectoration stick sputum; is more common in young adults, whereas prominent; wheezing wheezing not marked tamponade due to malignancy and/or renal marked failure occurs more frequently in elderly Pulse Rapid; pulses Rapid; may individuals alternans may be be feeble in present severe/ • A diagnostic strategy that combines a high prolonged degree of clinical suspicion; careful evaluation asthma; no pulses alternans of historical and clinical findings (e.g. dyspnea, Auscultation Triple rhythm, Normal heart pleuritic chest pain, tachypnea, and murmurs, sounds tachycardia); risk factors for venous pericardial rub thromboembolism (e.g. recent surgery or Breath sounds Expiration not Expiration prolonged, basal markedly immobilization, stroke, CHF, cancer, fracture crepts prominent prolonged; of the pelvis, femur or tibia, obesity, wheezing all pregnancy or recent delivery; estrogen over chest therapy; inflammatory bowel disease, and • Intensity of wheezing is unreliable. Some various genetic or acquired thrombophilia); patients with asthma do not wheeze and and corroborative findings from noninvasive some who wheeze do not have asthma diagnostic techniques (e.g. D-dimer, HTCT of • The presence of orthopnea or paroxysmal lungs) can improve diagnostic accuracy of nocturnal dyspnea (PND) is more suggestive PE. However, many cases of PE are indeed of cardiac failure than of lung disease clinically silent • Deep ‘sighing’ respiration (Kussmaul • Physical examination— Common physical respiration, air hunger) of acidosis, usually findings are listed in Table 16.3. seen in diabetic and uremic patients, or Cheyne-Stokes respiration (periodic RED FLAGS breathing), usually seen in cerebrovascular • Respiratory rate over 30/mit, pulse rate over disease, or poisoning, should not be 120/mit, and pulsus paradoxus greater than mistaken for acute dyspnea 18 mm Hg indicate a dangerously severe • Subcutaneous emphysema should raise episode of dyspnea suspicion of associated pneumothorax. • Dyspnea at rest, orthopnea, sweating, and • A review of medications may provide useful difficulty speaking in sentences, use of clues to the possible cause of the dyspnea, accessory muscles of respiration, decreased Dyspnea—Acute 113

Table 16.3: Physical examination findings in the mental status or consciousness indicate a diagnosis of acute dyspnea in adults and children life-threatening situation and constitute an Findings Possible diagnosis indication for urgent intubation • In a case of asthma, absence of wheezing , wheezing, pulsus paradoxus, Acute asthma, COPD accessory muscle use exacerbation (silent chest) or decreased wheezing can Wheezing, clubbing, barrel chest, COPD exacerbation indicate worsening obstruction decreased breath sounds • No single noninvasive test or clinical Fever, localized crepts, increased Pneumonia evaluation can definitively point to a diagnosis of PE, and this frequently missed Edema, JVP, S3 or S4, gallop rhythm, CHF, LVF hepatojugular reflux, murmurs, diagnosis may have fatal consequences basal crepts, hypertension • Cardiac tamponade is a medical emergency. Beck triad-distended JVP, Cardiac tamponade hypotension, muffled heart sounds Early diagnosis and treatment are crucial to Pulsus paradoxus, pericardial rub Cardiac tamponade, severe reduce morbidity and mortality. Untreated, asthma it is rapidly and universally fatal. Chest pain, localized crepts, friction DVT, pulmonary embolism rub, edema feet, calf swelling, REFERENCES recent child delivery Absent breath sounds, hyper Pneumothorax 1. Martinez-Moragon E, et al. Asthma patients’ resonance perception of dyspnea during acute bronchocon- Trauma, surgery, shock ARDS striction. Aech Bronconeumol 2003;39(2):67- Inspiratory stridor, rhonchi, Acute laryngo- 73.[ PMID: 12586046: Abstract]. retractions tracheobronchitis (Croup) 2. Bijl-Hofland ID, et al. Relation of the perception Stridor, drooling, fever Epiglottitis of airway obstruction to the severity of asthma. Stridor, wheezing, persistent Foreign body aspiration Thorax. 1999;54(1):15-19. [PMID: 10343625: pneumonia Abstract]. Wheezing, flaring, intercostal Bronchiolitis 3. Dyspnea. Mechanisms, Assessment, and Manage- retractions, apnea ment: A Consensus statement. American Thoracic Sighing Acidosis, hyperventilation Society. (1999). Am J Respir Crit Care Med; 159, 321-40. [PMID: 9872857: Free full text] CHAPTER 17 Dyspnea—Chronic

SYNOPSIS capacity. Although there are many tests or protocols developed to assess individual’s Breathlessness that persists for more than a functional capacity, they are prone for month may be termed as chronic dyspnea. This subjective errors by either overestimating or symptom is present in many different illnesses. underesti-mating their true functional Fortunately, only a few disorders are seen in capacity. Therefore the American Thoracic practice; therefore, a logical and time saving first Society (ATS) has issued standardized step is to do a rapid assessment of the patient’s guidelines for the 6-minute walk test (6MWT: vide general level of distress and vital signs to infra ↓↓), which is safe, easier to administer, exclude the causes for acute dyspnea.* The next better tolerated, and better reflects functional step is to evaluate the patient for the possible cardiopulmonary status and activities of daily causes of chronic dyspnea. living.1-5 A patient with chronic dyspnea may present with any of the following four grades based on DIFFERENTIAL DIAGNOSIS New York Heart Association classification: • Class I – Disease present but no dyspnea or Common dyspnea only on heavy exertion • Asthma • Class II – Dyspnea on moderate exertion • COPD (chronic bronchitis, emphysema) • Class III – Dyspnea on minimal exertion • CHF • Class IV – Dyspnea at rest. • IHD (angina: stable, unstable) It is more useful, however, to determine the • Postnasal drip syndrome amount of exertion that actually causes • GERD dyspnea, i.e. the distance walked, or the number • Morbid obesity (rapid weight gain) of steps climbed to assess the functional • Sedentary lifestyle (physical deconditio- ning) * Ref: Chapter 16: Dyspnea—Acute. • Psychogenic (GAD, PTSD, panic disorder). Dyspnea—Chronic 115

Occasional stain for Pneumocystis carinii pneumonia may be useful. • Anemia (chronic) • Bronchiectasis CXR • Pleural effusion (bacterial, malignant) • This can demonstrate effusion, pneumothorax, • Interstitial lung diseases (i.e. ILD, sarcoidosis, and cardiomegaly, signs of CHF, fibrosis, pneumoconiosis) tumor, or hilar lymphadenopathy • Valvular heart diseases (mitral stenosis, • In ILDs it may demonstrate a linear aortic stenosis, ASD, VSD) fibronodular, or fibroreticular infiltrate • Cardiac arrhythmias (AF) • In COPD such as chronic bronchitis and • Recurrent pulmonary embolism emphysema, signs of hyperinflation of the • Upper airway obstruction (foreign body, lungs, tapering vascular shadows, and tonsillar obstruction, vocal cord paralysis, bullous changes may be seen. external compression, tracheal tumors) Pulse Oximetry • Lung cancer (primary, metastatic). • Useful method for rapid assessment of Rare oxygenation. In severe COPD, ILDs, desatu-

• Pulmonary hypertension (usually secon- ration at rest with values of SPO2 less than dary to COPD, ILD) 90% is a sensitive indicator of gas exchange • Intracardiac shunts abnormalities. If abnormal, consideration • Cadiomyopathies should be given to obtaining arterial blood • Pericardial disease gas measurements. • Severe kyphoscoliosis ECG • Drug induced (cytotoxic agents, amiodarone, • In almost all forms of chronic pulmonary nitrofurantoin, gold) disease, ECG may show right axis deviation, • Neuromuscular diseases (Guillain-Barré right ventricular enlargement and strain, syndrome, myasthenia gravis, amyotrophic right atrial enlargement, atrial arrhythmias. lateral sclerosis, i.e. ALS). RBBB may occur in long-standing lung disease. Evidence of left ventricular disease INVESTIGATIONS—GENERAL (ischemia, hypertrophy), pericardial disease CBC may be seen in chronic left sided heart failure • Low Hb% and hematocrit values are • Sinus tachycardia is frequent in sever features of anemia anemia and thyrotoxicosis. • Leukocytosis may be seen in superadded pulmonary infection Metabolic Panel • Erythrocytosis may be seen with any chronic pulmonary or cardiac cause of • Changes in acid-base balance reflected by the chronic dyspnea bicarbonate level in a metabolic panel may • Eosinophilia may be seen in chronic asthma. provide a clue to dyspnea. In severe chronic lung diseases such as COPD, asthma, ILDs, Sputum neuromuscular disorders with , • Gram stain for pneumococcal pneumonia; the serum bicarbonate level may be increased ZN stain for mycobacteria; and Giemsa’s • Dilution hyponatremia may be seen in CHF. 116 Diagnosis: A Symptom-based Approach in Internal Medicine

Blood Chemistry Table 17.1: Diseases commonly associated with restrictive and obstructive lung diseases • Sr creatinine, and urea will often be found to be high in patients with severe anemia; and Restrictive breathing pattern Obstruction to airflow Intrinsic lung disease Lower airway obstruction presence of albuminurea, especially when Pneumonia Asthma associated with hypertension CHF Chronic bronchitis Pleural effusion and pleural COPD • Sr calcium value may be elevated in sarcoidosis. disease Emphysema Advanced malignancy Cystic fibrosis Lung fibrosis INVESTIGATIONS—SPECIFIC Sarcoidosis Acute respiratory failure External compression of bronchus PFT/Spirometry with pulmonary edema Lymph nodes, mediastinal Hyaline membrane disease mass, vascular aneurysm Collagen vascular disease • Formal spirometry differentiates restrictive Drugs: chemotherapeutics † and obstructive lung disorders (Table 17.1). Occupational toxic exposure Upper airway obstruction Lung transplant Laryngotracheobronchitis It can also provide information regarding CNS causes Epiglottitis severity of the disease and response to Guillain-Barré syndrome Foreign body Myasthenia gravis Bronchial stricture inhaled bronchodilators. Other measure- Poliomyelitis ments and lung volumes, and diffusion Diaphragm paralysis Others Others Alpha-1 antitrypsin capacities such as forced vital capacity (FVC), Morbid obesity deficiency forced expiratory volume in 1 second (FEV1), Flail chest Kartagener’s syndrome Spinal deformity Bronchomalacia total lung capacity (TLC), residual volume (RV), and diffusion capacity of lung for carbon monoxide (DLCO) are useful in B-type Natriuretic Peptide (BNP) differentiating various pulmonary and • Plasma BNP, a neurohormone, its major cardiac causes of dyspnea. However, results source is cardiac ventricles, suggesting that of spirometry need to be evaluated in relation BNP may be a more sensitive and specific 6,7 to reference values. indicator of ventricular disorders than other natriuretic peptides.It is released in response Methacholine Challenge Test to pressure/volume overload, resulting in • This test is used if the symptoms of dyspnea increased wall tension. The magnitude of are intermittent, or lung disease is suspected elevation is proportional to the severity of and PFTs are normal. heart failure. BNP test may be helpful, especially in patients who have coexisting Echocardiography cardiac and pulmonary disease, and are found to be very reliable in differentiating • Indicated in patients with cardiac causes of CHF from pulmonary disease.8-10 chronic dyspnea, especially if heart failure is suspected. Other indications include HRCT cardiac valvular dysfunction, pulmonary hypertension, and pericardial disease. • HRCT is especially helpful in diagnosing unsuspected ILD. It is the preferred test for diagnosing bronchiectasis, and can identify † The two breathing patterns frequently are seen together both acute and chronic PE, particularly in in one disease. larger vessels. Dyspnea—Chronic 117

HRCT Angiography Cardiopulmonary Exercise Testing (CPEx)

• Conventional pulmonary angiography is • This procedure helps quantify cardiac currently replaced by HRCT angiography, function, pulmonary gas exchange, venti- which has better sensitivity and specificity lation, and physical fitness. It is especially in patients presenting with isolated or useful in cases where no apparent cause for chronic dyspnea.11,12 dyspnea is found after a thorough evaluation or in patients who have multiple potential V/Q Scan causes for dyspnea. Parameters that are measured by computerized systems are • Unlike in acute massive PE wherein V/Q blood pressure, electrocardiography, heart scan usually shows major areas of decreased rate, ventilation, oxygen saturation, oxygen perfusion diagnostic of PE, this investigation uptake, and carbon dioxide output. In normal in chronic PE may show no abnormality. individuals, pulmonary capacity is greater Most V/Q scans revert to normal after 24 than cardiac. By determining the function of hours of the episode. both the cardiac and pulmonary systems, the relative degree of impairment can be used 24-hour Esophageal pH Monitoring to guide therapy. • GERD may be clinically silent, except for the symptoms of dyspnea and may require Bronchoscopy / Lung Biopsy ambulatory esophageal monitoring to confirm • Lung biopsy may be indicated in cases of the diagnosis. Studies have identified an ILD that are difficult to diagnose or when association between gastroesophageal reflux malignancy is suspected. and chronic dyspnea despite normal pulmo- nary function tests. Reflux may stimulate vagal CLINICAL NOTES reflexes that inhibit diaphragmatic function, thereby causing breathlessness. This etiology • The first step in the evaluation of patients with can be established by performing a 24-hour pH chronic dyspnea is to establish the primary monitoring. organ/system involved – pulmonary, cardiac, both, or neither EMG and NCS • Specific questions regarding change in weight, • These tests are useful for confirming and exercise habits, occupational exposures, differentiating such asthmatic triggers, cardiac risk factors as Guillain-Barré syndrome and myasthenia (diabetes, hyperlipidemia, hypertension, and gravis. tobacco abuse) psychiatric history, sources of stress and anxiety, or symptoms of GERD Noninvasive Cardiovascular Testing should be asked • In some patients with coronary artery disease, • History of connective tissue disorders such dyspnea may represent an anginal equivalent. as rheumatoid arthritis, polymyositis, and Noninvasive cardiovascular testing (e.g. stress scleroderma is suggestive of ILDs causing thallium, stress echocardiography, cardiac chronic dyspnea magnetic resonance imaging) and/or cardiac • History of endotracheal intubation, tracheo- catheterization should be considered for these stomy is suggestive of upper airway obs- patients. truction causing dyspnea 118 Diagnosis: A Symptom-based Approach in Internal Medicine

• In a patient with history of chronic, episodic • Chronic cough/dyspnea are commonly dyspnea with superficial/hilar lymphade- treated as ‘allergic’, which could have been nopathy, arthralgia, cutaneous nodules, and due to ILDs raised serum calcium is suggestive of sarcoidosis • Chronic dyspnea may present as an acute • Progressive dyspnea may be the initial event; e.g. acute LVF in CHF; pneumothorax manifestation of carcinoma of lung, breast, in chronic asthmatic; pulmonary embolism stomach, prostate, or other organs in valvular heart disease • Common physical findings are listed in • ILDs may present with minimal physical Table 17.2. signs or CXR findings, especially in early

Table 17.2: Clinical findings and causes of chronic dyspnea stages, despite the presence of significant dyspnea Clinical findings Cause • The presence of COPD doubles the risk of lung Intermittent breathlessness; prolonged expiration; wheezing; Asthma cancer in smokers, independent of their atopy; triggering factors smoking history.13,14 Tobacco abuse; barrel chest; COPD prolonged expiration; wheezing Orthopnea; PND; JVP; SELECTIVE GLOSSARY pedal edema; S3; CHF basilar crepts; hypertension; Six-minute walk test (6MWT)—The ability to CAD;DM Panic disorder; GAD; PTSD; Psychogenic walk for a distance is an easy way to measure Postprandial dyspnea GORD exercise capacity in patients with cardiac and Decreased or absent breath Pleural effusion; Pneumothorax pulmonary diseases. A variety of walk tests, sounds Hemoptysis Lung malignancy; pneumonia; Bronchiectasis; mitral stenosis; including self-paced walk tests, controlled- Arteriovenous malformation pacing incremental walk tests, and time-paced Recurrent pneumonia Lung malignancy; bronchiectasis; Foreign body tests are considered to be objective measure- Accentuated P2; right ventricular Pulmonary hypertension ments of functional capacity. The 6MWT is an heave; Murmur objective, submaximal exercise test method, Exposure to organic dust Pneumoconiosis History of immunosuppressive P. carinii pneumonia; TB; fungal used as a clinical indicator of the functional disease or therapy; AIDS capacity in patients with moderately severe History of intubation; tracheos- Upper airway obstructive disease impaired cardiopulmonary diseases such as tomy Drug exposure B-Blokers causing bronchospasm; Amiodarone / nitrofurantoin COPD, ILD, pulmonary hypertension, heart causing pneumonitis; failure, and peripheral arterial diseases, and methotrexate causing lung fibrosis ability to perform daily living activities. It is also performed to monitor therapy, or assess RED FLAGS the prognosis in patients with cardiac and • Dyspnea in older people may be associated pulmonary diseases. With 6MWT the instruc- with disease in a single or more likely tions to the patient are to “walk as far as you multiple organs can during 6-minutes” on a level and straight • The common causes of dyspnea are frequently track; and not an oval or circular track. The new over diagnosed when a less common cause of ATS guidelines provide a standardized dyspnea is actually present; e.g. dyspnea in approach for performing the test. In comparison an elderly smoker is commonly diagnosed as to traditional pulmonary exercise test, 6MWT bronchitis (smoker’s cough), which could needs less technical support or equipment, have been due to lung carcinoma making it a simple and inexpensive method to Dyspnea—Chronic 119 measure functional capacity. The six minute Thoracic Society. Am Rev Respir Dis 1991; 144(5):1202-18. [PMID: 1952453]. walk distance (6MWD) can be correlated with 7. Aggarwal AN, et al. Comparison of Indian patient’s height, BMI, Borg scale, spirometric reference equations for spirometry interpret- parameters and diffusion capacity. Absolute ation. Respirilogy 2007;12(5):763-8. [PMID: 17875069]. contraindications to the test include an history 8. Yap LB, et al. Natriuretic peptides, respiratory of unstable angina or MI during the previous disease, and the right heart. Chest 2004; month; relative contraindications include 126(4):1330-6. [PMID: 15486400: Free full text]. 9. Tsuchida K, et al. Plasma brain natriuretic peptide resting tachycardia (heart rate >120/mit), concentrations and the risk of cardiovascular uncontrolled hypertension, or arthritis and events and death in general practice. J Cardiol other musculoskeletal disease. 2008;52(3):212-23. Epub 2008 Aug 26. [PMID: 19027599: Abstract]. 10. Sirithunyanont C, et al. Role of the plasma brain REFERENCES natriuretic peptide in differentiating patients with congestive heart failure from other diseases. J 1. Enright PL. Respiratory Care: The Six-minute Med Assoc Thai 2003;86 Suppl 1:S87-95. [PMID: Walk Test. 2003;48(8):783-5. 12866774: Abstract]. 2. Al Ameri HF. Six minutes walk test in respiratory 11. Kontrus M, et al. Spiral-CT [corrected] in chronic diseases: A university hospital experience. Ann lung thromboembolism. Radiologe 1996 Jun; Thorac Med 2006;1:16-19. 36(6):496-502. Erratum in: Radiologe 1996; 3. Kervio G, et al. Intensity and daily reliability of 36(8):645. [PMID: 8767120: Abstract]. the six-minutes walk test in moderate chronic heart 12. Remy-Jardin M, Remy J. Spiral CT angiography failure patients. Arch Phys Med Rehabil 2004; of the pulmonary circulation. Radiology 1999; 85(9):1513-8. [PMID: 15375827]. 212(3):615-36. [PMID: 10478224: Abstract]. 4. Pereira de Sousa LA, et al. Six-minute Walk Test 13. Singh RB, et al. Tobacco consumption in relation in Patients with Permanent Cardiac Pacemakers. to causes of death in an urban population of north Cardiopulm Rehabil Prev 2008;28(4):253-7. India. Int J Chron Obstruct Pulmon Dis 2007; [PMID: 18628656: Abstract]. 2(2):177-85. [PMID: 18044690: Abstract]. 5. Roul G, et al. Does the 6-minute walk test predict 14. Woloshin S, et al. The risk of death by age, sex, the prognosis in patients with NYHA class II or III and smoking status in the United States: Putting chronic heart failure? Am Heart J 1998;136(3):449- health risks in context. J Natl Cancer Inst 2008 Jun 57. [PMID: 9736136: Abstract]. 18; 100(12):845-53. Epub 2008 Jun 10. Erratum in: 6. Lung function testing: Selection of reference J Natl Cancer Inst 2008;100(16):1133. [PMID: values and interpretative strategies. American 18544745: Abstract]. CHAPTER Facial Asymmetry 18 and Weakness

SYNOPSIS From therapeutic and prognostic point of view, it is critical to differentiate this peripheral Careful studies have shown that mild to (i.e. nuclear) nerve palsy from the central (i.e. moderate facial asymmetry is, in fact, the norm. supranuclear) lesions of the CN VII; the latter On average, both men and women have right manifests only in the lower divisions of the hemi-face dominance. This normal asymmetry seventh nerve because of the bilateral cortical is usually not prominent on visual scrutiny. representation. Thus, a central CN VII (upper Facial asymmetry is said to exist only when the motor neuron, i.e. UMN) lesion involves only asymmetry exceeds the balance that we accept the lower face (i.e. upper half escapes), while the as normal.1,2 usually benign and self-limited peripheral Symmetry of the face (i.e. facial configuration in (lower motor neuron, i.e. LMN) lesion affects the general) depends primarily on the functional entire half of the face on the affected side. Besides integrity of its muscles, and the movement of these the UMN and the LMN facial nerve palsy, facial facial muscles of each side is controlled by the seventh weakness and asymmetry is also seen in muscle cranial nerve (CN VII).* If both (i.e. right and left) or neuromuscular junction disorders. facial tracts are intact from the cortex (center) to the Patient with obvious facial asymmetry or periphery, the muscles will move symmetrically. weakness, besides disfigurement, suffer from Hence, any lesion in the course of its central and/or impaired function such as difficulty with speech peripheral pathway mainly manifests as weakness and eating. A less obvious but often of grave or asymmetry of facial muscles.† concern is the inability to express emotion on the affected side. This loss of nonverbal emotional * Most of the present discussion about facial asymmetry is related to acquired disorders of CN VII palsy. For facial communication (e.g. patient cannot register asymmetry not due to facial nerve palsy, refer to Page no. pleasure, laughter, surprise, interest and worry; 125, Table 18.5: Differential diagnosis of altered facial counter. the patient tends to sit with hand over the † Taste sensation in the anterior part of the tongue may affected side of face) can be extremely bothersome also be affected. 121 and may even lead to social isolation. Therefore, INVESTIGATIONS—GENERAL in order to minimize the potential for neurological CBC damage, its possible recurrence, and social • Leukocytosis in infection. implications, it is imperative that the diagnosis • May be helpful to rule out lymphoproliferative of the cause for facial asymmetry (Table 18.5) malignancies such as lymphocytic leukemia, and weakness be established quickly. the initial manifestation of which may be DIFFERENTIAL DIAGNOSIS peripheral facial palsy.

Common Blood Glucose

• Bell’s palsy (HSV-1,CMV, EBV, rubella, and • To evaluate for diabetes mellitus. mumps) • Cerebrovascular accidents (stroke) VDRL • CNS infections (bacterial, TB, abscess, • Indicated in neurosyphilis. malignant otitis media) • CNS tumors (posterior fossa tumors, CXR acoustic neuroma) • To exclude sarcoidosis or to rule out TB in • Diabetic neuropathy selected patients before treating with steroids. • Head trauma (fractures of the temporal bone). Occasional INVESTIGATIONS—SPECIFIC • Ramsay Hunt syndrome CT Skull • Guillain-Barré syndrome (GBS) • CT scan of the temporal bone for evidence of • Infections (HIV, cerebral malaria, Lyme temporal bone fracture. disease, chickenpox) • Associated anomalies of the external ear, • Tumors invading temporal bone (cholestea- middle ear, inner ear, etc. can be assessed. toma). MRI with Gadolinium Rare • Generally indicated in patients with • Infections (tetanus, leprosy, poliomyelitis, atypical features such as: diphtheria)  Hearing loss • Multiple sclerosis (MS)  Multiple cranial nerve deficit • Myasthenia gravis  Signs of limb paresis or sensory loss • Motor neuron disease  Lesion suggesting a posterior fossa lesion • Sarcoidosis as the cause of CN VII palsy  • Metastasis to temporal bone (from carci- To exclude neoplasms, stroke, MS, or other structural lesions. noma breast, bronchus, prostate) • Neoplasm of base of the skull or parotid gland CSF • Carcinomatous or leukemic meningitis • Indicated only in inflammation, granuloma, • Surgery of mastoid, parotid or malignancy is a consideration. • Melkersson-Rosenthal syndrome (MRS: vide • A mild pleocytosis of the CSF may be seen in infra ↓↓). Bell’s palsy. 122 Diagnosis: A Symptom-based Approach in Internal Medicine

EMG/NCS • When suspecting lyme disease in the absence of • To predict recovery, but not needed for diagnosis; skin lesions (erythema migrans), ask about travel most informative when at least three weeks and residence history, and carefully review have elapsed after the onset of facial palsy. other signs and symptoms (fever, arthralgia, lymphadenopathy, neuropathy, etc.) Lyme Titer • Associated symptoms such as hyperacusis, deafness, and abnormality of taste, salivation, • Lyme disease serology, i.e. enzyme immuno- and facial pain, etc. point to different sites of assay (EIA) or immunofluorescent assay facial nerve lesions (Table 18.1) (IFA); ELISA for Lyme disease; especially in • Onset—Acute onset is common with Bell’s endemic areas. palsy, diabetic neuropathy, TIA, CVA, Serum Calcium and Angiotensin-converting pregnancy, and trauma to facial nerve. CNS Enzyme Levels infection, abscess, acoustic neuroma, and brain tumor have subacute or gradual onset • If sarcoidosis is suspected; these levels are • Is there associated hemiparesis or hemiplegia? high in sarcoidosis. Presence of such associated neurological deficit of acute onset favors CVA or subdural or CLINICAL NOTES extradural hematoma. If hemiplegia or hemiparesis of acute onset is present on the • Careful observation of the patient’s face during conversation and at rest almost always reveals contralateral side, then brainstem thrombosis facial weakness. Additionally, the face may or hemorrhage must be considered. If the ‘droop’ on the side of lesion. Inspection of the deficit is gradual in onset, and on one side, face can also include overall muscle function consider a brain tumor, abscess, or brain during speech and expression. Occasionally degenerative disease blepharospasm due to facial nerve misdirec- • Evaluation of facial muscle innervated by CN tion (), or hemifacial spasm due to VII such as—wrinkling of the forehead (frontalis), inflammatory lesions, or posterior fossa tumor closing the eyes tightly (orbicularis oculi), closing may be noted the lips tightly/ whistling (orbicularis oris), • History is reviewed for mode of onset, pulling back the corners of the mouth as in associated symptoms, ear infection, herpes smiling (buccinator), and wrinkling the skin of zoster, tick bite, facial trauma, relevant surgery, the neck/frowning (platysma) - help to decide and systemic diseases such as diabetes whether UMN or LMN type of facial weakness mellitus, hypertension, and malignancy is present (Table 18.2) • Pregnancy and facial palsy—Reports have • A careful neurological examination may detect shown that during pregnancy the incidence focal deficit such as taste sensation in the of Bell’s palsy—including facial , and anterior 2/3rd of the tongue (lost in LMN type), recurrent LMN facial paralysis in successive corneal reflex, plantar response (lost in LMN pregnancies—is increased significantly type), evidence of cerebellar signs and CN VIII compared to nonpregnant women; most involvement (affected in acoustic neuroma) cases of Bell’s palsy occur in the third • Unilateral or bilateral lesions can be tested by trimester or early puerperium; onset is acute having the patient retract one corner of the and painful3-5 mouth at a time, winking one eye at a time, and Facial Asymmetry and Weakness 123

Table 18.1: Localization of facial nerve lesion Site Causes Features Cortex or brainstem- Cerebral infarction Contralateral paralysis of lower facial Supranuclear lesion: Tumor muscles with relative preservation of upper (above the facial nucleus) Multiple sclerosis muscles. Pons (nuclear or fascicular lesion) Pontine infarct Millard-Gubler syndrome;# Foville’s syndrome.## Basilar artery aneurysm Tumor Sarcoid Multiple sclerosis Vasculitis Syringobulbia CP angle (peripheral nerve Acoustic neuroma Ipsilateral facial ; loss of taste lesion) Meningioma to anterior 2/3rd of tongue due to Secondary neoplasm involvement of nervous intermedius; impaired salivary and tear secretion, hyperacusis (if CN VIII is not affected); additional CNs may be involved: deafness, tinnitus, vertigo (CN VII), sensory loss over face and absence of corneal reflex (CN V); ipsilateral ataxia (cerebellar peduncle). Internal auditory canal Bell’s palsy Same as above except CNs other, i.e. facial canal, Ramsay Hunt syndrome than CN 7th, 8th palsy: hyperacusis due to petrous temporal bone) Globus tumor paralysis of stapedes muscle; loss of taste Trauma from anterior 2/3rd of tongue. Stylomastoid foramina Bell’s palsy Facial paralysis of all muscles; taste and (skull base or within the face) Parotid gland tumor lacrimation preserved. Mumps GBS Sarcoidosis Trauma # Millard gubler syndrome—due to occlusion of the penetrating branches of the basilar artery in the pons. Its features are: lateral rectus palsy — cranial VI; ipsilateral facial paralysis — cranial VII; and contralateral hemiplegia; often accompanied by contralateral sensory loss — light touch and proprioception - due to medial lemniscal damage. However, this is not part of the defined syndrome. ## Foville’s syndrome—due to occlusion of the perforating branches of the basilar artery in the region of the pons. Its features are: unilateral facial palsy; paralysis of conjugate gaze towards the affected side; and contralateral hemiplegia.

elevating one eyebrow at a time. UMN lesion is appearance. It is an important physical sign, as usually unilateral as in CVA and neoplasm and it is most often seen in cases of multiple sclerosis rarely bilateral as in GBS and MS. LMN lesion and with neoplastic and inflammatory lesions may be unilateral or bilateral (Table 18.3) of the brainstem, and if noted makes brain • Facial is a rare form of involuntary imaging (MRI) mandatory movement affecting the facial muscles. It is • Mimic palsy, also known as emotional facial palsy clinically defined as continuous twitching of (EFP) refers to weakness or abolition of facial small bands or strips of muscles that give an movements during emotions like smiling or undulating or rippling appearance to overlying weeping, while voluntary movements do not skin, descriptively called as ‘bag of worms’ show any deficit. EFP has been described in 124 Diagnosis: A Symptom-based Approach in Internal Medicine

Table 18.2: Difference between UMN and LMN type of CN VII palsy UMN type LMN type • Upper face escapes; only lower face • Whole face is involved on one side affected, i.e. eyes can be closed, forehead wrinkled but teeth cannot be shown with weakness of lips and buccinator muscles • Emotional movement retained. • Emotional movements are lost In bilateral UMN lesions whole face is paralyzed and emotional movements are also affected • Bell’s phenomenon*—absent • Bell’s phenomenon*—present • Facial muscles—not atrophied • Facial muscles—fasciculations/atrophy on the affected side may be present • Taste sensation—preserved • Taste sensation—may be lost • Corneal reflex—present • Corneal reflex—lost • Hemiplegia—usually associated with • Hemiplegia—may be an isolated phenomenon; and ipsilateral hemiplegia or hemiparesis or if associated with hemiplegia, it is always crossed monoplegia • Plantar response—extensor on the • Plantar response—flexor on the paralysed side of the face; paralysed side of the face may be extensor on the opposite side • Examples—CVA, CNS neoplasms, MS, • Examples—Bell’s palsy, acoustic neuroma, GBS, syringobulbia, motor neuron disease Lyme disease * Bell’s phenomenon, i.e. if the patient tries to close his affected eye, the eyeball turns upwards and inwards.

Table 18.3: Causes of LMN facial weakness: unilateral and bilateral Unilateral facial weakness Bilateral facial weakness (facial diplegia) • Bell’s palsy • Bilateral Bell’s palsy • Ramsay Hunt syndrome • Bilateral parotid disease • Diabetes mellitus • Bilateral otitis media • Unilateral parotid disease: infection, • HIV stone, tumor, sarcoidosis • GBS • Unilateral otitis media • Sarcoidosis • HIV • Leprosy • Lyme disease • Postdiphtheritic palsy • Leprosy • Poliomyelitis • Acoustic neuroma, meningioma • Leukemia • Cholesteatoma • Melkersson syndrome, i.e. recurrent facial palsy with • Trauma: Petrous fracture facial edema, unilateral or bilateral; and lingua plicata (scrotal • Surgery on mastoid, parotid gland tongue) • Möbius syndrome, i.e. facial paresis with ophthalmoplegia· Myasthenia gravis (not due to facial palsy) • Myotonic dystrophy

association with lesions of anterior part of RED FLAGS frontal lobe, lesions in the neighborhood of optic thalamus, Parkinson’s plus syndrome • With bilateral facial palsy, although very rare, and postencephalitic parkinsonism. it’s important to rule out all other possible • A CN VII palsy (Bell’s palsy) is the most common diagnoses for facial weakness, including cranial nerve lesion and is the most common UMN and LMN disorders, with thorough 6 neurologic manifestation of sarcoidosis. diagnostic tests (Table 18.4). Facial Asymmetry and Weakness 125

Table 18.4: Etiology for bilateral facial weakness of HIV, paralysis can be directly due to the Bilateral nuclear lesions: Pontine viral infection. In later stages paralysis is • Infarction more likely to be associated with the • Hemorrhage opportunistic infections or tumors associated • Multiple sclerosis, vasculitis 8 • Tumor with severe immune deficiency. • Infection • Dissatisfaction with facial appearance seems • Syringobulbia to be a factor in many suicides. In a patient • Motor neuron disease • Möbius syndrome, i.e. facial paresis with ophthal- with facial asymmetry (Table 18.5), negative moplegia coping strategies may include avoidance of

Bilateral infranuclear lesions: social contact, alcohol misuse, and • Bell’s palsy aggression. It is dangerous for the physician • GBS to dismiss a complaint of this type or • HIV 9 • Poliomyelitis labelling these patients as ‘psychiatric’. • Postdiphtheritic palsy • Bilateral parotid disease SELECTIVE GLOSSARY • Bilateral otitis media • Leukemia • Melkersson syndrome, i.e. recurrent facial palsy Melkersson-Rosenthal syndrome—MRS is an with facial edema, unilateral or bilateral; and lingua uncommon condition of unknown cause. plicata (scrotal tongue) Several factors, such as infection, autoimmunity, Muscle disease: neurotropic factors, atopy, and hypersensitivity • Myasthenia gravis to food additives have been implicated in the • Myotonic dystrophy • Fascioscapulohumeral dystrophy pathogenesis, but none of them are proven. An autosomal dominant inheritance with variable Table 18.5: Differential diagnosis of altered facial counter expression has been proposed in some cases of • Trauma, burns, contractures MRS. • Hemiatrophy (e.g. localized scleroderma, Parry- Romberg syndrome) Although early manifestations of the • Hemihypertrophy· syndrome can start at any age, MRS generally • Lipodystrophy develops at the end of the second decade of life. • Unilateral postural edema • Paget’s disease, fibrous dysplasia The classical triad includes recurrent orofacial • Massive parotid gland swelling edema involving predominantly the lips • Acromegaly (macrocheilitis), peripheral facial palsy and • Cushingoid faces (moon face) • Micrognathia scrotal tongue, although it is accepted that the • Congenital — absence of condyle of mandible presence of two manifestations is sufficient to make the diagnosis. Facial palsy can be • Bilateral facial palsy seen in pregnancy may be a unilateral or bilateral; may tend to be recurrent sign of serious underlying disease. Some to such an extent that it’s sometimes described authors suggest that Bell’s palsy increases the as intermittent. Recurrences don’t follow any risk of hypertension and toxemia of pregnancy, pattern—each recurrence can be on the same whereas the pregnant state, in turn, may affect side, alternating side, or bilateral. Disturbances the course and severity of disease.7 of salivary, lacrimal and nasal secretion, • Peripheral facial palsy has been considered disorders of taste and vision, migraine, and as a possible neurological complication of the febrile symptoms occasionally accompany the early stages of HIV infection. In the early stage condition. MRS is an unusual cause of facial 126 Diagnosis: A Symptom-based Approach in Internal Medicine swelling that can be confused with angioedema. 3. Cohen Y, et al. Bell palsy complicating pregnancy: A review. Obstet Gynecol Suey 2000;55(3):184- Diagnosis of this syndrome can easily be missed, 8. [PMID: 10713984: Abstract]. as the obvious symptoms may look like Bell’s palsy. 4. Mari I, et al. Facial diplegias during pregnancy. However, unlike MRS, Bell’s palsy recurrences tend Presse Med 2000;29(40):2213-5. [PMID: 11196051: Abstract]. to be separated by wide time spans. 5. Gbolade BA. Recurrent lower motor neurone facial paralysis in four successive pregnancies. J Laryngol Otol 1994;108(7):587-8. [PMID: REFERENCES 7930897: Abstract]. 6. James DG. Differential diagnosis of facial nerve 1. Leigh W, et al. Are human preferences for facial palsy. Sarcoidosis Vasc Diffuse Lung Dis 1997; symmetry focused on signals of developmental 14(2):115-20 [PMID: 9306501: Abstract]. instability? Behavioral Ecology Advance Access 7. Mylonas I, et al. Idiopathic facial paralysis (Bell’s published on September 1, 2004, DOI 10.1093/ palsy) in the immediate puerperium in a patient beheco/arh099.Behav. Ecol. 15: 864-71. Web site: with mild preeclampsia: A case report. Arch http://beheco.oxfordjournals.org/cgi/reprint/15/ Gynecol Obstet 2005;272(3):241-3. Epub 2005 5/864. Accessed on 09-11-08. May 3. [PMID: 15868184: Abstract]. 2. Michael ER, et al. Detecting hemifacial asym- 8. Abboud O, et al. Isolated bilateral facial paralysis metries in emotional expression with three- revealing AIDS: A unique presentation. dimensional computerized image analysis. Proc Laryngoscope. 2008;118(4):580-4. [PMID: Biol Sci 2004;271(1540): 663-8. Web site: http:// 18197137: Abstract]. www.pubmedcentral.nih.gov/picrender. 9. McGrouther DA. Facial disfigurement. BMJ fcgi?artid=1691649&blobtype=pdf. Accessed on 1997;314(7086):991. [PMID: 9112836: Free full 09-11-08. text]. CHAPTER 19 Facial Swelling

SYNOPSIS DIFFERENTIAL DIAGNOSIS

Facial swelling, i.e. swelling of the central portion Common of the face—known as facial edema—is a condition • Obesity (BMI > 30 kg/m2) wherein there is fluid and/or excess subcuta- • Angioedema (hereditary, drug allergy, e.g. neous fat accumulation in the face.* It can be ACE-inhibitors) localized or generalized, and may even • Systemic disorder (CHF, acute glomerulo- sometimes spread to the neck and upper arms. nephritis, nephrotic syndrome, uremia, Sometimes, it precedes onset of either peripheral hepatic failure) or generalized edema. If the facial swelling is • Insect bites, stings mild, it may be difficult to detect; occasionally • Infection (cellulitis, including orbital the patient, or usually someone who is familiar cellulitis; erysipelas of the face) with patient’s appearance may report it before • Mumps it is noticed during assessment. Most of the time • Sinusitis (maxillary, frontal) facial swelling is not a cause for alarm, but when • Dental abscess the swollen area is inflamed, or there is • Myxedema difficulty in breathing, or the swelling does not • Cushing’s syndrome (iatrogenic, i.e. decrease over time, it becomes a cause of concern. exogenous steroid induced) Many causes are due to infection and allergy, • Trauma but it may be a sign of systemic disease. • Burns. However, the patient usually presents because of the abnormal facial features, expressions, and Occasional even disfigurement. • Hypoproteinemia (in hepatic, renal, and nutritional disorders) * Disorders of only facial subcutaneous and soft tissues are considered; those related to other facial organs (eyes, • Severe anemia of chronic disease nose, jaws, vascular, neoplasms, etc.) are excluded. • Trichinosis 128

• Salivary gland calculus CXR • Ludwig’s angina. • Pulmonary opacity, hilar lymphadeno- Rare pathy, mediastinal tumor, aortic aneurysm, • Cushing’s syndrome (noniatrogenic) etc. may be evident, causing superior vena • Superior vena caval syndrome caval obstruction • Cavernous sinus thrombosis • Bronchogenic carcinoma may lead to • Autoimmune disorders (dermatomyositis, ‘ectopic ACTH syndrome’, causing non- scleroderma, Sjögren’s syndrome, SLE) iatrogenic Cushing’s syndrome. • Extremes of temperature (frostbite, sun X-ray PNS burn) • Kaposi sarcoma • Opacity or a fluid level may be evident in • Burkitt’s lymphoma the involved sinus; bony erosion may • Morbihan’s disease1,2 (vide infra ↓↓). suggest malignancy.

INVESTIGATIONS—GENERAL INVESTIGATIONS—SPECIFIC CBC TFTs • Elevated THS values indicate hypothyroi- • Leukocytosis in infections, cellulitis, dental dism, cretinism. abscess. • Eosinophilia in allergic disorders, trichinosis. ANA • Anemia of iron, folate deficiency in chronic • To screen for underlying autoimmune disease. disorder. ESR Parotid Sialography • Elevated in infection, and autoimmune • To detect any abnormality and obstruction disorders. of the Stensen’s duct. Urinalysis CT/MRI Brain • Proteinuria, hematuria, and RBC casts in • For evidence of cavernous venus thrombosis, renal disease. Cushing’s syndrome (pituitary microadenoma Plasma Protein secreting ACTH tumor). • In hypoproteinemic edema, total plasma • In patients with CNC signs and symptoms protein level is less than 5 g/dl and the plasma due to trichinellosis. albumin content is below 1.5-2.5 g/dl. CT/MRI Lungs, Abdomen Urea, Creatinine • To confirm CXR lesions, and adrenal adenoma. • Elevated in renal failure. CT/MRI PNS Blood Glucose • For detailed evaluation of PNS; obscure • In diabetic patients, especially in Type 1 DM, lesions such as polyps, tumors may be insulin therapy may be associated with the evident causing recurrent sinusitis and facial development of transient edema. edema. 129

Plasma/Urinary Cortisol Table 19.1: Differential diagnosis of periorbital edema • In Cushing’s syndrome, especially in non- • Allergic – Angioedema, insect bite, sting (i.e. hives), contact iatrogenic type. eczema • Infections Muscle Biopsy (Bx) – Bacterial—cellulitis, sinusitis, cavernous sinus thrombosis, anthrax (cutaneous) • To confirm trichinella infestation. – Viral—infectious mononucleosis – Parasitic—trichinosis • Eye—infection—blepharitis, dacryocystitis CLINICAL NOTES • Iatrogenic – Drug induced—steroids, hormones • Evaluation of facial swelling requires conside- • Systemic edema ration of onset, severity, location, duration, – Nephrotic syndrome – Anemia—severe aggravating and ameliorating factors – Hypoproteinemia • Other causes of facial edema, such as edema – Subcutaneous emphysema secondary to congestive heart failure, renal • Endocrinologic – Hypothyroidism insufficiency, hepatic insufficiency, or venous – Graves’ orbitopathy stasis disease must be excluded – Cushing’s syndrome • Acute onset associated with pain and • Autoimmune disorder – Dermatomyositis tenderness is usual with infective and allergic – SLE lesions, whereas gradual onset indicate renal, • Trauma endocrine, and autoimmune disorders – Fracture of nasal, sinus, orbital bones – Foreign body • Recurrent painful swelling of the affected • Neoplastic parotid gland at meals and regressing – Retinoblastoma – Kaposi’s sarcoma afterwards is very characteristic of obstruction – Burkitt’s lymphoma to the duct of the gland by a stone – Superior vena cava syndrome • In patients with salivary gland enlargement, – Secondary tumors (eyelid, eyeball, nose, paranasal sinuses, brain) inquiry about symptoms of rheumatologic Periorbital xanthelasmata disease or ‘sicca syndrome’ (dry eyes, dry • Familial mouth) is important – Angioneurotic edema (i.e. C1 inhibitor deficiency) • A unilaterally enlarged painless parotid gland – Melkersson-Rosenthal Syndrome (i.e. neurological disorder characterized by facial with a facial palsy suggests parotid tumor; swelling, especially of the lips). bilateral involvement may indicate lymphoma, sarcoidosis, and Sjögren’s syndrome elevation of the tongue, or ophthalmoplegia • Periorbital puffiness—Its common causes (e.g. facial cellulitis, angioedema, Ludwig’s are stated in Table 19.1 angina) could be dangerous (causing • Drugs—History of steroid therapy and ); close monitoring/referral is allergic reactions to NSAIDs, antibiotics, indicated blood products, and vaccines may result in • Mediastinal lesion, e.g. bronchogenic periorbital or facial edema. carcinoma may present as facial edema due to compression/obstruction to the superior RED FLAGS vena cava • Any facial swelling involving deep facial • In lupus erythematosus, dramatic peri- spaces, as evidenced by fever, , orbital edema and erythema without any 130

evidence of other significant cutaneous or lymphedema or solid persistent facial edema in systemic involvement, though unusual, acne or rosacea. The chronic course, absence of could be the sole manifestation of cutaneous serological abnormalities and nonspecific lupus erythematosus. Therefore, every histopathological features, as well as resistance patient with persistent periorbital edema to therapy is the most important diagnostic should undergo histologic and immuno- criteria of this disease. Cases remain difficult to fluorescent evaluation, and lupus erythe- treat and can challenge afflicted patients both matosus should be included in the cosmetically and psychologically. differential diagnosis.3 • Unilateral facial swelling, involving orbital REFERENCES region, may signal cavernous sinus throm- 1. Jansen T, et al. Persistent erythema and edema of bosis, especially in immunocompromised the face associated with rosacea and lymph vessel and diabetic patients. dysplasia. Hautarzt 1998;49(12):932-5. [PMID: 9914893: Abstract]. 2. Hölzle E, et al. Morbihan disease—chronic persistent SELECTIVE GLOSSARY erythema and edema of the face. Hautarzt 1995; 46(11):796-8. [PMID: 8641887: Abstract]. Morbihan’s disease—It is a rare condition 3. Ghaninejad H, et al. Persistent periorbital edema characterized by chronic persistent erythema as a sole manifestation of cutaneous lupus erythematosus: Report of two cases. Dermatology and edema of the upper half of the face. Such Online Journal 2006 28;12(2):14.[PMID: 16638407: conditions have also been designated as chronic Free article]. CHAPTER Fever of Unknown 20 Origin

SYNOPSIS • Fever lasting more than three weeks • Failure to reach a diagnosis despite one week Fever or pyrexia is a common presentation in most of inpatient investigation. fields of medical practice. It is usually associated The criteria of three weeks were chosen with benign transitory infection. In most because it eliminates the prolonged but self- patients, the epidemiological guidelines and limiting viral and bacterial diseases, and incidence greatly help in the evaluation of the allows sufficient time for appropriate initial underlying cause, generally within a week, or investigations to be completed. However, “over the patient recovers spontaneously. It is only the past 40 years, health care has shifted from when fever prolongs, and the cause remains the inpatient to the ambulatory setting. As a unknown, that it causes a diagnostic challenge, result, it has now become widely accepted that and fever of such cases is labeled as Fever of the requirement for a one week evaluation in Unknown Origin (FUO). However, modern hospital be modified so that evaluation may diagnostic and imaging techniques enable early now be completed in an outpatient setting”.2,3 detection of a number of occult diseases such as In most cases the cause of fever becomes neoplasms, lymphomas, and connective tissue evident within two weeks, thus underlying the disorders in patients previously thought to have common axiom that FUO is more often an 1 FUO. unusual presentation of a common disease * Several authors have devised criteria for rather than a common presentation of a rare defining a FUO. Petrsdorf and Beeson defined disease. Conversely, failure to utilize clinical FUO in adults as: findings correctly, delay in ordering appropriate • Temperature higher than 38.3°C (> 101°F) on tests, and misinterpretation of test results have several occasions (i.e. fever does not have to all contributed to missed diagnoses. be continuous or daily, but occurs in Some experts have argued for a more majority of days of the illness) comprehensive definition of FUO that takes into * Petersdorf and Beeson (1964); Durrack and street (1991); account medical advances and changes in disease Lohr and Hendley (1977). states, such as the emergence of HIV infection and 132 an increasing number of patients with neutropenia • Sarcoidosis (neutrophil count < 500/microliter). Others contend • Temporal arteritis that altering the definition would not benefit the • Rheumatoid arthritis (RA), Still’s disease evaluation and care of patients with FUO.4-6 • Deep venous thrombosis (DVT). FUO demands great tenacity for constant observation, frequent careful physical Rare examination for the evidence of newer signs, • Viral (CMV, Epstein-Barr virus, Herpes Simplex) avoidance of unnecessary investigations at early • Carcinoma (hypernephroma, Hepatoma, stages, and above all an excellent rapport with colon carcinoma) the patient. “It is in the diagnosis of a febrile illness • Metastatic cancers (disseminated carcinoma) that the science and art of medicine come • Connective tissue disorders (SLE, PMR, PAN) 7 together”. With such an approach, FUO will but • Drug fever be a challenge in a minority of patients. However, • Endoprostheses, grafts, stents9-11 about one-third of patients have no diagnosis at • Hereditary periodic fever syndromes the end of the work up, and for them the prognose (Familial Mediterranean fever). is usually good. There is no algorithm to know which tests to order. Focused history and detailed INVESTIGATIONS—GENERAL physical status give important clues to decide (TABLE 20.1) about additional laboratories testing. An empirical † treatment is justified only in case of vital risk. CBC, PS. • Anemia will be revealed in a variety of DIFFERENTIAL DIAGNOSIS disorders such as malignancy, connective Common tissue disorders; leukocytosis in many infective, inflammatory diseases, and • Tuberculosis (TB, especially extrapulmonary leukemia; low platelets in leukemia; malarial and miliary) parasites; abnormal WBCs in leukemia; and • Abscesses (intra-abdominal, retroperitoneal, atypical lymphocytes in infectious mononu- and pelvic) cleosis, HIV, viral hepatitis can occasionally • Extraintestinal amebiasis8 help in the diagnosis. • Chronic active hepatitis • Hodgkin’s lymphoma, non-Hodgkin’s ESR lymphoma • A markedly raised ESR is common in TB, • HIV infection (pyogenic; atypical myco- malignancy, inflammatory and connective bacterial; fungal: Pneumocystic carinii, tissue disorders. candidiasis; viral). Culture Occasional • Blood (infective endocarditis), urine, and • Severe acute respiratory syndrome (SARS) abnormal fluid collection or secretion such as • Infective endocarditis (IE) from throat, urethra, cervix, abdominal, • Brucellosis pleural, and joint space for suspected infection. • Leptospirosis • Kala-azar †Examination by hematopathologist may be indicated in • Acute leukemia suspected hematologic malignancy. 133

Table 20.1: Minimum diagnostic work-up to fungal lesions, and Pneumocystic carinii qualify as FUO** pneumonia may be suspected. • Comprehensive medical history • Repeated physical examination Plain X-ray of Bones • Complete blood count and differential • In osteomyelitis, periosteal reaction and • Microscopic examination of blood film, routine blood chemistry (including lactic dehydrogenase, sequestration develop 10-15 days later; for bilirubin, and liver enzymes) earlier diagnosis radionucleotide bone scan • Blood sedimentation rate is preferred. • Urinalysis and microscopy • Chest radiography US Abdomen, Pelvis • Blood and urine culture (before initiation of antibiotic treatment) • To rule out intra-abdominal masses or • Antinuclear antibodies • Rheumatoid factor abscesses of liver, spleen, kidney, and pelvic • Serology for CMVs and Epstein-Barr virus organs. • HIV antigen and antibody tests • Hepatitis serology (if abnormal liver enzyme tests LFT result) • Angiotensin converting enzyme • Hepatic involvement in FUO is common; • CT scan of abdomen significant elevated values of transaminase • Q fever serology (if exposure risk factors exist) • Examination for specific endemic infectious disease levels indicate hepatitis; elevated alkaline in returning travellers or persons living in such phosphatase levels point to infiltration of the geographic areas (e.g. systemic leishmaniasis in liver. India, Mediterranean area, etc.) • Tuberculin test Sputum • Evaluation of any abnormal symptoms and findings ** Source: Siegenthaler Walter. Siegenthaler’s Differential • Gram’s stain, AFB, and culture. Diagnosis in Internal Medicine From Symptoms to Diagnosis, Thieme, 1st English ed. Chapter-4-Fever of Stool Microscopy and Culture Unknown Origin-Table 4.2 - Minimum Diagnostic work- • Ova, parasites, cysts, and occult blood on up to qualify as FUO, p. 114. microscopy.

Urinalysis Blood Glucose • WBCs in infection; granular or red cell casts in • To detect diabetes mellitus in previously renal inflammation; hematuria in infection, undetected patients. endocarditis, hypernephroma, and blood CSF dyscrasias. Proteinuria suggests renal disease. • In suspected cases with pyogenic, tubercular PPD or Mantoux Test meningitis, and viral encephalitis. • Should be done in all cases of FUO. Negative results are reported in miliary TB, sarcoidosis, INVESTIGATIONS—SPECIFIC Hodgkin’s disease, AIDS, or malnutrition. HRCT Abdomen/Pelvis

CXR • Recommended as one of the first • Usually detects infiltration, consolidation, investigations in FUO in the majority of effusion, masses, and lymphadenopathy patients with symptoms suggesting an even before they are clinically evident. intraabdominal abscess and lymphoma; in • TB—Parenchymal or miliary, primary and patients with suspected retroperitoneal metastatic malignancy, lymphoma, sarcoids, tumors or infections, or those with abnormal 134

LFTs. Even in asymptomatic patients with Leg Doppler Imaging FUO, a normal CT abdomen is very helpful • For evidence of superficial or deep venous in ruling our serious intra-abdominal or thrombosis. retroperitoneal pathology. Echocardiography Nuclear Imaging • Transthoracic echocardiography (TTE)— For • Between Gallium (Ga) 67, Technetium (Tc) evidence of infective endocarditis, to detect 99 m, or indium (In) 111, Tc 99 m is the tracer vegetations on the valve cusp, especially if of choice in localizing a potential infection blood cultures are negative. or inflammatory focus • Transesophageal echocardiography (TEE)— • 18F-fluorodeoxy glucose positron emission Considered to investigate suspected tomography, i.e. (18) F-FDG PET—Osteo- pacemaker lead infection in patients with myelitis can be diagnosed with a high degree negative transthoracic echocardiography.14 of certainty. Negative findings on (18) F-FDG PET essentially rule out orthopedic Serological Tests prosthetic infections. In patients with • May be helpful in disorders such as viral noninfectious inflammatory diseases, (18) F- hepatitis (anti-HAV IgM, HBsAg, anti-HCV); FDG PET is of importance in the diagnosis of HIV (ELISA, Western Blot); infectious large-vessel vasculitis and seems to be useful mononucleosis (heterophil test); antibodies in the visualization of other diseases, such against CMV infection, amoebiasis, brucellosis, as inflammatory bowel disease, sarcoidosis, toxoplasmosis; salmonella (Widal titer); and and painless subacute thyroiditis. In collagen vascular diseases (ANA, RF, patients with tumor fever, diseases Antineutrophil cytoplasmic antibody- commonly detected by (18) F-FDG PET ANCA). include Hodgkin’s disease and aggressive non-Hodgkin’s lymphoma, and also HRCT Chest colorectal cancer and sarcoma.12,13 • Miliary TB, which can be missed on normal FNAC and Directed Biopsies CXR, is better defined by HRCT. • A temporal artery biopsy (Bx) should be Endoscopic Procedures considered in elderly patients with FUO • Bronchoscopy, mediastinoscopy, EGD, • Color duplex ultrasonography of the temporal retrograde cholangiography, colonoscopy, arteries may be a helpful alternative to transrectal sonography, or laparoscopy may temporal artery biopsy help direct visualization, and biopsy • Lymph node biopsy will rule out procedures when organ specific manifes- lymphomas, TB, metastatic carcinomas, and tations are present. mycotic infections • Liver biopsy will detect granulomatous or CLINICAL NOTES metastatic lesions • Bone marrow biopsy can diagnose leukemia, • The first step should be to confirm the lymphomas, carcinoma, and granuloma. history of fever, its documentation, and • LD bodies may be noted in lymph node, exclusion of habitual, factitious, or drug-induced spleen, or bone marrow aspirate in patients fever (see text below) with kala-azar. • Fever patterns such as intermittent, relapsing, Fever of Unknown Origin 135

sustained may prove to be helpful but rarely antineoplastics, atropine and its compounds, diagnostic; it may aid in diagnosing cases of barbiturates, iodides, phenytoin, quinidine) tertian or quartan malaria, or Hodgkin’s must be considered in patients who are taking disease (with Pel-Ebstein fever characterized medications, including OTC drugs, because by 5-10 days of fever alternating with 5-10 elimination of the offending agent may solve days of afebrility) the problem and eliminate the need for • A single record of temperature in a febrile extensive investigations. If fever persists patient gives very little information. In all beyond 72 hours of stopping all possible cases of fever, a serial record of temperature is offending drugs then the likelihood of fever essential; four-hourly in acute cases and eight- being drug-induced is markedly reduced hourly in all other cases. A simultaneous • History of high risk sexual activity and I V drug record of pulse rate and respiration gives abuse need screening for HIV, viral hepatitis, additional information that may be clinically and infective endocarditis. History of alcohol useful abuse indicates cirrhosis, and hepatoma • The duration of fever prior to seeking medical • A past history of intermittent illness over a help may give some clues. The longer the period of years involving multiple organ duration of the fever, the less likely there is systems suggests the possibility of connective an infectious etiology; if it is of month’s tissue disease duration, then autoimmune or malignant • Fundoscopic examination may provide the disorders are the possibilities; when it’s more first clue to the diagnosis of tuberculosis if than a year or so, then granulomatous choroid tubercles are demonstrable. Ocular diseases are the probabilities 15 manifestations of systemic diseases such as • Naproxen test : The response to fever to scleritis, uvulitis in connective tissue disorders naproxen sodium may be helpful in that may provide clues to the diagnosis of obscure fever due to solid tumors and many fever. Hence, referral to an ophthalmologist in rheumatologic diseases (most notably Still’s the early stages of FUO is particularly useful disease) usually subside promptly, while • Physical examination—Must be thorough fever due to other causes may persist and often repeated. Symptoms and signs of • History of recent travel (malaria, SARS); pets, common diseases causing FUO are given in animal and insect contacts (toxoplasmosis, Table 20.2 brucellosis, leptospirosis, Lyme disease); • Fever associated with rash may be a viral occupation (brucellosis in abattoir workers, exanthem (e.g. rubella, varicella) or a clue to anthrax in leather workers); and recent a serious disease (e.g. meningococcemia, contact with persons exhibiting similar thrombocytopenia, erythema multiforme). symptoms (viral hepatitis, TB) are important aids in the diagnosis RED FLAGS • The family history should also be carefully elicited for hereditary causes of fever, such • Rule out habitual hyperthermia, i.e. exaggerated as familial Mediterranean fever. Diseases circadian rhythm, characterized by such as rheumatic fever, tuberculosis, temperature between 100 and 100.5°F in the lymphoma, etc. in other family members afternoon hours; other febrile symptoms must be enquired (chills, sweats, and tachycardia) are absent • Drug-induced fever (antihistamines, antibiotics, and initial tests are normal 136 Diagnosis: A Symptom-based Approach in Internal Medicine

Table 20.2: FUO—Common causes • Rule out factitious fever. Clues to the diagnosis Symptoms and signs Cause are a patient with medical knowledge or

Skin—Mucous membrane— Meningococcemia training, inconsistent histories, excessively petechial eruptions, high temperatures (105°-107°F, which are a Erythema chronicus migrans Lyme disease Pruritus Hepatitis, Hodgkin’s lymphoma, rare occurrence), normal pulse and respiratory hepatic -tumor Scalp—Tender cranial arteries Temporal arteritis rates at the time of fever, and rapid Seborrheic dermatitis HIV defervescence unaccompanied by diaphoresis Face— Butterfly rash SLE Eyes—Subconjunctival petechial, IE • A high index of suspicion of temporal (or splinter hemorrhages giant cell) arteritis, characterized by Dry eyes RA Conjunctiva—Icterus Hepatitis, leptospirosis, hepatic/ headache, fever, jaw claudication, visual pancreatic-malignancy Fundi—Roth spots IE symptoms, polymyalgia rheumatica, and Choroidal tubercle Miliary TB constitutional symptoms must be Retinal hemorrhages, Leukemia, lymphoma infiltrates maintained, since failure to do so, and to Oral cavity—Ulcers SLE institute appropriate treatment may lead Ears—Ear pain, diminished hearing; Otitis media, mastoiditis tympanic membrane- to permanent vision loss erythema, effusion • FUO should be presumed to be secondary to Neck—Stiffness Meningitis an infection (bacterial, parasitic, fungal, Thyroid—Tenderness Thyroiditis Lymphadenopathy TB, infectious mononucleosis, viral, rickettsial, and chlamydial) until lymphoma, sarcoidosis proven otherwise because infections cause Hands—Clubbing, Raynaud’s IE, SLE, RA phenomenon the majority of FUOs and can be life- Arms—Drug injection sites IV drug abuse Chest—Cough, hemoptysis, dyspnea, TB, lymphoma, malignancy threatening consolidation, effusion, rub • The diagnosis of TB may be delayed despite Cardia—Dental procedure, IE, pericarditis skin lesion, ‘varying’ murmurs, a high index of suspicion because of normal conduction disorder, rub CXR, negative skin and sputum test, and Abdomen–Tenderness, guarding, Hepatitis, cholecystitis, abscess, hepatosplenomegaly, mass kala-azar, infective endocarditis, inconclusive histopathologic examination. malignancy Repeated examination and work-up is Scrotum—Swelling, tenderness, mass Orchitis, seminoma, TB epididymitis indicated in patients with strong clinical Penis—Discharge, rash, ulcer HIV Digital rectal examination— Prostatitis, perianal abscess suspicion of TB Tenderness, mass • A high index of suspicion and familiarity Pelvic examination—Discharge, Pelvic inflammatory disease dysuria with the rapidly changing epidemiology of Bones and joints—Pain, tenderness, RA, PMR, Osteomyelitis, SARS is extremely useful in its early diagnosis swelling, metastatic deposits restricted and minimizing transmission movements Lower extremities—Calf Thrombophlebitis • Patients who are elderly, immunocom- swelling, promised, talking steroids or NSAIDs may tenderness, palpable cord not show evidence of fever, even in the Back—Tenderness, swelling over Spinal TB, Paravertebral/spinal presence of a severe infection spine, restricted painful epidural abscess, metastatic movements deposits • Patients who present with rash associated with FUO should have a skin biopsy (Bx) CNS—Altered consciousness Encephalitis; TB, cryptococcal unless the diagnosis is straightforward Focal deficit meningitis Brain abscess, mass lesion • Patients who are immunosuppressed (on corticosteroids, chemotherapy) or who have Fever of Unknown Origin 137

altered immune response due to disease 8. Shamsuzzaman SM, et al. Thoracic amebiasis. Clin Chest Med 2002;23(2):479-92. [PMID: (Hodgkin’s, HIV), are likely to have fever due 12092041: Abstract]. to infection caused by atypical organisms. 9. Victor F, et al. Pacemaker lead infection: Echocardiographic features, management, and REFERENCES outcome. Heart 1999;81(1):82-7. [PMID: 10220550: Abstract]. 1. Knockaert DC, et al. Fever of unknown origin in 10. Haaker R, et al. Osteomyelitis after endoprostheses. the 1980s. An update of the diagnostic spectrum. Orthopade. 2004;33(4):431-8. [PMID: 15146838: Arch Intern Med 1992;152(1):51-5. [PMID: Abstract]. 1728929: Abstract]. 11. Sharif MA, et al. Prosthetic stent graft infection 2. Ophry M, et al. A comprehensive evidence-based after endovascular abdominal aortic aneurysm approach to fever of unknown origin. Arch Intern repair. Vasc Surg 2007;46(3):442-8. [PMID: Med 2003;163:545-51. 17826231: Abstract]. 3. Vanderschueren S, et al. From prolonged febrile 12. Meller J, et al. 18F-FDG PET and PET/CT in fever illness to fever of unknown origin: The challenge of unknown origin. J Nucl Med 2007;48(1):35- continues. Arch Intern Med 2003;163(9):1033-41. 45. [PMID: 17204697: Free full text]. 4. Cunha BA. Fever of unknown origin. Infect Dis 13. Keidar Z, et al. Fever of unknown origin: The Clin North Am 1996;10:111-27. role of 18F-FDG PET/CT. J Nucl Med 2008; 5. Roth AR, et al. Approach to the adult with fever 49(12):1980-5. Epub 2008 Nov 7. [PMID: of unknown origin. Am Fam Physician 2003; 18997040: Free full text]. 68:2223-8. 14. Corrado G, et al. Pacemaker-induced infection: 6. Barbado FJ, et al. Fever of unknown origin: Classic Diagnosis by multi-plane transesophageal and associated with human immunodeficiency virus infection: A comparative study. J Med 2001; echocardiography. Cardiologia 1997;42(10): 32(3-4):152-62. [PMID: 11563813: Abstract]. 1083-6. [PMID: 9534285: Abstract]. 7. Kasper DL, et al. Harrison’s Principles of Internal 15. Agarwal PK, et al. Fever of unknown origin. J of Medicine 16th ed. Vol.I:p.106. Assoc Phy of India, (52),2004;317. CHAPTER 21 Gait Disorders

SYNOPSIS The feedback by these sensory systems is further integrated and modified by brainstem, basal Gait normally means the rhythmic stepping ganglia, cerebellar, and cortical influences. The movements to advance in space, i.e. the spinal cord coordinates muscles of locomotion manner or posture of a person while walking. in all the four limbs by its neural circuitery. The When a normal person walks (i.e. locomotion), cerebellum maintains proper position and he maintains an upright, erect posture; balance. The cortex and basal ganglia evoke balancing is easy, i.e. he is able to stand up walking motion and can modify the slow walk and remain upright against the force of to quick pace. gravity (equilibrium); the arms swing at the sides; turning is smoothly accomplished; and Thus, any lesion at: † cyclical stepping movements are well- • Lower level , i.e. motor system (muscles, coordinated*. The person is able to stand with nerves), joint/skeletal system, proprio- feet together without falling with eyes open ception (sensory) system, visual/ vestibular or closed. system, spinal cord The erect posture of the body is governed by • Middle level, i.e. brainstem, thalamus, basal four primary antigravity muscle groups: ganglia, cerebellum gastrocnemius/soleus group, the quadriceps • High level, i.e. cortical frontal lobe system— group, the glutei, and the erector spinae group. can lead to gait disorders. These muscles act on the information from the Patients with abnormal gait commonly three major sensory systems in the body: the complain of unsteadiness or imbalance, proprioceptive, vestibular, and visual systems. staggering, unsteady, walking like a ‘drunk sailor,’ veering, or having a fear of falling, which is * Gait consists of two phases: stance and swing. In the stance generally an expression of difficulty in maintaining phase the foot is in contact with the floor, and one limb bears all the body weight. In the swing phase the foot is † The anatomical structures that subserve the system of not touching the floor. This phase begins when the toe balance and locomotion are divided into low, middle, and comes off the floor and ends with the heel strike. high anatomical levels. Gait Disorders 139 upright posture, either while standing (balancing) Rare or walking (gait). In addition, they may complain • Scissors gait (i.e. spastic or paraparetic due of stiffness, cramping, numbness, easy fatigability, to bilateral UMN lesion, e.g. cerebral palsy; muscle wasting, foot drag, frequent tripping, or MS; cervical cord compression) difficulty climbing stairs and rising from a seated • Waddling gait (due to proximal muscle position. weakness, myopathy, myasthenia, bilateral Although the physical examination is the congenital dislocation of the hip) key in evaluating balance and gait disorders, • Stomping gait (i.e. sensory gait due to dorsal history is also important, mainly to delineate column disease, e.g. Vit B12 deficiency, tabes onset and temporal pattern and determine dorsalis, HIV myelopathy) whether symptoms are static, worsening, or • Magnetic gait (due to normal pressure improving overtime. The work-up depends on hydrocephalus, i.e. NPH: vide infra ↓↓) the presence or absence of other neurologic • Psychogenic gait (i.e. Bizarre gait in signs. somatization disorders).

DIFFERENTIAL DIAGNOSIS INVESTIGATIONS—GENERAL Common CBC

• Senile gait (i.e. cautious gait) • Leukocytosis in bone and joint infection, and • ‘Fear-of-falling’ gait1 (vide infra ↓↓) megaloblastic anemia in patients with dorsal • Hemiplegic gait (i.e. circumducting, spastic column disease. gait-due to unilateral UMN lesion, e.g. stroke; mass lesion, e.g. tuberculoma, tumor; ESR MS; and Brown-Sequard syndrome: vide • Elevated significantly in inflammatory joint ↓↓ infra ) disease, e.g. RA. • (i.e. painful gait due to joint, bone, or muscle lesion; e.g. trauma, previous X-ray bone/joint surgery, malunion, septic arthritis, osteomyelitis, OA, and RA) • As indicated in bone and joint disorders. • Cerebellar gait (i.e. ataxic or wide-based gait ECG due to drugs; e.g. phenytoin, alcohol, cerebellar ischemia, hemorrhage, and • In hypokalemia, ECG may show sinus acoustic neuroma) bradycardia and evidence of hypokalemia • Vertiginous gait (due to BPPV, labyrinthitis, (flattening of T waves, U waves in leads II, Ménière’s disease). V2, V3, and V4, and ST segment depression). In hyperkalemia, tall T waves may be seen. Occasional • Stepping gait (due to LMN lesion—unilateral INVESTIGATIONS—SPECIFIC or bilateral, e.g. common peroneal nerve MRI Brain/Spinal Cord palsy, foot drop) • Festinating gait (due to basal ganglia, • The most common initial imaging test is a extrapyramidal lesion; e.g. parkinsonism). brain/spinal MRI scan. This test enables to 140 Diagnosis: A Symptom-based Approach in Internal Medicine

look for structural abnormalities, stroke, or RA factor and ANA tumors • In autoimmune arthropathies. • Particularly useful to detect tumors of the posterior fossa, brainstem, and MS. Also Serum B and Folate Levels helpful to exclude other causes of neurological 12 deficit, e.g. arteriovenous malformation, • As indicated in megaloblastic anemia. including lesions causing compression of the spinal cord. EMG/NCS CT Brain • May be informative in inherited peripheral ↓↓ • Useful in acute stroke and to exclude mass neuropathy (Friedreich’s ataxia : vide infra , lesion. Charcot-Marie-Tooth disease) or myopathy.

CSF Genetic Testing • Leukocytosis in bacterial meningitis, • DNA testing for inherited neuropathies, cerebral abscess; eosinophils in helminthic Friedreich’s ataxia (FA), and muscular (neurocysticercosis) infection; low glucose dystrophy. in bacterial, TB infection; oligoclonal bands of IgG in MS; and cytology to detect Drug Screen malignant cells. • Especially for anticonvulsant medications. Serum Electrolytes Blood alcohol levels if intoxication is suggested. • Hyperkalemia or hypokalemia in familial periodic paralysis Muscle Biopsy • In patients with hypokalemia, serum potassium level decreases during attacks, but • In muscular dystrophy, polymyositis, and not necessarily below normal connective tissue disease. • In patients with hyperkalemia, serum CLINICAL NOTES potassium level may increase to as high as 5- 6 mEq/l. Sometimes, it may be at the upper • can indicate a serious limit of normal, and it seldom reaches medical emergency, especially when the cardiotoxic levels. problem is associated with any of these Muscle Enzymes additional symptoms:  Headache (raised ICP) • Increased levels of various muscle enzymes  Nausea or vomiting such as CK, AST (e.g. muscular dystrophy,  Decreased alertness polymyositis: vide infra↓↓); in the presence  Impaired coordination on only one side of polymyositis, CK levels can be elevated as of the body much as 50 times the reference level.  Recent viral illness/immunization TFTs (Guillain-Barré syndrome) • Proximal myopathy is known to occur in  Trauma. hyperthyroidism, and may A vascular or any lesion causing increased be seen in hypothyroidism. ICP, such as an abscess or a tumor needs to Gait Disorders 141

be urgently treated. It is therefore important such as Friedreich ataxia, ataxia telangiec- to note the mode of onset and progress tasia; and autosomal dominant such • The presence of associated symptoms and as spinocerebellar ataxia, episodic ataxia, etc.) signs such as: It is therefore important to look for subtle  Tinnitus, deafness, or vertigo suggests symptoms in family members. Eliciting Ménière’s disease, labyrinthine disease, or information by asking questions such as — eighth nerve lesion; are there relatives with clumsiness, frequent  Headache, nystagmus, or papilledema falling, late walking, early speech therapy, suggest a cerebellar tumor or acoustic unusual eye movements, deafness, poor neuroma; and handwriting, or other neurological problems,  Glove and stocking anesthesia with tendency to diabetes mellitus or mali- diminished reflexes suggest peripheral gnancies—are very helpful to trace the neuropathy or tabes dorsalis. hereditary etiology and genetic pattern • Acute onset hemiplegic gait with symptoms • Observing the patient stand and walk across of raised ICP is mostly due to contralateral the room and carefully observing his posture, stroke or head injury. Acute ataxic gait with gait initiation, base width, step rhythmicity, cerebellar signs (hypotonia, slurred speech, step length, and arm swing may indicate the and nystagmus) may be due insufficiency/ likely causative lesion (Table 21.1) thrombosis of to basilar artery/posterior • Tandem walk: Ask the patient to walk a straight inferior cerebellar artery; drug toxicity; line in tandem, i.e. heel to toe. This may alcohol abuse; or cerebellar hemorrhage reveal a gait abnormality not previously • Chronic gait disorders are usually due to obvious. It also exacerbates all existing gait CNS/spinal mass lesion, infection, nutrit- disorders, especially associated with ional deficiency, substance abuse, or autoim- vestibular and cerebellar disease. Patients mune disease such as MS with cerebellar disease (e.g. midline • Medications, e.g. diuretics, statins, steroids are cerebellar vermis lesion) will tend to fall known to cause myopathies leading to preferentially to the side of the lesion progressive weakness and wasting of skeletal • Ask the patient to walk on his heels. This can muscles, thus resulting in gait disorders. not be done by patients with distal muscle Drugs such as antiepileptics (particularly weakness or foot drop (L4 or L5 lesion) phenytoin and carbamazepine), antihista- • Ask the patient to walk on his toes. This can mines, benzodiazepines, sedatives-hypnotics, not be done by patients with Parkinson’s antidepressants, neuroleptics, alcohol, disease, cerebellar disease, or marked soleus chemotherapy, heavy metal poisoning (e.g. or gastrocnemius muscles (S1 lesion) lead, mercury, and thallium), and bromide • A thorough gait assessment should be intoxication are common and reversible causes performed in all older people. An abnormal of gait disorders gait may suggest a remediable risk factor for • A careful family history should be obtained falls, e.g. difficulty in getting out of a chair to determine if an inheritance pattern can be without arm support and initiate movement found. Many types of gait disorders are suggests Parkinson’s disease or limb-girdle hereditary, e.g. autosomal recessive ataxias dystrophy. The ‘Timed Up and Go’ (TUG) test, 142 Diagnosis: A Symptom-based Approach in Internal Medicine

Table 21.1: Common gait disorders Gait Pattern Cause Essential Senile gait Unsteady; careful; slow; short steps; Age-related without accompanying wide base; stooped posture; diminished neuropsychiatric abnormality; diffuse arm swing; no rigidity cerebral cortex dysfunction; multi- infract dementia Hemiplegic Extended leg; arms flexed; circum- Stroke duction (i.e. round and forward movement)of the affected leg Paraparetic (Scissor; wooden soldier) Stiffness (spasticity) of both legs; feet Cerebral palsy; cord compression; MS; remain on ground syringomyelia Cerebellar (drunken sailor) Wide-based; ; (reeling, Cerebellar lesion; alcoholism; myxe- unsteady, staggering towards lesion) dema; MS Antalgic Limping; avoidance of bearing full OA of the hip or knee; herniated disk; weight on the affected leg; limitation fracture of any of the bones of the limb; of range of movement due to pain in sprained ankle the extremity Stamping (sensory) High stepping; wide-base; bangs feet (diabetes down (stamps) clumsily; tends to look mellitus); posterior column lesions,

at them throughout the cycle (loss of (B12 deficiency-subacute combined position sense); positive Romberg’s sign degeneration of the spinal cord, HIV myelopathy); tabes dorsalis Steppage Foot drop; high lift to avoid tripping; Lateral popliteal nerve palsy; peroneal slaps on floor; unilateral or bilateral muscular atrophy; cauda equina tumor; Guillain-Barré syndrome; poliomy-elitis; lead intoxication Festinating (propulsive or Rigidity; shuffling (short accelerating Parkinson’s disease retropulsive) steps when walking); festination with stopped posture Waddling Wide-based; hips tilted alternately Proximal myopathy (muscular dyst- (glutei weak); waddling or rolling from rophy, polymyositis, dermatomyo- side to side; toe-walk; lumbar lordosis; sitis); congenital dislocation of the symmetrical hips; old polio Vertiginous Unsteady; falling to one side; postural BPPV; vestibular neuronitis; Ménière’s imbalance; vertigo; nausea; nystagmus disease; acoustic neuroma Psychogenic (bizarre) Different, dramatic verities; rare fall or Conversion disorders injury; Hoover sign positive Astasia-abasia Lack of motor coordination which Conversion disorders; rarely in (Blocq disease) leaves the patient unable to stand or children with posterior fossa tumor, walk unassisted but normal leg e.g. medulloblastoma movements can be done when in a sitting or lying down position.

in which the patient is asked to stand up from take longer than 30 seconds tend to need a sitting position without use of hands, walk assistance with many mobility tasks 10 feet, turn around, walk back, and sit down, • Gait disorders worse in the dark are due to is a valid procedure to readily assess gait lesions of the posterior column, e.g. Friedreich’s disorders.2,3 Patients who take less than 10 ataxia, pernicious anemia, MS, or tabes dorsalis seconds are usually normal, patients who • Romberg’s test (eyes-open-eyes-closed): Cerebellar Gait Disorders 143

ataxia can be differentiated from sensory his walking, the psychogenic patient is found ataxia by Romberg’s test, where removal of to perform well on the chair test (sitting the visual input dramatically reduces versus standing), showing improved ability compensatory ability in . to propel a chair forward than when seated.  Ask the patient to stand in one place with By contrast, a normal person performs his feet together. If he is able to stand with equally when walking or propelling utilizing his eyes open as well as eyes closed, the the chair. test is negative, i.e. normal.  If he is able to stand with eyes open, but RED FLAGS tends to fall with eyes closed (i.e. • In the elderly: removing visual input), the test is  Three “Ds” contribute to gait disorder; positive. The cause may be posterior viz. drugs, depression, and dementia; spinal column lesions due to tumor, vit these must be specifically looked for and B deficiency, cervical spondylosis, or 12 excluded before any other intervention. tabes dorsalis.  Acute onset gait disorder is likely to be  If he is unable to stand with eyes open due to acute systemic decompensation, and feet together, it indicates severe such as MI, stroke, or sepsis; a careful unsteadiness, commonly involving the systematic evaluation is indicated to peripheral and central vestibular system exclude such catastrophic presentations. and the cerebellum.  It is often not advisable to attribute gait • Fukuda test: Marching in place for 50 steps; disorder to a single disease because many abnormal if patient deviates close to 90° or different conditions (e.g. degenerative more, either to left or right. If abnormal, it joint disease, postural hypotension, and reflects vestibular disorder stroke) can present in similar gait • Hoover sign: It is a maneuver aimed to abnormalities. separate organic from nonorganic lower limb • In a patient with history suggestive of paralysis. The physician takes a position at secondary gain and normal neurological the foot of the supine patient and places one examination, except bizarre gait, strongly hand under the heel of the patient’s ‘weak’ favors malingering. leg while pressing down with the other hand on the good leg. Now the patient is asked to SELECTIVE GLOSSARY attempt to raise the affected ‘weak’ leg. In organic disease, the associated movement Brown-Séquard syndrome—It is associated with causes the unaffected heel to press injury to the lateral half of the spinal cord downward; in hysteria, the associated (involving interruption of the lateral corticospinal movement is absent tracts, posterior white column, and lateral • The chair test to aid in the diagnosis of spinothalamic tracts), usually as a result of psychogenic gait disorders: In this procedure penetrating trauma to the cervical or thoracic of ‘chair testing’ patient is asked to walk 20- spine. Multiple causes of Brown-Séquard 30 feet forward and backward toward the syndrome have been described in the literature. examiner. The patient is then asked to sit in a The most common cause remains traumatic injury, swivel chair with wheels and to propel the often a penetrating mechanism, such as a stab or chair forward and backward. Compared with gunshot wound or a unilateral facet fracture and 144 Diagnosis: A Symptom-based Approach in Internal Medicine dislocation due to a motor vehicle accident or fall. slow and clumsy walking, which often begins The condition is characterized by the following after normal walking has developed. Diagnostic clinical features (which are found below the level criteria of typical FA include: disease duration at of the lesion): contralateral hemisensory least 5 years, onset < 25 age, progressive ataxia of anesthesia to pain and temperature, ipsilateral gait and limbs, absent knee and ankle jerks, and loss of proprioception, and ipsilateral motor extensor plantar responses‡. As the disease paralysis. Tactile sensation is generally spared. progresses, ataxia affects the trunk, legs, and arms. The pure Brown-Séquard syndrome reflecting As the arms become grossly ataxic, both action hemisection of the cord is not often observed. A and intention tremors may develop. Eventually, clinical picture comprising fragments of the the patient is unable to walk because of the syndrome or the hemisection syndrome plus progressive weakness and ataxia, becoming additional symptoms and signs, known as wheelchair bound and ultimately bedridden. ‘Brown-Séquard–plus syndrome’, is more With disease progression, dysarthria and common.4 In the absence of trauma, this condition dysphagia appear, incapacitating the patient by needs to be differentiated from acute poliomyelitis, 20, and death by 25 (40 in autosomal dominant Guillain-Barré syndrome, cervical disk disease, form), especially due to cardiac failure. vertebral artery dissection, infection and Normal pressure hydrocephalus (NPH)—It is inflammatory causes. MRI is helpful to define characterized by Adam’s triad (impaired gait, the extent of spinal cord injury and is also helpful urinary incontinence and dementia) — and an when differentiating among nontraumatic anatomic abnormality, i.e. enlargement of the etiologies. CT myelography may be useful if MRI cerebral ventricles, which can be seen on CT or is contraindicated or not available. MRI of brain. The gait is typically wide-based ‘Fear of falling’ gait—It is largely a psychogenic with reduced step height, stride length, and gait disorder of the elderly that is often velocity, which gradually progresses to so-called unrecognized. It usually begins after a fall and is ‘magnetic’ gait (‘feet stuck to ground’ – due to characterized by a shuffling or sliding stride and simultaneous contraction of opposing muscles an intense need to hold on for support. It appears while walking), it becomes almost impossible for to be most common in elderly women, can be the patient to initiate gait. The urinary reversed by education, suggestion, and physical incontinence is of ‘urge’ type. The precise therapy, and is often mistaken for Parkinson pathogenesis of NPH is not known, but it is well- disease, or other gait disorders in the elderly. known that despite the absence of increased intracranial pressure, the drainage of CSF Friedreich’s ataxia—FA is the most common regularly induces transient clinical improvement, autosomal recessive ataxia; the major and ventriculosystemic shunting usually results pathophysiologic finding in FA is a “dying back in prolonged remissions. Recently, another phenomena” of axons, beginning in the periphery anatomic abnormality was described in NPH— with ultimate loss of neurons and a secondary a decrease in midbrain diameter on MRI that is gliosis. Classic FA is the result of a gene mutation restored to normal by ventriculosystemic at the centromeric region of chromosome 9 (9q13- shunting. The criteria to define cerebral 21.1) at the site of the gene encoding for the 210- aminoacid protein frataxin. Onset of FA is early, ‡Only diseases with decreased deep tendon reflexes and with gait ataxia being the usual presenting positive Babinski signs are Friedreich’s ataxia, amyotrophic symptom. Gait ataxia manifests as progressively lateral sclerosis, B12 deficiency and syphilis. Gait Disorders 145 ventriculomegaly precisely are vague and rheumatica. Later symmetric proximal muscle difficult to establish, and enlarged ventricles are weakness in the upper and lower extremities surprisingly common. Other disorders of elderly develops. Weakness of pharyngeal and laryngeal people such as Alzheimer’s disease, Parkinson’s muscles, interstitial lung disease, and inflam- disease, and cerebral atrophy may show mation of the myocardium may also occur. Serum enlarged ventricles, and demential disorders CK levels are usually elevated from 5-50 times may be difficult to differentiate from each other. the normal value. Other muscle enzymes — lactic dehydrogenase, aspartate aminotransferase, Polymyositis—It is an idiopathic inflammatory alanine aminotransferase, and aldolase — may be myopathy with symmetric proximal muscle elevated. Muscle biopsy is crucial in helping weakness, characterized by subacute or slowly diagnose PM and in excluding other rare muscle progressing symmetrical weakness, primarily diseases. MRI can be used to guide the site of affecting the proximal limb and trunk muscles. biopsy. The illness may occur at any age, but is most frequent in the fourth to sixth decade of life, REFERENCES women being more frequently affected than men. Although the initial inciting agent remains 1. KurlanR.”Fear of falling” gait: A potentially reversible psychogenic gait disorder. Cogn Behav unknown, possibilities include virus-mediated Neurol 2005;18(3):171-2. [PMID: 16175021: muscle injury, e.g. Coxsackie virus B1, HIV, Abstract]. Human T-lymphotropic virus 1 (HTLV-1) 2. Podsiadlo D, et al. The timed “Up & Go”: A test of basic functional mobility for frail elderly persons. Hepatitis B, influenza, echovirus, and adenovirus. J Am Geriatr Soc 1991; 39(2):142-8. [PMID: 1991946: Many drugs are known to cause myopathy, e.g. Abstract]. hydroxychloroquine, D-penicillamine, hyd- 3. Morris S, et al. Reliability of measurements obtained with the Timed “Up & Go” test in people ralazine, procainamide, phenytoin, ACE with Parkinson disease. Phys Ther 2001;81(2):810- inhibitors, and statins. Patients may report 8. [PMID: 11175678: Free full text]. 4. Koehler PJ, et al.The Brown-Séquard syndrome. muscle pain and tenderness, arthralgias or True or false? Arch Neurol 1986;43(9):921-4. [PMID: arthritis that may be confused with polymyalgia 3741208: Abstract]. CHAPTER Gastrointestinal 22 Bleeding

SYNOPSIS Melena is the passage of black, tarry stools containing altered blood; its characteristic color Gastrointestinal (GI) bleeding includes bleeding results from bacterial degradation, and from both upper and lower GI tract. hydrochloric acid acting on the blood as it travels The upper GI (UGI) bleeding is defined as through the GI tract. Thus, melena suggests that bleeding from source above the ligament of the blood has had time to be processed by the Treitz*, and includes the mouth, esophagus, intestinal tract, implying slower bleeding that stomach, and small intestine up to the originated in the UGI tract. About 100 to 200 ml duodenojejunal junction. of blood in the GI tract is essential to produce The lower GI (LGI) bleeding is usually defined melena which may persist for several days after as bleeding originating from below the ligament the bleeding has ceased. of Treitz, and includes the small intestine, colon, Hematochezia is passing bright red blood per and anal canal. rectum (BRBPR), the source of bleeding is usually The UGI bleeding manifests clinically as from the LGI tract; however, approximately 10- hematemesis and melena, and that of LGI 15% of patients presenting with acute severe bleeding as hematochezia. hematochezia have an UGI source of bleeding Hematemesis is vomiting of blood from the identified on upper endoscopy. UGI tract as defined above. Bright red or blood Occult GI bleeding (OGIB: Table 22.1) refers to streaked vomitus indicates fresh or recent chronic or intermittent loss of minute amount of bleeding; dark red, brown, or black vomitus (the blood of which the patient is unaware; i.e. there color and consistency of coffee-grounds) is insufficient bleeding to cause obvious melena indicates that blood has been retained in the or hematochezia. Chronic GI blood loss less than stomach and partially digested. 100 ml per day may cause no apparent change in stool appearance. Therefore, OGIB in an adult is

* An important anatomical landmark of the duodenojejunal identified by positive fecal occult blood test (FOBT) junction which divides GI tract as UGI and LGI portion. or as a manifestation of iron deficiency anemia. Gastrointestinal Bleeding 147

Table 22.1: Differential diagnosis of occult GI bleeding Table 22.2: Differential diagnosis of obscure GI bleeding Inflammation • Aortoenteric fistula • Peptic ulcer (esophagus, stomach, duodenum, • Dieulafoy’s lesion surgical anesthemosis) • Diverticula • Erosive esophagitis/gastritis • Extraesophageal varices (gastric, small bowel, # • Cameron lesion colonic) • IBD (ulcerative colitis, Crohn’s disease) • Hemobilia • Meckel’s diverticulum Infections • Neoplasms (small bowel) • Hookworm/ ascariasis/ whipworm/ strongyloidosis • Vascular ectasias • Amebiasis/ giardiasis • TB enteritis Neoplasms • Carcinoma, lymphoma, polyp recurrence is a substantial problem, especially for elderly patients with LGI bleeding.2 Additionally, Vascular • Portal hypertension the stability of the patient and the rate of bleeding • Hemangioma dictate the order in which various diagnostic • Dieulafoy’s lesion (ruptured mucosal artery: vide procedures should be conducted. Therefore, the ↓↓) infra goal is to identify, and if necessary, treat the source • Watermelon stomach## • Vascular enteric fistula of bleeding, while maintaining hemodynamic stability of such patient. Superstitious • Hemoptysis • Oropharyngeal (epistaxis) DIFFERENTIAL DIAGNOSIS Miscellaneous As noted above, the source of GI bleeding may • Long distance running be categorized into two broad groups: viz. UGI • Factitious • Hemobilia bleeding and LGI bleeding. #Cameron lesions are linear gastric ulcers or erosions positioned on the crests of mucosal folds at the A—UGI BLEEDING diaphragmatic impression in patients with large hiatus Common hernia. ##Watermelon stomach is the popular name for Gastric Antral Vascular Ectasia (GAVE) in which the lining of the • Peptic ulcer disease (PUD; H. pylori infection) stomach bleeds, causing it to look like the characteristic • Esophagitis (due to chronic GERD) stripes of a watermelon when viewed by endoscopy; it • Erosive gastritis (NSAIDs, aspirin, steroids, can occur in patients with diffuse systemic sclerosis. stress, alcohol). Occasional Obscure GI bleeding (Table 22.2) refers to bleeding that persists or recurs, and for which • Esophageal varices (cirrhosis of the liver, there is no obvious source found after routine portal hypertension) endoscopic (upper and lower) evaluation. • Mallory-Weiss tears (i.e. MW tears: vide infra ↓↓) Obscure GI bleeding, though uncommon, may • Erosive duodenitis. be clinically evident, manifesting as recurrent melena, hematochezia, iron deficiency anemia, Rare or positive FOBT. • Cancer of esophagus GI bleeding is most commonly a result of • Cancer of stomach benign pathology, which resolves spontaneously • Aortoduodenal (aortoenteric) fistula (primary and has favorable outcomes.1 However, long-term and secondary). 148 Diagnosis: A Symptom-based Approach in Internal Medicine

• Hemobilia (blood in bile) INVESTIGATIONS—GENERAL • Bleeding disorders (anticoagulant induced coagulopathy, thrombocytopenia) CBC •· Iatrogenic bleeding (due to anticoagulant • Baseline Hb – low in chronic bleeding. usage, e.g. heparin, warfarin, or thrombo- • A low hematocrit and MCV in a stable patient lytic therapy). suggests intermittent, chronic bleeding. B—LGI BLEEDING • Serial estimation of hematocrit (i.e. PCV) can be useful in assessing ongoing blood loss. Common Coagulation/Clotting Screen • Anal disease (fissure/ulcer, hemorrhoids) • Colitis—acute infections (bacterial, parasitic) • PT, PPT and platelet count—to assess • Colitis—chronic infections (TB, amoebiasis, bleeding diathesis, liver disease, and to ancylostomiasis). monitor anticoagulant therapy. • Blood group and cross matching, if bleeding Occasional is ongoing.

• Inflammatory bowel disease (IBD – ulcerative Serum Chemistry/Serology colitis, Crohn’s disease) • Blood urea is elevated disproportionately to • Pseudomembranous colitis (PMC) creatinine in patients with GI bleeding (due • Rectal varices (portal hypertension, splenic to reabsorption of blood from the bowel). vein thrombosis) • Electrolytes—if vomiting / diarrhea are ongoing. • Polyps/postpolypectomy bleeding. • HIV serology—as indicated.

Rare LFTs • AST, ALT, and Alk. Phosphatase — elevated • Colitis – ischemic, radiation in hepatitis, cirrhosis, and neoplasm. • Solitary rectal ulcer syndrome (SRUS: vide infra ↓↓)3,4 ECG • Diverticulosis/pseudodiverticulosis • To rule out cardiac ischemia due to • Colonic neoplasm (adenocarcinoma) hypovolemia and related factors, especially • Carcinoid tumor in the elderly. • HIV/AIDS colitis (Cytomegalovirus colitis, colonic histoplasmosis, Kaposi’s sarcoma of EGD the colon, and bacterial colitis) • Diagnostic procedure of choice for acute UGI • Colonic arteriovenous (AV) malformation bleeding; can demonstrate most lesions, e.g. (i.e. vascular ectasias, angiomas, angiodys- varices, esophagitis, PUD, gastric erosions, † plasias, and Heyde’s syndrome ) MV tear, and carcinoma • Systemic/iatrogenic bleeding disorder • Screening procedure in patients with • Vasculitis (PAN, Wegener granulomatosis). cirrhosis and portal hypertension, but without prior variceal hemorrhage † The Heyde’s syndrome consists of the association of • Advantages of early EGD include: confirmation gastrointestinal bleeding from angiodysplasia with aortic valve stenosis. of bleeding source in UGI tract; obtaining Gastrointestinal Bleeding 149

biopsy (Bx), and providing therapeutic 99mTc RBC Scanning measures which lessen transfusion require- • Like angiography, it is only of value in ments, need for surgery, and hospitalization. patients with active bleeding. The newer INVESTIGATIONS—SPECIFIC techniques involving dynamic imaging (more frequent acquisition of data), extra Sigmoidoscopy large field-of-view gamma cameras, and cine scintigraphy, or movie-mode displays have • Useful primarily in patients < 40 years of age for proved to have an accuracy of nearly 90% in minor bleeding due to low-lying anal disease. the localization of the bleeding site • Also most often employed in confirming Colonoscopy5,6 Meckel’s diverticulum. • First procedure of choice in LGI bleeding Abdomen US/HRCT diagnosis; may be performed urgently or electively depending on patient’s hemodyna- • May be indicated to diagnose associated mic status and risk-stratification criteria such disorders such as pancreatitis, aortic as positive FOBT in patient > 40 years of age aneurysm, ascites, metastasis, and aortic graft • Though colonoscopy is recommended for infection. patients with LGI bleeding, it may also be used Double-contrast Barium Enema in combination with EGD (i.e. bidirectional • May be an alternative in patients with endoscopy) for patients with upper GI bleeding, contraindications to colonoscopy. OGIB, or nondiagnostic EGD • Advantages include: direct visualization; access Small Bowel Imaging for tissue biopsy (Bx), and ability to treat • When endoscopy is undiagnostic, the small bleeding lesions primarily with heat probe, bowel is evaluated. Common procedures laser therapy, band ligation, or hemoclipping. employed are contrast radiography, i.e. UGI barium follow-through series, and push Angiography (Mesenteric) enteroscopy, which is an extension of EGD that • Used for active, heavy bleeding and/or if allows visualization up to 160 cm. of small colonoscopy is inconclusive bowel distal to ligament of Treitz; allows tissue • The main advantage include: accurate biopsy (Bx), and treatment of bleeding lesions localization of bleeding sites that are not up to 160 cm. of the proximal small bowel. identified by endoscopy Capsule Endoscopy10,11 • It may also permit therapeutic interventions, • It is a noninvasive visual evaluation of the entire e.g. vasopressin infusion and embolization. small bowel and esophagus, indicated in: Complications such as renal failure,  Suspected small intestinal bleeding in rebleeding may occur. persons with objective evidence of recurrent, obscure gastrointestinal bleeding Multidetector Computed Tomographic (MDCT) (e.g. iron-deficiency anemia, positive fecal Angiography7-9 occult blood test, or visible bleeding) who • MDCT angiography is a promising first-line have had EGD and colonoscopy within the modality for fast and accurate localization of past 12 months that have failed to identify acute GI and intraperitoneal bleeding. a bleeding source. 150 Diagnosis: A Symptom-based Approach in Internal Medicine

 For initial diagnosis in persons with • Nasogastric lavage should be performed in suspected Crohn’s disease without evidence patients with UGI bleeding. Nasogastric of disease on conventional diagnostic tests, lavage may be useful as a diagnostic including small-bowel follow-through and technique. A bloody lavage may be helpful upper and lower endoscopy. in predicting a high-risk lesion, particularly  For screening or surveillance of Barrett’s in hemodynamically stable patients without esophagus, and esophageal varices. hematemesis; a clear lavage may be helpful Echocardiography in predicting low-risk lesions. Nasogastric lavage can also facilitate endoscopic • There is a well-recognized association visualization by clearing blood and other between angiodysplasia and aortic stenosis gastric contents. A negative lavage, however, and replacement of the stenotic valve has does not exclude upper GI bleeding; the been reported to stop GI bleed in over 90% procedure carries a false-negative rate of 10%. of patients. Echocardiography should The bleeding in such cases may be therefore be a part of the investigations in intermittent or located in the duodenum. such cases.12-14 Aspiration of bilious, nonbloody material Laparotomy with Intraoperative Enteroscopy strongly indicates that no active duodenal 15, 16 • A last option in the diagnostic evaluation of bleeding is occurring nonemergent cases. • In UGI bleeding important historical information should include the onset, CLINICAL NOTES character, frequency, and quantity of hematemesis. Peptic ulcer pain is epigastric, • Confirm hematemesis; patients often confuse gnawing, rhythmic, and dull. GI malignancy vomiting up and coughing up blood. A history is associated with vague epigastric pain, of epistaxis, bleeding gum disorders, hemo- dyspepsia, or weight loss. Coughing, ptysis indicate sources other than GI tract. retching, or vomiting preceding hemate- Ideally viewing the vomit is the best way to confirm hematemesis mesis suggest MW tears • Confirm melena; black stools may result from • Although LGI bleeding is usually painless, a ingestion of iron salts, charcoal, beets, etc. history of abdominal pain, weight loss, fever, • Patients with severe bleeding may present diarrhea, vomiting, or partial small intestinal with signs of shock (tachypnea, tachycardia, or colonic obstruction are important findings hypotension; systolic blood pressure in the differential diagnosis of inflammatory, <100 mm Hg usually indicates <30% infectious, or malignant lesions. Diverticular reduction in blood volume), which in disease presents as painless with high patients with co-morbid disease such as IHD volume bleeding. Cancer and angiodysplasia may precipitate angina or MI because of present with symptoms of chronic blood loss hypoperfusion. However, resuscitative (anemia, fatigue, dyspnea on exertion) measures and appropriate level of patient • History of prior GI or vascular surgery, e.g. monitoring must be established before aortic bypass, and history of any comorbid diagnostic testing or specific therapeutic disease such as pancreatitis, cirrhosis, renal interventions failure, cancer, etc. precipitates hematemesis Gastrointestinal Bleeding 151

• A history of cutaneous bleeding (e.g. Table 22.3: Physical examination in GI bleeding purpura, ecchymosis) may indicate bleeding General or system Etiologies diathesis (e.g. hemophilia, hepatic failure) • Weight loss; cachexia • Systemic disease • Age is an important feature in discrimi- • Vitals—Pulse-tachycardia, • Significant blood loss – low volume; nating the source of LGI bleeding. For – BP—hypotension patients aged more than 50 years, ischemia, • Skin and mucous membrane: • IBD Erythema nodosum Liver disease colonic AV malformation, diverticulosis, and Jaundice Coagulation disorder malignancy are most common17 Pallor; ecchymosis Hereditary hemorrhagic telangiectasia; • Colonic AV malformations are most Cutaneous telangiectasis (Rendu-Osler-Weber:vide infra ↓↓) commonly found in the cecum, often Pigmented macules on the Peutz-Jeghers syndrome: vide associated with several systemic diseases, lips infra ↓↓ • Nose and oral cavity • Ectopic bleeding source-? present including atherosclerotic cardiovascular • Neck: JVP • Volume status disease, aortic stenosis (Heyde’s syndrome), Lymph nodes HIV, leukemia, metastasis • Cardia: Murmurs • Angiodysplasia associated with chronic renal disease, collagen vascular aortic stenosis disease, von Willebrand disease, and • Lungs: Basal rales/ crepitations • Volume status • Abdomen: • PUD; H. pylori cirrhosis of the liver Epigastric tenderness Cirrhosis of the liver; malignancy • Medications—NSAIDs, steroids, and use of Hepatosplenomegaly; Crohn’s disease; malignancy ascites Aortic aneurysm recreational drugs, cigarettes, or alcohol Mass increase the incidence of erosive gastritis or Bruit • Rectal examination: • Fissure; hemorrhoids; mass ulcer disease • Nasogastric aspirate • Bright red or ‘coffee-ground’ in UGI bleeding; positive for • Because of increasing number of elective aortic blood aneurysm repairs in the aging population, it is likely that more patients with secondary aortoenteric fistula will present with LGI • Positive FOBT may be the first sign of colon bleeding. Hence, a high index of suspicion is cancer or polyp, particularly in patients necessary for prompt diagnosis and above 45 years of age management of this life-threatening event • Solitary rectal ulcer syndrome should be • The clinical findings of initial physical considered in all patients with malignant examination and their possible etiologies are looking rectal tumors given in Table 22.3. • Aortoenteric fistula must be suspected in any patient presenting with UGI bleeding with RED FLAGS known aortic graft (e.g. prior aortic aneurysm • It is crucial to remember that identification repair). Urgent diagnosis and surgery is of a benign anorectal lesion (hemorrhoids, mandatory to prevent exsanguinating ulcer, etc.) does not eliminate the possibility hemorrhage of a more proximal cause of hemorrhage. In • Most commonly missed OGIB disorders general, patients with hemorrhoids related to UGI segment are: erosions in large identified by physical examination should hiatal ; AV malformations, and peptic still undergo thorough endoscopic ulcer on the first endoscopic evaluation evaluation of the colon to rule out other • The LGI lesions most commonly missed on pathological conditions (e.g. portal initial endoscopy are: AV malformations and hypertension, anorectal varices, etc.). neoplasms. Repeat upper, lower, or bidirec- 152 Diagnosis: A Symptom-based Approach in Internal Medicine

tional endoscopy may be essential depen- surface of skin and to mucous membranes often ding on clinical suspicion, and to ascertain rupture and bleed after slight trauma. The most that these lesions have not been overlooked. common clinical manifestation is spontaneous and recurrent epistaxis beginning at approximately 12 SELECTIVE GLOSSARY years of age. About 25% of individuals with HHT have GI bleeding, which most commonly begins Dieulafoy’s lesion—It is an abnormally large after age 40 years. Large AVMs often cause artery that penetrates the gut wall, mainly in the symptoms when they occur in the brain, lungs, proximal stomach, causing massive bleeding. or gastrointestinal tract, causing complications The lesion bleeds into the GI tract through a from bleeding or shunting, which may be minute defect in the mucosa, which is not a sudden and catastrophic. The diagnosis of HHT primary ulcer of the mucosa, but erosion is based on family history and the presence of probably caused on the submucosal surface by cutaneous or mucocutaneous telangiectases or the pulsatile arteriole protruding into the large visceral AVMs. HHT is caused by a mucosa. Dieulafoy’s lesion is most commonly mutation in ENG, the gene encoding endoglin located in the proximal stomach (75% of cases). or ACVRL1 (ALK1), the gene encoding the activin Lesion typically occurs within 6 to 10 cm of the receptor. Molecular genetic testing of these genes esophagogastric junction, generally along the detects mutation in 60-80% of individuals with lesser curvature of the stomach. Detection and HHT and is available on a clinical basis. identification of the Dieulafoy’s lesion as the source of bleeding can often be difficult, Mallory-Weiss syndrome—It is characterized by especially because most present with massive UGI bleeding secondary to longitudinal mucosal bleeding. Because of intermittent nature of lacerations at the gastroesophageal junction or bleeding, initial endoscopy is diagnostic in 60% gastric cardia; may occur after any event that of the cases, so repeated endoscopies are often provokes a sudden rise in intragastric pressure necessary. Similar lesions have been identified in or gastric prolapse into the esophagus secondary the duodenal bulb, jejunum, ileum, colorectum, to precipitating factors such as retching or anal canal, and even in bronchus. With the vomiting. The classic presentation consists of an advances in endoscopy and awareness of episode of hematemesis following a bout of Dieulafoy’s lesion as the cause of massive retching or vomiting. Hematemesis is present bleeding that can cause a high fatality rate if the in 85% of patients. Less common presenting condition remains unrecognized, it has gained symptoms include melena, hematochezia, the reputation of an unusual but important cause syncope, and abdominal pain. Excessive alcohol of bleeding, especially LGI hemorrhage. use has been reported in 40-75% of patients, and aspirin use in up to 30%. Hereditary hemorrhagic telangiectasia (HHT / Rendu-Osler-Weber Syndrome)—It is a Peutz-Jeghers syndrome—It appears to be a hereditary disease of vascular malformation germline mutation of the STK11 gene, located on transmitted as an autosomal dominant trait band 19p13.3. ; characterized by the combination affecting men and women, characterized by the of pigmented lesions in the buccal mucosa and presence of multiple arteriovenous malformations gastrointestinal polyps. Mucocutaneous pigmen- (AVMs) that lack intervening capillaries and result tation and melanin spots are typical, and are in direct connections between arteries and veins. present in more than 95% of cases. They appear Small AVMs (or telangiectases) close to the as small, flat, brown, or dark blue spots with an Gastrointestinal Bleeding 153 appearance of freckles, most commonly in the and clinical presentations may be confusing. The peribuccal area. The number, as well as the size lesions may mimic other rectal pathologies, and the location of polyps may vary from patient including primary or metastatic malignancy, and to patient. Isolated melanotic mucocutaneous lead to wrong diagnosis. pigmentation without gastrointestinal polyps has also been described because of the genetic REFERENCES variability of the syndrome. Presentation may 1. Thomopoulos KC, et al. Changes in aetiology and include — repeated bouts of abdominal pain in clinical outcome of acute upper gastrointestinal patients younger than 25 years, unexplained bleeding during the last 15 years. Eur J Gastroenterol Hepatol 2004;16(2):177-82. [PMID: intestinal bleeding in a young patient, and 15075991: Abstract]. menstrual irregularities in females. Family 2. Strate LL. Lower GI bleeding: Epidemiology and history of Peutz-Jeghers syndrome may be diagnosis. Gastroenterol Clin North Am 2005; 34(4):643-64. [PMID: 16303575: Abstract]. present. Many of the gastrointestinal lesions 3. Torres C, et al. Solitary rectal ulcer syndrome: will start developing early in life even if the Clinical findings, surgical treatment, and syndrome is clinically apparent in the second outcomes. Int J Colorectal Dis. 2007 Nov; 22(11):1389-93. Epub 2007 Aug 14. [PMID: and third decades of life. (Pigmented lesions 17701045: Abstract]. are present in the first years of life and may fade 4. Lis C, et al. Malignant tumors in the rectum at puberty, except for those on the buccal simulating solitary rectal ulcer syndrome in endoscopic biopsy specimens. Am J Surg Pathol mucosa, making diagnosis possible in pediatric 1998;22(1):106-12. [PMID: 9422323: Abstract]. patients with a high level of suspicion). Genetic 5. Al Qahtani AR, et al. Investigative modalities for massive lower gastrointestinal bleeding. World J counselling and proper screening for both Surg 2002 May; 26(5):620-5. Epub 2002 Mar 1. intestinal cancers and extraintestinal cancers [PMID: 12098057: Abstract]. should be implemented. 6. Suryakanth R, et, al Obscure Gastrointestinal Bleeding – The Role of Endoscopy. MedGenMed Solitary rectal ulcer syndrome (SRUS)—It is a 2006; 8(2): 38. Published online 2006 May 11. 7. Laing CJ, et al. Acute gastrointestinal bleeding: rare debilitating disorder of the rectum, Emerging role of multidetector CT angiography characterized by perianal chronic pain with and review of current imaging techniques. passage of blood and mucus. The macroscopic Radiographics 2007;27(4):1055-70. [PMID: 17620467: Abstract]. appearance varies from single to multiple ulcers 8. Duchesne J, et al. CT-angiography for the or even circumferential lesions. The pathogenesis detection of a lower gastrointestinal bleeding remains uncertain; however, trauma to the anterior source. Am Surg 2005;71(5):392-7. [PMID: 15986968: Abstract]. or circular rectal wall caused by straining due to 9. Zink SI, et al. Noninvasive evaluation of active functional disorders of defecation, and pelvic floor lower gastrointestinal bleeding: Comparison disorders are the main hypothesis. The diagnosis between contrast-enhanced MDCT and 99m Tc-labeled RBC scintigraphy. AJR Am J includes clinical symptoms associated with Roentgenol 2008;191(4):1107-14. [PMID: endoscopic lesion (erythema, ulcer or polypoid 18806152: Abstract]. lesion). Defecography, transrectal ultrasonography, 10. Li F, et al. Capsule endoscopy: A comprehensive review. Minerva Gastroenterol Dietol 2007; anorectal manometry, dynamic MRI, etc. are 53(3):257-72. [PMID: 17912188: Abstract]. suitable procedures that may be used to detect 11. Hara Amy K, et al. Imaging of Small Bowel Disease: the causative disorder. Histopathological Comparison of Capsule Endoscopy, Standard Endoscopy, Barium Examination, and CT. features of SRUS are characteristic and RadioGraphics 2005 25:697-711. [PMID: 15888619: pathognomonic; nevertheless the endoscopic Free full text]. 154 Diagnosis: A Symptom-based Approach in Internal Medicine

12. Morishima A, et al. Successful aortic valve 15. Aljebreen AM, et al. Nasogastric aspirate replacement for Heyde syndrome with confirmed predicts high-risk endoscopic lesions in patients hematologic recovery. Ann Thorac Surg 2007; with acute upper-GI bleeding. Gastrointest 83(1):287-8. [PMID: 17184682: Abstract]. Endosc 2004;59(2):172-8. [PMID: 14745388: 13. Henne S.[Recurrent gastrointestinal bleeding Abstract]. and aortic valve stenosis (Heyde syndrome): 16. Witting MD. “You wanna do what?!” Modern Need for valve replacement?] Z Gastroenterol. indications for nasogastric intubation. J Emerg Med 2007;45(3):245-9. [PMID: 17357954: Abstract]. 2007;33(1):61-4. Epub 2007 May 30. [PMID: 14. Batur P, et al. Increased prevalence of aortic stenosis 17630077: Abstract]. in patients with arteriovenous malformations of the 17. Boley SJ, et al. On the nature and etiology of gastrointestinal tract in Heyde syndrome. Arch vascular ectasias of the colon. Degenerative lesions Intern Med 2003;163(15):1821-4. [PMID: 12912718: of aging. Gastroenterology 1977 Apr; 72(4 Pt 1):650- Free full text]. 60. [PMID: 300063: Abstract]. CHAPTER 23 Headache

SYNOPSIS The primary headache disorders—those not associated with an underlying pathology—include The term headache may be defined as any painful migraine, tension-type, and cluster headache. or nonpainful discomfort perceived more than Secondary headache disorders—those attributed to momentarily in the cranial vault, the orbits, and an underlying pathologic condition—include any the nape of the neck, i.e. from the orbits back to head pain of infectious, neoplastic, vascular, drug- the suboccipital area*. induced, or idiopathic origin. The vast majority of It is often difficult to explain the pain of patients who present with headache have one of the headache. Hence it is sometimes equated to primary disorders, as serious secondary causes for ‘invisible misery’, where quite often nothing is presentation with head pain are rare. seen from outside and nothing is measurable 1 However, patients suffering from headaches on the inside. Some terms used by patients to usually fear serious brain disease, and may in explain their headache are—pressure, heaviness, fact be the harbinger of a life-threatening illness. tightness, throbbing, pounding, boring, bursting, Further, besides the conventional CT, MRI, MRA, or simply dull aching discomfort. PET, and SPECT scans, recent imaging modalities The diagnosis of headache nowadays is based such as functional MRI (f MRI) and voxel-based on the classification criteria of The International morphometry (VBM) on MRI has the potential to Headache Society (IHS). The new International change our concept of primary headache Classification of Headache Disorders (ICHD-II) disorders, requiring a radical reappraisal of the published in January 2004 classifies headache tenet of structural normality.5 disorders into 3 parts: part 1: primary headache, In the maze of such advanced neuroimaging part 2: secondary headache, part 3: neuralgias realities, their diagnostic outcomes, cost- and facial pain, and appendix. In total 14 different effectiveness, and their constant demand for headache groups and more than 170 headache novel imaging strategies, “whether it’s nobler 2-4 types are separated. to scan the brain or suffer the slings and arrows of the aggrieved patient or relative, that is the * Pain elsewhere in the face is not included. clinical problem.6, 7 156

Therefore, the clinician’s prime concern while • Ocular (acute narrow angle glaucoma, examining headache patients is, to try and refractory errors) distinguish the more common benign from the • Lumbar puncture headache. less common serious life-threatening causes of headache†, while maintaining a balanced Rare approach to diagnostic testing. • Thunderclap headache (i.e. TCH – vide infra ↓↓). DIFFERENTIAL DIAGNOSIS • Giant cell arteritis (GCA) • Benign intracranial hypertension Common • Cerebral venous thrombosis • Coital/sexual headache.8 • Systemic illness (febrile episodes: viral, typhoid, malaria) INVESTIGATIONS—GENERAL • Migraine • Tension headache CBC • Chronic daily headache • Rarely useful or definitive, except in a febrile • Psychogenic (depression, anxiety) patient. • Vascular (subarachnoid hemorrhage, i.e. SAH; intracerebral hemorrhage) ESR • CNS infections (i.e. meningitis: bacterial- Streptococcus pneumoniae, H. influenzae type b, • Elevated ESR (61-80 mm/hr) is useful to N. meningitidis; TB; viral – HIV, HSV2, EBV; support the diagnosis of GCA. parasitic – toxoplasma; fungal – cryptococcal‡) • Post-traumatic headache Skull X-ray • Premenstrual headache • Immediately after head injury; CT scan is • Drug induced (nitrates; calcium channel superior. blockers; phosphodiesterase type 5 inhibitors: sildenafil; insulin: hypoglycemia) X-ray PNS • Substance abuse (alcohol, caffeine, nicotine) • Useful if sinusitis is suspected – opacification, • Analgesic rebound headache (analgesics, fluid level, mucosal thickening may be NSAIDs, ergotamine) visualized. • Cervical spondylosis • Referred pain (sinus, dental, aural). INVESTIGATIONS—SPECIFIC

Occasional Blood Culture

• Cluster headache • Indicated in cases of CNS or systemic • Chronic subdural hematoma infection. • Accelerated/malignant hypertension • Neoplasms (space occupying lesions, i.e. SOL) Biochemistry • Electrolytes, urea, creatinine, blood glucose, † The list of differential diagnoses is one of the longest in all of medicine. LFT, TFTs, and VDRL may be indicated to ‡ Especially in patients with immunocompromised status. exclude secondary causes of headache. Headache 157

CXR/Spine X-ray • The sensitivity of lumbar puncture appro- aches 100% one to five days after the • To rule out the possibility of metastatic hemorrhage when photospectrometry is carcinoma/cervical spondylosis. used to detect xanthochromia in the fluid sample. CT

• Indicated in evaluating for PNS and MRI diagnosing SAH or intracerebral hemorr- • It is useful in further enhancing lesions hage in patients with acute and severe detected by CT, especially in patients with headache chronic headache • However, a normal CT scan, including fifth • MRI is superior in detecting posterior fossa generation multislice detector CT scan tumors and to demonstrate small aneurysms investigations and reports does not rule out • In patients with atypical or complicated an acute bleed; if the clinical suspicion headache patterns, e.g. a history of seizures remains high, a LP should be performed and/or focal neurological signs or symptoms, • Limitations of brain CT include inability to MRI is the preferred choice identify small hemorrhages in areas • MRI is the modality of choice in the diagnosis obscured by artifact or bone, inability to of headaches in patients with HIV/AIDS, who diagnose other conditions such as idiopathic have a wide variety of neuroimaging intracranial hypertension, meningitis, abnormalities, and also coexistence of carotid or vertebral artery dissection, and multiple pathologies, e.g. tuberculoma with some cases of cerebral venous sinus cerebral infarcts. thrombosis or pituitary apoplexy, and decay in sensitivity with time (sensitivity 92% day Temporal Artery Biopsy of rupture and 58% five days later).9 • Giant cells may be seen in temporal arteritis. CSF However, a normal biopsy does not exclude the disease as there may be segmental • CSF analysis is indicated when meningitis, involvement of the temporal artery. encephalitis, and SAH are diagnostic consi- deration PET/SPECT Imaging • LP should not be performed when increased ICP is suspected, until mass effect is ruled • Nuclear medicine examinations of the out§ cerebral circulation and metabolism can be • The totality of the evidence suggests that carried out in subgroups of headache patients lumbar puncture must still be performed after for diagnosis and evaluation of complications, a negative CT scan result in patients being when patients experience unusually severe evaluated for subarachnoid hemorrhage. 10 attacks, or when the quality or severity of attacks has changed.11 § Because a lumbar puncture can precipitate brain herniation and death in the presence of increased intracranial MR Angiography (MRA) pressure, a CT scan is warranted before the lumbar puncture is performed. • Useful to demonstrate small aneurysms. 158 Diagnosis: A Symptom-based Approach in Internal Medicine

IOP Table 23.1: Headache classified on the basis of time course • In patients with glaucoma, tonometry will Hyperacute (onset within seconds to minutes) show high intraocular pressure. • Subarachnoid hemorrhage • Intracerebral hemorrhage CLINICAL NOTES • Hypertensive crisis • Thunderclap headache • Five questions need to be answered when Acute (onset within minutes to hours) dealing with a patient with headache: • Intracerebral hemorrhage • Venous sinus thrombosis 1. Is it the only symptom (e.g. tension • Rapid increase in ICP (e.g. intraocular bleeding, headache); or associated with other vitreous hemorrhage symptoms (e.g. visual aura in migraine, • Occlusive hydrocephalus (intraventricular hemor- rhage, cerebellar infarction) neurological deficit in stroke)? • Migraine 2. Is it an acute, new-onset symptom (e.g. • Cluster headache CVD, temporal arteritis)? • Meningitis, encephalitis • Drugs (e.g. vasodilators, hypoglycemia) 3. Is it a chronic, recurring symptom (e.g. • Acute glaucoma migraine, substance use or abuse)? • Alcohol-hangover 4. Is it part of the systemic illness (e.g. SOL, Subacute (onset within days to weeks) depression)? • Raised ICP 5. Does it represent a potentially serious  Abscess  Tumor threat to life (e.g. stroke, temporal arteritis)?  Subdural hematoma • In clinical practice, one useful guide in  Hydrocephalus  determining the cause of headache is the time Benign intracranial hypertension • Temporal arteritis course, which can be usually separated into • Referred (sinuses, teeth, ears, jaws, cervical spine) acute, subacute, and chronic (Table 23.1). Chronic (lasting over months) Generally, patients with acute or subacute • Continuous: headaches are more likely to have significant  Tension headache pathology  Psychological – anxiety, depression, hypochondriasis • Since most patients with primary headache  Post-traumatic  Referred (as above) have very little by way of physical findings, • Intermittent a good history is often the most important  Migraine part of the headache consultation. A carefully taken history can establish the diagnosis of • History of trauma may cause concussion and

migraine, cluster, or tension-type headache postconcussion headaches; intracranial SOL

with sufficient confidence that no need will (Table 23.3), and cervical sprain, can also 12 exist for additional evaluation (Table 23.2) induce headaches • The most common type of headache in patients • History of substance abuse indicates the presenting for consultation is the non- possibility of ‘hangover’ headache migrainous vascular headache secondary to • History of bilateral, nonthrobbing headache systemic infection. These patients typically are that is worse in the morning, may awaken febrile and have symptoms of systemic illness. the patient at night, is typical of increased The neurological examination is normal and ICP. Immediate neuroimaging is necessary there is no neck rigidity. to ascertain the cause Headache 159

Table 23.2: Comparison of clinical features of primary headaches Migraine Tension headache Cluster headache Symptoms Photophobia; phonophobia; Disturbed memory or Parasympathetic overac- GI upset (e.g. anorexia, nausea, concentration; labile moods- tivity: all ipsilateral - lacrima- vomiting); ‘aura’ with brain irritability, restlessness; tion; red conjunctiva; scleral dysfunction(e.g. headache, sleep disturbance; fatigue injection; nasal congestion/ vertigo, dysarthria) rhinorrhea; ptosis; miosis of the eye; forehead and facial sweating Location/character Typically unilateral; intense Bilateral, all over the head; Always unilateral orbital, pulsatile, pounding, throb- weight-like or vise-like supraorbital, and /or tem- bing, and/or debilitating pressure; nonpulsatile; poral; severe excruciating distracting, but not stabbing or burning pain debilitating Frequency/duration Intermittent; 4 -72 hours Daily or near daily; 30 min- From 1 every day to 8 per few days; may be constant day; remission for few months or even years; 15 min 2 hours Triggers Stressful event; food Anxiety, stress, lack of sleep Alcohol; selected drugs like (chocolate, red wine); histamine or nitroglycerin skipping meals; changes in sleep/weather; hormone fluctuations

Table 23.3: Headache features suggestive of a space Table 23.4: Typical findings in symptomatic/secondary occupying lesion headache • New onset in adult life (>40 yr of age) or significant • Pressure pain/tenderness (sinus, temple) change in established pattern • Pathologic murmurs (neck, orbits) • Progressive in nature • Meningism (i.e. clouding of consciousness, vomiting) • Association with any of the following: • Meningitis (i.e. altered consciousness, neck  Nausea or vomiting not explained by migraine or stiffness, fever, photophobia, etc.) systemic illness • Cranial nerve palsy and other local motor/sensory  Nocturnal occurrence or morning awakening deficits  Precipitation or worsening by changes in posture, • Horner’s syndrome (triad of miosis, i.e. constricted Valsalva maneuver pupil; partial ptosis; and loss of hemifacial sweating,  Confusion, seizures, or weakness in extremities i.e. anhidrosis • Papilledema/retinal hemorrhage • Typical physical findings that may be noted in secondary or symptomatic headache are listed in Table 23.4 • An acute headache with papilledema and • The presence of nuchal rigidity should make focal neurologic signs, one should consider one think of a subarachnoid hemorrhage, cerebrovascular accident/hemorrhage, cerebral hemorrhage, meningitis, or cerebral cerebral abscess. With a chronic headache abscess and papilledema or focal neurologic signs, • An acute onset of a headache can be a serious one should consider a SOL such as a primary problem. It should be taken seriously because brain tumor or metastatic neoplasm an abrupt onset of a severe (worst headache • Headache that is always on the same side, ever experienced) occipital or generalized associated with seizures, visual distur- headache in a patient with no past history bances, focal neurological deficit, and audible of headache may mean a subarachnoid cranial bruit strongly indicates an arteriov- hemorrhage or meningitis enous malformation 160 Diagnosis: A Symptom-based Approach in Internal Medicine

• The presence of a tender superficial temporal Table 23.5: Which patients with headache require neuroimaging? artery should make one think of GCA (temporal arteritis), particularly in the elderly • Patients with older age (over 50-60 years old) with new headache • Cranial nerve palsies in the elderly are • Occipital location of pain

usually due to ischemia,but when they occur • Worsening headache with valsalva in conjunction with an elevated ESR and • Headache waking patient from sleep • Headache associated with syncope, nausea, or headache, they could be associated with sensory distortion GCA. However, when assessing an older • Sudden onset severe headache (reaching maximum person with a headache, the information intensity over seconds to a minute • HIV/AIDS patients with new or different headache obtained from the patient should be • Pregnant patients considered as carefully as any ESR result • Abnormal finding on neurologic examination • In complicated migraine such as ophthalmic / Source: The American College of Emergency Physicians hemiplegic/basilar artery migraine, signi- (ACEP) June 2008, Guidelines for evaluation of patients ficant neurologic complications may outlast with acute headache. the headache phase. Very rarely there may be permanent neurologic deficit RED FLAGS • A patient known to have migraine can • Any headache associated with systemic develop severe headache due to other symptoms or illness (including fever, intracranial conditions, and hence if there is persistent or progressive vomiting, stiff neck, any question about the diagnosis, further pregnancy, malignancy, immunocom- neuroimaging may be necessary promised state, and anticoagulant therapy) • If headaches are chronic and episodic, and there • Onset of new or sudden headache in an are no focal neurologic signs, papilledema, or elderly (especially in those age 40 years or nuchal rigidity, an imaging study can be older) has to be evaluated with caution postponed for a while until the response to treatment is evaluated. However, if the because it could herald a serious problem response to treatment is poor, neuroimaging is such as SOL, temporal arteritis, or vertebro- indicated (Table 23.5) basilar insufficiency • Establishing an open and honest physician- • Any headache with neurologic signs or patient relationship is essential for the proper symptoms (including altered mental status, evaluation and management of headache focal neurologic symptoms or signs, disorders.13 The reason for brain scan – CT or seizures, or papilledema) MRI—particularly with primary headache, • Prior headache history that is different (e.g. and its probability in the diagnosis should be headaches now are of different pattern or are made clear to the patient. Failing to provide rapidly progressive in severity or frequency) such explanation could cause anxiety in a • A negative temporal artery biopsy should patient, especially when the scans are either not delay treatment when clinical suspicion reported as normal or incidental (nonpatho- is strong logic) findings are noticed14 • Benign coital headache—Unless a clear • Often, the most important therapeutic history of benign recurrent events can be intervention is confident reassurance about obtained, the presentation of severe the absence of serious underlying neurologic thunderclap headache during intercourse disease. may require a full diagnostic assessment to Headache 161

rule out coital emergencies15 such as a REFERENCES subarachnoid hemorrhage. 1. Ravishankar K. J Assoc Phy India. Optimizing Primary SELECTIVE GLOSSARY Headache Management. 2006;54:928-34. 2. Web site - http://216.25.100.131/ihscommon/ Thunderclap headache (TCH)—As the name guidelines/pdfs/ihc_II_main_no_print.pdf. Accessed on 15-10-08. suggests (a single loud sound of thunder) TCHs 3. http://ihs-classification.org/en/02_klassifikation/. are hyperacute, severe headaches—like a boom Accessed on 15.10.08. of thunder, becoming severe in intensity within 4. Evers S. The new IHS classification. Background seconds to a minute of onset and usually fade and structure. Schmerz. 2004;18(5):351-6. over several hours. Some of these headaches, [PMID: 15349761 Abstract]. however, can last for more than a week. Clues 5. Desai SB. Primary headache and radiologist. Indian J Radiol Imaging 2004;14:353-4. Available in history and physical examination can point from: http://www.ijri.org/text.asp?2004/14/4/353/ to a possible serious underlying cause of TCH, 29519. Accessed on 15.10.08. such as subarachnoid hemorrhage, intracranial 6. Goadsby Peter J. To scan or not to scan in hematoma, cerebral venous sinus thrombosis, headache. BMJ 2004;329:469-70, doi: 10.1136/ cervical artery dissection, ischemic stroke, bmj.329.7464.469.[ Free full text] 7. Freeman JW. Headache reflections: The role of pituitary apoplexy, acute arterial hypertension, classification, narrative and focused intervention. spontaneous intracranial hypotension, third SD Med. 2008;61(8):301-3, 305. [PMID: ventricle colloid cyst, and intracranial 18819319 PubMed - in process, Abstract]. infections. Patients with TCH, who have 8. Chakravarty A. Primary headaches associated evidence of reversible, segmental, cerebral with sexual activity—some observations in Indian patients. Cephalgia. 2006;26(2):202-7. [PMID: vasoconstriction of circle of Willis arteries, and 16426276 Abstract]. normal or near-normal cerebrospinal fluid 9. American College of Emergency Physicians. evaluation are considered to have reversible Clinical Policy: Critical issues in the evaluation ** cerebral vasoconstriction syndrome (RCVS) . Primary and management of adult patients presenting to TCH is diagnosed when no underlying etiology the emergency department with acute headache. is identified. In accordance with the increased June 24, 2008. 10. American College of Emergency Physicians. utilization of cerebral imaging and availability Clinical Policy: Critical issues in the evaluation of noninvasive techniques to image the cerebral and management of adult patients presenting to vasculature, and interest in identifying causes the emergency department with acute headache. of thunderclap headaches, the list of potential June 24, 2008. Available at: www.acep.org/ causes is growing rapidly. Although workarea/downloadasset.aspx?id=8802. uncommon, patients with thunder-clap Accessed on 18-10-08. 11. Sandrini G, et al. Neurophysiological tests and headache are to be evaluated in an emergent neuroimaging procedures in nonacute headache: fashion as many of the underlying causes are Guidelines and recommendations. Eur J Neurol associated with a serious underlying brain 2004;11(4):217-24. [PMID: 15061822 Abstract]. disorder.16, 17 12. Gerald W. Smetana. The Diagnostic Value of Historical Features in Primary Headache Syndromes: A Comprehensive Review. Arch Intern Med. 2000; **Reversible cerebral vasoconstriction syndromes 160(18):2729-2737.[ Free full text] (RCVS) comprise a group of diverse conditions, all 13. Marks DR, et al. Practical evaluation and characterized by reversible multifocal narrowing of the cerebral arteries heralded by sudden (thunderclap), severe diagnosis of headache. Semin Neurol. 1997; headaches with or without associated neurologic deficits. 17(4):307-12. [PMID: 9474710 Abstract]. 162 Diagnosis: A Symptom-based Approach in Internal Medicine

14. Goadsby Peter J. To scan or not to scan in 16. Matharu MS, et al. Thunderclap headache: An headache. BMJ 2004;329:469-470, doi: 10.1136/ approach to a neurologic emergency. Curr Neurol Neurosci Rep. 2007;7(2):101-9.[PMID: 17324359 bmj.329.7464.469.[Free full text] Abstract] 15. Banerjee A. Coital emergencies. Postgrad med J. 17. Schwedt TJ. Clinical spectrum of thunderclap 1996;72(853):653-6. [PMID: 8944205 Free full headache.Expert Rev Neurother. 2007;7(9):1135- text]. 44. [PMID: 17868012 Abstract]. CHAPTER 24 Hearing Loss

SYNOPSIS World Health Organization, the term “deaf”† should only be applied to individuals with Hearing loss* is the subjective complaint of total or hearing impairment so severe that they cannot partial inability to hear sound in either one or both benefit from sound amplification or hearing aid ears. It can occur at any age; sudden or gradual in assistance; their sense of hearing is non- onset; its severity may vary from mild to severe to functional for ordinary purposes of life. The profound; and can be reversible, temporary, or cases included in this category will be those permanent, and make verbal communication difficult. having hearing loss more than 80dB (i.e. The intensity of sound is measured with the profound impairment) in the better ear, or total ‘decibel’, i.e. dB—a logarithmic unit (and not in loss of hearing in both ears. percentage linear scale)—whose reference unit is WHO grades of hearing impairment1 on the 0 on the audiogram. Generally, normal hearing is basis of pure tone audiogram is listed in the Table 24.1. from 0 to 20 dB, about the loudness of a soft Hearing loss can be classified as conductive, whisper. The thresholds in the 20 to 40dB region sensorineural, (Table 24.2) or both (mixed loss). constitute a mild hearing loss (e.g. with trouble Conductive hearing loss (CHL) occurs secondary to hearing ordinary conversation); 40 to 60 dB region lesions in the external auditory canal, tympanic constitute a moderate hearing loss (e.g. where membrane, or middle ear. These lesions prevent voice must be raised to be heard); and thresholds sound from being effectively conducted to the greater than 60 dB are considered severe hearing inner ear. Sensorineural hearing loss (SNHL) is caused loss (e.g. where people must shout to be heard). by lesions of either the inner ear (sensory - due to The term ‘deafness’ is used strictly when there deterioration of the cochlea) or the auditory is little or no hearing at all. According to the nerve (neural - lesions of the eighth cranial nerve). *Hearing loss is deterioration in hearing. Deafness is profound hearing loss. †The distinction between the terms “deaf”, “Deaf”, The term impaired hearing generally describes a wide “deafened”, and “hard of hearing” are based principally range of hearing losses, except deafness, and denotes on the individual’s preferred language (spoken or sign) disability that is commonly called as handicap by the rather than on the actual degree of hearing loss. society. 164

Table 24.1: WHO grades of hearing impairment Other common symptoms which may be Grade of Audiometric ISO value Impairment associated with hearing loss include headache, impairment (average of 500, 1000, to description otalgia, otorrhea, tinnitus, vertigo, development 2000, 4000 Hz) of weakness or asymmetry of the face, and an 0 (no impairment) 25 dBHL or less No or very slight (better ear) problems. Able to abnormal sense of taste. hear whispers The significance of hearing loss and its 1 (slight 26-40 dBHL or less Able to hear and impairment) (better ear) repeat words spoken impact on the health and productivity of those in normal voice at affected by it often go unrecognized. Although 1 meter 2 (moderate 41-60 dBHL or less Able to hear and loss of vision is readily acknowledged and impairment) (better ear) repeat words using raised voice at 1 meter vigorously treated, loss of hearing is often denied, 3 (severe 61-80 dBHL or less Able to hear some minimized, or ignored.2 Since either ignored or impairment) (better ear) words when shouted into better ear undiagnosed hearing loss—both in the young 4 (profound 81 dBHL or greater Unable to hear and and the old—besides causing physical disab- impairment (better ear) understand even a including deafness) shouted voice ility, can also lead to multiple consequences, including social isolation and depression, it is This distinction is important, because sensory vital that early diagnosis is made, particularly hearing loss is sometimes reversible and of reversible causes, in addressing these issues. seldom life-threatening. A neural hearing loss is rarely recoverable and may be due to a DIFFERENTIAL DIAGNOSIS potentially life-threatening brain tumor— Common commonly a cerebellopontine angle tumor. Mixed hearing loss (MHL) may be caused by severe • Cerumen impaction head injury, with or without fracture of the skull • Foreign body or temporal bone, by chronic infection, or by one • Otitis externa (secondary to obstruction), of many genetic disorders. It may also occur furuncle when a transient conductive hearing loss, • Otitis media with effusion (secretory) commonly from otitis media, is superimposed • Eustachian tube dysfunction on a sensorineural hearing loss. • Tympanic membrane perforation/retraction

Table 24.2: Common etiologies of hearing loss Conductive Sensorineural Cochlear (sensory) type Retrocochlear (neural) type • Cerumen impaction • Presbycusis • Acoustic neuroma • Foreign body • Noise-induced • Other CP angle tumors • Otitis externa/media • Ototoxic drugs • Herpes zoster • Eustachian tube dysfunction • Ménière’s disease • Cerebrovascular events • Tympanic membrane perforation • Neurosyphilis • Tympanic membrane retraction • Multiple sclerosis • Cholesteatoma • Genetic, e.g. Alport’s syndrome • Otosclerosis • Sudden idiopathic hearing loss • Middle ear tumors— • Trauma Benign/malignant • Trauma • Congenital—external ear/canal malformation 165

• Presbycusis TFTs • Labyrinthitis—viral, bacterial • Hypothyroidism and hyperthyroidism are 3, 4 • Noise induced hearing loss (NIHL). causes of SNHL. Occasional INVESTIGATIONS—SPECIFIC • Ménière’s syndrome • Otosclerosis Pure Tone Audiometry • Barotrauma • Useful test for discriminating the cause of • Ototoxic drugs (aspirin, loop diuretics, amin- oglycosides, phosphodiesterase-5 inhibitors, hearing loss. It measures the threshold levels and chemotherapeutic agents) (i.e. the intensity at which the patient is able • Systemic disease (diabetes mellitus, hypoth- to perceive sound correctly 50% of the times) yroidism, meningitis, syphilis). by presenting pure tones (i.e. electronically generated sounds of specific frequencies), the Rare intensity of which can be increased or • Acoustic neuroma decreased in 5dB steps. Air conduction and • Cholestatoma bone conduction thresholds for preset • Ear trauma, head injury frequencies for both the ears are assessed and • Systemic disease (multiple sclerosis, autoim- charted in the form of a graph called mune disorders) audiogram. The threshold for bone conduc- • Sickle cell disease tion is a measure of cochlear function. The • Genetic (autosomal dominant and autoso- difference in the thresholds of air and bone mal recessive) conduction (A-B gap) is a measure of degree • Psychogenic (pseudohyperacusis). of conductive deafness. The normal thre- shold is considered 0 dB hearing level (Hl); INVESTIGATIONS—GENERAL hearing loss is considered present if the CBC patient’s threshold is >25 dB Hl. When hearing loss is such as to require loud test • Leukocytosis in bacterial ear and labyrinth infection tones, intense tones presented to one ear may • Sickle cells may be seen on peripheral blood be heard in the other ear. In such cases, a smears. masking sound, usually narrow band noise, is presented to the nontest ear to isolate it. ESR Speech Audiometry • Elevated with inflammation and autoim- • In this test the patient’s ability to hear and mune hearing loss. understand speech is measured. Here Blood Glucose phonetically balanced words (single syllable words, e.g. pin, thin, day, bus) and words • Recurrent otitis externa raises suspicion of diabetes mellitus and warrants blood glucose with two equally accented syllables monitoring. (spondees), such as railroad, staircase, and baseball are delivered at 30 or 40 dB above Serology for Syphilis the patient’s speech reception threshold (SRT) • SNHL is caused by both congenital and and the percentage of words correctly heard acquired syphilis. by the patient is his discrimination sore (DS). 166

• A person with normal hearing or conductive disparity in speech discrimination between deafness will hear 95-100% of the words ears, abnormal neurologic examination, or correctly. DS falls markedly in sensorineural a combination of such symptoms. deafness, particularly of the neural type. Poor DS (below 85%) will affect the ability to Brainstem Auditory Evoked Responses understand speech, which is more marked (BAERs) in the presence of noise. • BAERs are tested by placing electrodes on the Tympanometry scalp overlying the auditory cortex and • Measures the compliance of the tympanic measuring the conduction of sound from the membrane to ambient air pressure, and does cochlea to the brain using a probe placed in not require patient participation. A probe the ear canal. A slowing in conduction between containing a sound source, microphone, and ears may indicate retrocochlear pathology, air pressure regulator is placed snugly with such as an acoustic neuroma. It has decreased an airtight seal into the ear canal. The probe sensitivity in the detection of small acoustic microphone records the reflected sound from tumors when compared to MRI scanning. The the tympanic membrane while pressure in main indication for this test is in evaluating the canal is varied. Normally, maximal asymmetric or unilateral SNHL when MRI is compliance of the middle ear occurs when the medically contraindicated or not tolerated by pressure in the ear canal equals atmospheric a claustrophobic patient. pressure. Abnormal compliance patterns Electrocochleography suggest specific anatomic disruptions, e.g. reduced compliance at ambient pressure is • Measures the earliest evoked potentials seen in otosclerosis or malleus fixation; generated in the cochlea and the auditory increased compliance at ambient pressure is nerve with an electrode placed on or through seen in ossicular discontinuity. In eustachian the eardrum. It can be used to assess and tube obstruction and middle ear effusion, monitor patients with Ménière’s disease. maximal compliance occurs with a negative pressure in the ear canal. CLINICAL NOTES

CT Scan of the Temporal Bones (without • It is important that a proactive approach is Contrast) adopted during consultation to detect • A CT scan is used to examine bony detail in hearing loss initially because the number of patients with suspected malformation of the people—especially the elderly—who seek external auditory canal, middle ear, or inner help for hearing symptoms is only a fraction ear, and to delineate bone erosion secondary of those affected. Few patients may complain to infection, cholesteatoma, or tumor. of decreased hearing or abnormal hearing; on many occasions it is the family member MRI of the Head (Gadolinium-enhanced) or the caregiver who initiates the assessment • To detect lesions of the cerebellopontine for hearing loss angle, MRI of the head and internal auditory • During consultation, eliciting history, or canal may be needed in cases of unexplained, counseling, it is important to remember that unilaterals SNHL that is associated with a individuals with hearing disability have 167

diverse degree of hearing loss, and their causes such as presbycusis, noise trauma, communication may be unintelligible. ototoxicity, tumor, or autoimmune disorders. Patience, understanding, and conversing Some forms may be intermittent, e.g. Ménière’s slowly and clearly (do not follow the natural syndrome. Unilateral hearing loss is most often instinct to shout) in patient’s first language associated with conductive causes, Ménière’s are extremely important in establishing disease, trauma and acoustic neuroma. Bilateral meaningful communication hearing loss is common with presbycusis, • Screening in adults can be successfully ototoxic drugs, noise trauma, and autoimmune carried out using the questionnaire from the disorders. History of fever, ear discharge, pain Hearing Handicap Inventory for the Elderly is associated with ear infection 5-7 Screening (i.e. HHIE-S) Version (Table 24.3). • Associated neurological symptoms—Tinnitus is common with Ménière’s syndrome; vertigo Table 24.3: Hearing handicap inventory for the elderly— screening (HHIE-S) version-questionnaire is associated with labyrinthitis. Focal In this test, the patient is asked the following questions: neurologic deficit suggest CNS tumor or 1. Does a hearing problem cause you to feel embarrassed vascular insufficiency, whereas fluctuating when you meet people? neurologic deficit may suggest multiple 2. Does a hearing problem cause you to feel frustrated when talking to a family member? sclerosis 3. Do you have difficulty hearing when someone • Work history—Factory workers, pilots, whispers? 4. Do you feel handicapped by a hearing problem? firefighters, engine drivers, and those 5. Does a hearing problem cause you difficulty when exposed to chronic, recurrent loud sound are visiting friends, relatives, or neighbors? prone to hearing loss, especially without the 6. Does a hearing problem cause you to attend religious services less often than you would like? use of protective equipment 7. Does a hearing problem cause you to have • Current and past medications should be arguments with family members? reviewed. Aspirin, loop diuretics, aminogly- 8. Does a hearing problem cause you difficulty when listening to television or radio? cosides, chemotherapeutic agents, etc. are 9. Do you feel that any difficulty with your hearing known to be ototoxic. FDA has received hampers your personal or social life? 10. Does a hearing problem cause you difficulty when reports of cases of sudden decreases or loss in a restaurant with relatives or friends? of hearing following the use of PDE-5 The patient responds to each question with “no” (0 inhibitors (sildenafil, tadalafil, and points), “sometimes” (2 points), or “yes” (4 points). vardenafil) for the treatment of erectile Interpretation of Total Scores: 0-8 = no handicap; 10-24 = mild to moderate handicap; 26-40 = severe dysfunction and for the treatment of handicap. Scores >10 suggest significant hearing pulmonary arterial hypertension8 impairment and necessitate follow-up. • Family history—May be positive in • History—Onset - age of onset helps to differentiate presbycusis, Ménière’s syndrome, otoscle- congenital and acquired causes of hearing loss, rosis, and acoustic neuroma e.g. unilateral hearing loss since birth is most • Physical examination—Evaluation of the external likely congenital, whereas adult onset unilateral ear to detect obvious causes of CHL, e.g. hearing loss should raise suspicion of a tumor. congenital malformations, atresia, obstruc- Sudden onset may due to viral infection, tion, infection, and tympanic membrane for perilymphatic fistula, barotrauma, stroke, or perforation, otitis media, and cholesteatoma. hemorrhage. A gradual onset is suggestive of A pneumatic bulb (pneumoscopy) is required 168 Diagnosis: A Symptom-based Approach in Internal Medicine

to accurately assess the tympanic membrane and Weber’s test are performed to differentiate and the aeration in the middle ear between CHL and SNHL. Table 24.2 illustrates • Cranial nerve testing—Particular attention common causes of CHL and SNHL should be paid to facial nerve function, • The characteristics of CHL are: because cranial nerves VII and VIII are closely 1. Negative Rinne test, i.e. BC > AC associated at the brainstem and in the 2. Weber’s lateralized (i.e. sound will be temporal bone. Unilateral V, VII and VIII heard better) to worst ear involvement suggests a cerebropontine angle 3. Normal absolute bone conduction lesion (usually a tumor). The trigeminal (V) 4. Speech discrimination is good and lower cranial nerves (IX through XII) can • The characteristics of SNHL are: also be affected by a lesion at the brainstem, 1. A positive Rinne test, i.e. AC> BC (normal such as acoustic neuroma presenting as pattern will be retained) hearing loss 2. Weber lateralized to better ear • Basic tests of hearing—Auditory acuity can 3. Reduced absolute bone conduction be assessed very crudely as follows: 4. Speech discrimination is poor. 1. Stand behind the patient, 3 feet away, i.e. about an arm’s length and request him RED FLAGS to close his eyes. (It is important that he • Earwax impaction should never be missed, cannot see your face as many deaf but it is common9, 10 patients can lip read). • Otitis media in the adult is uncommon; such 2. You need to mask the nontest ear, say by presentation in an elderly should be referred inserting your finger into it. for further evaluation to rule out an underlying 3. Whisper a few words at random from obstructive lesion of the eustachian tube, e.g. behind the test ear, (e.g. 31, 45, 17, 64, etc). nasopharyngeal carcinoma 4. The patient should be able to repeat these • Suspicion of cholesteatoma warrants back accurately. surgical consultation 5. Then perform the same test for the other • If patient is elderly and diabetic, be ear to get a rough measure of their hearing. suspicious of malignant otitis externa You could report this as (for example) “able • Patients who present with sudden SNHL to hear a quiet whisper (i.e. 0-20dB) at arms should have a CT/MRI scan to exclude length on the right ear, but only able to hear vascular ischemic event, acoustic neuroma, a loud conversational voice (i.e. 40-60dB) at arms multiple sclerosis, perilymph fistula, and length on the left”. other CNS disorders • Alternately, place your fingers approxi- • In elderly people, physical examination and mately 5 cm from one ear and rub them investigations should be focused to search for together. The patient should be able to hear alarming symptoms, which may suggest the the sound generated. Repeat for the other ear. cause of hearing impairment is something However, hearing levels are objectively and other than age-related presbycusis accurately assessed by pure tone audiometry • An individual’s confused behavior, poor job • Tuning fork tests—To assess air conduction performance, social isolation, depression, etc. (AC) and bone conduction (BC). Rinne’s test may be atypical presentation of hearing loss Hearing Loss 169

• Early identification of infants and children who Table 24.4: Some signs of hearing impairment in infants and young children are at risk of congenital or acquired hearing Parents should be alert to any signs of hearing impairment loss, and arranging for their timely referral is 11 and discuss them with their child’s health care provider. extremely important. (Tables 24.4 and 24.5). Some signs include: • Failure to startle at loud sounds REFERENCES • Not turning toward the sound of a voice or imitating sounds after about 6 months of age 1. Global burden of hearing loss in the year 2000. • Lack of babbling at 9 months of age Web site: http://www.who.int/healthinfo/statistics/ • Not using single words by 18 months of age bod_hearingloss.pdf. Accessed on 18-09-08. • Using gestures instead of words to express needs 2. Shohet Jack A, et al. Hearing loss: The invisible Parents should be concerned about hearing impairment disability. Postgrad Med Vol 104/No.3/Sept. in older children if they: 1998. • Develop vocabulary more slowly than their peers • Have speech that is difficult to understand or that is 3. Nelson DI, et al. The global burden of occupational too loud or too soft noise-induced hearing loss. Am J Ind Med 2005; • Often ask for words to be repeated 48(6):446-58. [PMID: 16299704]. • Turn on the TV too loud 4. Salama OE, et al. Cellular phones: are they • Appear inattentive at school and have difficulties detrimental? J Egypt Public Health Assoc 2004; learning to read or perform simple mathematics 79(3-4):197-223. [PMID: 16918147]. 5. Lichtenstein MJ, et al. Validation of screening tools for identifying hearing-impaired elderly in Table 24.5: Normal hearing in the very young child* primary care. JAMA1988;259(19):2875-8. [PMID: Age Expected response 3285039]. 6. Web site : http://www.aaiaudiology.com/questi 3 months Startles to a nearby loud sound, stirs or onnaire.html. Accessed on 18-09-08. awakens from sleep when someone talks 7. Website:http://www.ncbi.nlm.nih.gov/books/ or makes a sound, is soothed by mother’s bv.fcgi?rid=hstat6.table.6812. Accessed on 18-09-08. voice 8. Web site: http://www.fda.gov/CDER/drug/InfoSheets/ 6 months Looks toward an interesting sound, turns HCP/ED_HCP.htm. Accessed on 18-09-08. when name is called, makes “moo,” 9. Mahoney DF. Cerumen impaction. Prevalence “ma,” “da,” “di” sounds to toys, and and detection in nursing homes. J Gerontal Nurs “coos” when listening to music 10 months Makes own sounds, imitates some 1993;19(4):23-30. [PMID: 8473711]. sounds, understands “no” and “bye-bye” 10. Al Khabori M, et al. Magnitude of impacted earwax 18 months Understands many single words or in Oman, its impact on hearing impairment and commands, babbles in sentence-like economic burden of earwax on health services. patterns Indian J Med Sci 2007;61(5):278-85. [PMID: 17478958]. *Children who do not pass these minimal performance 11. Task Force on Newborn and Infant Hearing, standards or whose parents suspect there is a hearing Newborn and Infant Hearing Loss: Detection and loss at any age should be referred for testing. Intervention. Pediatrics 1999;103:527-30. CHAPTER 25 Hematuria

SYNOPSIS Hematuria can be classified as gross or microscopic depending on whether or not blood Blood in the urine, i.e. presence of red blood cells is visible to the naked eye. (RBCs) in the urine is called hematuria. A person Gross (macroscopic) hematuria, i.e. urine visibly red with hematuria may complain of voiding high with intact RBCs on microscopic examination can colored or altered urine color; it may be result from as little as 1 ml of blood in a liter of urine; described as yellow, orange, brown, brownish- therefore, the color does not reflect the quantity of black, greenish, or frankly red. These obser- blood loss. Besides, urine color changes can be vations must be given their due clinical affected by a variety of drugs, foods, and 1 significance. As Dr. Michael Farber, Director of endogenous resources; the resultant abnormal urine the Executive Health Program at Hackensack, coloration has been termed as pseudohematuria. University Medical Center in Hackensack, NJ, Microscopic hematuria is defined as three or states,” The appearance and smell of your more RBCs/HPF on microscopic examination urine—as well as the frequency with which you from two of three freshly voided, clean catch, have to go—can provide many clues to what else midstream urine samples. Confirmation on repeat is going on in your body…….a trip to the toilet testing is indicated to account for some degree of may be more revealing than you think”. 2, 3 hematuria noticed in normal healthy persons, as A normal healthy adult at his normal activity well as the intermittent nature of hematuria that excretes up to 2 million RBCs per day, which is found in some urological diseases. corresponds to 1 to 3 RBCs per high power field Physiological or benign hematuria is common and (HPF) on microscopic examination of urine can result from menstruation, febrile episode, specimen*; anything more than this is considered vigorous exercise, and bleeding from ejaculation. to be abnormal hematuria. However, patient should undergo repeat urinalysis, i.e. sequential urine microscopy, 48 to * The efficacy of hematuria screening using the dipstick 72 hours after cessation of such activity. No method to identify patients with significant urologic disease additional evaluation is necessary if the hematuria is controversial. The dipstick results should be confirmed with a microscopic examination of the centrifuged urinary is resolved. Patients with persistent hematuria sediment. require evaluation. 171

Isolated hematuria denotes hematuria without Occasional proteinuria or casts. Although such patients may • Intrinsic renal disease (poststreptococcal have structural glomerular abnormalities, they glomerulonephritis, nephritis, renal TB) appear to have low risk for progressive renal • Drug induced (aspirin, antiplatelets, and disease. Nevertheless, these patients should be anticoagulants) followed up for the development of proteinuria, • Infections (infective endocarditis, malaria, hypertension, and renal insufficiency. 4 HIV). Asymptomatic microscopic hematuria is without Rare features of significant renal disease (no • Malignancy (renal cell carcinoma, bladder/ proteinuria, normal renal function, and no prostate cancer) hypertension), and malignancy has been • Bleeding diathesis (coagulopathy, platelet excluded. Although no major organization dysfunction) currently recommends screening for microscopic • Hemoglobinopathies (sickle-cell disease) hematuria in asymptomatic adults, risk factors for • Hereditary (Polycystic kidney disease; significant disease should be taken into Hereditary nephritis, i.e. Alport’s syndrome consideration, and such high risk patients should : vide infra ↓↓; IgA nephropathy, i.e. Berger’s be considered for full urological evaluation after syndrome: vide infra ↓↓; Thin basement one properly performed urinalysis documenting membrane nephropathy: vide infra ↓↓) the presence of at least 3 RBCs/HPF.5-7 • Schistosomiasis (genitourinary) Hematuria may originate anywhere in the • Metabolic (hypercalcemia, hyperuricosuria) urinary tract, i.e. kidney, ureter, bladder, prostate • Vasculitis gland, or urethra. At times it may reflect a • Foreign body trauma. generalized disorder of the clotting mechanism. INVESTIGATIONS—GENERAL However, the overall objective in dealing with hematuria is to differentiate minor incidental CBC findings that do not require treatment to highly • Hb% reduced due to gross hematuria, significant lesions that are potentially serious by malignancy, blood dyscrasias, and CRF considering risk factors, comorbid conditions, • Hb% elevated due to polycythemia associated complications of procedures, and cost-effective with hypernephroma outcomes. • Leukocytosis in infection, inflammation • Thrombocytopenia in blood dyscrasias DIFFERENTIAL DIAGNOSIS • Peripheral blood smear may show characteristic sickled cells. Common ESR • Urinary tract infections (UTI: cystitis, urethritis, pyelonephritis) • Elevated in infection, malignancy, and • Renal calculi systemic vasculitis. • Prostate (BPH, prostatitis) Urine Dipstick • Sexually transmitted diseases • Nephropathy (diabetic, hypertensive, drug • Blood — used only for screening, must induced). confirm presence of RBCs on microscopy. 172

• Leukocytes due to infection, inflammation INVESTIGATIONS — SPECIFIC • Nitrites due to infection with urease- Multichemistry Profile producing organisms • Proteinuria suggests glomerulopathy. • Blood urea, creatinine, electrolytes, coagul- Urine Microscopy/Culture ation factors, ANA, and PSA to assess renal function; to exclude blood dyscrasias; • RBCs—Hematuria > 3/hpf • WBCs—Infection or inflammation collagen diseases, and to screen for prostatic • Casts—White or red cell casts usually carcinoma. indicate medical causes of hematuria Hb Electrophoresis • Crystals—Usually denote stone disease • Cytology—For assessment of bladder cancer • To screen for sickle cell hemoglobin. • Culture—To confirm suspected infection, HRCT—KUB and AFB • The current procedure of choice for the • Hematuria with pyuria without bacteriuria (i.e. sterile culture) suggests renal TB detection of urinary tract calculi • Phase contrast microscopy—May be helpful • It can also detect diseases that are mistaken in differentiating glomerular from lower tract for renal colic, e.g. appendicitis, diverti- hematuria (after excluding UTI). culitis, AAA. US IVP/IVU • Often the first choice for renal imaging. It can • For evaluation of urolithiasis, renal tumors, differentiate cysts from solid lesions. The bladder tumors, and renal trauma renal size, position, collecting system, • Studies have suggested that the omission of prostate, and bladder can be visualized. IVU as a routine investigation for painless Other abdominal and pelvic organs can also hematuria does not dramatically reduce the be assessed for their disorders detection rate of malignant conditions10 • Very helpful if the patient is allergic to IVP • Not indicated in patients with history of allergy dye, has compromised renal function, and for to IV contrast and compromised renal function. evaluating hematuria in pregnancy • In prospective studies, when US was Cystoscopy combined with a single plain abdominal • Important procedure to evaluate lesions radiograph, it proved to be superior to affecting urethra and bladder mucosa; urography as the primary imaging study in especially indicated in: this series.8, 9  All patients older than age 40 with gross X-ray KUB hematuria • Plain X-ray can detect radiopaque calcium  Patients older than age 40 with negative stones (>2 mm in size), occasionally cystine microscopic hematuria, IVP, and US reports stones, and foreign bodies  Patients suspected of having bladder • Radiolucent uric acid xanthine stones can not carcinoma even with negative IVP or be detected. cystourethrogram results. Hematuria 173

Urine for Schistosomiasis (e.g. muscle trauma, hypolipidemic drugs), the serum remains clear • This diagnosis can be made after schistosome • History should focus on any ingested eggs are detected in 10 ml of urine, ideally substances ( e.g. beets, food coloring agents, collected between 10 am until 2 pm, passed rifampicin, phenolphthalein, phenazopyri- through a polycarbonate membrane filter. dine) which may be the cause abnormal urine color, i.e. pseudohematuria, that can be Urine Cytology mistaken for blood; awareness of such a • First void urine collected in the morning on possibility can spare further evaluation three consecutive days enhances its sensitivity • Type of hematuria (gross or microscopic), its and specificity relationship to urination or timing of • Indicated in all patients who have risk factors hematuria, associated symptoms (recent sore for renal carcinoma, especially in the throat, fever, chills, loin pain, and radiation) evaluation of carcinoma in situ is important • If malignant or atypical cells are identified, • Three tube test—The source of hematuria may follow-up cystoscopy is indicated. be ascertained by this test: predominantly, initial hematuria results from anterior Biopsy: Renal / Bladder/ Prostate urethral disease; final hematuria results from diseases of the bladder neck or the prostate • Indicated in persistent hematuria with gland; and hematuria throughout the stream negative investigation findings, and evidence suggests a lesion higher in the bladder, ureter, of progression (increasing proteinuria, or kidney creatinine, and blood pressure), and here- • Menstrual history—It is important in women ditary nephropathies11 of childbearing age with history of blood in • Bladder biopsy for evidence of malignancy, the urine to ascertain that bleeding is from the and granuloma (tubercular, sarcoid, schisto- urinary tract and not vaginal in origin; cath- somiasis) eterization may be required to differentiate • Prostate malignancy. vaginal bleeding from other sources • Associated symptoms: CLINICAL NOTES  Painful hematuria is usually caused by UTIs, nephrolithiasis, renal infarction. • The red urine of hematuria must be  Hematuria with dysuria, frequency, distinguished from hemoglobinuria and urgency, and suprapubic pain usually myoglobinuria by demonstration of RBCs in denotes cystitis. the freshly voided urine. The presence of RBCs  Hematuria occurring two to three days after establishes the diagnosis of hematuria. If a nonspecific infection of the upper RBCs are absent, examination of the serum respiratory tract suggests IgA nephropathy. will distinguish hemoglobinuria from  A rash, joint pain, photosensitivity, or myoglobinuria. A sample of freshly voided Raynaud’s phenomenon point to a urine is obtained and centrifuged. In collagen vascular disease. hemoglobinuria (e.g. intravascular hemolysis  History of bleeding elsewhere such as due to sickle-cell disease, malaria), the bruising of the skin or nose bleed supernatant will be pink; and in myoglobinuria indicates blood dyscrasias. 174 Diagnosis: A Symptom-based Approach in Internal Medicine

 Painless hematuria may signify primary RED FLAGS renal disease such as tumor, polycystic • Painless gross hematuria in an elderly, in the kidney disease, or TB.  Foul smelling vaginal or urethral discharge absence of infection, is caused by malignancy may indicate risky sexual behavior or unless proved otherwise presence of foreign body. • Hematuria in elderly, which may be transient, • Family history of nephrolithiasis, polycystic intermittent, or asymptomatic, always warra- kidney disease, TB, or sickle-cell anemia nts a comprehensive evaluation to exclude suggests that these conditions as possible malignancy causes of hematuria. Hearing loss and renal • Persistent hematuria warrants thorough failure in male members in the family is seen evaluation when found in patients of any age in Alport’s disease. Hematuria without such • Hematuria associated with sterile pyuria is disorders in the family members may suggest genitourinary TB or interstitial nephritis until thin glomerular basement membrane disease proved otherwise (TBMD) • Artifactual hematuria12 though rare, is common • Past history of travel to endemic areas (Schis- in people with Münchhausen syndrome, tosome hematobium in Egypt); exposure to psychiatric patients, and drug addicts, chemical carcinogens (aniline dyes, tobacco suggesting renal colic. If suspected, requesting smoke) is suggestive of bladder tumor. History the person to void urine in presence of a witness of medications, analgesic abuse (renal papillary clears the confusion. necrosis), diabetes mellitus (nephrosclerosis), prostatic hypertrophy, trauma, etc. may be of SELECTIVE GLOSSARY diagnostic value Alport’s syndrome (hereditary nephritis)—It is • Physical examination—Common findings ass- a genetic progressive nephropathy in which ociated with hematuria are given in Table 25.1. glomerular and other basement membrane

Table 25.1: Common signs associated with hematuria System/organ Disorder

• Skin – petechiae, ecchymosis, lymphadenopathy, • Blood dyscrasias, clotting disorder, purpura on lower extremities Henoch-Schönlein purpura • Fever, renal angle tenderness • Renal inflammation – pyelonephritis • Fever, respiratory, flu-like illness • IgA nephropathy • Fever, sore throat, edema, hypertension • Poststreptococcal glomerulonephritis • Suprapubic tenderness • Bladder inflammation • Bilaterally enlarged kidneys • Hydronephrosis, polycystic disease • Unilateral renal mass • Neoplasm—hypernephroma, cyst, hydronephrosis • Hypertension, atrial fibrillation,valvular heart disease • Glomerulonephritis, renal embolism, infarction • Palpable bladder • Urine retention due to BPH, prostate cancer • Scrotal examination • Varicocele • Digital rectal examination • Prostate disease – BPH, malignancy, pelvic trauma • Hearing loss, hypertension, renal failure • Alport’s disease 175

collagen is abnormal. The disease is inherited as REFERENCES an X-linked trait; in some families, however, 1. Schimpf MO, et al. Can community-dwelling autosomal recessive and perhaps autosomal women reliably identify infected urine? Int dominant forms exist. The diagnosis of hereditary Urogynecol J Pelvic Floor Dysfunct 2007; nephritis is based on: a positive family history 18(11):1357-61. Epub 2007 Mar 14. [PMID: 17356798: Abstract]. (nephropathy, deafness particularly in male family 2. Sally Wadyka for MSN Health & Fitness. What members); audiometry, which detects high Your Urine is Telling You about Your Health. URL: frequency deafness that is clinically not apparent; http://health.msn.com/health-topics/ articlepage.aspx?cp-documentid=100182486. abnormalities of the eyes such as cataract, myopia; (accessed on 12-07-08) and renal biopsy (Bx). End-stage renal disease 3. Topham PS, et al. The value of urine screening in a develops in persons 20 to 40 years of age. young adult population. Fam Pract 2004;21(1):18- 21. [PMID: 14760038: Abstract]. IgA nephropathy (Berger disease)—It is a 4. Chow KM, et al. Asymptomatic isolated micro- primary renal disease of IgA deposition in the scopic haematuria: Long-term follow-up. QJM 2004;97(11):739-45. [PMID: 15496530: Abstract]. glomerular mesangium, and a frequent cause of 5. El-galley R, et al. Practical use of investigations in glomerular hematuria; occurs predominantly in patients with hematuria. J Endourol 2008;22(1):51- men between the ages 20 and 30. An episode of 6. [PMID: 18315474: Abstract]. gross (cola-colored urine), or microscopic 6. Grossfeld GD, et al. Evaluation of asymptomatic microscopic hematuria. Urol Clin North Am 1998; hematuria 1 to 3 days after upper respiratory 25(4):661-76. [PMID: 10026773: Abstract]. infection, or GI symptoms is the commonest 7. Grossfeld GD, et al. Asymptomatic microscopic presentation. Other findings include protein- hematuria in adults: Summary of the AUA best practice policy recommendations. Am Fam Physi- uria, hypertension, and abnormal renal function cian. 2001;63(6):1145-54. [PMID: 11277551: tests. The serum IgA level is increased; serum Abstract]. compliment levels are usually normal, and the 8. Andrews SJ, et al. Ultrasonography and abdominal radiography versus intravenous urography in renal biopsy (Bx) is the standard for diagnosis. investigation of urinary tract infection in men: Prospective incident cohort study. BMJ 2002; Thin Basement Membrane Disease (TBMD)— 324(7335):454-6.[PMID: 11859046: free full text]. It is also known as benign familial hematuria, 9. Spencer J, et al. Ultrasonography compared with — an autosomal dominant nephropathy defined intravenous urography in the investigation of adults with haematuria. BMJ 1990;301(6760):1074- by diffuse thinning of the glomerular basement 6.[ PMID: 2249070: Free full text]. membrane at electron microscopy examination 10. Mishra VC, et al. Role of i.v. urography in patients (normal = 300 – 350 nm). Characteristic features with haematuria. Scand J Urol Nephrol 2004; include: glomerular hematuria, minimal 38(3):236-9. [PMID: 15204378: Abstract]. 11. Shen P, et al. Useful indicators for performing renal proteinuria (<1.5 g/day), normal renal function, biopsy in adult patients with isolated microscopic and familial occurrence. Though mostly benign, haematuria. Int J Clin Pract 2007;61(5):789-94. Epub affected patient and family members should be 2007 Mar 16. [PMID: 17362478: Abstract]. 12. Englis M, et al. Simulated proteinuria and followed up for progressive hypertension or haematuria.Int Urol Nephrol 1983;15(2):181-6. disease progression. [PMID: 6629694: Abstract]. CHAPTER 26 Hemoptysis

SYNOPSIS specific volume of blood. Life-threatening hemoptysis may thus be defined as any hemoptysis that: (1) is Hemoptysis is defined as coughing up or >100 ml in 24 hour; (2) causes abnormal gas expectoration of blood from the respiratory exchange/airway obstruction; or (3) causes tract below the level of vocal cords, which can hemodynamic instability. The cut-off volume of be from the trachea, major airways, or lung 100 ml per 24 hours has been selected because it parenchyma, i.e. the tracheobronchial tree. is the smallest amount of hemoptysis that is The amount of blood expectorated is important because the rate of bleeding is a major reported in literature to threaten the life of the determinant of morbidity. The severity of patient. hemoptysis has been arbitrarily divided as mild, Hemoptysis has been further classified as moderate, or severe, depending upon the amount single if there is one episode of bleeding lasting of bleeding. It is mild if less than 30 ml of blood is up to seven days, but usually 1 to 2 days. It is expectorated per day, or there is only streaking, called recurrent when the bleeding continues for or only flakes of blood in the sputum is present. longer than seven days or there is break in the Hemoptysis is moderate if bleeding is between 30 continuity of at least 2 to 3 days. When pure to 200 ml per day, and severe if bleeding occurs in blood without sputum is expectorated, it is excess of 200 ml per day. Massive hemoptysis has called frank hemoptysis. been variably defined as blood loss of 200 to 600 Considering that the anatomic dead space ml or more within 48 hours. Since any definition in the airway is 100 to 200 ml in most adult is arbitrary, especially because the quantity of individuals, an amount of more than 300 ml. blood expectorated is difficult to quantify, poses the risk of aspiration into the lungs. The Ibrahim WH1 has proposed the use of the term threat to life is either by asphyxiation or life-threatening hemoptysis; so as to avoid the exsanguination. However, hemoptysis of any difference of opinion (with regard to quantity of degree and frequency needs thorough evaluation blood expectorated) applied to the general term because even a small amount of hemoptysis may massive which necessitates the identification of a herald serious and incurable disease.2 On the Hemoptysis 177 other hand, even a moderate amount of • Fungal infection (aspergillosis, pneumocystosis) hemoptysis is life-threatening in those with • Sarcoidosis compromised . Therefore, • Cystic fibrosis the aim of evaluation is three fold: • Pulmonary arterio-venous malformation • Locate the site of bleeding • Vasculitis (Wegener’s granulomatosis, SLE) • Determine the underlying cause, and • Cocaine lung (‘crack’ lung: vide infra ↓↓)6 • Decide the most suitable intervention/ • Factitious hemoptysis (vide infra ↓↓). treatment if bleeding persists, recurs, or is massive, and when to treat. INVESTIGATIONS—GENERAL Despite thorough evaluation, up to 30% of CXR patients show no identifiable etiology of their hemoptysis; these patients are classified as • May provide important information sugges- having cryptogenic hemoptysis, which may be a ting the bleeding source by showing a lesion harbinger of significant tracheobronchial with bleeding potential such as : patchy areas pathology.3-5 of consolidation (pneumonitis); bilateral basal congestion (pulmonary edema); apical DIFFERENTIAL DIAGNOSIS fibrocavitary lesion (TB); dilated bronchial walls (bronchiectasis); mass or coin lesion Common (neoplasm); or fungus ball in cavitary lesion • Bronchitis (acute or chronic) (aspergillosis) • Pneumonia (bacterial or viral) • However, additional follow-up testing (e.g. • Tuberculosis (pulmonary) bronchoscopy, CT thorax) is recommended • Bronchiectasis in patients presenting with hemoptysis in • Bronchogenic carcinoma. which the underlying cause was not detected at initial radiography, especially in those with Occasional risk factors : sex (male), age 50 years or older, 7, 8 • Other primary lung neoplasms (carcinoid and >40 pack year smoking history. tumors: vide infra ↓↓) • Metastatic malignancy Bronchoscopy • Lung abscess • This is the most important procedure for • Cardiovascular (CHF, mitral stenosis) localizing the site of bleeding. Also, the • Pulmonary embolism (PE) bleeding sites may be sampled for • Systemic coagulopathy histopathological analysis • Pulmonary contusion or trauma. • When to use rigid or flexible fiberoptic bronchoscopy or a combination of both is Rare controversial.9,10 Generally, rigid bronchos- • Foreign body aspiration copy is the preferred tool for massive • Parasitic infection (pulmonary amoebiasis, hemoptysis because of its greater suctioning hydatid disease) capacity of blood and clots, superior • Helminthic infection (paragonimiasis: vide visualization of the major airways, and infra ↓↓) adequate ventilation and airway control 178 Diagnosis: A Symptom-based Approach in Internal Medicine

• Flexible bronchoscopy is preferable in Mantoux Test patients with hemoptysis originating from • Used as an initial screening test in patients the upper bronchi. Besides it can also be used suspected with TB who have not received to provide direct therapy in cases of BCG immunization. continued bleeding • Bronchoscopy is also indicated in cases of ECG persistent or recurrent bleeding, and for smokers aged more than 40 years with a • Sinus tachycardia due to anxiety, and blood negative CXR study, because of the higher loss 11, 12 prevalence of lung cancer in this group. • The classical S1 Q3 T3 pattern indicative of Sputum Gram Stain, AFB Smear, Culture, and right heart strain with PE is rare; however, Cytology* nonspecific ST segment and/or T-wave abnormalities are more common. • Infecting organisms may be isolated such as in cases with pneumonitis, lung abscess, TB, Pulse Oximetry or cytological features of malignancy may be present. • To monitor for hypoxia.

CBC INVESTIGATIONS—SPECIFIC • Hb% reduced in chronic hemoptysis resulting HRCT Scan in IDA • Leukocytosis in upper and lower respiratory • This procedure is of immense value for the tract infections detection of bronchiectasis and undiagnosed • Eosinophilia in mycosis (allergic broncho- lung malignancy, i.e. when clinical suspicion pulmonary aspergillosis) or collagen-vascular for malignancy exists, but sputum and ↓↓ disease (Churg-Strauss syndrome: vide infra , bronchoscopy reports are noncontributory PAN) or equivocal • Platelets decreased in thrombocytopenia. • HRCT with IV contrast is presently ESR considered as an adjunct diagnostic modality in patients with high probability • Elevated in infection, inflammation, and of PE presenting with hemoptysis collagen-vascular disease. • Current opinion favors HRCT to bronch- Coagulation Screen oscopy as the first-line procedure for • Prothrombin time (PT) or partial prothr- screening patients with large and those with 13-15 ombin time (PPT) increased in disorders of massive hemoptysis. coagulation, and in patients with anticoagu- 16-19 lation therapy. Multidetector CT (MDCT) • Multidetector row CT with 3D volume rendering has enhanced the conventional *Molecular DNA technology (e.g. polymerase chain roles of thoracic CT. It permits noninvasive, reaction) may be performed on cultured specimens to provide a more rapid and definitive diagnosis in rapid, and accurate assessment of the cause mycobacterial infection. and consequences of hemorrhage into the Hemoptysis 179

airways and helps guide subsequent c-ANCA (Classical or Cytoplasmic Antineut- management. It provides an excellent rophil Cytoplasmic Antibodies) anatomy of the thorax, thereby increasing • Wegener’s granulomatosis is associated the diagnostic yield comprehensively. With with elevated levels. the advent of MDCT, there is paradigm shift in vascular imaging from conventional HIV catheter angiography to MDCT angiog- raphy, because this technique provides • Positivity increases risk of pulmonary TB, image quality that equals or surpasses that and mycosis. of conventional angiography. It is reliable in depicting clot and the pulmonary Lung Biopsy—(Bronchoscopic or Video- vascula-ture, and may also be used to assisted Thorascopic Surgery, i.e. VATS). evaluate thoracic venous anomalies (e.g. • May be essential to diagnose malignancy pulmonary arteriovenous malformations), (staging), sarcoidosis, and pulmonary and to plan therapy. In diffuse lung disease, fibrosis. this technique can increase nodule detection and help differentiate between small CLINICAL NOTES nodules and vessels. Recent advances in 3D volume rendering allow a fly through the • The first step in evaluating hemoptysis is to tracheobronchial tree and the thoracic ascertain that the blood is truly originating great vessels generating virtual endoscopic from tracheobronchial tree, and the under- views in real-time. lying cause of bleeding. Bleeding from sources other than lower respiratory tract, D-dimer i.e. upper airways and GI tract is called pseudohemoptysis (Table 26.1) • Used as an initial screening procedure; values • If a clearcut source of the pseudohemoptysis lower than the cut off level (<500 mg/ml or cannot be determined, the spitting of blood μ 500 g /l, by ELISA) rules out PE and obviate is assumed to be true hemoptysis. The the need for other tests, e.g. pulmonary possible symptom associated causes of angiography. hemoptysis is given in Table 26.2 • The rate, amount of blood loss, and clinical Echocardiography stability of the patient are critical parameters • To assess CHF with pulmonary edema and to ascertain for any further evaluation. In valvular heart disease such as mitral stenosis. patients with massive hemoptysis or in those • Can be used to diagnose PE, especially with with compromised respiratory functions, significant obstruction to pulmonary circul- the urgent need is to prevent aspiration and ation. stabilize the patient. The initial management in such situations is not diagnostic but V/Q Lung Scan therapeutic • Characteristics of the sputum, in terms of • Useful to diagnose PE although CT-pulmo- color and odor may be helpful in defining nary angiogram is the current gold standard. the disease process causing hemoptysis: foul 180 Diagnosis: A Symptom-based Approach in Internal Medicine

Table 26.1: Difference between hemoptysis and pseudohemoptysis Clinical features Hemoptysis Pseudohemoptysis • History • Dominant respiratory symptoms • Respiratory symptoms less likely; other GI symptoms—nausea, vomiting, pain abdomen-more likely. • Origin of blood • Tracheobronchial tree; lung • Oral cavity, larynx, esophagus; gastric or disease hepatic disease • Hematemesis and melena • Less likely • More likely • Color of expectorated blood • Bright red • Brown or black • Sputum examination • Frothy usually • Never or seldom • pH of expectorate • Alkaline • Acidic • Microphages and neutrophils • Present • Absent • Food particles in expectorate • Absent • Present

Table 26.2: Symptoms to diagnose in patients with hemoptysis Symptoms Causes • Fever, cough—Dry/with sputum • URTIs; bronchitis, pneumonia, lung abscess • Nausea, vomiting, melena, alcoholism, NSAIDs • Acid-peptic disorders; esophageal varices • DOE, orthopnea, pink frothy sputum • CHF; mitral stenosis • Cigarette smoking • Bronchitis; pneumonia; lung cancer • Weight loss • TB; COPD; lung cancer; HIV • Travel history • TB, amebiasis, paragonimiasis • Cancer elsewhere • Metastatic malignancy • Association with menses • Pulmonary endometriosis (catamenial hemoptysis) • HIV, immunosuppression • TB; neoplasia; Kaposi’s sarcoma • Risk factors for aspiration • Lung abscess; foreign body aspiration • Trauma • Iatrogenic lung injury • Anticoagulant use • Medication effect • Recurrent hemoptysis, patient with a “fat” file • Factitious hemoptysis

smelling sputum suggests a lung abscess; • History of coexisting disorders like cardiac pink, frothy sputum is suggestive of (valvular disease, heart failure); renal pulmonary edema; slight blood streaking in (nephrotic syndrome); SLE; or previous the sputum is most common with bronchitis; malignancy may give clues to the cause of frankly bloody sputum is seen in TB, PE, and hemoptysis, which may indicate additional bronchogenic carcinoma investigations to arrive at the diagnosis • Associated symptoms—History of cough, • Hemoptysis since childhood is likely due to dyspnea, sputum production over several congenital heart defects, bronchiectasis, years may suggest chronic bronchitis or cystic fibrosis, or blood dyscrasias bronchiectasis. Weight loss and fatigue may • Hemoptysis that accompanies menstrual suggest an underlying malignancy; fever and periods suggests pulmonary endometriosis night sweats might indicate TB • Medications, especially anticoagulants, • History of smoking†, occupational exposures might contribute to bleeding. Patients (e.g. asbestos, silica), drug abuse (crack lung), belonging to this class of hemoptysis are etc. are strong risk factors for massive those suffering from PE, cardiac valvular hemoptysis defects, or CHF • Physical examination—Besides the vital signs †Especially in a male sex, older than 40 years, and smoking (tachycardia, tachypnea, and hypotension history of more than 40 pack-years. Hemoptysis 181

Table 26.3: Physical signs to diagnose in patients with hemoptysis Physical signs Common causes • Vital signs—Tachycardia, tachypnea, and hypotension • Hypovolemia • Oral cavity/ENT—Bleeding gums, epistaxis, • Poor oral hygiene; dental trauma; aphthous ulcer; oropharyngeal ulcers bleeding disorder • Neck—Cervical and axillary lymphadenopathy • TB; pulmonary or intrathoracic malignancy; pulmonary Kaposi’s sarcoma • Skin—Ecchymosis or petechiae • Systemic bleeding disorders • Clubbing • Bronchiectasis; lung abscess; bronchogenic carcinoma • Bronchial breath sounds • Pneumonia • Localized reduced breath sounds/wheezing • Bronchial carcinoma; foreign body • Coarse crepts and rhonchi • Bronchitis, bronchiectasis • Pleural rub • Pneumonia; PE • Tachycardia, raised JVP, S3 gallop, ankle edema, • CHF • basal crepts • Rumbling mid-Diastolic murmur at apex • Mitral stenosis • Tachypnea, loud P2 • PE • Horner’s syndrome • Apical lung tumor; Pancoast tumor

with hypovolemia) which are critical in factor in diagnosing foreign-body aspiration stabilizing patients with massive hemoptysis, causing hemoptysis21 other common physical findings and their • Despite the most extensive investigations significance is given in Table 26.3. about 20-30% cases of hemoptysis remain undiagnosed. Such patients should be RED FLAGS followed up closely for a period of time sufficient to exclude significant underlying • Any male smoker with significant hemoptysis 22 should have a CXR, particularly if associated disease such as bronchogenic carcinoma. with weight loss • In an acutely breathless patient with SELECTIVE GLOSSARY hemoptysis, consider PE if there is no other Carcinoid Tumor—A type of slow growing obvious explanation for his symptoms. neuroendocrine tumor, derived from primitive Indeed, no single symptom or sign or stem cell, usually benign, and found in the combination of clinical findings is suggestive gastrointestinal system (most often in the 20 of pulmonary thromboembolism; further appendix), and sometimes in the lungs or other testing is required in the majority of patients sites; and characterized by attacks of severe • TB is on the increase with rising incidence of flushing of the skin, diarrheal watery stools, HIV/AIDS infection; consider this possibility bronchoconstriction, sudden drops in blood in every individual with risky sexual pressure, edema, and ascites. Symptoms are behavior caused by tumor secretion of serotonin, • Hemoptysis due to foreign body aspiration prostaglandins, and other biologically active can remain undiagnosed for years and may substances. lead to an incorrect diagnosis of asthma, bronchitis, or recurrent pneumonia. A high Churg-Strauss syndrome (allergic granulo- index of suspicion is the most important matosis and allergic angiitis)—It is a disorder 182 Diagnosis: A Symptom-based Approach in Internal Medicine that causes inflammation in blood vessels medical history, but discrepancies are detectable (vasculitis), which restricts blood flow to upon careful evaluation. They usually and readily various organs. The disease can occur at any provide consent for all invasive procedures, age, but it’s more commonly diagnosed in including thoracotomy. middle-aged people. People older than 65 years are unlikely to develop Churg-Strauss Paragonimiasis (pulmonary)—Caused by syndrome. Although the disease may involve Paragonimus westermani, a common lung fluke in any organ, including lungs, skin, gastroin- humans, commonly found in Asia, Africa, and testinal system, kidneys, muscles, joints and Latin America. Human infections occur where local heart, most commonly it affects lungs and people consume improperly cooked freshwater skin. The restricted blood flow to these crustaceans such as lobsters and crabs. Usually no organs can cause temporary or permanent symptoms are observed when the parasites damage. There are three stages of Churg- migrate in the peritoneal cavity. When parasites Strauss syndrome, namely, allergic (asthma, invade the lung, several symptoms including itching, polyp); hypereosinophilia (fever, weight loss, pleuritic and chest pain, cough, and rusty sputum abdominal pain, GI bleeding); and systemic vasculitis may be present. Pulmonary complications of (cough, dyspnea, diarrhea, hematuria). Churg- untreated heavy infection include interstitial Strauss syndrome is progressive, but not pneumonia, bronchitis, and bronchiectasis. everyone develops all three phases, and the Secondary complications may include phases don’t always develop in order. Without bronchopneumonia, lung abscess, pleural effusion, treatment, this disease may be fatal. or empyema. Ectopic paragonimiasis results in granulomatous lesions in the organs other than Cocaine lung—Popularly called as crack lung, the lung. The most commonly affected organs (the term crack characterizes the crackling sound include liver, spleen, omentum, and ovary. The most heard when cocaine freebase is smoked); cocaine serious illness is cerebral paragonimiasis. has multisystemic effects, and virtually every organ system may be a site of action. Crack lung, REFERENCES a syndrome usually occurring 1 to 48 hours after heavy cocaine smoking, is a hypersensitivity 1. Ibrahim WH. Massive haemoptysis: The definition should be revised (letter). Eur Respir J 2008;32(4): pneumonitis. It consists of the constellation of 1131-2: [PMID: 18827169: Free full text]. chest pain, cough with hemoptysis, dyspnea, 2. Jones R, et al. Alarm symptoms in early diagnosis bronchospasm, pruritus, fever, diffuse alveolar of cancer in primary care: Cohort study using General Practice Research Database. BMJ 2007; infiltrates without effusion, and pulmonary and 334:1040, doi: 10.1136/bmj.39171.637106.AE. systemic eosinophilia. [PMID: 17493982: Free full text]. 3. Savale, et al. Cryptogenic hemoptysis: From a Factitious hemoptysis (Münchhausen hemo- benign to a life-threatening pathologic vascular condition. Am J Respir Crit Care Med 2007; ptysis)—When a patient presents with history 175(11):1181-5. Epub 2007 Mar 1. [PMID: of hemoptysis, especially recurrent hemoptysis 17332480: Free full text]. with multiple normal reports from multiple 4. Löschhorn C Dieulafoy’s disease of the lung: A potential disaster for the bronchoscopist. hospitals, a factitious cause should be considered Respiration. 2006;73(4):562-5. Epub 2005 Aug when the medical history or the patient’s 18. [PMID: 16141709: Abstract]. behavior is unusual. Most patients are young in 5. Alasaly K, et al. Cryptogenic organizing pneumonia. A report of 25 cases and a review of age, and employees in the health care profession; the literature. Medicine (Baltimore). 1995; they generally have a somewhat reasonable 74(4):201-11. [PMID: 7623655: Abstract]. Hemoptysis 183

6. Tashkin DP. Airway effects of marijuana, cocaine, 15. Tak S, et al. Haemoptysis in patients with a normal and other inhaled illicit agents. Curr Opin Pulm : Bronchoscopy-CT correlation. Med 2001;7(2):43-61. [PMID: 11224724: Australas Radiol 1999;43(4):451-5. [PMID: Abstract]. 10901958: Abstract]. 7. National Guideline Clearinghouse 2007 May 16. Bruzzi JF, et al. Multi-detector row CT of 21:10606. hemoptysis. Radiographics 2006;26(1):3-22. 8. Lee CH, et al. Airway lesions presenting with a [PMID: 16418239: Abstract]. normal chest X-ray. Taiwan Yi Xue Hui Za Zhi. 17. Lawler LP, et al. Multi-detector row CT of thoracic 1989;88(5):498-502. [PMID: 2794950: Abstract]. 9. Pyng Lee, et al. Advances in Bronchoscopy- disease with emphasis on 3D volume rendering Therapeutic Bronchoscopy. JAPI;2004;52:905-14. and CT angiography. Radiographics 2001; 10. Johnson JL. Manifestations of hemoptysis. 21(5):1257-73. [PMID: 11553832: Abstract]. Postgrad Med 2002;112(4):101:13. 18. Das CJ, et al. Thoracic application of multi- 11. Sen RP, et al. Fiberoptic bronchoscopy for detector CT. Indian J Chest Dis Allied Sci. 2007; refractory cough. Chest 1991;99(1):33-5. [PMID: 49(1):29-36. [PMID: 17256564: Abstract]. 1984981: Abstract]. 19. Boiselle PM. Multislice helical CT of the central 12. Su WJ, et al. Chest roentgenographic guidelines airways. Radiol Clin North Am 2003;41(3):561- in the selection of patients for fiberoptic 74. [PMID: 12797606: Abstract]. bronchoscopy. Chest 1993;103(4):1198- 20. Tierney LM, et al. Current Med. Diag. & Treat. 201.PMID: 8131465: Free full text]. 2006;9:280 Disorders of the Pul. Circulation. 13. Revel MP, et al. Can CT replace bronchoscopy 21. Willett LL, et al. An unusual cause of chronic in the detection of the site and cause of bleeding cough. Foreign body aspiration. J Gen Intern Med in patients with large or massive hemoptysis? 2006;21(2):C1-3. [PMID: 16606374: Free full AJR Am J Roentgenol. 2002;179(5):1217-24. text]. [PMID: 12388502: Free full text]. 14. McGuinness G, et al. Hemoptysis: Prospective 22. Herth F, et al. Long-term outcome and lung cancer high-resolution CT/bronchoscopic correlation. incidence in patients with hemoptysis of unknown Chest 1994;105(4):1155-62. [PMID: 8162743: origin. Chest 2001;120(5):1592-4. [PMID: Free full text]. 11713139: Free full text]. CHAPTER 27 Hiccups

SYNOPSIS including a reported case of a man whose intractable hiccups lasting for four days Hiccups (hiccough) or singultus may be defined as completely ceased after sexual intercourse (i.e. a complex reflex arc phenomenon characterized ejaculation) with his wife.2 by involuntary, spasmodic contraction of A bout is any episode lasting more diaphragm, and respiratory intercostal muscles, than a few minutes. Chronic hiccups or those followed by abrupt closure of glottis, resulting in recurring as repetitive attacks are the ones the characteristic ‘hic’ sound. needing medical attention. Based on its duration, The reflex arc involves afferents, which travel hiccups are classified as: along with the vagus and phrenic nerve fibers, the  Acute—Any episode lasting up to 48 hours, pharyngeal plexus (C2-C4), and the sympathetic  Persistent or protracted—hiccups for >48 chain (T6-T12) to the brainstem ‘hiccup center’. The hours, and phrenic nerve (C3-C5) serves as the efferent  Intractable (diabolic)—hiccups for >1 pathway. Any irritation or stimulation along this month*. reflex pathway (i.e. peripheral—involving the vagus Though usually benign and self-limiting or phrenic nerve and structures adjacent to the annoyance, they can be a major cause of distress, diaphragm, or central—involving the CNS) can interrupting talking, eating, and sleeping, resulting result in hiccups (Table 27.1). Fluoroscopy reveals in weight loss, exhaustion, and depression; that only one hemidiaphragm is affected, with the occasionally it may even reflect serious underlying left diaphragm being more frequently involved than illness, often associated with organic conditions, the right, although bilateral involvement may occur. Hiccups are a common part of life, and * The world record stands at 68 years, with a gentleman called appear to serve no purpose in humans. It affects Charles Osborne, USA, who hiccupped continuously from 1922 1 to 1990. The hiccups started in 1922 at a rate of 40 times per everyone, at any age—and in utero —sometime minute, slowing to 20 hiccups per minute and eventually or the other, with its frequency being between 4 stopping on June 5, 1990, a total of 68 years. Despite his condition, and 60 per minute. Usually it is a short-lived Osborne was able to lead a normal life, and was even married two times. It has been estimated that Osborne hiccupped 430 annoyance that resolves spontaneously,or million times over the 68 year period. [ref. - http:// responds to one of several anecdotal remedies, en.wikipedia.org/wiki/Charles_Osborne_ (hiccups)]. Hiccups 185

Table 27.1: Common causes of hiccups CNS Infection (meningitis, encephalitis) Intracranial tumor Stroke, basilar artery insufficiency Trauma Surgery AV malformation Multiple sclerosis Metabolic Toxic (alcohol, drug abuse) Uremia Electrolyte imbalance Diabetic ketoacidosis Hyperventilation () Irritation of vagus or phrenic nerve and branches at the level of: Head and neck Foreign body in the ear Goiter Cervical tumor Thorax Gastric distension Pneumonia Empyema Gastroesophageal reflux disease Esophageal obstruction Mediastinal tumor Inferior wall myocardial infarction Pericarditis Aneurysm Abdomen Gastric distension Subdiaphragmatic abscess Bowel obstruction Hepatitis Cholecystitis Pancreatitis Pancreatic malignancy Peritonitis Tumor Surgical General anesthesia, postoperative Psychogenic Stress, excitement, hysteria specially advanced tumors of the digestive tract.3 • Sudden emotional excitement (laughing) Symptomatic relief to the exasperated patient while • Sudden temperature changes (hot then cold conducting a judicious evaluation to determine the liquids, hot then cold shower) cause is the initial approach in the management with • Psychogenic (anxiety) persistent hiccups. • Alcohol excess (acute or chronic). Occasional DIFFERENTIAL DIAGNOSIS • Metabolic (Uremia, diabetic ketoacidosis, Common electrolyte imbalance) • Neck (goiter) • Abdominal distension (aerophagy, carbonated • Thorax (pneumonia, reflux esophagitis, beverages, excess smoking, hurried-eating) cardiomegaly) 186 Diagnosis: A Symptom-based Approach in Internal Medicine

• Abdomen (subphrenic abscess, hepatitis, • Alkaline phosphatase elevated in hepatic hepatomegaly, cholecystitis, paralytic ileus) obstruction. • CNS infection (meningitis, encephalitis). Fluoroscopy of Diaphragmatic Movement Rare • Confirm diagnosis if malingering suspected • Determine if unilateral or bilateral before 4, 5 • Drugs (high dose steroids, benzodiazepines) invasive therapy, e.g. phrenic nerve block • Toxemia (hyperpyrexia, septicemia, peritonitis) surgery or phrenic nerve or diaphragmatic • Neoplasms (head and neck, esophagus, pacing. mediastinum, gastric, hepatic, pancreatic) • Thorax (pericarditis, inferior wall myocardial CXR infarction) • Consolidation, cavitation, hilar mass, media- • CNS (stroke, multiple sclerosis) stinal mass, effusion, and collapse due to • Foreign body in ear various causes such as pneumonia, malig- • Head trauma nancy, lymphoma, and aneurysm may be • Psychogenic (neurosis, hysteria). noted as etiological factors • Elevation of a hemidiaphragm may be due INVESTIGATIONS—GENERAL to phrenic nerve palsy from carcinomatous infiltration, diaphragmatic hernia, or hepato- CBC, Blood Film megaly on right side may be seen. • Leukocytosis in infection, e.g. subphrenic ECG7 abscess, pneumonia • Malarial parasites may be seen on blood film • In patients suspected with MI, arrhythmia, in patients with pyrexia as a cause of hiccups. pericarditis.

ESR INVESTIGATIONS—SPECIFIC

• Elevated in infection, malignancy. EGD • To evaluate in patients with reflux, acid-peptic Urea/Creatinine disorder, and esophageal carcinoma.8 • Elevated in uremia. US Abdomen Electrolytes—Na, K, Ca • To evaluate diaphragmatic movements, and subdiaphragmatic, hepatic, and gallbladder • Hyponatremia, hypokalemia, hypocalcemia, lesions. hypercalcemia, and hyperglycemia can precipitate hiccups CT Scan Chest • A study shows that for every 10 mEq/l • To define and identify pulmonary infection, reduction in serum sodium, patients likely tumors, mediastinal mass, and aortic to be 17 times at risk of developing hiccups.6 aneurysm.

LFT MRI Brain9

• ALT, AST values elevated in hepatitis, and • Indicated in patients with intractable hiccups cirrhosis (with or without neurological signs), e.g. Hiccups 187

raised intracranial pressure (with contrain- CLINICAL NOTES dication to lumbar puncture), intracranial bleeding, tumor, multiple sclerosis, and • Hiccups commonly occur as an isolated brief encephalitis symptom; they self-terminate or respond to • To differentiate psychogenic hiccup from simple maneuvers, and need no investiga- neurological disorder. tion or follow-up care. • In contrast, patients with persistent Bronchoscopy hiccups require thorough evaluation as they are frequently associated with • May be indicated to confirm a suspected lung underlying pathological process, mostly neoplasm with CT/MRI of chest with related to respiratory, abdominal, and subsequent biopsy (Bx). nervous systems. Therefore, the history Echocardiography and examination should be focused similarly. • To rule out pericardial effusion, pericarditis. • History includes—Onset, duration, assoc- iated symptoms and events (Table 27.2), CSF alcohol and drug abuse, surgery (craniotomy, • In patients suspected with meningitis, and thoracotomy, laparotomy), and past history encephalitis. of hiccups and its treatment.

Table 27.2: Symptoms and signs of common pathologic disorders associated with hiccups Symptoms and signs Possible disorders • Cough, sputum, fever, chest pain; lung consolidation, • Pneumonitis effusion, pleural rub • Above symptoms, dyspnea, weight loss, with possible • Bronchial tumor hemoptysis in a smoker; clubbing, lymphadenopathy • Above symptoms, stridor, hoarse voice, neck/chest • Extrinsic compression by mediastinal swelling, engorged veins over chest and neck, night mass (lung carcinoma, lymphoma, aortic aneurysm, sweats; Horner’s syndrome retrosternal goiter, dermoid cyst) • Bovine cough, hoarse voice, stridor, weight loss; • Intrinsic laryngeal lesion/Extrinsic compression (benign/ neck mass malignant) • Heartburn, regurgitation • Gastroesophageal reflux disease, hiatal hernia, acid- peptic disease • Progressive dysphagia, dyspepsia, weight loss • Esophageal compression (carcinoma of the esophagus), carcinoma stomach • Pain abdomen, referred to shoulder/scapula, fever, • Cholecystitis, hepatitis, subdiaphragmatic abscess • Alcohol excess, icterus, back pain, weight loss, • Hepatomegaly, pancreatitis/malignancy • Headache, neck stiffens, fever, altered • Meningitis, encephalitis, CNS mass lesion consciousness, seizures • Sudden onset headache, aphasia, visual defects, • Stroke, basilar artery insufficiency motor/sensory deficit • Oliguria, edema, hypertension • Uremia • Amelioration of hiccups by sleep, bizarre • Hysteria accompanying symptoms 188 Diagnosis: A Symptom-based Approach in Internal Medicine

• Physical examination includes head, neck REFERENCES

(thyroid, lymph nodes, neck vessels), ear 1. Marsál K. Ultrasonic assessment of fetal activity. (tympanic membrane irritation by foreign Clin Obstet Gynaecol 1983;10(3):541-63. [PMID: body), chest (consolidation, pleural effusion), 6360464: Abstract]. 2. Peleg R, et al. Case report: Sexual intercourse as abdomen (hepatomegaly, mass, distension), potential treatment for intractable hiccups. Can and CNS for neurologic deficit. Fam Physician. 2000;46:1631-2. [PMID: 10955182: Free full article]. • Presence of hiccups during sleep usually 3. Martínez Rey C, et al. Hiccup: Review of 24 cases. indicates an underlying organic cause; Rev Med Chil 2007;135(9):1132-8. Epub 2007 Nov whereas its absence during sleep indicates a 15. [PMID: 18064367: Abstract]. 4. Thompson DF, et al. Drug-induced hiccups. Ann psychogenic or idiopathic etiology. Pharmacother. 1997;31(3):367-9.[PMID: 9066948: • Pathologic laughing occurs in approximately Abstract]. 5. Bagheri H, et al. Drug-induced hiccup: A review 10% of patients with multiple sclerosis, of the France pharmacologic vigilance database. especially when patients have entered the Therapie. 1999;54(1):35-9. [PMID: 10216420: chronic stage.10 Abstract]. 6. George J, et al. Hyponatraemia and hiccups. Natl Med J India. 1996;9(3):107-9. [PMID: 8664818: RED FLAGS Abstract]. 7. Krysiak W, et al. Hiccups as a myocardial ischemia • Although benign hiccups occur less frequent symptom. Pol Arch Med Wewn 2008;118(3):148-51. [PMID: 18476462: Abstract]. in adult life, intractable hiccups are more 8. Khorakiwala T, et al. Hiccups: An unrecognized common in adult life symptom of esophageal cancer? Am J Gastroenterol. • Exclude multiple sclerosis in any patient with 2008;103(3):801. [PMID: 18341501]. 9. al Deeb SM, et al. Intractable hiccup induced by persistent hiccups as psychogenic, especially brainstem lesion. J Neurol Sci 1991;103(2):144-50. in young adults [PMID 1880531: Abstract]. 10. de Seze J, et al. Pathologic laughing and intractable • Persistent hiccups are reported to be an early hiccups can occur early in multiple sclerosis. manifestation of rare disorders such as Neurology. 2006;67(9):1684-6. [PMID: 17101907: Addison’s disease,11 Parkinson’s disease,12 Abstract]. 13 14 11. Hardo PG. Intractable hiccups—an early feature SLE, and herpes zoster of Addison’s disease. Postgrad Med J 1989; • Drug-induced hiccups are a known pheno- 65(770):918-9[PMID: 2616432: Free full text]. 12. Yardimci N. A diagnostic challenge of Parkinson’s menon; hence suspect any medication that a disease: Intractable hiccups. Parkinsonism Relat patient may be taking as a cause for persistent Disord. 2008; 14(5):446-7. Epub 2008 Mar 10. hiccups [PMID: 18329942: Abstract]. 13. Delèvaux I, et al. Intractable hiccup as the initial • In a patient with hiccups and hypercalcemia, presenting feature of systemic lupus erythematosus. prompt work up is indicated to rule out Lupus 2005; 14(5):406-8. [PMID: 15934443: Abstract]. 14. Reddy BV, et al. Persistent hiccups: A rare malignancy, notably breast and lung cancer prodromal manifestation of herpes zoster. Indian J and multiple myeloma. Dermatol Venereol Leprol 2007; 73:352-3. CHAPTER 28 Insomnia

SYNOPSIS  Short-term insomnia—lasts for few days to three weeks, e.g. medical illness, protracted stress, and Insomnia, commonly understood as insufficient or  Long-term insomnia (chronic insomnia)— unrestorative sleep, is a subgroup of various types insomnia occurring at least three times per of sleep disorders* as defined by DSM-IV-TR system. week for more than four weeks, and that it The profile of insomnia differs from patient causes either marked distress or interference to patient, and may even change over time with social or occupational functioning. within a given patient. It is therefore important to carefully categorize the individual’s sleep According to DSM-IV-TR criteria, primary disorder. Specifically, insomnia is known as, insomnia is sleeplessness that is not attributable ‘Disorder of Initiation and/ Maintenance of Sleep, to a medical, psychiatric, or environmental i.e. DIMS. As is evident, insomnia consists of two cause. Additionally: components: difficulty in initiating sleep (going  The predominant symptom is difficulty off to sleep) and difficulty in maintaining sleep initiating or maintaining sleep, or nonres- (remaining asleep). torative sleep, for at least 1 month.  The sleep disturbance (or associated daytime Clinically, insomnia is classified as: fatigue) causes clinically significant distress  Transient insomnia—lasting for few nights such or impairment in social, occupational, or as change in sleep schedule or environment, other important areas of functioning.  *Sleep disorders include 4 general groups: 1—Primary The sleep disturbance does not occur Sleep Disorders; 2—Dyssomnias - (a) - insomnia, i.e. exclusively during the course of narcolepsy, DIMS; and (b)- Hypersomnia(i.e. disorders of excessive breathing-related sleep disorder, circadian sleepiness such as narcolepsy, sleep apnea, Kleine-Levin syndrome, nocturnal myoclonus, e.g. restless legs rhythm sleep disorder, or a parasomnia. syndrome, periodic limb ); 3—  The disturbance does not occur exclusively Parasomnias (i.e. abnormal behaviors during sleep such during the course of another mental disorder as somnambulism, night-terrors, nightmares, enuresis); and 4—Sleep Disorder Related to Another Mental (e.g. major depressive disorder, generalized Disorder (i.e. secondary to medical/psychiatric disorders). anxiety disorder, a delirium). 190

 The disturbance is not due to the direct Occasional physiological effects of a substance (e.g. • Cardiac (PND, LVF) drug abuse, medication) or a general • Respiratory (asthma, COPD) medical condition. Conversely, secondary • Gastrointestinal (GERD) insomnia may arise from several recogni- • Endocrine (hyperglycemia, hyperthyroi- zable sources. dism, perimenopause) Patients with insomnia may present with • Renal (prostatism, BPH) nonspecific or unusual symptoms. They range • Neurological (peripheral neuropathy, from fatigue, lack of concentration, headache, dementia, psychosis, seizures, PD). irritability, myalgias, GI upset, problems with Rare interpersonal relationship, and overall • Sleep apnea syndrome (central and obstru- decreased quality of life. ctive : vide infra ↓↓) Most insomnia is transient or short-term in • Mental disorders (mania, hypomania, and duration; their diagnosis based mainly on schizophrenia) historical and physical findings. In problematic • Fatal familial insomnia (FFI: vide infra ↓↓). or chronic insomnia, review of medical and psychiatric history, and full polysomnography INVESTIGATIONS—GENERAL in a sleep laboratory may be essential to determine the source of sleep difficulty. CBC • Erythrocytosis may be seen in patients with DIFFERENTIAL DIAGNOSIS obstructive sleep apnea (OSA), or chronic lung Common disease.

• Sleep preoccupation (‘trying too hard to TFTs sleep’, unnecessary concern about inability • As indicated in hyperthyroidism. to sleep) ECG • Poor sleep hygiene • For evidence of cor pulmonale and cardiac • Biorhythm disruption (jet lag syndrome, arrhythmias. work shift change) • Psychosocial stressors (bereavement, Pulse Oximetry1-4 family-related stress) • Nocturnal oxygen desaturation (NOD)— • Pain of acute/chronic physical illness (injury, Evaluation of NOD may be used as a pyrexia, headaches, arthritis) screening test in patients with a high • Psychiatric (anxiety, depression) probability of OSA or sleep disordered • Substance abuse (alcohol, caffeine, cocaine, breathing. The absence of desaturation (at nicotine, benzodiazepines) the rate of at least 10 to 15 events per hour) • Substance withdrawal (rebound insomnia) may be used to exclude OSA • Medications (decongestants, bronchodila- • NOD may be an important contributor to IHD, tors, OTC agents) coronary restenosis in patients treated with • Chronic fatigue syndrome (CFS: vide infra ↓↓). stent placement, and metabolic syndrome. Insomnia 191

INVESTIGATIONS—SPECIFIC Actigraphy5 Sleep Diary† • A new technique that records individual’s activities during sleep and waking; useful in • Maintained for a period of two weeks to the diagnosis of primary sleep disorders, collect information on bedtime and time of hypersomnia, and parasomnia. rising, duration and quantity of sleep, timing and quantity of meals and exercise, and CT/MRI Brain ingestion of alcohol, drugs, and caffeine. The • In special circumstances such as history of findings are correlated with the patient’s trauma, Alzheimer’s disease, PD, MS, seizure subjective assessments of insomnia, and help disorder, and mass lesion. to determine sleep pattern of the patient, its severity, and causes; and also provides Mini-Mental State Examination (MMSE) and educative value to learn more about sleep Geriatric Depression Scale hygiene • In elderly patients these procedures may be • Other tools that may be used to assess necessary to identify comorbid conditions insomnia include—Epworth Sleepiness such as dementia and depression which Scale‡, Sleep disorders questionnaire§, often result in insomnia. Insomnia Severity Inventory, and the Drug Toxicology Screen Pittsburgh Sleep Quality Index**. • In occult cases of insomnia suspected to be Polysomnography (Sleep Study) due to substance abuse. • It involves monitoring and staging sleep, i.e. by recording brain waves with EEC, eye CLINICAL NOTES movements with electrooculogram (EOG), • History—A comprehensive sleep history and chin movements with EMG; breathing obtained from both the patient and the patterns, e.g. airflow, respiratory effort, patient’s bed partner is an important pulse oximetry, heart rate; limb movements, component in the initial evaluation of e.g. of the legs and occasionally arms with insomnia (Table 28.1) EMG, and body position. Most patients are • History should focus on age, onset and also monitored with remote audio and video duration, patient’s perception of sleep recordings to observe for behaviors and problem, coping mechanisms, day-time seizures. Polysomnography is used in naps, occupation, lifestyle, family and work- special circumstances, e.g. to exclude related stress, habits, travel, medications, primary sleep disorders. addiction, and any medical illness. This step helps to eliminate insomnia due to another †Available at: http://www.helpguide.org/life/pdfs/ medical, psychiatric, substance abuse or sleep_diary.pdf; http://content.revolutionhealth.com/ circadian rhythm disorder contentfiles/media-pdf-hw-form_tm4434.pdf; and • Nocturnal symptoms6—A specific enquiry http://www.shuteye.com/sleep-solutions/sleep-patterns/ sleep-diary.aspx should be made from the patient as well as ‡http://www.reliamed.com/Forms/SleepinessScale.pdf bed-partner about ‘nocturnal’ symptoms § http://www.tmj-sleep-pain.com/sleep-disorders.htm giving rise to transient or chronic insomnia. **http://www.consultgerirn.org/uploads/File/trythis/ issue06_1.pdf These include respiratory distress, , 192 Diagnosis: A Symptom-based Approach in Internal Medicine

Table 28.1: Taking a sleep history bed-wetting, sleepwalking, night terrors, night mares, etc. are typical of parasomnias General • Chief complaint, i.e. Nature of specific sleep problem • Physical findings such as obesity, hyper- • Onset, duration, and course of the symptoms tension, large neck, large tongue, or abnor- • Psychiatric/medical history • Life events/current social status malities in the ear-nose-throat examination • Drug use (prescribed or illicit) may be associated with OSA. Signs of • Daily routine, dietary habits, lifestyle psychiatric disorders and medical diseases • Sleep diary data assessment, if maintained • Recent weight gain/loss (diabetes mellitus, thyroid related to coronary disease, obstructive disorder, depression) respiratory disease, and neurologic system • Sleep environment (TV, noise, lights) should be evaluated7 • Family h/o sleep disorders (FFI). • Sleep apnea when suspected needs further Night time • Do you go to bed at the same time every night? evaluation of the predisposing factors for • How long does it take to fall asleep? (Sleep latency; obstruction to airways, including enlarged related to initiating sleep- due to poor sleep hygiene, tonsils and adenoids, micrognathia, stimulant medications, drugs, etc.) • Quality of sleep - sound sleep? Disturbed—Frequent macroglossia, and endocrinopathies such as wake ups? hypothyroidism and acromegaly • What do you do when you wake up at night? Watching TV? Reading? Take sedatives? • Although the need for sleep does not • Duration of sleep—estimated time spent sleeping at necessarily decrease with age, the incidence night (related to remaining asleep—due to alcohol, of sleep dysfunctions increases with age anxiety, depression, asthma, BPH, etc.) • Do you snore, feel chocked-up, or wake-up which are normally related to pathologic confused? (OSA) processes that are associated with aging, e.g. • Does your legs or arms jerk/kick during sleep? OA, LVF, BPH, and psychiatric disorders (PLMS) • Do you experience ‘creeping, crawling feeling’ in • Although insomnia is commonly viewed as the legs? (RLS) a symptom of anxiety and depression, Day time studies indicate that it often predates the • Are your waking times regular? emergence of these disorders, suggesting • Do you feel refreshed on waking? (depression) • Do you take naps in the daytime? that insomnia treatment could possibly • Time of napping, and its duration (excessive daytime prevent psychiatric morbidity. somnolence) • Do you fall asleep while driving, reading, watching RED FLAGS TV, or talking to friends? (narcolepsy) Questions for the sleep partner: Does he or she complain • An insomniac should be differentiated from of patient’s: a short sleeper who needs less than six hours • Loud snoring, gasping, chocking, or at times stop breathing? (OSA) of sleep per night and has no symptoms or • Legs and arms jerk/kick during sleep (PLMS) dysfunction • Temporary inability to talk or move when falling asleep or awakening? (sleep paralysis, cataplexy) • Potentially serious problems may be [PLMS—periodic limb movement syndrome; RLS— associated with OSA such as systemic and restless leg syndrome] pulmonary hypertension, corpulmonale, tachyarrhythmias, and IHD gasping (OSA); jerking of feet and legs • In patients with sleep apnea associated with (periodic limb movement disorder: vide CNS disfunction, consider intracranial infra:↓↓); and dyspepsia, cough, chest lesion (e.g. thalamic tumor), nocturnal discomfort (GERD, CAD). Symptoms such as seizures and drug abuse. Insomnia 193

SELECTIVE GLOSSARY of the upper airway that occur during sleep and lead to breathing cessation (defined as a period Chronic fatigue syndrome (CFS)—It is a clinical of apnea > 10 sec) despite persistent respiratory diagnosis characterized by an unexplained, efforts. Symptoms include restlessness, snoring, persistent or relapsing chronic fatigue that is of at recurrent awakening, morning headache, and least six months’ duration, and characterized by excessive daytime sleepiness. Anatomic risk four or more of the following symptoms present factors include obesity, an oropharynx concurrently for at least six months, namely- “crowded” by a short or retracted mandible, a impairment of memory or concentration; diffuse prominent tongue base or tonsils, a rounded pain; sore throat; tender lymph nodes; new head shape and a short neck, a neck circum- headaches; and nonrestorative sleep. Infectious, ference > 43 cm, thick lateral pharyngeal walls, immunological, neuroendocrine, sleep, and or lateral parapharyngeal fat pads. Other psychiatric mechanisms have been proposed as identified risk factors include postmenopausal etiological factors; however, a unifying etiology status, aging, and alcohol or sedative use. A for CFS has yet to emerge. Clinical evaluation is family history of sleep apnea is present in 25 to based upon above standardized guidelines, 40% of cases. Many people with OSA have including an assessment of functional impair- disorders such as hypertension, stroke, ments. Since there are no specific diagnostic tests diabetes, gastroesophageal reflux disease, or biological markers for CFS, the diagnosis is nocturnal angina, heart failure, acromegaly, made by ruling out other causes of fatigue such as and hypothyroidism. OSA can also be eating disorders, psychotic disorders, bipolar associated with cardiac arrhythmias (e.g. disorder, melancholic depression, and substance bradycardia, asystole). Diagnosis is based on abusewithin 2 years of the onset of fatigue. Trigger sleep history, and polysomnography. points, which suggest fibromyalgia, are absent in patients with CFS and fibromyalgia rarely coexist Periodic limb movement disorder (PLMD)—It is in the same patient. characterized by bilateral repeated, rhythmic, small-amplitude jerking or twitching movements 8 Fatal familial insomnia (FFI) —Fatal familial in the lower extremities and, less frequently, in insomnia is a rare inherited autosomal dominant the arms. These movements occur every 20 to 90 disorder characterized by degeneration of the seconds, mainly in nonrapid eye movement sleep, thalamus and progressive insomnia. It is caused and can lead to arousals, which are usually not by a mutation in the prion protein. Patients perceived by the patient. Rather, the presenting present in their 50’s with a progressive sleep complaint is poor sleep and daytime somnolence. disorder. There may be autonomic dysfunction. Occasionally, a bed partner may provide the Dementia and death usually occur within one year history of limb movements. following presentation. Measuring the cerebral Physical and neurological examinations are metabolic rate of glucose (CMRglc) with 2-[18F] normal. In some cases, excessive somnolence fluoro-2-deoxy-D-glucose PET in parallel with may be noted. Definitive diagnosis requires detailed clinical, neuropsychological examinations polysomnography. and polysomnography with EEG spectral analyses This condition and restless legs syndrome may help in presymptomatic diagnosis of FFI. are more common in older patients. Obstructive sleep apnea (OSA)—It is charact- Restless Legs Syndrome (RLS)/Ekbom erized by episodes of partial or complete closure syndrome—A disorder characterized by: (1) a 194 Diagnosis: A Symptom-based Approach in Internal Medicine desire to move the limbs, often with pares- lower brainstem lesions, stroke, Parkinson’s thesias or dysesthesias; (2) symptoms exacer- disease, COPD, CHF, diabetes mellitus, thyroid bated by rest and relieved by activity; (3) motor disease, medication effect, and other conditions. restlessness; and (4) nocturnal increase in The most common reported symptoms are severity of symptoms. Most patients, however, insomnia, frequent awakenings, a nonrestorative simply relate a vague, nonpainful, indescribable sleep, , shortness of breath, and excessive discomfort in the limbs and use terms, such as daytime sleepiness or fatigue. Sometimes, bed crawling, creeping, jittery, tingling, burning, partners report witnessed and mild itching, aching, etc. The unpleasant limb snoring. The laboratory findings are not helpful. sensations are precipitated by rest or inactivity, Primary central sleep apnea is frequently especially in bed at night or in the car, airplane, associated with OSA. When both forms are theater, etc. Motor activity characteristically present the condition is referred to as mixed sleep relieves the limb discomfort. Most patients apnea, i.e. sleep apnea syndrome. notice worsening of symptoms in the evening, usually in bed before sleep or in the middle of REFERENCES the night, followed by improvement early in 1. Fanfulla F, et al. The relationship of daytime hypo- the morning. In severe cases, patients experience xemia and nocturnal hypoxia in obstructive sleep symptoms both in the day and night. Although apnea syndrome. Sleep 2008;31(2):249-55. [PMID: 18274273: Abstract]. RLS is idiopathic in most cases, it can be 2. Thomas VD, et al. Predictors of nocturnal oxygen associated with several conditions, particularly desaturation in chronic obstructive pulmonary iron, folate, and B deficiency. The possible disease in a South Indian population. J Postgrad 12 Med 2002;48:101[Free full text]. secondary causes of RLS include cigarette 3. Carney RM, et al. Insomnia and depression prior smoking, varicose veins, hypothyroidism or to myocardial infarction. Psychosom Med 1990; hyperthyroidism, acute intermittent porphyria; 52(6):603-9. [PMID: 2287700: Free full text]. 4. Hayashi M. Nocturnal oxygen desaturation as a myelopathy or myelitis, carcinoma, and drug predictive risk factor for coronary restenosis after withdrawal from vasodilators, sedatives, coronary intervention. Circ J 2005;69(11): 1320- imipramine, or opiates. This condition may be 6. [PMID: 16247205: Free full text]. 5. Morgenthaler T, et al. Practice parameters for associated with uremia, diabetes mellitus, and the use of actigraphy in the assessment of rheumatoid arthritis. The diagnosis of RLS rests sleep and sleep disorders: An update for 2007. largely on clinical history. Polysomnography is Sleep 2007;30(4):519-29. [PMID: 17520797: rarely necessary. Abstract]. 6. Pressman MR, et al. Nocturia. A rarely recognized symptom of sleep apnea and other Sleep apnea: central—A condition associated occult sleep disorders. Arch Intern Med 1996; with multiple episodes of sleep apnea which are 156(5):545-50. [PMID:8604961: Abstract]. distinguished from obstructive sleep apnea (OSA) 7. Budhiraja R, et al. Sleep-disordered breathing and cardiovascular health. Curr Opin Pulm Med 2005; by the complete cessation of efforts to breathe. 11(6):501-6. [PMID: 16217175: Abstract]. This disorder is associated with dysfunction of 8. Cortelli P, et al. Presymptomatic diagnosis in central nervous system centers that regulate fatal familial insomnia: Serial neurophysiological respiration or cardiac dysfunction. This condition and 18FDG-PET studies. Brain 2006;129(Pt 3):668-75. Epub 2006 Jan 6. [PMID: 16399807: may be idiopathic (primary) or associated with Abstract]. CHAPTER 29 Jaundice

SYNOPSIS high colored urine (due to increased glomerular filtration of conjugated bilirubin), pale stools (as Jaundice (icterus) is yellowish discoloration of the excretion of bilirubin into the intestine is tissues, noticed especially in the skin, sclera*, and decreased), itching skin (presumably from the mucous membrane, due to excess accumulation of deposition of bile salts), etc. bilirubin—a reddish pigment of heme metabolism. Very often family members notice a yellow Hyperbilirubinemia may be due to excessive discoloring of the sclera or skin before the patient hemoglobin degradation/bilirubin overpro- notices. This objective or clinical jaundice is usually duction, defective hepatic uptake/conjugation, evident when the serum (conjugated) bilirubin or impaired excretion of bilirubin by the reaches 2-4 mg/ dl (40-80 μmol/l). Because elastin hepatobiliary system; i.e. interruption of the has a high affinity for bilirubin, and scleral tissue breakdown pathway at any of a number of is rich in elastin, jaundice is best detected by steps—from hemoglobin breakdown to uptake examining the sclerae; a second place to examine by the hepatocellular membrane to excretion into is underneath the tongue, i.e. frenulum of the the biliary system—will result in jaundice, with tongue. As jaundice deepens, the skin color may an increase in serum bilirubin. change from a yellow tinge to deep yellow and Patient occasionally present with complaints eventually, in long standing jaundice (e.g. chronic of ‘turning yellow’; usually the symptoms of extrahepatic biliary obstruction, primary biliary jaundice (excluding those in whom it is cirrhosis), to a greenish hue due to oxidation of secondary to hemolysis) referred by the patient bilirubin to biliverdin. are nonspecific, such as loss of appetite, nausea, Although jaundice in adults is typically vomiting, pain abdomen, lack of taste, lethargy, classified into prehepatic (due to hemolysis), hepatocellular (due to intrinsic liver disease), * The usual term scleral icterus is misleading, since bilirubin and cholestatic (obstructive—intrahepatic or is actually deposited in the vascular conjunctiva rather than posthepatic cholestasis) jaundice (Table 29.1), the avascular sclerae. (Talley NJ et al. Clinical examination: A Systematic Guide to Physical Diagnosis 2006, 5th ed. multiple mechanisms may be operative p.18). simultaneously; for instance in patients with 196

Table 29.1: Clinical approach to the patient with jaundice# Diagnostic factors Type of jaundice Hemolytic Hepatocellular Intrahepatic cholestatic Extrahepatic cholestatic Symptoms Mild jaundice; may be Nausea, vomiting, Deep jaundice, dark- Deep jaundice, dark-colored asymptomatic or back- fever, anorexia colored urine, light- urine, light-colored stools, ache, joint pain colored stools, pruritus, cholangitis, biliary pruritus colic Physical findings Pallor; Tender hepatomegaly, Tender Hepatomegaly, palpable splenomegaly* hepatomegaly gallbladder, abdominal mass Liver tests Bilirubin Total <6 mg/dl Variable Variable, may be <30 mg/dl >30 mg/dl Direct (i.e. conjugated) <20% >50% >50% >50% Alanine aminotransferase Normal >5-fold increase 2- to 5-fold increase <2- to 3-fold increase; >3- to 5-fold increase with cholangitis Alkaline phosphatase Normal <2- to 3-fold increase >3- to 5-fold increase >3- to 5-fold increase Prothrombin time Normal Prolonged Prolonged Prolonged Corrected by vitamin K …….. No Variable Yes Ultrasonography of liver Biliary dilatation No No No Yes Endoscopic retrograde Not necessary Not necessary Usually not Usually necessary cholangiopancreatography necessary *May or may not be present. # Source: Kamath Patrick S. Clinical Approach to the Patient with Abnormal Liver Test Results. Mayo Clin Proc 1996; 71:1089-95.

acute hepatitis, cirrhosis, prolonged biliary Occasional tract obstruction, familial and immaturity • Secondary to systemic infections (malaria; defects, jaundice may result due to both HIV; leptospirosis; infectious mononucleosis; intrinsic hepatocellular failure as well as cytomegalovirus, i.e. CMV; Ebstein B virus, hemolysis. In general, however, one mech- i.e. EBV; herpes zoster virus, i.e. HZV; herpes anism predominates, so that knowledge of the simplex virus, i.e. HSV; yellow fever) predominant form of plasma bilirubin • Autoimmune hepatitis (i.e. chronic active (conjugated or unconjugated) is of value in hepatitis) evaluating possible causes of hyperbilir- • Hepatic carcinoma (i.e. primary hepatoma) ubinemia.1 • Secondary hepatic carcinoma (from breast, stomach, bowel, lung, pancreas, and DIFFERENTIAL DIAGNOSIS ovary). Common Rare • Acute viral hepatitis (A, B and C) • Alcoholic liver disease (cirrhosis) • Hemolysis (hemolytic anemia, G6PD defi- • Extrahepatic obstruction (gallstones) ciency, sickle cell disease, thalassemia, ABO/ • Organ infection (cholangitis, cholecystitis, Rh incompatibility) liver abscess, chronic pancreatitis). • Biliary obstruction (stricture, cyst, malignancy) 197

• Drug toxicity (paracetamol, erythromycin,  Hemolytic jaundice: Urobilinogen rifampicin, isoniazid, oral contraceptives, positive, bile pigment negative; anabolic steroids, statins, methotrexate,  Hepatocellular jaundice: Urobilinogen phenothiazine, halothane) positive (may vary according to phase of • Hereditary disorders (Gilbert’s disease, disease), bile pigment positive; Crigler-Najjar syndrome, Wilson’s disease).  Cholestatic jaundice: Urobilinogen negative, bile pigment positive. INVESTIGATIONS—GENERAL Serum Bilirubin† CBC • Total bilirubin and bilirubin fractions allow • Anemia—in hemolysis, bleeding, malignancy determining whether the cause is due to • Reticulocytosis—in hemolysis excess production (i.e. indirect/unconjugate • WBC—leukocytosis in infection, such as predominant) or impaired conjugation (i.e. hepatitis, cholangitis direct/conjugated predominant) • PS—atypical lymphocytes may be seen in • If the conjugated fraction is more than 50% infectious mononucleosis. of the total, patient has conjugated hyperbi- lirubinemia; if the unconjugated fraction is ESR more than 90%, the patient has unconjugated • Elevated in infection, malignancy. hyperbilirubinemia. 2 Urinalysis Serum Albumin • Presence of bile pigments, i.e. bilirubinuria • It is a good indicator of hepatic functional reserve, suggests conjugation is taking place. but because of its long half-life (20-25 days), Bilirubinuria is the earliest abnormality in changes are slow in reflecting liver damage. hepatitis. It is present even when the serum Prothrombin Time (PT) bilirubin is normal. Hence, bilirubinuria in a febrile patient is diagnostic of hepatitis. Late • Since the activity of coagulation factor in the course of the disease, when deltabi- prothrombin is dependent on its synthesis by lirubin is formed, the test becomes negative, the liver, its estimation, i.e. PT is helpful in even though the patient continues to be icteric assessing the extent of damage in acute liver • Presence of urobilinogen, i.e. urobilinogenuria diseases and their prognosis eliminates the possibility of complete biliary • Determination of PT (Quick test) or partial tract obstruction, i.e. bile has entered the thromboplastin time (PTT) is generally intestine, where it undergoes enterohepatic sufficient metabolism. Urobilinogen appears in the urine • PT is prolonged in hepatocellular etiologies in the late preicteric phase of hepatitis, after and chronic liver disease bilirubinuria. At the height of jaundice, the • PTT can be prolonged in vitamin K deficiency hepatocytes cannot excrete bilirubin into the (e.g. in obstructive jaundice). In this case, PTT bile and hence urobilinogen disappears from the urine. It’s reappearance in the urine †When considered individually, none of the test analytes indicates that the patient is recovering in the LFT profile are biologically specific to liver tissues. However, when considered collectively, certain patterns of • Significance of urobilinogenuria and LFT abnormalities are suggestive of particular sub-groups bilirubinuria: of hepatobiliary pathologies. 198 Diagnosis: A Symptom-based Approach in Internal Medicine

normalizes within 12-24 hours after IV Acute Viral Hepatitis Serology Markers (A, B, administration of 5-10 mg vitamin K. C and D) Absence of normalization indicates serious • Generally the following viral hepatitis hepato-cellular damage (e.g. fulminant serology markers are tested: hepatitis or liver cirrhosis).  IgM anti-hepatitis A virus—(anti-HAV).  IgM anti-hepatitis B core antigen—(anti- Hepatic Transaminase Enzymes HBcAg). • Aspartate aminotransferase (AST/SGOT)  Hepatitis B surface antigen—(HBsAg). and alanine aminotransferase (ALT/SGPT)  Anti-hepatitis C virus antibodies—(Anti- are the two enzymes which are sensitive HCV; may need PCR for HCV-RNA). indicators of parenchymal cell integrity • If HBsAg is present, testing for coexisting • Although both transaminase enzymes are HDV by anti-HDV is appropriate‡ widely distributed in the body, ALT is • For the diagnosis of presumed chronic viral predominantly confined to the liver, and hepatitis, HBsAg and Anti-HCV serology, therefore, more specific for liver disease. Both using an approved enzyme immunoassay tests are sensitive indicators of hepatocellular (third generation, i.e. EIA-3), is the initial necrosis step. Again, testing for HDV is appropriate • In general AST is more specific for chronic if HBsAg is present liver disease and ALT for acute liver disease • Acute HEV infection can be diagnosed by the • In acute hepatitis, the transaminases are 10 presence of IgM anti-HEV and, later in the times above normal. In cholestatic jaundice, course, finding of IgG anti-HEV they are about 5 times above normal. Very • The interpretations of viral markers for acute high levels may be seen in drug-induced hepatitis A, B, and C, and chronic hepatitis hepatitis, especially paracetamol are summarized in Tables 29.2 to 29.4. • The HCV infection can also produce wide fluctuations in transaminases enzymes, Ultrasound (US) ranging from normal to three to four times • This is the most important noninvasive the normal range. This yo-yo phenomenon is a investigation in the evaluation of obstructive distinguishing characteristic of HCV (cholestatic) jaundice, e.g. gallstones and infection; therefore, the patient must undergo choledochal cysts, by detecting dilated bile serial testing for monitoring three to four ducts. False-negatives are generally due to times yearly throughout his or her lifetime inability to visualize the biliary tree, often due • A sudden fall in the transaminases in a sick to interposed bowel gas jaundiced patient is indicative of a bad • It also detects focal liver and pancreas prognosis, as it is seen in acute fulminant diseases like tumors, abscesses and cysts, hepatitis. (more than 2cm in diameter). It can identify generalized parenchymal disorders like Serum Alkaline Phosphatase (SAP) cirrhosis and fatty change. It is also of great • Useful in detecting early intra- or extrahepatic help in diagnosing small quantities of ascites. obstruction; high values (5 times normal) favor

obstruction, and a normal SAP virtually ‡Hepatitis D can only exist in the presence of hepatitis B, excludes this diagnosis. because it requires hepatitis B enzymes to replicate. Jaundice 199

Table 29.2: Definitions of viral hepatitis serology markers HAV: Hepatitis A virus, the infectious agent that causes HAV infection and hepatitis A. Anti-HAV: Total antibody to hepatitis A virus (HAV) detected in serum of persons with acute or resolved HAV infection; indicates a protective immune response to infection, vaccination, and passively acquired antibody. IgM anti-HAV: Immunoglobulin M antibody to HAV; positive test indicates acute HAV infection. HBV: Hepatitis B virus, the infectious agent that causes HBV infection, hepatitis B, and chronic liver disease. HBsAg: Hepatitis B surface antigen; initial screening test; positive test indicates an active HBV infection; its presence for more than six months in serum defines chronic infection. IgM anti-HBc: Immunoglobulin M antibody to hepatitis B core antigen; positive test indicates acute HBV infection. Anti-HBc: Antibody to hepatitis B core antigen; fractional into IgM and IgG components, i.e. IgM-anti-HBc and IgG- anti-HBc. IgM usually indicates acute infection (in the previous six months); IgG indicates more distant infection that may have been cleared by the immune system, or may persist, in which case +ve HBsAg, and +ve anti-HBc IgG confirm persistent chronic HBV infection. HBeAg: Hepatitis Be antigen; positive test correlates with HBV replication and high infectivity; often called “marker of infectivity”. Anti-HBs: Hepatitis B surface antibody; positive test indicates immunity from hepatitis B vaccination (if antibody concentration >10 milli IU/ml). HBV/DNA: Deoxyribonucleic acid from HBV; positive test indicates active replication; useful in monitoring response to treatment of HBV infection (by PCR-based assay). Precore mutant: Term used for patients who are hepatitis B positive (more than 105 copies/ml) and hepatitis Be antigen negative. YMDD mutant: Term used for patients on lamivudine therapy who become hepatitis B DNA negative initially and DNA positive subsequently. HCV: Hepatitis C virus, the infectious agent that causes HCV infection, hepatitis C, and chronic liver disease. Anti-HCV: Antibody to HCV; positive test indicates past or current infection with HCV. HCV/RNA: Ribonucleic acid from HCV; positive test indicates active infection. HDV: Hepatitis D virus, a viroid (incomplete virus) that requires an active (acute or chronic) HBV infection to replicate and cause delta hepatitis virus infection, delta hepatitis, and chronic liver disease.

Table 29.3: Initial serologic markers for acute viral hepatitis VIRUS Marker Status HAV IgM anti-HAV +ve Acute hepatitis A HBV HBsAg +ve Acute or chronic hepatitis B* HCV Anti-HCV +ve Acute or chronic hepatitis C ?Viral hepatitis HBsAg (-ve), Anti-HBc-IgM + IgG (-ve), IgM Role out CMV, EBV, HZV, HSV; drug/ other than A, B and anti-HAV (-ve), Anti-HCV (-ve) alcohol toxicity; sepsis; and incubating viral C hepatitis hepatitis (i.e. before appearance of antigens) *If positive, order test for IgM anti-HBc. (i.e. hepatitis B core IgM antibody; positive result indicate acute HBV infection)

Table 29.4: Serologic markers for chronic hepatitis based on etiology Type of hepatitis HBsAg Anti-HCV/HCV/RNA Anti-HDV/HDV/RNA Autoantibodies B+–– – C – + – 2-10% anti-LMK1 D + – + 10-20% anti-LMK 3 Autoimmune – May be + – ANA, possibly + ASMA, hepatitis LMA, LKM 1, etc. 200 Diagnosis: A Symptom-based Approach in Internal Medicine

• Duplex sonography is particularly helpful in Antimitochondrial Antibodies the diagnosis of portal hypertension, portal • Present in 85% of patients with primary vain thrombosis, and other venoocclusive biliary cirrhosis. Although not specific for diseases, e.g. Budd-Chiari syndrome. this disease, absence of this antibody is strong evidence against the diagnosis of primary INVESTIGATIONS—SPECIFIC biliary cirrhosis. Serum Amylase Autoantibody Tests • Elevated in chronic liver disease and • Autoimmune hepatitis is characterized by extrahepatic obstruction, e.g. pancreatic or positive test results for ANA, antismooth common bile duct obstruction by stone or muscle antibodies (ASMA), antibodies to carcinoma. liver/kidney microsomes (LKM), liver cell membrane antibodies (LMA), etc. HIV Serology • Indicated in patients with risk factors (vide Serum Copper/Ceruloplasmin cilinical notes). • Reduced in Wilson’s disease; most patients have a low ceruloplasmin level and low CT Scanning serum copper, and high urinary copper • CT scan is preferred where technical limitations concentrations. make ultrasound difficult to interpret. It detects smaller focal lesions in the liver, especially Serum Iron when combined with contrast injections, and • Elevated in hemochromatosis due to is useful for differentiating liver lesions secondary causes that are associated with (abscess, hepatoma, metastases, hemangioma, jaundice such as chronic hemolytic anemias, and adenoma). alcoholic liver disease, cirrhosis of liver, and hepatocellular carcinoma. Endoscopic Retrograde Cholangiopancreato- graphy (ERCP) Leptospirosis • This procedure is used in patients with a high • ELISA to detect IgM for leptospirosis may be likelihood of extrahepatic obstruction; it positive in 4-6 days; or PCR—most specific allows therapeutic interventions such as and sensitive for diagnosis in early stages. stone extraction, and stent placement. Coombs’ Test Magnetic Resonance Cholangiopancreato- • May be done in patients with unconjugated graphy (MRCP) hyperbilirubinemia or hemolytic anemia. • MRCP is indicated for patients with history of Liver Biopsy contrast allergy, and patients with altered anatomy, i.e. secondary to surgical procedures • Laparoscopy or US-guided liver biopsy is or congenital abnormalities; but it does not important to diagnose, grade, and stage a mass allow therapeutic interventions as in ERCP. in the liver, autoimmune hepatitis, hepatic cirrhosis/fibrosis, HCV infection, hemochro- X-ray matosis, congenital disorders, e.g. Wilson’s • An upper GI series may assist in finding a disease, and to evaluate abnormal or primary neoplasm in the GI tract. inconclusive biochemical or serological tests. Jaundice 201

CLINICAL NOTES elevated (>80%) indirect bilirubin level, Gilbert’s disease or hemolytic anemia is • Look for the presence of scleral icterus as this suggested; whereas direct hyperbi- is a vital clue in distinguishing jaundice lirubinemia (>50%) suggests Dubin-Johnson from other conditions which impart yellow/ syndrome. A normal urine urobilinogen will brown color to the skin (which is not make Gilbert’s disease even more likely. bilirubin), but the sclerae are spared, e.g. Autoimmune hepatitis has a strong genetic carotenemia§, lycopenemia **, hypothyroidism, predisposition. Besides a variety of pernicious anemia, nephrotic syndrome, autoimmune disorders can be associated with xanthomata, hemochromatosis, Addison’s autoimmune hepatitis, e.g. RA, thyroiditis, disease, paraneoplastic syndromes, and Graves’ disease, ulcerative colitis, vitiligo, etc drugs such as rifamycin, amiodarone, and • Is the jaundice acute or chronic? Acute onset mepacrine of jaundice suggests HAV infection, • History should always seek to evaluate risk cholangitis, acute biliary tract obstruction, or factors for hepatitis A, B, and C such as: acute liver failure. Gradual onset of jaundice  Travel from endemic areas (hepatitis A points to alcoholic liver disease, chronic liver and E). disease (e.g. HBV/HCV infection, chronic  Substance abuse—alcohol, anabolic active/persistent hepatitis, autoimmune steroids, IV drugs. hepatitis), liver failure, or malignancy. A  Viral exposures (hepatitis B and C)— lifelong history of jaundice suggests an illegal IV drug users, unsafe injection inherited metabolic or hemolytic cause practice, users of intranasal cocaine, • A patient with classical Charcot’s triad of upper accidental needle-stick injury from a abdominal pain, fever with chills, and jaundice person with hepatitis B/C, sexual should be regarded as having ascending promiscuity, blood transfusion/receiving cholangitis until proved otherwise clotting factors / transplant (especially • A patient with anemia and jaundice with no before 1992), dental extraction, kidney noticeable change in the appearance of the dialysis, acupuncture, tattooing, body urine and stools is suggestive of hemolytic piercing, health care workers in high-risk jaundice areas (e.g. dialysis units), and birth to an • Is the gallbladder enlarged? The finding of HBV/HCV-infected mother. an enlarged gallbladder with jaundice • Drug history—Especially antitubercular, suggests obstructive jaundice due to anti- leprosy, and antipsychotic drugs may neoplasm, such as carcinoma of the pancreas, give a clue about the cause of jaundice carcinoma of the bile ducts, or ampulla of • Family history helps in the diagnosis of classic Vater (Courvoisier’s law)††. genetic diseases such as Gilbert’s disease (vide infra ↓↓) or Wilson’s disease, †† hemochromatosis, and alpha1-antitrypsin Courvoisier’s law states that, in the presence of jaundice, deficiency. When liver functions show only an an enlarged gallbladder is unlikely to be due to gallstones; rather carcinoma of the pancreas or the lower biliary tree is more likely. This may be explained by the observation that §Jaundice is not to be confused with carotenemia in which the gallbladder with stones is usually chronically fibrosed skin turns yellow/orange from carotene deposits but the and so, incapable of enlargement. The converse of sclerae remain normal in appearance. Courvoisier’s law is not true; the cause of jaundice in a **Lycopenemia is orange-yellow skin discoloration due to the patient with a non-palpable gallbladder is not necessarily ingestion of large amounts of tomatoes. gallstones as 50% of dilated gallbladders are impalpable. 202

• Identify stigmata of chronic liver disease such bleed, ascites, and renal failure indicate as spider angiomata, palmar erythema, severe fulminant acute hepatitis gynecomastia, and testicular atrophy • Beware of asymptomatic jaundice, especially • Identify signs of portal hypertension such as in an elderly, as neoplasm—primary or dilated collateral abdominal veins, spleno- metastatic—is a common etiology. megaly, and ascites; and coagulopathy, e.g. bruising, bleeding, and petechiae SELECTIVE GLOSSARY • Presence of a greenish-brown corneal deposit Gilbert disease—It is a chronic, benign, of copper (Kayser-Fleischer ring), which is intermittent, and familial (autosomal recessive) often discernible only with a slit lamp is condition, occurs predominately in men, suggestive of Wilson’s disease characterized by intermittent jaundice in the • Imaging studies play a limited role, except absence of hemolysis or underlying liver disease. in suspected cases of malignancy or biliary Also known as unconjugated benign bilirubinemia obstruction and familial nonhemolytic jaundice, the • Because clinical signs are of little or no help unconjugated hyperbilirubinemia in Gilbert for identifying various causes of viral syndrome has been recognized as due to hepatitis, accurate diagnosis can only be underactivity of the conjugating enzyme system achieved with serologic and molecular testing bilirubin - uridine diphosphate glucuronyl (Table 29.5). Knowledge of the strengths and transferase (UGT-1)—the enzyme that conjugates limitations of these tests allows rational use bilirubin with glucuronic acid. The and interpretation of results. 3 hyperbilirubinemia is mild and, by definition, RED FLAGS less than 6 mg/dl. However, most patients exhibit levels of less than 3 mg/dl. Patients may report • HCV infection (vide infra ↓↓) must be ruled vague abdominal discomfort and general fatigue out in an otherwise asymptomatic patient for which no cause is found. Gilbert syndrome with persistently elevated ALT is usually diagnosed around puberty, possibly • All drugs, including herbal remedies and because of the inhibition of bilirubin glucur- illegal drugs, should be suspected as onidation by endogenous steroid hormones. In potential hepatotoxins. Iatrogenic (drug) older persons, the diagnosis is usually made jaundice is more dangerous than viral when unconjugated hyperbilirubinemia is noted hepatitis. This is because, if the diagnosis of on routine blood test results or unmasked by an drug induced hepatitis is missed and the intercurrent illness or stress. LFTs: with the drug is continued, the patient can die exception of unconjugated hyperbilirubinemia, • All patients with HIV infection should be standard liver function test results are normal. screened for viral hepatitis markers as A diagnosis of Gilbert syndrome can be made in coinfection of HCV, HBV, and HIV is common the presence of (1) unconjugated hyperbilirubi- due to shared modes of transmission. These nemia noted on several occasions; (2) normal coinfections accelerate the course of chronic results from CBC count, reticulocyte count, and liver disease and facilitate progression to blood smear; (3) normal liver function test 4, 5 cirrhosis and hepatocellular carcinoma results; and (4) an absence of other disease • In a jaundiced patient, signs of liver failure, processes or causes of unconjugated hyper- such as encephalopathy, coagulopathy, GI bilirubinemia. A simple and easily available Jaundice 203

Table 29.5: Hepatitis viruses: Interpretation of serologic and molecular findings Virus Interpretation / status Diagnostic test (marker) HAV • Acute infection • Anti-HAV-IgM (+) • Resolved infection and immunity • Anti-HAV-IgG (+) against reinfection; or vaccination response HBV • Acute • HBcAb IgM (+) • Acute or chronic • HBsAg (+) • Chronic active • HBsAg (+); HBeAg (+); HBV/DNA (+) • Chronic persistent • HBsAg (+); HBcAb IgG (+); HBeAb (+); HBeAg (–); HBV/DNA (–) • Resolved • HBsAg (–); HBc IGM/IgG Ab (+); HBeAb (+); HBs Ab (+): HBeAg (–); HBV/DNA (–) • Vaccination response • HBsAg (–); HBsAb-total (+); HCV • Acute/active • Anti-HCV (EIA +); RIBA (+); HCV/RNA (+) • Resolved • HCV Ab (+); HCV/RNA (–) HDV • Acute/active • Anti-HDV IgM (+); HDV/RNA (+) • Chronic • Anti-HDV-total (+); HDV/RNA (–) HEV • Acute • Anti-HEV IgM (+); • Active • HEV/RNA (+) Ab = Antibody; Ag = Antigen; EIA = Enzyme immunoassay; RIBA = Recombinant immunoblot assay. bedside oral ‘rifampin test’ †† is found to be useful (HCV infection has been called a silent to primarily distinguish Gilbert’s disease from epidemic).7 Besides, because of the long lag time other causes of unconjugated hyperbilirubinemic between initial infection and clinically evident disorders.6 Besides the usual laboratory methods, liver disease (20-25 years), early diagnosis of genetic analyses of the UDP glucuronyl HCV infection can be missed or delayed transferase gene can help in the diagnosis. The considerably. Production of antibodies against major importance of establishing this diagnosis HCV can be delayed by up to 12 weeks, and is to reassure patients that the disorder is benign about a third of infected individuals might not and inconsequential, that the prognosis is have detectable antibody at the onset of excellent, and that further investigations are not symptoms.8 Further, if symptoms do occur, the essential. most common complaints such as fatigue, abdominal pain, poor appetite, weight loss, and Hepatitis C viral infection—HCV infection is pruritus are nonspecific; most HCV-infected not usually diagnosed in the acute phase because patients have no hepatic symptoms. However, most patients are initially asymptomatic, and almost 40% of patients infected with HCV therefore, have not sought medical attention. develop at least one extrahepatic manifestation9 during the course of the disease such as mixed †† Rifampin increases total serum bilirubin levels in patients cryoglobulinemia, which is marked by skin with and without Gilbert’s syndrome. On fasting for 12 to involvement, marked by rashes, purpura, 24 h, an absolute increase of bilirubin to >1.9 mg/dl 2 to 6 h petechiae, urticaria, or necrotic ulcerations in after the administration of 900 mg of rifampin distinguishes patients with Gilbert’s syndrome from those without it. In the lower extremities (i.e. leukocytoclastic the nonfasting state, an increase in total serum bilirubin to vasculitis); rheumatological manifestations >1.5 mg/dl 4 to 6 h after the administration of rifampin such as joint and muscle aches, fibromyalgia; distinguishes persons with Gilbert’s syndrome from those without it. kidney disease such as membranoproliferative 204 Diagnosis: A Symptom-based Approach in Internal Medicine glomerulonephritis, nephrotic syndrome; background of the infection.10 It is, therefore, peripheral neuropathy; sicca syndrome (i.e. mandatory for the physician to become more pseudo-Sjögren syndrome); and lichen planus. aware of the optimal methods for screening, Higher rates of non-Hodgkin’s lymphoma, diagnosing, and treating this potentially 11 thyroiditis, hypothyroidism, and diabetes devastating condition. mellitus have also been observed in patients with HCV infection. These syndromes are important REFERENCES to recognise, as these extra-hepatic syndromes 1. Crawford James M. The liver and the biliary tract. may be the presenting features for which they In:Kumar, Cotran, Robbins, Eds. Basic Pathology, 6th edn. HARCOURT ASIA PTE. Ltd. seek medical attention. Frequently, extrahepatic 2. Riyaz A. Approach To jaundice (CME). Indian J manifestations are more serious than the hepatic Dermatol Venereol Leprol 1997;63:288-95. disease itself and present even in patients with 3. Saab S, Martin P. Tests for acute and chronic viral hepatitis: Finding your way through the alphabet persistently normal ALT levels. A distinct and soup of infection and superinfection. Postgrad Med major characteristic of hepatitis C is its tendency 2000;107(2):123-30. 4. Rockstroh JK, et al. European AIDS Clinical to cause chronic liver disease (i.e. cirrhosis, liver Society (EACS) guidelines for the clinical failure, and liver cancer) in the majority, in which management and treatment of chronic hepatitis B the liver injury persists for a prolonged period and C coinfection in HIV-infected adults. HIV Med. 2008;9(2):82-8.[PMID: 18257771 Abstract]. if not for life. Thus, testing for HCV RNA by PCR 5. Shrinivasan S, et al. Coinfection of hepatitis B and or transcription-mediated amplification (TMA) hepatitis C virus in HIV-infected patients in South is the only reliable test for the diagnosis of acute India.World J Gastroenterol 2007;13(37): 5015-20. [PMID: 17854146 Free full text]. infection. 6. Mousavi S, et al. Role of overnight rifampin test in Although, the annual incidence of acute HCV diagnosing Gilberts syndrome. Indian J Gastro- enterol 2005;24:108-10. has fallen in recent years, primarily because of 7. Fabris P, et al. Acute hepatitis C: clinical aspects, effective blood screening efforts and increased diagnosis, and outcome of acute HCV infection. education on the dangers of needle sharing, Curr Pharm Des. 2008;14(17):1661-5. [PMID: 18673189 Abstract]. hepatitis C infection is still relatively frequent 8. Maheshwari A, et al. Acute hepatitis C.Lancet. in certain populations. With more than 170 2008;372(9635):321-32. [PMID: 18657711 million chronic hepatitis C patients worldwide Abstract]. 9. Gumber SC, et al. Hepatitis C: A multifaceted and an increase in the related morbidity and disease. Review of extrahepatic manifestations. mortality projected for the next decade, an Ann Intern Med 1995;123(8):615-20. [PMID: 7677303 Free full text]. improvement in our ability to diagnose and treat 10. Kamal SM. Acute hepatitis C: A systematic review. patients with acute hepatitis C would have a Am J Gastroenterol 2008;103(5):1283-97. [PMID: significant impact on the prevalence of chronic 18477352 Abstract]. 11. Szabo E, et al. Viral hepatitis: New data on hepatitis hepatitis and its associated complications C infection. Pathol Oncol Res. 2003;9(4):215-21. particularly in countries with a high endemic Epub 2003 Dec 22. [PMID: 14688826 Abstract]. CHAPTER 30 Myalgia

SYNOPSIS Diagnosis begins with patient’s history, distinguishing muscle pain from muscle Myalgia* may be described as a poorly localized weakness, i.e. reduction in muscle power; muscle aching in a muscle or group of muscles, usually fatigability, i.e. inability to sustain the characterized as a deep aching sensation, but performance of an activity; or cramps, i.e. sometimes as a burning or electric sensation. In episodic involuntary contraction of muscles. The addition to the origin of myalgic pain in muscle pattern and severity of muscular pain, associated tissue per se (i.e. myopathies), diseases of subcutaneous tissue, facia, tendon, bones, joints, symptoms, medication use, and family history and peripheral nerves may also produce pain are helpful to determine whether the cause of that is referred to muscle. myalgia is a normal reaction to physical exertion or pathological infectious, inflammatory, Myalgia may be classified as: rheumatologic, endocrine, metabolic, electrolyte- • Acute—Less than a month, e.g. viral fever, induced, drug-induced, neurogenic, or genetic minor muscular strain disorders. • Chronic—More than 3-6 months, e.g. injury Advances in techniques such as application • Localized—involving one or few muscle of molecular genetics, electrophy-siology, and groups, e.g. compartment syndromes, perip- muscle biopsy have made a definitive diagnosis heral vascular disease possible for many myopathies. However, a • Generalized—Involving more than four areas, phenotypic approach to diagnosis according to e.g. drug-induced or toxic myopathies, the patient’s predominant pattern of weakness fibromyalgia, CFS is essential, which will be useful in selecting the • Episodic—e.g. metabolic myopathies most appropriate diagnostic studies to establish • Constant—e.g. inflammatory myopathies. a precise diagnosis, and inform the patient about *Myalgia should not be confused with muscle ‘weakness’, the nature and evolution of the disease, the i.e. reduction in muscle power; muscle ‘fatigability’, i.e. inability to sustain the performance of an activity; or therapeutic options, and to propose, when 1, 2 ‘cramps’, i.e. episodic involuntary contraction of muscles. indicated, genetic counseling. 206

DIFFERENTIAL DIAGNOSIS • Metabolic bone disease (osteomalacia, hyperparathyroidism) Common • Malignancy/ paraneoplastic syndromes • Muscle overuse syndrome (extreme physical • Porphyria(acute, intermittent) exertion) • Eosinophilic myalgic syndrome (EMS: vide • Weekend warrior syndrome† infra ↓↓) • Delayed onset muscle soreness (DOMS: vide • Hereditary myopathies (hypokalemic infra ↓↓) 3 myopathy, glycogen metabolism disorders). • Postinfectious (viral: Dengue, Chikungunya, HIV; bacterial: Influenza; nematode: INVESTIGATIONS—GENERAL ↓↓ Trichinosis: vide infra ) CBC • Localized muscle pain (trauma; mass, e.g. hematoma, neoplasm; fibrositis; tendinitis) • Eosinophil counts of 10,000-30,000 cells/μl • Psychogenic (depression, anxiety) are not unusual in a rare case of EMS. • Fibromyalgia‡ ESR • Chronic fatigue syndrome (CFS) • Dehydration (hyponatremia). • More than 50 mm/hr. with no other abnormality suggests PMR, though a normal Occasional ESR does not rule out this diagnosis. • Connective tissue disorders (RA, SLE, PAN, Urine PMR) • Endocrine myopathies (hypothyroidism, • Myoglobinuria causes red or cocacola thyrotoxicosis, diabetes mellitus, hyperlipi- colored urine in rhabdomyolysis. demia) CPR • Drug-induced/toxic myopathies4 (stains: • May be elevated prior to ESR. rhabdomyolysis: vide infra ↓↓, steroids, alcohol, diuretics, cimetidine, antiretroviral CK (with Isoenzymes) therapy) • Ischemic myalgia (DVT, intermittent • The CK level may be highly elevated (10 – claudication due to occlusive arterial disease). 100 times normal) in the inflammatory myop- athies, and can be moderately to highly Rare elevated in the muscular dystrophies. Other • Infectious myositis (poliomyelitis, rabies, conditions that can be associated with tetanus, Guillain-Barré syndrome, pyomyo- elevated CK levels include infections, sitis, gas gangrene, Toxoplasma myositis, alcoholism, and adverse reactions to Cysticercosis, Lyme myositis) medications. Metabolic (storage) myopathies • Inflammatory myopathies (polymyositis, i.e. tend to be associated with only mild to PM; dermatomyositis, i.e. DM) moderate elevations in CK levels. The CK level usually is normal in the electrolyte and †Recreational pursuits with poor conditioning or endocrine myopathies (notable exceptions appropriate training. ‡Formerly called as Fibromyositis or Myofacial pain are thyroid and potassium disorder syndrome. myopathies). 207

• However, the absence of an elevated serum X-rays CK level does not exclude myopathy. In • May be essential in trauma cases. addition, elevation of the serum CK does not necessarily imply that the muscle is the EMG 5, 6 primary site of abnormality. • Although changes seen on EMG are not • The serum CK level is the most sensitive for pathognomonic for any specific disease muscle disease, and it is rarely necessary to process, an abnormal EMG is useful to measure other enzymes that are released evaluate the extent and pattern of myopathic from injured skeletal muscles such as AST, process, and to evaluate for a neuropathy or ALT, or LDH, all of which are also elevated a disease of the neuromuscular junction. in hepatic disease. NCS INVESTIGATIONS—SPECIFIC • To exclude peripheral neuropathy. FBG, PPBG MRI • May be abnormal before other abnormalities • Muscle imaging, in particular MR, provides of this disease are manifest. diagnostic and follow-up information, especially in dystrophic, metabolic, and Calcium inflammatory myopathies • Hypercalcemia may be associated with hyper- • Useful to identify areas of abnormal muscle parathyroidism, or metastatic carcinoma. that are amenable to biopsy. Endocrine/Metabolic Panel Electrolytes • Where indicated, additional tests such as 24- • Hypokalemia is usually diuretic induced. hour urine cortisol testing to rule out Cushing’s disease; oral glucose load/growth Sr Alkaline Phosphate hormone assay to rule out acromegaly; and • Usually elevated in osteomalacia, hyperpara- vitamin D assay to rule out osteomalacia may thyroidism, metastatic carcinoma, Paget’s be obtained. disease. Muscle Biopsy/Genetic Analysis TFTs • If the diagnosis is still inconclusive after the history, physical examination, and laboratory, • High TSH values may be the only abnormality radiologic, and electromyographic evalua- of hypothyroidism; low TSH values with tions, a muscle biopsy is required for patients corresponding high T3 and T4 values confirm who have a suspected myopathy. The thyrotoxicosis. pathologic analysis of biopsy specimens ANA, RF focuses on the histologic, histochemical, • Likely to be positive in connective tissue electron microscopic, genetic, and biochemical disorders; if RF/ANA assay is positive, changes that are found in the affected muscle. additional studies such as double-stranded Molecular analysis of candidate genes is DNA, or antiphospholipid antibodies (lupus) becoming a major diagnostic tool in many may be obtained. muscle disorders. 208

CLINICAL NOTES  Grade – 3: active movements against gravity • It is vital to distinguish myalgia from articular  Grade – 2: active movements only with symptoms; if the lesion is in the muscle, the gravity eliminated pain is greater during active than passive  Grade – 1: traces contractions movement of the affected muscle; if in the  Grade – 0: no contraction. ligament or joint, the pain is about equal • Characteristic facies and bone structure of • It is also important to differentiate myalgia acromegaly suggest myopathy associated and myopathies due to disease of nervous with this disease. Lethargy, dry skin and hair, § system. The presence of muscle wasting , nonpitting edema, a husky voice suggest , sensory and motor changes, as hypothyroidism well as associated neurologic evidence favors • A rapid onset of myalgia in an elderly female neurogenic cause such as due to UMN, LMN, involving the muscles of the neck, shoulder, neuromuscular, motor neuron, or peripheral buttocks and thighs is diagnostic of PMR. The nerve disorder muscles below the elbows and knees are not • Historical aspects which are helpful in the affected in this condition diagnosis include: • Temporal artery thickening or tenderness  The age of the patient (myopathies since and bruits over carotid may be found in few birth and childhood, as against adult cases of PMR onset—usually acquired myopathies). • A gradual onset of generalized myalgia with  Recent events surrounding the occurrence multiple tender spots on both sides of the of myalgia (e.g. postexercise, new body, above and below the waist is typical of vocational activities, new drug intake). fibromyalgia. The diagnosis of fibromyalgia  Onset and progression of the disease (see is clinical. There is no laboratory or imaging classification above). tests to confirm this diagnosis  Preceding history of trauma, febrile illness. • Myalgia with significant and progressive leg  Occupation, hobbies (gardening), sports weakness causing difficulty in climbing (DOMS), and recreational activities stairs, squatting, getting into or out of a car, (tennis/golf elbow). rising from a chair, raising hands above the head, holding head up, combing hair, and  Drugs or toxin exposure. lifting objects strongly favor the diagnosis of  Food habits (trichinosis). inflammatory muscle diseases such as PM  Psychosocial history. and DM. In contrast to myasthenia gravis, PM  Family history (connective tissue disor- and DM do not cause facial or ocular muscle ders, hereditary myopathies). weakness • The muscle power should be tested at the • In DM, cutaneous manifestations can bedside by examining all muscle groups precede, follow, or develop together with bilaterally, which is usually graded as below: muscle weakness. Cutaneous findings  Grade – 5: normal power include rash on the neck (V sign), shoulders,  Grade – 4: active movements against and upper back (shawl sign), a purplish gravity and resistance (heliotrope) effusion on the upper eyelids, and scaly patches over the dorsum of §Muscle wasting which occurs secondary to neurological proximal and distal interphalangeal joints disease is usually referred to as amyotrophy. (knuckles), called Gottron’s sign 209

• Presence of associated symptoms or signs, involving the quadriceps muscle group, but may indicating involvement of organs or tissues also affect the hamstring, and triceps surae other than muscle, such as dyspnea, orthopnea, groups. Up to six hypothesized theories have respiratory failure, congestive heart failure, been proposed for the mechanism of DOMS, arrhythmias, cataracts, mental retardation, and namely: lactic acid, muscle spasm, connective hepatomegaly is valuable in the clinical tissue damage, muscle damage, inflammation diagnosis of hereditary myopathies (e.g. and the enzyme efflux theories. The mechanisms, myotonic dystrophy, Duchenne’s or Becker’s treatment strategies, and impact on athletic muscular dystrophies) performance remain uncertain, despite the high • Normal findings on a battery of investi- incidence of DOMS. Clinically, DOMS is a self- gation do not rule out organic disease, but limiting condition that usually requires no strongly suggest psychogenic disorders. treatment. RED FLAGS Eosinophilia-myalgia syndrome—The term EMS was coined in 1989 after a cluster of cases • As there is a close relation of PMR with giant with symptoms of incapacitating myalgias and cell arteritis (GCA), once the diagnosis of PMR eosinophilia were reported, most commonly in is entertained, it is prudent to question and people aged 35-60 years. This syndrome has been examine these patients for symptoms and only defined as varying degrees of myalgias and signs of GCA, such as headache, especially peripheral eosinophilia. In November 1989, for in temporal region, scalp tenderness, jaw pain, visual disturbance, tender temporal the purpose of nationwide surveillance, the US arteries, and signs of ischemic retinopathy Centers for Disease Control and Prevention on funduscopic examination. If GCA is (CDC) defined this syndrome according to 3 suspected, steroid therapy is indicated criteria:(1) a blood eosinophil count greater than • Since there is an increased risk of malignancy 1000 cells/μl, (2) incapacitating myalgia, and (3) in patients with DM and PM, they should be no evidence of infection (e.g. trichinosis) or offered age and risk specific cancer screening neoplastic conditions that would account for tests, such as chest/abdomen/pelvis CT, GI these findings. Studies confirmed a strong associ- tract imaging and mammography. Malig- ation between the use of a specific brand of L- nancies may be evident at the time of tryptophan and development of EMS; the best- presentation, but may not be detected until characterized of these is 1,1-ethylidenebis (L- months afterward in some cases. tryptophan) (EBT), a tryptophan dimer. However, contaminated L-tryptophan may not be the only SELECTIVE GLOSSARY cause of EMS. Symptoms other than myalgia Delayed onset muscle soreness (DOMS)—It is include arthralgia, peripheral edema, alopecia, a sensation of discomfort or soreness that occurs scleroderma-like skin changes, and various GI, 1 to 2 days after exercise, commonly due to pulmonary, and neurological manifestations. microinjury to the muscle or eccentric activity. Eosinophil counts of 10,000-30,000 cells/μl are It is most evident at the muscle/tendon junction not unusual, and the bone marrow shows hyper- initially, and then spreading throughout the plasia of eosinophil precursor cells. With the recall muscle. Symptoms can range from muscle of L-tryptophan from the market in November tenderness to severe debilitating pain, usually 1989, only a few new cases have been reported. 210 Diagnosis: A Symptom-based Approach in Internal Medicine

Rhabdomyolysis and Myoglobinuria—It is a quantity of larvae ingested, the species of disorder characterized by acute damage of the Trichinella (most notably T spiralis), and the sarcolemma of the skeletal muscle, leading to immune status of the host. After two weeks, release of potentially toxic muscle cell components majority of the patients have fever that peaks into the circulation, most notably CK and around the fourth week. Weakness and/or myoglobin, and is frequently accompanied by myositis follow; the muscles become stiff, hard, myoglobinuria. Therefore, the term myoglobinuria and edematous. Muscles with increased blood is often used interchangeably with the term flow, e.g. extraocular muscles, masseters, larynx, rhabdomyolysis. Myoglobinuria refers to an tongue, neck muscles, diaphragm, intercostals, abnormal pathologic state in which an excessive limb flexors, and lumbar muscles are most amount of myoglobin is found in the urine, frequently involved. Involvement of the imparting a cola-like hue, usually in association diaphragm may result in dyspnea. Other with myonecrosis, and a clinical picture of symptoms include: periorbital edema and rash weakness, myalgias, and edema. The condition (macular or petechial). CK levels are elevated to is etiologically heterogeneous and may result >15,000 U/l. Serology results are not positive from a large variety of diseases affecting muscle until 2-3 weeks after infection. They peak around membranes, membrane ion channels, and muscle the third month and may persist for years. In energy supply, including acquired causes (e.g. patients with CNS involvement, CT scanning exertion, crush injury and trauma, alcoholism, and MRI with contrast enhancement may reveal drugs, and toxins), and hereditary causes (e.g. 3- to 8-mm nodular or ring-like lesions. Muscle disorders of carbohydrate metabolism, disorders biopsy provides a definitive diagnosis; however, of lipid metabolism, or diseases of the muscle it is rarely recommended except in difficult cases associated with malignant hyperthermia). when serology tests are unhelpful. In many patients with idiopathic recurrent REFERENCES rhabdomyolysis, specific inherited metabolic defects have not been recognized up to now. Acute 1. Jackson CE. A clinical approach to muscle diseases. renal failure is the most serious complication, Semin Neurol 2008;28(2):228-40. [PMID: 18351524: Abstract]. which can be prevented by prompt, aggressive 2. Kohler A, et al. How should a muscular disease be treatment. In patients surviving acute attacks, studied? Rev med Suisse Romande 2003;123(1):45- 9. [PMID: 15095727: Abstract]. recovery of muscle and renal function is usually 3. MacIntyre DL, et al. Delayed muscle soreness. The complete. inflammatory response to muscle injury and its clinical implications. Sports Med 1995;20(1):24- Trichinosis—It is the result of infection by the 40.[PMId:7481277: Abstract]. nematode Trichinella spiralis. Humans are 4. Finsterer J. Medically induced myopathia. Nervenartz 2006;77(6):682-6, 688-93. [PMID: infected incidentally when they eat inadequately 16575599: Abstract]. cooked meat that contains larvae of Trichinella 5. Draeger A, et al. Statin therapy induces species. Most infestations do not cause ultrastructural damage in skeletal muscle in patients without myalgia.J Pathol 2006;210(1):94- symptoms, although heavy exposure can cause 102. [PMID: 16799920: Abstract]. various clinical manifestations, including 6. Dabby R, et al. Asymptomatic or minimally symptomatic hyperklemia: Histopathologic diarrhea, fever, myalgias, and prostration. correlates. Isr Med Assoc J. 2006;8(2):110-3. [PMID: Factors that may affect morbidity include the 16544734: Abstract]. CHAPTER 31 Nausea and Vomiting

SYNOPSIS It is important to differentiate vomiting from other physical phenomenon such as regurgi- Nausea* is an unpleasant sensation and an tation, rumination, and retching. impending desire before vomiting, usually Regurgitation is a passive phenomenon accompanied by autonomic signs such as pallor, indicating an effortless reflux of gastric contents hypersalivation, diaphoresis, tachycardia, and into the mouth, which may be due to mechanical tachypnea. obstruction of the esophagus, GERD, or Vomiting is a physical event that results in the esophageal motility disorders. speedy, forceful evacuation of gastric contents Rumination is also a passive phenomenon, through the mouth which may or may not be during which recently ingested food is regurgitated preceded by nausea. Vomiting may be a effortlessly into the mouth, whereupon it is re- protective physiologic mechanism that prevents chewed and swallowed or spat out. entry of potentially harmful substances into the Retching (spasmodic respiratory and GI tract. However, persistent vomiting can lead abdominal movements) is a strong involuntary to complications such as dehydration, metabolic effort to vomit, but occurs against a closed glottis, alkalosis, hyponatremia, hypokalemia, esophagitis, without bringing up emesis. gastritis, aspiration pneumonitis, and rarely Although nausea and vomiting are common Mallory-Weiss syndrome, or Boerhaave syndrome complaints†, they are usually self-limiting and (vide infra ↓↓) — irrespective of the cause of benign in nature. However, they may occasio- vomiting. nally herald serious etiologies. Hence careful *According to one Midwestern survey, nausea was not assessment is required; together with a understood by two-thirds of medical, surgical, and willingness to review and admit the patient if gynecologic patients queried. The expression sick at stomach, on the other hand, was the most common patient descriptor the diagnosis remains unclear. of nausea, and the expression throw up was consistently interpreted as vomiting.- Ref. RhodesVA et al. Nausea, † Though nausea and vomiting may occur independently, Vomiting, and Retching: Complex Problems in Palliative they are so closely related - produced by the same stimuli Care.CA Cancer J Clin 2001 51: 32-248. [PMID: 11577489: and can be viewed as a progressive response to increased Free full text]. stimulus - that they are considered together. 212

The American Gastroenterological Associa- • Obstruction (achalasia, pyloric stenosis, tion suggests a 3-step approach to the initial small/large bowel obstruction, strangulated evaluation of nausea and vomiting:1 hernia, volvulus). • Recognize and correct any consequences of Metabolic (DKA, gastroparesis: vide infra ↓↓, the symptoms, such as dehydration or hypertensive encephalopathy, uremia, elect- electrolyte abnormalities rolyte imbalance). • Try to identify the underlying cause and Ophthalmic (acute closed-angle glaucoma). provide specific therapy • Use empiric therapy if no cause can be found. Opportunistic infections (candida esophagitis, CMV or HSV infection in AIDS). DIFFERENTIAL DIAGNOSIS Rare Common • Torsion (testicular, ovarian) GI Disorders • Malignancy (esophagogastricduodenal/ pancreatic carcinoma, hepatoma, metastasis, • Gastritis (H. pylori infection; aspirin; NSAID; paraneoplastic syndrome: vide infra ↓↓) other drugs, e.g. oral steroids; excess alcohol; • Ischemia (mesenteric) stress; viral infections) • Metabolic (hypercalcemia, renal tubular • Acute infections (gastroenteritis, food acidosis) poisoning) • Endocrine (hyperparathyroidism, adrenal • Inflammation (appendicitis, peptic ulcer crisis: vide infra ↓↓) disease, viral hepatitis) • Poisoning (organophosphate compounds) • Motility disorder (GERD) • Hematologic (acute intermittent porphyria: • Colic (renal, biliary) vide infra ↓↓) • Functional ( NUD) • Psychogenic (bulimia nervosa, sitophobia, Systemic infections (febrile illness; RTI; UTI; conversion disorders) Septicemia) • Cyclic vomiting syndrome (vide infra ↓↓). Cardiac ischemia (MI: especially inferior/ posterior wall; CHF) INVESTIGATIONS—GENERAL CNS disorders (migraine; CVD: infarction, CBC hemorrhage; Infection: meningitis-viral, bacterial, • Leukocytosis in inflammation; microcytic TB; raised ICP: abscess, hematoma, and tumor) anemia due to occult blood loss and malignancy. Labyrinthine disorders (Motion sickness, Ménière’s disease, and Vestibular neuronitis) ESR Pregnancy (hyperemesis gravidarum, ectopic • Elevated in inflammatory and malignant pregnancy) disease. Postoperative (Paralytic ileus). Urea, Creatinine, Electrolytes

Occasional • Severe or protracted vomiting of gastric contents may lead to hypokalemia, uremia, GI Disorders or metabolic alkalosis or acidosis. • Inflammation (cholecystitis, pancreatitis, • Hyponatremia or hyperkalemia (or both) is peritonitis) commonly seen in adrenal crisis. Nausea and Vomiting 213

LFTs, Amylase, Lipase organomegaly, and mass lesion causing mechanical bowel obstruction. • Elevated in pancreaticobiliary disease. Endoscopy (i.e EGD/Sigmoidoscopy/Colono- scopy). CXR • To evaluate mucosal lesions (ulcers, malig- • Pneumonia, bronchitis, CHF, malignancy nancy), and to obtain biopsy specimens. may trigger vomiting. HRCT Abdomen AXR • To evaluate for abdominal mass or obstruc- tion. • Supine and upright AXRs are obtained in patients with severe pain or suspicion of CT Scan/MRI Head bowel obstruction, perforation, or ileus — to • In patients with suspected CNS cause or with look for dilated loops of small bowel or abnormal neurologic signs such as altered pneumoperitoneum. consciousness and papilledema.

ECG Upper GI/Barium Enema X-rays • With barium contrast and follow-through— • To rule out myocardial ischemia, infarction. to detect mucosal lesions (ulcers), obstruc- Blood Glucose tion, or mass lesion.

• Elevated in DKA; low in adrenal crisis. Nuclear Scintigraphy • Gastric emptying scintigraphic studies to Serum Calcium confirm gastroparesis.

• Elevated in hyperparathyroidism, malig- Audiometry nancy, and adrenal crisis. • Useful in patients with Ménière’s disease, labyrinthine disease. Urine Toxicology Screen • Ketones in DKA; porphobilinogen in porphyria. • To evaluate serum levels of drug effect, e.g. digoxin, theophylline, anticonvulsants or toxins, Pregnancy Test e.g. pesticides, insecticides causing vomiting.

• Urine hCG test for any women of child- CLINICAL NOTES bearing age. • The foremost aspect in history taking and INVESTIGATIONS—SPECIFIC examination is an attempt to recognize and correct any consequences of nausea and US Abdomen and Pelvis vomiting such as dehydration or electrolyte • Helpful in patients with gallbladder abnormalities, regardless of the underlying (cholecystitis, cholelithiasis), hepatic (hepa- cause (Table 31.1) titis, cirrhosis), and pancreatic disease (panc- • Warning signs such as fever, hypotension, reatitis, carcinoma); may reveal urolithiasis, severe dehydration, chest pain, severe 214 Diagnosis: A Symptom-based Approach in Internal Medicine

Table 31.1: Key questions in the evaluation of acute are invaluable in pointing to the correct nausea and vomiting diagnosis 1. Immediate therapy (for intravascular volume depletion) •· The precise features of vomiting, and its —Is it needed regardless of the cause? temporal relationship to food intake 2. Are symptomatic treatment and reassurance sufficient? generally provide a clue to the diagnosis For example: In patients with symptoms consistent with a— (Table 31.2). • Viral syndrome • Motion sickness Table 31.2: Vomiting—clinical correlation • Food intolerance Features of vomiting Possible causes • Emotional-stressful event 3. Is urgent workup needed to establish the cause? • Early morning hours, • Pregnancy(first trimester), For example: before eating alcohol abuse, depression, • In a pregnant woman increases ICP, uremia • Evidence of systemic disease • Shortly after eating • Esophageal disease, gastritis, ulcer disease, • Presence of chest pain gastric outlet obstruction, • Presence of CNS symptoms gastroparesis, gastric • History of drug / alcohol abuse or toxin exposure carcinoma, psychogenic • An immunocompromised patient • Delayed vomiting • Intestinal obstruction • Postoperative status • No clear relationship • Metabolic disorders, drugs, to meals toxins, • Vertigo, tinnitus • Labyrinthine disease abdominal pain, CNS symptoms, history of • “Projectile”, unaccompanied • Increased ICP immunosuppression, or older age should by nausea – Postoperative – “Bilious” – Gastric outlet obstruction prompt immediate evaluation and treatment – ”Putrid” – Intestinal obstruction, • Evaluation of vital signs (fever, pulse, and – “Feculent” gastrocolic fistula blood pressure to assess hydration, and • Only symptom for years • Psychogenic respiratory rate to look for acidosis-related hyperventilation); skin, eyes, mucous mem- • Associated symptoms such as fever, branes (dehydration, jaundice); and signs of headache, and myalgia (viral); severe

systemic disease e.g. tachycardia, S3 gallop, abdominal pain (obstruction); weight loss, pedal edema with CHF, are areas of key hematemesis, melena (ulcer, malignancy, importance Mallory-Weiss tear); jaundice (hepatitis, • Acute nausea and vomiting, i.e. symptoms hepatoma, and extrahepatic causes); diarrhea present for less than a week, is most often due (gastroenteritis); vertigo (labyrinthine to GI infection, inflammation, obstruction; disorders); photophobia (migraine); and systemic illness; drug toxicity; alcoholism; drug ingestion may suggest the cause of labyrinthine disorders; and occasionally underlying disease psychogenic conditions • History of peptic ulcer is an indicator of • Chronic nausea and vomiting, i.e. presence further ulceration, while patients with of symptoms over a week, may be due to a functional dyspepsia tend to be depressed or number of different conditions; the patient anxious, and tend to exhibit somatization, may describe intermittent symptoms lasting characterized by multiple symptoms and months or years. The common causes include frequent consultations gastritis, mechanical obstruction, gut motility • An inquiry into patient’s psychological and disorders (including diabetic gastroparesis), social history, and of symptoms that may drugs, labyrinthine disorders, and uremia. A indicate a psychological disorder is important. thorough history and physical examination Psychogenic vomiting is characterized by a Nausea and Vomiting 215

combination of features such as a lengthy intracranial hemorrhage (subdural hematoma, history of vomiting, superstitious vomiting, intracerebral bleeding, or contusion) must be often self-induced, evidence of psychological ruled out. disorders (anxiety, depression), and main- tenance of normal health despite long- SELECTIVE GLOSSARY standing vomiting Acute intermittent porphyria—It is inherited as • Though nausea and vomiting associated with an autosomal dominant pattern, caused by partial pronounced weight loss (>3 kg) seemingly deficiency of porphobilinogen deaminase activity, indicates serious disorders such as obstruction, malignancy, or mesenteric ischemia, it is leading to increased excretion of aminolevulinic common in functional or psychogenic dyspepsia acid and porphobilinogen in the urine. It remains due to sitophobia‡, i.e. an aversion to food or clinically silent in the majority, but may manifest, refusal to take nourishment usually in women beginning in the teens or 20s. • Physical signs of pregnancy, alcoholism, Clinical features include intermittent abdominal abdominal mass, peritonitis, obstruction, pain (may mimic acute abdomen), vomiting, and neurological signs (altered mental state, neck neurologic manifestations such as seizures, muscle stiffness, papilledema, and nystagmus), ear pain, tingling, numbness, weakness, paralysis, and examination (middle ear disease), ophthal- psychosis. Attacks are precipitated by numerous mic and funduscopic examination (raised factors, including drugs and intercurrent ICP, glaucoma), generally indicate the infections. In contrast to other forms of porphyria, underlying diagnosis cutaneous hypersensitivity is absent in acute • A distended abdomen associated with nausea intermittent porphyria. Diagnosis can be and vomiting may indicate paralytic ileus or confirmed by demonstrating increased amount of mechanical obstruction of the intestine. porphobilinogen in the urine during an acute Abdominal tenderness, distension, and attack. occasionally visible peristalsis suggest GI Adrenal crisis—It is characterized by profound obstruction. A succussion splash suggests asthenia, severe pain in the abdomen, muscle diabetic gastroparesis. cramps, nausea, vomiting, diarrhea, peripheral vascular collapse, and finally, renal shutdown RED FLAGS with azotemia. Body temperature may be low, • Acute nausea and vomiting may subside although severe fever often occurs, particularly within days, only to recur later to present a when crisis is precipitated by acute infection. chronic disorder, posing a more challenging Adrenal crisis may result from an acute diagnostic dilemma exacerbation of chronic insufficiency, usually • Persistent vomiting with hypercalcemia may caused by sepsis or surgical stress, adrenal be the initial presentation of asymptomatic hemorrhage (e.g. Waterhouse-Friderichsen hyperparathyroidism, underlying neoplasm syndrome [fulminant meningococcemia]) and or paraneoplastic syndrome anticoagulation complications. Steroid with- • In an intoxicated alcoholic patient with drawal is the most common cause of adreno- nausea and vomiting-acute pancreatitis and cortical insufficiency, and it almost exclusively causes a glucocorticoid deficiency. Sometimes, the ‡ Other terms used for ‘food’ phobia include ‘phagophobia’, diagnosis is considered only on discovery of i.e. fear of eating and ‘cibophobia’, i.e. fear of food. characteristic abnormalities of serum electrolytes, 216 Diagnosis: A Symptom-based Approach in Internal Medicine including low Na (< 135 mEq/l), high K (> 5 mEq/l), sinusitis, emotional stress, excitement, physical low HCO3 (< 15 to 20 mEq/l), and high BUN exhaustion, foods such as chocolate or cheese, (>20 mg/dl). A high index of suspicion is menstruation, hot weather etc. cannot always be therefore required in patients with unexplained pinpointed as easily as they can in children. Each fatigue, hyponatremia or hypotension. episode is similar to the previous ones. The episodes tend to start at about the same time of Boerhaave syndrome (Pronunciation: bu-r’hah- day, last the same length of time, and present ve-)—It denotes esophageal perforation or the same symptoms at the same level of intensity. rupture of the esophagus caused by increased CVS appears to be linked to migraines in some intraluminal pressure and distension during cases. Treatment with migraine medications retching or vomiting. The presence of a hole or often helps. Because other more common other type of opening in the esophageal wall diseases and disorders also cause cycles of facilitates the passage of esophageal contents into vomiting, many people with CVS are initially the mediastinum resulting in mediastinitis. The misdiagnosed until the other disorders can be most common cause of esophageal perforation is ruled out. To be diagnosed with CVS, a person injury during a medical procedure such as must have experienced at least two episodes of esophagoscopy or placement of a nasogastric intense nausea and unremitting vomiting or tube, and pathologic process such as neoplasm retching lasting hours or days. These episodes or gastric reflux with ulceration. Less common must be separated by weeks or months of causes include injuries from penetrating or blunt symptom-free intervals. There is no specific test trauma or injury to the esophagus during an that will confirm the diagnosis of CVS. Other operation on another organ, mechanical problem conditions that can produce vomiting, such as, such as violent retching or vomiting; ingestion of labyrinthine disease, metabolic disorders, CNS a foreign body or caustic agents. The condition often results in infection of the mediastinum and tumors, and pregnancy must be excluded. mediastinitis. The Mackler triad is the classic Gastroparesis—Literally translated, it means presentation of spontaneous esophageal rupture stomach paralysis—is a digestive disorder in is in a middle-aged man with a history of recent which the motility of the stomach is either vomiting or retching after dietary overindulgence and abnormal or absent. Normally, the stomach overconsumption of alcohol, with chest pain and contracts to move food down into the small subcutaneous emphysema. intestine for digestion. The vagus nerve controls Cyclic vomiting syndrome—CVS causes bouts the movement of food from the stomach through or cycles of severe nausea and vomiting that last the digestive tract. Gastroparesis occurs when for hours or even days, and alternate with longer the vagus nerve is damaged, and the muscles of periods of no symptoms. The disorder which has the stomach and intestines do not work normally. no known cause typically begins between the Food then moves slowly or stops moving ages of 3 and 7 years. Children tend to outgrow through the digestive tract (delayed gastric CVS when they are teenagers. While the disorder emptying). The most common cause of occurs most often in children, CVS can begin at gastroparesis is diabetes mellitus; other causes any age. Adult episodes tend to occur less often include hypothyroidism, vagotomy, gastric than they do in children, but they usually last bypass surgery,viral infections, medications such longer. Furthermore, the events or situations that as anticholinergics and narcotics, smooth muscle trigger episodes in adults such as coryza, disorders such as amyloidosis and scleroderma; Nausea and Vomiting 217

Parkinson’s disease; multiple sclerosis; and lastic disorder is telangiectasis, which can be idiopathic gastroparesis. Signs and symptoms of caused by breast cancer and lymphomas. gastroparesis are: heartburn, pain in the upper Lambert-Eaton myasthenic syndrome is a abdomen, nausea, vomiting of undigested neurologic PNS that can be caused by a variety food—sometimes several hours after a meal; of tumors including small cell lung cancer, early feeling of fullness after only a few bites of lymphoma, breast, colon and other cancers. food; weight loss due to malnutrition; abdominal Syndrome of inappropriate antidiuretic bloating, lack of appetite, and gastroesophageal hormone (SIADH) is an endocrine PNS, which reflux. Gastric emptying scintigraphy of a is seen in as many as 40% of patients diagnosed radiolabeled solid meal for 2 hours confirms the with small cell lung cancer. Symptoms generally diagnosis of gastroparesis. Performing the test develop (depending on body system affected) for a longer duration, up to 4 hours, has been over a period of days to weeks and usually occur proposed to increase the yield in detecting prior to tumor detection, which can complicate delayed gastric emptying in symptomatic diagnosis. Some paraneoplastic syndromes may patients. be confused with metastatic disease or spread Paraneoplastic syndromes—PNS can be defined of the cancer. The presence of the syndrome may as a group of symptoms that may develop due be the only indication that a patient has a to indirect and usually remote immune- malignancy or that a malignancy has recurred. mediated effects produced by tumor cell Specific diagnosis depends on demonstration of metabolites or other products which disrupt the specific autoantibodies in various tissues of the normal function of surrounding cells and tissue. body and imaging studies such as MRI, PET, and Body systems that may be affected by PNS SPECT scans. include neurological, endocrine, cutaneous, renal, hematologic, gastrointestinal, and other REFERENCE systems. The most common manifestations of 1. Quigley EM, et al. AGA technical review on nausea PNS are cutaneous, neurologic, and endocrine and vomiting. Gastroenterology 2001;120(1):263- disorders. An example of a cutaneous paraneop- 86. [PMID: 11208736]. CHAPTER 32 Pain—Chronic

SYNOPSIS Pain is generally divided into three categories: nociceptive, neuropathic, and Pain is defined by the International Association for mixed. Nociceptive pain develops from body the Study of Pain as, “an unpleasant sensory and tissue or organ—injured or damaged—and is emotional experience associated with actual or further divided into somatic and visceral pain. potential tissue damage, or described in terms of Somatic pain is typically related to specific such damage. It is unquestionably a sensation in a anatomic areas or structures, and therefore part or parts of the body, but it is also always well-localized, aching, stabbing, or throbbing unpleasant, and therefore also an emotional in nature, e.g. fibromyalgia, osteoarthritis, and 1 experience”. In other words pain is an inherently rheumatoid arthritis. Visceral pain is organ subjective phenomenon characterized by dis- based, less well localizes, dull, and cramping comfort (sensory), and distress (emotional feeling). in nature, e.g. irritable bowel syndrome, colitis, Many people report pain in the absence of and diverticulosis. Neuropathic pain, on the other tissue damage or any likely pathophysiological hand, involves damage to the nervous system cause; usually this happens for psychological characterized as burning, tingling, and reasons. There is usually no way to distinguish lancinating, and often occurring in the nerve their experience from that due to tissue damage. dermatome, e.g. trigeminal neuralgia, posther- “Many have a profound distrust of a diagnosis petic neuralgia, diabetic neuropathy, and based on symptoms alone when the symptom phantom limb. This pain may be associated with is pain, and basic research has not uncovered a sensory deficit, and occur with or without test that would yield an unequivocal sign”.2 nociceptive component. Metastatic cancer pain, Further, it is counterproductive to speculate low back pain, non-cardiac chest pain may be about whether the pain is 'real'. It is real to the of mixed pain origin. patients—if they regard their experience as pain, Clinically, pain can be categorized as acute and if they report it in the same ways as pain or chronic. In general, acute pain is distinguished caused by tissue damage, it should be accepted as being of recent onset; originating from an as pain.1, 3 identifiable biologic component such as an injury, Pain—Chronic 219 infection, metabolic, or degenerative disorder; Table 32.1: Factors affecting pain threshold* self-limited, the pain tends to abate as the tissue Threshold lowered Threshold raised heals; does not have much of psychological component; and is more amenable to pharma- Discomfort Relief of other symptoms Insomnia Sleep cologic intervention. Fatigue Understanding Chronic pain can be described as, “persistent or Anxiety Companionship recurrent pain, lasting beyond the usual course of Fear Creative activity Anger Relaxation acute illness or injury or more than 3 to 6 months, Sadness Reduction in anxiety and which adversely affects the individual’s well- Depression Elevation of mood being. A simpler definition for chronic pain is— Boredom Analgesics 4 Mental isolation Anxiolytics pain that continues when it should not”. Social abandonment Antidepressants The biological component of chronic pain is *Source: Robert T. Introducing Palliative Care, 3rd ed.; less well-understood than that of acute pain. It Symptom Management, p.66. appears that chronic pain constitutes a complex Table 32.2: Biopsychosocial factors related to mixture of pathophysiologic factors interacting chronic pain** with numerous psychological, social, and cultural Biologic factors factors, and also influenced by past experience • Not biologically useful and cognitive function, which can modulate the • Poorly defined, multiple pain / medical problems patient’s pain threshold, either upward or • Stress response (fight or flight) not present • Significant physical deconditioning present downward (Table 32.1). The biopsychosocial Psychosocial factors factors related to chronic pain is given in Table • Significant premorbid personality 32.2. These characteristics necessitate a systematic • May be an expression of psychosis or neurosis • Depression common multidisciplinary approach by physicians (such • Secondary gain present (litigation, worker’s as neurologists, anesthesiologists, oncologists); compensation) and nonphysicians (psychologists, chiropractors, • Sick role present, daily activities causing pain • Abnormal illness behavior (malingering/somati- acupuncturists, and hypnotists) to achieve a zation) often present satisfactory outcome. It is in this context that in • Physical, sexual, emotional abuse often present the diagnosis and management of chronic pain • Substance abuse often present * • Significant lifestyle disturbances (marital, familial, disorders the biopsychosocial approach is very vocational) often present much useful.5,6 However, diagnosis of the • Domestic violence often present etiology for chronic pain—biological or otherwise **Adopted and modified from International Association -is crucial on several stages such as investigations, for the Study of Pain (IASP-1994). treatment, and rehabilitation. Hence, it is essential to exclude, especially progressive or serious DIFFERENTIAL DIAGNOSIS conditions as soon as possible, so that intervention Common can be timely. Musculoskeletal Disorders • Chronic low back pain (lumbosacral disk

* Biopsychosocial approach — symptoms are viewed as a lesions, postlaminectomy syndromes, spon- product of multiple dynamic factors that develop dylopathies, spinal stenosis) synergistically in combination with certain genetic, • Chronic neck pain (cervical spondylosis, psychological, and environmental vulnerabilities”. (Weisberg MB, Clavel AL Jr. Why is chronic pain so difficult to radiculitis, stenosis, whiplash injury) treat? Postgrad Med 1999; 106(6):141-64). • Osteoarthritis 220 Diagnosis: A Symptom-based Approach in Internal Medicine

• Fibromyalgia • Metabolic (gout) • Myofascial pain (trigger points) • Reproductive- extrauterine (pelvic conges- • Chronic overuse syndromes (tendinitis, tion syndrome, dyspareunia, vulvodynia). bursitis) Rare • Post-traumatic pain. • Musculoskeletal (compression fracture of Neurological Disorders lumbar vertebrae, seronegative spondylosis, temporomandibular joint dysfunction, phan- • Headache (chronic daily headache, tension tom limb pain) headache, migraine) • Neurologic (glossopharyngeal neuralgia) • Central post-stroke pain (i.e. thalamic pain, • Autoimmune (temporal arteritis, polymyo- or Dejerine and Roussy syndrome) sitis) • Polyneuropathies (alcohol, HIV) • Nutritional deficiencies • Nerve compression or entrapment (sciatica, • Paraneoplastic disorders carpel-tunnel syndrome). • Complex regional pain syndromes (CRPS: vide infra ↓↓). Metabolic INVESTIGATIONS—GENERAL • Diabetes mellitus • Uremia. CBC

Gastrointestinal Disorders • Anemia due to chronic disease (normo- chromic microcytic). • Gastroesophageal reflux • Leukocytosis in infective lesions. • Peptic ulcer disease • Irritable bowel syndrome. ESR or CRP • To evaluate for inflammatory conditions; Psychological Disorders elevated in temporal arteritis, rheumatoid arthritis, and malignancy. • Depression • Anxiety Blood Glucose • Somatization • To detect and monitor diabetes mellitus. • Chronic fatigue syndrome • Da Costa syndrome (neurocirculatory Serum Calcium/Alkaline Phosphatase asthenia, effort syndrome, Soldier’s heart, • Metastatic bone disease (e.g. from breast, 7-9 Gulf war syndrome) lung, or kidney tumor) is the commonest Cancer pain syndromes (bone pain secondary to cause of elevated serum calcium and alkaline metastasis, visceral pain secondary to mass phosphatase levels effect). • In patients suspected with Paget’s disease – bone-specific alkaline phosphatase is more Occasional specific. • Autoimmune (RA, polymyalgia rheumatica) • Neurological (Postherpetic neuralgia, Urea, Creatinine, Electrolytes trigeminal neuralgia, postconcussive) • Gastrointestinal (IBD, pancreatitis, colitis, • In patients suspected with CRF, and uremic diverticulosis) polyneuropathy. Pain—Chronic 221

CPK NCS/EMG • Elevated in myopathies (polymyositis, • These two studies, which compliment one metabolic disorders, drugs, alcohol, and another, can often distinguish between muscular dystrophy). neurogenic and myogenic disorders • NCS distinguish between mononeuro- † INVESTIGATIONS—SPECIFIC pathies (e.g. due to trauma, compression, or X-ray/CT Scan entrapment) and polyneuropathies (e.g. due to metabolic, toxic, malignant, nutritional, • In patients suspected with bony abnormalities, autoimmune, or hereditary disorders) e.g. cervical, lumbosacral disk lesions; thoracic • In addition, they may also be helpful in outlet syndrome; compartment syndromes, excluding organic disorders when psycho- and neoplastic lesions genic pain or functional syndrome is suspected. • Lytic lesions may be the only finding early in Paget’s disease. Cancer Screen/Tumor Markers • Age and gender related cancer screening, e.g. MRI breast mammography, Pap smear, PSA, etc.; • To further evaluate CT scan lesions related and tumor markers, e.g. alpha-fetoprotein, beta to discogenic pain; spinal canal stenosis; chorionic gonadotropin, carcinoembryonic various bone and joint lesions; avascular antigen, etc. may be helpful in the evaluation necrosis, etc of patients suspected with cancer pain. • MRI is extremely helpful in the evaluation of pain that may be due to intracranial mass CLINICAL NOTES lesion; bony or soft-tissue lesions, abscess, • Although most patients have great difficulty metastatic deposits; facial pain due to in describing pain sensation, its assessment posterior fossa lesions; facial nerve lesions; is important and helpful diagnostically. orbital pain; abdominal and pelvic pain due Therefore, evaluation of a patient with to inflammation or malignancy. chronic pain should include the following: Bone Scan  Quality (pricking, lancinating, burning, • Helpful in evaluating pain due to a stress etc., i.e. somatic, visceral, or neuropathic, fracture, infection (osteomyelitis); and as explained above); chronic pain in bone cancer patients –  Is it bone pain? Bone pain may begin as a most commonly due to secondary deposits dull, constant ache that grows worse; it feels in spine, pelvis, extremities, ribs, and skull deep with boring, stabbing, throbbing, • Bone scanning is the most sensitive test cramping or gnawing sensation; usually for evaluating the extent of lesions in increases at night and may not subside the whole skeleton affected by Paget’s when sleeping; mostly due to metastatic disease. deposits; referred to a different area from the site of the problem;  Duration (acute, chronic, constant, or †Because of heterogenicity of the chronic pain and its intermittent); presentation, specific laboratory and imaging evaluation  must be targeted to specific condition and to rule out other Patient’s functional status (i.e. the impact life-threatening illnesses. of pain on patient’s daily activities such as 222 Diagnosis: A Symptom-based Approach in Internal Medicine

ability to perform household chores, work • Assess patient’s psychosocial status—A good tasks, leisure in interests, sleep, etc. with psychosocial and psychosexual history is the help of VAS, i.e. visual analog scale; ‡ needed when organic diseases are excluded or  A review of previous diagnostic studies coexisting psychiatric disorders are suggested. (careful reviewing of prior test reports is Obtain sufficient history to evaluate depression; essential to eliminate unnecessary anxiety disorder; somatization; physical or repetition); sexual abuse; drug abuse/dependence; and  An assessment of coexisting diseases and family, marital, or sexual problems conditions (i.e. biological causes such as • History of onset—Discord in family dynamics, musculoskeletal, neurologic, cardiovas- difficult social interactions, stressful work cular, respiratory, gastrointestinal, and environment, strained marital relationship, gynecological disease). sexual problems, and history of substance abuse, • The mnemonic “PQRST” is helpful when domestic violence, and absence of a clear dealing with painful conditions: pathophysiologic mechanism suggest a primary  “P” refers to precipitating or palliative psychosocial cause factors; this information may provide • Circumstances associated with the onset of clues for possible etiologies or associated pain is important; it helps to identify whether disorders; the patient’s complaints are related to  “Q” refers to quality of the pain (nocicep- biologic process, or is predominantly psyc- tive, neuropathic, or mixed - as described hological or psychosocial in origin above); • Physical examination—Its main purpose is  “R” stands for radiation and original to determine the possibility of underlying location of pain; radiating pain is biologic process. Each system, particularly characteristic of neuropathic pain; the ones pertaining to the patient’s  “S” stands for severity of pain: many special- presentation, and including complete ized clinical tools in multiple languages mental state examination (affect, mood, are available for pain assessment.10 ideation, and insight) is performed. Any Examples include unidimentional scales evidence of primary biologic process such as the visual analog scale (VAS), responsible for chronic pain is subjected to verbal rating scale (VRS), numerical further appropriate physical examination rating scale (NRS), and the pain faces and investigations. Table 32.3 illustrates scale, etc. (use score 1-to-10 rating scales: location-wise classification of common severe pain is defined as pain that is rated biological causes for chronic pain as 7 to 10 on a 0 to 10 VAS); • Assess for Waddell’s signs 11 (Table 32.4), and  “T” stands for timing, including onset, inconsistencies in the above examination; duration, and frequency—daily, paroxys- positive Waddell’s signs generally indicate a mal, seasonal, nocturnal, or diurnal. nonphysiological etiology of pain.

‡VAS: A tool used to help a person rate the intensity of RED FLAGS certain sensations and feelings, such as pain. The VAS for pain is a straight line with one end meaning no pain and • Any patient with unexplained, persistent the other end meaning the worst pain imaginable. A patient pain—somatic, visceral, or bone pain—should marks a point on the line that matches the amount of pain he or she feels. It can also be used to help choose the right be suspected of having malignant disease and dose of pain medicine. appropriate investigations performed. Pain—Chronic 223

Table 32.3: Location-wise classification of causes for chronic pain syndromes Headache/ Musculo- Low back Abdomen/ Peripheral facial pain skeletal pain pain pelvic pain nerve pain • Migraine • Trauma • Chronic disc disease • IBS • Diabetic neuropathy • Tension • Osteoarthritis • Osteoporotic fractures • IBD • Uremic neuropathy • Medication overuse • Rheumatoid arthritis • Spinal stenosis • Colic-biliary/renal • HIV neuropathy • Temporal arteritis • Gout/pseudogout • Seronegative spondylosis • Esophagitis • Toxic neuropathy • Trigeminal neuralgia • Drug myositis/statins • Epidural abscess • Gastritis • Paraneoplastic • Osteomyelitis • Tumor • Hepatitis syndromes • Postconcussive • Bursitis/tendinitis • Pancreatitis • B12 deficiency • Chronic otitis • Fibromyalgia • Pyelonephritis • Hereditary neuropathies • Sinusitis • Polymyalgia rheumatica • Endometriosis • Dentalgia • Polymyositis • Ovarian cyst • Meningitis • Dermatomyositis • Polycystic kidney • Abscess • SLE • Mesenteric thrombosis • Tumor • Trichinosis • Aortic aneurysm • Glaucoma • Lyme disease • Porphyria • Iritis • Paget’s disease • Sickle cell disease

Table 32.4: Waddell’s signs • Beware of the high rate of psychiatric comorbidities that exist with chronic pain Waddell’s signs are special nonphysiologic maneuvers used to evaluate persons when exam findings are disorders; and even when an organic cause inconsistent. They are: for a patient’s pain can be found, it is still wise 1. Superficial tenderness—Skin tenderness to light to look for other factors12 palpation over a wide area 2. Nonanatomic tenderness—Deep tenderness over • Beware of involvement of litigation or a wide area, crossing multiple anatomic evidence of secondary gain, e.g. issues such boundaries; often extending cephalad to the as indemnity, loss of financial stability, and thoracic spine or caudad to the sacrum 3. Axial loading—Eliciting low back pain when relationships

pressing down on the top of the patient’s head. • Chronic pain may trigger fear of death, 4. Rotation—Back pain when the shoulders and disability, or disease progression; therefore, pelvis are rotated passively in the same plane with the feet together. Normally, rotating the shoulders support and education may be important and pelvis together should not be painful as it does even for mild pain; stress that pain does not not stretch the structures of the back. always equal harm. 5. SLR—Observing an improvement of 30-40° when the patient is distracted, i.e. distracted straight leg raise, compared with formal testing. SELECTIVE GLOSSARY

6. Weakness—Cogwheeling, i.e. weakness that is § jerky, with intermittent resistance, of many muscle Complex regional pain syndrome —The groups upon manual muscle testing of strength CRPS 13, 14 is a neurologic disorder affecting 7. Sensory—Diminished light touch or pinprick central and peripheral nervous systems—a sensation in a stocking pattern, rather than a dermatomal pattern, in an individual who is not common mechanism may be injury to central or diabetic peripheral neural tissue — such as due to head 8. Overreaction—During the examination may be injury, stroke, tumor, burns, fractures, sprains, observed in several manifestations (e.g. dispro- portionate verbalization, facial grimacing, muscle operative procedures, trivial soft tissue injury, tension and tremor, collapsing, sweating). vaccination, and microtrauma. Persons of all Although Waddell’s signs can detect a nonorganic ages and both sexes are affected, and can involve component to pain, they do not exclude an organic cause. The presence of three or more positive findings may be §The terms currently in favor are complex regional pain syndrome clinically significant in terms of psychosocial issues or possible I (the equivalent of Reflex sympathetic dystrophy) and complex illness behavior. Isolated positive signs are of limited value. regional pain syndrome II, also known as causalgia. 224 Diagnosis: A Symptom-based Approach in Internal Medicine either the arms or the legs. CRPS is characterized account for the degree of pain and dysfunction. by pain, edema, stiffness, and discoloration. Pain A single, reliable, sensitive, and specific is intense and burning, out of proportion to the diagnostic test for CRPS is not available; injury, allodynia (perception of pain from a however, the disease is not fatal. nonpainful stimulus), or hyperalgesia (disprop- ortionate to the inciting event). Edema is usually REFERENCES one of the earliest findings. Stiffness may occur. 1. International Association for the Study of Pain. Web Discoloration may vary from intensely site: http://www.iasp-pain.org/AM/Template. erythematous to cyanotic, pale, purple, or gray. cfm?Section=General_Resource_Links&emplate=/ CM/HTML Display.cfm & ContentID=3058#Pain. The syndrome progress through a series of stages: Accessed on 04-11-08. 2. Bennett GJ. Neuropathic pain: A crisis of Acute stage—Usually warm phase of 2-3 definition? Anesth Analg. 2003;97(3):619-20. months: Pain is more severe than would be [PMID: 12933371: Free full text]. 3. Eisendrath SJ, et al. Chronic pain disorders. In: expected from the injury; burning or aching Tierney Jr et al, Eds. Current Medical Diagnosis quality; may be increased by dependency of the and Treatment. 2006, 45th edn. The McCraw Hill Companies, Inc. p. 1050. limb, physical contact, or emotional upset. The 4. http://www.theacpa.org/documents/ ACPA% affected area becomes edematous, may be 20Meds%202007% 20 Final.pdf. Accessed on 04- hyperthermic or hypothermic, and shows 11-08. 5. Turk DC, et al. psychological approaches in the increased nail and hair growth. Physical treatment of chronic pain patients – when pills, findings may be minimal; radiographs may scalpels, and needles are not enough. Can J psychiatry 2008; 52(4):213-23. show early bony changes. 6. Gatchel RJ, et al. The biopsychosocial approach to chronic pain: Scientific advances and future Dystrophic phase—Vasomotor instability for several directions. Psychol Bull. 2007;133(4):581-624. months: Edematous tissue becomes indurated; skin [PMID: 17592957: Abstract]. 7. Wooley CF. Where are the diseases of yesteryear? becomes cool and hyperhidrotic with livedo DaCosta’s syndrome, soldier’s heart, the effort reticularis or cyanosis; hair may be lost, and nails syndrome, neurocirculatory asthenia—and the become ridged, cracked, and brittle. Hand dryness mitral valve prolapse syndrome.Circulation 1976; 53(5):749-51. becomes prominent, and atrophy of skin and 8. Thomas HV, et al. Pain in veterans of the Gulf War subcutaneous tissues becomes noticeable. Pain of 1991: A systematic review. BMC Musculoskelet Disord. 2006; 7:74. [PMID: 16987407: Free full text]. remains the dominant feature. It usually is constant 9. Stimpson NJ, et al. Prevalence of reported pain, and is increased by any stimulus to the affected area. widespread pain, and pain symmetry in veterans of the Persian Gulf War (1990-1991): The use of pain Stiffness develops at this stage. Radiographs may manikins in Persian Gulf War health research. Mil show diffuse osteoporosis. The 3-phase bone scan Med 2006;171(12):1181-6. [PMID: 17256678: Abstract]. is usually positive. Duration is 3-12 months from 10. Web sites: http://www.britishpainsociety.org/ onset. pain_scales_eng.pdf; http://www.partnersagainst pain.com/ professional-tools/pain-assessment- Atrophic phase—Usually cold extremity with scales.aspx?id=3. atrophic changes: Pain spreads proximally, may 11. Fishbain DA, et al. A structured evidence-based review on the meaning of nonorganic physical diminish in intensity, but persists with occasional signs: Waddell signs. Pain Med 2003;4(2):141-81. flare-ups. Skin is thin and shiny; edema is absent; [PMID: 12911018 Abstract]. 12. Kasper DL, et al (Eds). Harrison’s Prin. of Internal contractures may occur. Radiographs indicate Med. 2005, 16th edn. Vol. I: p.75. marked demineralization. 13. http://www.emedicine.com/pmr/TOPIC123.HTM. Accessed on 08-11-08. The diagnosis of CRPS is excluded by the 14. http://www.emedicine.com/emerg/TOPIC497. existence of any condition that would otherwise HTM. Accessed on 08-11-08. CHAPTER 33 Palpitation

SYNOPSIS closely related phenomenon, they are not synonymous. The symptom of palpitation The term palpitation refers to conscious awar- does not necessarily mean that an arrhythmia eness of one’s own heartbeat, usually with an is present, e.g. sinus tachycardia with anxiety; increase in frequency or force, with or without conversely, an arrhythmia can occur without irregularity in rhythm. It is generally an the sensation of palpitation*—an entity described unpleasant feeling. However, individual patients as asymptomatic or silent arrhythmia, e.g. vary greatly in sensitivity to palpations—healthy patients may be concerned with even isolated sudden cardiac death (SCD) due to ventricular ectopic beats, e.g. patients with cardiac neurosis; fibrillation (VF) in diabetics, and asymptomatic while patients with higher risks and advanced atrial fibrillation (AF) in untreated patients with heart disease, e.g. hypertrophic cardiomyopathy a history of AF. may be completely unaware of serious The causes of palpitation vary from benign arrhythmias such as AF and even VT. Thus, the conditions requiring no therapy to life-threat- intensity of the symptoms does not necessarily ening conditions requiring urgent monitoring, correlate with the seriousness of the underlying treatment, and referral. condition. However, in the vast majority of patients, Palpitations mean different things to different palpitation is benign, and expensive and costly people. It is described by a variety of sensations, investigation is not warranted. Attention to e.g. pounding, thumping, fluttering, jumping, characteristics that identify patients at high racing, or skipping a beat. It is, therefore, risk for serious causes of palpitations will help important to establish exactly what is meant. define the much smaller percentage of patients Though it is classically suggestive of an who require more extensive diagnostic testing arrhythmia (i.e. loss or abnormality of rhythm), and management of their condition.1 it occurs in a wide variety of disorders of cardiac and noncardiac origin. *“All palpitations are not arrhythmias and many Although palpitations and arrhythmias are arrhythmias do not palpitate”. 226

DIFFERENTIAL DIAGNOSIS asymptomatic.† In the event of a patient experiencing palpitations, a concurrent ECG Common may be diagnostic, but this is often difficult, • Physiological (sinus tachycardia with stress, as the timing of palpitations may not coincide exercise) with the ECG recording. • Coronary artery disease (CAD: stable angina, • ECG findings between episodes can include: unstable angina, MI, SCD)  Short PR-interval and delta waves • Left ventricular failure (LVF) indicating preexcitation. • Arrhythmias (ectopics, AF, SVT, VT, VF,  Long QT-interval due to drugs, or long WPW syndrome) QT-syndrome. • High-output states (anemia, fever, internal  Left atrial abnormality, indicating AF. hemorrhage, pregnancy)  Marked LVF, deep septal Q waves in I, • Psychiatric disease (generalized anxiety disorder, aVL, and V4-6, indicating HOCM with panic attack, depression, and somatization) AF. • Drugs (prescribed and abused)  Complete heart block, LBBB, or torsade • Stimulants (caffeine, alcohol, nicotine, de pointes. cocaine).  Pathological ‘q’ waves, indicating prior Occasional MI, and therefore a focus for ventricular • Metabolic disorders (hypoglycemia, hyper- arrhythmias. thyroidism, menopause, electrolyte imba- CBC lance-hypokalemia, hypomagnesemia) • Hb < 10 g/dl; blood smear suggestive of iron • Valvular heart disease (mitral and aortic deficiency anemia. regurgitation). Blood Glucose Rare • Hypoglycemia (blood glucose generally • Pheochromocytoma < 50 mg/dl) causing palpitations • Mitral valve prolapse (MVP) • Cardiomyopathies INVESTIGATIONS—SPECIFIC • Long QT-syndrome (LQTS) • Pacemaker syndrome (endless-loop tachy- Ambulatory ECG (AECG) Recording2/Holter cardia: vide infra ↓↓) Monitoring (Table 33.1) • Congenital heart disease (cyanotic heart disease, Ebstein anomaly). • Generally indicated if symptoms due to arrhythmia are occurring at least daily, INVESTIGATIONS—GENERAL particularly when associated with organic heart disease. Heart rhythm is monitored for ECG 24 to 48 hours. Patients are asked to maintain • Palpitations may or may not be associated † with ECG changes. In the majority of patients Although a normal ECG cannot exclude the possibility of an arrhythmia or CAD, it tends to imply preserved left there are no ECG changes at rest while ventricular systolic function. Palpitation 227

Table 33.1: The indications for ambulatory ECG Table 33.2: Common indications/contraindications for monitoring for symptoms of arrhythmia are as follows2: EPS in patients with palpitations Class I—## Investigations of symptoms (1) Patients with unexplained syncope, near syncope or • History of persistent palpitations of possible cardiac episodic dizziness without obvious cause. origin (2) Patients with unexplained recurrent palpitation. • Recurrent, unexplained syncope of possible cardiac origin Class IIb— • Presyncope with impaired left ventricular function (1) Patients with episodic shortness of breath, chest pain Interventions or fatigue that is not otherwise explained. • Potentially life-threatening arrhythmias requiring (2) Patients with neurologic events when transient atrial intervention fibrillation or flutter is suspected. • Sustained ventricular tachycardia (3) Patients with symptoms such as syncope, near syncope, • Unexplained ventricular ectopy episodic dizziness or palpitation in whom a probable • Hypertrophic cardiomyopathy with ventricular cause other than an arrhythmia has been identified but tachycardia in whom symptoms persist despite treatment of this • Uncontrolled or recurrent AF refractory to other cause. conventional therapy • Symptomatic sinus bradycardia Class III— • Second and third degree atrioventricular blocks (1) Patients with symptoms such as syncope, near • Long QT syndrome syncope, episodic dizziness or palpitation in whom • Rhythm disorders in patients with pacemakers and other causes have been identified by history, physical defibrillators examination or laboratory tests. Evaluation (2) Patients with cerebrovascular accidents, without • Evaluation of therapy in patients with accessory AV other evidence of arrhythmia. pathways ______• Evaluation of efficacy of pharmacotherapy in patients ## Class I – general agreement is that the test is useful and with life-threatening arrhythmias· effective. Class II – frequently used, but there is a divergence • Evaluation of patients for catheter ablation of opinion with respect to its utility. Class IIa – weight of procedures or antitachycardia devices evidence/opinion is in favor of usefulness/efficacy. Class IIb – usefulness/efficacy is less well established by evidence/ Contraindications opinion. Class III – general agreement that the test is not • Severe aortic stenosis useful, and in some cases may be harmful. • Unstable coronary disease • Left main stem stenosis • Substantial electrolyte disturbance a diary documenting the time and describing the symptoms during the monitoring period. Subsequently the patient’s symptoms are Continuous —Loop Event Recorder correlated with documented rhythm abnor- • The event monitor is a patient activated malities. (i.e. conventional) device. These monitors Electrophysiological Studies (EPS)3 are generally worn for a period of up to 30 days, continuously recording the • Indicated in patients with potentially life- patient’s under-lying rhythm, but require threatening arrhythmias and episodes of SCD the patient to manually trigger, i.e. to with successful resuscitation; EPS assist in activate the device to save the inform- their subsequent management by means of ation. The loop recorder provides the antiarrhythmic drugs, pacemakers, or rhythm strip generated during the two implantation of automatic implantable minutes preceding and following the cardioverter defibrillator (AICD). Common episode of palpitation. Conventional event indications/contraindications for EPS appear monitoring is successful only when the in Table 33.2. patient is aware of symptoms as they occur, 228 Diagnosis: A Symptom-based Approach in Internal Medicine

and is capable of pressing the signal button Table 33.3: Recommendations for echocardiography in promptly. Newer event recorders have patients with arrhythmias and palpitations5 programmable automatic triggers for rapid Class I and slow heart rates. The advantages over 1. Arrhythmias with clinical suspicion of structural Holter monitoring are that, a symptom heart disease 2. Arrhythmia in a patient with a family history of a dairy is not needed and the higher yield of genetically transmitted cardiac lesion associated collected data is useful for detecting with arrhythmia, such as tuberous sclerosis, rhabdomyoma, or hypertrophic cardiomyopathy arrhythmia associated with palpitation. 3. Evaluation of patients as a component of the work- Continuous Mobile Cardiac Outpatient up before electrophysiological ablative procedures 4 Class IIa Telemetry (MCOT) 1. Arrhythmia requiring treatment • It has several advantages over traditional 2. TEE or intracardiac ultrasound guidance of radiofrequency ablative procedures ambulatory monitoring systems in the Class IIb diagnostic evaluation of symptoms such as 1. Arrhythmias commonly associated with, but palpitations, dizziness, and syncope. MCOT without clinical evidence of heart disease can detect asymptomatic clinically significant 2. Evaluation of patients who have undergone radio- frequency ablation in the absence of complications arrhythmias, and was especially useful to (In centers with established ablation programs, a post- identify the cause of presyncope/syncope, procedural echocardiogram may not be necessary) even in patients with a previous negative 3. Postoperative evaluation of patients undergoing the Maze procedure to monitor atrial function workup. This outpatient monitoring system Class III allows patients to undergo daily medication 1. Palpitation without corresponding arrhythmia or dose titration in the outpatient setting, thus other cardiac signs or symptoms 2. Isolated premature ventricular contractions for avoiding hospitalization. which there is no clinical suspicion of heart disease Pacemaker Evaluation arrhythmias and palpitations are given in • In patients who complain of palpitation with Table 33.3. pacemaker. TFTs Exercise ECG/TMT • Hyperthyroidism is associated with AF, • Indicated in patients who are known to have PSVT, and CHF. or suspected to have CAD. Echocardiography Urea, Creatinine, Electrolytes • May be indicated in patients suspected of • Dehydration and hypovolemia may be valvular heart disease, CHF, or any structural associated with arrhythmias. abnormality. The ACC/AHA Guidelines for the Clinical Application of Echocardiography Urine state that, “Unless there are other indications • 24 hours urine collection for vanillylmandelic for testing, echocardiography need not be acid (VMA) assay. performed in a subject with palpitation for which an arrhythmic basis has been ruled Drug Levels out.5” The ACC/AHA indications for echocard-iography in patients with • To assess for drug toxicity, e.g. digitalis. Palpitation 229

CLINICAL NOTES Table 33.4: Clues to arrhythmia in clinical disorders • An important step in the evaluation of Clinical disorder Clues palpitation is to establish or exclude the • Systemic hypertension • Vasodilators (nitrates, presence of underlying structural heart calcium channel disease such as CAD, CHF, valvular stenosis blockers); pheochromocytoma or regurgitation, cardiomyopathy, and • Coronary artery • Ventricular arrhythmias; congenital cardiac disorders, and to detect life- disease heart blocks threatening cause of palpitation that place • Heart failure • Digitalis toxicity; hypokalemia of diuretics patients at risk of sudden death—VT and VF • Diabetes mellitus • Hypoglycemia • Any evaluation of palpitations must first • Bronchial asthma • Bronchodilators confirm that the patient is hemodynamically (methylxanthines, beta- stable, and that the symptoms are not life- agonists) • Thyrotoxicosis • Sinus tachycardia, Atrial threatening, which in many cases can often fibrillation be made from history, physical examination, • Congenital deafness • Congenital long QT and ECG findings, which are sufficient to syndrome • Antiarrhythmic or • Acquired long QT determine the nature of the problem antidepressant drugs disorder • A patient with palpitation is usually asympt- • Diuretics • Hypokalemia omatic at the time of physical examination, • Pre-excitation • Reentry tachycardias and the diagnosis of arrhythmia may pose a real problem if the arrhythmia is not present • Associated symptoms such as chest pain (angina, at the time of examination. One solution is MI); dyspnea (LVF, MI, pulmonary embolism); to request the patient to present as soon as lightheadedness, dizziness, or sweating (syncope, possible at the onset of palpitation. However, hypoglycemia, pheochromocytoma); may if the history and physical evaluation indicate hemodynamic instability and mandate indicates the possibility of any serious further evaluation arrhythmia, it is prudent to monitor the • Evidence of anxiety or depression should be patient (Table 33.4) sought in patients presenting with palpita- • History—In a study reported by Summerton tions without clinical evidence of cardiov- 6 N et al, characteristic historical factors ascular disease. Psychological factors may contributory to new-onset clinically signif- influence the perception of palpitation as icant palpitations include: unpleasant and abnormal and thereby  Current medical problems, e.g. thyroid prompt consultation. Psychological factors disease, asthma, anemia, anxiety, should therefore be integrated into the depression, perimenopause diagnosis of palpitation  Past history of hypertension, CAD, • A family history of SCD or syncope may valvular heart disease, congenital heart suggest an inherited dilated or hypertrophic disease, cardiomyopathy cardiomyo-pathy (HCM)‡, congenital LQTS,  Family history of thyroid disease, palpitation or Brugada syndrome (BrS: vide infra ↓↓). In  Consumptions—Cigarettes, alcohol, general, first-degree relatives under 40 with coffee—per day frequency, and duration a family history of SCD must be investigated  Current medications, e.g. benzodiaze- pines, ACE-inhibitors, diuretics, OHA, ‡ The apical variant of HCM, also known as ‘Japanese or insulin, beta-blockers, antianginals, Asian variant’, is rare and often poses a diagnostic thyroxin, antidepressants. challenge. 230

• Palpitations since childhood suggest an • Physical examination—Possible evidence of idiopathic SVT, WPW syndrome, or LQTS organic heart disease may include: • Resolution of symptoms due to palpitation hypertension; signs of CHF (rales, cardio- with vagal maneuvers such as breath-holding megaly, acute pulmonary edema, third heart or the Valsalva maneuver in hemodyna- sound, jugular pressure greater than 16 cm, mically stable patients suggests PSVT and positive hepatojugular reflex); and • An episode of palpitation on assuming an cardiac murmurs. Other signs may include upright position after bending over, and tachycardia/bradycardia, pedal edema, aborted by lying down suggest ‘postural hepatomegaly, and pleural effusion. Some orthostatic tachycardia syndrome (POTS: vide clinical disorders associated with palpita- infra ↓↓)’, i.e. atrioventricular nodal reentry tions may provide clues to the nature of the tachycardia (AVNRT) arrhythmia (Table 33.5) • An episode of polyuria that follows • Cardiac examination—Common cardiac palpitations may suggest supraventricular murmurs/disorders associated with palpit- arrhythmias ation are given in Table 33.6. • Palpitations associated with restlessness, Table 33.5: Clues to the nature of palpitations warm and sweaty palms, fine termer, Nature of palpitations Clues / Clinical significance protruding eyes, and enlarged thyroid Missed beat followed by heavy Atrial or ventricular premature (goiter) is due to hyperthyroidism beat, or thump in the chest contraction with compensatory • The use of medications, drugs, and stimulants pause Rapid regular palpitations Sinus tachycardia should be questioned and quantified. Almost (regular like a clock) Supraventricular tachycardia all antiarrhythmic drugs have a proarrhy- Rapid irregular palpitations Ventricular tachycardia (like in an obstacle race) Atrial fibrillation thmic potential, i.e. they may worsen existing Atrial tachycardia with varying arrhythmia or provoke new arrhythmias in block Sudden palpitations with Atrial flutter with varying block some patients. Phenylpropanolamine, a sudden cessation (like a light Paroxysmal supraventricular frequent ingredient in diet pills and cold switch) tachycardia Reentry tachycardia remedies, is one of the many sympatho- Tachy-brady of sick sinus mimetics that can cause arrhythmias. syndrome Eyedrops that include beta-blockers have been blamed in some cases of bradycardia Table 33.6: Cardiac murmurs and disorders • Palpitations as a result of varieties of arrhythmias associated with palpitation may be provoked by excess consumption of Cardiac murmurs/signs with Disorder alcohol even in healthy individuals (holiday palpitation heart syndrome: vide infra ↓↓) Midsystolic click, often followed MVP • Palpitations due to AF are the most common by systolic murmur Triple apical impulse, loud S , HOCM arrhythmia in the elderly (secondary to 4 harsh, holosystolic murmur hypertension, and CAD) along left sternal border, • To help characterize the palpitations, increased with Valsalva requesting the patient to simulate their rhythm maneuver, decreased with squatting, associated with by tapping his finger on a hard surface can be mitral regurgitation, AF, VT quite informative. The physician can also help Laterally displaced apical Dilated

the patient by tapping out examples of rapid impulse, S3, S4 gallop, CHF, cardiomyopathy or irregular rhythm that has been experienced associated with AF, VT 231

RED FLAGS tation—in the absence of exertion or hyperdynamic states—should not be autom- • Any person, including a child, with symptoms atically attributed to anxiety; the patient of palpitations, recurrent loss of consciousness, could be suffering from POTS.8 collapse associated with exertion, atypical seizures with a normal EEG, or with any SELECTIVE GLOSSARY documented arrhythmia must be thoroughly evaluated by cardiologists, especially to Brugada syndrome (BrS)—Since its intro- screen for inherited cardiac diseases such as duction as a clinical entity in 1992 (originally WPW syndrome, HOCM, LQTS, and BrS. described by Pedro and Joseph Brugada), the BrS Screening should be considered in all first- has attracted great interest because of its high degree relatives (parents, siblings and incidence in many parts of the world, and its children) of anyone who has died under association with high risk for sudden death in 40 yrs from an inherited heart condition or young and otherwise healthy adults, and less unexplained sudden cardiac episode frequently, in infants and children. Sudden and • Do not overlook MI, including silent MI and unexpected death syndrome (SUDS) of young unstable angina as a cause of arrhythmia adults during sleep is endemic in Japan and manifesting as palpitations, especially in the Southeast Asia. SUDS characteristics include the elderly following: (1) victims are relatively young, • Palpitations associated with syncope and healthy men leading normal lives; (2) death often presyncope merit a complete cardiovascular occurs during sleep late at night; and (3) autopsy evaluation; sustained or nonsustained VT findings are usually negative. The syndrome must be ruled out typically manifests during adulthood, with a • Sudden onset of palpitations in an apparently mean age of sudden death of 41±15 years. The healthy person associated with ECG evidence youngest patient clinically diagnosed with the of PSVT is suggestive of WPW syndrome. syndrome is 2 days old and the oldest is 84 years Following the termination of the tachycardia, old. BrS is a primary electrical disease resulting an ECG should be performed during the sinus in abnormal electrophysiologic activity in right rhythm to screen for WPW syndrome. They ventricular epicardium. Recent genetic data need periodic observation as they are linking the BrS to an ion channel gene mutation potentially at an increased risk of dangerous (SCN5A) provides further support for the ventricular arrhythmias, including SCD. hypothesis. The syndrome is characterized by— Although relatively uncommon, SCD may be (a) a peculiar ST segment elevation in the right the initial presentation in patients with precordial leads; often accompanied by apparent tachyrhythmias due to WPW syndrome conduction block in the right ventricle; • Although an underlying psychiatric illness (b) structurally normal heart; and (c) a propensity should be considered in appropriate patients, for life-threatening ventricular tachyrhythmias. it does not obviate the need for a complete The higher intercostal space V (1) to V (3) lead evaluation to exclude a cardiac origin of ECG could be helpful in detecting Brugada palpitation; true arrhythmias do occur in such patients. Although two types of the ST-segment patients; PSVT may masquerade as panic elevation are present, the coved type is more attack, leading to misdiagnosis7 relevant to the syndrome than the saddle-back • Sinus tachycardia recorded during palpi- type. ST segment elevation in the right chest 232 Diagnosis: A Symptom-based Approach in Internal Medicine leads is observed in a variety of clinical settings in patients who usually drink little or no alcohol. (e.g. acute septal ischemia, pericarditis, Recently, similar reports indicated that ventricular aneurysm, and in some normal recreational use of marijuana may have similar variants like early repolarization), and is not effects. Palpitations are the most common unique or highly specific for the BrS. A clear symptom. These can be intermittent or distinction cannot be made on the basis of an persistent, depending on the presence or absence ECG alone. However, ST segment elevation in of sustained arrhythmia and the ventricular the right precordial leads in the absence of response to atrial fibrillation. Patients with rapid ischemia, electrolyte or metabolic disorders, ventricular responses can present with near pulmonary or inflammatory diseases or syncopal symptoms, dyspnea on exertion, and abnormalities of central or peripheral nervous angina. The most common rhythm disorder is system may identify the BrS. In such cases, the atrial fibrillation, which usually converts to term “idiopathic” is appropriate. The ECG normal sinus rhythm within 24 hours. Atrial manifestations of BrS are often dynamic or flutter, isolated ventricular premature beats, concealed, and may be unmasked or isolated atrial premature beats, junctional modulated by sodium channel blockers tachycardia, and various other rhythm distur- (ajmaline, procainamide and flecainide), a bances may occur with less frequency. The febrile state, vagotonic agents, α-adrenergic holiday heart syndrome should be considered agonists, β-adrenergic blockers, tricyclic or particularly as a diagnosis in patients without tetracyclic antidepressants, a combination of overt heart disease presenting with new onset glucose and insulin, hypo- and hyperkalemia, atrial fibrillation. Though recurrences occur, the hypercalcemia, and alcohol and cocaine toxicity. clinical course is benign and specific antiarr- Imaging techniques, endocardial biopsy and hythmic therapy is usually not warranted. cardiac catheterization are useful in ruling out Arrhythmia monitoring and observation are structural cardiac abnormalities. Finally, adequate in many patients. extension of the testing to family members is also Pacemaker syndrome—First described in 1969 by important because of high incidence of familial Mitsui et al as a collection of symptoms associated occurrence. Currently, implantable cardiac with right ventricular pacing. In a general sense, defibrillator implantation is the only proven pacemaker syndrome can be defined as the effective therapy in preventing sudden death in symptoms associated with atrioventricular patients with the BrS, and is indicated in dyssynchrony. The symptoms of pacemaker symptomatic patients, and should be considered syndrome included dyspnea on exertion, in asymptomatic patients in whom VT/VF is paroxysmal nocturnal dyspnea, orthopnea, inducible at time of electrophysiologic study. palpitations, hypotension, pre-syncope, and even Holiday heart syndrome—The association syncope. Heart failure signs include elevated neck between alcohol use and rhythm disturbances, veins, rales, and pedal edema. Physical exam can particularly supraventricular tachyarrhythmias often reveal cannon A-waves. Additional in apparently healthy people is called “holiday symptoms attributed to pacemaker syndrome heart syndrome”. The syndrome was first include easy fatigability, malaise, headache, and described in persons with heavy alcohol the sensation of fullness and pulsations in the consumption, who typically presented at head and neck. In the era of physiological dual weekends or after holidays, but it may also occur chamber pacing, the diagnosis is often forgotten, Palpitation 233 but pacemaker syndrome may still occur. The heart and produce similar signs and symptoms diagnosis of pacemaker syndrome requires a high such as dehydration, anemia, or hyperthyroidism. index of suspicion and the correlation of symptoms or relative hypotension with periods of ventricular REFERENCES pacing. The electrocardiogram should be 1. Zimetbaum P, et al. Evaluation of patients with inspected carefully for loss of atrial capture, palpitation. NEJM 1998;338(19),1369-73. particularly when anti-arrhythmic drugs which 2. Crawford MH, et al. ACC/AHA Guidelines for Ambulatory Electrophysiology. A report of the increase the pacing threshold have been American College of Cardiology/American Heart prescribed. In addition, environmental sources of Association Task Force on Practice Guidelines. J electromagnetic interference, both within and Am Coll Cardiol 1999;34(3):912-48. [PMID: 10483977]. Website: http://content.onlinejacc.org/ outside the hospital environment can result in cgi/content/short/34/3/912. (Accessed on 22-07-08) pacemaker malfunction and aggravating 3. Visit http://content.onlinejacc.org/cgi/content/full/ symptoms of pacemaker syndrome. 48/11/2360 for ACC/AHA guidelines for the use of EPS. Postural orthostatic tachycardia syndrome 4. Olson JA, et al. Utility of mobile cardiac outpatient telemetry for the diagnosis of palpitations, (POTS)—It is an under recognized but persistent presyncope, syncope, and the assessment of autonomic disorder in young patients, usually therapy efficacy. J Cardiovasc Electrophysiol females aged 15 to 50 years, with a variety of 2007;18(5):473-7. [PMID: 17343724: Abstract]. 5. Cheitlin MD, et al. ACC/AHA Guidelines for the symptoms and variable outcome. Patients with Clinical Application of Echocardiography. A report this condition exhibit orthostatic intolerance (OI) of the American College of Cardiology/American and excessive tachycardia. Excessive tachycardia Heart Association Task Force on Practice Guide- lines (Committee on Clinical Application of Echo- with POTS has been defined as a rapid (within 10 cardiography). Developed in collaboration with the minutes) increase in heart rate by more than 30 American Society of Echocardiography. Circulation beats per minute or a heart rate that exceeds 120 1997;95(6):1686-744.[ PMID: 9118558]. Web site: “http://circ.ahajournals.org/cgi/content/full/95/6/ beats per minute. Patients with POTS can 1686.%20(Accessed on 22-07-08) experience difficulty with daily routines such as 6. Summerton N, et al. New-onset palpitations in general practice: Assessing the discriminant value housework, shopping, eating, and attending work of items within the clinical history. Family Practice or school. The possibility exists that all forms of 2001;18;383-92. OI, including POTS, result from central 7. Lessmeier TJ, et al. Unrecognized paroxysmal supraventricular tachycardia. Potential for misdia- hypovolemia even without tachycardia. Adults gnosis as panic disorder. Arch Intern Med with POTS do not have hypotension, whereas 1997;157(5):537-43. [PMID: 9066458: Abstract]. children may exhibit hypotension. Many patients 8. Masuki S, et al. Excessive heart rate response to with POTS are intolerant of exercise. “Idiopathic” orthostatic stress in postural tachycardia syn- drome is not caused by anxiety. J Appl Physiol POTS must be distinguished from other 2007;102(3):896-903. [PMID: 17110507: Free full conditions that can reduce venous return to the text]. CHAPTER 34 Polyuria

SYNOPSIS evidence of increase in the total output of urine; this phenomenon is attributed to multiple Polyuria is a highly subjective symptom, and factors, such as reversal of the normal diurnal generally defined as the production of abnormally variation in urine flow, behavioral or environ- large amount of urine, i.e. 3 liters or more in 24 mental factors, overactive bladder, and path- hours in an adult.* ologic conditions, e.g. CHF, CRF, nephrotic Under normal physiological conditions urine syndrome, anxiety, primary sleep disorders, and production is about 1-2 L per day. The chief sleep apnea.1-3 determinant of urine volume is the intake of fluids, Polyuria implies water or solute (i.e. osmotic) which in turn is influenced by individual’s dietary diuresis, which can be differentiated by the habits, temperature, mental state, physical activity, estimation of urine (and also serum) osmolarity.† general health, and medications. An average person excretes between 600 to It is important to differentiate true polyuria 800 mOsm of solutes per day, primarily as urea from other similar urinary symptoms such as and electrolytes. Generally, increased urine urinary frequency, which is the need to urinate osmolarity (hyperosmolarity) is observed in many times during the day or night, but in solute diuresis (i.e. rich in solutes), and normal or less than normal volumes; and urinary decreased values (hyposmolarity) in water urgency, which implies a strong desire to void diuresis (i.e. poor in solutes). Table 34.1 classifies urine with a sensation of impending micturition, polyuria and its differential diagnosis in terms without a concomitant increase in the volume of solute verses water diuresis. of urine, e.g. in cystitis or benign prostatic Though urine osmolarity can help distinguish hypertrophy. Although polyuria may also a solute (osmotic) from water diuresis, a urine accompany nocturia, many individuals com- specific gravity (Usg) by urinometer also correlates plaining of the latter—sometimes called as nocturnal polyuria syndrome — have no objective † The urine osmolarity is a measure of the concentration of the urine and is primarily determined by the level of *Polyuria is also defined as urine output > 50 ml/kg per antidiuretic hormone. Normal urine osmolality value day. (random sample):100 – 1,200 mOsm/kg H2O. Polyuria 235

Table 34.1: Solute vs water diuresis—differential Table 34.2: Differential diagnosis of diabetes insipidus diagnosis Cranial diabetes insipidus Nephrogenic diabetes insipidus 1-A—Solute (osmotic) diuresis: (due to excessive filtration Trauma (head injury) Drugs (lithium, demeclocycline) of a poorly reabsorbed solute) Vascular Renal disease • Glucosuria (Diabetes mellitus, DKA) Hemorrhage/thrombosis Renal tubular acidosis • Urea diuresis (high-protein parental infusions) Aneurysm Pyelonephritis • Mannitol or glycerol infusion Sheehan’s syndrome Polycystic kidney disease • Radiographic contrast media Infections Metabolic Meningitis Hypercalcemia • CRF Encephalitis Hypokalemia • Alcohol abuse Cerebral abscess 1-B—Nitriuretic syndromes: (due to excessive chronic Granulomatous disease Postrenal transplantation sodium loss) Tuberculosis Sickle cell disease Sarcoidosis Genetic defect • Diuretics Langerhans cell histocytosis Sex-linked recessive • Hypernatremia (IV saline) Tumors Psychogenic polydipsia • Addison’s disease Craniopharyngioma Compulsive water drinking • Salt-wasting nephropathy Metastases (from breast) Schizophrenia 2-A—Water diuresis: (too much water intake) Postsurgical CNS disease Removal of pituitary Multiple sclerosis • Psychogenic polydipsia/water intoxication/over adenoma hydration Postradiotherapy (cranial) Idiopathic • Hypothalamic disease (infiltration or infarction Familial affecting thirst center) DIDMOAD • Drugs (diuretics) Idiopathic 2-B—Inability of kidneys to conserve water CDI (vasopressin sensitive): DIFFERENTIAL DIAGNOSIS • Pituitary ablation, tumor, cyst, aneurysm, trauma, meningitis, hemorrhage, thrombosis, metastasis, Common Sheehan’s syndrome. • Diabetes mellitus (undiagnosed, poorly 2-C—NDI (vasopressin insensitive): controlled, Type 1, diabetic ketoacidosis) • Acquired tubulointerstitial renal disease (e.g. hypercalcemia, hypokalemia, analgesic nephropathy, • Diuretic therapy (loop diuretics, mannitol) obstructive uropathy) • Hyperalimentation therapy (amino acids, • Drugs (lithium) glucose) • Genetic disorders • Chronic renal failure • Analgesic nephropathy with urine osmolarity and gives important • Hypercalcemia (osteoporosis treatment, information that reflects the concentrating ability bony metastasis, hyperparathyroidism) of the kidneys, provided there is no reason to • Alcohol abuse (beer potomania‡) suspect increased excretion of larger solutes such • Anxiety (acute). as glucose, urea, radiocontrast media, etc. A Occasional random early morning Usg of 1020 (700 mOsm/kg) or more in the absence of sugar or protein excludes • Recovering obstructive uropathy a serious concentrating defect. However, urine • Recovering acute tubular necrosis (acute osmolarity is a better measurement of renal renal failure) hydration status than Usg.4-6 • Drugs (lithium, antibiotics: Demeclocycline; When the initial evaluation fails to establish antifungals: Amphotericin; antineoplastic; the cause of polyuria, a water deprivation test is and antivirals agents) necessary. Further, a vasopressin test enables the ‡The ingestion of large quantities of beer, sometimes differentiation between cranial diabetes insipidus, referred to as beer potomania or binge beer drinking, can produce polyuria with associated hyponatremia that may i.e. CDI, and nephrogenic diabetes insipidus, i.e. be severe enough to produce CNS symptoms ranging from NDI. (Table 34.2). confusion to seizures and stupor. 236 Diagnosis: A Symptom-based Approach in Internal Medicine

• CNS disorders (infections:meningitis,  Afterwards, collect all urine in a special cerebral malaria,7 HIV; mass lesions; trauma; container for the next 24 hours, postneurosurgery status).  On day 2, urinate into the container on Rare getting up in the morning,  Cap the container. Keep in the refrigerator or • Psychogenic polydipsia (obsessive compul- in a cool place during the collection period. sive disorder, schizophrenia) • Drug-induced thirst (anticholinergics, leading Serum Urea, Creatinine, Electrolytes to excessive water drinking) • Plasma urea, creatinine levels increased in • AV nodal re-entry tachycardia renal failure • Radiographic contrast media • High level of serum sodium suggests CDI • Multiple endocrine neoplasia and NDI • Sickle cell anemia • Low levels of sodium suggest NDI or • Genetic defects ( Wolfram syndrome, i.e. WS compulsive water drinking. or DIDMOAD syndrome: vide infra ↓↓). Serum Calcium INVESTIGATIONS—GENERAL • Hypercalcemia causes solute (osmotic) Urinalysis diuresis and NDI.

• Glucose and possible ketones in diabetes Ultrasound mellitus • To assess renal size, obstruction, tumors, and • Leukocytes, proteinuria, hematuria with cysts renal disorders • Contracted kidneys with loss of corticome- • Usg-Very low in diabetes insipidus (DI) and dullary differentiation in CRF. psychogenic polydipsia. INVESTIGATIONS—SPECIFIC CBC • Normochromic anemia in CRF 24-hour Urinalysis • Peripheral smear may show sickle cells. • Estimation of various urine components Blood Glucose permit calculation of the solute excretion rate • Fasting, 2 hours post 75 g oral glucose, and and thus lead to the cause of polyuria. These HbA1c. To confirm and monitor diabetes tests may include: Volume, specific gravity, mellitus. osmolality, urea, creatinine, electrolytes, calcium, glucose, ketones, and drug screen 24-hour Urine Specimen for example, mannitol, and glycerol. • The total volume must exceed 3L in 24 hours and helps to avoid errors attributable to Water Deprivation Test§ variations in circadian rhythm and also to This test is indicated to differentiate between differentiate from urinary frequency • The usual method followed (in adults) is as CDI and NDI – their both partial versus complete below:  On day 1, urinate into the toilet on getting §Contraindicated in volume depleted patients and in the up in the morning, presence of hypernatremia. Polyuria 237 versions—in a well-hydrated patient, who is  High levels in NDI (partial or complete); likely to have one or the other. Steps include: primary psychogenic polydipsia; ectopic 1. After an overnight solid food and water ADH syndrome; certain drugs, e.g. (liquids) restriction**, frequent (hourly) chlorpropamide, phenothiazine. 8 body weight, and urine osmolarity are • The expected response is given in Table 34.3. measured, until 2-3 successive stable US of Neck values of urine osmolarity are obtained • May be useful to locate parathyroid adenoma or weight loss exceeds 3-5%. At this point in patients with hyperparathyroidism. the test is completed (or terminated). These values represent the patient’s CT/ MRI maximum baseline osmolarity, and under • Of brain—for evidence of pituitary- these conditions urine osmolarity should hypothalamic tumors be > 800 mOsm/kg. A value < 200 suggest • Of parathyroid—for evidence of adenoma. severe NDI or CDI; a value between 200- 800 may reflect partial NDI or CDI. Renal Biopsy 2. Desmopressin acetate, i.e. DDAVP • May be indicated in patients with unexplained (1-deamino-8D-arginine vasopressin), is polyuria, e.g. autoimmune disorders, acute given in an initial dose of 5-10 mcg. tubular necrosis, and to diagnose renal intranasally (or 1 mcg subcutaneously or dysfunction in transplanted kidney. intravenously). Two more hourly urine osmolarities are recorded to determine CLINICAL NOTES response to exogenous hormone: • The first differentiation that needs to be  Urine osmolarity markedly increased clarified is that:’ Is it truly polyuria or just → CDI. urinary frequency?  Urine osmolarity — slight or no • History can sometimes distinguish true → response NDI. polyuria (i.e. frequent passage of large • However, measuring osmolarity of plasma/ quantity of urine) from frequency of urination urine after water deprivation test does not (i.e. frequent passage of small amounts of distinguish partial NDI from psychogenic urine). If essential, a 24 hours urine collection polydipsia. (see above) objectively confirms true polyuria when volume is > 3 L. Associated symptoms Plasma Vasopressin (ADH) include polydipsia, urgency, frequency, nocturia, and incontinence • When results are ambiguous, the plasma • Massive polyuria (10-20 L/day) is usually due vasopressin assay is a useful adjunct in the to DI, diabetes mellitus, (especially Type 1), diagnosis of DI and psychogenic polyuria: or psychogenic polydipsia  Low levels are consistent with CDI • Mild polyuria would suggest mild diabetes (partial or complete). mellitus, chronic nephritis, renal tubular acidosis, and hyperthyroidism • A transient polyuria is sometimes noticed in **In patients producing > 10 L of urine/day, water restriction is only done during the day under close supervision and is migraine, asthma, and supraventricular not done after midnight. tachycardia 238 Diagnosis: A Symptom-based Approach in Internal Medicine

Table 34.3: Classification of causes of diabetes insipidus on basis of water deprivation 8

Clinical state Water deprivation Endogenous Exogenous ADH effect on ADH Plasma Urine Osm. level* Plasma Osm* Urine Osm* Normal >3% rise >800 High None Cranial DI Complete >3% rise <200 Absent Increase >30% Partial >3% rise 300–700 Low Increase >10% Nephrogenic DI Congenital >3% rise <300 High None Acquired >3% rise 300–700 High None Primary/psychogenic >3% rise >600 High Increase <10% Polydipsia POsm = Plasma osmolarity (mOsm/kg); UOsm = Urine osmolarity (mOsm/kg);*= At the end of water deprivation period, prior to exogenous vasopressin, administration. • Abrupt onset of polyuria with craving for ice endocrine and autoimmune disease is an water (due to stimulation of osmoreceptors in important lead to the diagnosis of CDI / NDI the back of the throat) suggests CDI, e.g. due • Drug history—A significant number of drugs to pituitary disorders. Nocturia is common precipitate polyuria by various mechanisms. • The next step, i.e. after confirming true Over-vigorous diuretic therapy in edematous polyuria is: Is this water diuresis or solute states is a common cause of polyuria. diuresis? Generally: Anticholinergics produce dryness of mouth;  Urine osmolarity > 350 mOsm/L suggests patients may therefore ingest excessive solute diuresis, quantity of water, causing polyuria.  Urine osmolarity < 250 mOsm/L suggests Nephrotoxic drugs such as NSAIDs, ACE water diuresis, and inhibitors, aminoglycosides may precipitate  Urine osmolarity between 250-350 mOsm/L acute tubular necrosis, which can result in may be due to either water or solute severe polyuria in the recovery phase. Opiates diuresis. This differentiation can be by inhibit ADH secretion and may produce CDI, calculating total solute excretion on a 24 whereas lithium and demeclocycline may hr urine collection (see 24 hr urinalysis produce NDI above). • Physical examination should include • Further, water diuresis needs to be evaluation of the following: differentiated from CDI and NDI. Patient’s  Hydration status, i.e. body weight, pulse, history, investigations, and in selected cases BP, mucous membrane, skin turgor, and water restriction test/ desmopressin test help urine output. to achieve this objective  Signs of malignancy, e.g. cachexia, • History of head trauma; transsphenoidal lymphadenopathy, palpable mass. surgery; CNS disease (e.g. meningitis,  Target organ involvement, e.g. retinopathy, tuberculosis, CVA, multiple sclerosis, parkin- neuropathy with diabetes mellitus. sonism, pituitary-hypothalamic tumor,  Abdomen—for mass and organomegaly. metastatic deposits); psychiatric illness,  Neurologic exam—to evaluate neurologic diabetes mellitus, renal disease (e.g. chronic deficit associated with mass lesion, nephritis); malignancy (hypercalcemia); encephalopathy. Polyuria 239

 Genitourinary exam — for penile, scrotal, syndrome is also known as DIDMOAD, the testicular, prostate, and pelvic masses. acronym for diabetes insipidus, diabetes mellitus, • NDI—The characteristic features are: optic atrophy and deafness, which summarizes the  An inability to concentrate urine main clinical features in WS patients, although some adequately with fluid restriction, patients have additional clinical findings including  The occurrence of dilute urine in the ataxia, hypogonadism, hydronephrosis and presence of normal or increased psychiatric illnesses. The gene associated with the osmolarity, and syndrome, called WFS1, is located in the 4p16.1  Lack of responsiveness to vasopressin. region. Patients present with diabetes mellitus • CDI—The characteristic features are: followed by optic atrophy in the first decade, cranial  Dilute urine, diabetes insipidus and sensori-neural deafness in  Mild hyperosmolarity, and the second decade, dilated renal outflow tracts early  Responsiveness to vasopressin. in the third decade, and multiple neurological • Psychogenic polydipsia—Typically:  Both the serum and urine osmolarity are abnormalities early in the fourth decade. Other low, and abnormalities include primary gonadal atrophy.  Lack of responsiveness to vasopressin. Death occurs premat-urely, often from respiratory failure associated with brainstem atrophy. Most RED FLAGS patients eventually develop all complications of this progressive, neurodegenerative disorder. Though • Think beyond diabetes mellitus in patients there is no treatment to reverse the underlying with polyuria with urine negative for mechanism of neurodegeneration, early diagnosis glucose, consider DI. Review history; refer and adequate hormonal replacement could improve for more detailed investigations as indicated quality of life and survival.9, 10 • Unexplained polyuria in any patients with hypercalcemia—investigate for multiple REFERENCES endocrine neoplasia (Chapter 14, Page no. 95 “Dyspepsia”. Review family histories in detail 1. Natsume O. A clinical investigation of nocturnal endocrine tumors (thyroid, parathyroid, polyuria in patients with nocturia: A diurnal variation in arginine vasopressin secretion and its pituitary) are often present in other family relevance to mean blood pressure. J Urol 2006; members 176(2):660-4. [PMID: 16813917: Abstract]. • Beware of complications in patients with 2. Asplund R. The nocturnal polyuria syndrome psychogenic polydipsia. Though DI has not (NPS). Gen Pharmacol 1995;26(6):1203-9. [PMID: 7590108: Abstract]. been reported to result in renal failure, 3. Weiss JP, et al. New aspects of the classification of psychogenic polydipsia may result in water nocturia. Curr Urol Rep 2008;9(5):362-7. [PMID: intoxication, leading to hyponatremic 18702919: Abstract]. 4. Shirreffs SM. Markers of hydration status.Eur J Clin encephalopathy with headache, weakness, Nutr 2003;57 Suppl 2:S6-9. [PMID: 14681707: nausea, vomiting, diarrhoea, confusion, Abstract]. seizures, coma, and even death. 5. Voinescu GC, et al. The relationship between urine osmolality and specific gravity. Am J Med Sci 2002;323(1):39-42. [PMID: 11814141: Abstract]. SELECTIVE GLOSSARY 6. Chadha V, et al. Measurement of urinary concentration: A critical appraisal of metho- Wolfram syndrome (WS)— It is a rare, autosomal dologies.Pediatr Nephrol. 2001;16(4):374-82. recessive, and neurodegenerative disease. The [PMID: 11354785: Abstract]. 240 Diagnosis: A Symptom-based Approach in Internal Medicine

7. Schubert S, et al. Central diabetes insipidus in a 9. Barrett TG, et al. Wolfram (DIDMOAD) syndrome. patient with malaria tropica. J Endocrinol Invest. J Med Genet 1997;34(10):838-41. [PMID: 9350817: 2006;29(3):265-6. [PMID: 16682843: Abstract]. Free full text]. 8. Tzamaloukas AH, et al. Physiology of urinary 10. Viswanathan V, et al. Wolfram syndrome. J Assoc concentration and dilution and diabetes insipidus. In: Mandal AK, Ed. T B of Nephrology for Asian- Physicians India 2008;56:197-9. [PMID: 18697639: Pacific Physicians.2nd edn. p.18, Jaypee; 2004. Abstract]. CHAPTER 35 Pruritus

SYNOPSIS into four categories: cutaneous itch (pruritoceptive, e.g. scabies, urticaria, insect bite, dermatitis); Pruritus* is defined as an unpleasant cutaneous neuropathic itch (e.g. postherpetic neuropathy, sensation that provokes the desire to scratch or multiple sclerosis); neurogenic itch (e.g. rub the skin to obtain relief. As a physiological cholestasis, uremia); or psychogenic (e.g. nociception, pruritus leads to the removal of delusional state of parasitophobia).2 harmful agents such as insects, and irritant Most pruritic disorders can be diagnosed substances such as dust and dirt from the skin with high degree of accuracy based on history, surface, and thus helps defend the skin against harmful external agents. physical features of dermatosis, and appropriate Pruritus is the cardinal symptom of most investigation. However, a minority of patients dermatologic disorders, and may be further presenting with itching per se, without any rash, qualified as burning, tingling, or pricking by the or with scanty clinical findings can pose a patient. In addition to the skin, it can occur on any particularly challenging diagnostic and epithelial surface, such as the conjunctiva (e.g. therapeutic dilemma, besides significantly allergic conjunctivitis); oropharynx (due to food affecting their quality of life. allergy, or oral allergic syndrome: 1 vide infra ↓↓); and anogenital region (sea below). It may be DIFFERENTIAL DIAGNOSIS localized, generalized, paroxysmal, or unremitting. Common It may be associated with a primary dermatological disorder, or manifest as a symptom of an internal • Urticaria systemic process. • Psoriasis Based on advances in the understanding of • Atopic dermatitis† or atopic eczema the peripheral and central origin, itch is classified †The terms atopic dermatitis and atopic eczema have been used *Some authors use the term itch if there are skin lesions synonymously; however, dermatitis denotes inflammation expressed, and pruritus if there are no primary skin of the skin, and eczema, besides itching, shows ill-defined alterations, known as “pruritus sine materia”; however, its areas of redness, scaling, crusting, and lichenification. common practice to use these two terms—pruritus and Dermatosis is defined as any disease of the skin in which itch—as synonyms. inflammation is not necessarily a feature. 242

• Irritant contact dermatitis (e.g. soaps, • Primary biliary cirrhosis chemicals, cosmetics, jewelery, latex) • Hypereosinophilic syndrome • Food allergy (peanuts; eggs; food additives, • Cutaneous T cell lymphoma (Mycosis preservatives, and flavoring agents) fungoides) • Drug allergy/hypersensitivity (aspirin, • Systemic carcinoma opiates) • Psychogenic (anxiety, depression, psychosis, • Miliaria (prickly heat)/sunburn/solar dermatitis delusion of parasitosis: vide infra ↓↓, • Infections (folliculitis; dermatophytosis, e.g. dermatitis artefacta). tinea corporis, tinea cruris, tinea pedis) • Infestations and bites (scabies, pediculosis, INVESTIGATIONS—GENERAL ticks, honeybees) • Intestinal parasites/helminthic infections CBC (hookworm, giardia, strongyloidiasis, trichinosis, cutaneous larva migrans) • Microcytic hypochromic anemia with IDA • Lichen planus • In PVR: RBC count increased (often 7 to 10 • Lichen simplex chronicus million/cu mm), hematocrit above normal (at • Dry skin (asteotic dermatitis) times >60%), increased Hb, WBC and platelet • Aging (senile pruritus). counts also invariably elevated • Eosinophilia with atopy, or intestinal Occasional helminthic infection. • Uremic pruritus Urinalysis • Cholestatic pruritus (extrahepatic obstruc- tion, hepatic failure, cirrhosis) • May reveal proteinuria, hematuria, and • Infections (HBsAg, HCV, HIV) granular or red blood casts in patients with • Pregnancy (i.e. pruritus gravidarum, or renal disease. cholestasis of pregnancy) • Postmenopausal. Stool Examination

Rare • Ova and/or cysts of helminthic or protozoan disease may be found • Ichthyosis • Stool for occult blood in patients aged 40 • Dermatitis herpetiformis years or older. A positive result suggests • Endocrine disorders (hyperthyroidism, possible malignancy in the GI tract. hypothyroidism, carcinoid syndrome, diabetes mellitus, hyperparathyroidism) Microscopy of Skin Scrapings • Hematological disorders (IDA, pernicious anemia, leukemia) • The mite, ova, and feces may be identified • Neurologic disorders (poststroke pruritus3 under light microscope in Scabies infestation. • Myeloproliferative disorders (polycythemia Potassium Hydroxide (KOH) 10-20% Mounts rubra vera, i.e. PVR; multiple myeloma) • Lymphomas (Hodgkin’s and non-Hodgkin) • For evidence of hyphae, and spores of • Mastocytosis dermatophytes. 243

Blood Glucose Serum Protein Electrophoresis

• Elevated with diabetes mellitus. • To screen for myeloproliferative disorders, and paraproteinemias. Serum Calcium Urine for 5-Hydroxyindoleacetic Acid • Elevated with hyperparathyroidism secondary (5-HIAA) to renal disease, paraneoplastic syndromes, malignancies, and Paget disease. • Increased levels of urinary 5-HIAA may be detected in patients with liver metastasis, or LFTs carcinoid syndrome.

• Elevated conjugated serum bilirubin, alkaline Antimitochondrial Antibody phosphatase, AST, ALT, and PT with hepatic cholestasis, cirrhosis, and viral hepatitis. • Positive for most patients with primary biliary cirrhosis. Blood Urea, Creatinine, Electrolytes US Abdomen • Elevated urea, creatinine, and hyperkalemia with chronic renal failure. • Dilated bile ducts indicate biliary obstruction; the site and cause of obstruction may be TFTs visualized. Decreased renal size in chronic renal disease and in patients suspected with • Low TSH and high T4 with hyperthy- polycystic kidney disease, multiple cysts may roidism; high TSH with low T4 with be visualized. US of the neck provides hypothyroidism. information regarding enlarged parathyroid glands, thyroid nodules, and lymph nodes. CXR

• May reveal hilar lymphadenopathy, or a mass HRCT—Chest and Abdomen lesion in patients with Hodgkin’s disease, or • HRCT of the chest (when abnormal findings bronchogenic carcinoma. are noted on CXR examination) to confirm hilar lymphadenopathy or mass lesion in INVESTIGATIONS—SPECIFIC patients with Hodgkin’s disease, or bron- Serum Ferritin chogenic carcinoma respectively. HRCT of the abdomen and pelvis to visualize the mesenteric, • Decreased values confirm IDA; low serum hepatic, portal, and splenic hilar lymph nodes ferritin levels in elderly patients with in patients with Hodgkin’s disease and non- chronic pruritus may assist in diagnosing Hodgkin’s lymphoma. malignancy. ERCP (Endoscopic Retrograde Cholangio- Serology pancreatography) • To rule out HBV (HBsAg), HCV (anti-HCV), • Should be performed in patients suspected with and HIV infection in patients with risk primary sclerosing cholangitis, choledocholi- factors. thiasis, or obstructive malignancy. 244

Lymph Node Biopsy worsening in winter suggest xerosis; itching worse in the evening may be • Presence of Reed-Sternberg cells is characteristic associated with scabies; itching awakening of Hodgkin’s disease. the patient at night may represent systemic disease; bath itch, i.e. itching that Bone Marrow Aspirate and Biopsy typically occurs during cooling after a hot • May be indicated to establish the presence shower may precede the development of of myelofibrosis (e.g. PVR, chronic myeloid PVR by several years.  leukemia). Drugs (erythromycin, INH, anabolic steroids, oral contraceptives), including Skin Biopsy for Direct Immunofluorescence recreational drugs (opioids, alcohol)— with Special Stains current and/or recent past.  Ingestion of any unusual or new foods. • May be needed to confirm primary derma-  OTC products the patient uses on his / her tologic conditions such as dermatitis herpe- skin, or scalp. tiformis, mycosis fungoides, Paget’s disease of  Menstrual history—in women of child- the nipple, and bullous pemphigoid; or to bearing age. confirm a systemic cause such as mast-ocytosis.  History of any systemic illness (bronchial asthma; thyroid, hepatic, or renal disorder; Radioallergosorbent Tests (RASTs) or Patch erythropoietic porphyria, HIV). Test  History of any psychiatric illness, emotional stress. • Positive patch test may support offending  History of recent travel (hepatitis, cause for allergic contact dermatitis. helminthic, or parasitic infection).  History of previous skin disease (e.g. Tumor Markers vitiligo, ichthyosis) or atopy.  The work environment (chemicals, • Age appropriate cancer screening such as irritants). PSA, alfa fetoprotein may be indicated in few  Home environment—other members patients with obscure cause. experiencing itching, pets, carpet in bedroom. CLINICAL NOTES • The diagnosis of most pruritic disorders is • History suggests whether pruritus is primary possible on the basis of pattern distribution, (i.e. dermatological), or secondary (i.e. i.e. basic morphology, shape, size, color, and systemic), and often provides clues to its cause. predilection to specific sites of the skin. Common questions include the following:‡ Tables 35.1 and 35.2 illustrate common causes  Location, duration, and timing of sym- of localized and generalizes pruritus ptoms of pruritus, e.g. day, night, • In addition to the skin, examination of other seasonal, at work, or at home. organ systems for organomegaly, lympha-  Provocative factors, e.g. itching onset or denopathy, goiter, pregnancy, and signs of anemia, arthritis, or psychiatric disorders is ‡A structured questionnaire such as ‘Eppendorf itch important questionnaire’ is found to be a valuable tool for evaluating • Pruritus associated with generalized rash is chronic idiopathic pruritus and its unique features (Ref. PMID: 12100181). common with urticaria, atopic dermatitis, Pruritus 245

Table 35.1: Differential diagnosis of localized pruritus Table 35.2: Differential diagnosis of generalized pruritus • Scalp/neck • Dermatologic disease – Seborrheic dermatitis – Urticaria – Lichen simplex – Xerosis (dry skin) – Psoriasis – Atopic dermatitis • Trunk – Contact dermatitis – Urticaria – Bullous pemphigoides – Contact dermatitis (axillae, waistline) – Dermatitis herpetiformis – Erythrasma – Mastocytosis – Psoriasis (periumbilical) • Drugs/food hypersensitivity – Scabies – Aspirin, NSAIDs – Seborrheic dermatitis – Antibiotics, chemotherapeutics • Inguinal region – Nitrates, monosodium glutamate (food – Candida preservatives, flavoring agents) – Contact dermatitis • Infective disease – Erythrasma – Scabies – Pediculosis – Pediculosis – Scabies – HIV/AIDS – Tinea cruris • Parasitic infections • Genital (i.e. scrotal, anal, or vulval) region – Hookworm, pinworm, ascariasis – Local irritants (fabrics, tampons, sanitary wear) – Giardiasis – Intertrigo (excessive perspiration, moisture) – Oncocerciasis – Contact dermatitis (hygiene products, barrier • Systemic disease contraceptives, douches) – Chronic renal failure (uremic pruritus) – Lichen simplex – Intrahepatic cholestatic pruritus (e.g. viral – Candidiasis hepatitis, drug-induced cholestasis, carcinoma of – Dermatophytes (Tinea cruris) liver, biliary cirrhosis) – Parasites (pinworm, scabies, pediculosis, tricho- – Extrahepatic cholestatic pruritus (e.g. common moniasis) bile-duct calculus, stricture, carcinoma of pancreas) – Venereal (herpes, gonorrhea, chancroid, LGV, – Pruritus gravidarum syphilis) • Endocrine disorders – Bacterial (erythrasma) – Hyper-and hypothyroidism – Anorectal disease (hemorrhoids, fissure, fistula, – Hyperparathyroidism rectal prolapse, polyps, warts, malignancy) – Diabetes mellitus – Dermatologic disease (Psoriasis, seborrheic – Gout dermatitis, atopic dermatitis) • Hematopoietic disorders – Valval disease (atrophic vulvovaginitis; VIN, i.e. – IDA vulva intraepithelial neoplasia; malignancy) – PVR • Hands • Malignancy – Contact dermatitis – Hodgkin’s lymphoma – Scabies – Non-Hodgkin’s lymphoma – Eczema – Leukemia – Dermatitis herpetiformis (elbows) – Carcinoid syndrome • Legs • Psychiatric disease – Stasis dermatitis (venous eczema) – Delusion of parasitosis – Atopic dermatitis (popliteal fossa) – Depression – Dermatitis herpetiformis (knees, buttocks) – Lichen simplex chronicus (malleoli) – Neurotic excoriation scabies, and pemphigus. Presence of hepato- • Feet megaly or jaundice is indicative of obstructive – Intertrigo jaundice, hepatitis, malignancy of liver, or – Contact dermatitis – Pitted keratolysis biliary cirrhosis. Symptoms of polyuria, – Tinea pedis polyphagia, and polydipsia would suggest 246 Diagnosis: A Symptom-based Approach in Internal Medicine

diabetes mellitus, hyperthyroidism, and Table 35.3: Physical signs in pruritus pregnancy. Fine stippling (pitting) of the nails Sign Comments is highly suggestive of psoriasis Auspitz sign Removal of scales causing punctate • Signs—Common dermatological signs in bleeding spots, e.g. psoriasis, actinic pruritic disorders are described in Table 35.3 keratosis. Butterfly sign A sign on the back of the patient, i.e. • Of all the malignancies known to induce upper mid-back area between the pruritus, Hodgkin’s disease is the most scapula, of relative hypopigmentation or normal skin in combination with common areas of postinflammatory • Carcinoma of any organ may produce hyperpigmentation in surrounding itching, but this is most frequently associated locations accessible to the patient’s hands. As most patients cannot reach with involvement of the stomach, liver, and the upper mid-back area between pancreas the scapulas, an examination of this • Pruritus of the nostrils is characteristic of area can help ascertain if a skin disease is present, because any lesions found fourth-ventricle tumors of the brain; it can in that area are unlikely to have been be extremely severe and is a sign of an caused by scratching. Conversely, if the advanced tumor skin there is clear but the surrounding area is damaged, this is a strong • Hyperthyroidism is the most common cause indicator of an organic or psychological of endocrine pruritus disorder. • Patients with Parkinson’s disease, patients Darier’s sign Yellowish brown or brown black macules or plaques which tend to who become acutely ill and are hospitalized, become red, itchy, and urticate easily and patients with HIV infection often have if they are rubbed, e.g. urticaria seborrheic dermatitis pigmentosa (cutaneous mastocytosis). • Uremic pruritus is most often seen in patients Dermographism Light pressure or rubbing causing receiving hemodialysis. However, the (skin writing) widespread weal-and-flare reactions condition is not due to elevated serum urea with itching and burning; e.g. atopy, thyroid diseases, diabetes, levels. Pruritus is relatively absent in persons menopause, infectious, systemic or with acute renal failure malignant diseases, scabies, • Dermatitis herpetiformis is usually drug reaction, and psychic disorders. Köbner Development of new plaques in associated with celiac disease (i.e. gluten phenomenon response to external trauma, e.g. sensitive enteropathy, which commonly psoriasis, lichen planus, bullous presents with gastrointestinal symptoms pemphigoides, sarcoidosis, Kaposi’s sarcoma. including chronic diarrhea, weight loss, Leser-Trélat sign An abrupt appearance of multiple abdominal bloating and anorexia, and seborrhoic keratoses (also known as deficiency related signs to malabsorption seborrheic warts, keratosis pigmentosa, and verruca senilis) that of iron, folic acid, vitamin B12 and vitamin rapidly increase in their size D, such as osteoporosis) and number. Pruritus may be the only • While dealing with dermatological diseases symptom of the sign of Leser-Trélat. This sign is linked to a variety of suspected due to psychiatric disorder, cancers but is it’s rare, even among physicians should be aware that the skin patients with cancer. lesions are often an appeal for help; direct Nikolsky’s sign Pressure applied in a sliding motion to the lateral aspect of the blister leads confrontation should be avoided if possible, to extension of the blister and or and instead, a supportive environment and a removal of the epidermis in the area stable physician-patient relationship should Contd... Pruritus 247

Contd... reactions between pollens and different food immediately surrounding the blister. have been described. The OAS is an adverse In pemphigus vulgaris this sign is reaction to the ingestion of certain “trigger” positive, whereas in bullous pemphigoides it is absent. foods (fresh, raw fruits or vegetables), and is Wickham’s striae Intensely pruritic, violaceous, flat, especially prevalent in atopic individuals such polygonal, well-demarcated papules as in people with asthma or hay fever. Most of variable size, marked by criss-cross whitish streaks, e.g. lichen planus. patients give a history of oral symptoms like oral irritation, throat tightness, lips, oral and throat be fostered, often initially through short swelling, oral mucosal blebs. These local 4, 5 frequent office visits. Once the patient symptoms quickly disappear and are not establishes trust in the physician by means of particularly serious, but they may proceed to a stable relationship, the physician can help urticaria, asthma, abdominal pain. Severe recognise the psychological impact of the forms of OAS may resemble or precede food- disorder and recommend consultation with a induced anaphylaxis (which suggested the psychiatrist. term ‘oral allergy syndrome’).Thus, detection and recognition of OAS is important. OAS RED FLAGS diagnosis is based on the patient’s history and • Itching in elderly individuals, especially RAST. Treatment of OAS includes food persistent and generalized itching, should be avoidance, drugs and specific immunotherapy. screened for an underlying systemic disease Patients with pollen allergy should be informed (see table above), including malignancy. about the possibility of hypersensitivity to • The incidence of non-Hodgkin’s lymphoma certain fruits and vegetables. is significantly increased in patients with Delusion of Parasitosis—It is a rare psychiatric 6 dermatitis herpetiformis. disorder in which the patient has a fixed, false • If lesions of atopic eczema involve the nipple, belief that he or she is infested by bugs, mites, which may be either retracted or obliterated, worms, parasites or other living creatures. Even Paget’s disease must be excluded by biopsy. though it is a psychiatric disorder, these patients Unilateral eczema may be the only indication usually present to a dermatologist because they of a ductal adenocarcinoma. are convinced that they have a dermatological • Psychopathologic dermatological disorders problem. Patients with delusions of parasitosis such as delusion of parasitosis, psychosis; as generally reject psychiatric referral. The well as due to systemic disease such as HIV, diagnosis of delusions of parasitosis can often uremic pruritus, carcinoid syndrome can be be made on the basis of the history alone; severe enough to cause the patient to commit however, these beliefs may be brought about by suicide.7 drug use, or abuse, CVD, neurosyphilis, schizophrenia, psychotic depression, hypoc- SELECTIVE GLOSSARY hondriasis, or an obsessional fear that parasites Oral Allergy Syndrome (OAS)8—History of are present in the body. Therefore, it is important OAS goes back to 1987 year, when Amlot for the to make sure that the patient does not have an first time used this name for pollen-food cross- organic skin disorder, and the delusion is not reactive reactions. Since then many kinds of secondary to another mental or physical illness. 248 Diagnosis: A Symptom-based Approach in Internal Medicine

REFERENCES 5. Schneider G, et al. Psychosomatic cofactors and psychiatric comorbidity in patients with chronic 1. Amlot PL, et al. Oral allergy syndrome (OAS): itch. Clin Exp Dermatol 2006;31(6):762-7. [PMID: Symptoms of IgE-mediated hypersensitivity to 17040260: Abstract]. foods; Clin. Allergy. 1987;17(1):33-42. [PMID: 6. Collin P, et al. Malignancy and survival in 3829369: Abstract]. dermatitis herpetiformis: a comparison with coeliac 2. Twycross R, et al. Itch: scratching more than the disease. Gut. 1996;38(4):528-30. [PMID: 8707082: surface. QJM 2003;96(1):7-26. [PMID: 12509645: Free full text]. Free full text]. 7. Bellmann R, et al. Treatment of intractable pruritus 3. Kimyai-Asadi A, et al. Poststroke pruritus; in drug induced cholestasis with albumin dialysis: Stroke, 1999;30(3):692-3 [PMID: 10066875: Free full text]. A report of two cases; ASAIO J. 2004;50(4):387-91. 4. Jojn K, Anjeli K. Dermatitis artifacta. In: Lebwolh MG, [PMID: 15307554: Abstract]. Heymann WR, Berth-Jones John, Coulson Ian. Eds. 8. Doroszewaka G, et al. Oral allergy syndrome— Treatment of Skin Disease—comprehensive therapeutic problem; Otolaryngol Pol 2006;60(6):917-22. strategies, 2nd edn, p.154.Mosby Elsiver. 2006. [PMID: 17357673: Abstract]. CHAPTER 36 Red Eye

SYNOPSIS • Epidemic keratoconjunctivitis (EKC)* • Blepharitis The common term red eye, which is due to • Pingueculitis hyperemia or engorgement of the superficial • Pterygium visible conjunctival, episcleral, or ciliary vessels, • Corneal abrasion† is applied to a variety of distinct infections and • Superficial foreign body. inflammatory disease processes that involve one or more tissue layers of the eye, i.e. eyelids, Occasional conjunctiva, cornea, sclera, and uveal tract. Most cases are due to benign or self-limiting • Acute angle closure glaucoma (AACG) conditions; however, several signs and symptoms • Scleritis/episcleritis may herald a serious ocular disorder, and a few are • Keratitis (corneal infection, corneal ulcer) vision-threatening, and can lead to permanent vision • Iritis (anterior uveitis) loss, e.g. corneal ulceration and acute glaucoma. • Orbital cellulitis (due to paranasal sinusitis, “The emergency physician must be adept at infected tooth)5 recognizing red flags from the history and physical • Trauma (contusion; penetrating wounds; examination that necessitate immediate treatment burns—arc eye, chemicals) and referral. In addition, it is imperative for the • Subconjunctival hemorrhage (blood dysc- emergency physician to recognize the need for rasias; systemic febrile disease: Measles, immediate versus elective ophthalmologist falciparum malaria, leptospirosis) consultation for the various conditions.” 1 • Cluster headache (migrainous neuralgia).

DIFFERENTIAL DIAGNOSIS *The most commonly associated serotypes include Common adenovirus 8, 19, and 37. †Corneal abrasions, i.e. superficial or partial trauma to • Conjunctivitis (viral, bacterial, allergic, and corneal epithelium; often caused by fingernails, makeup Keyboard conjunctivitis): vide infra (↓↓).2-4 applicators, dust, and vegetative matter. 250

Rare vitreous hemorrhage, intraocular foreign bodies, orbital tumors and trauma, high • Keratoconjunctivitis sicca (old age; Serone- resolution ultrasound examination is found gative spondyloarthropathies; Sjögren’s to be a safe, noninvasive, inexpensive, syndrome; medications—anticholinergics, atraumatic and accurate means of evaluating antihistamines, antidepressants) 6 the eye. • Thyrotoxicosis (Graves’ disease) • Granulomatous disease (TB, sarcoid) Orbital CT Scan • Spirochetal disease (syphilis, Lyme disease) • Orbital vascular tumors (cavernous hem- • In orbital trauma, to rule out fracture of angiomas, carotid-cavernous sinus fistula, orbital bones; or associated with intracere- meningiomas, arteriovenous malformation). bral, or subarachnoid hemorrhage.

INVESTIGATIONS—GENERAL RF, ANA ESR • To screen for autoimmune diseases (RA, Sjögren syndrome, uveitis). • Elevated significantly in inflammatory and autoimmune disorders, e.g. scleritis, uveitis. HLA-B27

Blood Glucose • If iritis/uveitis is suspected—to find the underlying cause, e.g. HLA-B 27 typing for • To detect diabetes and to monitor blood glucose, ankylosing spondylitis. especially in nonhealing corneal ulcers. Syphilis Serology INVESTIGATIONS—SPECIFIC • VDRL, fluorescent treponemal antibody Gram’s Stain of Conjunctival Exudates absorption (FTA-ABS) test in cases with scleritis, and posterior uveitis. • May show predominant polymorphs and bacteria in bacterial conjunctivitis; lympho- CLINICAL NOTES cytes in viral conjunctivitis; and eosinophils in allergic conjunctivitis. • History should focus on:  Onset—Conjunctivitis generally has rapid Culture of Exudate onset (within hours), while a small FB will • Especially in corneal disease and in cases that produce a sudden hyperemia within are resistant to therapy. minutes. Abrupt onset with copious Immunofluorescent PCR Tests purulent discharge in a sexually active patient is typical of hyperacute bacterial • For Chlamydia and herpes-specific antigen, conjunctivitis, which is most often especially in posterior uveitis. associated with N. gonorrhoeae.  Pain and photophobia—A patient with Orbital US conjunctivitis may complain of mild • Red eye per se does not warrant US; but in irritation and has normal light sensitivity. patients suspected with retinal detachment, Their presence indicates serious under- Red Eye 251

lying disease process, including keratitis,  Ocular trauma—Any conjunctival and glaucoma, uveitis, and orbital cellulitis. corneal abrasion, contusion, and FB are  Discharge—Patients will often complain that important causes of red eye. their lids are stuck together in the morning  Contact lens use—They are prone to cause when they wake up. It is typically due to infection or the contact lens-induced acute matting of eyelashes on the discharge, and red eye (CLARE: vide infra ↓↓) or overwear does not occur in iridocyclitis or glaucoma. syndrome. A corneal ulcer may also be accompanied • Sexual history and history of urethral by exudation. The type of ocular discharge—It must be elicited in suspected discharge may be helpful to determine the gonococcal infection; it is important to ask cause of conjunctival inflammation; e.g. about sexual contacts as this is a highly profuse purulent discharge is typical of contagious infection. Prompt investigation N. gonorrhoeae infection; a mucopurulent must be ensured, which if left unnoticed, or purulent discharge suggests a bacterial could subject the patients to a great deal of infection; a serous, ropy (i.e. sticky anxiety and distress thread-like) discharge is most commonly • Associated systemic problems may be associated with viral or allergic ocular helpful to determine the possible cause; e.g. conditions. recent URTI or history of atopy (viral  Itching—Usually indicates an allergic conjunctivitis); diabetes/hypertension conjunctivitis. (subconjunctival hemorrhage, glaucoma);  Unilateral or bilateral—Conjunctivitis, thyrotoxicosis, rheumatoid arthritis and though initially present in one eye, the other autoimmune diseases (keratocon- second eye becomes involved a few days junctivitis sicca, scleritis) later. However, chronic unilateral or • Topical medications, i.e. conjunctivitis bilateral conjunctivitis (or red eye) may medicamentosa, due to antiglaucoma drugs, be due to meibomianitis or less common gentamicin, topical vasoconstrictors (rebound entities, e.g. occult FB, keratitis, nasol- hyperemia), topical drugs with preservatives, acrimal duct obstruction, or conjunctival artificial tears; and systemic drugs, e.g. neoplasm. antiplatelet/antithrombotic agents, etc. can  Visual changes—Do not rely on patient’s cause red eye subjective assessment of blurring of • The basic examination should include: vision. Blurred vision (BV) often indicates  Visual acuity—VA must be recorded with serious ocular disease, e.g. AACG. BV that every patient with an eye involvement. It improves with blinking suggests a is usually normal in conjunctivitis unless discharge or mucus on the ocular surface; cornea is involved and in AACG, and otherwise, it’s prudent to check the visual uveitis. acuity (VA) using Snellen’s chart and pin  Eyelids—Inflamed in blepharitis, FB hole card. under the eyelid.  Colored halos—Rainbow as fringes or  Conjunctiva—For the nature and location colored halos seen around the point of of hyperemia. light are a danger symptom suggesting  Pupillary abnormalities and corneal AACG as a cause of the red eye. opacities are explained in Table 36.1. 252 Diagnosis: A Symptom-based Approach in Internal Medicine

Table 36.1: Red eye—Differential diagnosis Disease Distribution of redness/pain Vision/photophobia Corneal surface Pupil IOP Acute Peripheral, diffuse, with irritation Normal, no photophobia Normal Normal Normal conjunctivitis Scleritis / Segmental, often around cornea; Normal, no photophobia Normal Normal Normal episcleritis aching pain, tenderness Acute iritis Maximum around cornea; painful Blurred, with photophobia Dull Constricted, Normal with radiation to brow, temple, nose. irregular; may or low be no light reflex Acute glaucoma Mainly circumcorneal, severely Markedly blurred, halos Hazy, dull Mid-dilated, Elevated painful with nausea, vomiting around light, with fixed, no light photophobia reflex Corneal ulcer Mainly circumcorneal; painful Usually, blurred, with Dull, fluorescein Normal Normal photophobia dye stains ulcer Subconjunctival Localized; painless Normal, no photophobia Normal Normal Normal hemorrhage Herpes simplex Unilateral, circumcorneal, Blurred but variable; Abnormal Normal Normal keratitis Dendritic ulcer with photophobia

 IOP (tonometry)—Elevated in acute persisting red eye, consider other causes such glaucoma (normal IOP- 10-21 mm Hg). as AACG, occult FB, trauma, and neoplasm.  Slit-lamp examination—To detect corneal • Recurrent subconjunctival hemorrhage with and ocular FBs. no known cause, a work-up for hematologic  Fluorescein dye test—Every patient with disorder is indicated. conjunctivitis should have fluorescein • A gritty sensation is common in conjuncti- staining in each eye to ensure that a vitis, but the presence of FB must be corneal aberration, ulcer, or herpetic excluded. dendrites is not missed. • Hyperacute bacterial conjunctivitis needs  Direct ophthalmoscopy—When performed emergent referral to prevent corneal from a distance of 15 cm, can detect involvement, including perforation and opacities in the cornea, lens, and vitreous. visual loss, which could also be due to The fundus and optic disc, looking for therapeutic misadventure with topical increase in the cup-disc ratio, which may steroid usage. Therefore, it’s prudent to signify presence of acute glaucoma, can refrain from treating any patients with also be evaluated. steroids without consultation. • Periauricular lymph nodes may be palpable • Beware of allergy or toxicity to topical in viral, chlamydial conjunctivitis, and acute medications, i.e. iatrogenic, (including gonoccocal infection. cosmetics) as a cause of persisting symptoms. • Never use mydriatics when examining red RED FLAGS eye—acute glaucoma may be precipitated; • All patients with severe eye pain (suggesting they also act as temporary decongestants, and increased IOP), photophobia, and corneal mask hyperemia. haziness require immediate ophthalmic • Syphilis—It being a multisystem, multi- referral. symptom disorder is a great mimic. Therefore, • In a patient with acute onset, unilateral it is important to always keep this condition headache, vomiting, acutely painful eye, or in mind when encountering patients with Red Eye 253

anterior uveitis, chorioretinitis, retinal repeat occurrences. Patient who have had a vascular occlusion, and chronic anterior CLARE should be educated and fitted with daily segment inflammation.7 Further manifest- wear lenses. ations of syphilis can be complicated by Keyboard conjunctivitis—An inconspicuous concurrent HIV infection; hence, always way of spread of conjunctivitis—by the use of consider HIV infection, e.g. CMV retinitis and keyboards of shared computers, at places like a Kaposi’s sarcoma in patients with syphilis. library, internet café, classrooms, etc. Shared keyboards and mouse are usually the culprits. SELECTED GLOSSARY Transmission of conjunctivitis is nearly certain, Contact lens-induced acute red eye (CLARE)8— if a patient with conjunctivitis/ carrier used the Contact lenses offer a unique and viable mode same keyboard earlier. Other examples of of visual correction and are also of therapeutic conjunctivitis (i.e. red eye) due to fomite value in a range of ocular disorders. However, transmission include objects such as mobile several reports in the literature have clearly phones, land phones, TV remote tools, fridge or shown that contact lens wear is not totally door handles, contaminated vehicles, shovels, compatible with ocular physiology, and is clothing, bowls/buckets, brushes, tack, and associated with various complications. Evidence clippers. Symptoms of conjunctivitis usually also suggests that an increased number of these start within a day or two. complications are seen with hydrogel lenses used on an over-extended contact lens wearing REFERENCES time or improperly used contact lenses in a 1. Mahmood AR, et al. Diagnosis and management closed eye environment (during sleep). Some of of the acute red eye. Emergency medicine clinics these conditions include inflammatory responses of North America 2008;26(1):35-55. such as Contact Lens Induced Acute Red Eye 2. Bal SK, et al.10-minute consultation. Red eye. BMJ 2005;331:438 (20 August), doi:10.1136/ (CLARE), and Culture Negative peripheral bmj.331.7514.438. Ulcers (CNPU), and sight threatening responses 3. Chauhan R. “Keyboard Conjunctivitis”. Annals Internal Medicine 7 April 2006. http:// such as infectious keratitis. While the etiology www.annals.org/cgi/eletters?lookup=by_ of a CLARE response is not clearly understood, date&days=7#2899. it is seen that the condition is distinct and 4. Feingold EK. The outbreak of conjunctivitis at Dartmouth. N Engl J Med 2003;348(25):2577-8. typically presents with the patient waking in the [PMID: 12815147]. early hours with discomfort and pain in the 5. Youssef OH, et al. Odontogenic orbital cellulitis. involved eye. Other symptoms include an Ophthal Plast Reconstr Surg. 2008;24(1):29-35. [PMID: 18209637]. intolerance to lens wear associated with redness, 6. Hossain GA, et al. High resolution ultrasound of lid swelling and mild to moderate amount of ophthalmic patients in a tertiary hospital. Mymen- singh Med J 2007;16(1):50-6. [PMID: 17344780: photophobia. Clinical signs include severe Abstract]. bulbar and limbal injection, and the presence of 7. Wuepper KD. “Red eye” as the presenting sign of diffuse subepithelial to anterior stromal syphilis d’emblée. Calif Med 1967;107(6):518-20. [PMID: 6078899]. infiltration in the periphery of the cornea. Most 8. Sankaridurg PR, et al. Gram-negative bacteria and often the presentation is unilateral and epithelial contact lens induced acute red eye. Indian J Ophthalmol [serial online] 1996 [cited 2008 Sep 23]; involvement is usually minimal. Further, patient 44:29-32. Available from: http://www.ijo.in/ who has endured an episode is susceptible to text.asp?1996/44/1/29/24602. CHAPTER 37 Sexual Dysfunction

SYNOPSIS 3. Cannot be accounted by another Axis I (i.e. clinical syndrome) disorder or substance Sexual dysfunction*, in either sex, is often the result effect. of a complicated interaction of biological, Based on these criteria, the common sexual psychological, and interpersonal difficulties dysfunctions as classified by DSM-IV-TR may between sexual partners, and may be defined as a be grouped as follows (Table 37.1): consistent long-term inability to respond in a way In men: - Erectile dysfunction (ED: vide that characterize the normal sexual response cycle. infra ↓↓), The normal sexual response cycle, as classified - Premature ejaculation (PE: vide by DSM-IV-TR system, comprises four phases: infra ↓↓), 1. Desire—Fantasies and desire about sex activity, - Retarded ejaculation, and 2. Arousal—Pleasure and physiological response, - Retrograde ejaculation (vide infra ↓↓). 3. Orgasmic—Release of sexual tension and In women:- Frigidity (i.e. female sexual rhythmic bodily response, and arousal disorder—FSAD: vide 4. Resolution—General relaxation and well infra ↓↓), being; the anatomic structures involved in - Orgasmic dysfunction (vide infra sexual response return to a baseline state. ↓↓), and The DSM-IV-TR system specifies three criteria - Vaginismus (vide infra ↓↓). which are essential during the process of In both: - Dyspareunia (vide infra ↓↓), evaluation for sexual dysfunction. They are: - Low libido (i.e. hypoactive sexual 1. Symptoms have to be recurrent or persistent, desire disorder—HSDD), and 2. Cause marked distress or interpersonal - Sex aversion disorder. difficulty, and Sexual dysfunction can be primary (meaning lifelong or never normal before), secondary

* Sexual dysfunction due to gender identity, homosexuality, (meaning acquired with normal function and paraphilias is not discussed. before), selective (such as only with a particular 255

Table 37.1: Classification of sexual dysfunction Table 37.2: Common conditions and agents affecting sexual function Disorder Male Female Psychosocial • Sexual desire •Alibido/low libido/ •Alibido/low libido/  Psychiatric: Anxiety, depression, PTSD disorder sexual phobia/ sexual phobia/  Psychosocial: Ignorance, poor relationship, poor aversion aversion • Sexual arousal •Erectile •Failure of arousal sexual drive, performance anxiety, prior sexual disorder dysfunction (absence of vaginal failure, negative attitude lubrication) Medical • Orgasmic disorder • Premature • Anorgasmia  Cardiovascular: Angina, previous MI ejaculation /  Retarded Respiratory: Asthma, COPD ejaculation  Endocrine: Diabetes mellitus, hypothyroidism, • Sexual pain •Painful ejaculation/ • Vaginismus/ hyperthyroidism disorder Dyspareunia Dyspareunia  Metabolic: Atherosclerosis, hepatic failure, renal failure  Neurological: Stroke, peripheral neuropathy, spinal partner), generalized (due to complex, deep rooted cord disorders  Gynecological: Vaginitis, PID, endometriosis, fibroid, causes), or due to combined factors. postmenopausal vaginal atrophy Since sexual dysfunction is quite common,  Arthritic: Arthritis from any cause but not obvious, it is essential that physicians  STD: herpes, gonorrhea  Aging: Andropause, menopause assume a proactive role. Every effort should be Surgical made to differentiate between psychogenic/  Phimosis, hydrocele, episiotomy scarring, prostatectomy, functional and organic sexual dysfunction, mastectomy (poor body image), oophorectomy, colostomy, amputation assessed via standard questionnaires such as Drugs the International Index of Erectile Function and  Prescribed: Antihypertensives, antidepressants, Female Sexual Function Index (see below). In an antipsychotics, mood regulators, antihistamines, hypnotics, sedatives, hormones, anabolic steroids, obvious psychogenic case, expensive and time- corticosteroids consuming investigations should be avoided.  Substance abuse: Alcohol, opium, cocaine, barbiturates However, if an organic cause is suspected to be Genetic the basis of sexual dysfunction, every effort  Peyronie’s disease should be made to discern that organic cause as • Post-traumatic stress disorder (PTSD: vide early as possible, and refer to the appropriate infra ↓↓) specialist for further investigations and • Sexual enactment factors (lack of penile/ management. vaginal stimulation, lubrication; unfavorable sexual positions) DIFFERENTIAL DIAGNOSIS (TABLE 37.2) • Genital (phimosis) • Endocrine (diabetes mellitus, hypothyroi- Common dism, thyrotoxicosis) • Psychogenic factors: • Cardiac (hypertension, CAD)  Personal problems (young men-new • Metabolic (atherosclerosis, dyslipidemia, partner, anxiety, depression) obesity) • Medications (antihypertensives, antidepres-  Relationship problems (poor communi- sants, anxiolytics, etc.) cation, unresolved conflicts, lost trust, ↓↓ • Substance abuse (alcohol, tobacco, opioids, Widower’s syndrome: vide infra ) cocaine)  Psychosexual problems (sexual perfor- • Pregnancy (especially in the first and last mance anxiety, prior sexual failure, trimester) negative learning and attitude about sex) • Aging/postmenopausal. 256

Occasional TFTs

• Vaginal/pelvic disorders (infection—vaginitis, • Elevated TSH with diminished FT4 values in PID; fibroid, tumor; childbirth injury) primary hypothyroidism, and subnormal/ • Neurogenic (stroke) undetected TSH levels with elevated T3 or T4 • Postsurgical (prostatectomy, pelvic adhesive or both in thyrotoxicosis disease). • TFTs are also useful to discover subclinical hyperthyroidism (T3, T4 normal, TSH und- Rare etected); and subclinical hypothy-roidism • Neurogenic (brain tumor, spinal injury/ (T4 normal, TSH raised) which may be compression) responsible for sexual dysfunction. • Endocrine (prolactinoma, Addison’s disease, hypogonadism) Chemistry Panel • Vascular occlusive disease (Leriche’ syn- drome: vide infra ↓↓) • LFTs, urea, creatinine, and VDRL as indicated. • Congenital disease/malformation (Peyronie’s Serum Testosterone-free (AM Sample) disease: vide infra ↓↓) • Genital trauma. • Low levels in patients with diminished libido, or any signs of diminished secondary INVESTIGATIONS—GENERAL sexual characteristics, i.e. mild or otherwise Blood Glucose asymptomatic androgen deficiency, or hypogonadism. • Diabetes mellitus is a common cause of ED. Present evidence supports ED as a significant Microscopy/Culture marker for diabetes, particularly in younger • Vaginal secretions (vaginitis, gonococcal); patients. Men 45 years old or younger with prostate (prostatitis). ED were more than twice as likely to have diabetes mellitus as men without ED, and men INVESTIGATIONS—SPECIFIC with ED 46 to 65 years old were likely to have diabetes. Thus, markers of ED may represent Serum Prolactin (PRL) an early warning for the development of • If serum testosterone levels are low, serum diabetes, which is particularly important PRL should be measured. considering many diabetic patients remain High (>20 ng/ml) levels—either due to undiagnosed for several years. Therefore, hypothalamic-pituitary lesion (suppressing fasting, two hour postprandial blood glucose, and HbA1c estimation should be GnRH) or drug induced—are observed in 1-3 patients with low libido, in women with obtained. little or no history of menstruation, and Lipid Profile gynecomastia. • Hyperlipidemia, along with hypertension and LH and FSH diabetes mellitus, is a risk factor for metabolic syndrome which often coexists with ED; • Serum LH and FSH estimation helps to therefore its estimation is important.4,5 differentiate the etiology of sexual dysfunction, Sexual Dysfunction 257

either due to testicular (Leydig cell) failure or US Testis and Pelvis hypothalamic-pituitary lesion. • To assess testicle/epididymis size, enlarge-  If LH and FSH are normal or low, and PRL ment, growth, congenital abnormality, and is also normal, then the diagnosis is adnexal, uterine lesions. hypothalamic-pituitary lesion.  If LH and FSH are high, and PRL is CT/MRI Scan normal, then the diagnosis is testicular (Leydig cell) failure. • As indicated in patients with pituitary adenoma  If LH and FSH are low, but PRL is high, (hyperprolactinemia with normal LH, FSH). pituitary adenoma needs to be ruled out. CLINICAL NOTES Nocturnal Penile Tumescence (NPT) • Detection of sexual dysfunction in a patient • Penile erections during REM sleep support or a couple depends upon asking appropriate psychogenic etiology, and eliminate signifi- questions because many are reluctant to cant neurologic, vascular, or endocrine initiate discussion of their sex lives. Further, causes of ED. what is regarded as normal sexual function, and therefore, what is thought to be impaired Intracavernosal Injection and Sexual Stimulation or unsatisfactory sexual performance depends in part on the expectations of the • To assess penile vascular function. couple concerned. For example, one couple Penile Duplex US may regard it as normal that the woman is regularly unable to achieve orgasm, whilst • To evaluate vascular function within the another may seek treatment. It is also a fact penis, i.e. in the cavernous arteries, before that many physicians have their own and after injection of a vasodilator such as inhibitions in taking detailed sexual history prostaglandin E1, e.g. in Peyronie’s disease. from the patient. Some of the potential Duplex US can also evaluate blood flow barriers cited for reluctance to address sexual velocities to the clitoris, labia, urethra, and health issues include: embarrassment, feeling vagina. ill-equipped or inadequate training to elicit sexual history, belief that sexual history is Perineal and Clitoral Electromyography not relevant to the chief complaint, and time constraints.6,7 Thus both patients and • To detect sensory neuropathy in pudendal physicians need to curtail their inhibitions, nerve pathway, and in evaluating the and begin to take the first steps toward better autonomic innervation of the clitoris due to sexual communication diabetes mellitus and alcoholism. • Patients prefer to communicate their Pelvic Arteriography symptoms related to sexual dysfunction in the privacy of verbal communication with • In young men with arterial insufficiency as their physician. A respectful, open-minded, the cause for their ED, and who are candidates and relaxed approach is essential. Questions for reconstructive surgery. should be asked in a matter-of-fact, yet 258 Diagnosis: A Symptom-based Approach in Internal Medicine

sensitive manner, avoiding jargon. A simple detailed, i.e. in-depth sexual history is way to do this is by simply asking, “how needed8 are things going for you sexually?”, or, “how • Loss of NPT—At the very beginning a is your sex life? Is everything all right?”; this carefully taken sexual history helps to rule type of inquiry should elicit a clear, quick, out organic causes of sexual dysfunction, and direct response such as “everything is especially treatable ones. An alerting sign is fine.” Any other answer may suggest a loss of male morning erection, i.e. loss of potential sexual dysfunction in him or her NPT during REM sleep. A history of erection which should be followed up (with consent) that occurs nocturnally, during masturbation, with specific questions to identify problems or during foreplay, or with other sexual associated with various phases of sexual partners eliminates significantly neurologic, response cycle (see above). If the patient is vascular, or endocrine cause of ED. For women part of the couple, the couple should be there can be a similar loss of nocturnal vaginal interviewed together lubrication • It is not unusual for some patient to be • Hidden agenda—Although some patients unaware of an association between their may present directly with a complaint of medical problem and underlying sexual sexual dysfunction, many will present with dysfunction. For example, patients with unexpected add-on problem at the end of obesity, tension headache, chronic backache, consultation as hidden agenda or exit problem vaginal discharge, pelvic pain, etc. This is an or parting shot. The exit problem or parting shot opportunity for the physician to recognize is usually the patient’s main reason for such an association and tactfully include consultation. Examples wherein such situation inquiry about sexual dysfunction is commonly encountered are: • A two way approach may be adopted in  Sexual inquiry as part of current illness obtaining sexual dysfunction history: The management screening method and the in-depth approach.  Sexual inquiry as part of health If the sexual history seems unrelated to the check-up chief complaint, a few screening questions  Premarital sexual concerns will suffice. Questionnaires have been  Important life events, e.g. marriage developed to collect data regarding ED  Exposure to STD (International Index of Erectile Function —  † Medication side-effects IIEF and female sexual dysfunction (Female  Infertility, menopause, andropause. Sexual Function Index—FSFI‡) to assess the • Despite a seemingly indirect or ‘by-the-way’ severity and impact of therapy in such nature of such encounters, the issue must be patients which may be useful to understand recognized and treated with considerable the nature and scope of the patient’s importance problem. If the complaints have direct • History—Includes age, mode of onset, bearing to the chief complaints, a more duration, libido (i.e. sex drive), situational context, foreplay, fantasies, frequency, † Web site: Accessed on 16-11-08 ‡web site:Accessed on 16-11-08 during intercourse Sexual Dysfunction 259

• Sexual history—Includes early experiences Table 37.3: Assessment of historical features for (sexual abuse), sexual knowledge, attitude sexual dysfunction towards sexuality, past sexual practices, current • Define the problem—As it appears to each partner, sexual relationship, self-pleasuring practices and in their own words fantasies, homosexual experiences, personal • Onset, course—Always a problem, or after a period of normal functioning body image, and any past negative sexual • Any other partner—Sexual functioning in other experiences such as sexual assault, incest context, problem confined to one or other partner, • Stress—Current stress factors such as elicit history individually • Sexual drive—Early morning or nocturnal penile interfamily problems with children, elders, erection, sexual thoughts /feelings of sexual arousal, death, and extrafamilial factors such as stress masturbation, frequency of intercourse from occupation, legal, and financial matters • Knowledge and fears—Misconceptions, religious belief, strict religious upbringing sex education, create problems in the sexual relationship sexual techniques • Habits—Such as nicotine use, alcohol intake, • Interpersonal relationship—Either partner shy, low and illicit drug use should be documented self-esteem, aggressive, marital conflicts • Psychiatric disorder—Especially depression, guilt • Medication history—Important in all indivi- about sexual impulses, PTSD duals with sexual dysfunction. The onset, • Substance abuse—Alcohol, drugs • Associated illness—Medical or surgical frequency, and duration of the sexual side • Reason for present consultation—To elicit history effects of drugs are variable, which can be of any recent adverse psychosocial developments, confirmed by ‘drug holiday’ biological factors such as newly diagnosed disease or surgical intervention • Mental state examination—May be indicated to exclude psychiatric disorders and to explore  General—Secondary sex characteristics. guilt, shame, anger and other emotional . Gynecomastia in men (hepatic cirrhosis, elements associated with sexual dysfunction digoxin, spironolactone, testicular • Family history—Includes parental influences, tumor, hypogonadism, Klinefelter’s cultural and religious influences, family syndrome: vide infra ↓↓). violence, and relationship with siblings . Galactorrhea in women (pregnancy, drugs, • Past history—Any disease, injury, or surg- hypothyroidism, hyperprolactinemia). ery that could affect sexual functioning . Blood pressure, peripheral pulses, • Table 37.3 briefly states historical features xanthelasma. for the assessment of sexual dysfunction . Thyroid (goiter, nodules), chest, and mentioned above abdomen. • Vasculopathy has come to be recognized as  Neurologic: the most common cause of ED, which has . Sensation, tendon reflexes (peripheral elevated ED’s importance in the primary care neuropathy). setting as a sentinel to underlying cardiovas- . Anal sphincter tone (inconsonance, cular disease. Identification of cardiovas- pelvic floor childbirth injury). cular risk factors should be a routine part of . Bulbocavernous reflex (lower motor the evaluation for ED, and is as important as neuron lesion). taking the patient’s sexual, medication, and  Male: 9 psychosocial histories . Penis (malformation, discharge, ulcer). • Physical examination—The important basic . Scrotum, testis, epididymis (cryptor- aspects include: chism: vide infra ↓↓). 260 Diagnosis: A Symptom-based Approach in Internal Medicine

. Rectal examination (fissure, hemorr- Erectile dysfunction (ED)—Persistent or recurrent hoids, prostate). partial or complete failure to attain or maintain  Female: erection until completion of sexual activity. ED . External genitalia (inflammation). becomes more common with age, but is not part of . Introitus (intact hymen, remnants of the normal aging process. ED is a symptom of other hymenal ring, rigidity). potentially serious medical conditions. It may . Vagina (atrophy, discharge stenosis). indicate incipient cardiovascular disease,  Pelvic examination (adnexal mass, PID). neurologic degeneration, hormonal imbalances,  Rectal examination (as above). psychological issues, and even marital problems. Therefore, it’s important to perform basic physical RED FLAGS and psychological evaluation of the patient and • Avoid moral or religious judgement of evaluate the risk factors for any impending disease. patient’s behaviour. Respect patient’s Female sexual arousal disorder (FSAD)— reluctance to disclose all sexual and Persistent or recurrent inability to achieve or relationship details, especially during the maintain sufficient sexual excitement, expressed initial discussion. as a lack of excitement or a lack of genital or other SELECTIVE GLOSSARY somatic responses such as adequate lubrication- swelling response of sexual excitement. It’s Cryptorchism (or Cryptorchidism)—It is usually due to psychological conflicts; altered defined as failure of the testis to descend from hormonal balance (testosterone, estrogen, its intra-abdominal location into the scrotum. prolactin, and thyroxin); may be associated with The exact etiology of cryptorchidism is not depression or medication effect. However, a detail known. It usually presents at birth or by history is essential to rule out inadequate, preadolescence; however, it can present at any focussed, sexual stimulation and duration of age. In one-third of patients, the condition is sexual activity. bilateral. Patients present with the condition or the parents bring the child with nonpalpable Hypoactive sexual desire disorder (HSDD)— testis. Physical examination reveals a It is the persistent or recurrent deficiency (or nonpalpable testis in the scrotum. The most absence) of sexual fantasies or thoughts and/ common location of the cryptorchid testis is or the lack of receptivity to sexual activity. It’s in the inguinal canal (72%), followed by usually due to reaction to sexual dysfunction, prescrotal (20%) and abdominal (8%) chronic illness, surgery, major depression, locations. US, CT, MRI, arteriography, and chronic anxiety, and marital discord, hyper- laparoscopy are used for diagnosis. Testicular prolactinemia, or CNS depressants. malignancies occur in 10% of men with cryptorchid testis. The primary treatment of Klinefelter’s syndrome—KS, 47, XXY and its cryptorchid testis is orchiopexy. variants, is the most common chromosomal Dyspareunia—Persistent or recurrent genital aberration among men, associated with hypo- pain, during or after sexual intercourse, in either gonadism (small testes, azoospermia/oligosp- sex; much more common in women, and ermia), gynecomastia in late puberty, and uncommon in men (usually organic in men, e.g. infertility. Sexual dysfunction symptoms include Peyronie disease). erectile dysfunction, and subnormal libido. Other Sexual Dysfunction 261 symptoms include fatigue, weakness, osteopo- to penile angulation or an hour-glass like rosis, language impairment, academic difficulty, deformity with distal flaccidity. It usually and psychiatric disorders involving anxiety, affects only the erect penis. Sexual intercourse depression, neurosis, and psychosis. Infertility can become painfully difficult or impossible. and gynecomastia are the two most common Genetic susceptibility is thought to play a symptoms that lead to diagnosis, but many role. Penile X-ray and ultrasound can demon- cases of KS remain undiagnosed because of strate calcified and noncalcified plaques substantial variation in clinical presentation. respectively. Corpus cavernosography can help MRI brain findings indicate a reduction in left to demonstrate cavernosus deformity and temporal lobe gray matter, a finding that is vascular blockage. consistent with the verbal and language deficits Post-traumatic stress disorder (PTSD)—PTSD associated with KS. Chromosomal studies are is a psychological condition that is triggered indicated in prepubertal males with low by experiencing or witnessing severe trauma testosterone and elevated FSH and LH levels to that constitutes a threat to the physical assess for Klinefelter syndrome. A semen integrity or life of the individual or of another analysis (as per the WHO guidelines) is person; these events being extreme in nature, indicated if fertility is an issue. not necessarily outside the normal range of human experience, but such as to arouse Leriche syndrome—It is used to describe intense fear, helplessness or horror, e.g. natural chronic lower limb ischemia characterized by: disasters, violent personal assaults, rape, war, Intermittent claudication in the buttocks; pale, severe automobile accidents, or the diagnosis cold legs; sexual impotence; and absent femoral of a life-threatening condition. Sexual assault pulses. It is caused by aortoiliac obstruction on women probably is the most important (e.g. saddle embolism at bifurcation of the aorta). cause of PTSD. Four categories of criteria are The vessels above and below may be relatively needed to accurately diagnose PTSD. normal.  First, a traumatic event occurred in which Orgasmic dysfunction—It is also called inh- the person witnessed or experienced actual ibited male/female orgasm or retarded ejacul- or threatened death or serious injury, and ation of the male; wherein there is persistent or responded with intense fear, horror or recurrent delay in, or absence of orgasm helplessness. following a normal arousal phase during sexual  Second, on exposure to memory cues, the activity—the individual may be sexually person has reexperiencing symptoms, such aroused but orgasm is impaired or absent. as intrusive recollections, nightmares, flashbacks or psychologic distress. Peyronie’s disease (synonyms: Penile fibrosis,  Third, the patient avoids trauma-related Induratio penis plastica)—A condition characterized stimuli (avoid thoughts, feelings, conversa- by hardening of the penis due to the formation tions, places or people that arouse recollec- of fibrous plaques on the dorsolateral aspect of tions of trauma), and feels emotionally numb. the penis, usually involving the membrane  Fourth, the person has increased CNS (tunica albuginea) surrounding the erectile arousal, manifested by difficulty falling or tissue (corpus cavernosum penis). This may staying asleep, irritability or outburst of eventually cause a painful deformity of the shaft anger, difficulty concentrating, hypervigi- or constriction of the urethra, or both, leading lance, and startle response. 262 Diagnosis: A Symptom-based Approach in Internal Medicine

The symptoms persist for at least one month intercourse (coitus), usually due to sexual trauma and significantly disturb the patient’s social (rape, childhood sexual abuse); or as a conseq- or occupational functioning (or both). Acute uence of dyspareunia, e.g. childbirth, surgery, PTSD is diagnosed when the symptoms have gynecologic pathology, atrophic vaginitis; and lasted for 1-3 months as against chronic PTSD, also due to strict religious upbringing; or psych- where symptoms have lasted for more than 3 ogenic factors. months. The importance of this distinction lies in the fact that active treatment in acute PTSD Widower’s syndrome: It refers to a male who may reduce the high risk of developing chronic experiences erectile dysfunction (with a new sex PTSD. Although level of exposure to traumatic partner) secondary to guilt feelings relating to stressor is directly related to the psychological his dead spouse. impact, other factors contribute to develo- pment of PTSD. Thus history of previous panic REFERENCES disorders, previous trauma, child abuse, drug 1. Davies KP, et al. Markers of erectile dysfunction. abuse, as well as socioeconomic and demo- Indian J Urol 2008;24:320-8. graphic factors and ethnicity, appear to be risk 2. Ma RC, et al. Erectile dysfunction predicts factors for vulnerability to PTSD.10,11 coronary heart disease in type 2 diabetes. J Am Coll Cardiol 2008;51(21):2045-50. [PMID: Premature ejaculation (PE)—Persistent or 18498959: Abstract]. recurrent ejaculation with minimal sexual 3. Koppikar N, et al. Recent advances in the treatment of erectile dysfunction in patients with diabetes stimulation before, on or shortly after penet- mellitus. Endocr Pract 2003;9(1):52-63. [PMID: ration and before the person wished it (taking 12917094: Abstract]. into account age, frequency, and situation); more 4. Lee JH, et al. Erectile dysfunction as a coronary common in younger men and often resolves with artery disease risk equivalent. J Nucl Cardiol 2008;15(6):800-3. Epub 2008 Sep 12. [PMID: increasing experience. 18984455: Abstract]. Retrograde ejaculation—Sexual climax with- 5. Ponholzer A, et al. Is the metabolic syndrome a risk factor for female sexual dysfunction in sexually out the release of semen from the penis; occurs active women? Int J Impot Res 2008;20(1):100-4. when the semen passes into the bladder rather Epub 2007 Sep 20. [PMID: 17882275: Abstract]. than along the urethra. It is common after 6. Merrill JM, et al. Why doctors have difficulty prostatectomy, neurologic disorder (Parkinson’s with sex histories. South Med J 1990;83(6):613-7. [PMID: 2356491: Abstract]. disease, lumbar or sacral damage), and some 7. Wimberly YH, et al. Sexual history-taking antihypertensives (methyldopa). among primary care physicians. J Natl Med Assoc 2006;98(12):1924-9.[PMID: 17225835: Sex aversion disorder—Persistent or extreme Abstract]. aversion to and avoidance of all (or almost all) 8. Nusbaum MR, et al. The proactive sexual health genital sexual contact with a sexual partner; history. Am Fam Physician 2002;66(9):1705-12. applies mostly to female sex with history of [PMID: 12449269: Free full text]. 9. Miner MM, et al. Erectile dysfunction: A sentinal sexual assault, severe negative self-esteem, marker for CVD in primary care. Cleveland clinic marital discord, and in women complaining of J of Med. (74), S3, May 2007. gynecological symptoms, e.g. pelvic pain, 10. DeJonghe ES, et al.Women survivors of intimate partner violence and posttraumatic stress vaginal bleeding, and other sexual dysfunctions. disorder: Prediction and prevention. J Postgrad Vaginismus—Persistent or recurrent invol- Med 2008;54:294-300. untary muscle constrictions of outer third of 11. Kishen R. Post-traumatic stress disorder in the critically ill patients. Indian J Crit Care Med 2006; vagina that prevents penile insertion and 10:163-6. CHAPTER 38 Sweating Abnormalities

SYNOPSIS Excessive sweating, called as hyperhidrosis, is sweating beyond what is necessary to maintain Eccrine sweat glands are distributed all over the normal thermoregulation. Clinically, it may be body surface,* but are most dense on the forehead, defined as a condition where noticeable sweating palms and soles, and in the axillae. They open occurs under different conditions, where it would directly on the skin and their secretion, commonly not be normally expected to occur or occurs in called as ‘sweat’ (perspiration), is regulated by the excess,4 often causing occupational disability and body temperature center in the hypothalamus (the social embarrassment. Patients usually present sudomotor system which controls sweat output) via because of abnormal wetness, sweaty palms, the sympathetic cholinergic mediator. Any stained clothing, offensive odor, and change in fluctuations in the sudomotor autonomic activity, † the pattern of sweating. Patients report that they consisting of frontal operculum, hypothalamus, brainstem, spinal cord, sympathetic chain ganglia, are even embarrassed to hold the hands of those peripheral nerve, or eccrine sweat glands may result they love. in sweating abnormalities. Hypohidrosis and anhydrosis is reduced or Sweating (i.e. insensible loss) is necessary to complete absence of sweating respectively; the maintain body’s normal thermoregulatory individual is unable to deliver sweat to the skin mechanism, and fluid and electrolyte hemostasis. surface in the presence of appropriate stimuli. The amount of sweat produced or its response to The etiology of sweating abnormalities, i.e. physiological stimuli of heat, emotion, or eating hyperhidrosis and hypohidrosis, can be primary varies greatly by different individuals under (idiopathic or essential) or secondary to a various conditions, and therefore, it is difficult to number of diseases and drugs. It may also be define sweating abnormality—normal, excessive, localized or generalized, although such a strict or deficient—in an individual.1-3 categorization may not be always possible in a clinical setting. Unilateral, transient (lasting 1 to * Except the nailbeds and some mucosal surfaces. 3 days) hyperhidrosis typically involving the † Adjoining parts of the frontal, parietal and temporal lobes. face and arm have also been documented.5, 6 264

Whereas hyperhidrosis is usually benign, Occasional anhidrosis may predispose to hyperthermia. • Localized hyperhidrosis (palmoplantar, Either hyperhidrosis or anhidrosis may accompany axillary, craniofacial) a more serious underlying disorder. Correct • Alcohol and drug withdrawal diagnosis depends on determining the anatomical • Medications (antipyretics, insulin, venla- pattern of sweating and localizing the lesion faxine, tricyclic antidepressants, pilocarpine, within the autonomic nervous system.7 physostigmine) Sweating abnormalities, especially hyperhi- • Other infections (endocarditis, brucellosis). drosis, can interfere with employment and social relationships, and cause immense anxiety to the Rare suffering individual. Therefore, it is being recognized increasingly, and its treatment • Neoplasm (lymphoma, insulinoma, pheo- modalities are gaining widespread attention. chromocytoma, carcinoid syndrome) However, in the majority of patients with hyper- • Intrathoracic lesion (paroxysmal unilateral hidrosis, providing scientific explanation, and hyperhidrosis due to cervical rib, apical reassurance that excess sweating is not the conse- bronchial carcinoma) quence of pathological condition once medical • Neurologic diseases (hypothalamic lesions, causes have been ruled out is crucial in their Harlequin syndrome: vide infra ↓↓, autonomic symptomatic management. dysfunction) • Spinal cord lesions (posttraumatic syringo- DIFFERENTIAL DIAGNOSIS myelia) • Endocrine (hyperpituitarism) Can be considered separately for hyperhidrosis • Olfactory hyperhidrosis (facial sweating and hypohidrosis: from perfume smell) A—Hyperhidrosis • Gestatory hyperhidrosis (pathological— Frey’s syndrome: vide infra ↓↓) Common • Poisoning (cholinesterase inhibitors, organo- phosphorus compounds) • Excessive exposure to heat, humidity, and • Familial (nail-patella syndrome: vide infra ↓↓) vigorous exercise‡ • Anxiety disorders§ B—Hypohidrosis and Anhidrosis • Infectious febrile diseases (typhoid, malaria, TB, HIV) Common • Shock and syncope (myocardial ischemia, • Ductal obstruction (Miliaria, sweat retention stroke, sepsis) syndrome, prickly heat) • Hypoglycemia • Systemic disorder (Heat stroke) • Hyperthyroidism • Damage to sweat gland (scar, trauma, • Menopause surgery, irradiation, scleroderma) • Gestatory hyperhidrosis (physiological— spicy food). Occasional

‡ Thermal sweating is governed by the hypothalamus. • Local denervation (leprosy, xerotic dermatitis, § Emotional sweating is governed by the cerebral cortex. segmental vitiligo) 265

• Medications (anticholinergics, antihist- Purified Protein Derivative (PPD) amines) • To screen for TB. • Autonomic peripheral neuropathy (diabetes mellitus, uremia, alcoholic) HIV • Myxedema. • As indicated in immunodeficiency disorders. Rare CXR • Hypothermia • Sjögren’s syndrome • To rule out parenchymal lesions, tuber- • Multiple system atrophy (MSA)8 culosis, lymphoma, or a neoplasm. • Congenital (hypohidrotic ectodermal dysplasia). INVESTIGATIONS—SPECIFIC INVESTIGATIONS—GENERAL Blood Culture

CBC • In enteric fever, endocarditis, sepsis, and in • Leukocytosis in bacterial infection, heat infections due to immunodeficiency disease. stroke; abnormal WBCs in leukemia; malarial Iodine Starch Test parasites in malaria. • Mapping out areas of excessive sweating, i.e. ESR for direct visualization of the affected areas, may be done by the iodine starch test. The • Elevated in infection, malignancy, lymphoma, affected area is sprayed with a mixture of 0.5 and autoimmune disease. to 1 gram of iodine crystals and 500 gram of soluble starch. Areas that produce sweat will TFTs turn black. • Elevated FT4 with low TSH suggest underlying hyperthyroidism or thyrotoxicosis; elevated Urinary Catecholamines TSH suggests hypothyroidism. • To rule out possible pheochromocytoma.

Blood Glucose Urinary 5-Hydroxyindoleacetic Acid (5-HIAA)

• May reveal diabetes mellitus or hypoglycemia. • To screen patients suspected of carcinoid To confirm nocturnal hypoglycemia—in tumor; very high excretion rates of 5-HIAA diabetic patients suspected with nocturnal occur in carcinoid syndrome. sweating—blood glucose estimation around early hours of the morning must be done. Biopsy

Urea, Electrolytes • In patients with localized hyperhidrosis (e.g. focal axillary hyperhidrosis), eccrine nevus, • Elevated urea, creatinine and low sodium, eccrine angiomatous hemartoma, etc. biopsy potassium in heat stroke. is indicated. 266

Sudomotor Testing9 Excess sweating restricted to palms, soles, and axillae may be indicative of a normal • In rare disorders such as idiopathic hyper- response to everyday events, or if it is more hidrosis, MSA, etc. sudomotor testing such as generalized, may suggest an underlying Quantitative Sudomotor Axon Reflex Test medical disorder, commonly due to hyper- (QSART), Silastic sweat imprint test, and Ther- thyroidism and menopause. moregulatory Sweat Test (TST) may be • If sweating occurs primarily at night indicated. These tests have a high sensitivity and specificity for delineating the postganglionic (Table 38.1), then inquiry into fever, cough, sudomotor function and site of lesion. expecto-ration, hemoptysis, weight loss, and other symptoms of esophageal reflux CLINICAL NOTES disorder and neoplasm should be sought. Tuberculosis, HIV infection, esophageal • It is to be remembered that sweating varies reflux, and menopause are known to be the with age because sweat glands function most frequently associated disorders with immaturely in infants and less active in night sweats, defined as “sweating at night elderly patients. As a result, patients in these even when it isn’t excessively hot in your age-groups may fail to display sweating 10 bedroom within the previous month”. associated with its common causes. • Paroxysms of sweating are common with • An important step in determining the cause anxiety disorders, menopause, carcinoid of sweating abnormality is whether it is syndrome, and pheochromocytoma. generalized or localized. • A drug history is inquired with a check for • Generalized hyperhidrosis is common in adults use of antipyretics, insulin, anticholinergics, and is usually secondary to severe physio- antihistamines, and alcohol. logic stress (shock, pain); a metabolic • Physical examination—May include presence of disorder (diabetes mellitus, hypoglycemia, weight loss (diabetes mellitus, hyperthy- thyrotoxicosis, menopause, pheochromo- roidism; tachycardia (panic attack, hyperthy- cytoma); febrile illness, drug effect, or roidism, and heat stroke); hypotension (syncope, malignancy. Therefore, it is essential to investigate for the underlying disorder. autonomic dysfunction); hypertension, facial • Localized hyperhidrosis (palmoplantar, axillary, flushing (pheochromocytoma, carcinoid craniofacial) is often primary (idiopathic) and syndrome); fever or defervescence. unlike generalized hyperhidrosis, usually • The patient is examined for signs of other begins in adolescence, but it can begin in systemic disorders such as tuberculosis childhood or even in infancy. (segmental collapse, pleural effusion), • In generalized hyperhidrosis sweating is hyperthyroidism (goiter, lid lag, exophthal- common during both waking and sleeping mos, and ophthalmoplegia), lymphoma, hours; whereas in local hyperhidrosis sweat- malignancy (regional lymphadenopathy, ing usually reduces at night time and disap- splenomegaly), endocarditis (new or chang- pears during sleep. ing heart murmur), peripheral neuropathy • History with regards to severity, extent, (paresthesias with sensory, motor, and periodicity, duration, and its impact on the autonomic nerve dysfunction), and alcohol daily activities of the individual are noted. abuse (icterus, hepatomegaly). 267

Table 38.1: Causes of night sweats SELECTIVE GLOSSARY Causes Common examples Frey syndrome—It is a known complication after Infections TB (Mycobacterium tuberculosis) Lung abscess parotidectomy, and manifestations range from Endocarditis HIV (Mycobacterium avium complex) erythema related to eating to copious gustatory Fungal (histomycosis, coccidiomycosis) sweating. The cause is believed to be an aberrant

Malignancy Hodgkin’s and Non-Hodgkin’s lymphoma connection of the parasympathetic fibers to the Leukemia sweat gland of the overlying flap of skin. Solid tumors—Neoplasm (primary or metastatic) Harlequin syndrome**—A term originally Drugs/substance abuse Antipyretics, insulin, antipsychotics, reserved for patients with asymmetrical facial antihistamines, drug withdrawal in addicts—alcohol, heroin, opioids flushing and sweating without ocular signs of Horner’s syndrome, is a rare autonomic Endocrine Diabetes mellitus (nocturnal hypoglycemia) Hyperparathyroidism condition characterized by flushing and Endocrine tumors (pheochromocytoma, carcinoid tumor) sweating that occurs only on one side of the face and may occur for no apparent reason or in Others Menopause Premature ovarian failure response to such things as heat and exercise. Pregnancy Since unilateral facial flushing can also be the Anxiety/panic disorder Chronic fatigue syndrome first symptom of more serious conditions such Prinzmetal’s angina Gastroesophageal reflux disease as malignancy or stroke, a thorough diagnostic Obstructive sleep apnea investigation is required to determine the Sleep terror Dumping syndrome underlying etiology of the condition. Occa- Hypoglycemia of various causes sionally, patients with Harlequin syndrome Diabetes insipidus Takayasu’s arteritis display symptoms that are also seen in Adie’s Temporal arteritis syndrome (tonic pupils with hyporeflexia) or Ross syndrome (tonic pupils with hypo- RED FLAGS reflexia and segmental anhidrosis). The groups of symptoms seen in these syndromes, • Hyperhidrosis in hypoglycemia, acute however, indicate a wider spread of autonomic coronary syndrome, and autonomic hyper- deficits than those seen in pure Harlequin reflexia (spinal cord injury); and hypohid- syndrome, with involvement of other parts of rosis or anhidrosis in heat stroke indicate the nervous system. This point should be medical crisis. considered when making the differential • Hyperhidrosis beginning later in life should diagnosis. The syndrome is usually of benign prompt a search for secondary causes such nature and does not require treatment unless as systemic diseases, adverse drug reactions, neurovascular compression signs and or metabolic disorders. symptoms are present. • Older patients may not exhibit sweating because of a decreased sweating mechanism; hence they are at increased risk of developing ** The term Harlequin syndrome is also used to describe an autosomal recessive skin disorder that represents the heatstroke in high temperature. most severe form of congenital ichthyosis. 268

Nail Patella Syndrome (NPS)—It is inherited 2. Aoki K, et al. The effect of diurnal variation on the regional differences in sweating and skin blood as an autosomal dominant trait involving flow during exercise. Eur J Appl Physiol Occup organs of both ectodermal and mesodermal Physiol 1995;71(2-3):276-80. [PMID: 7588701: origin. The diagnostic tetrad includes Abstract]. 3. Schestatsky P, et al. Skin autonomic reactivity to fingernail dysplasia, absent or hypoplastic thermoalgesic stimuli. Clin Auton Res 2007; patellae, the presence of posterior conical iliac 17(6):349-55. Epub 2007 Nov 29. [PMID: 18049833: Abstract]. horns, and deformation or luxation (i.e. 4. Sato K. Disorders of eccrine sweat gland. In: hypoplasia) of the radial heads. Patients often Fitzpatrick TB, et al. Dermatology in General complain of palmoplantar hyperhidrosis. medicine. 4th ed. 1993. P.40-53. 5. Labar, et al. Unilateral hyperhidrosis after cerebral Kidney disease and glaucoma are now infarction. Neurology 1988;38:1679-82. [PMID: recognized as part of the syndrome. The most 3185901: Abstract]. 6. Rousseaux M, et al. Late contralateral Hyperhidrosis serious complication associated with NPS is in Lateral Medullary Infarcts Stroke 27:991-5. nephropathy. The correct diagnosis is rarely [PMID: 8623124: Free full text]. 7. Cheshire WP, et al. Disorders of sweating. Semin established during childhood because the nail Neurol 2003;23(4):399-406. [PMID: 15088261: and patella abnormalities may not become Abstract]. apparent until later in life. 8. Dinadio V, et al. Anhidrosis in multiple system atrophy: A preganglionic sudomotor dysfunction?. Mov Disord 2008;23(6):885-8. [PMID: 18361470: REFERENCES Abstract]. 9. Gibbons, et al. QDIRT: Quantitative direct and 1. Green BG, et al. Individual differences in temperature indirect test of sudomotor function Neurology 2008 perception: Evidence of common processing of 70: 2299-2304. [PMID: 18541883: Abstract]. sensation intensity of warmth and cold. Somatosens 10. Mold JW, et al. Prevalence of night sweats in primary Mot Res. 2007;24(1-2):71-84. [PMID: 17558924: care patients: An OKPRN and TAFP-Net coll- Abstract]. aborative study. J Fam Pract 2002; 51:452–6. CHAPTER 39 Swelling of the Legs

SYNOPSIS potentially life-threatening condition, e.g. deep venous thrombosis is associated with pedal Swelling of the legs is commonly due to systemic edema, diagnosis is simplified by determining edema state. Edema is the excessive accumulation localization of edema, i.e. whether one or both of fluid in the tissues (or serious sacs*) due to legs are involved, its onset—sudden or gradual, increase in the volume of interstitial fluid (ISF), presence of pain, and other signs and symptoms i.e. increase in the extravascular portion of the of inflammation, and associated systemic extracellular compartment. In an adult, the ISF symptoms such as breathlessness, jaundice, should expand by at least 2 liters† before the unexplained weight gain, sleep apnea, etc. abnormality is clinically recognized as pitting edema, i.e. persistence of indentation of the skin DIFFERENTIAL DIAGNOSIS following pressure. In response to gravity, dependent edema first Common appears in the feet and ankles in an ambulatory ‡ • Cardiac (CHF-particularly right sided patient, commonly called pedal edema . The failure, corpulmonale) patient usually complains of swollen legs, • Hepatic (cirrhosis of the liver) swelling of ankles towards evening around the • Renal (nephrotic syndrome, i.e. NS; acute top of the boot, weight gain, enlarged abdominal glomerulonephritis; chronic renal failure) girth, and puffiness of the face, particularly in • Venous disease (deep venous thrombosis, i.e. the morning. DVT; superficial venous insufficiency: Although a variety of clinical conditions, varicosity, postsaphenous vain harvest) ranging from benign, e.g. dependent edema, to • Drugs (calcium channel blockers) • Endocrine (myxedema) * Pleura, peritoneum, pericardium, etc. referred to as ‘third • Infection (cellulitis) spaces’. • Parasitic (lymphatic filariasis) †At least 15% increase in body weight is necessary to demonstrate pitting edema. • Idiopathic edema (i.e. cyclical edema in ‡Presacral edema appears in bed-bound patients. women: vide infra ↓↓) 270

• Premenstrual syndrome • Microscopically—Urine sediment may show • Pregnancy (normal, preeclampsia) fat-body casts in NS. • Armchair legs (prolonged legs dependency). Serum Protein (Total) Occasional • Cardiac (chronic constrictive pericarditis, • Decreased in cirrhosis, NS, malnutrition, tricuspid valvular disease) malabsorption, and neoplasms. • Venous/lymphatic obstruction (i.e. secondary Lipid Profile3 lymphedema, e.g. due to abdominal or pelvic mass, tumor, lymph node resection, irra- • Hyperlipidemia in NS, which typically diation) includes: • Lipedema  Increase in lipoprotein (a), LDL, VLDL, • Pretibial myxedema (Graves’ disease) and/or IDL fractions. • Rebound edema (sudden stoppage of diu-  No change or decrease in HDL. retics/diuretic abuse)  Increase in LDL: HDL cholesterol ratio. • Chronic laxative abuse (hypokalemic edema)  Increase in triglyceride levels. • Malnutrition/malabsorption • Hypercoagulability state (vide infra ↓↓: LFT antiphospholipid syndrome, i.e. APS).1, 2 • An elevated serum bilirubin level; abnormal Rare transaminases, and alkaline phosphatase; and reduced albumin level are common • Popliteal cyst rupture with hepatocellular and cirrhosis of the liver. • Gastrocnemius muscle rupture • Retroperitoneal fibrosis TFTs • Congenital (i.e. primary lymphedema, e.g. Milroy’s disease). • Abnormal TSH values can point to either hypothyroidism or hyperthyroidism. INVESTIGATIONS—GENERAL ECG CBC • For evidence of LVH, hypokalemia. • Iron deficiency anemia, megaloblastic anemia may be seen in nutritional deficiency diseases. INVESTIGATIONS—SPECIFIC • Leukocytosis in cellulitis, thrombophlebitis, DVT. Duplex US (Compression US) with Doppler • It is the preferred first line investigation for Urinalysis the evaluation of patients with superficial • Mild-to-moderate proteinuria (under 3.5 g/ and deep venous thrombophlebitis and day). venous insufficiency. It is easy to perform, less • Hematuria, RBC casts in acute glomerulo- expensive than most high-tech studies, can nephritis. be performed as a portable examination, and • Heavy proteinuria (> 3.5 g/day) is most often with proper attention to technique, sensitivity 4, 5 associated with NS. of this test is approximately 97%. Swelling of the Legs 271

D-dimer Test erythrocytic aggregation would appear to be of value in patients presenting recurrent with • A positive plasma D-dimer test, in association arterial or venous thromboembolic events. with Duplex US of lower limbs and HRCT of lungs favor DVT and PE respectively.6 Biopsy Brain Natriuretic Peptide (BNP) • Renal biopsy in glomerulonephritis and NS. • CT guided biopsy to confirm retroperitoneal • Helpful to rule out CHF in patients with fibrosis. dyspnea. Magnetic Resonance Venography § (MRV) CLINICAL NOTES • 3D-gadolinium-enhanced test may be • The initial clinical approach is to distinguish recommended in patients in whom DVT of between unilateral and bilateral pedal lower extremity (or occlusion of the large edema (Table 39.1). systemic veins, e.g. occlusion of the superior Table 39.1: Causes and localization of vena cava) is strongly suspected but US is swelling of the legs equivocal. The positive diagnosis and extent Unilateral Bilateral of DVT can be easily detected and monitored 7, 8 • DVT • CHF by this noninvasive MRV technique. • Chronic venous • Cirrhosis of the liver insufficiency US/CT Abdomen/Pelvis • Cellulitis / abscess • Nephrotic syndrome • To detect secondary pressure effects from • Lymphedema— • Acute glomerulonephritis secondary causes abdominal/pelvic mass, including ascites • Arthritis • Chronic renal failure • CT/MRI of the abdomen is preferred to • Trauma • Hypoproteinemia • Compartment • Bilateral DVT diagnose retroperitoneal fibrosis (as a cause syndrome (chronic) of venous thrombosis, or DVT). • Ruptured Baker cyst • Chronic venous insufficiency Echocardiogram • Ruptured • Drugs gastrocnemius muscle • To evaluate for thromboembolic etiology in • Erythema nodosum • Lymphedema—secondary CHF and valvular heart disease causes • An echocardiogram is recommended in • Kaposi’s sarcoma • Lipedema • Neoplasm • Idiopathic edema (cyclical) patients who are at risk for pulmonary • Lymphedema—primary • Pregnancy hypertension, and in patients over age 45 • Lymphedema praecox • Armchair legs with leg edema of unclear etiology. • Congenital venous • Constricting garments malformation

9 Serology for Hypercoagulability State • Duration—Acute onset (usually <72 hours) • Plasma homocysteine level, lupus anti- is common with thrombophlebitis, DVT, coagulant, anticardiolipin antibodies, anti-beta cellulitis, ruptured popliteal cyst, etc. 2 glycoprotein 1 antibodies, and a study of the Gradual onset is common with systemic cardiac, hepatic, and renal disorders; chronic venous insufficiency, lymphatic and venous § The standard investigation contrast venography is now replaced by Duplex US; the former is in most cases; they obstruction, etc. Intermittent edema is a are expensive, invasive, and associated with a small but common feature of idiopathic (cyclical) real incidence of phlebitis. edema that is common in obese women. 272

• Is the pedal edema pitting or non-pitting, i.e. the day progresses, then venous insufficiency solid? (Table 39.2). is most likely. Table 39.2: Common examples of pitting vs • A common but under-recognized cause of leg nonpitting edema edema is pulmonary hypertension, which Pitting edema Nonpitting is often associated with sleep apnea. Findings • CHF • Myxedema (deposition that may increase suspicion of sleep apnea of mucinous material) include loud snoring or apnea noted by the • Cirrhosis of the liver • Parasitic, e.g. filariasis sleep partner, daytime somnolence, or a neck • NS • Allergic, e.g. angio- circumference >17 inches. • Hypoproteinemia with neurotic edema • Is the patient taking any drugs that could severe anemia, e.g. • Postoperative, e.g. protein-losing excision of malignant cause the edema? Among the drugs that enteropathy, starvation, regional lymph nodes should be considered are corticosteroids; nutritional edema. hormones—progesterone, estrogen, andro- • Pericardial effusion • Neoplastic, e.g. lymphatic • Constrictive pericarditis blockage by malignant- gens; NSAIDs; antihypertensive drugs— tissue calcium channel blockers, vasodilators, beta- • Drugs, e.g. calcium • Post-thrombotic adrenergic blockers; hypoglycemics— channel blockers syndrome pioglitazone, rosiglitazone; antidepressants — • Venous obstruction/ • Idiopathic in women insufficiency • Scleroderma trazodone, and chemotherapeutic agents. • Beriberi (epidemic • Congenital, e.g. Milroy’s • Morning and evening chart of patient’s dropsy) disease weight—Patients should weigh themselves nude and with an empty bladder before food • Is it lipedema or lymphedema? Lipedema (a form or fluids in the morning and at bedtime. A of fat maldistribution with sparing of feet) mean weight gain >1 kg is consistent with exclusively affects women and is a bilateral idiopathic edema.10 and symmetrical deposition of fat in the lower extremities, without involving the feet; • Physical examination—Lower limbs should whereas in lymphedema the swelling starts be examined in the erect and recumbent in the most distal part of the foot(marked positions for dilated superficial veins and foot and toe involvement); this differentiates perforators. the two conditions. • Homans’ sign, if positive (pain on dorsiflexion • History of recent limb immobilization or of the ankle), indicates DVT. confinement to bed following surgery, • Signs of systemic illness associated with pregnancy, or history of cancer favors the swelling of the legs include—Periorbital edema, diagnosis of DVT. jaundice, spider angioma, peau d’orange skin, • Associated symptoms—Dyspnea on exertion, gynecomastia, ascites, hepatomegaly, cardio- orthopnea, or paroxysmal nocturnal dyspnea megaly, distended neck veins, gallop rhythm, suggests heart failure as the cause of leg tachycardia, lung crepitations, hypertension, edema. Jaundice, palmar erythema, spider and lymphatic obstruction. angiomata, and hepatomegaly suggests cirrhosis of the liver. Generalized edema and RED FLAGS swelling of the eyelids (peri-orbital) is typical with NS. If the leg swelling is absent • Patients with unexplained acute lower limb or minimal after recumbency but develops as swelling should have duplex sonography Swelling of the Legs 273

done since DVT is difficult to exclude on Table 39.3: Causes of hypercoagulability clinical grounds. • Any painless unilateral leg swelling in Acquired • Antiphospholipid syndrome (APS) women over age 40 years needs detail • Hyperhomocysteinemia investigations to exclude intraabdominal • Inflammatory disorders: Ulcerative colitis lymphatic and venous obstruction, especially • Heparin-induced thrombocytopenia • Myeloproliferative disorders compressing gynecologic malignancy. • Estrogens: Contraceptive pills, hormone replacement • Bilateral leg edema, in the absence of signs of therapy CHF, and without lung disease, may be a Inherited useful marker for underlying pulmonary • Activated protein C resistance (factor V hypertension and obstructive sleep apnea, Leiden) 11, 12 • Protein C deficiency especially in obese patients. • Protein S deficiency • Pedal edema in patients with unexplained • Dysplasminogenemia thrombosis is known to occur due to combined • Abnormal plasminogen ** • Antithrombin deficiency thrombotic lesions of peripheral veins as well • Prothrombin 20210A allele as the arteries such as in hypercoagulability • Elevated factor VIII state, e.g. lupus, APS, occult malignancy, etc. Risk Factors It is of major importance to make this • Disseminates intravascular coagulation diagnosis so that patients can be treated with • Connective tissue disorders • Malignancy the most effective therapy for secondary • Liver disease prevention. • Pregnancy • Bed rest SELECTIVE GLOSSARY • Surgery • Trauma Hypercoagulable states—It can be defined as a group of inherited and/or acquired molecular a positive family history. Clinical suspicions occur defects that are associated with a predisposition to when patients are seen with unexpected venous venous thrombotic events (including upper- and thromboembolic disease, recurrent thrombosis, lower-extremity DVT with or without PE, cerebral or thrombosis at unusual sites, such as the brain, vein thrombosis, and intraabdominal venous portal vein, or hepatic vein. In addition, this entity thromboses); arterial thrombosis (including should be considered in cases of unanticipated myocardial infarction, stroke, acute limb ischemia, arterial occlusive disease of the central nervous and splanchnic ischemia); or both. Although most system, extremities, mesenteric vessels, or cardiac inherited conditions appear to increase solely the risk tree. of venous thromboembolic events, some of the 13 acquired conditions have been associated with both Antiphospholipid syndrome (APS) —It is venous and arterial thrombosis (Table 39.3). The probably the most common of the hyper- best clue for the presence of hypercoagulability is coagulable disorders, which has received considerable attention from the medical community because of its association with a ** Venous thrombosis occurs mostly in the lower limbs, number of serious clinical disorders, including with or without pulmonary embolism, and cerebral ischemia and transient ischemic attacks, followed by arterial and venous thromboembolism, acute coronary ischemia are the most common arterial events. ischemic encephalopathy, recurrent pregnancy 274 loss, thrombocytopenia, and livedo reticularis. thyroid disorders. In addition, exaggerated It can occur within the context of several postural abnormalities, psychological or diseases, mainly autoimmune disorders, and is emotional disturbance, eating disorders, and then called secondary APS. However, it may also abuse of diuretic or laxative are also associated be present without any recognizable disease, with the onset of edema. It may also be or so-called primary APS. The syndrome occurs associated with discomfort in the areas of fluid most commonly in young to middle-aged adults; accumulation (including symptoms of the however, it also can occur in children and the carpal tunnel syndrome, nonarticular rheuma- elderly. This syndrome is the most common tism, and headaches, sometimes with pseudo- cause of acquired thrombophilia, associated tumor cerebri). Key features are periodic with either venous or arterial thrombosis or episodes of edema in women who have weight both. It is characterized by the presence of changes not clearly related to the menstrual antiphospholipid antibodies, recurrent arterial cycle. The diagnosis is usually one of exclusion. and venous thrombosis, and spontaneous abortion. Patients are often asymptomatic until REFERENCES suffering from thrombotic events of this 1. Triplett DA. Antiphospholipid antibodies and syndrome such as DVT, pulmonary embolism, thrombosis. A consequence, coincidence, or CVA, myocardial infarction, cardiac valvular cause? Arch Pathol Lab Med. 1993;117(1):78-88. [PMID: 8418768: Abstract]. dysfunction, and skin ulcers. In a rare patient 2. Brick RL. Antiphospholipid thrombosis syndromes. with APS, a potentially devastating syndrome Clin Appl Thromb Hemost. 2001;7(4):241-58. known as catastrophic APS (Asherson’s syndrome) [PMID: 11697705: Abstract]. 3. Kronenberg F. Dyslipidemia and nephrotic occurs, leading to massive venous thrombo- syndrome: Recent advances. J Ren Nutr embolism, thrombotic microangiopathy, and 2005;15(2):195-203. [PMID: 15827892: Abstract]. multiple organ failure. According to the 4. Andrews EJ Jr, et al. Sonography for deep venous thrombosis: Current and future applications. International Consensus statement, at least one Ultrasound Q. 2005;21(4):213-25. [PMID: clinical criterion (vascular thrombosis, 16344726: Abstract]. pregnancy complications) and one laboratory 5. Labropoulos N, et al. Thrombosis in unusual sites of the lower extremity veins. J Vasc Surg criterion (lupus antioagulant, antipcardiolipin 2008;47(5):1022-7. Epub 2008 Mar 21. [PMID: antibodies) should be present for the diagnosis 18358674: Abstract]. of APS. 6. Righini M, et al. D-Dimer for venous thrombo- embolism diagnosis: 20 years later. J Thromb Idiopathic edema14—It includes entities such Haemost 2008;6(7):1059-71. Epub 2008 Jul 1. [PMID: 18419743: Abstract]. as cyclical edema, periodic edema, and fluid 7. Carpenter JP, et al. Magnetic resonance venography retention syndrome. It is an orthostatic edema for the detection of deep venous thrombosis: accompanied by excessive weight gain from Comparison with contrast venography and duplex Doppler ultrasonography. J Vasc Surg morning to evening that primarily affects 1993;18(5):734-41. [PMID: 8230557: Abstract]. premenopausal women, most common in 8. Laissy JP, et al. Assessment of deep venous their third and fourth decades. Although the thrombosis in the lower limbs and pelvis: MR venography versus duplex Doppler sonography. cause is not clear, a number of hormonal AJR Am J Roentgenol 1996;167(4):971-5. [PMID: abnormalities are postulated to be involved. 8819396: Abstract]. These include rennin-angiotensin-aldosterone 9. Tazi Z, et al. Value of an extensive biological study in venous or arterial thromboses. Presse Med 1996; axis, vasopr-essin, atrial natriuretic factor, 25(11):531-6. [PMID: 8731796: Abstract]. dopamine, hypothalamic disorders, and 10. Marks AD. Intermittent fluid retention in women. Swelling of the Legs 275

Is it idiopathic edema? Postgrad Med tive sleep apnea. Arch Intern Med 2000;160 1983;73(6):75-83. [PMID: 6856543: Abstract]. (15):2357-62. [PMID:10927734: Abstract]. 11. Blankfield RP, et al. Bilateral leg edema, pulmonary 13. Gezer S. Antiphospholipid syndrome. Dis Mon hypertension, and obstructive sleep apnea: A 2003;49(12):696-741. [PMID: 14679358: Abstract]. cross-sectional study. J Fam Pract 2002;51(6):561- 14. Streeten DH. Idiopathic edema. Pathogenesis, 4. [PMID:12100781: Abstract]. clinical features, and treatment. Endocrinol Metab 12. Blankfield RP, et al. Bilateral leg edema, Clin North Am 1995;24(3):531-47. [PMID: obesity, pulmonary hypertension, and obstruc- 8575408: Abstract]. CHAPTER 40 Syncope

SYNOPSIS often asymptomatic and no longer remember the event when seen by a physician. Syncope, commonly described as fainting, passing Often the cause of syncope is benign and out, or blackout, is defined as a symptom complex the condition is self-limiting; but, concerns that is composed of a sudden, and transient loss that well-appearing patients may be at risk of consciousness, associated with an inability ‡ for potentially serious disorder (e.g. acute to maintain postural tone, followed by coronary syndrome, malignant dysrhythmia, spontaneous and complete recovery, without aortic dissection, and pulmonary embolism, as * medical intervention. well as neurologic emergencies, such as Syncope is distinct from vertigo, seizures, subarachnoid hemorrhage) often leads to coma, and states of altered consciousness. extensive diagnostic evaluation or hospital Vertigo and dizziness do not result in loss of admission. However, many studies have consciousness or postural tone. Vertigo is also demonstrated low yield of nondirected associated with a sense of motion. Aura, violent diagnostic testing.1, 2 The pivotal role of the muscular spasms, sphincter disturbances, physician, therefore, is to identify those disorientation, and gradual return to conscious- relatively few patients with life-threatening † ness suggest a seizure. processes, and the majority with benign Evaluation of a patient with syncope is often disorders needing risk stratification§, which will problematic because episode usually occurs help device an optimum evaluation and outside hospital, and accurate historical management plan for each patient. information (usually by an observer) is often lacking or conflicting. Moreover, patients are ‡ It is said that, ‘unless proved otherwise, syncope should be considered as an aborted second death’. § Risk factors for adverse outcomes include: age >45 years, * i.e - ‘without any neurologic deficit and without using structural heart disease, history of CAD, CHF, coexisting any electrical or chemical cardioversion’. other systemic disease, ECG with non-sinus rhythm, family † Ref. Chapter 10: Convulsions, p. 63; and Chapter 47: history of sudden death, and younger individual with Vertigo, p. 323 for details. exertional syncope. 277

DIFFERENTIAL DIAGNOSIS during syncope (if faceable) is very helpful for any evidence of arrhythmia. (Table 40.1). Common A normal ECG in a patient with syncope may • Vasovagal (common faint) indicate good prognosis. • Situational syncope (cough, micturition, Table 40.1: ECG abnormalities in patients with Syncope defecation) • Evidence of ischemia/infarction (recent or old) • Postural hypotension (medications: Alpha • LVH (hypertension, aortic stenosis, HOCM) blockers, nitrates, diuretics; diabetic autonomic • RVH (PE or pulmonary hypertension) • Bradyarrhythmias or tachyarrhythmias neuropathy, pronged bed rest; varicose veins) • LBBB or bifascicular block (conducting system • Hypoglycemia (insulin, OHAs) disease) • Signs of pericarditis or electrical alternans (cardiac • Coronary artery disease (MI). tamponade) • Classical/nonspecific ECG signs of PE Occasional • WPW syndrome • Cardiac arrhythmia (heart block; Stokes- • Long QT interval • Brugada syndrome (partial RBBB with elevated ST Adams-Morgagni syndrome: vide infra ↓↓; segments in leads V1-3 and peculiar downsloping WPW syndrome: vide infra ↓↓; sick sinus of the elevated ST segments + inverted T waves in ↓↓ those leads) syndrome: vide infra ; SVT; VT; Torsade de • Arrhythmogenic right ventricular dysplasia (RBBB, pointes: vide infra ↓↓; drug induced long QT QRS complex > 110 msec in leads V 1-3, inverted T syndrome, e.g. amiodarone, cisapride, wave or epsilon wave. erythromycin, gatifloxacin, thioridazine) • Structural heart disease (aortic stenosis, Blood Glucose HOCM, pulmonary stenosis) • Functional hypoglycemia may cause syncope • Cerebrovascular (TIA, stroke) in susceptible individuals under stress. Drug • Neurological (atypical absence/atonic induced hypoglycemia is common in diabetics ↓↓ seizures, basilar migraine: vide infra ) on insulin or oral hypoglycemic agents (OHA), • Circulatory failure (shock, hemorrhage). which are often responsible for syncopal Rare episodes. • Cardiac arrhythmia (Long QT syndrome: CBC Congenital or drug induced) • Low Hb% (due to chronic blood loss, e.g. GI • Psychogenic (anxiety, hyperventilation, bleeding). hysterical) • Pulmonary hypertension Urea, Creatinine, Electrolytes • Pulmonary embolism • To assess hydration status; hypokalemia, • Carotid sinus hypersensitivity hyponatremia due to diuretic use; hypo- • Pacemaker syndrome kalemia or hyperkalemia can precipitate • Prosthetic heart valve dysfunction. arrhythmias.

INVESTIGATIONS—GENERAL INVESTIGATIONS—SPECIFIC ECG CXR

• A 12-lead ECG should be ordered for all • Evaluation of a select number of etiologies of patients with syncope. A rhythm strip syncope may be aided by CXR. Pneumonia, 278 Diagnosis: A Symptom-based Approach in Internal Medicine

CHF, lung mass, effusion, and widened CT/MRI Brain mediastinum can all be seen if present, and • Useful in patients with evidence of seizure, may guide therapy stroke disorder, new neurologic deficits, or • In elderly patients and in patients who are in patients with head trauma secondary to debilitated, pneumonia may precipitate syncope. syncope; pneumonia may occur in the absence of symptoms and signs in this class of patients. Head-up Tilt-Testing

Cardiac Enzymes • Indicated especially in patients with recurrent or severe disorder of syncope as • Indicated in patients in whom syncope due well as for high-risk patients (i.e. those at to cardiac origin is highly suspected, and those risk for injury if they faint). Hemodynamic who give a history of chest pain with syncope, response such as heart rate, blood pressure dyspnea with syncope, or exertional syncope. response, and ECG evidence for asystole associated with syncope are monitored. The Stress ECG test is used when cardiac causes of syncope • Indicated in patients with history of cardiac have been reasonably excluded. syncope, or cardiac risk factors are suggestive Electrophysiology Study (EPS) of IHD. • An invasive procedure; may be indicated in Echocardiography patients with abnormal ECG reveling conduction abnormalities or arrhythmias; • Advised in syncopal patients who have an also in patients with recurrent unexplained evidence of CHF, structural cardiac disorder syncope, with or without structural heart (congenital or acquired), prosthetic valvular disease, and with negative results on tilt- dysfunction, cardiomyopathy, cardiac tumors, table testing. pulmonary hypertension, or abnormal ECG findings. Evaluation of left ventricular function Implantable Loop Recorder (ILR) and ejection fraction is useful in the management of such patients. • These gadgets have up to two years worth of ECG recording capability and storage of Holter Monitor cardiac rhythm. The device is programmed to store in memory cardiac rhythm after • Ambulatory Holter monitoring for 48 to 72 automatic or patient triggered activation, hours may be useful in patients with which provides high degree of ‘symptom-ecg’ episodic syncope potentially associated with correlation. This procedure is indicated only cardiac arrhythmias or silent ischemia. in patients with chronic unexplained syncope or in whom tilt-table test is negative. Carotid Doppler US Electroencephalography (EEG) • Indicated if clinically there is evidence of carotid bruit or history suggestive of • Indicated in selective patients in whom vertebrobasilar insufficiency (diplopia, seizure is suspected or complicates syncopal hemiparesis). attacks. Syncope 279

Psychiatric Evaluation Table 40.2: Red Flag symptoms in syncopal patients Symptoms Causes • Indicated in patients with major depression, generalized anxiety disorder, panic, and • Chest pain, with or • Myocardial ischemia or without palpitations or infarctions, aortic dissec- substance abuse disorders. dyspnea; symptoms may tions, dysrhythmias, or be present as a presyn- pacemaker malfunction CLINICAL NOTES copal prodrome, follow- ing syncope, or both • History is crucial to establish whether the • Dyspnea • CHF, pulmonary embolism, tension patient did have an episode of transient loss of pneumothorax consciousness, and under what circumstances • Severe headache or • TIA, stroke, subarachnoid it occurred, e.g. prolonged standing, hearing new neurological deficits, hemorrhage, trauma bad news, physical exercise, micturition, etc with prodromal symptoms such as vertigo, • An eyewitness to the event can help determine dysarthria, diplopia, if seizure activity such as tonic-clonic muscle and ataxia spasms, sphincter incontinence, or confusion • Abdominal or back pain • GI acute bleeding, e.g. after the spell was present. Presence of features ruptured abdominal aortic aneurysm; or in the such as aura, abrupt loss of consciousness, pregnant patient, an ectopic sensory hallucinations, Déjà vu/jamais vu pregnancy or placental experiences, confusional states, motor abruption. automatism, prolonged amnesia, and history • Strenuous exertion just • Cardiac outflow before syncope, especi- obstruction due to aortic of alcohol withdrawal, and head trauma ally in young athletes stenosis, HOCM, mitral favor seizure attacks with a cardiac murmur stenosis, pulmonary stenosis, pulmonary • Specific red flag symptoms such as chest pain, embolus, left atrial dyspnea, headache, and abdominal pain myxoma, or pericardial associated with syncopal event should raise tamponade. concern about life-threatening causes, (Table 40.2); these should be excluded initially as of CAD, arrhythmia, vasomotor instability, they require immediate diagnostic evaluation, autonomic failure, polyneuropathy, and the use treatment, or hospital admission of polypharmacy—all of which can contribute • Other associated symptoms and clinical features to syncope. Besides, elder persons can present (e.g. cardiac, neurologic, abdominal, or with atypical symptoms complicating syncope respiratory) may facilitate diagnosis of an such as unexplained falls or lapses in memory. underlying disorder such as acute coronary Therefore, advanced age is an independent risk syndrome (ACS), seizure, GI hemorrhage, ectopic factor for syncope pregnancy, or pulmonary embolism (Table 40.3) • Vasovagal syncope is the most common type of • Age—Noncardiac causes tend to be more syncope, often initiated by a stressful, painful, common in young adults, while cardiac or catastrophic experience. Premonitory syncope becomes increasingly more frequent symptoms such as nausea, sweating, pallor, with advancing age. Syncopal episodes in palpitation, and a ‘sense of doom’ are usual elderly patients are difficult to evaluate due to • Situational syncope, e.g. on prolonged standing multiple coexisting illness, medications, and (postural syncope), while urinating (micturition physiological impairment as a result of aging. syncope), on coughing (tussive syncope) are also Advancing age heralds an increased frequency common, especially in the elderly 280 Diagnosis: A Symptom-based Approach in Internal Medicine

• In patients with no known structural heart Table 40.3: Clinical features suggestive of specific syncopal etiology disease, a family history of unexplained cardiac death increases the likelihood of Symptoms or findings Tentative diagnosis HOCM or congenital long QT syndrome Episode occurs on Vasovagal syncope prolonged standing • Carotid sinus syncope typically occurs in Immediately on standing Orthostatic hypotension relationship to head and neck movements, (any cause) shaving, or wearing of tight collars around After cough, micturition, Situational syncope the neck (carotid sinus hypersensitivity) defecation, swallowing, • Effort (postexertional) syncope typically laughing occurs in patients with aortic stenosis, Prodromal symptoms Vasovagal syncope of nausea, sweating, hypertrophic cardiomyopathy, pulmonary lightheadedness, blurred hypertension, mitral stenosis, or CAD vision, preceding pain, fever, unpleasant event • Cardiogenic syncope due to arrhythmia is Lacerated tongue, Seizure often sudden in onset with loss of jerking limbs, confusion, consciousness regardless of patient’s posture; no memory of episode, chest pain may also occur if the patient has sense of déjà or jamais vu IHD or aortic stenosis Sudden, transient loss Arrhythmia of consciousness without • Syncope associated with brainstem dys- prodrome, underlying function symptoms such as diplopia, ataxia, heart disease, palpitation or vertigo are features of TIA involving Syncope on exertion CAD, HOCM, mitral vertebrobasilar system stenosis, pulmonary hypertension • A comprehensive drug history is important Syncope on head turning Carotid sinus in assessing whether medications have or pressure on the hypersensitivity contributed to syncopal episode. Drugs carotid sinus commonly implicated in syncope include the Associated with headaches Migraine, seizure following: Associated vertigo, TIA  dysarthria, diplopia Antihypertensive drugs  Dizziness/ syncope and Atrial myxoma Vasodilators—nitrates murmur with changing (left sided) or  Beta-blockers, digitalis, antiarrhythmics position (from sitting to thrombus:vide infra ↓↓  Tricyclic antidepressants, phenothia- lying, bending, turning over in bed) zine, quinidine, amiodarone (long QT Medication (QT-drugs) Long QT syndrome syndrome) Frequent syncope, somatic Psychogenic disorder  Alcohol, cocaine, sedatives symptoms, with negative  Diuretics (electrolyte imbalance) clinical or lab work-up  OHA, insulin. • Physical examination—Especially cardiac • Orthostatic hypotension, i.e. decline in blood examination for heart rate, rhythm (arrhy- pressure greater than 20 mm Hg systolic, or thmia); blood pressure (postural hypo- diastolic greater than 10 mm Hg, or both, tension, hypertension); carotid bruit (TIA); immediately upon rising from supine to presence of S4 gallop, and crescendo- standing position is a common cause of decrescendo murmur (aortic stenosis); late syncope, especially in the elderly, in diabetics, systolic murmur and nonejection click or those with autonomic neuropathy which changes in quality and radiation Syncope 281

(mitral valve prolapse); and pericardial rub SELECTIVE GLOSSARY (cardiac tamponade) are important Adams-Stokes attacks—The term refers to a brief • The patient should have a detailed neurologic episode of cardiac arrest due to either asystole or examination, including baseline mental status, ventricular fibrillation. This characteristi-cally evaluation for cranial nerve deficits, motor occurs in patients with heart block in whom deficits, deep tendon reflex lateralization, and sensory deficits either the ventricular pacemaker suddenly fails, • If the cause of the syncope is not readily or in whom ventricular arrhythmias are apparent after initial clinical evaluation, superimposed on the heart block. Prior to an then a decision has to be made whether attack, patient may become pale; heart rhythm certain categories of ‘syncope–prone– experiences a temporary pause, and collapse may patients’ require admission to hospital. follow. Normal periods of unconsciousness last Examples of such subset of patients approximately thirty seconds; but if the attack warranting hospitalization include: is prolonged, convulsions may occur. The return  Elderly patients >60 years with no of consciousness is accompanied by flushing as apparent cause of the syncope blood flows once more through vessels dilated  Sudden syncope occurring in a non-erect by hypoxia. patient with no premonitory symptoms Atrial myxomas—These are the most common or prodrome primary heart tumors, originating from the fossa  Sudden syncope occurring during exertion ovalis region of the atrial septum, usually  Sudden syncope in a patient with a family occupying the left atrium. About 90% are solitary history of syncope or sudden death and occur sporadically. Approximately 10% are  Patient has overt evidence of structural familial, transmitted in an autosomal dominant heart disease by history or examination mode and can be part of several syndromes such  Patient has an abnormal ECG. as Carney syndrome (vide infra ↓↓). Multiple RED FLAGS tumors occur in approximately 50% of familial cases and are more frequently located in the • Occasionally, syncope may be confused with ventricle. Most myxomas are pedunculated with atonic seizure (i.e. ‘drop attack’, with sudden variable composition—from dense fibrous tissue loss of postural muscle tone, consciousness with or without calcification to friable briefly impaired, patient may collapse); EEG myxomatous tissue with propensity for is indicated for differentiation peripheral embolization. The mobility of the • Carotid sinus massage (to terminate tach- tumor depends upon the extent of its attachment ycardias) should be attempted only under to the interatrial septum and the length of the closely monitored conditions (with stalk. Symptoms are produced by mechanical resuscitative equipment stand-by to manage interference with cardiac function or the rare episode of asystole). It should not be embolization, and range from nonspecific and attempted in patients if carotid bruit is constitutional to sudden cardiac death. Clinical present or with h/o recent stroke, TIA, or MI features include positional syncope, i. e. dizziness • Patients with recurrent syncope of undeter- occurs as the patient changes position; dyspnea, mined etiology (so called malignant vasovagal pedal edema (CHF); TIA, stroke, seizures syncope3): who have no prodrome are at risk (cerebrovascular embolization); or features of for injury to themselves or to others. collagen vascular disease. In about 20% of cases, 282 Diagnosis: A Symptom-based Approach in Internal Medicine myxoma may be asymptomatic and discovered brady syndrome. It consists of a broad range of as an incidental finding. Signs and symptoms of electro-physiological abnormalities, including mitral stenosis, endocarditis, mitral inappro-priate sinus bradycardia, sinus arrest, regurgitation, and collagen vascular disease can sinus node exit block, chronic atrial fibrillation, simulate those of atrial myxoma. A high index of and bradycardia-tachycardia syndrome. The suspicion aids in the diagnosis. Although disease is commonly observed in older patients transesophageal echocar-diography is more with a history of concomitant heart disease, but sensitive, 2-dimensional echocardiography is may also be observed in any age group, usually adequate for diagnosis. including adolescents and children. Its clinical Basilar Migraine (BM)—Described by Bickerstaff manifestations vary widely. In the early stages in 1961, BM is a rare variant of migraine which of SSS, most patients are asymptomatic. As the frequently affects young women and girls, disease advances, however, patients often seek consists of headache accompanied by dizziness, medical attention for bradycardia-related ataxia, tinnitus, decreased hearing, nausea and symptoms. Syncope, near-syncope, and vomiting, dysarthria, diplopia, loss of balance, dizziness are the most frequently reported bilateral paresthesias or paresis, altered complaints, followed by palpitations, angina, consciousness, syncope, and sometimes loss of or shortness of breath. Thromboembolic consciousness. Localized vertebrobasilar vaso- complications are a frequent cause of morbidity constriction leading to transient posterior and mortality. Sudden cardiac death is possible at any point during the disease. Pacemaker circulation ischemia may contribute to the placement is the cornerstone of treatment for symptomatology of the disorder. Complications symptomatic SSS. of basilar migraines include remote possibility of a basilar artery infarction. Torsade de Pointes—A malignant form of polymorphic ventricular tachycardia that is Carney Syndrome—Carney first described an characterized by heart rate between 200 and autosomal dominant multiple neoplasia 250 beats per minute, and QRS complexes with syndrome featuring cardiac, endocrine, changing amplitude and twisting of the points cutaneous, and neural tumors, as well as a (‘turning of the points ‘). The term also describes variety of pigmented lesions of the skin and the syndrome of tachycardia with prolonged mucosae, which includes myxomas in breast, ventricular repolarization, long QT intervals skin, thyroid gland, or neural tissue; potty exceeding 500 milliseconds or bradycardia. pigmentation of skin and mucous membranes Torsades de pointes may be self-limited or may such as lentigines (i.e. flat brown discoloration progress to ventricular fibrillation. The patient of skin), pigmented nevi, or both; and endocrine usually has syncopal attacks without premo- overactivity such as Cushing syndrome. This nition that lasts few seconds or seizures. It is syndrome belongs to a group of genetic commonly due to electrolyte imbalance or long disorders, the lentiginoses, which include Peutz- QT drugs. There may also be history of conge- Jeghers, LEOPARD, and Laugier-Hunziker nital deafness or family history of sudden death. syndromes. The most serious manifestation of the Carney complex is cardiac myxomas. Wolff-Parkinson-White (WPW) syndrome— WPW (preexcitation) syndrome is the most Sick Sinus Syndrome (SSS)—It is also known common accessory pathway SVT. WPW is as Sinus Node Dysfunction (SND), or tachy- mainly idiopathic or congenital, although it is Syncope 283 more common among patients with hyper- conduct in an antegrade direction; consequently, trophic or other forms of cardiomyopathy, the above ECG abnormalities do not appear. transposition of the great vessels, or Epstein’s However, it conducts in a retrograde direction and anomaly. In classic (or manifest) WPW thus can participate in reentrant tachycardia. syndrome, antegrade conduction occurs over Symptoms of WPW syndrome may include both the accessory pathway and the normal palpitations, chest pain, dizziness, dyspnea, or conducting system during sinus rhythm. The rarely sudden death. accessory pathway, being faster, depolarizes some of the ventricle early, resulting in a short PR REFERENCES interval and a slurred upstroke to the QRS 1. American College of Emergency Physicians complex (delta wave). The delta wave prolongs Issues Guidelines for Treatment of Syncope. Ann QRS duration to >0.1 sec, although the overall Emerg Med. 2007;49:431-444; and Barclay L. Medscape News. April 30, 2007. configuration, apart from the delta wave, may 2. Brignole M, et al. Guidelines on management appear normal. Depending on the orientation of (diagnosis and treatment) of syncope-update 2004. the delta wave, a pseudoinfarction pattern Q-wave Executive Summary. Eur heart J. 2004;25 (22):2054-72. [PMID: 15541843]. Web site: http:/ may be present. Because the early depolarized /eurheartj.oxfordjournals.org/cgi/content/full/25/ parts of the ventricle also repolarize early, the T- 22/2054. Accessed on 26-12-08. 3. Khan Gabriel M. Heart Disease Diagnosis and wave vector may be abnormal. In concealed WPW Therapy-A Practical Approach. Chap.15 Syncope, syndrome, the accessory pathway does not p. 473. 2nd ed. Humana Press. CHAPTER 41 Tingling and Numbness

SYNOPSIS segmental demyelination (e.g. Guillain-Barré syndrome); compression (e.g. carpel tunnel Abnormal cutaneous sensations such as tingling, syndrome); infarction (e.g. vasculitis); and numbness, pricking, shooting, cutting, stabbing, infiltration (e.g. malignancy). aching, burning, constricting, band-like, shock- These mechanisms lead to various sensory like, etc. are caused by altered sensory nerve symptoms and signs (as noted above) resulting function. Such sensations which are perceived from lesions at almost any level of the nervous by an individual (i.e. subjective), without an system, including cortex (e.g. stroke syndromes), apparent stimulus, excepting pain, are called thalamus (e.g. Dejerine-Roussy syndrome), paresthesias. Dysesthesias denotes all types of brainstem (e.g. lateral medullary syndrome, i.e. abnormal or unpleasant sensations, even painful Wallenberg’s syndrome), spinal cord (e.g. ones, whether a stimulus is present or not. Brown-Séquard syndrome, syringomyelia), While paresthesias and dysesthesias are nerve roots (radiculopathies, plexopathies), and subjective sensory phenomenon, other abnormal nerve trunks (neuropathies). objective sensory abnormalities found on Peripheral nerve disorders are the most examination include hypoesthesia (decreased common causes of paresthesias and dysesthesias sensation to light touch, pressure, warm or cold affecting a variety of peripheral nerve cells and stimuli), anesthesia (absent sensation to the same fibers, including motor, sensory, and autonomic stimuli plus pinprick), hyperesthesias (exaggerated fibers. These are broadly referred to as peripheral pain perception to touch), and allodynia (the neuropathies (PNs). perception of a nonpainful stimulus as painful, even Most PNs affect both A and C types of nerve excruciating). fibers to some extent. However, a single fiber type This abnormal sensory dysfunction can result may be predominantly affected in some disorders; from six principal mechanisms, namely: Wallerian e.g. C-fibers, i.e. small-fiber neuropathy (SFN), in degeneration (e.g. from trauma or nerve infarction); diabetes mellitus, and alcoholism. As small fibers axonal degeneration, sometimes referred to as dying- subserve pain and autonomic functions, these back phenomenon (e.g. metabolic diseases); neuropathies usually present with pain and 285 temperature loss, painful dysesthesias, autonomic Table 41.1: Upper and lower extremity compression/ dysfunction (anhydrosis, orthostatic hypotension, entrapment neuropathies gastroparesis), or a combination. These patients Upper extremity Lower extremity will have normal motor function and deep tendon • Cervical radiculopathies • Lumbosacral disc reflexes. (C5-C6orC7) syndromes (disc The large fibers, i.e. A fibers are myelinated • Brachial plexus neuritis herniation with nerve root motor fibers. These fibers are responsible for (C5-T1) compression (L4-L5 and • Thoracic outlet syndrome L5-S1) motion control, proprioception and vibration. (C5-T1) • Sciatic nerve syndromes The clinical presentation in patients with large- • Long thoracic nerve (L4-S3) fiber neuropathy (LFN) are impaired vibration, compression (winged • Femoral nerve neuropathy scapula - C5,6) (L2-L3-L4) gait instability, weakness, numbness, small • Median nerve compression • Lateral femoral cutaneous muscle wasting, absent tendon jerks, but (carpal tunnel syndrome- nerve compression C6-T1) (meralgia paresthetica-L2- preservation of most cutaneous sensation. • Ulnar nerve palsy L3) Dysesthesias, if present at all, tend to be tingling (tardy ulnar palsy/claw • Posterior tibial nerve or segmental/band-like. Sensation for touch is hand-C8-T1)) compression • Radial nerve palsy (wrist (tarsal tunnel syndrome-L5- carried by both small and large nerve fibers. drop, Saturday night S2) Although the diverse etiologies can make the palsy, crutch palsy- • Peroneal nerve diagnosis of PNs quite challenging, a systematic (C5-T1) compression (foot drop-L4-S1) approach that classifies PNs on the basis of clinical features, taking into account the mode of • Renal failure onset (i.e. acute or chronic), type of peripheral • Herpes zoster (postherpetic neuralgia) nerve fiber that may be involved (i.e. sensory, • HIV/AIDS. motor, or autonomic), distribution (area of innervation of a nerve or central afferent system), Occasional associated neurologic symptoms and signs; and • Drugs (Table 41.3) aided by specific laboratory evaluation and • Nutritional deficiencies (B1, B12, folic acid) electrodiagnostic (EDx) tools will help in the final • Restless legs syndrome diagnosis of the disorder. • Guillain-Barré syndrome • Cranial nerve neuropathies (Trigeminal DIFFERENTIAL DIAGNOSIS neuralgia, facial palsy) Common • Hypothyroidism • Leprosy • Diabetes mellitus - Type 1, 2; including IGT • Syphilis (tabes dorsalis) • Alcoholism • Sarcoidosis • Upper extremity neuropathies (Tables 41.1 • Lyme disease and 41.2) • Metabolic (hypokalemia, hypocalcemia, • Lower extremity neuropathies (Tables 41.1 ). and 41.2) • Acute stress disorders Rare • Hyperventilation • Vasculitis syndromes (Wegener’s granulo- • Stroke syndromes matosis) 286 Diagnosis: A Symptom-based Approach in Internal Medicine

Table 41.2: Common causes of peripheral neuropathies Table 41.3: Drug induced polyneuropathies by distribution of involvement Antibiotics Distribution Causes Chloramphenicol Chloroquin A - Transient Dapsone upper/lower limbs Normal, neurapraxia Ethambutol Ethionamide B - Upper limbs Isoniazid • Bilateral Linezolid – glove and stocking Peripheral neuropathies Metronidazole – along cervical nerve Cervical radiculopathies Nitrofurantoin roots Brachial nerve neuropathy Lipid-lowering drugs Thoracic outlet syndrome Statins • Unilateral Antiretroviral drugs – peripheral nerve Carpal tunnel syndrome Chemotherapeutics lesions Leprosy Cisplatin Thoracic outlet syndrome Cytarabine Herpes zoster Vinblastine C - Lower limbs Vincristine Cardiovascular • Bilateral Ace-inhibitors – glove and stocking Peripheral neuropathies Amiodarone – more on exertion Spinal (lumbar) canal Hydralazine stenosis Rheumatologic • Unilateral Lumbosacral Allopurinol radiculopathies (infection, Colchicine disc herniation, Gold spondylosis, Miscellaneous tumor) Meralgia Disulfiram paresthetica (lateral Interferon alfa femoral cutaneous Lithium phenytoin neuropathy) Herpes Pyridoxin zoster Statins Thalidomide

• Multiple myeloma INVESTIGATIONS—GENERAL • Hodgkin’s disease (non-Hodgkin’s lymphoma) CBC • Paraneoplastic syndrome • Malignancy • For evidence of iron deficiency anemia, and • Diphtheria macrocytic anemia. • Porphyria • Leukocytosis in infection. • Toxins (organophosphorus compounds, lead, arsenic) ESR • Dejerine-Roussy syndrome (thalamic pain • Elevated in systemic and inflammatory syndrome) processes. • Chronic inflammatory demyelinating poly- radiculoneuropathy (CIDP) Blood Glucose, Urea, Creatinine, Electrolytes • Hereditary (Charcot-Marie-Tooth synd- • As indicated for possible diabetes mellitus rome). or renal disease. 287

CXR pathologic basis of the polyneuropathy • To rule out lung carcinoma and sarcoidosis. when EDx studies cannot conclusively distinguish an axonal from an acquired X-ray segmental demyelinating disorder. • In suspected trauma (e.g. Colles’ fracture) or Lyme Titer peripheral nerve compression as in hematoma, hypothyroidism, acromegaly. • In endemic areas with related Lyme disease manifestations. INVESTIGATIONS—SPECIFIC HIV TSH • In patients with risk factors. • In suspected hypothyroidism.

Rheumatology Screen Serum B12 and Folate Levels • RF factor, ANA to evaluate for connective • In suspected nutritional deficiency or if CBC tissue disease. shows macrocytic/dimorphic anemia. Angiotensin-converting Enzyme Level CSF Analysis • As indicated in sarcoidosis. Urine for Porphobilinogen • May be useful in the diagnosis of inflammatory (e.g. Guillain-Barré synd-rome), infectious (e.g. • In cases suspected with porphyria. Lyme disease, HIV), and a variety of immune- Nerve Conduction Study (NCS) mediated PNs (e.g. vasculitic neuropathies). • NCS predominantly attempts to distinguish the type of PN—axonal from demyelinating Serum Protein Electrophoresis and Immuno- neuropathies. The former are characterized fixation by decreased amplitude and to a lesser extent • For multiple myeloma or osteosclerotic slowing on NCS; the latter show more marked myeloma (as seen in POEMS syndrome). slowing of the nerve conduction velocity. The most common type of axonal PN, a distal, Toxic Screen symmetric, and predominantly sensory type, is called a dying-back neuropathy. • Serum or urine drug / heavy metal screening if toxic neuropathy suspected. CT/MRI • As indicated in stroke; cervical, thoracic, Genetic Test spinal compressive syndromes; thoracic outlet syndrome; multiple sclerosis. • For hereditary neuropathies or inherited • MRI of the brachial plexus may show metabolic disorders affecting nerves; evidence of infiltrating Pancoast lesion. Dejerine-Roussy syndrome, HMSA, type 1 Nerve Biopsy (Charcot-Marie-Tooth disease), etc. • Nerve biopsy, (sural nerve biopsy), may be CLINICAL NOTES used to assist in the diagnosis of some inflammatory, infectious, and metabolic • In normal persons tingling and numbness PNs. Nerve biopsy may help to establish the can occur transiently after sitting or sleeping 288 Diagnosis: A Symptom-based Approach in Internal Medicine

in awkward positions (sleeping with the • The most common causes of PNs are arms above the head or sitting with the legs diabetes and alcoholism. In the absence of tightly crossed). This is due to sustained these two risk factors, obtain additional pressure on the nerve. These paresthesias historical information, including history of causing temporary physiological paralysis trauma (compression/entrapment neuro- but not degeneration, followed by complete pathies), recent viral illness (Guillain-Barré and rapid recovery are called neurapraxia. syndrome), drug and toxin exposure (Table • There are three types of PNs: 41.2), occupation (exposure to industrial  Mononeuropathy—Characterized by a focal agents, pesticides), special diets (nutritional abnormality of a single nerve and usually deficiencies), travel (Lyme disease), and risk results from local nerve trauma or factors for AIDS compression; • History of cancer, collagen vascular disease  Mononeuropathy multiplexes (multifocal (vasculitis), hypothyroidism, and leprosy neuropathy)—Characterized by asymmetric can be associated with PNs abnormalities in more than one nerve • A detailed family history should include trunk, which may occur simultaneously inquiries as to the presence of gait abnormality, or over days to years; and muscular dystrophy, hammer toe, high arches,  PN—Characterized by symmetrical abnor- etc. to rule out inherited disorders such as malities of sensation, motor strength, or Charcot-Marie-Tooth Disease (CMT) both. • Onset—Generally gradual over months to • Symptoms—Depend on the nerves affected; may involve sensory, motor, years as in diabetes, alcoholism, renal failure, and/or autonomic systems. vasculitis, malignancy, etc. Causes of acute  Sensory—Tingling and numbness (pares- onset PNs include trauma, ischemic thesia); burning sensation (dysesthesia); neuropathies, compartment syndromes, decreased sensation (hypoesthesia), loss of Guillain-Barré syndrome, porphyria, and sensation (anesthesia), exaggerated pain Lyme disease perception (hyperesthesia), and stoking- • Distribution (Tables 41.4 and 41.5)—Since glove pattern. sensory nerves innervate particular regions  Motor—Mainly muscular weakness, muscle (dermatome)* of the body, correlating the cramping and fasciculation causing symptoms to areas of its supply is an difficulty with activities of daily living. important method to identify the nerves Distal muscles are affected initially, e.g. involved. For instance, the median nerve weakness of dorsiflexion of the toes is innervates the thumb, the first two fingers, common; diminished ankle reflex is often half of the ring finger, and the part of the hand an early sign. Proximal muscles are to which they connect, i.e. C6-C7 dermatome. involved later, except for inflammatory The ulnar nerve innervates the other half of neuropathies such as PAN and SLE. the ring finger, the little finger, and the  Autonomic—Abnormal (i.e. absent or remainder of the hand, i.e. C8 dermatome. excessive) sweating is an early symptom; postural hypotension, constipation, diarrhea, erectile dysfunction, and urinary *Generally sensory loss does not occur in the entire corresponding dermatome; there is commonly a focus of retention occur only with advanced paresthesias, dysesthesias, etc. within a wider area of autonomic involvement. impaired sensation in that dermatome. Tingling and Numbness 289

Table 41.4: Neuropathies by pattern of involvement • More diffuse involvement of an entire limb Localization Pattern Most likely may be caused by involvement of the diagnoses brachial (C5 to T1) or lumbosacral plexus Mononeuropathy Single nerve, Direct trauma, (L1 to S3). e.g. ulnar nerve, compression, median nerve, entrapment(e.g. • Most often, PNs produce symptoms that are cranial nerve carpal tunnel generalized and relatively symmetric, syndrome, Tic conforming to a distal-to-proximal gradient douloureux) typical of stocking and glove distribution in Multiple Simultaneous Infections, mononeuropathy or sequential granuloma, the hands and feet, e.g. diabetes mellitus (mononeuropathy involvement vasculitis, • Unilateral involvement is seen in contralateral multiplex, of several multiple multifocal nerves, evolving entrapments disease of the brainstem, thalamus, or cortex, neuropathy) over days to (e.g. sarcoidosis) e.g. stroke syndromes years • Multiple sclerosis may cause symptoms in Polyneuropathy Longest nerves Metabolic, drugs, several, widely separated areas first (distal, toxic, hereditary stocking-glove (e.g. diabetes • Physical examination is performed to pattern) mellitus) evaluate for possible systemic processes that Radiculopathy One or more Herniated disk, may be contributing to the neuropathic nerve roots spondylosis, process. Weight loss, fever, skin rash, icterus, herpes zoster lymphadenopathy, arthropathy, organo- Polyradiculo- Proximal and Guillain-Barré neuropathy distal weakness, syndrome, CIDP, megaly are significant signs for possible sometimes paraproteinemias systemic neurologic disorder asymmetrical • Palpable thickened and/or tender peripheral Plexopathy Brachial Trauma nerves along with anesthetic skin patches Idiopathic Neoplasm are typical of leprosy Radiation • Motor examination—Distal muscle groups Lumbosacral Diabetes are affected initially. Loss of muscle power Neoplasm Idiopathic progresses from distal to proximal. Deep Radiation tendon reflxes are diminished or absent • Sensory examination—Which sensory tests Table 41.5: Neuropathies by pattern of involvement (i.e. pain, touch, temperature, and vibration) Focal Multifocal to include in the physical examination • Trauma • Diabetes mellitus depends on the clinical setting • Ischemic lesions • Nutritional deficiencies – Diabetes mellitus • HIV/AIDS • For patients with sensory complaints, testing – Polyarthritis nodosa • Leprosy for all the above four sensory modalities is – Reynolds’s disease • Sarcoidosis necessary to uncover sensory dissociation, i.e. • Entrapment neuropathies • Vasculitis • Compressive – Polyarthritis nodosa preservation of touch and vibration neuropathies sensation, but loss of pain and temperature • Leprosy – Systemic lupus erythematosus sensation, which is an important clue to • Sarcoidosis • Multiple sclerosis incomplete spinal cord diseases such as in • Neoplastic infiltration • Chronic inflammatory syringomyelia, spinal stroke (i.e. infarction demyelinating polyradiculo- of the anterior spinal artery), and Brown- neuropathy (CIDP) Séquard syndrome. 290 Diagnosis: A Symptom-based Approach in Internal Medicine

• For screening diabetic feet and limbs, matosus. Eliciting a full history, though often Semmes-Weinstein monofilament (5.07/10 difficult in this population, is vital for gram) is recommended. The typical accurate diagnosis and treatment. distribution of paresthesia is distal and • Leprosy must always be considered in a patient symmetric, the feet being affected first in a with a combination of skin and neural disorder. stocking distribution followed by the hands • In the case of Guillain-Barré syndrome, the in a glove distribution. intensity of neuropathy may affect the • The presence of Tinel’s sign is useful to localize a muscles of respiration, necessitating the use nerve injury. The Tinel’s sign refers to paresthesias of ventilatory support. elicited by tapping along the course of a nerve. • Paresthesias and dysesthesias involving multiple • Clinically LFNs can be distinguished from cranial nerves palsies and radiculopathies, SFNs during sensory testing—Loss of although similar in presentation to PNs, should vibration and proprioception indicates alert one to the possibility of leptomeningeal LFNs, while loss of pain and temperature metastasis; nerve biopsy is strongly indicated in sensation is due to SFNs. Loss of sensation etiologic diagnosis. for light touch may be due to LBNs or SFNs. • An often dominating arm pain, which mainly • Autonomic examination—Blood pressure radiates into the ulnar region, is a sign of the measurement in supine and standing posture infiltration of the plexus and the C8 and T1 roots. to check for signs of postural hypotension. The possibility of Pancoast lesions, typically • Fundoscopy and examination of cranial caused by apical adenocarcinoma or squamous nerves—It is important to detect optic pallor cell carcinoma of the lung should be considered due to drug toxicity, hereditary demyelinating not only in the presence of brachial plexopathy, diseases, etc. Diabetes mellitus, leprosy, but also when C8 or T1 radiculopathy is found, sarcoidosis, malignant lymphomas, myelomas, usually associated with ipsilateral Horner etc. are known to involve cranial nerves† (V, syndrome, characterized by miosis with a VII, IX, X, and XII) besides causing PNs. pupil that is slow to dilate, a mild (1-2mm) ptosis, ipsilateral anhydrosis and apparent RED FLAGS enophthalmos. • Although human rabies is rare cause of PNs, • Upper extremity paresthesias could be the sole clinicians and public health workers should manifestation of coronary syndrome, especially suspect rabies when a history of possible in individuals with cardiac risk factors. animal contact is known or when unexplained • In older patients, PNs is not an uncommon atypical progressive neuropathy or unusual presentation of many chronic illnesses, febrile encephalitis is observed.1 including neoplasms and inflammatory processes such as systemic lupus erythe- REFERENCE

1. Human Death Associated with Bat Rabies— † With the exception of second cranial nerve. California, 2003 JAMA 2004;291(7):816-7. CHAPTER 42 Tinnitus

SYNOPSIS  Common subtypes include: Otologic, neurologic, infectious , metabolic, drug- Tinnitus is a common disorder with many related, and psychogenic. possible causes. It is defined as any sound or 2. Objective: noise in the ears or head not attributable to an  Also audible to the clinician (with the external sound. It may be ringing, hissing, help of a placed over head humming, and buzzing squealing, clicking, or and neck structures near the patient’s popping noises. ear). Tinnitus may be unilateral or bilateral;  Much less common than subjective transient or continuous. It may be acute—the tinnitus. episode usually lasting for seconds to minutes,  Most common subtype is pulsatile tinnitus*. but may persist for days to weeks; commonly  May indicate treatable underlying due to noise trauma, or drug effect. Chronic medical condition. tinnitus may persist for more than 6 months.  Frequently due to a vascular or neuro- At the outset tinnitus should be differentiated muscular condition: a tumor within the from auditory hallucinations in which a person hears head, neck, or brain; or a structural defect voices, various kinds of music or sounds, which in the ear, usually the inner ear. are generally considered to be a symptom of The evaluation of a patient with tinnitus psychiatric or neurological disorders. includes history, ENT-status examination, Types of tinnitus—There are two categories: audiological and vestibular findings, imaging 1. Subjective:  Audible only to the patient. * Pulsatile tinnitus is the type of ear noise that is perceived  More common form and may have its as a rhythmic pulsing that often synchronizes in time with origin in the external ear, middle ear, the heartbeat. It can be experienced as a thumping sound. It is sometimes referred to as vascular tinnitus because in inner ear, VIIIth nerve, or central nervous the majority of cases, it is related to disturbances in the system. blood flow. 292 investigations and, if necessary, examination by • Psychogenic (anxiety, depression) other specialists. Many medical and nonmedical • Ototoxic drugs (aspirin, NSAIDs, quinine, treatments exist, with varying degrees of success quinolones, loop diuretics, beta blockers, and safety. Once the physician determines that aminoglycosides, antipsychotics, anti- the patient does not have a life-threatening or neoplastics, sedatives, narcotics). obviously treatable underlying condition, the patient should be counseled, reassured that the Physiological tinnitus is not a life-threatening disease, and • Presbycusis(sensorineural hearing loss with offered appropriate treatment. All patients with physiological aging). tinnitus can benefit from patient education and preventive measures, and oftentimes the Occasional physician’s reassurance and assistance with the psychologic aftereffects of tinnitus can be the • Noise induced permanent tinnitus3 (i.e. therapy most valuable to the patient.1,2 NIPT: in factory workers, auto mechanics, airplane workers, rock musicians, military DIFFERENTIAL DIAGNOSIS personnel with frequent exposure to gunfire, and those working around loud engines) Common • Eustachian tube dysfunction These may be considered under three groups, • Head and neck injuries (labyrinthine namely: Otologic, nonotologic, and psychogenic. concussion) • Neoplastic disorders (acoustic neuroma, Otologic glomus jugulare tumor: vide infra ↓↓).

• Cerumen impaction Rare • Foreign body • Ear infection (acute otitis externa; otitis • Severe anemia, leukemia media: acute and chronic; labyrinthitis : • Temporomandibular joint (TMJ) dysfunc- viral, herpes zoster—geniculate ganglion) tion (subluxation, arthritis, ankylosis, • Otosclerosis synovitis) • Ménière’s disease • Atherosclerotic, vascular disorders (carotid • Positional vertigo (BPPV) artery aneurysm, arteriovenous malfor- • Barotrauma/dysbarism.† mation, vascular tumors) • Neurologic (palatomyoclonus, idiopathic Nonotologic stapedial muscle spasm) • CNS diseases (multiple sclerosis) • Migraine syndromes (migraine equivalent, • Autoimmune inner ear disease (Cogan’s acoustic migraine) disease: vide infra ↓↓). • Labile blood pressure (hypertension/ hypotension) INVESTIGATIONS—GENERAL • Diabetes (hypoglycemia) • Thyrotoxicosis CBC, ESR

†Injury following pressure changes; includes injury to • Leukocytosis with infective ear disorders the eustachian tube, ear drum, lung and stomach. may be seen Tinnitus 293

• Severe anemia, including pernicious anemia, sensorineural hearing loss or vestibular is rare causes of pulsatile tinnitus4 disorders of the peripheral type. Most • Polycythemia vera, indicated by markedly neoplasms and anomalies are best seen on elevated Hb% and hematocrit is known to bone algorithm CT studies. cause transient neurological symptoms such as headache, tinnitus, dizziness, blurred MRI Scan vision, and paresthesias • Elevated ESR is usually noted in autoimmune • For patients with nonpulsatile tinnitus, MR vestibulitis and neoplastic conditions. imaging is the study of choice to exclude a vestibular schwannoma or other neoplasm FBG, PPBG of the cerebellopontine angle cistern. For asymmetric hearing loss or unilateral • To detect diabetes. tinnitus, Gadolinium-enhanced MRI of the Audiogram internal auditory canals is indicated to look for an acoustic tumor, and it is the procedure • A complete audiogram with pure tone and speech of choice for evaluating patients with thresholds, speech discrimination, acoustic suspected temporal bone tumors. reflexes, and impedence testing is performed even if the patient is unaware of hearing loss. MRI Cerebral Angiography • A formal audiogram establishes a base from which to pursue more advanced diagnostic • Often indicated if vascular pathology— testing. usually manifested as pulsatile tinnitus, e.g. arteriovenous malformations, vascular Tympanogram anomalies, and aneurysms of the carotid in the ear is suspected. • Tympanometry helps to identify previously undetected middle ear effusions, changes in X-ray tympanic membrane stiffness caused by a patulous eustachian tube, or myoclonus of the • Of the mastoids and petrous bones, and skull stapedial muscle or the muscles of the palate. X-rays if associated with head injury.

INVESTIGATIONS—SPECIFIC CSF

Biochemistry • Helpful in diagnosing multiple sclerosis and • Urea, creatinine, electrolytes, lipids, VDRL, central nervous system syphilis. FTA, ABS—if indicated by history and examination. Brainstem Evoked Potentials • In patients suspected with multiple sclerosis. TFTs

• If thyroid disorders suspected. CLINICAL NOTES • Occasional tinnitus can occur in individuals CT Scan with normal hearing, and most experience • CT may be indicated for the assessment of it in silent surroundings. Phantom noises, patients with conductive hearing loss and that mimic ringing in the ears associated 294 Diagnosis: A Symptom-based Approach in Internal Medicine

with tinnitus, can be experienced by people such as advanced or very young age, renal with normal hearing in quiet situations, or hepatic impairment, pregnancy, or according to a new research.5 history of hearing loss, or excessive and loud • Evaluation of tinnitus includes, besides noise exposure. otoaudiological examination, an evaluation • Ongoing audiologic monitoring for possible of psychosocial wellbeing of the patient, with ototoxicity may be helpful when prolonged special attention to signs of depression.6 use of ototoxic agents is needed. • Is it subjective or objective? (see above) • Continued counseling about the risk of • Objective tinnitus is unusual, but it may indicate hearing loss is warranted if the patient is glomus tumors, arteriovenous malformations, exposed to damaging sounds. carotid stenosis, aneurysms, anemia, a patent • Counselling, preferably including general eustachian tube, or myoclonus. information leaflet, is the cornerstone in the • If it is subjective, is it unilateral or bilateral? management of tinnitus in the vast majority In general, pulsatile tinnitus, unilateral of patients. There is no cure for tinnitus in tinnitus, and tinnitus associated with other the common sense of the word, especially in unilateral otologic symptoms represent chronic cases. Many learn to live with their tinnitus when they are convinced of the non- potentially more serious underlying disease 7 threatening nature of their problem. Patients than bilateral tinnitus. can obtain relief from the symptom with • Episodic tinnitus suggests Ménière’s disease. assistance from clinicians who are familiar Pulsatile tinnitus suggests a vascular origin. with tinnitus management strategies. Auscultation over the neck, periauricular area, orbits, and mastoid should be performed. RED FLAGS Tinnitus of venous origin can be suppressed by compression of the ipsilateral jugular vein. • Tinnitus plus unilateral hearing loss should • Acute tinnitus, which can last days or weeks, increase suspicion for acoustic neuroma. may be caused by ear infection, medications, • The presence of other neurologic signs along head or neck injury, excessive sound with vertigo and deafness would suggest exposure, earwax, and changes in blood multiple sclerosis, advanced acoustic pressure or metabolism. With appropriate neuroma, basilar artery occlusion or evaluation, such underlying conditions insufficiency, brainstem tumors, and central usually can be identified and treated, often nervous system syphilis. with resultant resolution of tinnitus. • The severity of tinnitus varies from • Chronic tinnitus (persistence for 6 months occasional awareness of a noise to an unbearable sound that drives some persons or more) can also result from these conditions 9,10 and is more likely to occur in people who to contemplate suicide. have hearing loss. SELECTIVE GLOSSARY • Concurrent medical conditions to be considered include diabetes, hypertension, Cogan’s syndrome— It is a chronic inflammatory thyroid disorders, hyperlipidemia, infection, disorder that most commonly affects young 8 anemia, B12 or zinc deficiency. adults. Clinical hallmarks are interstitial • Ototoxic drugs should be used with keratitis and vestibuloauditory dysfunction. particular caution in patients who have risk Typical Cogan’s syndrome consists of flares of factors that predispose them to ototoxicity, interstitial keratitis and sudden onset of Ménière- Tinnitus 295 like attacks (nausea, vomiting, tinnitus, and nerve palsy, hypoglossal nerve palsy, or Horner vertigo and hearing loss). Life-threatening aortic syndrome. Because of the insidious onset of insufficiency develops in 10% of reported cases. symptoms, these tumors often go unnoticed, Atypical Cogan’s syndrome (audiovestibular and delay in diagnosis is frequent. Because of dysfunction with other types of inflammatory the location and extent of involvement, glomus eye disease) is associated with vasculitis in 20% jugulare tumors present a significant diagnostic of cases, and has a less favorable prognosis than and management challenge. typical Cogan’s syndrome. Glomus Jugulare Tumor—A relatively rare, REFERENCES usually benign neoplasm—a paraganglioma 1. Alleva M, et al. Tinnitus. Primary Care arising from sympathetic or parasympathetic 1990;17(2):289-97. [PMID: 2196610]. paraganglia outside the adrenal gland— 2. Noel CA, et al. Tinnitus. Diagnosis and treatment of this elusive symptom. Geriatrics 2003;58(2):28- originating in the chemoreceptor tissue of the 34. [PMID: 12596495]. carotid body, glomus jugulare, glomus 3. Axelsson A, et al. Tinnitus induced by tympanicum, and aortic bodies. Glomus tumors occupational and leisure noise. Noise Health 2000;2(8):47-54. [PMID: 12689461]. are encapsulated, slowly growing, highly 4. Cochran JH Jr, et al. Tinnitus as a presenting vascular, and locally invasive tumors. Although symptom in pernicious anemia. Ann Otol most paragangliomas are sporadic, they can be Rhinol Laryngol 1979;88(2 Pt 1):297. [PMID: 443725]. familial. Glomus jugulare tumors occur 5. American Academy of Otolaryngology, Head predominantly in women in the fifth and sixth and Neck Surgery (2008, January 4). Silence decades of life. The most common symptoms May Lead To Phantom Noises Misinterpreted As Tinnitus. ScienceDaily Retrieved September 21, are conductive hearing loss and pulsatile 2008, from http://www.sciencedaily.com- / tinnitus. Other aural signs and symptoms are releases/2008/01/080101093825.htm ear fullness, otorrhea, hemorrhage, bruit, and 6. Zoger, et al. Relationship between tinnitus severity and psychiatric disorders. Psychosomatics 2006 the presence of a middle ear mass. Significant 47:282-8 [PMID: 16844885: Free full text]. ear pain is uncommon. Involvement of the inner 7. Waldvogel D, et al. Pulsatile tinnitus—a review of 84 patients.J Neurol 1998;245(3):137-42. ear produces vertigo and sensorineural hearing [PMID: 9553842]. loss. Cranial nerve involvement produces 8. Ochi K, et al. Zinc deficiency and tinnitus. Auris hoarseness and dysphagia. The presence of Nasus Larynx 2003;30 Suppl:S25-8. [PMID: 12543156]. jugular foramen syndrome (paresis of cranial 9. Frankenburg FR, et al. Tinnitus, psychosis, and nerves IX-XI) is pathognomonic for this tumor, suicide. Arch Intern Med 1994;154(20):2371, but it usually follows one year after the initial 2375. [PMID: 7944860]. 10. Lewis JE, et al. Tinnitus and suicide. Clin symptoms of hearing loss and pulsatile tinnitus. Otolaryngol Allied Sci 1994;19(1):50-4. [PMID: Less commonly, glomus tumors produce facial 8174302: Abstract]. CHAPTER 43 Tiredness

SYNOPSIS of a serious and uncommon disease,1, 2 or more commonly a normal occurrence as a result of full Tiredness* is one of the most common and day’s work, or sustained physical activity, or as a difficult presenting symptom to assess. Being a result of multiple potentially modifiable factors, constitutional and nonspecific symptom, it may be less well-defined and explained by patients which may be fully treated, or at least alleviated, than symptoms associated with specific thus increasing the well-being of the individual as functions. Regardless of the cause, individulas well as potentially slowing the progression of 3 may describe their sense of tiredness variously disability. In many cases no diagnosis can be made, as exhaustion, weakness, loss of interest, low leading the patient to repeat consultations, lab vitality, fatigue, or feeling tired all the time work, and multiple diagnoses.4 Therefore, it is (TATT)—too tired to participate in family chore, important for the physician to narrow down the work, or even leisure activities. It is often vast differential diagnosis with an emphatic, accompanied by a strong desire to rest or sleep. structured approach, with an aim of cultivating a Tiredness, being a nonspecific symptom, is respectable and therapeutic relationship without multicausal, which can neither be quantified nor extravagant investigations.5 can be diagnosed with laboratory or imaging studies. Analyzing the symptom and reaching a DIFFERENTIAL DIAGNOSIS diagnosis demands considerable skill, since tiredness may indicate the first subtle manifestation Common

*Tiredness, fatigue, and weakness, though used • Physiological (overbusy lifestyle, sedentary interchangeably, convey different meanings. Tiredness is a lifestyle) state of subjective feeling of listlessness or lethargy which • Psychological (depression, anxiety, fibro- can occur at rest; whereas fatigue is an excessive tiredness ↓↓ on mental or bodily activity, lack of energy, which occurs myalgia: vide infra ) in tasks requiring sustained effort. Weakness denotes a • Acute postinfection syndromes (mostly demonstrable reduction or loss of the strength or force of muscle contraction or power. Exhaustion is extreme fatigue, postviral syndromes) a marked loss of strength. • Chronic infections (TB, hepatitis, HIV, AIDS) 297

• Medications (diuretics, beta-blockers, ESR antihistamines, tranquilizers, OTC agents) • Elevated in infection (TB, HIV); inflammation • Substance abuse (alcohol) (RA, PAN); and malignancy. • Systemic illness (anemia, hypothyroidism, Blood Glucose diabetes mellitus, obesity, COPD, dehy- dration) • Both hyperglycemia and hypoglycemia cause • Pregnancy (early stages) tired feeling. • Menopausal syndrome. LFTs • Markedly elevated liver enzymes when the Occasional liver is damaged by infections like hepatitis • Major organ failure (cardiac, renal, liver) or by toxins like alcohol and certain drugs † • Sexual dysfunction • In a jaundiced patient an elevated bilirubin • Sleep disorders‡ level is seen • Chronic fatigue syndrome (CFS). • With chronic illnesses the albumin tends to gradually fall to low levels. Rare Urea, Electrolytes and Creatinine • Burnout syndrome (vide infra ↓↓) • An elevated serum urea or creatinine with • Hematological (leukemia, polycythemia) dehydration or if the kidney function is • Malignancy (neoplasms) impaired • Lymphoma/granuloma • Hyponatremia and hypokalemia in patients • Neurological (dementia, PD, MS) on diuretic therapy • Endocrine (Addison’s disease, thyrotoxi- • Hyponatremia with hyperkalemia in cosis, hyperparathyroidism) Addison’s disease • Hypokalemia or hyperkalemia in periodic • Electrolyte/metabolic causes (hypercal- paralysis syndrome. cemia, sodium, potassium, periodic paralysis syndrome: vide infra ↓↓) TFTs • Connective tissue disease (RA, PMR, SLE) • Elevated THS with low FT4 in hypothyroidism. • Neuromuscular disorders (myasthenia gravis: vide infra ↓↓). Pregnancy Test • A urine or serum beta HCG level in all women INVESTIGATIONS—GENERAL of childbearing age may be indicated.

CBC INVESTIGATIONS—SPECIFIC • To assess the type and severity of anemia— CXR generally IDA due to nutritional deficiency, chronic disease, or chronic blood loss. • In patients with history of TB, tobacco CHF, • Leukocytosis in pyogenic infection. smokers, and infection. • Marked leukocytosis with atypical WBCs in Chronic Infection Screening leukemia. • TB, malaria, brucellosis, infective endocarditis, † Ref. Chapter 37 ‘Sexual dysfunction’. p 254 hepatitis serology (HBsAg, HCV antibodies), ‡ Ref. Chapter 28 ‘Insomnia’. p 189 and viral markers (CMV, EBM). 298 Diagnosis: A Symptom-based Approach in Internal Medicine

HIV and VDRL Serology Bone Marrow Biopsy/Aspirate

• Should be considered in any patient whose • In patients suspected with leukemia, history of sexual risk factors and examination lymphoma, lymphoproliferative disorders, is suggestive of the infection. and neoplastic disease.

RF and ANA MRI Brain

• To screen for rheumatologic and autoimmune • If MS is suspected. disorders. Polysomnography (Sleep Study) Plasma Cortisol (8 AM-10 AM Specimen) • As indicated in patients with chronic • Decreased serum cortisol (<3 mg/dl) generally, insomnia. indicates Addison’s disease. Cancer Screening Muscle Enzymes CK, CK-MB • Age and gender-related cancer screening – for • Increased levels in polymyositis, dermato- breast cancer, cervical cancer, endometrial myositis, muscular dystrophy, drug-induced cancer, colorectal cancer, lung cancer, and myopathy (e.g. corticosteroids, statins, prostate cancer; or specific diagnostic methods gabapentin, colchicine, cyclosporin). may be indicated in patients with obscure cause of tiredness. Tensilon (Edrophonium) Test CLINICAL NOTES • The Tensilon test is best suited for examining focal weakness of ocular or pharyngeal • The primary purpose of evaluating a patient muscles in suspected myasthenia gravis. If with tiredness is to identify its source or the lid ptosis is a result of myasthenia gravis, contributing factors. Exhaustive, unfocussed one will observe dramatic improvement in evaluations are not likely to be rewarding the ptosis within 30-45 seconds after IV • It is very useful to ask patients to define their Tensilon; lid ptosis typically will reappear 2- understanding of ‘tiredness’. Characterizing 3 minutes later. The Tensilon test is positive the patient’s complaints in terms of onset, in more than 90% of patients who have associated symptoms, variability in symptoms, myasthenia gravis. stressors, precipitating and alleviating factors, pre-existing medical conditions, and EMG medications can help in narrowing the potential causes of tiredness and direct the • In patients with neuromuscular trans- initial investigations mission disorder (myasthenia gravis). • Similarly, family issues, including children, Muscle / Tissue Biopsy relatives, diverse, death, abuse, violence, trauma, financial difficulties, and habits • Distinguishes between neurogenic and should also be assessed myopathic disease • Psychogenic—Tiredness existing for greater than • Tissue biopsy to confirm malignancy. 6 months, fluctuating in its severity, commonly Tiredness 299

associated with family or social stressors, mood Table 43.1: Tiredness: Historical symptoms and disturbances, and associated with either possible etiologies insomnia or early morning awakening Symptoms Etiologies (depression) is more likely to be psychogenic. The Weight loss Neoplasm; endocrine patient presents with multiple and non-specific disorders (diabetes symptoms with a normal physical examination. mellitus, • Organic—Tiredness from organic causes is hyperparathyroidism, thyrotoxicosis, Addison’s acute in onset and shows a progressive disease); chronic infection course; stressors are often absent; family (TB, infective endocarditis, dynamics is sound and supportive. Sleep HIV) disturbances may be present, but is often Weight gain Obesity, hypothyroidism, Cushing’s syndrome related to the underlying disease process. Prolonged fever Infective disease (TB, Tiredness is less in the morning and worsens brucellosis, infectious with activity. The patient presents with mononucleosis, associated symptoms (Table 43.1), and the endocarditis, toxoplasmosis) physical examination usually suggests Alcohol, drug abuse, Cirrhosis of the liver, potential underlying cause tobacco smoking systemic toxic effect, •A mixed category of tiredness is more COPD, lung malignancy common which involves any of the above Polyuria Diabetes mellitus, diabetes entries occurring in combination. One insipidus, hyperparathyroidism, abnormality discovered may be treated and chronic renal failure, resolved without changing the patient’s hypercalcemia, Cushing’s symptoms of tiredness (e.g. hypothyroidism syndrome or malignancy with depression). A balanced Intermittent tiredness Myasthenia gravis, familial periodic paralysis approach is essential to solve such problems Tiredness precipitated Periodic paralysis • In patients with tiredness, recognition of the on carbohydrate meal, syndrome symptoms of sleep deprivation is essential, after exercise as many such patients do not have a clear Female, tiredness after Fibromyalgia awareness of their own sleepiness. Therefore, minimal exertion, hyperalgesic aches a detailed ‘sleep history’ (Ref. Table 28.1, page and pains, insomnia no.192) is mandatory, because sleep disorders TATT, with no weight loss Psychogenic disorder are often associated with excessive daytime or abnormal work-up sleepiness which can be misunderstood by Dyspnea, palpitation, Anemia (nutritional the individual as tired feeling6, 7 increased sweating deficiency of iron, folic • Physical examination— May reveal depressed acid, malabsorption syndrome); CAD; cardiac patient with characteristic sad facial expre- valvular disease, COPD; ssion; skin pallor, petechiae, ecchymoses, thyrotoxicosis purpura (anemia, leukemia); skin pigmen- tation (Addison’s disease); lymphadenopathy (hypothyroidism, hyperthyroidism). Cardiac (infection, leukemia, metastasis ); hepatosp- and lung examination may reveal the presence

lenomegaly(infections, cirrhosis, malignancy, of S3 gallop, wheezing, or rales suggesting a leukemia); stigmata of alcohol or drug abuse cardiopulmonary etiology. A neurologic (gynecomastia, palmar erythema, needle examination may identify neuromuscular tracks, infected skin lesions); and thyromegaly disease as the cause (e.g. diplopia, ptosis, 300 Diagnosis: A Symptom-based Approach in Internal Medicine

dysphagia, dysarthria, limb weakness in energy conservation stage the person typically myasthenia gravis). tries to compensate for stress with behaviors like procrastination, decreased sexual desire, social RED FLAGS withdrawal, cynicism, apathy, resentment, and substance abuse. However, it’s typically not until • A person may present his symptoms of the final exhaustion stage that the person realizes tiredness as a hidden agenda or a ticket of entry: that something is very wrong; symptoms include i.e. to discuss symptoms related to some sadness, extreme fatigue, severe headache, and personal beliefs, e.g. sexual dysfunction or HIV even suicidal ideation. Underlying depression or infection, and psychological symptoms. Such anxiety is common in such people—especially if factors may be more important to the there’s suicidal ideation. A short-term psycho- individual than fatigue or tiredness itself. therapy or psychopharmacotherapy may be Eliciting detail emphatic history usually indicated for stabilization, although taking a uncovers these hidden agendas which simple break can cure some burnout. reassures individual’s help-seeking behavior.8 • Avoid exhaustive, unfocussed work up; they Fibromyalgia—It is a poorly defined, complex, are not likely to be rewarding and in fact may chronic, and disabling disorder that causes be counterproductive, reinforcing the widespread pain and stiffness in the muscles, patient’s belief in an existence of an insidious tendons, and ligaments with multiple tender points unidentified medical illness. (trigger points); most frequent in women aged 20-50. • Chronic tiredness, lasting over six months, for Symptoms include generalized fatigue or tiredness, which diagnosis is elusive, should not be reduced physical endurance, pain in specific areas confused with CFS; however, the criteria for of the body, especially neck, shoulders, chest, back CFS may be considered for further evaluation. (upper and lower), hips and thighs, insomnia or • Chronic tiredness with depression or anxiety, poor sleep, sensations of numbness or swelling suicidal ideation, and psychomotor retardation (although swelling is not actually present), chronic demands careful attention.9 headaches, morning stiffness, worst on first arising, along with unrefreshing sleep and fatigue. It is SELECTIVE GLOSSARY commonly associated with conditions such as depression, anxiety, viral infection, CFS, eating Burnout Syndrome—It is a popular term rather disorders, physical or sexual abuse, IBS, tension than a scientific diagnosis denoting a severe state headache, migraine, and hypothyroidism. Physical of exhaustion and cynicism that occurs frequently examination is normal except for trigger points; there among individuals who do ‘people-work’ of some are no specific tests for fibromyalgia; lab work up is kind. Heavy workload, long hours, prolonged normal. stress, poor coping mechanisms, low self-esteem are all associated with burnout syndrome. Some Myasthenia Gravis— It is an autoimmune condition experts think the condition progresses through in which autoantibodies are developed against the stages—alarm (stress arousal), resistance (energy acetylcholine receptors of neuromuscular junctions. conservation), and exhaustion. During the first The disease presents as fluctuating weakness and stage, the person is irritable, forgetful, anxious, fatigability of voluntary muscles. The muscles of and unable to concentrate. Physical symptoms the eyes, head and neck are most commonly may include hypertension, palpitations, bruxism, affected. Diplopia or unilateral ptosis is the initial insomnia, headaches, and GI problems. In the symptoms in the majority. In severe cases, limb Tiredness 301 and trunk muscles are involved and respiratory and swallowing difficulties are extre- function may be compromised. Myasthenia gravis mely rare. may be life-threatening when respiratory muscles  Between attacks, patients often expe- are affected (myasthenic crisis). Initial symptoms rience muscle spasms or difficulty may be subtle and only apparent at the end of the relaxing their muscles, a condition known day or when the patient is fatigued. Exacerbations as myotonia. of myasthenia gravis may be precipitated by the  Attacks usually begin in early childhood use of anesthesia, narcotics or sedatives. Other Giving oral glucose or glucose and subcutaneous autoimmune conditions, such as thyroid diseases insulin may trigger a hypokalemic attack, and rheumatoid arthritis, are more common in myasthenia gravis patients and their families. The whereas giving potassium may trigger a diagnosis is confirmed by the Tensilon test, hyperkalemic attack. Because this primarily is electromyographic studies, and the finding of an inherited condition, the most important elevated acetylcholine receptor antibodies. aspect of diagnosis is obtaining a family history. Periodic Paralysis Syndrome— (Familial Periodic REFERENCES Paralysis, Anderson-Tawil Syndrome)— It is a rare 1. Kenter EG, et al. Once tired, always tired? inherited autosomal dominant condition that causes Limitations in function over time of tired patients occasional episodes of severe muscle weakness, in Dutch general practice. Eur J Gen Pract commonly associated with thyroid disorders. 2007;13(2):67-74.[ PMID: 17534742 : Abstract]. 2. Avlund K, et al. Onset of mobility disability among Episodic bouts of severe weakness in the arms and community-dwelling old men and women. The role legs are the most prominent symptoms. Typically of tiredness in daily activities. Age Ageing. 2003; these bouts occur during sleep, especially after 32(6):579-84. [PMID: 14599997: Free full text]. 3. Avlund K, et al. Factors underlying tiredness in strenuous activity. Cold, stress, and alcohol may also older adults. Aging Clin Exp Res 2007;19(1):16-25. produce attacks. Other, less common, symptoms [PMID: 17332717: Abstract]. may include weakness in the eyelids and face 4. Gialamas A, et al. Investigating tiredness in Australian general practice. Do pathology tests muscles, muscle pain, arrhythmias, difficulty help in diagnosis? Aust Fam Physician breathing or swallowing. The two most common 2003;32(8):663-6. [PMID: 12973880: Abstract]. 5. Ridsdale L, et al. Patients who consult with types of periodic paralysis are hypokalemic and tiredness: Frequency of consultation, perceived hyperkalemic. Some specific features to the type of causes of tiredness and its association with periodic paralysis include: psychological distress. Br J Gen Pract 1994;44(386):413-6. [PMID: 8790655: Free full text]. • Hypokalemic: 6. Guilleminault C, et al. Excessive daytime sleepiness: A  Potassium levels are low during attacks. challenge for the practising neurologist.Brain  Frequency of attacks varies from daily to 2001;124(Pt 8):1482-91. [PMID: 11459741: Free full text]. 7. Black J, et al. Recent advances in the treatment and yearly. management of excessive daytime sleepiness. CNS  Attacks usually last between 4 to 24 hours, Spectr 2007;12(2 Suppl 2):1-14; quiz 15. [PMID: but can last for several days. 17277717: Free full article]. 8. Ridsdale L, et al. Tiredness as a ticket of entry. The  Attacks usually begin in adolescence, but role of patients’ beliefs and psychological they can occur before age 10. symptoms in explaining frequent attendance. • Hyperkalemic: General Practice Fatigue Group. Scand J Prim Health Care 1999;17(2):72-4. [PMID: 10439488:  Potassium levels are high during attacks. Abstract].  Attacks are usually shorter (lasting 1–2 9. Norton PJ, et al. Suicidal ideation and anxiety hours), more frequent, and less severe disorders: Elevated risk or artifact of comorbid depression? J Behav Ther Exp Psychiatry 2008 Jan than the hypokalemic form; breathing 18. [PMID: 18294614: Abstract] CHAPTER 44 Urinary Frequency

SYNOPSIS desire to micturate. Similarly, increase urine output, i.e. polyuria, will result in increased In an adult, urinary frequency, i.e. the number of frequency of micturition. voids per day varies considerably, depending on Normally in an adult with an average fluid factors such as age, gender, weather, intake of intake, the act of micturition is initiated (as a fluids, food habits, voiding habits, cultural, and reflex) when the urine volume is about 300- social influences. 400 ml, and occurs 4 to 8 times during the day, At the physiologic level, urination (also and none or once during the night. Urinary known as micturition, voiding) is a reflex frequency, strictly speaking, occurs when there mechanism (spinobulbospinal reflex), is increased need to urinate more often facilitated and inhibited by higher brain without a concomitant increase in the volume centers (pontine micturition center), and of urine. With no accepted reference range;1-3 subject to voluntary facilitation and urinary frequency may be arbitrarily defined inhibition. The normal bladder capacity in an as frequent urge to urinate without being able adult is approximately 500 ml, but it can be to pass much urine; patients may complain that voluntarily overridden until the content they are is voiding more often than they used reaches 600-800 ml, when the conscious urge to, but the total volume not exceeding 3L per to void becomes difficult to ignore. However, day. If the total volume is >3L, it is termed * the micturition reflex can yet be voluntarily polyuria. Two or more night time voids is termed nocturia, and urinary urgency is sudden inhibited until it is appropriate to begin compelling urge to urinate (patient has to voiding (e.g. a toilet is reached). Any hurry to the toilet), often accompanied by condition which interferes with such bladder pain. compliance of the bladder wall, diminished bladder capacity, and increased irritability of the bladder or urethra will lead to repeated * Ref. Chapter 34 Polyuria p. 234 303

It is critical to differentiate urinary frequency DIFFERENTIAL DIAGNOSIS from urinary incontinence†, i.e. involuntary release Common of urine or loss of bladder control. The four common types of urinary incontinence include: • Urinary tract infections (UTIs—cystitis, vaginitis, Stress incontinence— Characterized by urine urethritis, pyelonephritis, prostatitis) leakage associated with increased abdominal • Urethral syndrome‡ pressure from laughing, sneezing, coughing, • Benign prostatic hypertrophy (BPH) climbing stairs, or other physical exertion. • Calculus (ureteric, bladder) Urge incontinence—A sudden, intense urge to • Diabetes mellitus (Type 1 and 2) urinate, followed by an involuntary loss (i.e. • Diuretics leaking) of urine. In urge incontinence, the • Pelvic inflammatory disease (PID) bladder is said to be overactive; it’s contracting even • Urinary incontinence when it isn’t full. Urge incontinence usually • Anxiety neurosis entails urgency, frequency, or nocturia. These • Pregnancy symptoms are often referred to as the OverActive • Cold weather. Bladder syndrome (OAB). Occasional Overflow incontinence—It is incomplete bladder emptying, associated with frequent or constant • Interstitial cystitis dribbling of urine, secondary to impaired • Overactive bladder (irritable bladder) detrusor contractility or bladder outlet • Renal tuberculosis (tubercular cystitis) obstruction. • Urethral strictures • Pelvic space-occupying lesion (fibroid, Mixed incontinence—It is the coexistence of ovarian cyst, carcinoma) stress and urge incontinence, characterized by • Reiter’s syndrome (i.e. urethritis, arthritis, involuntary loss of urine associated with and conjunctivitis). urgency as well as exertion, cough, sneeze, or any effort that increase intraabdominal Rare pressure. These urinary symptoms, i.e. frequency, • Diabetes insipidus—cranial and nephrogenic urgency, incontinence, and nocturia are commonly • Malignancy (bladder, prostate, rectum) seen overlapping in patients with urologic and • Neurogenic—spastic bladder (e.g. sacral systemic disorders.4, 5 The prevalence increases spinal cord lesion, trauma) with age, and is more common in women. In the • Parkinson’s disease elderly, it is very common in both sexes. However, • Multiple sclerosis decisions concerning management depend on the • Urinary tract foreign body cause of the frequency and the degree of bother • Postradiotherapy fibrosis. that it causes the patient.

† According to the International Continence Society, urinary ‡ incontinence is defined as a condition of involuntary urine Symptoms suggestive of cystitis and urethritis, usually in loss that is objectively demonstrable and is a social or post-menopausal women with atrophic vaginitis, and post- hygienic problem. coital sexual trauma. 304

INVESTIGATIONS—GENERAL Urea, Creatinine Urinalysis • Elevated with decreased renal function from chronic obstruction. • Microscopy§—leukocytes (10 or more ** WBCs /cu. mm in fresh unspun mid- Electrolytes stream urine sample), possible hematuria, granular casts, and red-cell casts are • Especially diuretic induced hypokalemia is generally seen in UTIs. important as it is responsible for the excess mortality observed in patients with diuretic Quantitative Culture for Bacteriuria treated essential hypertension and cardiac abnormalities. • A conventional threshold count of >100,000 (i.e.>105) bacteria/ml indicates active infection Pregnancy Test • In symptomatic patients a count of 100 to 10,000 (i.e. 102 to 104) bacteria /ml is • In all women of childbearing age with missed recognized as an infection periods. • Count of <10,000 (i.e. 104) bacteria /ml in the absence of therapy largely rules out INVESTIGATIONS—SPECIFIC bacteriuria†† but pathogenic organisms may be present Urine Culture • Count of 10,000 to 100,000/ml should be • Midstream clean-catch urine culture is repeated and cultured. indicated only in relapse, reinfection, and conventional therapy resistant UTIs, and in Suprapubic Aspiration/ Catheterization those with predisposing conditions such as • The presence of bacteriuria of any degree (i.e. complicated UTIs‡‡, diabetes mellitus, or any growth of pathogenic organisms) in immunocompromised state. suprapubic aspirates or of ≥102 bacteria /ml US of Kidneys, Ureter, and Bladder (KUB) of urine obtained by catheterization is virtually diagnostic of UTI. • To detect renal size, calculus, obstruction, mass lesion, and to measure postvoid urine CBC volume in BPH • US of pelvis for prostate hypertrophy§§ in • Leukocytosis in acute UTIs • Peripheral blood eosinophilia may be an men, and lesions of uterus, ovaries in women. 6 initial manifestation of eosinophilic cystitis. CT Scan of KUB (vide infra ↓↓). • Contrast-enhanced CT for diagnosis and Blood Glucose follow-up of complicated UTIs • Dual-phase helical CT of kidney allows • Diagnosis of diabetes mellitus. different phases of excretion to be studied

§ Urine ‘dipstick’ test—both false-positive and false- ‡‡ negative results are common. Complicated UTI indicates a UTI that occurs in a patient ** Early morning urine (EMU) sample preferred. with a structural or functional abnormality of the †† Bacteriuria denotes the presence of bacteria in the urine, genitourinary tract. which may be symptomatic or asymptomatic. §§ Transrectal US is preferred. 305

(nephrographic phase compared to corti- • Toileting record—One of the most helpful comedullary phase) and can define the extent components of the history is the record kept of the disease and identify significant by the patient or caregiver during a 48- to complications and obstruction 72-h period. The chart records the volume • Renal masses, bladder, and prostate tumors and time of each void or incontinent episode. and calculi, including lucent, low-density A detail list of questionnaire and 24 hr calculi (e.g. uric acid stones) are well seen on bladder diary is an extremely valuable tool 9 helical CT scan to differentiate various voiding symptoms • Limiting nonenhanced spiral CT (NECT) is • Clarify whether frequent urination is associated the preferred choice in patients who do not with excessive urination, or frequent attempts have classical symptoms of renal colic; older to urinate with only reduced urine output; the patients, and in those with a contraindi- former indicates frequency with polyuria, e.g. cation to the administration of intravenous in diabetes mellitus, and the latter frequency contrast media.7 alone, e.g. in UTIs, BPH • An approximate estimate of how much fluids Intravenous pyelography (IVP) or Intravenous the patient is consuming in a day helps to *** Urography (IVU) determine hydration status, detect excessive • Largely replaced by US and CT scanning,8 thirst in diabetes mellitus and diabetes insipidus, but still plays a role in the diagnosis of and also detect habitual overdrinking calculus disease. • Caffeine intake, alcohol abuse, and diuretics cause frequent urination. Some medications cause MRI Brain/Spine nephrogenic diabetes insipidus, e.g. lithium, leading to frequency and excess voiding • Indicated if cranial diabetes insipidus, e.g. • Sexual history helps in assessing risk of polyuria due to pituitary craniopharyn- sexually acquired urethritis gioma is suspected • Past history of CNS infection such as • To rule out spinal cord lesion from trauma, meningitis or hypothalamic-pituitary surgery tumors, or spina bifida. is the common cause of diabetes insipidus resulting in polyuria and frequency Cystoscopy • Associated symptoms like fever, chills, loin • Indicated for patients with persistent pain radiating to groin, dysuria, urgency, irritative voiding symptoms—frequency, terminal dribbling of urine, acute retention of urgency, dysuria, or hematuria urine, etc. are pointers to UTIs, calculi, and BPH • To diagnose bladder lesions such as cystitis, • Morbid anxiety is a common cause of urinary stone, tumor, and urethral strictures. frequency; usually associated with other genitourinary and sexual symptoms such a CLINICAL NOTES dysuria, impotence, and frigidity. Other symptoms of anxiety such as palpitation, • Ask the patient how many times a day he or sweating, hyperventilation, dizziness, and she voids, and how this compares to previous headache are also present pattern of voiding • Physical examination includes assessing state *** Magnetic resonance urography is preferred over IVU. of hydration, vital signs, abdominal palpation 306

for distended bladder due to retention or predominantly with eosinophils, associated with urethral obstruction. In women, pelvic fibrosis with or without muscle necrosis. The examination, and in men digital rectal cause of EC remains unclear, although it has been examination should be performed. Abnormal associated with various etiological factors, such neurological findings such as deep tendon as allergy, bladder tumor, bladder trauma, or absence of the bulbocaver- parasitic infections and chemotherapeutic nosus reflex suggest the possibility of agents. EC is, probably, caused by the antigen- underlying neurologic lesion. antibody reaction. This leads to the production of various immunoglobulins, which, in turn, RED FLAGS cause the activation of eosinophils and initiates the • UTI in male—In every male who has even inflammatory process. The most common symptom complex consists of frequency, one episode of UTI, a careful search must be hematuria, dysuria and suprapubic pain. made for possible cause; history of sexual Cystoscopy and biopsy are the gold standard for exposure may need direct inquiry diagnosis. Additional laboratory evidence • In all women of childbearing age, exclude supporting the diagnosis includes proteinuria, pregnancy by doing a pregnancy test if a microscopic hematuria and peripheral eosinophilia, period has been missed. The chances of an the last one occurring in few patients. There is no unrecognized pregnancy presenting with curative treatment for this condition. Current polyuria can thus be minimized treatment modalities include transurethral resection • Urinary tract TB is a common masquerade; of the bladder lesion along with nonspecific presenting in various systemic and genito- medical therapy, such as nonsteroidal urinary symptoms. Diagnosis depends on antiinflammatory agents or steroids. Because the constant awareness, especially in patients lesion tends to recur in spite of the above therapy, with sterile pyuria long-term follow-up is mandatory’. 10, 11 • In patients with irritative voiding symptoms associated with neurologic signs such as REFERENCES diplopia, blurred vision, paresthesia, consider neurogenic bladder—multiple sclerosis is a 1. Latini JM, et al. Voiding frequency in a sample of asymptomatic. American Men. J Urol strong possibility 2004;172(3):980-4. [PMID: 15311017: Abstract]. • Not all prostate hyperplasia is benign; 2. van Haarst EP, et al. The 24-h frequency-volume chart in adults reporting no voiding complaints: periodic prostate cancer screening is indicated Defining reference values and analyzing in select cases. Prostate cancer often is variables. BJU Int 2004;93(9):1257-61. [PMID: asymptomatic despite extensive spread 15180618: Abstract]. 3. Fitzqerald MP, et al. Urinary habits among • Interpret elevated prostate specific antigen asymptomatic women. Am J Obstet Gynecol (PSA) with caution, as it may be elevated in 2002;187(5):1384-8. [PMID: 12439535: Abstract]. both BPH and prostate cancer. 4. Clemens JQ, et al. Overlap of voiding symptoms, storage symptoms and pain in men and women. J Urol 2007;178(4 Pt 1):1354-8. [PMID: 17706719: SELECTIVE GLOSSARY Abstract]. 5. Barry MJ, et al. Overlap of different urological Eosinophilic Cystitis(EC)—It is a ‘rare symptom complexes in a racially and ethnically clinicopathological condition characterized by diverse, community-based population of men and women. BJU Int 2008;101(1):45-51. [PMID: transmural inflammation of the bladder 17868419: Abstract]. 307

6. Lin HH, et al. Blood eosinophilia, corticoadrenal 9. Web sites: http://misc.medscape.com/pi/editorial/ insufficiency and eosinophilic cystitis. Urol Int clinupdates/2008/12690/art-blaivas.fig2.pdf; http:/ 2008;80(2):219-21. [PMID: 18362497: Abstract]. /misc.medscape.com/pi/editorial/clinupdates/ 7. Mendelson RM, et al. Renal colic: A prospective 2008/12690/art-blaivas.fig3.pdf. Accessed on evaluation of non-enhanced spiral CT versus 02.10.08. intravenous pyelography. Australas Radiol 2003; 10. Teegavarapu PS, et al. Eosinophilic cystitis and its 47(1):22-8. [PMID: 12581050: Abstract]. 8. Wang JH, et al. Prospective comparison of unenhanced management. Int J Clin Pract 2005;59(3):356-60. spiral computed tomography and intravenous [PMID: 15857336: Abstract]. urography in the evaluation of acute renal colic. J Chin 11. Itano NM, et al. Eosinophilic cystitis in adults. J Med Assoc 2008;71(1):30-6. [PMID: 18218557: Abstract]. Urol 2001;165(3):805-7. [PMID: 11176473: Abstract]. CHAPTER Urticaria and 45 Angioedema

SYNOPSIS lips, periorbital areas, or genitalia. Occasionally there may be swelling of the tongue or pharynx Urticaria* is a heterogeneous group of disorders which can be life-threatening, but the larynx is characterized by production of ‘wheals’, (also virtually never involved.1 The pruritus that called as ‘hives’), i.e. itchy, transient, erythe- usually accompanies urticaria is conspicuously matous, or pale, edematous swellings of the superficial layers of the dermis which blanch on absent in angioedema. pressure; each individual lesion is short-lived, Urticaria and angioedema may coexist. lasts for few minutes to several hours, seldom Angioedema accompanies urticaria in approxi- more than 24 hours; episodes may recur daily mately 40% of patients, another 40% of patients or several times each day for days, or years. have hives alone, and about 20% of patients have 1 Wheals are rounded, oval, or ill-defined closely angioedema but not urticaria. placed lesions which may coalesce to form Based on its duration, urticaria is classified various shapes and sizes from a few millimeters into: to few centimeters. Any part of the body may be Acute—If the symptoms last less than 6 weeks; affected, trunk being more commonly involved etiological trigger is more likely to be identified than extremities or face. in acute urticaria such as drug reactions, and Angioedema is a condition which involves food or contact allergies. subcutaneous or submucosal tissue (rather than the dermis), with sudden, diffuse, nontender Recurrent acute urticaria—This is recurrent swelling of the involved parts, primarily of the episodes of urticaria, each episode lasting less than six weeks. * Urticaria was described in 1772 by Heberden W. as “little elevations upon the skin in the ‘nettle’ rash that often Chronic—If there are recurrent episodes occurring appears involuntarily and seldom stays many hours in the daily or almost daily for longer than six weeks. same place. There is nobody exempt from ‘them’ and by far the greatest number experience any other evil from it The history itself can be regarded as the most besides the intolerable anguish arising from the itching...“ valuable diagnostic tool in identifying causes of (Heberden W. Of the Nettle Rash Transactions: College of chronic urticaria; extensive laboratory studies Physicians, London, 1772; 2; 173). 309 provide little information beyond that suggested Occasional by the patient’s history and physical examination. • Physical urticaria (dermographism; cholinergic From the patient perspective, chronic urticaria; cold urticaria; solar urticaria) urticaria affects as many dimensions of the • Pregnancy (Pruritic urticarial papules and health-related quality-of-life as some life- plaques of pregnancy, i.e. PUPPP)4 threatening diseases or well-recognized disabling chronic skin disorders, such as Rare psoriasis or atopic dermatitis. Recent trials have highlighted the serious disability of patients with • Systemic disease (connective tissue diseases): chronic urticaria, including loss of sleep and Juvenile RA, SLE, vasculitis: vide infra ↓↓; energy, social isolation, altered emotional endocrine disorders: Hashimoto’s thyroiditis, reactions, and difficulties in aspects of daily Graves’ disease, diabetes mellitus; neoplasms: living. The disability is of the same order as that lymphoma, leukemia, carcinoma, myeloma, experienced by patients with severe chronic Sweet’s syndrome: vide infra ↓↓ ischemic heart disease.2, 3 • Skin diseases: Urticaria pigmentosa, i.e. mastocytosis; dermatitis herpetiformis; DIFFERENTIAL DIAGNOSIS pemphigoid; amyloidosis • Psychogenic urticaria: Depression, anxiety, Common (the In’s of hypersensitivity urticaria). stress • Infections (occult bacterial infection involving • Genetic: Autosomal dominant hereditary sinuses, teeth, gums, gallbladder, chest, angioedema, i.e. HAE: vide infra ↓↓. genitourinary tract; mycoplasma, H. pylori enteritis; viral infections: hepatitis A, B, and INVESTIGATIONS—GENERAL C, infectious mononucleosis; fungal infections: dermatophytosis, candidiasis) CBC • Infestations (protozoal and helminthic: • WBC count may be elevated in systemic or Strongyloidiasis, giardiasis, amoebiasis, dermal infection; eosinophilia would prompt malaria) a search for parasitic diseases, vasculitis, or • Ingestions (foods and food additives: eggs, drug reactions. sea-food, nuts, metabisulfites, tartrazine, azo dyes) ESR † • Injections, i.e. drugs (aspirin, penicillin, • An elevated ESR suggests the possibility of sulfonamides, opiates, ACE-inhibitors, blood an underlying systemic disease. products, herbal products) • Inhalants (pollens, mold spores, animal Urinalysis danders, house dust, aerosols) • Insect stings or bites (mosquitoes, flies, ants, • Proteinuria or hematuria may be due to either bees, spiders) a primary renal disease or secondary to • Contact urticaria (latex sensitivity, hair connective tissue disorder. bleaches, kumkum, cosmetics, lipsticks, sunscreens, dental prosthesis, dental filling). Stools

† Drugs taken as long as a month prior to the onset of • To detect ova or cysts of helminthic or symptoms may induce urticaria. protozoal infection. 310 Diagnosis: A Symptom-based Approach in Internal Medicine

INVESTIGATIONS—SPECIFIC in acute infection or in patients who are chronic carriers; anti-HCV; and H. pylori fecal Challenge Testing for Physical Urticaria antigen test. • This may be performed as indicated by patient’s history; e.g. test for dermographism Skin Prick Test or Patch Test by stroking patient’s skin by a blunt, narrow • To determine specific allergens responsible object (tongue blade); pressure urticaria by for urticaria, anaphylaxis, or food reactions; application of pressure for defined time and however, diagnosis of allergy to a specific intensity; cold urticaria by ice cube test; allergen cannot be made on the basis of aquagenic urticaria by challenging with tap testing alone; it requires correlation of the test water at various temperatures; solar urticaria results with the clinical history. by exposure to defined wavelengths of light, red cell protoporphyrin, fecal protoporphyrin, Serum Immunoglobulin Analysis and coproporphyrin. • IgE concentration by RAST and ELISA Throat and Urine Culture method may be indicated in patients suspected with allergy due to food, insect • In patients with history of fever and sore bite, or latex allergy. Immunoassay is throat for streptococcal infection. appropriate for patients in whom skin testing cannot be done (e.g. those who are unable to Multichemistry Screening Panel discontinue use of interfering medications, • LFTs for evidence of hepatocellular or those who have severe dermatographism or obstructive jaundice; urea, creatinine, and eczema, and those who have had a near-fatal electrolytes for renal disorders (pyeloneph- reaction to an allergen).5 ritis, glomerulonephritis, nephrotic syndrome, 6 renal failure); serum glucose for evidence of Autologous Serum Skin Test (ASST) diabetes mellitus, and serum calcium to screen • Indicated in all the patients with chronic for malignancy. urticaria because a positive test is suggestive but not diagnostic of an autoimmune basis TFTs for the patient’s chronic urticaria. Confir- • TFTs, including thyroid autoantibodies mation is needed by in vitro testing of the (antithyroglobulin and antimicrosomal patient’s serum for the anti-FCeRIa or the antibodies) may be helpful, given the anti-IgE autoantibodies. In vitro ‘the basophil association of chronic urticaria with histamine release assay’ is currently the gold Hashimoto’s disease, and Graves’ disease. standard for detecting functional auto- Annual reassessment of TFTs in euthyroid antibodies. However, it is available only at a patients may be indicated who have elevated few research centers and cannot be performed antibody titers. as a routine.

Serology Serum Complement1

• IgM anti-HAV; IgM anti-HBc; HBsAg, i.e. • Complement determinations are not indicated Hepatitis B surface antigen may be present for patients who have urticaria alone (since Urticaria and Angioedema 311

the values are normal), nor need they be done Table 45.1 : Clinical classification and features of when angioedema accompanies chronic urticaria/angioedema urticaria, since patients with a hereditary or Physical urticaria* Morphology/comments acquired deficiency of C1 inhibitor do not • Dermographic urticaria • Linear wheals have hives. Only in patients who present with (rubbing, scratching) angioedema alone, as in HAE, is • Cholinergic urticaria • Small transient wheals; measurement of C4 indicated, followed by a (sweating due to anxiety, with surrounding determination of the levels and function of strenuous work, hot bath, flare; extends from neck to C1 esterase inhibitor, if C4 levels are below alcohol) thigh normal. • Cold urticaria (cold • Small or large wheals; stimuli–wind, drink) associated with cryopathies Cold Agglutinins and Cryoproteins • Solar urticaria • Lesions on photo exposed (sun exposure) parts; associated with • In patients with cold urticaria; presence of erythropoietic cryoglobin suggests chronic hepatitis or protoporphyria malignancy. • Delayed pressure • Urticaria develops 2-6 hr urticaria after pressure, lasts for ANA (sustained pressure) 12-72hr.; e.g. buttocks (prolonged sitting); waist • May be indicated in patients with chronic (tight underclothes); hands (in manual labor) urticaria with features of connective tissue • Contact urticaria • Induces by biologic or disease such as Raynaud’s phenomenon, chemical skin contact; e.g. arthralgia, photo sensitivity, and rash. latex sensitivity; cosmetics • Urticarial vasculitis • Chronic urticaria, Skin Biopsy frequently lasting >24 hr, more painful than itchy, • Helpful in patients with urticaria that persist associated with extracut- aneous manifestations for more than 24 hours; chronic urticaria; or such as fever, arthralgia, urticaria associated with fever, arthralgia, nephritis, and leaving and elevated ESR suggesting urticarial areas of discoloration as vasculitis. lesions resolve; may be triggered by infection, drugs, or malignant CLINICAL NOTES disease; skin biopsy is diagnostic • The diagnosis of urticaria is primarily • Angioedema • Occurs with or without clinical; based on a good history, physical, urticaria; angioedema and systemic examination (Table 45.1) without urticaria may indicate a C1-esterase • History should include enquiry about: inhibitor deficiency, e.g.  Drug exposures (prescription drugs, HAE; commonly involves herbal, and vitamin supplements) the lips, eyelids, face,  Food exposures extremities, and genitalia in an asymmetr-ical  Physical triggers manner  Infection exposures, especially viral *defined by the specific physical stimulus. hepatitis 312 Diagnosis: A Symptom-based Approach in Internal Medicine

 Hobbies and occupational exposures RED FLAGS  Travel details • Since fatal reactions are known to occur with  Insect stings or bites challenging testes for foods or drugs, they are  Family history of atopy indicate only in rare cases with compelling  Lifestyle, exercise, habits, stress. reasons to confirm the causative allergen with • Maintaining daily diet diary and occurrence 7,8 of skin lesions for fixed duration (2 to 4 weeks), facilities available for monitoring the patient. including drugs ingested and activities may • Any patient with tongue edema or edema of be helpful in guiding the etiology. However, the floor of the mouth and laryngeal edema it’s to be noted that hypersensitivity reactions should be hospitalized for airway monitoring. can develop at any time despite years of • Patients with chronic urticaria, suspected to be uneventful exposure due to urticarial vasculitis need to be fully • Because of the effervescent (i.e. appearance investigated for evidence of other autoimmune varying in minutes over hours) nature of the connective tissue disease or other internal organ urticaria, its features may be difficult to involvement. evaluate on a particular occasion. However, • Beware of most serious drug reactions such careful examination of the skin lesion is as erythema multiforme (EM), Stevens- important because special forms of urticaria Johnson syndrome (SJS), and toxic epidermal have special features, e.g. dermographism, necrolysis. cold urticaria, cholinergic urticaria, etc • A comprehensive physical examination of SELECTIVE GLOSSARY skin, lymph nodes, eyes, joints, throat, neck, Hereditary Angioedema—HAE is an autosomal ears, lungs, heart, and abdomen can uncover dominant condition caused by a deficiency of the important diagnostic clues that may help plasma protein C1 inhibitor that afflicts 1 in 10,000 diagnose comorbidities such as connective to 1 in 150,000 persons. HAE has been reported tissue disorders, thyroid disease, and in all races, and no sex predominance has been lymphoreticular neoplasms found. It manifests as recurrent attacks of intense, • The most common cause of acute urticaria is massive, localized edema without concomitant drug reaction; however, up to 50% of cases pruritus, often resulting from one of several of acute urticaria a cause is not identified known triggers such as trauma, surgery, dental • A chronic urticaria, frequently lasting more manipulation, or accidents. However, attacks can than 24 hours, more painful than itchy, occur in the absence of any identifiable initiating associated with extracutaneous manifestations event. The most commonly involved viscera are such as fever, arthralgia, nephritis, COPD, and the respiratory and gastrointestinal systems. leaving areas of discoloration as lesions resolve, Involvement of the upper airways can result in is suggestive of urticarial vasculitis • Patients who have both urticaria and severe life-threatening symptoms, including the angioedema tend to have more severe and risk of asphyxiation, unless appropriate persistent disease than patients with only one interventions are taken. This condition can be of the disorders differentiated from angioedema in that urticaria • Despite a complete examination and does not occur, the lesions are not pruritic, and extensive laboratory studies, a cause of the lesions are nonresponsive to antihistamines chronic urticaria is usually not identified. and epinephrine. Historically, 2 types of HAE Urticaria and Angioedema 313 have been described—an acquired form of this with or without treatment. Sweet’s syndrome disorder may also be observed, sometimes in does not appear to be as rare as it seems though a association with an underlying lymphoma. It is full blown classical picture may not be observed important to consider this disorder in the in each case. Raised, erythematous and painful differential diagnosis of unexplained, episodic plaques, particularly if they are asymmetrical, cutaneous angioedema or abdominal pain. especially in females, should arouse the suspicion Quantitative and functional analyses of C1 of this entity. This is more likely in patients who esterase inhibitor and complement components have underlying malignancy. C4 and C1q should be performed when HAE is Urticarial vasculitis—It is thought to be due to suspected. immune complex mediated inflammation (i.e. Sweet’s syndrome (Acute febrile neutrophilic hypersensitivity vasculitis). Although the dermatosis or acute neutrophilic dermatosis)— prevalence of urticarial vasculitis is low, it is Named after Dr Sweet from Plymouth, England, nevertheless important to recognize because this who first described this condition in 1964, is a disease can be associated with other systemic reactive process to an internal condition such as conditions (e.g. SLE, Henoch-Schönlein syndrome) URTI, vaccination, pregnancy, IBD, RA, leukemia, and is amenable to effective treatment. It is more internal malignancy, and drugs, e.g. NSAIDs, common in women than in men, and it usually cotrimoxazole. It may also occur as a result of presents in the fourth decade of life. If skin lesions external triggers such as needle prick, biopsy or have an urticarial appearance and last longer than insect bite. In some patients they arise only in sun 24 hours in the same location, urticarial vasculitis exposed areas, but in others no underlying should be considered. Typically these urticarial- condition is found. It is characterized by the like lesions are: abrupt onset of tender, red-to-purple papules, and • Less pruritic and more painful than observed nodules that coalesce to form plaques. The with true chronic urticaria plaques usually occur on the upper extremities, • More prominent on lower extremities face, or neck and are typically accompanied by • May be palpable and purpuric fever and peripheral neutrophilia. It most often • Following resolution may leave pigmented occurs in middle-aged women, but men, children changes in the skin. and the elderly may also be affected. Common Angioedema may accompany urticarial symptoms include high or moderate fever; vasculitis. In addition, urticarial vasculitis may arthralgia; and one or more tender red papules be associated with systemic signs and symptoms or plaques which enlarge and persist for several such as fever, arthralgia, arthritis, uveitis, weeks, they may have blisters, pustules or ulcers, episcleritis, hematuria, wheezing, chest pain, and sometimes they appear to clear in the center. and diarrhea. Histopathologic findings include Sometimes other organs are affected including swelling of endothelial cells, neutrophilic bones, nervous system, kidneys, intestines, liver, perivascular infiltration, extravasation of heart, lungs, muscles and spleen. Investigations erythrocytes, leukocyto-clasis (nuclear dust), and may reveal: raised ESR or CRP, indicating fibrinoid deposits around blood vessels. systemic inflammatory disease; raised WBC count Hemorrhage and edema of the dermis may also (neutrophil leukocytosis); and numerous occur. The clinical course is usually benign, on neutrophil inflammatory cells on skin biopsy, average lasting 3 years. The prognosis varies, without leukocytoclastic activity. Sweet’s lesions depending on whether the diagnosis is resolve eventually without leaving a mark or scar, normocomplementemic urticarial vasculitis 314 Diagnosis: A Symptom-based Approach in Internal Medicine syndrome (NUVS) or hypocomplementemic 4. Brzoza Z, et al. Pruritic urticarial papules and plaques of pregnancy. J Midwifery Womens Health urticarial vasculitis syndrome (HUVS). NUVS is 2007;52(1):44-8.[PMID: 17207750: Abstract] more benign than HUVS, but both disorders are 5. Volcheck GW. Which diagnostic tests for common rarely fatal. allergies? Where to start when you face an allergy puzzle. Postgrad Med 2001;109(5):71-85. REFERENCES 6. Yadav S, Upadhyay A, Bajaj AK. Chronic urticaria: An overview. Indian J Dermatol 2006;51:171-7. 1. Kaplan AP. Chronic Urticaria and Angioedema. N 7. Wang Jet, et al.A. Food anaphylaxis. Clin Exp Allergy Engl J Med 2002;346(3):175-90. 2007;37(5):651-60. [PMID: 17456212: Abstract]. 2. Greaves MW, Sabroe RA. ABC of Allergies. Allergy 8. Rezvani M, et al. Anaphylactic reactions during and the skin. I-Urticaria. BMJ 1998;316:1147. 3. Grob JJ, et al. Urticaria and quality of life. Clin Rev immunotherapy. Immunol Allergy Clin North Allergy Immuno 2006;30(1):47-51. [PMID: Am 2007;27(2):295-307. [PMID: 17493504: 16461995: Abstract]. Abstract]. CHAPTER Vaginal Bleeding— 46 Abnormal

SYNOPSIS • At a time when it is not expected, such as before age 10 (precocious menstruation), Vaginal bleeding, as the term suggests, involves during pregnancy, or after menopause. bleeding from the vagina, which may happen The following terms (Table 46.2) are used to to a woman at any stage of her life.1-3 There are describe AVB related to the menstrual cycle, i.e. two types of vaginal bleeding. The normal vaginal abnormal uterine bleeding (AUB), on the basis of bleeding, with its characteristic features (Table its duration, amount, and frequency of the bleeding. 46.1), called as menstruation, which occurs with the onset of ovulation beginning with menarche Table 46.2: Terminology to describe (between 10-16 years of age), and ends with menstrual dysfunction (AUB) menopause (between 45-55 years of age). Term Definition Table 46.1: Characteristics of menstruation Menorrhagia Prolonged (>5 days) or excessive (>80 ml) menstrual bleeding at Characteristics Average Range regular intervals (21-35 days) Menarche 12-13 years 10-16 years Metrorrhagia Irregular, frequent menstrual Cycle length 26-28 days 21-35 days bleeding that is not prolonged or Duration of flow 3-5 days 2-7 days excessive (acyclic bleeding) Amount of flow 30-40 ml 10-80 ml Menometror- Prolonged or excessive menstrual Onset of menopause 47-50 years 45-55 years rhagia bleeding at irregular and frequent intervals Abnormal vaginal bleeding (AVB) may be Polymenorrhea Regular menstrual bleeding at inter- defined as bleeding from the vagina due to a vals of less than 21 days (frequent disorder in the vagina or related reproductive menses or shortened cycle) Oligomenorrhea Menstrual bleeding at intervals of organ, particularly the uterus, and which may more than 35 days, but less than 90 occur in association with or independent from days (infrequent menses) menstruation. Thus, vaginal bleeding is Amenorrhea No menstrual bleeding for 90 days considered to be abnormal if it occurs: (3 usual cycle lengths) or longer Intermenstrual Menstrual bleeding (usually not • When there is a significant deviation from the excessive) between otherwise regu- normal menstrual cycle, i.e. menstruation, and lar menstrual cycles 316

Categorizing particular bleeding pattern as • Endocrine (Hypothyroidism, hyperthy- defined above is one way of considering cases of roidism) AUB. Although each category of menstrual • Trophoblastic disease dysfunction has a particular list of causes, • Postcoital bleeding. necessary testing, and treatment; ‘there is no consistent relationship between abnormal Rare bleeding patterns and their causes’.4 Since AVB • Malignancy (endometrial, cervical, ovarian, can present in many forms, pinpointing the cause for bleeding abnormality can be challenging. vulvar, vaginal, secondary tumors) However, with the basic knowledge of menstrual • Metropathia hemorrhagica (Cystic glandu- physiology, and a thorough approach, the lar hyperplasia) problem can be managed with confidence. • Choriocarcinoma • Liver, renal disorders DIFFERENTIAL DIAGNOSIS • Endocrine (PCOS, Addison’s disease, Cush- ing’s syndrome, prolactinoma) Common • Bleeding disorders (von Willebrand’s dise- • Physiologic (ovulatory bleeding, i.e. midcycle ase, thrombocytopenia, leukemia, hemo- ovulation; hypothalamic-pituitary-ovarian philia, thalassemia) immaturity as in perimenarcheal age; • Drugs (anticoagulants, NSAIDs) transition to premature ovarian failure as in perimenopausal women) • Foreign bodies (forgotten tampon, IUDs). • Dysfunctional uterine bleeding (DUB)* • Traumatic lesions (sexual abuse, domestic • Uterine fibroids violence, rape, ruptured hymen). • Complications of early pregnancy (abortion: Threatened, incomplete, complete or mis- INVESTIGATIONS—GENERAL sed) Pregnancy Test • Ectopic pregnancy • Pelvic inflammatory diseases (PIDs: STDs, TB • If premenopausal, urine β-hCG; if ectopic endometritis, salpingitis, cervicitis, vaginitis) pregnancy is suspected serum β-hCG-preg- • Breakthrough bleeding (BTB) on oral/ injec- nancy test will be more definitive. tables contraceptives, HRT • Benign disorders (cervical or endometrial CBC polyps, cervical erosion, adenomyosis, endo- metriosis) • Hemoglobin—Low Hb in chronic AUB; • Postmenopausal atrophic vaginitis (endo- however, a patient may have normal Hb and metrial atrophy). hematocrit in spite of a heavy menstrual flow. Occasional Excess menstruation may result in iron deficiency, but iron deficiency anemia is a late • Complications of late pregnancy (placenta previa, abruptio placenta, premature labor, manifestation of excessive menstrual flow. subinvolution of the placental site) Therefore, a history of excessive menstrual flow should not be discounted simply on the *DUB is a symptom complex that includes any condition basis of normal hemoglobin valve of AUB in the absence of pregnancy, neoplasm, infection, and other pathology of the female genital tract as well as • Leukocytosis in PID other systemic cause of abnormal bleeding. • Thrombocytopenia in bleeding disorders. 317

Coagulation Profile than 5 mm. Increased endometrial thickness is associated with endometrial hyperplasia, • Platelet count, PT, PTT, bleeding time. endometrial polyps, fibroids, and endome- trial cancer. When the endometrial echo is Blood Sugar greater than 5 mm, or is indistinct or indeter- • Diabetes mellitus is a risk factor for endo- minate, an enhanced view is required with metrial carcinoma, and women with PCOS SIS or hysteroscopy. An endometrial echo of have been recognized to have an increased less than 5 mm is associated with malignancy incidence of diabetes mellitus (and adverse in less than 0.5% of cases. cardiovascular events which constitute ‘metabolic syndrome’). Saline Infusion Sonography (SIS): Conventional and 3D-SIS Pap Smear • To diagnose intracavitary lesions, endo- • To screen for cervical cancer, cervicitis. metrial hyperplasia, and carcinoma. Current indications for SIS include: Cervical Culture  Abnormal bleeding in premenopausal or postmenopausal patients; • For gonococcal, trichomonas, and chlamy-  Evaluation of an endometrium that is dial infection. thickened, irregular, immeasurable, or Thyroid Function Test poorly defined on conventional TVUS;  Irregular-appearing endometrium with • TSH, FT4, for possible thyroid dysfunction TVUS in women using tamoxifen; in patients suspected with anovulatory  The need to differentiate between sessile cycles. and pedunculated masses of the endo- metrium; and INVESTIGATIONS—SPECIFIC  Presurgical evaluation of intracavitary Pelvic US fibroids. • “SIS is a simple and elegant examination that • To detect uterine and ovarian abnormalities yields additional information over TVUS of (bicornate uterus, tumors, PCOS), hyda- the uterus. Because the walls of the endo- tidiform mole, and to establish the cause of metrium are separated by SIS, they can be bleeding in pregnancy. evaluated individually. Focal abnormalities are beautifully displayed by this technique. Transvaginal Ultrasound (TVUS) This information can then be used to direct • Invaluable in the initial evaluation in women the intervention. Biopsy of diffuse abnor-

at low risk for endometrial cancer. Adnexa, malities can be performed with a blind

ovaries, fibroids, and the endometrium for technique, whereas focal abnormalities are its thickness (i.e. endometrial echo) can be best approached with a visually guided biopsy. assessed to decide whether the patient SIS requires minimal patient preparation, has requires further evaluation with saline very few complications, and is well-tolerated

infusion sonography (SIS) and hysteroscopy. by patients. Given its advantages over other

Normally the endometrial echo measures less techniques for uterine evaluation, SIS will 318 Diagnosis: A Symptom-based Approach in Internal Medicine

likely play an even larger role in pelvic imaging Serum Testosterone, Free Testosterone, in future”5 17-Hydroxyprogesterone • Further, three-dimensional saline infusion • In women with hyperandrogenic symptoms sonography (3D SIS) is found to be valid and and signs – serum testosterone > 60 ng/dl reliable in women suspected of having supports the diagnosis of PCOS intrauterine abnormalities, and may indeed • If serum testosterone > 150 ng/dl, then 17- have relevant clinical value in addition to hydroxyprogesterone estimation is indi- conventional SIS.6 cated to rule out functional adrenal or Hysteroscopy ovarian neoplasm.

• Flexible hysteroscopy allows direct visuali- Urinary Gonadotropins zation of the endometrium and it can be used • High titers in trophoblastic disease like for directed biopsy and removal of small hydatidiform mole (molar pregnancy) or polyps. choriocarcinoma. Coagulation Profile • von Willebrand panel, including von Wille- Abdominal CT Scan brand antigen and ristocetin cofactor assay, • To evaluate for adrenal or ovarian tumor in and other tests for intrinsic qualitative women with hyperandrogenic symptoms platelet disorders are indicated in adole- and signs with elevated serum testosterone scents and in patients with family history and DHEA-S. of bleeding diathesis if a bleeding disorder is highly suspected. MRI of Pituitary

Serum Progesterone • To detect adenoma; prolactinomas are the • To determine ovulatory or anovulatory most common hormone-secreting pituitary status adenomas. • In ovulatory cycles—preovulatory serum pro- gesterone values are <1 ng/ml; and post- Endometrial Biopsy (EMB) ovulatory serum progesterone values are • EMB is indicated in women older than 35 > 5 ng/ml years of age who have AUB associated with • In anovulatory cycles, serum progesterone increased risk factors for endometrial values never exceed 5 ng/ml. hyperplasia and endometrial cancer. Biopsy is also indicated for patients aged 18 to 35 LH, FSH years with risk factors for endometrial cancer. Risk factors include: • Ratio of LH: FSH >3 indicates PCOS; FSH  Obesity > 40 U/ml indicates imminent ovarian failure.  Diabetes mellitus Prolactin (PRL)  Infertility  Chronic anovulation (anovulatory for at • Hyperprolactinemia needs to be ruled out least 1 year) in women with anovular cycles.  Postmenopausal, not on HRT Vaginal Bleeding—Abnormal 319

 New onset AUB in postmenopausal is helpful to differentiate between vaginal (i.e. woman on HRT uterine) and extrauterine (i.e. gastrointestinal  Suspected PCOS or genitourinary) causes of AVB  Tamoxifen therapy. • Rule out or confirm pregnancy, if premeno- pausal—Because bleeding can indicate a CLINICAL NOTES complicated pregnancy, possible pregnancy should always be considered in a woman of • Confirm source of vaginal bleeding—uterine child-bearing age. Spotting to minimal bleeding or extrauterine. It is not uncommon for a may be normal, but any bleeding during woman to be unaware of the exact source of an unexpected and AVB. She may just pregnancy needs to be evaluated. Heavy bleeding before 12 weeks may indicate serious complain that she has noticed blood on her problem, including abortion (threatened, undergarments or on the tissue paper after incomplete, and missed), molar pregnancy, or wiping external genitalia and that she cannot ectopic pregnancy; and that occurring after 12 find a reasonable explanation for such weeks may be due to placenta previa abnormal bleeding—it being significantly different from her previously established • In premenopausal women—is the bleeding pattern of menstrual flow. Therefore, the first ovulatory or anovulatory? Normal ovulation and foremost thing to do is to obtain careful is necessary for regular menstrual cycle; a history to ascertain that the blood is flowing distinction between ovulatory and anovula- from the vagina, and not from the rectum or tory bleeding is critical because causes and mixed with urine (i.e. associated with bowel therapies are distinct (Tables 46.3 and 46.4) movements or urination), thus focusing on • All women with evidence of severe bleeding genital etiologies, predominantly uterine on physical examination (e.g. pallor, hypo- (AUB). Examination of stools for the presence tension) should be fluid resuscitated and of blood (hematochezia) and urine (hematuria) emergently hospitalized.

Table 46.3: Differentiation of ovulatory and anovulatory cycles Criteria Ovulatory cycles Anovulatory cycles History Regular cycle length; Prolonged bleeding at irregular intervals Ovulation pain (mittelschmerz); after not having a menstrual period for Premenstrual molimina (breast soreness, several months; subjective symptoms bloating—fluid retention, weight gain, preceding the cycles are absent and mood change), dysmenorrhea (cramps, back pain) Cervical mucus Preovulatory cervical thin mucus discharge is usually observed halfway between menstrual cycles Basal body temperature Biphasic pattern Monophasic pattern record Serum progesterone Preovulatory < 1 ng/ml Never exceeds 5 ng/ml; usually level Postovulatory > 5 ng/ml preovulatory values Premenstrual endometrial Secretory endometrium Proliferative and possibly hyperplastic biopsy changes Common examples Physiologic normal variants; fibroid, DUB, hypothalamic dysfunction— polyps, PID, systemic disorders secondary to stress, depression, eating disorders, obesity; adolescence; BTB; endometrial hyperplasia 320 Diagnosis: A Symptom-based Approach in Internal Medicine

Table 46.4: Differential diagnosis of abnormal resulting in irregular, heavy menses and vaginal bleeding (AVB) probably dysmenorrhea. Once ovulation Ovulatory bleeding Physiologic: and menstruation are regularly esta- Midcycle ovulation (Mittelschmerz) blished, the cycle follows a predictable Anatomic lesion: pattern (Table 46.1) and any deviation can Fibroids; PID; be considered as AUB. cervical-infection, polyp, cancer; IUD  Menstrual history—The first day of last Systemic disease: menstrual period should be included in Bleeding diathesis; hepato- all adult female patients, i.e. the date that renal disorder Local disorders: the menstrual flow began. Many patients Foreign body; trauma; assume that occurrence of any bleeding infection; urethral prolapse; is a ‘period’. Also, for many women, growth monthly may mean once every calendar Anovulatory bleeding Hypothalamic dysfunction: Premenarcheal month, so that a period on day 1 and day perimenopausal; stress, 27 of the same month, while normal, may weight loss, heavy strike her as having periods twice a exercise Excess androgen, prolactin, month. Failure to make this distinction cortisol can result in misleading information. A Hypothyroidism menstrual calender^ (over three or more PCOS Oral contraceptive use: months) can be a very useful guide. The Inadequate estrogen quantity (the passage of ‘clots’ or inability dose to control bleeding with tampons is Postmenopausal Endocrine pathology: significant and indicates heavy bleeding), Fibroid; polyp; cancer ‡ Cervical pathology: duration, and frequency of bleeding Erosion; polyp; cancer with respect to previous menstrual cycles Vaginal pathology: are recorded. Any significant deviation Atrophic vaginitis Pregnancy Early pregnancy: from normal should be noted and Abortion: patient’s cycles are categorized as in Complete; incomplete; Table 46.2. inevitable; missed Late pregnancy:  Postcoital bleeding (any bleeding after Placenta previa; abruptio intercourse or in association with placenta; douching) is suggestive of cervical Retained products of dysplasia, or endocervical polyps. gestation Ectopic pregnancy  Postmenopausal bleeding (any bleeding occurring in a postmenopausal woman • The history should determine the following at least 1 year after cessation of cycles) information: should be evaluated for endometrial  Age of onset of bleeding, age of onset of puberty. hyperplasia and carcinoma. Though premenarchal bleeding may be ^ associated with precocious puberty, local Visit web site -http://www.americanpregnancy.org/ pathology, as well as adrenal and ovarian gettingpregnant/ovulationcalendar.html ‡ tumors must be ruled out. In adolescence, It is not uncommon for women to change their sanitary products frequently for hygienic reasons or because of AUB is common in the first 2-3 years after personal preference or concern for toxic shock syndrome menarche due to many anovulatory cycles, than because of heavy flow. Vaginal Bleeding—Abnormal 321

• Associated symptoms—Pain, discharge, fever,  Pap smear and biopsy of any lesion in nausea, vomiting, dysuria; symptoms of the genital tract. hyperthyroidism (fatigue, weight loss, sweating, palpitation); hypothyroidism Digital Rectal Examination (DRE) and (fatigue, cold intolerance, constipation); Proctoscopy symptoms of hyperprolactinemia (headache, nipple discharge, galactorrhea); symptoms • May be warranted to identify alternative of virilization (excess hair growth); bleeding sources of bleeding such as rectal or urethral. diathesis (easy bruisability, petechiae, epi- staxis, gingival bleeding); etc. should be RED FLAGS addressed • In a woman of reproductive age, pregnancy • Sexual history—Sexual abuse and activity, including high risk behavior, and domestic should always be ruled out despite a nega- violence screening is recommended tive history of sexual activity • Personal and family history—Marital status, • AUB in a woman of reproductive age must parity, infertility, epilepsy, and blood dys- be considered a complication of pregnancy crasia. Smokers have higher incidence of until proved otherwise menstrual dysfunction • Vaginal bleeding in a postmenopausal • Medications§—Oral contraceptives, anticoa- woman must be considered a malignancy gulants antidepressants, antiepileptics, anti- until proved otherwise psychotics, opiates, Tamoxifen, and herbal • Reevaluate patients diagnosed with hyper- preparations (ginseng, ginkoba, soya supple- plasia with atypia for persistent or ments) worsening hyperplasia within 3-6 months of • Physical examination—Evidence of puberty treatment (breast development, axillary and pubic • Vaginal bleeding that occurs before hair growth); virilization, hirsutism; pubertal development or normal menarche hypothyroidism (dry skin, coarse hair, bradycardia, delayed reflexes); hypert- should raise suspicion of nonendocrine hyroidism (sweating, weight loss, palpit- causes; rule out adrenal and ovarian tumor, ation); abdominal distension, tenderness, including rhabdomyosarcoma (sarcoma hepatomegaly, splenomegaly; skin pete- botryoides) chiae; etc. • AUB during adolescence should be attri- buted to a coagulation disorder until proven Pelvic Examination otherwise  Inspection of genitalia—Anatomy, dis- • AUB before menarche may warrant pelvic charge, foreign body, evidence of trauma, examination under general anesthesia to and source of bleeding—uterine or extra- exclude focal lesions such as trauma, sexual uterine. abuse or assault, and malignancy  Other lesions—Polyps, fibroids, pelvic • Any AVB/AUB should be investigated in mass. women taking Tamoxifen or Raloxifene § Common medications, which increase the cytochrome because the resulting side effects of these P450 enzymatic processes in the liver, may induce more drugs (indicated in breast cancer) include rapid metabolism of steroid hormones, thereby decreasing an increase in the risk of endometrial cancer their bioavailability and result in AUB that is secondary to a relative insufficiency of estrogen or progesterone. and thrombosis. 322 Diagnosis: A Symptom-based Approach in Internal Medicine

REFERENCES 4. Kilbourn CL, et al. Abnormal uterine bleeding: diagnostic considerations, management options. 1. Hill NC, et al. The etiology of vaginal bleeding Postgrad Med 2001;109(1):137-50. in children. A 20-year review. Br J Obstet 5. Berridge, Debra L, et al. Saline infusion sonohys- Gynaecol 1989;96(4):467-70. [PMID: 2751960: terography: Technique, indications, and imaging findings. J Ultrasound Med 2004;23:97-112. Abstract]. [PMID: 14756358: Abstract]. 2. Fishman A, et al. Vaginal bleeding in premenar- 6. de Kroon CD, et al. The clinical value of 3-dimen- chal girls: A review. Obstet Gynecol Surv 1991; sional saline infusion sonography in addition to 46(7):457-60. [PMID: 1876356: Abstract]. 2-dimensional saline infusion sonography in 3. Aribarg A, et al. Vaginal bleeding in young child- women with abnormal uterine bleeding: Work in ren. Southeast Asian J Trop Med Public Health progress. J Ultrasound Med 2004;23(11): 1433- 2003;34(1):208-12. [PMID: 12971537: Abs-tract]. 40. [PMID: 15498907: Abstract]. CHAPTER 47 Vertigo

SYNOPSIS such as giddiness†, dizziness, fainting; or symptoms of disequilibrium, such as inability Vertigo can be defined as a hallucination of an to maintain normal gait and normal posture abnormal sensation of rotation or imbalance of either (Table 47.1). Therefore, the words that patients the self or the surroundings (e.g. rotating, spinning, use to describe their symptoms of ‘vertigo’ are tilting, and swaying). Patients may feel that they significant because a number of seemingly are moving while the surroundings remain still synonymous terms often relate to distinct (subjective vertigo), or that the surroundings move physiological mechanisms. while they are stationary (objective vertigo), or that The five sensory modalities which cons- both they and the surroundings are in motion.* It is tantly monitor position and motion are: Vision, usually associated with headache, pallor, sweating, vestibular end organs, proprioception, touch nausea, vomiting, hyperventilation and imbalance. and pressure, and cerebellum. Normally the The patient tends to keep his head immobile out of brain integrates the input from each of these fear of a fresh attack and is disinclined to walk, sensory modalities giving a comprehensive especially in crowded surroundings. image of position and motion in space. This In practice, however, it is unusual for patient process enables us to maintain balance, move to complain of vertigo, i.e. the majority do not about, and interact with other objects. However, present solely with true spinning vertigo—that pathology affecting the central nervous system, they are moving relative to the surroundings, eyes, ears, locomotor system, and other systems or that the surrounding is moving, and that the such as hemopoietic system, cardiovascular and symptoms are (or not) provoked by head move- endocrine systems may all alter the delicate ments when they are at rest, sitting or lying † down. Most commonly patients complain of Giddiness is an unpleasant sensation of disturbed relation to surrounding objects in space. Dizziness, however, is symptoms suggestive of presyncopal episode, an imprecise term, generally used collectively to describe all types of equilibrium disorders, including giddiness, * The distinction between subjective and objective vertigo light-headedness, imbalance, ataxia, vertigo, or minor is probably of not much localizing value. episodes of mental confusion. 324

Table 47.1: Causes of dizziness Symptom description Characteristics Possible etiologies Vertigo: Spinning or whirling; Illusion of motion of self Dysfunction of vestibular system— “like getting off a (subjective) or environment peripheral or central merry-go-round”; (objective) “the ground tilts up and down; like being on a boat at sea”. Disequilibrium: Poor balance, but not Impaired balance or coordination; Cerebellar lesion; brainstem lesion; dizzy; “the problem is unsteady gait extrapyramidal disorder; bilateral in my legs”. vestibular dysfunction; peripheral neuropathy Presyncope: Patient senses impending loss Cerebral hypoperfusion—causes Lightheadedness; of consciousness; often with numerous fainting; “I feel like I systemic symptoms—nausea, will pass out”. diaphoresis, dimness of vision, blackout; inciting event Multiple sensory deficit: Often elderly people afflicted by Multiple concurrent problems; visual “I am unsteady on my a variety of ills that summate to impairment, deafness, peripheral feet”; “I am afraid I impair the patient’s ability to ambulate neuropathy, painful or disabling will fall”. unassisted; dramatically improved by orthopedic disorders, and the use of a cane or the supporting muscle weakness arm of a companion Ill defined Histrionic but vague description; Psychogenic nonspecific complaints balance of neural information resulting in • Ménière’s syndrome (vide infra ↓↓) disequilibrium and vertigo. Hence, proper • Migraine (aura, basilar migraine) understanding of etiopathology, i.e. central • Multiple sensory deficit syndrome‡ (vide (brain) or peripheral (inner ear, 8th cranial infra ↓↓) nerve); coupled with systematic, efficient and • Systemic disorders (hypotension, cardiac formal evaluation is required in order to provide arrhythmia, hypoglycemia) appropriate management and rehabilitation. • Psychogenic (hyperventilation, anxiety, panic attack, agoraphobia, somatization, DIFFERENTIAL DIAGNOSIS conversion, depression). Common Occasional • Ototoxic drugs (aminoglycoside antibiotics, • Physiological (motion sickness) aspirin, frusemide, phenytoin, quinine) • Positional vertigo (vertebrobasilar ischemia, • Epilepsy (aura in temporal lobe epilepsy) cervical spine dysfunction, or benign paro- • Physical (barotrauma, noise trauma) xysmal positional vertigo, i.e. BPPV) • Head injury (posttraumatic labyrinthine • Vestibulopathy (vestibular neuronitis, laby- concussion, perilymph fistula). rinthitis, herpes zoster) • Vascular (subarachnoid hemorrhage, verte- ‡ brobasilar ischemia, brainstem infarct, cere- This term usually refers to elderly persons who often bellar infract, lateral medullary syndrome, have altered sensory inputs or premature aging of the i.e. PICA syndrome: vide infra ↓↓) vestibular nuclei. 325

Rare stroke, cerebellar hemorrhage or infarction; and multiple sclerosis. • Cerumen impaction (common but rare cause of vertigo) Brainstem Evoked Response (BSER) • Neoplastic (acoustic neuroma, vide infra↓↓, tumors of brainstem, and floor of IVth ventri- • Useful screening test in patients with sus- cle) pected central causes of vertigo. A normal • CNS degenerative disease (MS, cervical OA, BSER safely excludes an acoustic neuroma. syphilis) If BSER is abnormal, an imaging procedure, • Endocrine disorders (hypothyroid, adrenal such as MRI, is indicated. insufficiency) • Post-ENT surgical status (stapedectomy, Carotid Doppler Ultrasound tympanoplasty) • Hereditary (otosclerosis). • To evaluate patency of the vessels and to screen for evidence of plaque precipitating INVESTIGATIONS—GENERAL TIAs. CBC ECG/Holter Monitor • Elevated WBC counts in infection. Elevated hematocrit (polycythemia) predisposes to • To screen for arrhythmia. CVA. Decreased Hb% in anemia. EEG ESR • In suspected cases of complex partial seizure. • May be elevated in bacterial infection, TB, and malignancy. X-ray Cervical Spine

INVESTIGATIONS—SPECIFIC • May be useful in demonstrating vertebral foraminal encroachment, which sometimes Audiometry compromises arterial blood flow to the brainstem • Pure tone audiogram, speech discriminating and the peripheral auditory apparatus. testing, and tympanometry performed in all patients with significant hearing loss or CLINICAL NOTES tinnitus; valuable in differentiating labyrin- • Since classifying patient’s complaints of vertigo thine rather than cerebral cortex or brain- is made specifically on the basis of a careful stem lesions as the cause of vertigo. history, it is important to ask the patient to CT Head describe symptoms in detail. It will then become apparent whether the patient is suffering from • Indicated in patients with head trauma to vertigo or other similar symptoms. Important identify fractures and CVA. historical information include:  The symptoms in the patient’s own MRI and Angiography words (is it vertigo or something else?) • Acoustic neuroma and other CP angle  Onset, duration, episodic or continuous tumors; acute vertigo with risk factors for condition. 326 Diagnosis: A Symptom-based Approach in Internal Medicine

 Is vertigo central, peripheral origin, or  Valsalva-induced nystagmus (closed general medical cause? glottis, pinched nostrils).  Is vertigo due to urgent causes or non-  Hyperventilation-induced nystagmus. urgent causes?  Romberg test, Fukuda test.  Are there any correctable underlying  Finger-nose (past-pointing) test. diseases? • Detection of nystagmus is critical because it is  Hearing loss, imbalance, aural fullness, the only objective sign of vertigo. Nystag- tinnitus (as in Ménière’s syndrome). mus can occur spontaneously or in response  Aura, headache, diplopia, dysarthria to changes in eye or body position. Peripheral (central causes). vestibular disorders usually cause horizon-  Aggravating factors (as with head tal or rotatory nystagmus, whereas brain- movement, postural change, travel, stem disorders are reflected by vertical noise, exercise). nystagmus  Recent head trauma or viral upper • Vestibular testing. The most common and useful respiratory infections (as in perilymph test is the Bárány or Dix-Hallpike maneuver. The fistula, vestibular neuronitis). patient is asked to turn his head. A rapid  Past history of similar attacks or risk factors for atherosclerosis. change in position from sitting to supine  Is it a psychogenic vertigo? (with head hanging over the edge of the  Does it need ENT or neurology consult? examination table) will produce active rotatory nystagmus when head is turned so • The points which help determine true vertigo are:  Element of rotation. that the affected ear is facing the floor. This  Associated with nystagmus, ataxia, may be accompanied by nausea nausea, vomiting. • Weber’s and Rinne’s test help in differentiating  Attack reproduced by rapid head move- conductive loss from sensory neural hearing ments. loss. Conductive hearing loss is seen in cases • Past medical history of aural infection, of otitis media and early stages of Ménière’s head injury, diabetes, hypertension, CAD, disease, while sensory neural hearing loss is CVA, migraine, epilepsy,1 or psychiatric seen in ototoxicity and tumors of the audi- disorders are helpful in the diagnostic tory nerve evaluation • Cerebellar dysfunction can be evaluated • All past and present medications should be initially by observing the gait, Romberg test, assessed with particular attention to Fukuda test, and finger-nose test§ aminoglycoside antibiotics, anticonvul- • Cardiovascular examination with special sants, antihypertensives, and high dose emphasis for orthostatic changes in BP, salicylates carotid bruits, murmurs and arrhythmias • Important bedside examinations for vertigo is helpful in selected cases include: • Neurological examination includes evalua-  Detection of spontaneous nystagmus. tion of cranial nerves, in particular fundoscopy  Barany rotation (head-shaking nystagmus– horizontal and vertical). §  Dix-Hallpike (Nylen-Barany) maneuver. Ref. Chapter 21 Gait disorders. p. 138 Vertigo 327

for papilledema or optic atrophy (II), ocular outweigh vestibular causes. Therefore, in movements (III, IV, and VI), corneal reflex** the elderly, it is more sensible to consider (V), and facial movements (VII) vertigo (along with other conditions which • Otoscopy can detect otitis media, serous otitis frequently accompany it) as part of a more or cholesteatoma general syndrome2 • Onset and duration—Generally, central • In an elderly sudden onset of severe vertigo, vestibular disorders, i.e. central vertigo, are headache, nausea and vomiting, usually characterized by gradual and insidious associated with other neurological symp- onset of continuous imbalance, whereas a toms, such as diplopia, dysphasia, hemi- peripheral vestibular disorder, i.e. peripheral paresis—but without hearing loss or vertigo, is classically characterized by tinnitus—is strongly suggestive of verte- sudden, short lived (of few hours) episodes brobasilar insufficiency of vertigo (Table 47.2). • Sudden, episodic vertigo, associated with Table 47.2: Vertigo: Causes and onset of attack progressive unilateral hearing loss and Acute tinnitus, lasting from hours to days is •CVA, TIA: vertebrobasilar event; subarachnoid suggestive of Ménière’s disease hemorrhage; cerebellar infarct • Vertigo precipitated by positional factors, • Head trauma, concussion •Infections – otological – vestibular neuronitis i.e. vertigo on arising from supine to sitting • Tumor or standing position; vertigo with sudden •Seizure neck movements, accompanied by nystag- Recurrent mus, but without hearing loss, is suggestive •CVA, TIA •Ménière’s disease of cervical spine dysfunction, vascular • Tumor ischemia, or BPPV •Migraine •Seizure • Mild vertigo (vague sensation of motion) •Toxic – drugs, substance abuse with prominent tinnitus, progressive •Multiple sclerosis unilateral sensorineural hearing loss, and •Syphilis •Surgery/otological/ENT procedures loss of corneal reflex strongly suggests •Psychogenic cerebellopontine angle tumor—usually Positionally provoked vertigo acoustic neuroma •Benign passional vertigo • Vertigo with multiple neurological signs • Cervical sprain, OA, whiplash injury •Vascular—Anterior vestibular artery occlusion, and symptoms, such as blurring or loss of verte-brobasilar artery insufficiency vision, diplopia, dysarthria, paresthesia, •Postsurgical (head/neck/ENT) status and ataxia is suggestive of multiple sclerosis • Central cause (vide infra ↓↓) • Age—In young adults psychological causes • Vertigo that is increased by a loud noise predominate, whereas vestibular disorders (Tullio phenomenon, i.e. vestibular hyper- do in the middle age. In the elderly, sensitivity to sound) and Valsalva maneuver cerebrovascular and cardiac disorders, suggests perilymphatic fistula combined with multiple sensory deficits • Organic vertigo is accompanied by nystag- mus; a psychogenic etiology is almost cer- ** Abnormal or absence of corneal reflex on the affected tain when nystagmus is absent during a side may be the first signs of CP angle tumors. vertiginous episode. 328 Diagnosis: A Symptom-based Approach in Internal Medicine

RED FLAGS with none of the audiovestibular symptoms classically associated with AN. Clinician • In elderly age group patients with risk factors awareness of the atypical clinical symptoms may for stroke, possibility of vascular vertigo lead to earlier detection of these lesions.3 Further, should always be considered in both acute the natural history of AN is yet not totally known, prolonged vertigo and recurrent vertigo but most of them have the tendency to slow • In a patient with acute vertigo, it is important growth, sometimes without any kind of to distinguish vestibular neuronitis from an symptoms during the individuals entire time.4 inferior cerebellar infarction. A stroke involving Considering ANs natural history, there is a the inferior cerebellum can be a neurosurgical possibility for conservative treatment for emergency marked by cerebellar swelling these tumors. and brainstem compression. Patients with The definitive diagnostic test for patients with cerebellar infarct are unable to stand or walk. ANs is gadolinium-enhanced MRI. Gadolinium This is the main distinguishing feature from contrast is critical because nonenhanced MRI can vestibular neuronitis miss small tumors. If suspicion is high, and MRI is • Majority of cerebellar infarct patients have a contraindicated, air-contrast cisternography has cardiac source of embolism, requiring specific high sensitivity and can detect relatively small cardiac evaluation and management. intracanalicular tumors. SELECTIVE GLOSSARY Ménière Disease—Ménière’s syndrome is a Acoustic neuroma (AN)—It is also known as disease of the inner ear (resulting from non- vestibular schwannomas, and are nonmalignant suppurative disease of the labyrinth) that is tumors of the 8th cranial nerve. Most commonly characterized by attacks of severe vertigo, they arise from the Schwann cell investment of tinnitus, fluctuating hearing loss, and ill- the vestibular portion of the vestibulocochlear described aural sensations of fullness with nerve. Less than 5% arise from the cochlear nerve. spontaneous recovery in hours to days. As the tumor expands, it projects from the internal Ménière’s disease usually develops between the auditory meatus into the cerebellopontine angle ages of thirty and fifty, and is slightly more and compresses the cerebellum and brainstem. common in women than in men, and in 50% of The 5th cranial nerve and later the 7th cranial Ménière’s patients become bilateral. The most nerve are affected. AN occurs in two forms—a consistent pathological finding in Meniere’s sporadic form, and a form associated with an syndrome is an increase in the volume of the inherited syndrome called neurofibromatosis endolymphatic fluid and distension of the type II (NF2). About 95% of all cases are sporadic. canals, hence the term endolymphatic hydrops. Clinical manifestations include hearing loss, Although some specific causes such as bacterial, headache, vertigo, tinnitus, and facial pain. viral, and syphilitic infections may lead to the Unilateral sensorineural hearing loss – sudden, same pathological changes and symptoms, the progressive, or fluctuating — is the most common majority of cases are idiopathic. The prognosis symptom present at the time of diagnosis. Vertigo, is for progressive reduction in hearing along dysequilibrium, headaches, facial numbness or with increasing frequency of attacks. Some facial weakness are uncommon presenting patients stabilize with no subsequent attacks symptoms among patients with AN. A significant of severe vertigo, but they are left with residual number of patients with AN present atypically, hearing loss. Vertigo 329

Multiple Sclerosis (MS)—An idiopathic inflamm- resulting in difficulty with activities of daily atory demyelinating disease of the CNS, mainly living and even falls. Medication is usually affecting young adults, and characterized by not helpful unless there is clear vertigo due destruction of myelin in the central nervous to inner ear dysfunction. However, Patients system. Patients with MS commonly present with can be helped by increasing their sensory an individual mix of neuropsychological input by using a cane, not to support a weak dysfunction, which tends to progress over years leg, but by dragging it along the ground, to decades. Clinical manifestations include visual which increases sensory input through the loss, extraocular movement disorders, and arm where the cane is held. The individual paresthesias, loss of sensation, weakness, has a better sense of stability and ‘where the dysarthria, spasticity, ataxia, and bladder ground is’, and many times can walk more dysfunction. The usual pattern is one of recurrent steadily and safely. attacks followed by partial recovery. The diagnosis PICA (Posterior inferior cerebellar artery) Syn- of MS is based on a classic presentation (i.e. optic drome—The PICA syndrome, also known as neuritis, transverse myelitis, internuclear lateral medullary syndrome, or Wallenberg’s syndrome, ophthalmoplegia, paresthesias), and on the is the most common brainstem stroke. It is identification of other neurologic abnormalities, typified by vertigo, ipsilateral hemiataxia, which may be indicated by the patient’s history dysarthria, ptosis and miosis. Patients often and examination. Typical findings on an MRI also have Horner’s syndrome (unilateral ptosis, help to establish the diagnosis of MS. Patients miosis and facial anhidrosis). There also may with atypical pre-sentations and/or a normal or be saccadic dysmetria (overshoot), saccadic atypical MRI may require evoked potential pulsion (pulling of the eye during vertical studies, to uncover subclinical neurologic saccades toward the side of lesion). Diagnosis is abnormalities, or cerebral spinal fluid (CSF) generally via MRI. Prognosis is generally good analysis, which also serves to exclude treatable with full or near full recovery expected at disorders and document MS-like immune 6 months. activity in the CNS. REFERENCES Multiple Sensory Deficit Syndrome—This term usually refers to elderly persons who 1. Neubauser H, et al. The interrelations of migraine, vertigo, and migrainous vertigo. Neurology. often experience dizziness as a result of 2001;56(4):436-41. [PMID: 11222783: Abstract]. altered sensory inputs or premature aging 2. Tinetti ME, et al. Dizziness among older adults: of the vestibular nuclei. Visual impairment A possible geriatric syndrome. Ann Intern Med 2000;337-44. [PMID: 10691583: Free full text]. (cata-racts), deafness (presbycusis), 3. Mackle T, et al. Atypical clinical presentations of decreased ability to feel their legs (peripheral vestibular schwannomas. Otol Neurotol 2007; neuropathy), painful or disabling orthopedic 28(4):526-8. [PMID: 17414179: Abstract]. 4. Penido Nde O, et al. Vestibular Schwannoma: disorders, and muscle weakness collectively Spontaneous tumor involution. Rev Bras Oto- alter the patient’s perception of space, rhinolaryngology (Engl Ed) 2007;73(6):867-71. fluidity of motion, and confidence in walking, [PMID: 18278239: Free full text]. CHAPTER 48 Vision Loss—Gradual

SYNOPSIS 6/18 to light perception, or a visual field of less than 10 degree from the point of fixation, but who uses, or As the world population ages, vision loss is potentially able to use, vision for the planning or becoming a major public health problem. execution of a task.” 2 Researchers for the Johns Hopkins Bloomberg However, to allow comparison with other School of Public Health, and the London School studies, the commonly used WHO classification of Hygiene and Tropical Medicine found that, (Snellen) of low vision as: “best corrected visual without extra intervention, the global number acuity < 6/18 to 3/60, and blindness as best of blind individuals would increase from 44 1 corrected visual acuity < 3/60 to NPL, i.e. no million in 2000 to 76 million in 2020. Therefore, perception of light” is generally used. any type of vision loss, low vision, or visual In order to facilitate the screening of visual impairment (e.g. blurred vision, double vision, acuity by nonstandardized personnel, in the night blindness, loss of central or peripheral absence of appropriate vision charts, the WHO vision) is a symptom of great concern to everyone. has now added, “inability to count fingers in Vision loss means that a person’s eyesight daylight at a distance of 3 meters”, to indicate less cannot be corrected to normal level, making it than 3/60 or its equivalent visual impairment.3 difficult or impossible to do daily tasks without Many causes of vision loss are very serious glasses, contact lenses, surgery, or other medical conditions, requiring immediate or assistance. This can lead to loss of independence urgent care, where delay can lead to loss of vision, and reduced quality of life. This type of vision e.g. retinal detachment, or loss of life, e.g. occipital loss does not include complete blindness, because stroke. Even transient blindness or loss of vision there is still some sight and it can sometimes be cannot be ignored because it can result from improved with the use of visual aids. serious conditions such as TIA, hypertension, WHO defines a person with low vision as: diabetes mellitus, and epilepsy. Therefore, the key “One who has impairment of visual functioning even to successful diagnosis lie in the history, age of the after treatment and/or standard refractory correction, and patient, and the pattern of field loss, backed up by has a visual acuity in the better eye of less than an examination of the eye through a dilated pupil. 331

DIFFERENTIAL DIAGNOSIS • Nutritional amblyopia (pernicious anemia, (TABLE 48.1) malabsorption syndrome) • Hereditary optic neuropathy (Leber’s) Common* • Neurosyphilis • Senile cataract • Choroidal melanoma • Chronic glaucoma • Homocystinuria. • Diabetic maculopathy • Hypertensive retinopathy INVESTIGATIONS—GENERAL • Age-related macular degeneration (ARMD) CBC • Gradual inferior retinal detachment • Chronic papilledema • Severe anemia can cause retinal hemorrhage • AIDS (CMV retinitis). and exudates Table 48.1: Causes of progressive bilateral vision loss • Increased hematocrit, WBC and platelet cell count in hypercoagulable states, e.g. retinal Site of lesion Examples vascular occlusions. Ocular Chronic glaucoma; senile cataract Retina ARMD; retinal disease, e.g. diabetic ESR retinopathy, hypertensive retinopathy, retinitis pigmentosa, choroidoretinitis • Elevated in malignancy, temporal arteritis. Optic nerve Optic neuropathies; optic nerve compression, e.g. glioma, aneurysm Blood Glucose/HbA1C Optic chiasma Chiasmal compression, e.g. pituitary tumor, craniopharyngioma Occipital cortex Tumors; degenerative conditions • To monitor diabetes mellitus.

Lipid Profile Occasional • To evaluate hyperlipidemia, including serum • Optic nerve compression (mass lesion) homocysteine levels. • Intracranial tumors • Intraorbital tumors Coagulation Screen • Retinitis pigmentosa • Complications of cataract surgery (inflam- • PT, PPT, lupus anticoagulant, Factor V Leiden, mation, retinal detachment, posterior cap- antithrombin III, protein C, protein S, etc. are sular fibrosis). indicated in patients with hypercoagulable states, e.g. retinal vascular occlusions. Rare TFTs • Toxic amblyopia (drugs/toxins – alcohol, anticholinergic agents, amiodarone, cortico- • In severe hyperthyroidism extraocular steroids, chloroquin, digoxin, ethambutol, muscle entrapment (thyroid oculopathy) isoniazid, lithium, streptomycin, sildenafil, may cause progressive loss of visual acuity and tobacco) and visual field. IOP (Tonometry)

* In children common causes of visual failure are congenital • Elevated in acute glaucoma; greater than cataract, retinitis pigmentosa and retinoblastoma. 30 mm of Hg is highly suspicious. 332 Diagnosis: A Symptom-based Approach in Internal Medicine

Visual Field (Perimetry) CLINICAL NOTES

• Scotomas are common with glaucoma. • Patients may not mention an eye complaint • Hemianopias, quadrantanopias in optic during initial discussion; however, a nerve lesions. proactive approach (i.e. direct questions) to uncover any serious eye condition needs to INVESTIGATIONS—SPECIFIC be adopted during consultation, especially in the elderly with comorbid diseases such Fluorescein Angiography as diabetes and hypertension. Few simple • In diabetic and hypertensive retinopathy, questions, e.g. — ‘are you able to read and retinal arterial/venous occlusion. newsprint or see TV; are your glasses adequate; are you being treated for any eye US of Eye and Orbits disease; when you last consulted your ophthalmologist’ — will alert the physician • Helpful in detecting intraocular tumors, of an underlying disorder. orbital tumors, retinal detachment, vitreous • The symptom of vision loss should be changes, thyroid oculopathy, and intraocular investigated further by asking following foreign bodies. questions:  Onset—sudden, gradual or progressive CT Scan Skull, Orbits/MRI Brain  Unilateral or bilateral eye involvement • As indicated to diagnose tumor, multiple  Is the vision impaired all the time sclerosis. (cataract, ARMD) or only at nights (retinitis pigmentosa) Carotid Doppler Scan  Is the vision impaired only in part of visual field? e.g.—can the patient see • To assess carotid/vertebral circulation, and objects directly in front of him but not stenosis in CVD and TIA. those to the left and right without moving his head? This distinction between Echocardiogram central and peripheral visual loss is • To exclude embolic source in valvular heart useful. Central visual loss implies defective disease, subacute bacterial endocarditis, and retinal vision formation, e.g. macular atrial myxoma. disease, optic neuropathy. Peripheral visual loss is more subtle, especially when the Visual Evoked Response (VER) onset is gradual, and implies extrama- cular retinal disease or a defect in the • Most useful in the diagnosis of retinitis visual pathway, e.g. hemianopia. pigmentosa, optic nerve disease, and • Associated symptoms: occasionally in demyelinating disorders, e.g.  Pain on eye movements—common in multiple sclerosis. optic neuritis, frequently precedes the onset of visual loss; Temporal Artery Biopsy  Flashing lights with eye movements and • In patients with temporal (giant cell/cranial) floaters, i.e. photopsia—common in arteritis. retinal detachment Vision Loss—Gradual 333

 Colored halos around lights, i.e. Table 48.2: Visual field defects with localization of lesion whenever patient looks at white light, he Vision defect Localization/examples sees it as if white light is split into its Tunnel vision Concentric diminution of field, e.g. component colors, red being outermost, glaucoma, late papilledema. seen in prodromal stage of angle closure Enlarged blind Early papilledema (optic nerve glaucoma, and cataract. spot head enlargement) • Current medications:4 Systemically administered Central scotoma, Optic nerve head to chiasmal drugs produce a wide variety of adverse effects i.e. loss of central lesion, e.g. demyelination, mecular vision vascular, toxic, nutritional. on the visual system; e.g. amiodarone, Unilateral field Optic nerve lesion, e.g. tumor, ethambutol, linezolid, sildenafil, long-term use loss, i.e. monocular vascular. of glucocorticoids, phenothiazine, adrenergic field defect agents, certain β2-adrenergic agonists, and Bitemporal Optic chiasma lesion, e.g. pituitary hemianopia tumor anticholinergic agents. Hemonymous Lesion behind optic chiasma, i.e. • Associated disorders, e.g. tuberculosis, hemianopia optic tract to occipital cortex diabetes mellitus, hypertension, hyperlipi- Upper quadrant Optic radiation (Temporal), e.g. demia, thyroid disease, autoimmune disease, homonymous tumor, vascular and malignancy. hemianopia • Past history of ocular disease or surgery, e.g. Lower quadrant Optic radiation (Parietal) homonymous orbital trauma, FB, corneal ulcer. hemianopia • Family history, e.g. developmental cataracts, Homonymous Occipital cortex corneal dystrophies, retinitis pigmentosa, hemianopia with central vision Leber’s hereditary neuropathy. (macula) sparing • Physical examination includes tests for—  Visual acuity for distance and near, with and without glasses (Snellen chart) in all • Systemic examination for any collaborative instances (except in chemical trauma†). evidence for loss of vision is important. For  Visual field: (Table 48.2). example:  Analysis of central visual field with an  Stenotic vascular disease (carotid or Amsler grid (to locate macular blind spots vertebral artery atherosclerotic disease, and areas of distortion and wavy lines) arteritis, dissection) used in daily self-monitoring for the  Cardiac disease (hypertension, endo- progression of macular degeneration. carditis, atrial myxoma, valvular dis-  Pupillary reaction: (ref. swinging flashlight orders) test, chapter 49: Vision Loss Sudden.)  Autoimmune disease (RA, ankylosing  Fundus examination (ophthalmoscope) spondylitis, giant cell arthritis, SLE) with dilated pupil to assess the red reflex,  Granulomatous disease (sarcoidosis) optic disk for papilledema, and retina for  Hematological (anemia, hypercoagulable presence of hemorrhage, cotton wool spots. states, antiphospholipid syndrome)  Neurological (head injury, mass lesion, seizures, MS) † In chemical exposure, the dictum is ‘treat first, examine later’; copious irrigation should be initiated before  Psychological (conversion syndromes, attempting a visual acuity examination. malingering). 334

RED FLAGS junctival bleeding, which can be ominous, e.g. in patients with bleeding dyscrasias. • Documentation of the initial visual acuity and visual field, and their subsequent REFERENCES assessment can be important in a disability or malpractice lawsuit. 1. Web site: http://www.jhsph.edu/publichealthnews/ press_releases/PR_2003/ Frick_Vision2020.html- • The presence of a cataract in relatively young 33.1KB. Accessed on 16-12-08. patient (e.g. juvenile diabetic cataract) is 2. Change of Definition of blindness. Web site: http:/ unusual and shall prompt ophthalmic consult. /www.who.int/blindness/Change %20 the % 20 • Gradual vision loss associated with Definition % 20 of % 20 Blindness.pdf. Accessed on 25.09.08. progressive early morning headache is an 3. National Programme For Control of Blindness. indication of intracranial neoplasm; urgent Web site: http://www.nihfw.org/ndc-nihfw/html/ referral is indicated. Programmes/National Programme For Control of Blindess.htm. Accessed on 25.09.08. • Prompt ophthalmic referral is prudent in all 4. Li J, et al. Drug-induced ocular disorders. 2008; intraocular hemorrhages, including subcon- 31(2):127-41. [PMID: 18217789: Abstract]. CHAPTER 49 Vision Loss—Sudden

SYNOPSIS Table 49.1: Time-scale development of visual loss Sudden vision loss (SVL) or acute visual loss is Sudden: less than 1 hour an ophthalmic emergency requiring immediate • Amaurosis fugax • Central retinal artery occlusion medical attention to avert permanent visual • Acute angle closed glaucoma impairment. • Vitreous hemorrhage SVL means anything from instantaneously • Migraine to over the course of a week (Table 49.1). It can Within 24 hours • Central retinal venous occlusion be total, partial, transient, or permanent; • Hysteria involving either one or both the eyes. Less than 7 days Patients with SVL present with variable • Retinal detachment symptoms. Some patients describe it as a gray-black • Optic neuritis curtain that moves up or down, fogging, blurring, • Endophthalmitis (after injury or postoperative) dimming vision, halos around lights, flashing lights, Up to several weeks/months/gradual • Papilledema and ‘spider webs’ in peripheral vision. • Malignant hypertension The physician’s role is to recognize the signs • Cataracts and symptoms of SVL, assess the vision rapidly, • Diabetic retinopathy • Macular degeneration obtain an immediate ophthalmic consult, and • Chronic glaucoma stabilize the patient until the patient is seen by • Compression of visual pathway an ophthalmologist. • Retinitis pigmentosa

DIFFERENTIAL DIAGNOSIS • Central retinal venous occasion (CRVO) Common • Cerebrovascular accidents • Acute angle closure glaucoma (AACG) • Transient ischemic attack (anterior circulation) • Vitreous hemorrhage • Migraine (ophthalmoplegic). 336

Occasional • Visual field: • Nonarteritic anterior ischemic optic  A quick assessment of the vision may be neuropathy 1 (NAION: vide infra ↓↓) done, testing each eye separately. • Arteritic anterior ischemic optic neuropathy  If possible, assess acuity using a Snellen chart (AAION,* e.g. temporal arteritis) at 3 meters instead of 6; if the patient sees the • Central retinal artery occlusion (CRAO) top letter (6/60), it would be recorded as 3/60. • Retinal detachment  If the acuity is less than 3/60, check if the • Posterior uveitis patient can count fingers (CF) at a distance • Cortical blindness. of one meter, or see hand movements (HM).  If he cannot CF or see HM, check if he can Rare perceive a bright light (by shining the • Trauma (optic nerve injury, ruptured globe) bright light in each eye), and note • Acute demyelinating optic neuritis2 (multiple whether there is perception of light (PL) sclerosis) or not (no PL or NPL). • Malingering.  Checking the confrontation fields, with HM in the four quadrants give an idea of INVESTIGATIONS—GENERAL AND visual field loss. SPECIFIC • Swinging flashlight test: (objective)  This test is performed to test for relative (Ref. Chapter 48: Vision Loss – Gradual p. 330) afferent pupillary defect (RAPD)†, also called CLINICAL NOTES as Marcus Gunn pupil.  The test is performed by having the patient • Many causes of loss of vision (sudden and look into the distance and then shining a gradual) have a vascular etiology and light into one eye, thus eliciting pupillary generally affect older patients. In these cases constriction in that eye and consensual it is important to search for and treat constriction in the other eye. The light is systemic hypertension, diabetes, cardiac, then quickly moved in front of the other and carotid disease pupil, which normally should constrict • In addition to historical notes explained in further. If this additional constriction does the Chapter 48 ‘Vision Loss – Gradual’, (p. 330), not occur and the pupil dilates instead, the following physical examination should RAPD is present. The test is repeated several be performed in rapid sequence times. The presence of RAPD requires • As the patient’s assessment of visual loss and further evaluation by an ophthalmologist. its severity is highly subjective, a quick • Causes of SVL are generally grouped in two, objective assessment of the vision should be namely, bilateral and unilateral, most of them done after testing each eye separately with either being transitory, and few causing a Snellen chart, whenever possible. permanent visual loss. (Tables 49.2 and 49.3).

* There are 2 types: arteritic and nonarteritic. AAION is an inflammatory vasculitis, and NAION is a diagnosis of † RAPD is always unilateral. Since light in one pupil causes exclusion, which is made in the absence of provable both pupils to constrict, quickly switching from one eye arteritis. NAION is more common than AAION due to to the other will give a “relative” indication of the temporal arteritis. NAION is the most common acute optic functioning of each eye and optic nerve. If both eyes are neuropathy and one of the most common causes of sudden equally dysfunctional, no “relative” defect would be vision loss in the elderly. found; hence ‘bilateral’ RAPD does not exist. Vision Loss—Sudden 337

Table 49.2: Bilateral vision loss of sudden onset • Due care must also be taken not to diagnose • Migraine with usual aura seemingly inappropriate behavior (due to • Vertebral artery spasm/embolism vision loss) as of psychogenic in origin • Bilateral optic nerve damage • Beware of acute presentation of vision loss • Occipital lobe infarction • Occipital lobe trauma that is actually of chronic (gradual) onset, but suddenly noticed by the patient.

Table 49.3: Unilateral vision loss of sudden onset SELECTIVE GLOSSARY • Amaurosis fugax • Migraine with visual aura Nonarteritic Anterior Ischemic Optic Neuropathy • Central retinal artery/vein occlusion (NAION)3,4— It refers to an idiopathic ischemic • Acute angle closed glaucoma • Retinal detachment process of the anterior portion of the optic nerve. • Vitreous hemorrhage The typical presentation is sudden and painless • Temporal arteritis • Optic neuritis (e.g. multiple sclerosis) visual loss with examination features of an optic • Ischemic optic neuropathy neuropathy. Among the various associated risk factors are optic disk morphology (crowded disk), • Hysterical blindness or loss of vision—A advanced age, systemic arterial hypertension, purely functional loss of vision can be diabetes mellitus, hyperlipidemia, nocturnal assumed when the orientation while hypotension, hemoconcentration, hemodilution, walking is intact, pupillary light reflex is and hypercoagulable states. Since the introduction normal, and visual field is markedly of PDE-5 inhibitors for the management of erectile restricted or inconsistent on repeated dysfunction 10 years ago, there have been a number examination. If the patient indicates a of reports of patients developing, within hours of unilateral loss of vision, the examination PDE-5 inhibitor use, permanent visual loss due to should be conducted in such a way that the NAION. In some of the cases, visual loss recurred patient is unaware of which eye is being upon rechallenge with the drug. However, as the tested or the actual size of the optotypes. bulk of the evidence suggesting a relationship between PDE-5 inhibitor use and NAION comes RED FLAGS from case reports and small series, it is difficult to • In an elderly with SVL—Exclude temporal ascertain if a cause-effect relationship truly exists. arteritis that is typically associated with However, following a series of such case reports, high ESR; timely high-dose steroids will WHO and FDA have labelled the association avert permanent visual loss in the affected between use of PDE-5 inhibitors and risk of NAION eye and protects the other eye from the same as ‘possibly’ causal. NAION has also been reported fate. This is one critical situation where a in patients taking several other medications, physician takes immediate precedence over specifically sumatriptan, amiodarone, and nasal an ophthalmologist decongestants. • Beware of atypical presentations, e.g. Since NAION is not a disease entity but rather nausea, vomiting, or abdominal pain, and/ or the common pathogenetic pathway of a large a seemingly innocuous red eye; AACG may variety of diseases and conditions, and is often be missed the result of several interacting factors, there is 338 Diagnosis: A Symptom-based Approach in Internal Medicine no ‘standard therapy’ for NAION. Careful Ophthalmol 2007;91(11):1551-5. [PMID: 17947271: Abstract]. interdisciplinary work up in NAION frequently 2. Brass SD, et al. Acute demyelinating optic reveals previously unrecognized diseases neuritis: A review. Front Biosci 2008;13:2376- requiring treatment according to internal 90. [PMID: 17981719: Abstract]. 3. Unsold R, et al.Anterior ischemic optic neuropathy: medicine standards. Etiology, pathogenetic mechanisms and therapy. Ophthalmologe. 2008;105(9):867-82. [PMID: REFERENCES 18810458: Abract]. 4. Thurtell MJ, et al. Nonarteritic anterior ischemic 1. Danesh-Meyer HV, et al. Erectile dysfunction optic neuropathy with PDE-5 inhibitors for drugs and risk of anterior ischaemic optic erectile dysfunction. Int J Impot Res 2008 Jun 5. neuropathy: Casual or causal association? Br J [Epub ahead of print]. [PMID:18528398: Abract]. CHAPTER Weakness in the 50 Arms and Legs

SYNOPSIS Grade Muscle examination Weakness of the limbs is one of the most common 0/5 No muscle movement (i.e. complete paralysis) 1/5 Variable muscle movement (i.e. flicker of complaints presented to the physician, which contraction possible), but no movement at the may be part of any debilitating illness such as joint systemic infection, malignancy, or psychiatric 2/5 Movement is possible at the joint, but not against gravity disorder. In such cases there are usually pointers 3/5 Movement against gravity possible, to the cause of suspected disorder. But, when but not against added resistance limb weakness, i.e. true lack of strength is the 4/5 Movement against resistance possible, but less than normal only principal complaint, it is more likely that 5/5 Normal strength there is an underlying neuromuscular disease. Since weakness of neuromuscular origin is 3 – The neuromuscular junction transmission manifested by objective evidence of reduced system muscular strength, physically testing the strength 4 – The skeletal muscle of an individual muscle or muscle group is an important early step in the evaluation of Normal muscle strength depends princi- weakness.* The following standardized physical pally on normal functioning of a relay of the findings are followed in grading muscle strength above four systems, and any dysfunction at one on the scale of 0 to 5 ‘out of five’. or more of these four levels, which includes Neuromuscular diseases that result in limb malfunction in the cerebral hemisphere, brain- weakness are best understood on the basis of stem, spinal cord, nerve roots, peripheral nerves, neuroanatomy of the motor pathways, which myoneural junctions, and within the muscle consists of four integrated systems: itself can manifest in neuromuscular diseases. 1 – The upper motor neuron (UMN) system 2 – The lower motor neuron (LMN) system DIFFERENTIAL DIAGNOSIS Common * Muscle must be tested in such a way that the examiner’s and the patient’s strength are fairly evenly matched. • Cerebrovascular disease (stroke): 340

TIA; cerebral infarction/thrombosis/ • Spinal cord infarction (cerebral spinal artery embolism; Intracranial hemorrhage: thrombosis). subarachnoid hemorrhage/Subdural hematoma Rare • Trauma: Head injury; spinal cord injury: Vertebral • Cerebral venous sinus thrombosis: displacement, fracture Cavernous sinus thrombosis • Infections: Superior sagittal vein thrombosis Bacterial — Meningitis, TB; tuberculoma. • Multiple sclerosis or other demyelinating Viral — Meningitis, encephalitis, herpes, disorder and HIV • Motor neuron disease: Cerebral abscess Progressive muscular atrophy Spinal epidural abscess Amyotrophic lateral sclerosis (ALS) • Peripheral neuropathies: Progressive bulbar palsy Diabetes mellitus • Muscular dystrophy Alcoholism Nutritional deficiencies—thiamine, • Neuromuscular junction disease (Myas- thenia gravis) vit.B12, folic acid • Cervical and lumbar radiculopathies: • Spinal cord disease (syringomyelia, syringo- Cervical spondylotic myelopathy bulbia) Lumbar disc. herniation. • Metabolic (acute porphyria) • Infections (poliomyelitis, tetanus, rabies, Occasional syphilis). • Hypertensive encephalopathy • Trauma (chronic subdural hematoma) INVESTIGATIONS—GENERAL • Infections: Protozoal (malaria, toxoplasmosis) CBC Helmenthic (cysticercosis, hydatid disease) • Hb may be reduced in chronic infection / Fungal (cryptococcus, Candida) inflammation; exacerbates muscular weakness. • Intracranial neoplasm (glioma, meningioma) • Pernicious anemia is common in nutritional • Spinal cord neoplasm (both intramedullary deficiency causing weakness. and extramedullary) • Metastases (cerebral and spinal: from breast, bronchus, prostate) ESR • Inflammatory (Guillain Barré syndrome , i.e. GBS) • Elevated in infection, inflammation, auto- • HIV associated myelopathy immune disorders. • Entrapment neuropathies: Brachial plexus lesion (Erb-Duchenne) Ulnar nerve palsy (claw hand) Blood Glucose Radial nerve palsy (wrist drop, Saturday • To monitor hypoglycemia and hypergly- night palsy) cemia associated with weakness, neuro- Median nerve palsy (carpal tunnel syndrome) Peroneal palsy (foot drop) pathy. 341

Biochemistry and Metabolic Panel • Elevated, 2 to 3 times normal in MND.

• LFT, urea, electrolytes, calcium – to evaluate Serum Acetylcholine Receptor Antibody Titer associated disorders. • Elevated levels in myasthenia gravis. Thyroid Function Tests ANA • Hypothyroid and thyrotoxicosis can cause muscular weakness • In rheumatologic myopathy: If ANA is • Myasthenia gravis (thymic tumor) may be positive, additional work up may include associated with thyrotoxicosis. rheumatoid factor (rheumatoid arthritis), antidouble-stranded DNA or antiphospho- CT Scan Brain lipid antibodies (lupus), or anticentromere • Ideally it should be done on every patient antibodies (scleroderma). with stroke as soon as possible. If the deficit is Tensilon (Edrophonium chloride) Test secondary to hemorrhage, it will immedia- tely be apparent (and such patients should • In myasthenic patients, IV administration of not be anticoagulated) endrophonium, there is an obvious • It is important to correlate CT scan findings improvement in strength of weak muscles with patient’s neurologic examination; lasting for about 5 minutes. patients with old or clinically silent infarcts may be irrelevant to the acute situation. Urine

X-ray Skull, Cervical and Lumbosacral Spine • Estimation of urinary aminolaevulinic acid, • To evaluate fracture of skull vault or base porphobilinogen, and porphyrin in patients • Spinal X-rays for fracture, infection, inflamma- with porphyria. tion, degenerative, and metastatic lesions. CT—Thorax CXR • CT of the anterior mediastinum may be • May show lytic bone or mass lesion due to indicated in patients suspected with bronchial cancer thymoma (neoplastic change) in myasthenic • Lateral and anteroposterior view of CXR may patients with associated disorders demonstrate thymoma. • A thymic shadow on CT scan may normally be present through young adulthood, but INVESTIGATIONS—SPECIFIC enlargement of the thymus in a patient > 40 1, 2 Blood Culture years old is highly suspicious of thymoma.

• For specific bacterial, viral, fungal organisms MRI—Cervical and Lumbosacral Spine causing meningitis, encephalitis. • Useful in obtaining more information about Creatine Kinase (Total)—(CK) lesions already seen on CT scans and in • Markedly elevated, 10 to 200 times normal, diagnosing white matter lesions, e.g. in muscular dystrophy, and inflammatory multiple sclerosis, and lesions in the posterior myopathies fossa. 342

Magnetic Resonance Angiography (MRA) • CSF electrophoresis normally detects oligoclonal bands in multiple sclerosis. • Indicated to investigate abnormalities of intracerebral vessels such as arterial (berry) Nerve Conduction Study (NCS) aneurysms or arteriovenous malformations, or to delineate blood supply of tumors prior • In various neuropathies to assess damage to to surgery. peripheral nerves, and to determine whether the lesion is focal, diffuse, axonal, or US (Duplex Scanning) of Carotid and demyelinating. Vertebral Arteries in the Neck Electromyography (EMG) • Used as a screening tool to obtain information about the degree of respective arterial • Used to investigate disorders of neuro- stenosis in patients with stroke. muscular transmission such as myasthenia gravis and myopathic disorders such as CSF Analysis muscular dystrophies.

• Immediate lumbar puncture is indicated in Muscle Biopsy suspected cases of CNS infection (without evidence of increased intracranial pressure) • Confirms that the weakness is due to a • When a CT scan is not available and primary disorder of muscle and to distinguish anticoagulants are anticipated; bloody or between various muscle diseases. Using MRI xanthochromic CSF should be a contraindi- to identify focal areas of muscle abnormality cation to anticoagulation can increase the diagnostic yield from muscle • Gram’s stain of CSF sediment will show biopsies. organisms in majority of untreated bacterial meningitis cases. India ink preparation for CLINICAL NOTES cryptococcus and AFB stains for TB bacilli • A thorough history is essential to distinguish are usually positive between primary (i.e. intrinsic) muscle • CSF culture should include bacteria (aerobic and weakness from ambiguous terms such as anaerobic), TB, brucella, fungi, and viruses fatigue and asthenia (Table 50.1). • CSF for cryptococcal capsular antigen should • Fatigue is a subjective feeling of weakness be done when fungal meningitis is suspected, characterized by an inability to perform a task especially in those who are immuno- after multiple repetitions; in contrast, a compromised patient with primary muscle weakness is • CSF for syphilis serology, e.g. venereal unable to perform the first repetition of task. disease research laboratory test (VDRL), Asthenia is a sense of exhaustion in the fluorescent treponemal antibody absorption * absence of muscle weakness . test (FTA-ABS) • The next step is assessment and localization • CSF IgG and measles antibody titers must be 3 of muscle weakness which includes: obtained if subacute sclerosing panence- phalitis (SSPE) is suspected * Fatigue and asthenia can coexist with primary muscle • PCR amplification of viral gene sequence can weakness which may lead to delay in the diagnosis of muscle disease because weakness is misinterpreted as be performed in patients suspected with viral fatigue/asthenia; specific screening tools may be essential encephalitis and myelitis to differentiate them. 343

Table 50.1: Common causes of fatigue and athenia to occlusion of anterior spinal artery • Anemia (common in patients with aortic athero- • Anxiety sclerosis, aortic aneurysm) • Addiction—abuse-alcohol, narcotics • Subacute onset weakness in the limbs, i.e. • Cardiac disease CHF • Chronic fatigue syndrome evolving over a few days or weeks, is usually • Depression seen in diseases such as meningitis, • Dehydration and electrolyte disorders encephalitis, neoplasms, multiple sclerosis, • Deconditioning/sedentary lifestyle • Drugs — adverse effects myasthenia gravis, and dermatomyositis • Diabetes • Chronic limb weakness, which evolve over • Fibromyalgia weeks or months (some overlap with • Hypothyroidism • Infection — chronic-TB, hepatitis, HIV disorders mentioned above), include motor • Pain—chronic neuron disease, most neuropathies, and • Pregnancy/postpartum • Pulmonary – COPD many genetic muscular diseases • Renal – ESRD • The combination of UMN and LMN signs in • Sleep disorders a patient is an important clue to the diagnosis of motor neuron disease, e.g. ALS 1. Distribution: • The combination of distal muscle weakness  a few muscles and sensory loss is commonly due to  a limb (monoparesis) peripheral neuropathy  both lower limbs (paraparesis) • The combination of proximal muscle  both limbs on one side (hemiparesis) weakness without sensory loss is commonly  all four limbs (quadriparesis). 2. Type of weakness: due to myopathy  upper motor neuron lesion • History should be focused to elicit infor-  lower motor neuron lesion mation that will provide clues to the cause  both UMN and LMN, or neither. of weakness: (Table 50.2) 3. Evolution of weakness:  Onset—to establish if acute or chronic  sudden and improving  Alteration of consciousness, headache,  gradually worsening over days or weeks visual disturbances  evolving over months or years  Gait—disturbances of equilibrium The time course of the onset of weakness,  What muscles are affected by the i.e. (evolution) is usually helpful in deter- weakness? e.g. foot, lower leg, thigh, mining the possible etiology. upper arm, lower arm, facial, or back • Generally the rate of onset of limb weakness  Are both sides of the body affected by may be divided into acute, subacute, and weakness and is it symmetrical? This chronic information helps determine which • Acute onset limb weakness is typical vascular joints, muscles and /or nerves may be events, affecting contralateral UMN path- affected, e.g. peripheral muscle weakness ways, resulting in either hemiparesis or due to peripheral neuropathy is sym- hemiplegia metrical compared with individual nerve • Sudden onset weakness in all four limbs or nerve root disease which should be (tetraparesis) or in both legs (paraparesis) is suspected if weakness is asymmetrical or seen with spinal cord infarction, usually due confined to one limb 344

Table 50.2 : Historical clues for neuromuscular weakness  History of trauma—It can determine possible cause of muscle weakness Findings Probable diagnosis  Exercise history—Muscle overuse may Acute weakness with Stroke; spinal cord injury neurologic deficit(s) cause muscle weakness. Intermittent neurologic TIA • Past medical history—Diabetes and chronic deficit renal failure can cause peripheral neuropathy Fever, coryza, headache Viral meningitis, encephalitis which may result in muscle weakness; diabetes, Fever, otitis, sinusitis Bacterial meningitis, cerebral hypertension and high cholesterol are risk abscess Risky sexual exposure, Gonococcal, syphilis, HIV factors for cerebrovascular disease (stroke) Urethral discharge which may result in muscle weakness; Symptoms of raised Mass lesion pernicious anemia may cause subacute intracranial pressure combined degeneration of the cord and muscle Exercise-provoked Myasthenia gravis weakness weakness. History of TB, malignancy may Heat-induced symptoms Multiple sclerosis suggest infection or mass lesion (hot sun, hot shower, • Dietary history—Vit. B12 deficiency can cause fever); double vision- peripheral neuropathy which may result in blurring; multiple neurologic deficit, muscle weakness exacerbations and • Medications—Some medications can cause remissions peripheral neuropathy, e.g. amiodarone, Neck / back pain with or Cervical spondylosis, without radiation degenerative disk disease phenytoin, nitrofurantoin; some medi- Rash around eyelids, Dermatomyositis, cations may increase risk of thrombotic difficulty arising from polymyositis cerebrovascular disease (stroke), e.g. oral a chair contraceptive pill, hormone replacement Positive medication Drug-induced myopathy history (statins, steroids, anti- therapy; some medications can increase the retrovirals) risk of hemorrhagic stroke, e.g. warfarin Positive family history Muscular dystrophy, • Cigarette smoking—It is a major risk factor autoimmune disorder for cerebrovascular disease • Alcohol history—It can be a cause of  If there is limb weakness, are the facial muscles peripheral neuropathy also affected by weakness?—weakness of the • Family history—Strokes, diabetes, high muscles of the face associated with weakness cholesterol, hypertension, hereditary motor of the limbs would suggest a diagnosis of and sensory neuropathy, Duchenne muscular cerebrovascular disease, a mass in the brain dystrophy or spinal cord • Physical examination includes:  Aggravating factors—They help to  Gait, neck stiffness determine the cause of muscle weakness,  Glasgow coma scale , (GCS) i.e. level of e.g. muscle power decreases with use in consciousness myasthenia gravis  Blood pressure, palpation of all peripheral  Recent viral infection—May suggest a viral pulses including carotids for bruits; illness itself as the cause of muscle cardiac examination for arrhythmias, weakness, e.g. influenza or Guillain- Barré murmur syndrome (symptoms begin 7-10 days  Optic fundi for papilledema, diabetes and after the infective illness) hypertensive retinal lesions. Weakness in the Arms and Legs 345

• Examination of motor system includes: must be excluded before a vascular or  Observation for gait, involuntary move- thromboembolic cause for stroke is ments, muscle symmetry (left to right and considered. proximal vs. distal), atrophy, especially in • Acute spastic paraparesis, i.e. bilateral lower shoulder, hands, thigh muscles. limb paresis with increased tone, such as in  Muscle strength, deep tendon reflexes prolapsed disk, traumatic vertebral fracture/ including plantar response, clonus, displacement, collapsed vertebra, etc. is a fasciculations and coordination of upper medical emergency. and lower limbs. • Myasthenia gravis should be strongly  Testing for range of movements in a suspected in any patient who reports variety of joints may be necessary. excessive weakness at the end of the day. The • Examination of sensory system includes – complaints of weakness are often bizarre, testing sensation of upper and lower limbs interpreted frequently as psychiatric for pain, touch, temperature and vibration disorder, especially since routine neurologic sensation. Examination of each nerve of the examination is normal in most patients. limb is important. • Beware of Pancoast tumor of the lung in a • Arm drift or pyramidal drift of an upper limb: patient with upper limb weakness with Rather subtle weakness may be detected by painful neuropathy (due to neoplastic having the patient close the eyes and hold infiltration of the lower trunk of the brachial both arms, palm up, extended at the wrist and plexus), especially when Horner’s syndrome elbow. With a pyramidal (UMN) lesion, the is present. affected limb drifts downwards and • Paraneoplastic neurologic syndromes must medially. The forearm tends to pronate and be considered in the diagnosis of unusual, the fingers flex slightly. This sign is often first progressive neuromuscular syndrome. to occur, sometimes before weakness or reflex • Rule out lesions of extrapyramidal tracts (e.g. Parkinsonism) or cerebellar pathways which changes become obvious. may also present as weakness, but without RED FLAGS objective evidence of decreased muscle strength. • The following diseases, though not a part of primary neurologic etiology, must be REFERENCES excluded in a patient with muscular disorder, 1. Maher MM, et al. Imaging of thymoma. Semin which can otherwise cause significant Thorac Cardiovasc Surg. 2005 spring; 17(1):12-9. morbidity and mortality: 1-Adrenal insuffi- [PMID: 16104356: Abstract]. 2. Gamsu G, et al. Magnetic resonance imaging of ciency; 2-Electrolyte imbalance: sodium, benign mediastinal masses. Radiology. potassium, and magnesium; 3- Hypercalcemia; 1984;151(3):709-13. [PMID: 6718731: Abstract]. 4- Porphyrias; and 5- Rabies. 3. Allen CMC, et al. Neurological disease. In: Haslett Christopher et al. Editors, Davidson’s Principles • Complicated migraine, postictal (Todd’s) and Practice of Medicine. 19th edn. Churchill paralysis, hypoglycemia, cardiac arrhythmia Livingstone, 2002. CHAPTER 51 Weight Loss

SYNOPSIS weight is an important strategy in any clinical practice. Maintenance of body weight is determined by the Clinically, UWL is defined as loss of 5% or balance of caloric intake, absorption, utilization, more of usual body weight* over a period of 6 and metabolic rate which is regulated by an months, especially when progressive. It is also intricate network of neural and hormonal factors. categorized as significant when the weight loss is: In a healthy individual, body weight is 5% in one month, 7.5% in three months, and 10% in maintained at a stable ‘set-point’, which tends to six months.1 A severe weight loss is defined as any peak in the fifth to sixth decades of life. Once weight loss higher than those percentages in the same time has peaked, there is a relative stability, i.e. remaining interval stated above. This magnitude of weight loss stable until age 65 to 70. After the seventh decade can occur in people of all ages, and usually involves the elderly subject tends to develop very small underlying systemic disease, especially in the decrements in weight at a rate of 0.1 to 0.2 kg/year. elderly, resulting in increased morbidity and Therefore, any unusual weight loss should not be mortality rates. Therefore, an organized work up is dismissed as part of the aging process. essential for accurate and timely diagnosis. In the Whereas dieting, self-starvation, and eating majority, investigations based on symptoms and disorders (i.e. anorexia nervosa and bulimia physical findings reveal the underlying cause; a nervosa) explain most cases of intentional weight specific cause is not identified in approximately 15 loss (IWL), unintentional weight loss (UWL) can be to 25% of patients. In such minority of undiagnosed difficult to evaluate because of its nonspecific patients, it is always worth reviewing the patient’s concept and myriad diagnostic possibilities. Some history, and a period of watchful waiting is patients may be undisturbed by their weight loss, may welcome it, and may even mistakenly attribute it to their attempts to loose weight. * Ideal body weight can be estimated based on height. For However, when a marked fall in weight is the sole men, 106 lb (48.2 kg) is allotted for the first 5 ft, then 6 lb (2.7 kg) is added for each inch above 5 ft; for women, 100 lb or dominant symptom, it may suggest an organic (45.5 kg) is given for the first 5 ft, with 5 lb (2.2 kg) added etiology. Therefore, routine determination of body for each additional inch. 347 preferable to blind pursuit of additional diagnostic • Neurologic (dementia, Parkinson’s disease, testing that may yield few useful data, if the results stroke) of these initial tests are normal.2 • Metabolic (hypercalcemia, hypokalemia) • Endocrine (Addison’s disease). DIFFERENTIAL DIAGNOSIS INVESTIGATIONS—GENERAL Common CBC • Infection (aggressive TB, occult abscess, giardiasis, HIV/AIDS) • Hb reduced in infection, malignancy • Psychiatric (depression, bipolar disorder, • Leukocytosis due to infection in HIV personality disorders) • Elevated MCV in alcoholism • Diabetes mellitus (poorly controlled Type 1 • Macrocytic anemia in malabsorption, food and Type 2) faddism, and IBD. • Nonmalignant GI disorders (PUD, advanced liver disease) ESR • Malignancy (gastrointestinal, hepatobiliary, lungs, breast, genitourinary, ovarian, prostate, • Elevated frequently in infection, malignancy. lymphomas) Urinalysis • Chronic drug use (digoxin, metformin, opiates, cytotoxics) • Glucose with diabetes mellitus; ketone • Food faddism (eating disorders: anorexia bodies with DKA and malnutrition. nervosa, bulimia, and Eating Disorder-Not • Proteinuria, hematuria in renal disorders. Otherwise Specified, i.e. ED-NOS:3 vide infra ↓↓) Blood Glucose • Substance abuse (alcoholism) • Physiologic anorexia of aging (poor dentition, • To detect and monitor diabetes mellitus xerostomia, altered taste). • Hypoglycemia in Addison’s disease.

Occasional HIV

• Nonmalignant GI disorders (chronic panc- • In patients with any sexual risk factor. reatitis, gastroparesis) • Hyperthyroidism Urea, Creatinine, Electrolytes • Organ failure (advanced CHF, COPD, • Progressively increasing levels in renal hepatic, and renal disease) failure • Social stressful events (economic hardship, • Hyponatremia with hyperkalemia in isolation). Addison’s disease. Rare Tuberculin or PPD Test • Substance misuse (diuretics, laxatives, • A positive reaction (≥10 mm of induration) cocaine, amphetamine) indicates TB infection; may be negative in • Nonmalignant GI disorders (IBD, mala- patients with severe weight loss and AIDS. bsorption, celiac disease) 348

LFTs to detect esophageal (including Barrett’s esophagus), gastric, or colonic malignancy, • Elevated bilirubin, and transaminases; especially in elderly patients with chronic usually associated with hypoproteinemia in loss of weight hepatic failure. • Distal duodenal or proximal jejunum biopsy TFTs may help to identify the cause of malabsorp- tion such as celiac disease • Decreased TSH with increased FT4 in • Colonoscopy may be performed to screen for primary hyperthyroidism. malignancy in patients with IBD. Serum Calcium CT / MRI Abdomen • Hypercalcemia in malignancy, myeloma, and • Valuable to identify distant metastasis and Addison’s disease. direct invasion of adjacent structures (usually CXR preoperatively).

• Often reveals infiltrates (e.g. tuberculosis, Fecal Fat pneumocystic carinii pneumonia due to opportunistic infections), mass (neoplasm), • The standard collection is for 72 hours, on a lymphadenopathy (lymphoma, sarcoidosis), normal diet containing at least 100 g of fat fibrosis, and cardiac failure. daily. Excretion of more than 10 g of fat/day of fat is abnormal and warrants further Stool evaluation for malabsorption. • Ova and parasites; occult blood in colorectal Antigliadin Antibodies carcinoma. • Cryptosporidium (in AIDS) can be detected • IgG or IgA antigliadin antibodies may be with modified acid-fast stain. detected in patients with celiac disease.

INVESTIGATIONS—SPECIFIC Other Screening Procedures

US Abdomen / Pelvis • In women, mammography and cervical Pap ≥ • May be indicated to evaluate suspected smear; PSA in men aged 50 years and in abdominal masses (with guided needle specific patients with risk factors. aspiration and biopsy),e.g. abscesses, • Mesenteric duplex US: In elderly patients organomegaly, ascites, lymphadenopathy, suspected with mesenteric ischemia. and biliary-tract dilatation. • Morning (AM) cortisol / ACTH stimulation • Bilateral small, scared echogenic kidneys test or cosyntropin stimulation test: Low (<10 cm) suggest chronic renal failure. plasma cortisol (<3 mcg/dl) at 8AM is diagnostic, especially if accompanied by Endoscopy simultaneous elevation of the plasma ACTH • Gastroscopy or colonoscopy with cytologic level (usually >200 pg/ml) is diagnostic of brushings and biopsies of suspicious lesions Adrenal insufficiency. 349

CLINICAL NOTES • Symptoms and signs—The key topics to cover in the history should include the American • The initial approach to evaluating a patient with Cancer Society’s seven warning signs of UWL is to verify that weight loss has occurred, cancer. Therefore, the review of systemic and its duration. This can be done directly by symptoms must include history of fever, verifying patient’s records if available; or cough, dyspnea, abdominal pain, dysphagia, indirectly by noting physical evidence of dyspepsia, nausea, vomiting, change in bowel weight loss such as a change in clothing size or as observed by a family member. Once weight habits, melena, hematochezia, headache, and loss is confirmed, special attention should be other neurologic symptoms. Common clinical focused on the following: findings associated with weight loss are given • Diet—Its composition, including total calory in Table 51.1. intake per day† Table 51.1 : Weight loss - clinical correlation • Food habits—Especially in young women; their attitude towards food intake and body image Associated symptom Common causes and/or sign should be assessed. Disturbed body image may Appetite—normal or Diabetes mellitus, be a clue to the presence of an eating disorder increased hyperthyroidism, bulimia, • Lifestyle factors—Exercise; tobacco and pheochromocytoma alcohol consumption; drug abuse; sexual Appetite—diminished, Anorexia nervosa, behaviour are important and frequently lead anorexia medication effect, drug abuse, uremia, liver / to other concerns cardiac failure, • Medications—Prescribed (ACE-inhibitors, malabsorption digoxin, NSAIDs, theophylline, metformin), Fever Infection—TB, HIV; and over-the-counter should be reviewed collagen disease Lymphadenopathy Infection, leukemia, • Psychosocial factors—A thorough evaluation lymphoma, sarcoidosis of sources of stress, depression, or special Thyromegaly Hyperthyroidism situational problems is important. All elderly Thyroid nodule Toxic adenoma patients with weight loss should undergo Abdominal mass Hepatomegaly, ‡ screening for dementia and depression which splenomegaly, renal mass, may provide evidence of a mood or eating pancreatic neoplasm disorder Abnormal rectal/pelvic Prostate, cervical, uterine findings lesion • Appetite—Weight loss in spite of increased Hyperpigmentation, Addison’s disease appetite and intake suggests diabetes hypotension mellitus, thyrotoxicosis, or bulimia; whereas Abnormal CXR TB, CHF, COPD, weight loss with normal or decreased neoplasm appetite is usually due to other systemic Anorexia, normal physical Anorexia nervosa, uremia, examination, normal CXR substance abuse, disorders such as infection, organ failure, malabsorption, occult malignancy, and psychologic illness. malignancy (pancreatic)

RED FLAGS † Web site: www.mna-elderly.com; for Mini Nutritional • A high index of suspicion is essential to Assessment tool. diagnose eating disorders; patients can be ‡ Refer to Mini-Mental State Examination (MMSE) and Yesavage’s Geriatric Depression Scale in standard text- very manipulative, critical, and secretive, and books. commonly lie about food intake 350

• Consider depression in most patients with any specific eating disorder, and therefore weight loss. It may be the primary cause or present with subsyndromal cases of anorexia may coexist with any secondary illness nervosa or bulimia nervosa. Examples include: • UWL, when accompanied with anorexia, • A female of anorexia nervosa, except that she may be the only sign of malignancy has regular menses • Occult malignancy must be regarded as the • A female of anorexia nervosa, without weight most common cause of weight loss in the loss • A female frequently indulging in self- absence of major symptoms and signs induced vomiting after eating even a small • Continued weight loss should be monitored food intake even if the initial evaluation is nondiagnostic • A female repeatedly chewing and spitting • Weight loss may be the initial presentation out, but not swallowing large amounts of of diabetic ketoacidosis food. • Beware of the potential for associated substance abuse. REFERENCES

SELECTIVE GLOSSARY 1. Rakel TB of Fam Med 7th edn. Part IV: Nutrition and Family Medicine; p.1097. Eating Disorder-Not Otherwise Specified— 2. Metalidis C, et al. Involuntary weight loss. Does a negative baseline evaluation provide adequate ED-NOS(DSM IV TR-307.50) is an emerging reassurance? Eur J Intern Med 2008;19(5):345-9. issues in Eating Disorders; this diagnosis is given Epub 2007 Nov 26.[PMID: 18549937: Abstract]. to patients who have significant eating disorder 3. Kondo DG, Sokol MS. Eating disorders in primary care: A guide to identification and treatment. symptoms, but do not meet the full criteria for Postgrad Med 2003; 114: Nov (online article). NOTE

INDEX

A Age Aortic of menarche 45 dissection 50 Abdominal related macular degeneration stenosis 49 angina 10 331 Aortoduodenal fistula 147 CT scan 318 Agnosia 73 Aphasia 73 distension 1 Airway obstruction 111 Appendicitis 9, 10 pain 7, 8 Albuminuria in renal disorders 2 Apraxia 73 wall pain 10 Alcoholic Arrhythmias 226 Abnormal vaginal bleeding 315, hepatitis 3 Arterial blood gases 110 320 liver disease 196 Arthralgia 29 Acid fast stain 69 Alkaline phosphatase 2, 220 Arthritis 29 Acoustic neuroma 165, 328 Allergic rhinitis 69 Ascariasis 84 Acute Alport’s syndrome 174 Ascites 2 abdomen 9 Alzheimer’s disease 74, 79 Aseptic abortion 9 abdominal Ambulatory Asherman’s syndrome 19 conditions 14 ECG 226 Aspergillosis 177 pain 9 EEG 65 Aspiration 69 angle closure glaucoma 249, Amenorrhea 18, 315 Asteotic dermatitis 242 335 Aminotransferases 2 Asthma 114 backache 37 Amyotrophic lateral sclerosis 104, exacerbation 69 bacterial gastroenteritis 10 340 Atrial myxomas 281 bronchitis 69 Anal disease 148 Atrophy of vulva and vaginal skin chest pain 53 Analgesic 23 cholecystitis 9 nephropathy 235 Atypical chest pain 54 closed angle glaucoma 212 rebound headache 156 Autoantibody tests 200 coronary syndrome 48 Anaphylactic laryngeal edema 111 Autoimmune exacerbation of COPD 108 Ancylostoma duodenale 84 disease 19, 75, 333 hydramnios 9 Anemia 115, 197 disorders 128 intermittent porphyria 215 Angioedema 127, 308 Autologous serum skin test 310 laryngotracheobronchitis 109 Angioneurotic edema 109 Autonomic neuropathy 60 leukemia 132 Angiotensin-converting enzyme narrow angle glaucoma 156 122 B pancreatitis 9 Anhidrosis 264 Back pain 36 porphyria 340 Anorectal Bacterial infection 10 postinfection syndromes 296 and pelvic floor function tests Balloon expulsion test 59 respiratory distress syndrome 59 Barotrauma 165 109 manometry 59 Barrett’s esophagus 104 stress Anorexia nervosa 19, 58 Basilar migraine 282 disorders 285 Antalgic gait 139 Bell’s palsy 121 reaction 26 Anterior uveitis 249 Bence Jones protein 38 systemic illness 26 Antiacetylcholine antibodies 101 Benign urinary retention 9 Antibiotic-related diarrhea 60 breast disorders 42 viral hepatitis 196, 199 Antigliadin antibodies 348 disorders 316 Adams-Stokes attacks 281 Antimitochondrial antibodies 200 hematuria 170 Addison’s disease 10, 297 Antiphospholipid syndrome 273 intracranial hypertension 156 Adenocarcinoma 148 Anti-Smith antibody 32 neoplasm 99 Adrenal crisis 215 Anxiety 25, 220 prostatic hypertrophy 303 352

Berger disease 175 Carcinoid tumor 148, 181 Choroidal melanoma 331 Biliary Carcinoma of Chromosomal abnormalities 19 ascites 3 anus 60 Chronic colic 10 bronchus 43 active hepatitis 132 Biopsy 265, 271 colon 58, 60 anovulation 318 Bladder incontinence 63 rectum 60 backache 37 Bleeding 146 Cardiac bronchitis 114 diathesis 171 and bronchial asthma 112 daily headache 156 disorders 316 arrhythmias 49, 115 dyspnea 118 Blepharitis 249 causalgia 49 fatigue syndrome 193, 206, 220 Blind ending vagina 23 disease 333 glaucoma 331 Body enzymes 50, 278 illness 19 spasm 63 ischemia 212 infections 75, 148, 296 twitching 63 murmurs 230 low back pain 219 Boerhaave syndrome 216 syndrome X 49, 55 neck pain 219 Bone Cardiopulmonary exercise testing oral steroids 38 marrow aspirate and biopsy 117 overuse syndromes 220 244 Carney syndrome 282 pain 219 scan 221 Carotid syndromes 223 Bowel incontinence 63 Doppler papilledema 331 Brain scan 332 renal failure 235 and meningeal biopsy 77 ultrasound 325 subdural hematoma 156 natriuretic peptide 271 sinus hypersensitivity 277 Churg-Strauss syndrome 181 tumors 64 Casino’s test 3 Cirrhosis 3 Brainstem Cataract surgery 331 Clitoromegaly 23 auditory evoked responses Cauda equina syndrome 38 Clostridium difficile 60 166 Cavernous Cluster headache 156, 249 evoked potentials 293 hemangiomas 250 CMV retinitis 331 Breakthrough bleeding 316 sinus thrombosis 128 CNS Breast 44 Celiac sprue 60 diseases 292 abscess 43 Central disorders 212 cancer 44, 45 post-stroke pain 220 infections 121 lump 42, 42, 45 retinal venous occasion 335 tumors 121 Bronchiectasis 69, 70, 115, 177 Cerebellar gait 139 Cocaine lung 177, 182 Bronchitis 49, 177 Cerebral Coccydynia 38 Bronchogenic carcinoma 69, 70, malaria 121 Cogan’s syndrome 294 177 venous thrombosis 156 Cold Bronchoscopy 71, 110, 117, 187 Cerebrovascular accidents 121, abscess 43 Brown-Séquard syndrome 143 335 weather 303 Brucellosis 132 Cervical Collagen disease 30 Brugada syndrome 231 and lumbosacral spine 341 Colon malignancy 84 B-type natriuretic peptide 116 culture 317 Colonic Budd-Chiari syndrome 3 spondylosis 156 arteriovenous 148 Burkitt’s lymphoma 128 Chair test 143 neoplasm 148 Burnout syndrome 297, 300 Charcot-Marie-Tooth syndrome 286 Common gait disorders 142 Chest Complex regional pain syndromes C pain 48 220, 223 wall Concealed accidental hemorrhage Calcium 207 bruising 49 9 channel blockers 156 syndrome 49 Congenital heart disease 226 Cancer of Cholecystitis 10 Connective tissue disease 132, 297 esophagus 147 Cholelithiasis 10 Constipation 57 stomach 147 Cholestatic Constrictive pericarditis 2 Cancer pain syndromes 220 jaundice 197 Contact lens Capsule endoscopy 149 pruritus 242 induced acute red eye 253 Carbohydrate malabsorption 91 Cholestatoma 165 use 251 Carbon monoxide poisoning 111 Choriocarcinoma 316 Conversion disorder 10 Index 353

Coombs’ test 200 Diarrhea 83, 87 Episcleritis 249 Core-needle biopsy 44 Dieulafoy’s lesion 152 Erectile dysfunction 260 Corneal Digital mammography 43 Erosive abrasion 249 Diphtheria 286 duodenitis 147 infection 249 Direct ophthalmoscopy 252 gastritis 147 ulcer 249 Disorders of Esophageal Coronary cerebral cortex 19 manometry 92, 100 angiography 51 genital outflow tract 19 motility disorders 99 artery disease 226, 277 hypothalamus 19 pH heart disease 54 ovary 19 manometry 93 ischemia 91 pituitary 19 monitoring 117 spasm 49 Disseminated carcinoma 132 varices 147 Costochondritis 49 Distended bladder 2 webs 99 Cough 68 Diuretic therapy 235 Esophagitis 147 Cranial nerve Diverticular disease 9 Esophagogastroduodenoscopy 71 neuropathies 285 Diverticulitis 60 Estrogen-progestin challenge test testing 168 Diverticulosis 58, 148 22 Creatine kinase 341 Dizziness 324 Eustachian tube dysfunction 164 Creutzfeldt-Jakob disease 75 Drug fever 132 External genitalia 23 Crohn’s disease 59 Dry skin 242 Extrahepatic obstruction 196 Cushing’s syndrome 127, 128 Ductal obstruction 264 Extraintestinal amebiasis 132 Cutaneous T cell lymphoma 242 Duodenal ulcer 96 Cyanotic heart disease 226 Dysfunctional uterine bleeding 316 F Cyclic Dysmenorrhea 10 citrullinated peptide antibody Dyspareunia 260 Facial 32 Dyspepsia 90 edema 127 vomiting syndrome 216 Dysphagia 97 myokymia 123 fibrosis 177 lusoria 105 nerve lesion 123 Dyspnea 108 palsy 122, 285 D spasm 63 E swelling 127 Da Costa syndrome 220 Factitious Damage to sweat gland 264 Early menarche 45 fever 136 D-Dimer test 271 Eating disorder 58 hemoptysis 177, 182 Deep venous thrombosis 132 Eccrine sweat glands 263 Fasting serum gastrin 93 Degenerative Ectopic pregnancy 9, 316 Fatal familial insomnia 193 disease 75 Edrophonium chloride test 341 Fecal disorders 64, 74 Ekbom syndrome 193 fat 348 Dejerine-Roussy syndrome 286 Emotional facial palsy 123 impaction 60 Delusion of parasitosis 247 Endocrine leukocytes 84 Dementia 73 disorders 58, 75, 242 occult blood 10 Dental abscess 127 hormone assays 21 Female Depression 220 Endometrial athlete triad 19 Dermatitis herpetiformis 242 ablation 19 sexual arousal disorder 260 Dermatomyositis 128 biopsy 318 Festinating gait 139 Dexamethasone suppression test function 18 Fibromyalgia 49, 220, 300 22 Endoscopic Fluorescein Diabetes retrograde angiography 332 insipidus 235, 238, 303 cholangiopancreatography 200, dye test 252 mellitus 19, 91, 220, 235, 285, 243 Food 303, 318 ultrasound 12 allergy 242 Diabetic Eosinophilia-myalgia syndrome poisoning 60, 84 autonomic neuropathy 84 209 Foreign body gastroparesis 4 Eosinophilic aspiration 109, 177 ketoacidosis 111 cystitis 306 trauma 171 maculopathy 331 esophagitis 99, 105 Fractures of temporal bone 121 neuropathy 60, 121 pneumonia 69 Free testosterone 21 354 Diagnosis: A Symptom-based Approach in Internal Medicine

Frey syndrome 267 Hepatitis Imperforate hymen 19, 23 Friedreich’s ataxia 144 C viral infection 203 Implantable loop recorder 278 Fukuda test 143 viruses 203 Infection of diverticulum 60 Fulminant hepatic failure 3 Hepatobiliary Infective endocarditis 132 Functional disease 91 Infertility 318 chronic constipation 57 neoplasms 91 Infestations diarrhea 1 dyspepsia 90, 93 Hepatocellular jaundice 197 Inflammatory bowel disease 84, GI disease 49 Hereditary 148 GI disorders 1, 4 angioedema 312 Injuries of breast 43 Fungal infection 177 hemorrhagic telangiectasia 152 Insomnia 189 nephritis 174 Intercostals neuritis 49 G periodic fever syndromes 132 Interstitial Hernia 9 cystitis 303 Herpes zoster 49, 285 Gag reflex 103 lung disease 69, 115 Hiatal hernia 99 Gait disorders 138 Intestinal obstruction 9, 58 Hirschsprung’s disease 58, 59, 61 Gallstones 49 Intra-abdominal Histocompatibility antigen test 39 Gastrinoma 91 lump 2 HIV 84, 265, 287, 347 Gastroesophageal reflux 220 malignancy 91 infection 132 Gastrointestinal Intracardiac shunts 115 bleeding 146 serology 71, 76, 200 Hodgkin’s disease 286 Intracranial tumors 331 disorders 220 Intraorbital tumors 331 Gastroparesis 91, 216 Holiday heart syndrome 232 Holter monitor 27, 278, 325 Intravascular ultrasound 51 Geriatric depression scale 191 Homans’ sign 272 Intravenous Gestatory hyperhidrosis 264 Homocystinuria 331 pyelography 305 GI disorders 212 Hoover sign 143 urography 305 Giant Hperhidrosis 264 Iodine starch test 265 cell arteritis 156 Human leukocyte antigen 32 Ionizing radiation exposure 45 ulcers 96 Hydatid cyst 3 Irritable bowel syndrome 220 Giardiasis 1 Hypercalcemia 91, 96, 171 Irritant contact dermatitis 242 Gilbert’s disease 201, 202 Hyperemesis gravidarum 212 Ischemic bowel disease 91 Glomus jugulare tumor 295 Hypereosinophilic syndrome 242 Isolated hematuria 171 Gluten sensitivity 60 Hypertensive retinopathy 331 Gram stain 69, 250 Hyperthyroidism 60, 64 J Granulomatous disease 250, 333 Hypertrophic cardiomyopathy 49 Graves’ disease 250, 270 Hyperuricosuria 171 Jaundice 195, 196 Guillain-Barré syndrome 111, 115, Hyperventilation 285 121, 285 Hypoactive sexual desire disorder K 260 Kala-azar 132 H Hypoalbuminemia 2 Kallmann’s syndrome 19 Hypoglycemia 64 Kaposi sarcoma 128 Harlequin syndrome 267 Hypohidrosis 264 Karyotyping 22 Head Hypohidrotic ectodermal dysplasia injury 64 265 Keratitis 249 trauma 121 Hypothalamic-pituitary-ovarian axis Keratoconjunctivitis sicca 250 Headache 155 18 Keyboard conjunctivitis 253 Hearing loss 121, 163, 164 Hypothermia 265 Klinefelter’s syndrome 260 Hypothyroidism 285 Heat stroke 264 L Helminthic infection 177 Hypoxic dementia 75 Hysteroscopy 22, 318 Hematemesis 146 Labile blood pressure 292 Hematochezia 61, 146 I Labyrinthine disorders 212 Hematuria 170 Labyrinthitis 165 Hemiplegic gait 139 Iatrogenic bleeding disorder 148 Laparoscopy 13, 22 Hemobilia 148 Ichthyosis 242 Laryngoscopy 103 Hemolytic jaundice 197 Idiopathic edema 274 Late menopause 45 Hemoptysis 176 IgA nephropathy 175 Laxative abuse 84 Hemorrhagic colitis 84, 88 Imminent eclampsia 9 Left ventricular failure 226 Hepatic transaminase enzymes 198 Immunofluorescent PCR tests 250 Leiomyoma 99 Index 355

Leprosy 285 Menarche 315 biopsy 129, 140, 207, 342 Leptospirosis 132, 200 Ménière’s enzymes 101, 140 Leriche syndrome 261 disease 292, 327, 328 overuse syndrome 206 Lichen syndrome 165 Muscular dystrophy 340 planus 242 Menopausal syndrome 297 Musculoskeletal disorders 219 simplex chronicus 242 Menopause 26, 264 Myalgia 205 Limb Menorrhagia 315 Myasthenia gravis 121, 300 jerking 63 Menstrual dysfunction 315 Myocardial infarction 111 paralysis 63 Menstruation 315 Myofascial pain 16, 220 Lipoma 43 Mesenteric Liver biopsy 200 adenitis 10 N Löffler’s syndrome 69 ischemia 84 Long QT-syndrome 226 Metabolic Nail patella syndrome 268 Low acidosis 109 Naproxen test 135 back pain 36, 39 disorders 58, 226 Nausea 211 calorie diet 58 syndrome 1 Neoplastic disease 75 fiber diet 58 Metastatic Nephrotic syndrome 3 Lower cancers 132 Nerve extremity neuropathies 285 malignancy 177 biopsy 287 limbs 286 Methacholine challenge test 116 motor neuron system 339 conduction study 287, 342 Methylenedioxy-methamphetamine Ludwig’s angina 128 Neurocirculatory asthenia 220 67 Lumbar puncture headache 156 Neuromuscular Metropathia hemorrhagica 316 Lung diseases 115 Metrorrhagia 315 abscess 69, 177 junction disease 340 Migraine 64, 156, 335 biopsy 117 junction transmission system syndromes 292 cancer 115 339 Migrainous neuralgia 249 Lyme Neuropathic pain 218 Mimic palsy 123 disease 121, 250, 285 Neurosyphilis 331 Mitral titer 122, 287 Night sweats 267 stenosis 69 Lymph node biopsy 244 Nociceptive pain 218 valve prolapse 26, 50, 226 Lymphoma 69 Nocturia 234 Mittelschmerz pain 10, 15 Nocturnal Mixed M penile tumescence 257 ascites 4 Magnetic incontinence 303 polyuria syndrome 234 gait 139 pain 218 Nonarteritic anterior ischemic optic resonance Morbihan’s disease 128, 130 neuropathy 337 angiography 342 Motility disorder 212 Non-cardiac chest pain 48, 54 cholangiopancreatography Motion sickness 212 Nonepileptic seizures 63, 64 12, 200 Motor neuron disease 121, 340 Non-Hodgkin’s lymphoma 132, venography 271 Müllerian dysgenesis 19 286 Malabsorption syndrome 2, 60 Multidetector computed Noninvasive cardiovascular testing Malignant hypertension 64, 156 tomographic angiography 149 117 Malingering 38 Multiple Nonspecific abdominal pain 10 Mallory-Weiss cranial nerve deficit 121 Normal syndrome 152 endocrine neoplasias 95, 236 pressure hydrocephalus 75, 80, tears 147 myeloma 286 144 Mammography 43 sclerosis 121, 303, 329 vaginal bleeding 315 Mantoux test 133 sensory deficit syndrome 329 Nutritional deficiencies 75, 220 Massive system atrophy 265 liver metastasis 3 ulcers 96 O pulmonary embolism 109 Multislice computed tomography Mastocytosis 242 52 Obesity 127, 318 Meigs syndrome 5 Munchausen Obscure GI bleeding 147 Melanosis coli 88 hemoptysis 182 Obstructive Melena 146 syndrome 16 lung diseases 116 Melkersson-Rosenthal syndrome Muscle sleep apnea 193 125 356 Diagnosis: A Symptom-based Approach in Internal Medicine

Occult Perineal and clitoral PPD test 347 blood in carcinoma 2 electromyography 257 Pregnancy 2, 212 GI bleeding 146 Perineometry 59 test 11, 19, 213, 297, 316 Ocular trauma 251 Periodic Premature Odynophagia 102 limb movement disorder 193 ejaculation 262 Oligomenorrhea 315 paralysis syndrome 301 ovarian failure 19 Oral allergy syndrome 247 Peritoneal Premenopausal woman 46 Orbital carcinomatosis 3 Premenstrual headache 156 cellulitis 249 tuberculosis 3 Primary CT scan 250 Peritonitis 2 amenorrhea 18, 19 US 250 Persistent anemia 61 cerebral tumors 75 vascular tumors 250 Peutz-Jeghers syndrome 88, 152 hypothyroidism 19 Organ Peyronie’s disease 261 Prinzmetal’s angina 49 failure 91 Pheochromocytoma 226 Prion disease 75 infection 196 Photophobia 250 Proctalgia fugax 5 Organic dyspepsia 93 Phyllodes tumor 43 Progestin challenge test 21 Orgasmic dysfunction 261 Pill-induced esophagitis 99 Progressive Osteoarthritis 30, 219 Pingueculitis 249 bilateral vision loss 331 Osteoporosis 38 Plasma bulbar palsy 340 Otologic 292 Otosclerosis 165 cortisol 298 muscular atrophy 340 Otoscopy 327 protein 128 systemic sclerosis 105 Ototoxic drugs 165 vasopressin 237 Prolactin secreting adenoma 19 Ovarian tumor 9, 23 Plasmoprotein electrophoresis 38 Prostate cancer 171 Pneumocystis carinii pneumonia Prosthetic heart valve dysfunction P 69 277 Pneumocystosis 177 Prothrombin time 197 Pacemaker syndrome 109, 226, Pneumonia 49, 69, 70, 177 Pruritus 241, 246 232, 277 Pneumoperitoneum 2 Pseudo diarrhea 86 Paget’s disease 38 Pneumothorax 50 Pseudodiverticulosis 148 Pain 218, 250 Polycystic Pseudohemoptysis 179 Pancreatic kidney disease 171 Pseudomembranous colitis 2, 84, ascites 3 ovarian syndrome 19 89, 148 malignancy 91 Polymenorrhea 315 Psoriasis 241 Pap smear 317, 321 Polymyositis 145 Psychiatric Paracentesis 13 Polysomnography 191, 298 disease 226 Paragonimiasis 182 Polyuria 234 disorder 26, 99 Paralytic ileus 212 Poncet’s disease 35 Psychogenic Paraneoplastic Porphyria 286 cough 69 disorders 220 Portal hypertension 3, 148 gait 139 syndromes 217, 286 Parasite infection 60, 177 Post GI tract surgery. 84 nonepileptic seizure 63 Parasitic infestation 10 Postcoital bleeding 316 Psychological disorders 220 Parkinson’s disease 58, 61, 303 Posterior Pterygium 249 Parotid sialography 128 fossa tumors 121 Puborectalis electromyogram 59 Patch test 244, 310 inferior cerebellar artery 329 Pudendal nerve terminal motor Peak expiratory flow rate 70, 109 Postinfectious cough 69 latencies 59 Pelvic Postmenopausal atrophic vaginitis Pulmonary 49 arteriography 257 316 amoebiasis 177 floor dysfunction 58, 61 Postpolypectomy bleeding 148 arterio-venous malformation inflammatory diseases 303, 316 Postradiotherapy fibrosis 303 177 Penile Post-traumatic contusion 177 duplex US 257 headache 156 embolism 49, 111, 177 fibrosis 261 pain 220 function tests 110 Peptic ulcer disease 10, 49, 91, stress disorder 261 hypertension 50, 115 147, 220 Postural orthostatic tachycardia Pulse oximetry 70, 109, 115, 190 Perforated peptic ulcer 9 syndrome 233 Pure tone audiometry 165 Pericardial disease 115 Potassium hydroxide 242 Purified protein derivative 71, 265 Index 357

Q Secondary amenorrhea 18-20 Somatic pain 218 Secreting tumors 26 Spinal Quantitative culture for bacteriuria Senile canal stenosis 38 304 cataract 331 cord pruritus 242 disease 340 R Serum injury 60 albumin 197 Spirochetal disease 250 Radioallergosorbent tests 244 alkaline phosphatase 198 Splenic Ramsay Hunt syndrome 121 amylase 200 flexure syndrome 4 Rapid urease test 92 ascites albumin gradient 3 vein 148 Rectal bilirubin 197 Spondyloarthropathies 30, 37 biopsy 59 calcitonin 86 Spontaneous bacterial peritonitis 6 sensation 59 calcium 122, 220 Sputum 69, 115, 133 varices 148 electrolytes 65, 140 Squamous cell papillom 99 Recurrent ferritin 243 Status asthmaticus 108, 111 acute urticaria 308 gastrin 86 Steatorrhea in malabsorption pulmonary embolism 115 immunoglobulin analysis 310 syndromes 2 ulcers 96 insulin 27 Stenotic vascular disease 333 Red iron 200 Stepping gait 139 eye 249 lipase 3 Still’s disease 132 flag symptoms 279 progesterone 318 Stomping gait 139 hot joint 35 prolactin 21, 256 Stool Regurgitation 211 protein 243, 270 antigen test 92 Reiter’s syndrome 303 testosterone 256, 318 fat 85 Renal urea 236 Stroke syndromes 58, 285 biopsy 237 uric acid 31 Subarachnoid hemorrhage 156 calculi 171 Severe Subconjunctival hemorrhage 249 cell carcinoma 171 acute respiratory syndrome Substance abuse 26, 156 colic 10 109, 132 Sudan stain 85 tuberculosis 303 anemia of chronic disease 127 Sudomotor testing 266 Restless legs syndrome 193, 285 kyphoscoliosis 115 Superficial foreign body 249 Reticulocytosis 197 psychogenic stress 19 Superior vena caval syndrome 128 Retinitis pigmentosa 331 Sex aversion disorder 262 Swallow test 103 Retrograde ejaculation 262 Sexual Sweating abnormalities 263 Retromammary abscess 43 abuse 316 Sweet’s syndrome 313 Reversible cerebral dysfunction 254, 255, 259, 297 Swelling of legs 269, 271 vasoconstriction syndrome 161 function 255 Synovial Rheumatic fever with arthritis 30 Sexually transmitted diseases 171 biopsy 32 Rheumatoid arthritis 30, 132 Sheehan’s syndrome 19 fluid analysis 32 Sick sinus syndrome 282 Rheumatology screen 287 Syphilis 250, 285 Sickle cell Romberg’s test 142 Systemic anemia 236 Rumination syndrome 5 carcinoma 242 disease 165, 171 Rupture uterus 9 coagulopathy 177 Sipple’s syndrome 95 disease 10, 19, 60, 165 Six-minute walk test 118 S disorders 26, 127 Sjögren’s syndrome 106, 265 illness 156 Salicylate poisoning 111 Skeletal muscle 339 infections 212 Saline infusion sonography 317 Skin Salivary gland calculus 128 biopsy 311 Sarcoidosis 121, 132, 177, 285 prick test 310 T Schatzki ring 99 Skull X-ray 156 Tabes dorsalis 285 Schistosomiasis 171 Sleep Tachypnea 111 Schwartz ring 105 apnea 194 Tamoxifen therapy 319 Scintigraphic expulsion of disorders 64, 297 Tandem walk 141 artificial stool 59 Smoker’s cough 72 Temporal Scissors gait 139 Soft tissue rheumatism 32 arteritis 132 Scleritis 249 Solitary rectal ulcer syndrome 148, artery biopsy 157, 332 Scleroderma 128 153 358 Diagnosis: A Symptom-based Approach in Internal Medicine

Temporomandibular joint 292 compression 285 Vertiginous gait 139 Tensilon test 298, 341 back pain 36 Vertigo 323 Tension extremity neuropathies 285 Vestibular testing 326 headache 156 GI Videofluoroscopic swallowing pneumothorax 111 barium series 86 function study 101 endoscopy 39 Thalamic pain syndrome 286 Viral malignancy 91 Thin basement membrane disease gastroenteritis 60 175 limbs 286 hepatitis serology markers 199 Thoracic radiculopathy 49 motor neuron system 339 infections 10 Three tube test 173 respiratory tract infection 9 Thunderclap headache 156, 161 Uremia 220 Virilizing ovarian tumors 19 Thyroid function tests 317, 341 Uremic pruritus 242 Visceral pain 218 Thyrotoxicosis 292 Urethral Vision loss 330, 335 Tietze’s syndrome 49 strictures 303 Vitamin B2 assay 76 Tinnitus 291 syndrome 303 Vitreous hemorrhage 335 Tiredness 296 Urge incontinence 303 Vomiting 211 Tissue biopsy 298 Urinary von Willebrand’s disease 316 Tongue bite 63 catecholamines 265 Torsade de pointes 282 frequency 302 W gonadotropins 318 Toxemia of pregnancy 64 incontinence 303 Toxic megacolon 2 Waddling gait 139 tract foreign body 303 Transesophageal echocardiography Wallenberg’s syndrome 329 tract infections 9, 171, 303 134 Water deprivation test 236 urgency 234 Transient ischemic attack 335 Weber’s and Rnne’s test 326 Urine 206, 213, 228, 341 Transthoracic echocardiography Weekend warrior syndrome 206 culture 304 134 cytology 173 Wegener’s granulomatosis 148, Transvaginal ultrasound 317 dipstick 171 177, 285 Traveler’s diarrhea 60 for catecholamines 27 Werner’s syndrome 95 Trichinosis 127, 210 for porphobilinogen 287 Whipple’s disease 60 Trigeminal neuralgia 285 for schistosomiasis 173 Whooping cough 69 Triple diagnosis test 44 Urticaria 241, 308 Widower’s syndrome 262 Trophoblastic disease 316 Urticarial vasculitis 313 Wolff-Parkinson-White syndrome Tubercular abdomen 4 Uterine size 23 282 Tuberculosis 69, 132, 177 Uterovaginal agenesis 19 Wolfram syndrome 236, 239 Tuberculous abscess 43 Tumors invading temporal bone V X 121 Turner’s syndrome 19 Vaginal X-ray bleeding 315 Tympanogram 293 cervical spine 325 septum 19 Tympanometry 166 KUB 172 Valvular heart disease 115, 226 U Vascular dementia 74, 79 neck 99, 109 Vasculitis 148, 171 PNS 128, 156 UGI bleeding 147 syndromes 285 skull 341 Ulcerative colitis 59, 60 Ventilation-perfusion scans 51 Unstable angina pectoris 49 Ventricular tachycardia 111 Z Upper Vertebral Zenker’s diverticulum 106 airway cough syndrome 69 arteries 342 and lower extremity collapse 37 Zollinger-Ellison syndrome 86, 91

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