Section 9

Section Editor: Jyotirmoy Pal Clinical Medicine

113. Approach to Ascites 119. Anatomic Localization of Classical Neurological Veerendra Singh Symptoms 114. Approach to Acute-on-Chronic Failure Uddalak Chakraborty, Avik Mukherjee, Jyotirmoy Pal Anshuman Elhence, Abhinav Anand, Shalimar 120. Clinical Signs of Diaphragm Dysfunction 115. Approach to a Patient with Chronic Dyspnea of Atanu Chandra, Aritra Kumar Ray, Arkapravo Hati Undetermined Etiology 121. Approach to Chest Pain in Emergency Manish Kumar, Krishna Kumar, DP Singh Partha Sarkar, Adrija Chatterjee 116. “Choice versus Chance”: Mathematics behind 122. Approach to a Case of Anemia Clinical Decision-making Manoj Kumar Srivastava Alladi Mohan, Alladi Vikramchandra 123. Approach to Aphasia 117. Approach to Syncope in Emergency Room Jyotirmoy Pal, Tarun Kumar Paria, Purbasha Biswas, Prasanta Kumar Bhattacharya Manisankar Bhattarcharya 118. Nailing the Diagnosis through Nail Changes Bidita Khandelwal, Pradeep Balasubramanian

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113 Approach to Ascites

Veerendra Singh

Abstract Ascites, the collection of fluid in the peritoneal cavity, can originate from hepatic, malignant, cardiac, renal, and infectious diseases. , tuberculosis, and malignancy are the most common causes in Indian patients. Ultrasonography and paracentesis with ascetic fluid examination are the modalities used to establish the etiology. Sodium restriction and diuretics are mainstay of treatment of ascites due to cirrhosis. Ascites due to other causes requires specific treatment. For refractory ascites large volume paracentesis along with infusion of albumin is used. Liver transplantation is the gold standard therapy. Despite the advances in modern medicine, development of ascites is associated with poor prognosis and high mortality.

Introduction Ascites Due to Cirrhosis Commonly presenting with abdominal swelling, ascites Portal and renal salt and water retention are is a pathological fluid collection in the peritoneal cavity. the key mechanisms of ascites in cirrhosis. Ascites denotes The common causes of ascites are cirrhosis, tuberculosis, the transition from a compensated to a decompensated malignancy, cardiac failure, pancreatitis, and nephrotic stage of cirrhosis. Initially ascites is uncomplicated, not syndrome. The management depends on the etiology of infected, and responds well to diuretics.1 As disease ascites from hepatic to extrahepatic causes and on the progresses, ascites ceases to respond to diuretics stage of ascites from uncomplicated to refractory stage. (refractory ascites) and renal dysfunction supervenes (hepatorenal syndrome). Causes of Ascites Uncomplicated ascites is subdivided into three grades: Various causes of ascites are shown in Table 1. In India, mild, moderate, and massive ascites. Refractory ascites has 2 cirrhosis of liver is most common cause of ascites followed two subtypes: diuretic-resistant and diuretic-intractable. by tuberculosis versus malignancy in developed countries. Sometimes more than one condition may coexist with Complications of Cirrhosis significant management implications. Alcoholic patients can have cirrhosis with cardiomyopathy, tuberculosis, Spontaneous Bacterial Peritonitis or malignancy. For management, perspective ascites is Spontaneous bacterial peritonitis (SBP), a lethal grouped under two heads: ascites due to cirrhosis or due complication, results from ascitic fluid infection in to causes other than cirrhosis. absence of an intra-abdominal infective focus.

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TABLE 1 Causes of ascites

Portal hypertension Infections Miscellaneous zz Cirrhosis liver zz Bacterial peritonitits zz Pancreatitis zz Alcoholic hepatitis zz Tubercular peritonitis zz Hypoalbuminemia zz Hepatic congestion zz HIV associated periotonitis zz Nephrotic syndrome —— Congestive cardiac failure Malignancies zz Lymphatic leakage —— Constrictive pericarditis zz Peritoneal carcinomatosis zz Myxoedema —— Hepatic venous outflow obstruction zz Primary mesothelioma zz SLE zz Portal zz Hepatocellular carcinoma zz Non-cirrhotic zz Metastatic liver disease zz Pseudomyxoma peritonei

Hepatic Hydrothorax Evaluation and Diagnosis Pleural effusion develops in approximately 5–10% Clinical Assessment of patients with cirrhosis due to transdiaphragmatic Ascites may be asymptomatic or may just produce an movement of fluid from peritoneal cavity to pleural space.3 increase in abdominal girth described as tightness of cloths Patients usually have minimal ascites. Pleural effusion is or belt. Massive ascites produces abdominal discomfort, right sided in 85%, left sided in 13%, and bilateral in 2% umbilical eversion, hernias, and breathlessness. Physical cases. examination is not significant in mild ascites. In moderate ascites, flank dullness and shifting dullness are sensitive Ascites due to Causes other findings. Massive ascites produces marked distension of than Cirrhosis abdomen. Signs of liver disease and portal hypertension should be sought. Hepatic, renal, and cardiac status In malignancy and tuberculosis tumor cells and tubercles should be assessed. lining the peritoneum produce protein rich fluid. Pancreatitis, heart failure, nephrotic syndrome, and Pathological Assessment hypothyroidism may cause ascites. Routine urine examination, complete blood counts, blood sugar, liver function tests, viral markers (HBV, HCV, Malignant Ascites and HIV), serum screatinine, NT-Pro BNP, and thyroid Malignant ascites occurs secondary to: function tests should be obtained. „„ Peritoneal carcinomatosis: malignant infiltration of peritoneum Imaging „„ Massive hepatic metastasis Ultrasound is the best modality to document the presence „„ Profound desmoplastic response to infiltrating breast of ascites. It can provide information about cause of cancer ascites (fibrosis in cirrhosis, nodules in HCC, or liver „„ Chemotherapy induced nodular regenerative hyper­ metastasis). Fibroscan is a new modality to document plasia fibrosis of liver. Doppler sonography can detect portal Two-thirds cases of malignant ascites are caused by or hepatic vein thrombosis. Contrast enhanced CT, peritoneal carcinomatosis from adenocarcinomas of echocardiography, upper GI endoscopy, and colonoscopy , stomach, colon, ovary, uterus, lungs, or breast. may be ordered in select conditions. MRI using gadolinium The remaining are caused by hapatocellular carcinoma or scan can demonstrate enhancement of peritoneal lining in hepatic metastases. peritoneal carcinomatosis.4

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TABLE 2 Tests of ascitic fluid Diffrentiation of ascites based on hepatic venous TABLE 3 pressure gradient measurement Routine tests Additional tests Causes of ascites WHVP FHVP HVPG zz Appearance zz Gram stain and culture zz Total protein zz AFB smear, culture and Cirrhosis Increased Normal Increased zz Serum ascites albumin adenosine deaminase activity Cardiac ascites Increased Increased Normal gradient (SAAG) zz Glucose and lactate Malignant ascites Normal Normal Normal dehydrogenase zz Cell count peritoneal tuberculosis zz Amylase concentration FHVP, free hepatic venous pressure; HVPG, hepatic venous pressure zz Cytology and carcinoembryonic gradient; WHVP, wedged hepatic venous pressure antigen level zz Triglyceride level Serum-ascites Albumin Gradient Serum-ascites albumin gradient (SAAG) is the difference Abdominal Paracentesis between albumin concentration in the ascitic fluid and Once the presence of ascites has been confirmed, the that in the serum both collected at the same time. It etiology of ascites is best determined by paracentesis. is a very useful tool to establish the presence of portal Between 20–50 mL of ascitic fluid should be aspirated and hypertension. A SAAG value more than 1.1 g/dL reflects examined (Table 2). portal hypertension and indicates the ascites is due to increased pressure in the hepatic sinusoids. The SAAG has been found to be superior to the total protein Appearance concentration for the differential diagnosis of ascites.5 In ascites due to portal hypertension the fluid is clear and straw colored. Turbid fluid can result from infection Hepatic Venous Pressure Gradient or malignancy. Milky fluid, chylous ascites results from Hepatic venous pressure gradient (HVPG) is direct lymphatic disruption due to malignancy, trauma, and measure of hepatic sinusoidal pressure measured via a congenital abnormalities. Bloody ascites could be due catheter in right femoral or internal jugular vein. Portal to traumatic tap or malignant ascites. Blood in traumatic hypertension is defined as HVPG value more than 6 mm fluid clots but in malignant ascites does not clot. Hg (Table 3).

Total Protein Laparoscopy Protein levels are useful in determining etiology of ascites. Laparoscopy offers the advantages of visual inspection Traditionally ascitic fluid is grouped into: of the peritoneal cavity and obtains targeted biopsies for „„ Exudate with protein concentration more than histological studies. With the availability of new imaging 2.5 g/dL. techniques, the need for laparoscopy in determining the „„ Transudate with protein concentration less than cause of ascites has decreased. 2.5 g/dL. Exudative ascites occurs secondary to peritoneal Diagnostic Developments processes (malignancy, tuberculosis) or post-hepatic New novel diagnostic markers such as leukocyte esterase sinusoidal hypertension with normal sinusoids (heart reagent strips for diagnosing SBP, viscosity measurement failure, hepatic vein, or inferior venacava obstruction) of ascitic fluid to discriminate between portal and whereas transudative ascites results from increased non-portal hypertension, vascular endothelial growth sinusoidal portal hypertension (cirrhosis). Total protein factor (VEGF), bacterial DNA for documenting bacterial levels are also useful in determining susceptibility to translocation, and markers of poor prognosis such infection. Patients with ascitic fluid protein less than 1.0 g/ as endotoxin and peptidoglycan/β-glucan have been dL are prone to develop SBP. proposed but still need validation.

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Approach to a Patient of New Onset Ascites Evaluation of Tubercular Ascites See Flowchart 1. In tuberculous peritonitis, the smear for acid-fast bacilli is rarely positive and culture is positive only in about 50% Evaluation of Infection of cases. Polymerase chain reaction for MTB has a high sensitivity (94%).7 Adenosine deaminase activity (ADA) Cell Counts is a reliable marker of tuberculous ascites. Mononuclear A predominance of neutrophils indicates an acute intra- cell predominant leucocytes >500/cc, total protein more abdominal . An ascites PMN count greater than 3 g/dL, LDH >90 units/L, or ADA >36–40 IU/L has a than 250/mm³ establishes diagnosis of SBP.6 Predominant sensitivity of 100% and a specificity of 97% for of peritoneal mononuclear cells indicate tubercular ascites. tuberculosis. Laparoscopy with peritoneal biopsy and histopathology is the gold standard for diagnosis of Smear and Bacterial Culture peritoneal tuberculosis.8 Recommended stepwise Culture samples of ascetic fluid for both aerobic and approach for the diagnosis of peritoneal tuberculosis is anaerobic bacteria should be inoculated at the bedside detailed in Flowchart 2. into a blood culture bottle. Evaluation of Malignant Ascites Ascitic Fluid Glucose and LDH Levels Abdominal ultrasound and CT may be useful to demonstrate Ascetic fluid LDH higher than serum LDH (ratio >1.00) the primary malignancy or hepatic metastases but seldom and ascetic fluid glucose below 50 mg/dL suggests confirms the diagnosis of peritoneal carcinomatosis. secondary bacterial peritonitis. Analysis of the ascetic fluid is the most important step in

Flowchart 1: Approach to a patient of new-onset ascites

Asc prot, ascites total protein level; CUS, cardiac echosonography, HVPG, hepatic vein pressure gradient

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Flowchart 2: Algorithm for diagnostic strategies in tubercular ascites

ADA, adenosine deaminase; IGRA, interferon gamma release assays

„„ Infective ascites: Appropriate antibacterial therapy TABLE 4 Ascitic fluid findings in malignant ascites „„ Tubercular ascites: Anti-tubercular therapy along with SAAG Ascitic fluid Cytology large volume paracentesis for severe ascites protein „„ Pancreatic ascites: Conservative measures like salt Peritoneal Low High High up to 97% restriction and diuretics carcinomatosis „„ Malignant ascites: Does not respond to sodium Liver metastasis High Low Negative restriction or diuretics. Large volume paracentesis (LVP), transcutaneous catheter placement, peritoneo­ the diagnostic work-up (Table 4). Laparoscopy may be venous shunt, and autopumps are used required to confirm the diagnosis. Treatment of Ascites due to Cirrhosis Treatment of Ascites Except for liver transplant, none of the therapies improves the survival. However, treatment of ascites not only Ascites due to Causes other than Cirrhosis improves the quality of life but prevents SBP, a lethal Treatment is to be directed at the underlying cause: complication. The development of ascites in a patient of

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cirrhosis denotes a poor prognosis with a median survival In patients with massive ascites, the method of choice of 1.5 years so these patients should be considered for liver is LVP followed by diuretic agents and a low sodium diet.12 transplant. Approach to a patient of new ascites has been summarized in Flowchart 3. Sodium Restriction and Diuretics According to the European Association for the Study of the Therapeutic Options for Refractory Ascites Liver, patients with cirrhosis and grade 1 ascites do not need 9 Large Volume Paracentesis diuretics and a low sodium diet. In patients with grade 2 ascites, sodium consumption is restricted to 2 g sodium In normal clinical practice, the first-line therapeutic (5.2 g of dietary salt) per day along with diuretic therapy. intervention is large volume paracentesis repeated every The goal of diuretic treatment is a loss of weight up to 1.0 2–3 week. Between 5–6 L of the ascitic fluid is removed in kg/day if both ascites and edema are present and up to 0.5 combination with I/V infusion of albumin (6–8 gm/L of kg/day in patients with ascites alone.10 Spironolactone, an fluid drained) to prevent paracentesis-induced circulatory aldosterone antagonist, is preferred as the initial diuretic. dysfunction. Recommended starting dose is 50–100 mg/day. Addition of a loop diuretic, furosemide or torsemide, potentiates Peritoneovenous Shunt effect of spironolactone. The maximum dose of diuretics Peritoneovenous shunt (PVS) drains ascitic fluid into recommended is a combination of spironolactone 400 the venous system. With laparascope a shunt is placed mg/day with furosemide 160 mg/day.11 from peritoneal cavity to superior vena cava close to

Flowchart 3: Treatment strategies for patient of cirrhosis with new onset ascites

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Flowchart 4: Treatment strategies for patient of cirrhosis with refractory ascites

the entrance of right atrium. A valve at the venous end recommend using TIPS only in patients who require prevents backflow of blood into the tubing. PVS has been frequent LVP. reported to improve glomerular filtration rate in patients with renal insufficiency. However, long-term results were A Patient with Contraindications to TIPS worse due to infection, shunt thrombosis, disseminated „„ In malignant ascites implantation of a permanent intravascular coagulation, and air . Pleurx® tunneled peritoneal catheter allows drainage of small amount of ascitic fluid (<2 L/day) in small 13 Surgical Portosystemic Shunt portions. ® „„ An automatic low-flow pump (Alfapump ) moves In portosystemic shunt the portal vein is used as an ascetic fluid to the bladder in small portions (5–10 outflow tract to relieve portal hypertension. However, mL) every 5–10 min. It may serve as a “bridge” to liver because of high surgical mortality, they are seldom used transplantation. nowadays. Liver Transplantation Transjugular Intrahepatic Portosystemic Shunt Liver transplantation is the definitive treatment for Transjugular intrahepatic portosystemic shunt (TIPS) is a ascites, as it eliminates portal hypertension and all other non-surgical portacaval . In this procedure, accompanying complications of liver cirrhosis. Overall, 1 a tract is created between branches of hepatic and portal year survival after liver transplantation exceeds 75%. . Portal pressure reduction improves renal blood flow Approach to manage refractory ascites is shown in and glomerular filtration rate. Current clinical guidelines Flowchart 4.14

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Novel Therapies in Refractory Ascites References V2 Receptor Antagonists . 1 Moore KP, Wong F, Gines P, et al. The management of ascites in cirrhosis: report on the consensus conference of the International Satavaptan, a selective V2 vasopressin receptor antagonist, Ascites Club. Hepatology. 2003;38:258-66. acts on the distal renal tubule to increase water excretion, . 2 Arroyo V, Ginès P, Gerbes AL, et al. Definition and diagnostic making it an attractive novel drug for patients who do not criteria of refractory ascites and hepatorenal syndrome in cirrhosis. respond to conventional diuretics. International Ascites Club. Hepatology. 1996;23:164-76. 3. Cardinas A, Kellether T, Chopra S. Review article hepatic hydrothorax. Aliment Pharmacol Ther. 2004;20:271. Vasoconstrictors 4. Low RN, Sigeti JS. MR imaging of peritoneal disease: comparison of Clonidine, a centrally acting α2-agonist, when used contrast-enhanced fast multiplanar spoiled gradient-recalled and with spironolactone decreases the need for diuretics. spin-echo imaging. Am J Roentgenol. 1994;163:1131-40. . 5 Runyon BA, Montano AA, Akriviadis EA, et al. The serum-ascites Midodrine, an α1-adrenoreceptor agonist, increases albumin gradient is superior to the exudate-transudate concept sodium excretion in patients with cirrhosis and refractory in the differential diagnosis of ascites. Ann Intern Med. 1992;117: ascites without azotemia. In an RCT by Hanafy et al., 215-20. midodrine (15 mg/day) and rifaximin (1.1 g/day) added . 6 Runyon BA. Management of Adult Patients with Ascites Due to to diuretics, increased diuresis and improved short-term Cirrhosis: Update 2012. survival.15 Terlipressin, a V1 receptor agonist, improved . 7 Portillo-Gomez L, Morris SL, Panduro A. Rapid and efficient detection of extra-pulmonary Mycobacterium tuberculosis by PCR the glomerular filtration rate and induced natriuresis in analysis. Int J Tuberc Lung Dis. 2000;4:361-70. patients with cirrhosis and ascites without HRS. Despite 8. Guirat A, Affes N, Rejab H, et al. Role of laparoscopy in the diagnosis the positive results of the aforementioned studies, of peritoneal tuberculosis in endemic areas. Med Sante Trop. the addition of clonidine or midodrine to the diuretic 2015;25:87-91. treatment in refractory ascites is not recommended by . 9 European Association for the Study of the Liver (EASL); clinical practice guidelines on the management of ascites, spontaneous current guidelines. bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010;53:397-417. Conclusion 10. Jalan R, Hayes PC. Hepatic encephalopathy and ascites. Lancet. 1997;350:1309-15. Ascites, commonly presenting as abdominal swelling, is 11. Runyon BA. Care of patients with ascites. N Engl J Med. 1994;330: accumulation of free fluid in peritoneal cavity. Cirrhosis, 337-42. tuberculosis, and malignancy are the common causes of 12. Fortune B, Cardenas A. Ascites, refractory ascites and hyponatremia ascites. Mild ascites is asymptomatic but large ascites causes in cirrhosis. Gastroenterol Rep (Oxf). 2017;5:104-12. abdominal discomfort and breathlessness. Ultrasonography 13. Narayanan G, Pezeshkmehr A, Venkat S, et al. Safety and efficacy of detects the presence of ascites. Paracentesis with fluid the PleurX catheter for the treatment of malignant ascites. J Palliat Med. 2014;17:906-12. examination establishes etiology of disease. Sodium restriction 14. Hanafy AS, Hassaneen AM. Rifaximin and midodrine improve and diuretic therapy is the mainstay of cirrhotic ascites clinical outcome in refractory ascites including renal function and treatment. Ascites due to causes other than cirrhosis requires short-term survival. Eur J Gastroenterol Hepatol. 2016;28:1455-61. specific treatment. In refractory ascites, LVP with albumin 15. Yamada T (Ed). Guadalupe Garcio-Tsao, Ascites and Its infusions, TIPS, PVS, and automatic pumps are helpful. Liver Complications: Textbook of Gastroenterology. transplantation is the gold standard therapy. Despite the advances in modern medicine, development of ascites is associated with poor prognosis and high mortality.

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Approach to Acute-on-Chronic 114 Liver Failure

Anshuman Elhence, Abhinav Anand, Shalimar

Abstract Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by hepatic and/or extra-hepatic organ dysfunction in a patient with chronic liver disease. Multiple definitions exist in the literature. Irrespective of the definition, ACLF is associated with high short-term mortality. The syndrome is dynamic, and daily estimation of prognostic scores and organ dysfunction can predict the prognosis. A multidisciplinary team involving hepatologists, liver transplant surgeons, intensive care specialists, radiologists and pathologists is essential for the comprehensive management of patients with ACLF. Early identification and treatment of the acute precipitant is as essential as intensive monitoring, nutrition, antibiotics, albumin, and supportive care for extra-hepatic organ dysfunction. Liver transplantation remains the definitive treatment, albeit with its limitations. Physicians need to recognize the entity early, refer to multidisciplinary care centers, explain the prognosis, and prime the family members for the need for liver transplantation.

Introduction include different etiologies (acute precipitants and chronic liver disease), and different clinical presentations Acute-on-chronic liver failure (ACLF) syndrome is of hepatic and extra-hepatic insults. Comparison of the characterized by abrupt hepatic decompensation major definitions—including EASL-CLIF, APASL, and secondary to an acute insult in a patient with chronic NACSELD and World Gastroenterology Organisation liver disease, associated with high short-term mortality. (WGO)—is shown in Table 1. An important difference Overall, there are more than 20 definitions of ACLF is the inclusion of patients with chronic liver disease (all available in the literature. Different definitions of ACLF stages of fibrosis) in the APASL definition (Flowchart 1); provided by the European association for the study of in contrast, the EASL-CLIF and NACSELD definitions the liver-chronic liver failure (EASL-CLIF), Asian Pacific include patients with cirrhosis only. Patients with prior Association for the study of the liver (APASL), and North decompensation are excluded in the APASL definition, American Consortium for the Study of End-stage Liver while they are included in the EASL-CLIF and NACSELD Disease (NACSELD) in Asia, Europe, and the USA, definitions. respectively have led to more confusion, rather than unifying the recognition of this syndrome.1-4 Acute Decompensation vs. ACLF Definition Acute decompensation (AD) refers to an event in the natural The overall concept of defining ACLF is to identify high- history of cirrhosis characterized by the development of risk patients with high short-term mortality. The possible jaundice, ascites, variceal bleed, or encephalopathy. AD reasons for the different definitions of ACLF syndrome when associated with organ failure is defined as ACLF.

MU-114.indd 715 29-01-2021 14:55:19 716 SECTION 9 Clinical Medicine ACLF is a syndrome in patients in patients is a syndrome ACLF disease with liver with chronic diagnosed or without previously which is characterized cirrhosis, decompensation hepatic acute by (jaundice failure in liver resulting of the INR) and and prolongation extra-hepatic organ one or more with is associated that failures mortalityincreased within a period 3 months and up to of 28 days onset from Expert group than 3 months Less stage of disease (any liver Chronic fibrosis) - Both and extra-hepatic hepatic Not defined WGO Infection-related ACLF— Infection-related of defined as the presence failures— organ or more two need shock, III/IV HE, grade or renal ventilation for therapy replacement multicenter Prospective, with patients study—507 infection Infection ≥2 OF ? 30 days Cirrhosis only and Both compensated decompensated HIV transplant organ Prior malignancyDisseminated Infection CLIF-C ACLF MELD, NACSELD Initial arbitrary cut-off of bilirubin and INR. based updated 2019 consensus (>3,300 cases) on AARC data essential—jaundice failure Liver than 4 weeks Less stage disease (any liver Chronic of fibrosis) cirrhosis Compensated HCC cirrhosis decompensated Prior Hepatic AARC Score ACLF is an acute hepatic hepatic is an acute ACLF as jaundice insult manifesting (serum bilirubin ≥5 mg/dL (INR ≥ 1.5) and coagulopathy) by within 4 weeks complicated and/or encephalopathy ascites with previously in a patient or undiagnosed diagnosed disease/cirrhosis, liver chronic and a high 28-day mortality APASL Acute decompensation Acute (as per SOFA-CLIF failure Organ score) High 28-day mortality rate of 15%) threshold (predefined z z z CANONIC study—1343 included AD patients prospectively OF essential or failure renal Isolated of (2 or more) combination any 6 OFs any Cirrhosis only and Both compensated decompensated HIV Milan beyond criteria HCC and extrahepatic both Hepatic CLIF-C ACLF 3 months EASL-CLIF Based on the presence of the three of the three Based on the presence major characteristics: z z z Comparison of various definitions of acute-on-chronic liver failure liver definitions of acute-on-chronic of various Comparison TABLE 1 TABLE Basis of definition Clinical presentation inclusion Patient exclusion Patient precipitants Acute models Prognostic Time interval since interval since Time insult and acute of ACLF development Definition AARC, APASL ACLF research consortium; ACLF, acute-on-chronic liver failure; AD, acute decompensation; APASL, Asia Pacific Association for the study of liver diseases; diseases; the study of liver for Association Pacific Asia APASL, decompensation; acute acute-on-chronic AD, failure; liver consortium; ACLF, research ACLF AARC, APASL human HIV, encephalopathy; hepatic HE, carcinoma; hepatocellular HCC, liver; of study the for failure-consortium; Association liver CLIF-C, European chronic EASL, North American Consortiumthe study of end stage liver for disease; NACSELD, end stage liver model for MELD, immunodeficiency ratio; normalized virus; INR, international Organisation. Gastroenterology World WGO, Assessment; Failure Sequential Organ SOFA, failure; organ disease; OF,

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Flowchart 1: APASL and EASL-CLIF definition of acute-on-chronic liver failure

Approach to ACLF The APASL-ACLF-AARC score includes bilirubin, INR, hepatic encephalopathy (HE), lactate, and creatinine with The definition of ACLF embodies the basic constituents of an overall score ranging from 5 to 15. Based on the AARC the syndrome—an acute precipitant on a background of score, ACLF is graded into grade 1 ACLF (score 5–7), grade underlying chronic liver disease leading to organ failure 2 ACLF (8–10), and grade 3 ACLF (>10) with predicted 28- and high short-term mortality. Each of the constituents day mortality of 13%, 45%, and 86%, respectively.1 must be addressed separately (Flowchart 2). While assessing prognosis in patients with ACLF, it is Prognosis and Scoring Systems important to use the scores as defined by definition, that is, use AARC score, if ACLF is defined by APASL definition The Child-Turcotte-Pugh (CTP) score and model for end- and EASL-CLIF C ACLF in patients defined by EASL-CLIF stage liver disease (MELD) do not accurately assess the definition. risk of patients with ACLF. The EASL-CLIF and APASL divide ACLF into three grades of severity based on short- term mortality. As per the EASL-CLIF, the 28-day mortality Dynamic Assessment of the Prognostic Score in grade 1 ACLF [defined as single renal failure (creatinine ACLF is a dynamic syndrome; therefore, it is important >2.0 mg/dL) or any other single organ failure with renal to assess patients daily for changes in organ failures and dysfunction (creatinine 1.5–2 mg/dL)] is around 20–25%, scores. A change in the score helps in early detection of grade 2 ACLF (2 organ failures) is 35–40%, and grade 3 deterioration and warrants change in the management ACLF (3 or more organ failures) is 70–80%. A linear score plan. Patients showing an improvement in the grade of has been proposed CLIF-C ACLF (based on 6 organ failure ACLF over the first 3 days are associated with a better scores, age, and total leukocyte count), which correlates outcome. The grade of ACLF between day 3 and 7 predicts with outcomes. outcome better than the grade at presentation.

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Flowchart 2: Evaluation of patients with acute-on-chronic liver failure

ACLF, acute-on-chronic liver failure; ANA, anti-nuclear antibody; Anti-HBc, antibody to hepatitis B core antigen; ASMA, anti-smooth muscle antibody; bDNA, bacterial deoxyribonucleic acid; Beta hex, beta-hexosaminidase; BMI, body mass index; CDT, carbohydrate deficient transferrin; CRP, C-reactive protein; GGT, gamma-glutamyl transferase; HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HEV, hepatitis E virus; IgM, immunoglobulin M; KF, Kayser-Fleischer; LKM-1, liver-kidney microsomal-1; MALDI-TOF, matrix assisted laser desorption ionization-time of flight; MCV, mean corpuscular volume; PCT, procalcitonin.

Role of Liver Biopsy hepatitis B presenting as ACLF, use of antiviral drugs such as tenofovir disoproxil fumarate (TDF) is associated with a A liver biopsy is not routinely recommended in the better outcome. For hepatitis E virus infection, no specific management of patients with ACLF. It may be indicated therapy is recommended. Patients with autoimmune when the diagnosis is unclear, clinical suspicion of hepatitis (AIH)-ACLF without hepatorenal syndrome autoimmune hepatitis, or Wilson disease. The presence and sepsis can be considered for a trial of steroids.1 of neutrophilic infiltration, bilirubinostasis, mega- In patients with Wilson disease, chelation therapy is mitochondria are markers of poor prognosis in alcoholic recommended. Also, consideration should be given to hepatitis. Since patients with ACLF often have concomitant early liver transplantation (LT) in those categorized as ascites and coagulopathy, if indicated, a transjugular route likely to have poor prognosis, as documented by new is recommended over a percutaneous one. Wilson Index of more than 11. Plasmapheresis can be tried as a bridge to LT in patients with fulminant presentation of Management Wilson disease. Management of Acute Precipitants Drugs are another important precipitant of ACLF. The common drugs include anti-tuberculosis therapy and Withdrawal of the acute insult is essential to stall complementary and alternative medicines. A detailed the inflammatory cascade (Fig. 1). Etiology specific history of drugs should be elicited at presentations and all interventions are effective. Patients with active alcoholism drugs should be stopped. benefit from abstinence. It is unclear whether use of Patients with acute variceal bleed (AVB) need to be corticosteroids is associated with mortality benefit in managed with resuscitation, splanchnic vasoconstrictors patients with alcohol-related ACLF. Steroids are associated and endoscopic therapy. In select cases, placement of with increased risk of infections; their use needs to be preemptive (<72 hours of presentation) transjugular individualized and justified in each case depending on intrahepatic portosystemic shunt (TIPS) can be the risk-benefit ratio. In patients with reactivation of considered. Among patients with uncontrolled bleeding

MU-114.indd 718 29-01-2021 14:55:20 Approach to Acute-on-Chronic Liver Failure CHAPTER 114 719 The management approach to acute-on-chronic to approach management The failure liver 1: Fig.

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rescue TIPS is an option, such patients usually have a poor Coagulation outcome. Prophylactic transfusion of plasma, based on the Bacterial infections are present in 10–30% of ACLF international normalized ratio (INR), is not recommended. patients at admission, and another 30–50% may develop Similarly, prophylactic transfusion of platelet may not an infection during the hospital stay. Choice of empirical be of use in the absence of active bleeding. Viscoelastic antibiotics depends on the setting. For community rd tests such as thromboelastography (TEG) and rotational acquired infections a 3 generation cephalosporin is a thromboelastometry (ROTEM) should be used to guide good choice. For nosocomial infections, piperacillin/ transfusion in cases, which require an invasive procedure tazobactam is preferred for areas with low-prevalence or develop bleeding complications. of multidrug resistance organisms (MDROs), while carbapenems are preferred in areas of high MDRO, with Circulatory or without a gram positive glycopeptide for areas of high methicillin resistant Staphylococcus aureus (MRSA). In patients with circulatory failure, noradrenaline Appropriate antibiotics according to local sensitivity should be considered as a first-line agent. Vasopressin or patterns need to be administered at the earliest once terlipressin can be an alternative second line agent. culture reports are available.5 Respiratory Management of Extrahepatic Organ Failures Respiratory failure should be managed with ventilatory Renal support using either noninvasive ventilation or invasive ventilation, as tolerated, if the PaO2/FiO2 is less than 200. Acute kidney injury (AKI) in ACLF can arise due to Low tidal volume lung protective ventilation should be structural as well as functional causes. The withdrawal of considered, and therapeutic paracentesis done to aid in diuretics and volume expansion with albumin is the first decreasing work of breathing. step. Terlipressin and noradrenaline can be considered with data suggesting that the former is more effective in General Management the management of the hepatorenal syndrome. Renal ACLF patients should be managed in an intensive care replacement therapy (RRT) indications include symptoms unit (ICU). The higher mortality rate in ACLF should not of uremia, volume overload, hyperkalemia, and metabolic deter physicians from providing ICU care. The overall acidosis. Continuous RRT involves very slow blood outcomes in ACLF patients are similar to patients with and dialysate infusion and is preferred in patients with other diseases, matched for the severity of the illness. hemodynamic instability. Alternatively, a shorter hybrid Nutrition is essential in patients with ACLF and a diet procedure called slow-low efficiency dialysis (SLED) can comprising of 35–40 kcal/kg/day and protein intake of 1.5 offer shorter procedure times of 6–12 hours, maintaining g/kg/day is recommended. Supplementation with trace hemodynamic stability as well. elements and vitamins should be considered (Fig. 1). Cerebral The use of albumin is recommended for its oncotic effects in presence of renal failure, spontaneous bacterial Management of HE includes evaluation and management peritonitis, prevention of post-paracentesis circulatory of precipitants (Fig. 1). Hyperammonemia is associated dysfunction, as well as for its anti-inflammatory and with HE. Baseline hyperammonemia and persistent antioxidant pleiotropic effects. The uses of non-selective hyperammonemia are associated with poor outcomes beta-blockers and carvedilol have been shown to be safe in patients with ACLF. Lactulose and rifaximin are and their discontinuation is not recommended. useful first-line drugs that help in reducing ammonia. The role of L-ornithine L-aspartate (LOLA), L-ornithine Definite Management phenylacetate (LOPA), and sodium benzoate have not been studied in ACLF patients. Elective intubation to Liver Transplantation prevent aspiration may be considered in patients with LT is the definite management of ACLF. There are no advanced (grade 3 and 4) HE. validated criteria for appropriate selection of candidates

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for early LT. Early LT within the first week should be offered an experimental therapy and should not be used outside to those having poor prognosis at presentation (MELD of clinical trials. >30 or AARC >10) without multiple organ failures and sepsis.1 Dynamic monitoring with prognostic scores may Futility of Care help in early identification of patients who are at risk for If LT is not available or contraindicated, presence of four poor outcome. Recent data suggests that LT is feasible, or more organ failure and a CLIF-C ACLF score more than even in ACLF-3 cases who have 5–6 organ failures and is 64 is associated with a high mortality approaching 100%. associated with a 1-year survival rate of more than 80% as In such situations, relatives should be explained about the compared to less than 10% among those not transplanted. poor outcomes. Optimal timing of LT is crucial to have the best outcomes. There are no established delisting criteria for LT in Prevention of ACLF ACLF; however, transplant is not recommended in the presence of active sepsis. Prevention of ACLF is of paramount importance. This can be achieved by preventing the acute triggers such as Emerging Therapies viral hepatitis—by universal vaccination (hepatitis B) and Artificial Liver Support Systems secondary prophylaxis with antivirals, abstinence from Molecular adsorption and recirculating system (MARS) alcohol, and careful consideration before prescription of and fractionated plasma separation and adsorption hepatotoxic drugs. However, despite active search, the (FPSA-Prometheus) have not shown any survival benefit trigger may not be detectable in up to 40% cases and is in ACLF. Bioartificial liver support systems that substitute often attributed to pathological bacterial translocation detoxification, biotransformation, and synthetic function occurring due to a combination of increased gut as well by utilizing either human hepatoblastoma cell lines permeability and dysbiosis. Potential therapies targeting or porcine hepatocytes are promising. The recent creation this aspect of pathogenesis are being evaluated. of 3D liver organoids using hepatic progenitor cells or induced pluripotent stem cells might evolve as options for The Role of a Physician therapeutic use in future. It is important for physicians to identify patients with Plasma Exchange poor prognostic factors early, so that they can be referred to higher centers for further treatment. Patients with Plasma exchange appears to be promising in small series. ACLF should ideally be managed at a center with a RCTs are needed to evaluate its role in management of ACLF. multidisciplinary team comprising of hepatologists, Liver Regeneration gastroenterologists, LT surgeons, and critical care Since human liver has a huge regenerative potential specialists. About one-third of patients reaching a referral due to the presence of progenitor cells, as evidenced hospital have an evidence of bacterial infection, making by rapid regeneration after donor hepatectomy, it them poor candidates for LT. Hence, it is important to refer can also recover following acute insults. Contrasting patients early, when they can still undergo LT. It is also results have been reported with granulocyte-colony the responsibility of the referring physician to explain the stimulating factor (G-CSF), RCTs are needed before routine prognosis and prime the relatives to the need of LT. recommendation. Both bone marrow and umbilical cord derived mesenchymal stem cells have shown improvement Conclusion in liver function when transfused via a peripheral vein. It is essential to recognize ACLF as a distinct entity with Fecal Microbiota Transplantation high short-term mortality and potential reversibility. Prompt recognition and treatment strategy can result in a transplant- Evolving data suggests a potential role in alcohol-related free survival of close to 50%. ACLF not eligible for steroids or LT. Presently FMT remains

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References 3. Jalan R, Yurdaydin C, Bajaj JS, et al. Toward an improved definition of acute-on-chronic liver failure. Gastroenterology. 2014;147(1):4-10. 1. Sarin SK, Choudhury A, Sharma MK. Acute-on-chronic liver failure: 4. Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure consensus recommendations of the Asian Pacific association for the is a distinct syndrome that develops in patients with acute study of the liver (APASL): an update. Hepatol Int. 2019;13(4):353-90. decompensation of cirrhosis. Gastroenterology. 2013;144(7):1426-37. 2. Bajaj JS, O’Leary JG, Reddy KR, et al. Survival in infection-related 5. Shalimar, Rout G, Jadaun SS, et al. Prevalence, predictors and impact acute-on-chronic liver failure is defined by extrahepatic organ of bacterial infection in acute on chronic liver failure patients. Dig failures. Hepatology. 2014;60(1):250-6. Liver Dis. 2018;50(11):1225-31.

MU-114.indd 722 29-01-2021 14:55:21 CHAPTER Approach to a Patient with Chronic Dyspnea of 115 Undetermined Etiology

Manish Kumar, Krishna Kumar, DP Singh

Abstract Dyspnea is a very common complaint encountered by medical professionals working both in general medical outpatient practice and also in emergency setup. Pulmonary and cardiac etiology are most commonly encountered; however, other causes like hematological or psychogenic causes are not very uncommon. A prompt and accurate diagnosis requires meticulous examination followed by proper use of investigative tools as per protocol.

Introduction failure, asthma, ischemic heart disease, interstitial lung disease (ILD), and impaired psychological condition are Dyspnea is a common presenting symptom that is some of the most common causes of chronic dyspnea. encountered by clinician in everyday practice. It is said to be chronic if it is present for more than 4 weeks.1 Dyspnea is a debilitating symptom that affects the overall quality Definition of life, exercise tolerance, morbidity, and mortality in The American Thoracic Society (ATS) defines dyspnea various disease states. It is a better predictor of mortality as “subjective experience of breathing discomfort that than angina in patients with cardiac disease and forced consists of qualitatively distinct sensations that vary expiratory volume in 1 second (FEV1) in patients with in intensity. The experience derives from interactions chronic pulmonary disease.2 In patients with chronic among multiple physiological, psychological, social obstructive pulmonary disease (COPD) and sedentary and environmental factors, and may induce secondary adults, chronic dyspnea leads to low adherence to exercise physiological and behavioral responses.” The ATS training programs, decreased functional status, and poor statement also reiterates the importance of self-reporting psychological health. by patients, as dyspnea can be perceived only by the 3 The exact mechanisms of dyspnea are still not very well person experiencing it. understood. Several recent studies have emphasized on the multidimensional nature of dyspnea. The perception Epidemiology of dyspnea depends on varying cortical integration It is difficult to ascertain the exact prevalence of chronic of several afferent and efferent signals that involves a dyspnea in general population as different studies complex chain of events. incorporate both acute and chronic dyspnea. Individuals Chronic dyspnea is most frequently either due to above age of 70 years have higher prevalence of chronic respiratory or cardiac cause. However, in about one third dyspnea. Studies have shown that almost half of the of cases, the etiology is multifactorial.1 COPD, cardiac patients admitted to acute tertiary care hospitals and

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one-fourth of patients in ambulatory settings present with to complete full sentence while talking is observed. Clinical dyspnea.4 The prevalence of mild to moderate dyspnea signs of pallor, cyanosis, clubbing, and pedal edema are ranges from 9% to 13% in adults according to some important. The symmetry of chest wall movements with population-based studies. This figure is around 25–27% in respiration should be observed. 5 persons older than 70 years. The hemodynamic stability of patient is confirmed by measuring the vital signs. Pulsus paradoxus (i.e., decrease Clinical Assessment in systolic of more than 10 mm Hg during A proper history and clinical examination is of utmost inspiration) could be due to cardiac causes such as importance. More than two-thirds of the patients need pericardial disease, restrictive heart disease, or cardiac diagnostic testing beyond clinical examination. The initial tamponade. Pulmonary disease such as COPD, asthma, clinical assessment of a patient with chronic dyspnea is large bilateral pleural effusion, tension pneumothorax, directed toward determining the underlying cause, which and may also be present with pulsus is fundamental for management and subsequent referral paradoxus. Increased work of breathing is evident by to a specialist if needed. According to a study amongst supraclavicular retraction, use of accessory muscles of patients with chronic dyspnea who were referred to a respiration and sitting with the hands braced on knees, specialist cardiologist or respiratory clinic at a tertiary that is, tripod position. These signs are indicative of center, only 51% were appropriately referred as per their increased airway resistance or stiffness of lungs and chest 1 final diagnosis. This improper initial referral leads to wall. significant delays in final diagnosis. Dullness on percussion of chest wall is indicative of The history and findings from physical examination pleural effusion. Likewise hyperresonance is a sign of have low positive predictive value (PPV) individually emphysema or pneumothorax. On auscultation, wheeze, and are more useful as negative predictive factors. crepitations, and diminished breath sounds are vital clues However, usually the clinical findings are considered in to the etiological diagnosis. combination, hence they are more likely to provide greater On examination of cardiovascular system, signs of right diagnostic accuracy. heart failure like elevated jugular venous pressure (JVP), History peripheral edema, accentuated pulmonary component of second heart sound, S3 gallop rhythm, and presence of The history given by the patient in his own words is of murmur are important. utmost importance. The effect of position, environmental In a study done by Pratter et al., an algorithmic stimuli, timing, aggravating, and relieving factors are approach to diagnosis of chronic dyspnea was found to helpful in arriving at a provisional diagnosis. For example, be helpful in correct diagnosis in 99% of the cases.6 At orthopnea indicates congestive heart failure (CHF), the initial visit, the patient underwent Tier 1 testing and and nocturnal dyspnea is suggestive of CHF or Asthma. subsequently the clinician made a diagnosis. Patient was Chronic persistent dyspnea is suggestive of COPD, ILD, subjected to Tier 2 and 3 testing if needed (Flowchart 1, and chronic thromboembolic disease. A previous history of drug induced or occupational lung disease, ischemic Table 1). heart disease is very vital. If the patient complains of There are various scales to measure dyspnea, but dyspnea in the upright position with relief in supine the two most commonly used are Medical Research position, that is, platypnea, it could be suggestive of left Council Scale for pulmonary disease and New York Heart atrial myxoma or hepatopulmonary syndrome.3 Association functional classification for cardiac diseases (Table 2 and Box 1). Physical Examination A thorough physical examination is imperative for Investigations assessment of cause, severity and proper management. It A number of diagnostic tools may be helpful in the initial starts during history taking itself when the patient’s ability the workup of a patient with chronic dyspnea.

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Flowchart 1: Algorithm for evaluation of a patient presenting with dyspnea6

TABLE 1 Causes of dyspnea7

Type Subtype Probable diagnosis

Pulmonary Airways COPD, asthma, bronchiectasis, airway mass, vocal cord dysfunction

Interstitial ILD, passive congestion, malignancy, radiation exposure

Alveolar Chronic pneumonia, malignancy, emphysema

Vascular Pulmonary emboli, PAH

Extrinsic Pleural effusion, obesity, kyphoscoliosis

Cardiac Myocardial Ischemic heart disease, cardiomyopathy, HFrEF, HFpEF

Arrhythmia Atrial fibrillation, tachycardia, bradycardia

Pericardial Restrictive/Constrictive pericarditis, pericardial effusion

Valvular Aortic /Aortic regurgitation/Mitral stenosis/Mitral regurgitation

Congenital heart disease Intracardiac shunt, Eisenmenger syndrome

Neuromuscular Neurogenic Diaphragmatic paralysis, GB syndrome, myasthenia gravis, ALS

Muscular Muscular dystrophy, myositis, metabolic abnormalities, thyroid disease

Other causes Anemia Iron deficiency

Pain Pleural disease, postoperative period

Psychological Anxiety, depression, hyperventilation ALS, amyotrophic lateral sclerosis; COPD, chronic obstructive pulmonary disease; ILD, interstitial lung disease; PAH, pulmonary arterial hypertension.

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TABLE 2 Medical Research Council Dyspnea Scale8

MRC Dyspnea Scale zz Breathless only with strenuous exercise zz Short of breath when hurrying on the level or up a slight hill zz Slower than most people of the same age on a level surface or have to stop when walking at my own pace on the level zz Stop for breath walking 100 meters or after a walking few minutes at my own pace on the level zz Too breathless to leave the house or breathlessness while dressing or undressing

9 elevated bicarbonate levels. Here arterial blood gas (ABG) BOX 1 NYHA Classification analysis may prove to be useful.3,7 A. Class I: Symptoms with more than ordinary activity B. Class II: Symptoms with ordinary activity Electrocardiography C. Class III: Symptoms with minimal activity An electrocardiogram (ECG) is a relatively cheap and 1. Class IIIa: No dyspnea at rest readily available investigation that may suggest any 2. Class IIIb: Recent dyspnea at rest D. Class IV: Symptoms at rest underlying cardiac problem, which may be the cause for dyspnea. It may show evidence of ischemic heart disease, prior myocardial infarction resulting in systolic Chest Radiography dysfunction, or valvular heart disease. In a study done amongst patients with chronic dyspnea, 8% were found After initial clinical assessment, chest X-ray is the most to have atrial fibrillation on ECG. Among these patients valuable tool for diagnosis. Hyperinflated lung fields 80% were later diagnosed as having dyspnea due to an are suggestive of chronic obstructive lung disease. underlying cardiac disease.1 Low lung volumes are seen in interstitial edema or fibrosis, diaphragmatic dysfunction or impaired wall motion. The evidence of interstitial disease, pulmonary Spirometry infiltrates should be looked in pulmonary parenchyma. Spirometry is a useful test for detecting obstructive and Pulmonary venous hypertension is suggested by restrictive ventilatory defects. It is especially useful when prominent pulmonary vasculature in upper zones. airway diseases such as bronchial asthma or COPD Enlarged central pulmonary suggest pulmonary are suspected. However, it is underused in clinical arterial hypertension (PAH). Enlarged cardiac shadow practice due to lack of time and resources. In a study of could be due to dilated cardiomyopathy or valvular heart patients with chronic dyspnea in primary care setting, the disease. CHF may present as bilateral pleural effusion diagnostic accuracy after clinical assessment was 55%, on X-ray. Unilateral effusion may be due to carcinoma, which increased to 72% after spirometry test.1,2 pulmonary embolism, parapneumonic effusion, or even heart failure.1,3 Echocardiography Echocardiography is a vital tool to assess cardiac Laboratory Investigations structure and function. In patients with chronic dyspnea, A complete blood count is essential to assess the echocardiography can identify conditions such as heart hemoglobin levels for anemia, which may cause dyspnea failure (HFrEF), ischemic heart disease, valvular heart or polycythemia, which may indicate chronic hypoxemia. disease, , and pericardial B-type natriuretic peptide detects cardiomyocyte strain. pathology. According to recommendations from Hence, this can be used to differentiate between cardiac International Heart Failure guidelines, echocardiography and respiratory causes of dyspnea. Chronic respiratory should be done at the earliest during the diagnostic failure may cause carbon dioxide retention resulting in workup of high-risk patients with chronic dyspnea. It is

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noninvasive, can be easily performed even at the bedside Tertiary Investigations in ICU or ER and has no side effects like radiation in CT Depending upon the results of initial investigations, scan. more specialized investigations are done if needed to determine the cause of chronic dyspnea. Imaging Ultrasound modalities such as cardiac MRI, CT, coronary angiography, Chest ultrasound provides a wealth of information stress echocardiography, lung ventilation/perfusion (V/Q) and it can be performed quickly and easily in critically scan are done if required. Coronary angiography may ill patients. It has a higher diagnostic accuracy than a also be done for assessment of coronary disease combination of physical examination and chest X-ray. or pulmonary pressure. Bronchoscopy, muscle biopsy, or Various patterns such as in acute interstitial syndrome, surgical lung biopsy are other tools. A FeNO test, or exhaled pneumothorax, pleural effusion, consolidation, etc. can nitric oxide test, determines the lung inflammation and be identified. It avoids ionizing radiation, and hence is its suppression with steroids in patients with allergic or quite safe. Lung ultrasound can also be used to guide fluid eosinophilic asthma.11 management and perform therapeutic procedures such as 10 thoracocentesis. Cardiopulmonary Exercise Test (CPET) Chest Computed Tomography (CT) In patients having dyspnea, which is out of proportion to known cardiorespiratory disease, CPET can provide CT scan of chest is most commonly used after an valuable information. It involves incremental testing abnormal chest X-ray. It has a high sensitivity for diffuse of exercise capacity while the patient is seated and parenchymal lung disease. It is also helpful in early continuously monitored on a stationary bicycle. CPET detection of ILD or pulmonary emphysema. Although it measures intake of oxygen, elimination of carbon dioxide, is not the recommended modality, but still cardiomegaly and minute ventilation, while exercising on the bicycle. and pulmonary edema can also be detected on CT chest. It is helpful in confirming the diagnosis of psychogenic The only disadvantage of CT scan is the risk of radiation dyspnea. In a study among patients with chronic dyspnea, exposure. Hence, careful patient selection with assessment 90% with normal CPET results were diagnosed to be of risk and benefits should be done by the clinician prior having a non-cardiorespiratory cause for dyspnea.12 to the CT scan. CT pulmonary angiography (CTPA) can be used to detect acute pulmonary embolism or chronic thromboembolic pulmonary hypertension (CTEPH). Treatment The optimal approach in the treatment of chronic Advanced Respiratory Function Tests dyspnea involves interventions that reduce the ventilatory The advanced respiratory function tests are also valuable demand, improve ventilatory capacity and respiratory in detecting chronic dyspnea of respiratory etiology. The mechanics and take care of the psychogenic aspect as well. diffusing capacity of lung for carbon monoxide (DLCO) Supplemental O2 is usually given if resting O2 saturation assesses the ability of lungs to transfer oxygen to blood. level is below 88% or if the saturation falls to this level DLCO can be reduced both in PAH and ILD. DLCO in with work or sleep. Supplementary oxygen has shown to 2,3 isolation is not sufficient to confirm or differentiate improve mortality, especially in patients with COPD. between the above two conditions. DLCO may predict Multiple interventions are often required and they mortality in a number of lung diseases, severe PAH, may have additive or synergistic effects. Some of these cancer, and various ILDs.1 interventions include oxygen therapy, bronchodilators, Test for bronchial hyperresponsiveness by broncho­ noninvasive ventilation, exercise training, lung volume provocation helps in diagnosis of patients with suspected reduction surgery, etc. asthma having normal spirometry. A study showed Opiates alter affective component of dyspnea and hyperresponsiveness to challenge testing in 34% of reduce the respiratory drive. Psychological counseling, patients with chronic dyspnea. Among these 69% were behavioral therapy, and anxiolytics have favorable effects diagnosed with asthma or COPD.1,3 on affective dimension of chronic dyspnea. An important

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component of dyspnea management is cardiac and . 4 Grønseth R, Vollmer WM, Hardie JA, et al. Predictors of pulmonary exercise training. dyspnoea prevalence: results from the BOLD study. Eur Respir J. 2014;43(6):1610-20. . 5 Carette H, Zysman M, Morelot-Panzini C, et al. Prevalence and Conclusion management of chronic breathlessness in COPD in a tertiary care center. BMC Pulm Med. 2019;19(1):95. The diagnosis of patients presenting with chronic dyspnea in 6. Pratter MR, Abouzgheib W, Akers S, et al. An algorithmic approach primary or tertiary care is challenging. Chronic dyspnea is most to chronic dyspnea. Respir Med. 2011;105(7):1014-21. common due to a cardiorespiratory cause. However, one third . 7 Bostwick D, Hatton ND, Mayeux JD, et al. The approach to the of patients have multifactorial etiology. Common comorbidities patient with chronic dyspnea of unclear etiology. Advn Pulm Hyper. such as obesity and deconditioning often contribute to 2018;16(3):103-11. . 8 Bestall JC, Paul EA, Garrod R, et al. Usefulness of the Medical symptomatology. This increases diagnostic difficulty and Research Council (MRC) dyspnoea scale as a measure of problems in management. Evidence-based algorithms are disability in patients with chronic obstructive pulmonary disease. helpful to improve the diagnosis and subsequent management Thorax.1999;54(7):581-6. of patients presenting with chronic dyspnea. 9. Bredy H, Ministeri M, Kempny A, et al. New York Heart Association (NYHA) classification in adults with congenital heart disease: relation to objective measures of exercise and outcome. Eur Heart J References Qual Care Clin Outcomes. 2018;4(1):51-8. 10. Guttikonda SNR, Vadapalli K. Approach to undifferentiated dyspnea 1. Ferry OR, Huang YC, Masel PJ, et al. Diagnostic approach to chronic in emergency department: aids in rapid clinical decision-making. dyspnoea in adults. J Thorac Dis. 2019;11(17):2117-28. Int J Emerg Med. 2018;11:21. . 2 Laviolette L, Laveneziana P. ERS Research Seminar Faculty. 11. Miskoff JA, Dewan A, Chaudhri M, et al. Fractional exhaled nitric Dyspnoea: a multidimensional and multidisciplinary approach. Eur oxide testing: diagnostic utility in asthma, chronic obstructive Respir J. 2014;43(6):1750-62. pulmonary disease, or asthma-chronic obstructive pulmonary 3. Kasper DL, Fauci AS, Hauser SL, et al. Harrison’s Principles of Internal disease overlap syndrome. Cureus. 2019;11(6):4864. Medicine, 20th edition. New York: McGraw-Hill Medical Publishing 12. Albouaini K, Egred M, Alahmar A, et al. Cardiopulmonary exercise Division; 2015. p. 20. testing and its application. Postgrad Med J. 2007;83(985):675-82.

MU-115.indd 728 02-02-2021 18:14:47 CHAPTER “Choice versus Chance”: Mathematics behind 116 Clinical Decision-making

Alladi Mohan, Alladi Vikramchandra

Abstract In their everyday clinical practice, doctors are faced with decisions related to investigations, interventions, or therapeutic options. These decisions are sometimes routine and simple, but may be complicated on other occasions. Clinical decision-making is challenging because, these decisions are not only unavoidable but also must be made under uncertain conditions. Mathematics underlying decision-making includes basic mathematical language of probability and Bayes’ theorem. Understanding these mathematical principles and judicious application of diagnostic reasoning can help clinicians in arriving at the appropriate course of action in a rational, scientific, and objective way.

Introduction occurrence of an event. Mathematically, probability of an event A occurring is denoted as P[A] and is read as “P of A”; Clinicians have to make decisions in daily practice this value ranges from 0.0 to 1.0.4 either regarding the choice of diagnostic testing or regarding therapeutic options or interventions. These Summation Principle decisions are unavoidable, and are often made intuitively under uncertain conditions and, therefore, constitute a If in a given clinical situation, let us assume that four significant challenge. In this chapter we have attempted possible outcomes A, B, C, and D can occur by chance. The to provide an overview regarding the mathematics behind summation principle states that the “sum of probabilities” decision-making. of all these four possible chance events (outcomes) equals 1.0.4 This is mathematically written as:

Basic Mathematics P[A] + P[B] + P[C] + P[D] = 1 To understand the science of clinical decision-making, an understanding of the basic mathematical language Joint Probability of probability and Bayes’ theorem is essential. Bayes’ The concomitant occurrence of a number of events is theorem is a mathematical rule that defines how existing termed as “joint probability” of occurrence of those beliefs should be revised or modified when new evidence events.4 The joint probability of occurrence of two events A 1-3 becomes available. and B is expressed as P[A,B].

Probability Conditional Probability In the context of clinical decision-making, probability The probability that an event A occurs, given that the event is defined as a measure of the belief regarding the B is known to occur is termed “conditional probability” of

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event A given occurrence of event B. This is expressed in statistical notation as (P[AB]).4 We can also express the relationship between joint and conditional probabilities by the following formula: P[A and B] = P[AB] × P[B]

Independence In a clinical situation, if the “conditional probability” of event A, given that event B occurs, is identical to the “unconditional probability” of event A occurring, then, the events A and B are probabilistically considered to be Fig. 1: Important conditional probabilities used in clinical practice independent.4 This relationship is expressed as: occurring given the test result R can be calculated using  P[A B] = P[A] the formula: The “joint probability” of occurrence of independent P[RDi] × P[Di] events is governed by the “product rule” which states: P[RD1] × P[D1] +…….+P[RDi] × P[Di]+…….+ P[RDn] × P[Dn] P[A,B] = P[A] × P[B] Odds Summation Principle for Joint Probabilities Odds of an event are defined by the number of occurrences The summation principle for joint probabilities states divided by the number of non-occurrences. For example, that if B1, B2, B3, and B4 are mutually exclusive events odds of a disease = No. of persons who develop disease (i.e., only one of these can occur), and A is another event, during follow-up/No. of persons who do not develop then, probability of occurrence of event A is given by the disease. formula: If p is the probability of an event occurring, then, the P[A] = P[A,B1] + P[A,B2] + P[A,B3] + P[A,B4] probability that the event will not be occurring is denoted For computing the probability of an event from several as (1−p). Then, the odds favoring the occurrence of the conditional probabilities, the “averaging out” method is event are calculated as p/(1−p); and the odds against the used. event occurring are calculated as (1−p)/p. Bayes’ theorem can also be expressed in terms of odds Bayes’ Theorem as: In clinical practice, diagnostic tests are performed to P[D+R] P[D+] P[RD+] ascertain the definitive diagnosis. The possible results P[D–R] P[D–] P[RD–] that are obtained on performing such a diagnostic test Posterior odds Prior odds Likelihood ratio are listed in Figure 1 and Table 1. The performance of Here, D+ = disease present; D− = disease absent; R = the diagnostic test is evaluated using a “gold standard” for test result; P[D+R] denotes the probability of the disease categorization of the subjects as “having disease” or “no being present given the test result. disease.” In this situation, Bayes’ theorem can be applied to estimate the probability of the disease given a positive or a negative test result. Generally, the possibilities of two Likelihood Ratio disease states (disease is present/absent) are considered. The likelihood ratio (LR) of a positive test result is the ratio However, several disease states D1, D2, and so on (up of the probability of occurrence of the test result in persons to Dn) can also be considered. Then, by applying Bayes’ with or without the disease. theorem, the revised probability of any one disease (Di) LR for a positive test result = sensitivity/(1−specificity)

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TABLE 1 Probabilities associated with the test results shown in

Variable Probability notation Estimate of probability

Sensitivity True-positive rate; frequency of positive test results in persons with disease P[T+D+] TP/(TP+FN)

Specificity P[T-D-] TN/(TN+FP) True-negative rate; frequency of negative test results in persons with disease

False-negative rate P[T-D+] FN/(TP+FN) Frequency of negative test results in persons with disease

False-positive rate P[T+D-] FP(TN+FP) Frequency of positive test results in persons without disease

Predictive value of positive test P[D+T+] TP/(TP+FP) Frequency of disease in persons with a positive test result

Predictive value of negative test P[D-T-] TN/(TN+FN) Frequency of non-disease in persons with a negative test result FN, false negative; FP, false positive; TN, true negative; TP, true positive

Similarly, LR for a negative test result = (1−sensitivity)/ specificity Post-test odds can be computed from the “pre-test odds” and LR, using the formula: Post-test odds = pre-test odds × LR

Some Applications of Bayes’ Theorem in Clinical Medicine Some of the applications of the aforementioned mathematical principles that are used in clinical medicine for decision-making3,5,6 are briefly described below.

Receiver-operator Characteristic Curve The receiver-operator characteristic (ROC) curve is plotted with 1-specificity (false positive rate) on the X-axis against sensitivity on the Y-axis. The ROC curve graphically portrays the trade-off between sensitivity and specificity for different chosen criteria (cut-off values) of positivity for the test result4,7,8 and facilitates the identification of Fig. 2: Receiver-operator characteristic (ROC) curve along with 95% the optimum threshold or cut-off value (Fig. 2, thick confidence bands (dotted lines). The ROC curve represents a graphical description of the “dynamic trade-off” between more accurate arrow). Some examples for the use of ROC curve analysis identification of subjects with disease versus those without disease. in decision-making include, defining the cut-off value Each point on the ROC curve represents a potential cut-off value with of carotid intima media thickness as a surrogate marker an associated sensitivity. Area under the ROC curve (AUC) is a measure for subclinical ,9 glycosylated hemoglobin of the overall performance and ranges between 0 and 1. The line 10 segment drawn from (0,0) to (1,1) represents the chance diagonal and (HbA1c) for the diagnosis of diabetes mellitus, among this has an AUC = 0.5. Therefore, a diagnostic test with an AUC greater others. than 0.5 is better than “pure chance” in correctly categorizing a cut-off

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Decision Analysis 2. Mohan A, Srihasam K, Sharma SK. Diagnostic reasoning: approach to clinical diagnosis based on Bayes’ Theorem. Medicine update. While evaluating patients in everyday practice, a clinician Available from http://apiindia.org/wp-content/uploads/pdf/ takes into consideration the data obtained from the medicine_update_2008/chapter_75.pdf. history and physical examination findings. On the 3. Phelan PS. The value of Bayes’ theorem for pure likelihood clinical basis of information thus gathered, clinicians, based reasoning. J Eval Clin Pract. 2018;24(4):782-3. on their previous experience and intuitive thinking, . 4 Weinstein MC, Fineberg HV, Elstein AS (Eds). Clinical Decision Analysis. Philadelphia: WB Saunders; 1980. p. 351. formulate a diagnostic work-up plan. Even though this . 5 Kadane JB. Bayesian methods for health-related decision making. intuitive approach has the advantage of being flexible, it is Stat Med. 2005;24(4):563-7. subjective and varies between various clinicians. 6. Ashby D, Smith AF. Evidence-based medicine as Bayesian decision- “Clinical decision analysis” approach has remarkably making. Stat Med. 2000;19(23):3291-305. influenced decision-making in a rational way under 7. Kumar R, Indrayan A. Receiver operating characteristic (ROC) curve conditions of uncertainity4,11-14 and has facilitated for medical researchers. Indian Pediatr. 2011;48(4):277-87. . 8 Obuchowski NA, Bullen JA. Receiver operating characteristic choosing the best possible course of action.4,11-14 It is an (ROC) curves: review of methods with applications in diagnostic explicit, quantitative and prescriptive approach to clinical medicine. Phys Med Biol. 2018;63(7):7TR01. decision-making. In this approach, probabilities of arriving . 9 Mohan A, Sada S, Kumar BS, et al. Subclinical atherosclerosis in at a choice or chance decision, utility of the outcome from patients with rheumatoid arthritis by utilizing carotid intima-media each of the options are considered and logical structure thickness as a surrogate marker. Indian J Med Res. 2014;140(3): of the problem called “decision tree” is constructed. The 379-86. 10. Mohan A, Reddy SA, Sachan A, et al. Derivation & validation of decision tree is analyzed by considering the probability glycosylated haemoglobin (HbA1c) cut-off value as a diagnostic of each outcome along with its associated utility and test for type 2 diabetes in South Indian population. Indian J Med the path with the highest expected value is chosen to Res. 2016;144(2):220-8. arrive at a clinical decision. Clinical decision analysis has 11. Pauker SG, Kassirer JP. The threshold approach to clinical decision been applied in various commonly encountered clinical making. N Engl J Med. 1980;302(20):1109-17. situations to arrive at a decision.14-17 12. Zarin DA, Pauker SG. Decision analysis as a basis for medical decision making: the tree of hippocrates. J Med Philos. 1984;9(2):181-213. 13. Pauker SG, Kassirer JP. Decision analysis. N Engl J Med. 1987;316(5): Conclusion 250-8. 14. Mohan A, Pande JN, Sharma SK, et al. Bronchoalveolar lavage Clear understanding of the mathematics underlying decision in pulmonary tuberculosis: a decision analysis approach. QJM. making and judicious application of diagnostic reasoning can 1995;88(12):269-76. help clinicians in arriving at the appropriate course of action in 15. Hogendoorn W, Moll FL, Sumpio BE, et al. Clinical decision analysis a rational, scientific and objective way. and markov modeling for surgeons: an introductory overview. Ann Surg. 2016;264(2):268-74. 16. Bae JM. The clinical decision analysis using decision tree. Epidemiol References Health. 2014;36:e2014025. . 1 Kallner A. Bayes’ theorem, the ROC diagram and reference values: 17. Liu Z, Du M, Li X, et al. Imaging features and clinical decision analysis definition and use in clinical diagnosis. Biochem Med (Zagreb). of 110 cases of intrapulmonary lymph nodes. Thorac Cardiovasc 2018;28(1):010101. Surg. 2019;68(7):652-58.

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Approach to Syncope in 117 Emergency Room

Prasanta Kumar Bhattacharya

Abstract Syncope, characterized by transient loss of consciousness due to cerebral hypoperfusion, is a common clinical condition requiring emergency medical attention. Emergency room approach to syncope entails its diagnosis and differentiation from other causes of transient loss of consciousness such as epilepsy, vertebrobasilar insufficiency, hypoglycaemia and psychiatric illnesses; risk stratification into high- and low-risk etiologies; and management. Vasovagal syncope and syncope due to orthostatic , which carry low-risk, usually have uneventful outcomes. Syncope due to underlying cardiac causes is usually difficult to diagnose and carry a poorer prognosis, and commonly requires hospitalization for further evaluation and management. In developed countries having well-equipped syncope units, most cases of syncope can be managed and discharged from the emergency room. However, in developing countries like India, lacking such facilities, high-risk cases of syncope should ideally be hospitalized for further evaluation and management.

Introduction psychogenic causes like psychogenic pseudosyncope, and non-epileptic seizure; vertebrobasilar insufficiency, Syncope is the loss of consciousness (LOC) occurring hypoxemia, narcolepsy with cataplexy; and hypoglycemia.4 transiently due to cerebral hypoperfusion. It is The term presyncope is commonly used to describe a characterized by a rapid onset of the LOC, which occurs for a short duration, with a spontaneous complete condition resembling the prodrome of syncope, but which 1 recovery.1 Syncope is a common presenting problem, is not followed by actual LOC, probably because the accounting for 1–3% of all emergency department visits hypoperfusion of the brain in presyncope does not result with up to 50% being hospitalized.2-5 The LOC is associated in LOC. Most of the times syncope presents as a medical with a brief period of actual or apparent LOC, along with emergency necessitating prompt management in the loss of awareness during this period of unconsciousness, emergency ward. However, differentiating it from the other associated with abnormal motor control and loss of common causes of T-LOC, as well as identifying patients responsiveness.1 Transiently occurring LOC (T-LOC) with syncope with potentially life threatening etiologies can be due to either head trauma, or can be due to non- poses as a challenge in management especially in the traumatic causes. Syncope falls under the latter group, emergency room (ER) settings. Therefore, the main focus but has to be differentiated from other conditions within should be in diagnosing syncope, differentiating it from this sub-group of non-traumatic causes, important other common causes of T-LOC and its risk stratification among these are various forms of generalized seizures; for hospitalization and optimum management.

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TABLE 1 Types of syncope with underlying mechanism and causes

Type Mechanism Causes

Neurally mediated (reflex zz Transient alteration in reflexes maintaining zz Vasovagal syncope or vasovagal) syncope cardiovascular homeostasis zz Reflex syncope, e.g.: zz Transient vasodilatation/loss of vasoconstrictor —— Post-micturition syncope tone plus bradycardia with resultant loss of —— Gastrointestinal blood pressure control —— Carotid sinus syndrome —— Ocular

Syncope due to Sympathetic vasoconstrictor failure ± failure zz Primary autonomic failure of compensatory tachycardia with resultant zz Peripheral neuropathy with secondary autonomic hypotension on standing failure, e.g.: —— Diabetes mellitus zz Drug-induced zz Volume depletion

Cardiac syncope Arrhythmia and/or leading zz Arrhythmia: to decreased cardiac output —— Bradyarrhythmias (sinus node dysfunction), high grade type II AV block, complete heart block —— Tachycardia-bradycardia syndrome —— Ventricular tachyarrhythmias zz Structural heart disease: —— Valvular heart disease —— Hypertrophic cardiomyopathy —— Atrial myxoma

Approach to Syncope in the Step-by-step approach in management of syncope BOX 1 Emergency Room in the emergency room 1,3 zz Confirmation of diagnosis of syncope by differentiating from Classification and Etiology of Syncope other common causes Syncope can be classified into three broad groups: zz Determination of the cause of syncope „„ Reflex (neurally mediated), or vasovagal syncope zz Risk assessment of syncope „„ Syncope due to orthostatic hypotension zz Management strategy based on risk profile „„ Cardiac syncope In about one-third of cases the etiology of syncope is unexplained,6 while in 10–15% of patients the etiological Confirmation of Diagnosis of Syncope by diagnosis of syncope remains unclear even after thorough Differentiating from Other Common Causes evaluation using current diagnostic guidelines.7,8 The Syncope occurs due to a transiently occurring global different types of syncope, their underlying mechanism of cerebral hypoperfusion. Since cerebral hypoperfusion development and common causes are outlined in Table 1. cannot be clinically determined one has to depend on the clinical parameter of T-LOC for a diagnosis of syncope. Step-by-Step Approach in the Management of But T-LOC can occur due to various causes other than 9,10 Syncope in the Emergency Room syncope as already mentioned. Setting aside the traumatic Step-by-step approach in the management of syncope causes of T-LOC from our current discussion, the various in the ER settings can be broadly sub-divided under the common non-traumatic causes of T-LOC (Table 2) should following headings (Box 1): be brought into the differential diagnosis of syncope

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immediately after the event. Muscle aches may occur after TABLE 2 Common causes of transient loss of consciousness both syncope and seizures, but are more severe and long Causes of transient Types/Causes lasting after a seizure. Unlike syncope, seizures are rarely loss of consciousness provoked by emotions or pain. Further, while incontinence Syncope zz Reflex/vasovagal of urine may occur with both seizures and syncope, fecal zz Orthostatic hypotension incontinence very rarely occurs with syncope.4 zz Cardiac Epileptic seizures zz Generalized seizures Syncope versus Hypoglycemia zz Partial seizures Insulin induced hypoglycemia in diabetes mellitus may Metabolic zz Hypoglycemia cause T-LOC, which is usually preceded by features of Psychogenic zz Psychogenic pseudosyncope sympathetic overactivity like tremor, palpitations, anxiety, zz Psychogenic non-epileptic seizures sweating, hunger, and paresthesia. Hunger is particularly Uncommon zz Transient ischemic attack not a typical premonitory feature of syncope. Additional zz Sub-arachnoid hemorrhage neuroglycopenic features in hypoglycemia include zz Subclavian steal syndrome fatigue, weakness, dizziness, and cognitive and behavioral symptoms, which are not found in syncope. Diagnostic in any patient brought to the ER with T-LOC without difficulties of hypoglycemia may occur in those with strict any apparent cause.1 Some of the common causes from glycemic control and repeated hypoglycemic episodes which syncope has to be frequently differentiated include leading to blunting of the characteristic warning symptoms seizures, hypoglycemia, narcolepsy with cataplexy, and of hypoglycemia, or hypoglycemia unawareness. certain psychiatric disorders. Syncope versus Cataplexy Syncope versus Seizures Patients with cataplexy, which occurs in about two-thirds Syncope and seizure are the two most common causes of of patients with narcolepsy, experience an abrupt onset of T-LOC and differentiation between the two is not always partial or complete loss of muscular tone lasting for short as easy.1,2 Both generalized and partial seizures may durations of 30 seconds to 2 minutes; usually triggered by be confused with syncope, although there are several strong emotions like anger or laughter. Unlike syncope, differentiating points between the two. Similar to the tonic- consciousness is maintained throughout the attacks, and clonic movements of generalized seizures involuntary there are no premonitory symptoms. movements like myoclonus may occur in up to 90% cases of syncope, along with mild flexor and extensor posturing. Syncope versus Common Psychiatric Ailments Likewise, partial or partial-complex seizures with Various psychiatric disorders like generalized anxiety, secondary generalization are commonly preceded by an panic disorders, major depression, and somatization aura, which should be differentiated from the premonitory disorders are associated with an apparent LOC. These features of syncope. Further, autonomic manifestations should be considered in individuals who faint frequently of seizures like cardiovascular, urogenital, pupillary, and without prodromal symptoms. In such patients there cutaneous manifestations may mimic the premonitory is rarely any injury in spite of repeated falls; and there features of syncope; the arrhythmias associated with are no clinically significant hemodynamic changes like the cardiovascular manifestations may even lead to hypotension and bradycardia associated with these LOC. Nevertheless, the presence of accompanying episodes which is found typically in vasovagal syncope. non-autonomic auras may help differentiate these episodes in seizures from syncope. Among the points of differentiation between seizures and syncope, the Determination of the Cause of Syncope LOC in seizures is usually more than 5 minutes duration Once a diagnosis of syncope has been made in the ER and with prolonged postictal drowsiness and disorientation, other likely causes of T-LOC have been clinically excluded, whereas in syncope the patient regains orientation almost one should look for any serious underlying cause for the

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syncope. In about 50% of cases the cause can be identified also usually have history of structural heart diseases, in the ER; the serious among them are usually some and their physical examination and ECG findings are non-cardiovascular causes like a ruptured abdominal usually abnormal. Structural heart disease13 and primary aortic , an upper gastrointestinal bleeding or a arrhythmias14 are major risk factors for sudden cardiac subarachnoid hemorrhage.2 Underlying cardiovascular death and overall mortality. These patients are candidates conditions especially arrhythmias are less frequently for further investigations such as echocardiography, ECG recognized in the ER unless it is present in the ECG on monitoring, and other sophisticated tests and referral admission.11 to specialists. These patients should not be discharged from the ER and preferably hospitalized for specialist Risk Assessment of Syncope consultations and special tests mentioned. When the cause of syncope cannot be ascertained in the ER, subsequent management should be guided by Clinical Evaluation in the Emergency Room Setup assessing the risk of a serious outcome in the future, Some specific baseline investigations should be carried especially a major cardiovascular event or sudden cardiac out in the ER setup. An ECG is important because a death. Such risk stratification includes determining the normal ECG practically rules out any cardiological cause type of syncope and the patient’s risk factors for a cardiac of syncope, except for transient arrhythmia. First-degree event.1,2,9 heart block is neither associated with a cardiac nor There are three major types of syncope as described reflex cause of syncope. An estimation of the random earlier (Table 1). Syncope, which is thought to be due to blood glucose should be done to exclude hypoglycemia, either reflex or postural cause, is likely to be at low risk of which may present as collapse or seizure. Estimation of serious outcome. Patients with syncope of cardiac origin hemoglobin and the hematocrit will exclude anemia, and are usually at a higher risk of serious coucomes.1 The 2018 blood loss as a cause of syncope. Blood tests for troponin European Society of Cardiology (ESC) guidelines for the and D-dimer should be done when myocardial ischemia- diagnosis and management of syncope provide a list of related syncope or pulmonary embolism is suspected.1 A high-risk and low-risk features for risk stratification of chest X-ray or a CT brain is routinely not required.2 syncope in the ER.1 These are based on certain clinical features of the syncopal attack, past history of the patient, Special Tests and Investigations and findings in the ECG. Carotid Sinus Massage Management Strategy Based on Risk Profile Carotid sinus massage (CSM) should be considered Patients who have low-risk features are usually due to in patients over the age of 40 years with reflex syncope 1 reflex or postural syncope. These patients usually have of unknown origin. In patients with history or clinical either some prodromal features or typical precipitating features of reflex syncope, if CSM causes symptomatic event(s). There may be a history of recurrent syncope, and bradycardia and/or hypotension one can diagnose carotid 2,15 the physical examination and ECG are usually normal. sinus syndrome. The outcome in patients with reflex syncope is usually very good. Syncope due to postural hypotension also has a Active Standing to Measure Postural Blood Pressure low risk, but the prognosis is poorer than in reflex syncope Postural hypotension is a progressive and sustained fall of due to their comorbidities.12 These patients can be usually more than 20 mm Hg of systolic or more than 10 mm Hg discharged from the ER without hospitalization. Some of diastolic blood pressure (BP) from baseline or a patients with frequent episodes of syncope or syncope- decrease in systolic BP to less than 90 mm Hg. In classic related injuries are usually referred to special clinics for orthostatic hypotension the time from upright position further evaluation.2 to abnormal BP response is less than 3 minutes and in Patients who have high-risk features usually do not have delayed orthostatic hypotension it is more than 3 minutes. associated prodromal symptoms or typical precipitating It is important that the procedure should be done by the events like in those with low-risk features. These patients clinician and not delegated to other ER staff.2,16

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ECG Recording Conclusion In addition to the standard 12-lead ECG, the patient Syncope is a common medical emergency. In the ER setting it is should be put on continuous ECG monitoring if cardiac very important to first differentiate it from other serious causes arrhythmia is suspected to be the cause of the syncope. of transient LOC like seizure or hypoglycemia. Thereafter, It has been found that ambulatory ECG monitoring one should try to find out the underlying cause of syncope. in unexplained syncope can identify arrhythmia to be A thorough history and clinical examination, and an ECG can the cause for the syncope in about 10% patients with a most of the time distinguish the high-risk group of syncope diagnostic yield in about 75% of such cases.17 due to heart diseases from those with lower risks due to orthostatic hypotension or reflex syncope. Additional tests like carotid sinus massage, echocardiography, cardiac troponin, or Echocardiography ECG monitoring may be required in the ER setting. Those with a Patients with a heart murmur or history of structural heart high risk require urgent investigation and hospitalization. disease requires an echocardiographic examination. One has to differentiate a benign flow murmur from a murmur of aortic stenosis and hypertrophic cardiomyopathy.18 References . 1 Brignole M, Moya A, de Lange FJ, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. Troponin to Rule Out Acute Coronary Syndrome 2018;39(21):1883-948. Where ECG changes are consistent with acute myocardial . 2 Reed MJ. Approach to syncope in the emergency department. Emerg Med J. 2019;36(2):108-16. ischemia high sensitivity troponin test should be done to 19 . 3 Runser LA, Gauer RL, Houser A, et al. Syncope: evaluation and rule out acute coronary syndrome. differential diagnosis. Am Fam Physician. 2017;95(5):303-12. . 4 Syncope FR. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Decision Regarding Hospitalization Longo DL and Loscalzo J (Eds). Harrison’s Principles and Practice of Medicine, 20th edition. NYC (USA): McGraw-Hill Education; Across the world the hospitalization rate of patients 2018;20:122-9. with syncope attending the emergency department is . 5 Tyagi LK, Singh V, Gaur K, et al. Epidemiology, pathophysiology quite high. About one half of these patients attending and treatment of different types of syncope: a review. Global J the emergency department are usually hospitalized; and Pharmacol. 2009;3(3):166-70. 6. D’Ascenzo F, Biondi-Zoccai G, Reed MJ, et al. Incidence, etiology and approximately half of the admitted patients would be predictors of adverse outcomes in 43,315 patients presenting to discharged with no clear diagnosis, even after extensive the emergency department with syncope: an international meta- investigations.20 Many of the hospitalizations for syncope analysis. Int J Cardiol. 2013;167(1):57-62. are unnecessary;2 two-thirds of serious outcomes occur 7. Brignole M, Ungar A, Casagranda I, et al. Syncope Unit Project (SUP) while the patient is in the ER and the rate of serious investigators. Prospective multicentre systematic guideline-based management of patients referred to the syncope units of general outcomes after the patient is shifted out of the ER is hospitals. Europace. 2010;12(1):109-18. actually quite low, being as low as 3.6% at one-month . 8 Mitro P, Kirsch P, Valocˇik G, et al. A prospective study of the 1 follow-up. Hospitalization is indicated mainly for patients standardized diagnostic evaluation of syncope. Europace. requiring syncope-related treatment and those with 2011;13(4):566-71. severe comorbidities or syncope-related injury caused 9. Costantino G, Sun BC, Barbic F, et al. Syncope clinical management in the emergency department: a consensus from the first by the primary event. In developed countries where international workshop on syncope risk stratification in the there are specialized syncope clinics with facilities for emergency department. Eur Heart J. 2016;37(19):1493-8. investigations and treatment in the ER setups patients with 10. Sun BC, Costantino G, Barbic F, et al. Priorities for emergency higher risk profiles can be managed in the ER settings and department syncope research. Ann Emerg Med. 2014;64(6):649-55. so hospitalization can be rationalized.21,22 However, since 11. Reed MJ, Henderson SS, Newby DE, et al. One-year prognosis after such advanced syncope units are not commonly available syncope and the failure of the ROSE decision instrument to predict one-year adverse events. Ann Emerg Med. 2011;58(3):250-6. in developing countries patients with high-risk should be 12. Ricci F, Fedorowski A, Radico F, et al. Cardiovascular morbidity and ideally hospitalized for further evaluation and appropriate mortality related to orthostatic hypotension: a meta-analysis of management. prospective observational studies. Eur Heart J. 2015;36(25):1609-17.

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13. Colivicchi F, Ammirati F, Melina D, et al. Development and after initial evaluation in the emergency department: the PATCH-ED prospective validation of a risk stratification system for patients study. Emerg Med J. 2018;35(8):477-85. with syncope in the emergency department: the OESIL risk score. 18. RCEM Learning. Syncope. Available from https://www.rcemlearning. Eur Heart J. 2003;24(9):811-9. co.uk/reference/syncope/ [Accessed 2020]. 14. Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. 2015 ESC 19. Reed MJ, Newby DE, Coull AJ, et al. Diagnostic and Guidelines for the management of patients with ventricular prognostic utility of troponin estimation in patients presenting arrhythmias and the prevention of sudden cardiac death: the Task with syncope: a prospective cohort study. Emerg Med J. 2010;27(4): Force for the Management of Patients with Ventricular Arrhythmias 272-6. and the Prevention of Sudden Cardiac Death of the European 20. Quinn JV. Yield of diagnostic tests in evaluating syncopal Society of Cardiology (ESC). Eur Heart J. 2015;36(41):2793-867. episodes in older patient: invited commentary. Arch Intern Med. 15. Brignole M, Moya A, de Lange FJ, et al. Practical instructions for 2009;169(14):1299-305. the 2018 ESC Guidelines for the diagnosis and management of 21. Costantino G, Perego F, Dipaola F, et al. Short- and long-term syncope. Eur Heart J. 2018;39(21):43-80. prognosis of syncope, risk factors, and role of hospital admission: 16. van Wijnen VK, Ten Hove D, Gans ROB, et al. Orthostatic blood results from the STePS (Short-Term Prognosis of Syncope) study. J pressure recovery patterns in suspected syncope in the emergency Am Coll Cardiol. 2008;51(3):276-83. department. Emerg Med J. 2018;35(4):226-30. 22. Quinn J, McDermott D, Stiell I, et al. Prospective validation of 17. Reed MJ, Grubb NR, Lang CC, et al. Diagnostic yield of an the San Francisco Syncope Rule to predict patients with serious ambulatory patch monitor in patients with unexplained syncope outcomes. Ann Emerg Med. 2006;47(5):448-54.

MU-117.indd 738 29-01-2021 14:54:43 CHAPTER

Nailing the Diagnosis 118 through Nail Changes

Bidita Khandelwal, Pradeep Balasubramanian

Abstract Nail, a cutaneous appendage, serves as an invaluable tool in unveiling the underlying systemic diseases. The nail changes can precede or coexist with the underlying systemic diseases. The presence of a particular nail change in several or all the nails is the feature of systemic disease or associated dermatologic disorder. The nail changes can involve various components of the nail such as nail matrix, nail plate, nail bed, or periungual tissue. In this chapter, we have discussed about various nail changes, specific features to identify them and its usefulness in delineating the associated systemic diseases comprehensively.

Introduction Nail changes serves as window for diagnosis of several systemic diseases. Hippocrates in 5th century described clubbing to be associated with several systemic diseases.1 Since then several nail changes were found to be associated with systemic diseases. The nail changes in isolation or as a complement help to diagnose underlying disease. Nail changes can precede or can occur coexist with systemic disorders. Fingernail changes are more reliable than toenail changes since toenail changes can be altered by trauma. The components of nail unit is illustrated in Figure 1. In this chapter, comprehensive facts regarding identification of nail changes and the systemic diseases Fig. 1: Components of nail unit associated with them are discussed. An important fact that needs to be emphasized upon is that trauma to the nail matrix or nail can result in several nail changes which Koilonychia (Spoon-shaped Nails) will be confined to the trauma inflicted nail only. Whereas It is characterized by concave dorsal surface of the the nail changes due to the systemic diseases will be seen nail (Fig. 2). It is due to fragility of nails coupled with uniformly involving all the nails. The nail disorders that increased pressure exerted at the lateral and distal edges will be discussed are briefed in Table 1. of the nails that make these edges to get reverted. The

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Classification of nail changes pertaining to systemic TABLE 1 diseases

Abnormalities of Abnormalities of nail color nail surface zz Koilonychia zz Leukonychia (total, striate, & punctate) zz Beau’s lines zz Terry nails Apparent zz Clubbing zz Muehrcke’s lines leukonychia* zz Pitting zz Lindsay nail zz Longitudinal zz Splinter hemorrhages ridging zz Melanonychia zz Pterygium zz Cyanosis zz Icterus zz Yellow nail syndrome zz Nicotine staining Abnormalities in Abnormalities in periungual region Fig. 2: Koilonychia nail attachment zz Onycholysis zz Periungual zz Pterygium zz Paronychia *Apparent leukonychia is due to the changes in the nail bed, which makes the nail look white

central aspect is depressed since it’s tightly attached to nail bed.2 Koilonychia can be congenital, acquired, or idiopathic. Iron deficiency anemia is the most common systemic cause followed by hemochromatosis, Raynaud’s phenomenon, or systemic lupus erythematosus and among high altitude inhabitants.3,4 It can also develop due to trauma to the nail matrix area, occupational exposure to petroleum-based solvents.5

Beau’s Lines Fig. 3: Beau’s lines These are transverse lines or ridges, which are parallel to lunula of the nails (Fig. 3). They develop due to acute febrile illnesses, acute myocardial infarction, malnutrition, usually seen involving all the nails (Fig. 4). Clubbing is chemotherapeutic drugs, or trauma to nail matrix area. It extensively studied and it forms an integral component of occurs due to temporary cessation of nail growth. Nail general physical examination. Clubbing can be hereditary, grows at a rate of 3.5 mm per month approximately.6 acquired, or idiopathic. Considering this fact, the distance of these lines from The causes for clubbing can be remembered by the the cuticle tells about the time period before when the mnemonic CLUBBING which include: systemic disease had resulted. The width of the line tells „„ Cardiac diseases: congenital cyanotic heart diseases, about the duration of illness. acyanotic congenital heart diseases with reversal of shunt, infective endocarditis, atrial myxoma Clubbing „„ Lung diseases: lung abscess, bronchiectasis, emphy­ Clubbing refers to the nail change featured by increased sema, mesothelioma, cystic fibrosis, tuberculosis, longitudinal and transverse curvature of nail plate pulmonary AV malformation, tuberculosis with combined with soft tissue hypertrophy of the digital pulp cavitation

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Fig. 4: Clubbing Fig. 5: Onycholysis

„„ Ulcerative colitis & Chron’s disease (inflammatory TABLE 2 Causes of unilateral and unidigital clubbing bowel disease) „„ Biliary cirrhosis (primary), cirrhosis due to other Causes of unilateral clubbing Causes of unidigital clubbing causes zz Aortic or subclavian artery zz Median nerve injury „„ Bronchogenic carcinoma (most commonly small cell) aneurysm zz Tophaceous gout zz Axillary artery aneurysm zz Sarcoidosis „„ Idiopathic zz Brachial AV fistula zz Trauma „„ Congenital zz Recurrent dislocation of „„ Gastrointestinal: malabsorption (celiac disease) shoulder zz Pancoast tumor Miscellaneous causes: HIV, sarcoidosis, Hodgkin’s disease, zz thyroid disorders, thymus tumor, and acromegaly. zz Clubbing is caused by proliferation of connective zz Hemiplegic stroke tissue (fibroblasts, blood vessels, and bone tissue) and edema under the influence of VEGF (Vascular Endothelial Following are the grades of clubbing: Growth Factor) or PDGF (Platelet Derived Growth Factor) „„ Grade 1: Fluctuation of nail bed the levels of which get increased due to hypoxia or 7 „„ Grade 2: Increased anteroposterior and transverse malignancies. diameter of nails Unilateral and unidigital clubbing can be caused by „„ several factors as mentioned in the Table 2. Grade 3: Increase in pulp tissue resulting in drumstick There are three famous geometric forms associated appearance of the fingers with clubbing namely: „„ Grade 4: Hypertrophic osteoarthropathy (HOA) „„ characterized by deep pain in the distal extremities Lovibond angle: It is the angle between the nail plate 7 and the proximal nail fold. It is usually less than 160° more during night and on dependency but increases beyond 180° in clubbing. „„ Curths angle: It is the angle at the distal interphalangeal Onycholysis joint. Normally it is 180°. But in clubbing, it is reduced It is characterized by detachment of nail plate from nail bed to less than 160°. resulting in whitish or yellowish coloration (Fig. 5). This „„ Schamroth sign: It is featured by the obliteration color change is due to the presence of air column beneath of the diamond shaped space which is formed by the detached portion of the nail plate. It can result due to approximation of the distal interphalangeal joint and numerous factors namely local causes (trauma, working the nail plate of the right and left identical digits. in wet environment), cutaneous disorders (psoriasis,

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Fig. 6: Pterygium of the nail Fig. 7: Leukonychia

onychomycosis), and systemic causes (hyperthyroidism). Punctate Leukonychia Onycholysis in hyperthyroidism is called “Plummer’s It is characterized by white dot or streak seen involving nails.”8 nail(s). It is caused by trauma to the nail plate or nail matrix, commonly due to nail biting or habitually picking Pterygium the proximal nail fold. It is the extension of the proximal nail fold over the surface of nail plate commonly seen in lichen planus (Fig. 6). Mees’ Lines Pterygium inversum is a condition in which the nail bed It is a classic example of striate true leukonychia, which is tissue is attached to the distal under surface (ventral seen involving the whole width of the nails. They do not surface) of the nail associated with obliteration of distal fade on application of pressure and they grow out with groove. It is commonly seen in scleroderma. time.10 Though it is characteristically known to occur in Arsenic toxicity, it is also reported in carbon monoxide Leukonychia poisoning, congestive cardiac failure, renal failure, due to chemotherapeutic medications, Hodgkin’s disease, and It denotes the white coloration of the nails (Fig. 7). If the 11 white color is due to abnormal keratinization it causes pneumonia. true leukonychia whereas the changes in nail bed lead to apparent leukonychia. Apparent leukonychia fades on Terry Nails application of pressure to the surface of the nails whereas It is featured by whitish (pale) proximal portion and true leukonychia remains unaltered. True leukonychia normal vascular band distally. It is seen associated with grows out along with the growth of the nail plate whereas congestive cardiac failure, adult-onset diabetes mellitus, apparent leukonychia persists since it is due to the peripheral , hemodialysis, and HIV.12 changes in the nail bed. Altered nail bed vascularity is a probable pathogenesis.

Total Leukonychia Muehrcke’s Lines It is most commonly congenital or can develop secondary to These are apparent leukonychia featured by paired white renal failure, liver disorders, protein losing enteropathies, lines, which run parallel to the lunule most commonly following acute illnesses.9 seen on the 2nd, 3rd, and 4th fingernails. They fade on

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Fig. 8: Lindsay nails Fig. 9: Splinter hemorrhages

application of pressure and they do not grow out with time. It is commonly caused by chronic hypoalbuminemia and chemotherapeutic medications (commonly by doxorubicin and cyclophosphamide).13 The localized edema of nail bed that compresses the vasculature is hypothesized as the pathogenesis.

Half and Half Nail (Lindsay Nail) It is characterized by normal proximal half and brownish discoloration of distal half of the nail (Fig. 8) and is seen in patients with chronic renal failure.14 It is due to increased vascular proliferation in the distal nail bed.

Splinter Hemorrhages Fig. 10: Longitudinal melanonychia These are tiny linear red or brown streak oriented linearly and longitudinally (Fig. 9). It occurs due to extravasation from subungual blood vessels. Its occurrence in many Melanonychia or all the nails indicates systemic cause. Subacute It is featured by black discoloration of the nail most bacterial endocarditis is the most common systemic cause commonly in the form of longitudinal black line followed by SLE, antiphospholipid antibody syndrome, (longitudinal melanonychia) (Fig. 10). It occurs due to Raynaud’s disease, rheumatic heart disease, rheumatoid trauma, racial factors, smoking, iron deficiency anemia, arthritis, internal malignancies, and medications (aspirin, hemochromatosis, thyroid disease, Addison’s disease, HIV warfarin, chemotherapeutic medications, tetracycline, infection, and medications (antimalarials, minocycline, and ganciclovir).3,15-17 Certain dermatologic diseases like phenytoin, psoralens, sulfonamides, zidovudine, psoriasis and lichen planus can also be associated with doxorubicin, methotrexate, and azathioprine).18 It can be splinter hemorrhages. due to melanoma, which is characterized by pigmentation

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of the proximal nail fold (Hutchinson sign), irregular black Periungual Telangiectasia pigmentation of nail plate and wider band size. It serves as an important marker in the diagnosis of SLE, scleroderma, and dermatomyositis. It is also seen in Nicotine Staining of Nails diabetes mellitus, COPD, and rheumatoid arthritis. It is characterized by yellowish discoloration of the nails seen in chronic smokers. Paronychia Cyanosis It is the inflammation of the nail fold(s) (Fig. 11). Acute The bluish discoloration is due to the change in the color paronychia is commonly caused by staphylococcus, the of the nail bed, which is seen through the nail plate. It is presence of which needs ruling out diabetes. Chronic seen in the conditions causing peripheral cyanosis such paronychia is seen commonly among those who use as cold exposure, congestive cardiac failure, peripheral detergents over a long span of time. vascular disease. Transient cyanosis preceded by pallor and followed by erythema is the sequence of color change Psoriatic Nail Changes in Raynaud’s phenomenon. Psoriasis is considered as systemic disease nowadays due to its association with metabolic disorder. Coarse Icterus pitting, longitudinal ridging, salmon patch, oil drop sign, In hyperbilirubinemia, the nails appear yellowish. and subungual hyperkeratosis are some of the classical nail changes in psoriasis (Fig. 12). The presence of nail Yellow Nail Syndrome changes in a patient with psoriasis predicts increased chances of development of psoriatic arthritis, especially It refers to the triad of yellowish color change of the nails, distal interphalangeal arthritis type.20 lymphedema and pleural effusion. It usually develops in the adults but can occasionally occur during childhood also.19 Onychomycosis It is the fungal infection of the nail unit caused by dermato­ Red Lunula phytes or non-dermatophyte molds (Fig. 13). It can be It is seen in collagen vascular disorders, psoriasis, cardiac of various colors such as white, yellow, gray, or black. failure, cirrhosis, chronic obstructive pulmonary disease Onychomycosis is of four types based on the portion of (COPD), and carbon monoxide poisoning.19 nail it affects namely:

Fig. 11: Acute paronychia Fig. 12: Coarse nail pits in psoriasis

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References 1. Myers KA, Farquhar DR. The rational clinical examination. Does this patient have clubbing? JAMA. 2001;286(3):341-7. 2. Razmi TM, Nampoothiri RV, Dogra S. Koilonychia in iron deficiency. QJM. 2018:111(4):271-2. . 3 Lawry M, Daniel CR 3rd. Nails in systemic disease. In: Scher RK, Daniel CR (Eds). Nails: Diagnosis, Therapy, Surgery, 3rd edition. Philadelphia: Elsevier Science Limited; 2005. pp. 147-69. . 4 Sawhney MP. Ladakhi koilonychia. Indian J Dermatol Venereol Leprol. 2003;69(2):79-80. 5. Alanko K, Kanerva L, Estlander T, et al. Hairdresser’s koilonychia. Am J Contact Dermat. 1997;8(3):177-8. . 6 Yaemsiri S, Hou N, Slining MM, et al. Growth rate of human fingernails and toenails in healthy American young adults. J Eur Acad Dermatol Venereol. 2010;24(4):420-3. . 7 Agarwl R, Biad R, Sinha DP. Clubbing: the oldest clinical sign in Fig. 13: Onychomycosis medicine. CHRISMED J Health Res. 2019;6:72-5. . 8 Zaic MN, Daniel CR. Nails in systemic disease. Dermatologic Therapy. 2002;15:99-106. „„ Distal subungual onychomycosis (common type) . 9 Mittal RR, Jassal JS, Jain C, et al. Leuconychia totalis. Indian J is often seen in those whose feet or hands remain Dermatol Venereol Leprol. 2000;66(6):312-3. moist for prolonged duration. In diabetics and 10. Chesnut G, Taylor S, Belin E. Mees lines and Beau lines. Cutis. 2013;91(150):147-1. immunocompromised individuals, it is thicker and 11. Singal A, Arora R. Nail as a window of systemic diseases. Indian resistant to therapy, Dermatol Online J. 2015;6(2):67-74. „„ Proximal subungual onychomycosis is usually seen in 12. Tosti A, Daniel CR, 3rd, Piraccini BM, Iorizzo M. Color Atlas of Nails. immunocompromised individuals, Heidelberg: Springer Verlag; 2010. p. 3. „„ Superficial white, and 13. Gregoriou S, Argyriou G, Larios G, et al. Nail disorders and systemic disease: what the nails tell us. J Fam Pract. 2008;57(8):509-14. „„ Total dystrophic type. 14. Goodman GJ, Nicolopoulos J, Howard A. Diseases of the generative nail apparatus. Part II: nail bed. Australas J Dermatol. 2002;43(3): Pseudomonas Nail Infection 157-70. It causes greenish discoloration of the nails. It is seen 15. Varotti C, Ghetti E, Piraccini B M, et al. Subungual haematomas in a patient treated with an oral anticoagulant (warfarin sodium). Eur J commonly in whom the hands or feet remain wet for Dermatol. 1997;7(5):395-6. prolonged duration. 16. Ghetti E, Piraccini BM, Tosti A. Onycholysis and subungual Acknowledgement: Journal of the American Academy of hemorrhages secondary to systemic chemotherapy (paclitaxel). J Eur Acad Dermatol Venereol. 2003;17(4):459-60. Dermatology for the figures. 17. Lorenzi S, Iorizzo M, Tosti A, et al. Skin rash and splinter hemorrhages from ganciclovir. J Dermatolog Treat. 2003;14(3):177-8. Conclusion 18. Mendiratta V, Jain A. Nail dyschromias. Indian J Dermatol Venereol Leprol. 2011;77(6):652-8. Nails serve as an invaluable tool to diagnose the underlying 19. Motswaledi MH, Mayayise MC. Nail changes in systemic diseases. systemic diseases and thus it is important to identify the nail SA Fam Pract. 2010;52(5):409-13. changes. Nails can be easily examined and is a convenient 20. Raposo I, Torres T. Nail psoriasis as a predictor of the development diagnostic tool and thus the importance of including the nail of psoriatic arthritis. Actas Dermosifiliogr. 2015;106(6):452-7. changes as a part of general physical examination should always be emphasized.

MU-118.indd 745 03-02-2021 16:53:01 CHAPTER Anatomic Localization of Classical Neurological 119 Symptoms

Uddalak Chakraborty, Avik Mukherjee, Jyotirmoy Pal

Abstract Anatomical localization means the site of lesion responsible for a patient’s symptoms and signs. Neurological localization requires a comprehensive understanding of anatomy and physiology of the nervous system. The process of localization shall begin during history taking, may be refined during clinical examination, and shall be reassessed after relevant diagnostic studies. Despite the advent and use of modern neuroimaging, nothing can replace a clinician’s acumen to localize based on history and examination.

Introduction localizing signs or symptoms, which may misguide the clinician. In this chapter, we will try to localize lesions “I believe a neurologist who can happily spend based on a few common neurological symptoms. 3 days examining a patient for challenging anatomical localization will also be able to make a correct diagnosis within 3 minutes in acute stroke. The most important Weakness outcome of a neurological examination is anatomical Weakness is a characteristic and common motor localization.”1 Localization is derived from the Latin neurodeficit, which may or may not be accompanied by word locus which means site. The diagnostic exercise of other symptoms per se. First of all, true weakness should determination of the site of nervous system affected by a be differentiated from apparent weakness, either a vague disease process, from the signs and symptoms, is termed feeling of tiredness or even malingering which may present as localization in neurology. like organic weakness. Proper clinical examination noting Some authors argue that emphasis on anatomical especially the distribution of weakness, any distractibility localization over years has hindered the development and a properly conducted Hoover’s test may differentiate of therapies in neurological diseases including epilepsy, between these. After identification of true weakness, it migraine, Guillain-Barré syndrome, Parkinson’s disease, should be categorized into an upper motor neuron type multiple sclerosis and ischemic stroke, etc. However, the (UMN) or lower motor neuron type (LMN) weakness, diagnosis of idiopathic epilepsy, migraine, and Parkinson’s differentiating features of which are given in Table 1. disease still remains clinical. Specialized neuroimaging UMN weakness predominantly affects extensors of may have complemented the clinical diagnosis, but can upper limbs and flexors of lower limbs. hardly replace it; there lies the importance of localization. Common neurological symptoms can be localized Hemiparesis by meticulous history taking and appropriate clinical Weakness of upper limb, trunk, and lower limb of one side examination, but sometimes one should be aware of false of body is usually the commonest presentation of stroke.

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cruciate hemiparesis. The neuroanatomical explanation Differentiation of UMN and LMN weakness based TABLE 1 on symptoms involves the complex somatotopic and anatomical segregation of the CSTs in the decussation at the lower UMN lesion LMN lesion medulla oblongata or cervicomedullary junction. At this Tone Spastic Flaccid level, the ventromedially located arm fibers decussate Wasting Nil/Minimal Significant Wasting rostral to the leg fibers, and a lesion at this specific point Fasciculation Absent May be present can lead to this entity.3

False Localization in Hemiparesis TABLE 2 Possible localization of hemiparesis Kernohan’s Notch Syndrome (Fig. 2): A supratentorial Site of lesion Features lesion may lead to transtentorial herniation of the temporal Cerebral lesion zz Contralateral cortex: Distal pre­ lobe, with compression of the ipsilateral cerebral peduncle Complete hemiparesis: dominant distribution of mild to against the tentorial edge; since this is above the pyramidal Involvement of moderate weakness with seizures, decussation, this may lead to a contralateral hemiparesis. same side of face loss of cortical sensations, agnosia, (predominantly lower aphasia, etc. Occasionally, the hemiparesis may be ipsilateral to the half) with ipsilateral zz Contralateral subcortical (corona side of lesion, and hence false-localizing; this occurs when hemiparesis can be radiata): Faciobrachial weakness the contralateral cerebral peduncle is compressed by the commonly localized in with aphasia, homonymous visual 4 the internal capsule. field defects. free edge of the tentorium. zz Internal capsule: Dense hemiplegia, Monoparesis may be localized to cerebral cortex or hemianopia, hemianesthesia.2 subcortex due to selective involvement representing that Brainstem zz Cranial nerve palsy LMN type with particular limb. contralateral hemiparesis—crossed hemiparesis zz Ipsilateral Horner’s syndrome due Paraparesis to involvement of sympathetic Weakness of both lower limbs may also be a common trunk. May also be seen in ipsilateral thalamic lesions. presenting symptom. We have to differentiate UMN and zz Ipsilateral hemiataxia due to LMN type of lesions from history and clinical examination involvement of cerebellum and its (Table 3). connections. Features suggestive of myelopathy include a definite Cervical cord zz Ipsilateral hemiparesis sparing face level below which sensory modalities may be impaired/ zz Ipsilateral loss of vibration and joint position sense with contralateral absent; LMN weakness at the level of lesion and UMN pain and temperature loss, usually weakness below the level of lesion and bladder/bowel one to two segments below the disturbance. lesion (Brown-Sequard syndrome) Patient may complain a girdle-like sensation suggestive zz LMN findings at the level of lesion. of the sensory level of cord involvement. False localization: Compressive lower cervical or upper thoracic myelopathy Hemiplegia means complete loss of motor function on may produce spastic paraparesis with a mid-thoracic that side. girdle sensation.5 Hemiparesis is usually due to involvement of Cerebral cause of paraparesis may be accompanied contralateral corticospinal tract (CST) from cerebral by seizure, headache, etc. Cauda equina and conus cortex to lower medulla or ipsilateral CST in case of a medullaris may be differentiated based on symptoms as high-cervical cord lesion. Localization of hemiparesis is in Table 4. demonstrated in Table 2. CST with possible sites of lesion in hemiparesis has been shown in Figure 1. Quadriparesis Cruciate hemiparesis: Weakness of ipsilateral upper limb Weakness of all four limbs; may be again categorized into with contralateral lower limb weakness is termed as UMN and LMN (Table 5).

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Fig. 2: Kernohan’s notch syndrome

TABLE 3 Possible localization of paraparesis

Type of Localization lesion UMN zz Central nervous system above lumbosacral cord. zz Commonly in thoracic cord zz Rarely in cervical cord zz Occasionally, midline cerebral lesion like parasagittal meningioma LMN zz Conus medullaris zz Cauda equina zz Anterior horn cells in lumbar cord zz Motor root of nerves of lower limb zz Motor nerves of lower limb zz Neuromuscular junction zz Muscle

Negative symptoms: Numbness, difficulty in coordination of limbs in dark places or closure of eyes (Table 6). Pattern of sensory abnormalities have been shown in Figure 3. Localization of sensory abnormalities are given in Table 7. Fig. 1: Corticospinal tracts with possible levels of lesion in hemiparesis Incoordination In a patient with gait imbalance, we have to rule out any Sensory Abnormalities nerve and muscle disorder, spinal cord or basal ganglia Positive symptoms: Tingling (pins and needles), burning, disorder. band like, itch, aching. Localization of ataxia has been discussed in Table 8.

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TABLE 4 Cauda versus conus medullaris

Cauda equina Conus medullaris Pain Severe, asymmetric, radicular Less common Sensory loss Asymmetric lower limbs, patchy Symmetric saddle anesthesia Motor loss Asymmetric Symmetric Sphincter involvement Less common and late Common and early

TABLE 5 Possible localization of quadriparesis

Type of lesion Localization Features UMN Cervical cord Cervical myelopathy: False localization: zz Weakness of all muscles below a particular level. Thoracic sensory level, paresthesia, clumsiness, zz Sensory loss below a circumferential level. and atrophy of hands. zz Sphincter disturbance High cervical cord/foramen magnum: zz Neck stiffness, suboccipital pain in C2 distribution. zz Electric shock like sensation on flexion of neck. zz Sequential weakness (Ehrlich’s phenomenon) zz Downbeat nystagmus, cerebellar ataxia (foramen magnum) zz Onion skin pattern of sensory loss of face Brainstem Cranial neve palsies, Horner’s syndrome, Internuclear ophthalmoplegia Brain (bihemispheric lesion) Pseudobulbar palsy (emotional lability/incontinence, spastic dysarthria) LMN Anterior horn cells Pure motor weakness, prominent wasting, distal>proximal Polyradiculopathy Predominant proximal weakness with sensory symptoms. False-localizing radiculopathy may occur in Idiopathic Intracranial Hypertension and cerebral venous sinus thrombosis and may manifest as acral paresthesias, backache and radicular pain, and less often with motor deficits Polyneuropathy Distal symmetric weakness with sensory impairment in glove and stocking distribution. Neuromuscular junction Predominant proximal pure motor weakness with diurnal variation, fatiguability. Muscle Pure motor weakness without diurnal variation, fatiguability.

Speech Disorders Distribution of symptoms in reference to sensory TABLE 6 A communication disorder in the form of slurred speech, and autonomic fibers strained/effortful speech, monotonous low volume Fibers Symptoms speech, word finding difficulty, comprehension difficulty, Small fibers Burning, painful dysesthesia, autonomic and naming problems should be recognized at first.7,8 dysfunction Dysarthria as difficulty of articulation should be segregated from aphasia; if dysarthria present, it may be Large fibers Sense of imbalance, limb incoordination, tingling localized depending on the following types: Autonomic Postural dizziness, fainting, heat or cold „„ Spastic dysarthria: Pseudobulbar/UMN involvement intolerance, sphincter dysfunction „„ Flaccid dysarthria: LMN involvement

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Fig. 3: Pattern of sensory abnormalities. Principal patterns of loss of sensation. (a) Thalamic lesion: sensory loss throughout opposite side (rare). (b) Brainstem lesion: contralateral sensory loss below face and ipsilateral loss on face. (c) Central cord lesion, e.g., syrinx: ‘suspended’ areas of loss, often asymmetrical and ‘dissociated’, i.e., pain and temperature loss but light touch intact. (d) Hemisection of cord/unilateral cord lesion = Brown-Séquard syndrome: contralateral spinothalamic (pain and temperature) loss with ipsilateral weakness and dorsal column loss below lesion. (e) Transverse cord lesion: loss of all modalitiesm, including motor, below lesion. (f) Dorsal column lesion, e.g., MS: loss of proprioception, vibration, and light touch. (g) Individual sensory root lesions, e.g., C6, D5, L4. (h) Polyneuropathy: distal sensory loss

„„ Monotonous, hypophonic speech: Extrapyramidal „„ Expressive and comprehension difficulty: Global involvement aphasia „„ Clumping of syllables with undue separation: Cerebellar „„ Isolated repetition difficulty: Conduction aphasia involvement „„ Preserved repetition with execution/comprehension difficulty: Isolation/transcortical aphasia. Localization of aphasia may be done as follows: „„ Reduced fluency with difficulty in word finding and Visual Loss impaired repetition: Broca’s aphasia First of all, one shall be able to differentiate between „„ Comprehension difficulty in terms of word and decreased ability to see things, double vision or loss of sentences with impaired repetition: Wernicke’s aphasia pieces of visual field.

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TABLE 7 Possible localization of sensory symptoms TABLE 8 Possible localization of ataxia

Site of Features Type of ataxia Features lesion Frontal Magnetic gait with out of proportion Cerebral zz Cortex: Cortical sensation impaired. May affect ataxia, spasticity. lesion only a portion of contralateral part represented by the affected homunculus.6 Sensory zz Paresthesia, numbness with zz Internal capsule: Uniform involvement of aggravation of symptoms in the dark, contralateral side with or without weakness. high steppage gait. zz Thalamus: Contralateral hemisensory loss; zz Peripheral nerve (Large fiber): contralateral hyperalgesia and allodynia (Dejerine- Sensory symptoms in glove and Roussy syndrome). stocking distribution. Brainstem zz Contralateral side sensory involvement. zz Dorsal root ganglion: Non length zz Ipsilateral sensory loss in face with contralateral dependent profound pure sensory hemisensory loss in body—usually in lateral symptoms. medullary lesion. zz Posterior column: Definite spinal Spinal zz Complete transection: Sensory loss below a level. level cord zz Spinal hemisection: Brown Sequard syndrome zz Medial lemniscus: Brainstem (ipsilateral vibration loss and proprioception loss symptoms with contralateral pain, temperature loss) Peripheral Vestibular Prominent vertigo with vomiting, zz Selective dorsal (posterior column) or lateral cord nausea, and relative sparing of speech. (spinothalamic tract) involvement. zz Central cord: Suspended sensory loss with sacral Cerebellar zz Dysmetria, cerebellar speech, and sparing; dissociative anesthesia. False localization other symptoms, with or without Nerve Focal symptoms depending on root of involvement Frontocerebellar brainstem symptoms may localize root in a dermatomal pattern. Sensory symptoms may be pathway damage, may the lesion in cerebellum and its minimal in case of single root involvement, due to result in incoordination connections. considerable overlap by adjacent root territories. of the contralateral zz Usually ipsilateral lesion leads to limbs, mimicking ipsilateral symptoms. Sensory Pure sensory involvement in non-length dependent 7 ganglion asymmetric fashion with sensory ataxia.6 cerebellar dysfunction. zz Appendicular involvement suggestive of cerebellar hemisphere Plexus Diffuse symptoms corresponding to two or more involvement, while truncal adjacent roots usually associated with motor deficits. involvement may be localized to Peripheral Sensory impairment in the distribution of the affected vermis; cerebellar speech due to nerve peripheral nerve; symmetric in case of polyneuro­ paravermal involvement; and a pathies or asymmetric in case of mononeuropathy/ combination of all may be seen in mononeuritis multiplex. pancerebellar disease.

Monocular visual loss is suggestive of lesion in the eye Localization of visual loss has been shown in Table 9. itself or optic nerve anterior to the optic chiasma. Pattern of involvement of visual field and their Binocular visual loss is suggestive of bilateral optic respective localization has been shown in Figure 4. nerve lesion or a chiasmal/retrochiasmal lesion.9 Visual loss correctable by pin hole/glasses: Refractive Headache error. Headache is one of the most common symptoms we Visual loss not correctable by pin hole: Opacity in come across in our day-to-day practice. The pain sensitive ocular media/neurological illness. structures in the cranium which may give rise to headache are as follows: Color Vision „„ Scalp and aponeurosis Acquired disturbance of color vision is suggestive of optic „„ Middle meningeal artery neuropathy and maculopathy; color desaturation being „„ Dura mater and dural sinuses one of the earliest manifestations of optic neuropathy. „„ Falx cerebri

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TABLE 9 Possible localization of visual loss

Site of lesion Features Ocular media Eye pain, lacrimation, redness, no improvement in vision with pin hole

Anterior visual pathway zz Monocular vision loss zz Central scotoma/altitudinal field defect in one eye zz Impaired color vision zz Orbit: Isolated optic neuropathy zz Optic canal/intracranial site: Other cranial nerves may be involved (III, IV, VI) zz Lesions close to optic chiasma: Junctional scotoma

Posterior visual pathway zz Binocular visual loss zz Homonymous/heteronymous hemianopia zz Color vision may be impaired

Cortical defect zz Ventral occipitotemporal defect: —— Visual agnosia, prosopagnosia, topographognosia zz Dorsal occipito-temporal defect: —— Akinetopsia, Simultagnosia, optic ataxia, ocular motor apraxia

Fig. 4: Localization of visual field loss

MU-119.indd 752 29-01-2021 14:54:31 Anatomic Localization of Classical Neurological Symptoms CHAPTER 119 753

„„ Proximal segments of the large pial arteries References „„ Cranial nerves V, VII, IX, and X 1. Chaudhuri A. Localization in clinical neurology. Journal of the Royal „„ Cervical nerves C1, C2, and C3 Society of Medicine. 2006;99(5):219. doi:10.1258/jrsm.99.5.219. Headache may result due to inflammation, traction, . 2 Ray BK, Approach to Hemiparesis, Bedside Neurology: Clinical compression, or malignant infiltration of these structures. Approach, 1st edition. New Delhi: Jaypee Brothers Medical Primary involvement of these structures may give rise Publishers; 2020. pp. 101-6. to primary headaches, which have little localizing value, . 3 Jeong HY, Chung EJ, Kim EG, et al. Anatomical findings of hemiplegia cruciata in multiple sclerosis. Korean J Clin Neurophysiol. while secondary involvement, for example, trauma, raised 2014;16(1):39-41. Available from https://doi.org/10.14253/ intracranial tension may give rise to secondary headaches. kjcn.2014.16.1.39 In case of an extracranial structure as the source 4. Kernohan JW, Woltman HW. Incisura of the crus due to contralateral of headache, the site of pain is precise, for example, brain tumor. Arch Neurol Psychiatry. 1929;21:274-87. inflammation of extracranial artery in giant cell . 5 Ochiai H, Yamakawa Y, Minato S, et al. Clinical features of the localized girdle sensation of mid-trunk (false localizing sign) can be localized to the tender vessel. appeared in cervical compressive myelopathy patients. J Neurol. Lesions of paranasal sinuses, teeth, eyes, upper 2002;249(5):549-53. cervical vertebrae have less sharp localization, but pain is . 6 Ray BK. Approach to Peripheral Neuropathy, Bedside Neurology: referred in a regional distribution. Clinical Approach, 1st edition. New Delhi: Jaypee Brothers Medical Infratentorial lesions tend to produce an occipitonuchal Publishers; 2020. pp. 48-9. distribution of headache, while supratentorial lesions . 7 Gado M, Hanaway J, Frank R. Functional anatomy of the cerebral 10 cortex by computed tomography. J Comput Assist Tomogr. produce a frontotemporal headache. 1979;3(1):1-19. Among the primary headaches, cluster headache and 8. Lahiri D. Approach to Speech and Language Dysfunction, Bedside trigeminal cephalgias have a periorbital location while Neurology: Clinical Approach, 1st edition. Ray BK (Ed). New Delhi: migraine is usually unilateral and tension type headache Jaypee Brothers Medical Publishers; 2020. pp. 206-9. is bilateral in distribution. . 9 Ray BK. Approach to Cranial Neuropathies, Bedside Neurology: Clinical Approach. 1st edition. New Delhi: Jaypee Brothers Medical Publishers; 2020. pp. 116-7. Conclusion 10. Khadilkar SV, Soni GS. Headache. Neurology Simplified, 3rd edition, New Delhi; CBS Publishers & Distributors Pvt Ltd; 2020. pp. 200-1. In this chapter, the authors have tried to give an overview of anatomical localization of a few classical neurological symptoms. Despite the recent advances in neuroimaging and electrodiagnostics, the importance and significance of anatomical localization is still indispensable, as it can guide the clinician to focus on a particular neuroanatomical substrate and even cut the need of unnecessary extensive investigations. We hope that this overview serves as a useful guide to the clinicians in day-to-day practice.

MU-119.indd 753 29-01-2021 14:54:31 CHAPTER

Clinical Signs of 120 Diaphragm Dysfunction

Atanu Chandra, Aritra Kumar Ray, Arkapravo Hati

Abstract Diaphragm is a musculofibrous structure separating thorax and abdomen. While unilateral diaphragmatic weakness is mainly secondary to inflammatory, infiltrative or traumatic etiologies; bilateral weakness mainly happens in systemic neurological or myopathic disorders. Unilateral weakness is usually asymptomatic. Abdominal paradox is a characteristic clinical sign of diaphragm weakness. Sniff test is a very important diagnostic test for assessment of unilateral weakness. Thorough history, meticulous examination, and appropriate investigations are of paramount importance to evaluate and plan for management.

Introduction It is formed of a peripherally located muscular part and The term “Diaphragmatic dysfunction” is used to describe a non-contractile central fibrous portion, which is again mainly three conditions—diaphragmatic eventration, divided into costal, sternal, and lumbar muscular groups. weakness, and paralysis of diaphragm.1 Eventration The muscular component of the diaphragm is composed can be defined as a persistent and permanent elevation of Type 1 (slow, fatigue resistant) and Type 2 (fast) fibers. rd th th of a part or all of the hemidiaphragm due to thinning.1 Phrenic nerve, which originates from the 3 , 4 , and 5 Diaphragmatic weakness may be described as a partial cervical nerves (C3, C4, and C5) almost exclusively provide impairment of the strength of the muscles of diaphragm the afferent neurological supply to diaphragm. Both the to produce and maintain adequate pressure required for phrenic nerves descend anterior to the scalene muscles ventilation. On the other hand, paralysis of the diaphragm and then travel between the subclavian arteries and veins is used to denote complete impairment of this capacity.2 in the neck to enter into the thorax. The right phrenic nerve Based on the etiology, this disorder can be unilateral or travels caudally anterior to the brachiocephalic trunk bilateral; permanent or temporary. Diaphragmatic flutter along the right atrium and finally enters the abdominal is another rare variety of diaphragm dysfunction which is cavity. The left phrenic nerve travels along the left ventricle characterized by repeated and variable cycles of regular caudally and supplies the diaphragm. and involuntary contractions of diaphragm. Features of Diaphragmatic thickness is variable with gradual diaphragmatic flutter are dyspnea, epigastric pulsations, tapering from anterior to posterior costal areas and from and pain in the thoracoabdominal region. the costal insertions toward central tendon. Under normal situation, the diaphragm functions as a piston to generate Anatomical Considerations flow as it descends in the thoracic cavity and displaces the Diaphragm is the musculofibrous structure, which contents of abdominal cavity caudally thereby causing separates the abdominal cavities from thoracic cavities. elevation of the lower portion of thorax. The negative

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intrathoracic pressure thus created results in an inflow of „„ Central neurological disease: Multiple sclerosis, stroke, air from mouth to lung, thereby creating tidal volume. rhizotomy. „„ Idiopathic. Etiology The etiologies of diaphragmatic dysfunction are described in Table 1. Causes of unilateral diaphragm weakness: „„ Infiltrative or compressive processes: Goiter, Causes of bilateral diaphragm weakness: pathological lymph nodes, mediastinal or pulmonary „„ Neurological disease: Multiple sclerosis, amyotrophic malignancy, cervical arthrosis, and spondylosis. lateral sclerosis, medullary transection, Guillain-Barré „„ Inflammatory disease: Shingles, post-viral, syndrome, severe cervical spondylosis, poliomyelitis, mononeuritis, chronic inflammatory demyelinating chronic inflammatory demyelinating polyneuropathy. polyneuropathy, parsonage—Turner syndrome. „„ Myopathy: Malnutrition, dysthyroidism, muscular „„ Traumatic lesions: Central venous cannulation, nerve dystrophies, amyloidosis, corticosteroid use, post- blockade’, heart/lung/liver transplant, neck/heart viral critical illness/ventilator induced diaphragm surgery, chiropractic manipulation. dysfunction, disuse atrophy/inactivity.

TABLE 1 Etiology of diaphragmatic dysfunction

Anatomical location of the lesion Disease Cerebral cortex zz Cerebrovascular accident (CVA) Internal capsule zz Arnold-Chiari disease zz Vascular accident Spinal cord zz Traumatic injury to the cord zz Degenerative (severe spondylosis) Central nervous system (CNS) zz Multiple sclerosis (MS) Motor neurons zz Amyotrophic lateral sclerosis (ALS) zz Post polio syndrome zz Paraneoplastic neuropathy zz Syringomyelia zz Spinal muscular atrophy (SMA) Brachial plexus zz Traumatic injury to the plexus zz Idiopathic zz Iatrogenic (Obstetric procedures, anesthetic blockade, radiotherapy) Phrenic zz Compression/infiltration (mediastinal neoplasms) zz Trauma3 zz Guillain Barre syndrome4 infection—Pneumonias,5 Lyme disease,6 Herpes zoster, HIV infection7 zz Amyotrophic neuralgia (Parsonage-turner syndrome)8 zz Thoracic surgeries9 zz Others (Hypothyroidism,10 Malnutrition,11 Diabetes,12 Benign thyroid hypertrophy,13 , porphyria, Charcot-Marie-Toot14 disease) zz Idiopathic15 Lung zz Obstructive airway diseases (Asthma and COPD) Neuromuscular junction zz Lambert-Eaton syndrome16 zz Myasthenia gravis zz Botulism17 Muscular zz Steroid myopathy18 zz Pompe disease19 zz Myositis zz Muscular dystrophies zz Mechanical ventilation20

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„„ Connective tissue disease: Dermatomyositis, mixed paralysis and rarely occurs in unilateral cases. When connective tissue disease, systemic lupus erythe­ abdominal paradox is seen in unilateral diaphragmatic matosus/shrinking lung syndrome. paralysis, it indicates generalized respiratory muscles „„ Idiopathic. weakness. The mechanism of abdominal paradox has „„ Sepsis. been described in Figures 1A to D.

Clinical Features Sniff Test Unilateral diaphragmatic paralysis: Patients are usually Fluoroscopy of diaphragm is very important to evaluate asymptomatic but may have limited ability to exercise.21 diaphragmatic function.25 The motion of the diaphragm They may also have dyspnea on exertion and in supine is assessed by doing a rapid and short inspiratory effort position. Symptoms are more severe in persons with through nostrils (also known as “Sniff test”). In normal obesity or with other comorbidities including cardiac and persons, diaphragm will move caudally. In unilateral pulmonary pathology.22 They may also have symptoms of diaphragmatic paralysis, paradoxical (cephalad) movement gastroesophageal reflux and nocturnal hypoventilation.23 is seen on the side of paralysis. There is no diagnostic value It is often diagnosed as an incidental finding on chest of this test in case of bilateral diaphragmatic paralysis. skiagram as an isolated elevation of hemidiaphragm. False negative results may be obtained due to sudden Clinical examination is rather nonspecific. On caudal motion of the paralyzed diaphragm at the onset auscultation, decreased breath sounds are heard at the of inspiration, which is misinterpreted as contraction. base of affected hemithorax. Reduced diaphragmatic This phenomenon happens due to abrupt relaxation excursion may be clinically detected by percussion of the of abdominal muscles at the beginning of inspiration lower rib cage at the end of expiration and inspiration following active contraction at expiration. False positive respectively. Occasionally, paradoxical thoracoabdominal results may be seen in about 6% cases. movement occurs during sleep. Bilateral diaphragmatic paralysis: Patients may show dyspnea on lying down (orthopnea). Respiratory distress, Diagnosis which occurs sometimes during rest, may be exacerbated Diaphragmatic dysfunction is most often suspected at the time of immersion in water.24 Most of the patients after the incidental finding of an isolated elevation of with this disorder present with sleep disorders and hemidiaphragm on chest skiagram or during evaluation features of significant hypoventilation. of unexplained dyspnea. Diagnosis is mainly based On clinical examination, cyanosis, superficial, on imaging modalities including radiography, chest and rapid respiration, bilaterally diminished breath ultrasound, and fluoroscopy. Tests include: sounds or abdominal paradox may be noted. In bilateral „„ Lung function test is often performed as a first-line diaphragmatic paralysis, inspiration occurs due to investigation to quantify and assess the physiological contraction of the accessory muscles of respiration such impact of diaphragm weakness. as scalene and sternocleidomastoid along with external —— In unilateral diaphragmatic weakness, functional intercostals. residual volume (RV) and total lung capacity Abdominal paradox: The characteristic clinical sign (TLC) are normally preserved. Vital capacity of diaphragmatic dysfunction is abdominal paradox.25 (VC) is mildly decreased to approximately 75% of During inspiration, when there is rib cage expansion, predicted value26 and 10–20% further decrease is paradoxical inward motion of abdomen does occur. When noted in supine position.27 accessory inspiratory muscles of the rib cage and neck —— In bilateral diaphragmatic weakness, VC usually contract as compensatory mechanism and lower pleural reaches 50% of predicted values and 30–50% pressure, the flaccid diaphragm moves in a cephalad further decrease is noted in supine position. RV direction with inward movement of the abdomen. This remains elevated and TLC can even get reduced. abnormal breathing pattern is mainly seen in supine „„ Radiologic fluoroscopy (real time view) with sniff position. It is mostly seen in bilateral diaphragmatic maneuver to depict paradoxical motion.25,28

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A B

C D

Figs. 1A to D: (A) Normal contraction of the diaphragm during quiet inspiration. (B) In supine position, both the rib cage and abdomen move outward. (C) When the diaphragm is paralyzed, the negative intrathoracic pressure pulls the diaphragm and the abdominal viscera toward the thoracic cavity, thereby generating a negative abdominal pressure. (D) In supine position, it is noted how the negative abdominal pressure creates a paradoxical movement during inspiration and the abdomen moves inward

„„ Ultrasound to look at the movement of the diaphragm Common alternative causes of an elevated hemi­ TABLE 2 and changes in the muscle thickness. It is noninvasive, diaphragm on imaging simple, readily available, and widely used both in the research and clinical setting. It is used to assess ‘False’ hemidiaphragm Extra-diaphragmatic to assess Tdi (static measurement of diaphragm paralysis disease thickness) and TFdi (inspiratory diaphragm thickening zz Morgagni hernia zz Subphrenic abscess fraction). zz Bochdalek hernia zz Pulmonary or mediastinal mass „„ Sleep studies: Polysomnography with concomitant zz Hiatal hernia zz Pulmonary embolism noninvasive ventilation may be considered routinely zz Traumatic rupture zz Ascites as this approach has both a therapeutic and diagnostic zz Lung resection zz Asymmetrical emphysema value. Sleep disordered breathing (SDB) can be zz Lipomas zz Atelectasis seen both in unilateral and bilateral diaphragmatic weakness and it becomes more prominent with the progression of the disease. Early consideration of „„ Stimulation of phrenic nerve in the neck by magnetic or polysomnography is very important in such patients. electrical stimulation. „„ „„ Cardiopulmonary exercise testing. Transdiaphragmatic pressure measurement (measure „„ Chest X-ray: The common alternative causes of an of strength of diaphragm). elevated hemidiaphragm on imaging have been „„ Electromyography (EMG), a test which records and depicted in Table 2. evaluates electrical activity produced by skeletal „„ Maximum inspiratory mouth pressures. muscles.

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TABLE 3 Comparison between unilateral and bilateral diaphragmatic paralysis

Diagnostic tools and Unilateral diaphragmatic paralysis Bilateral diaphragmatic paralysis treatment History Neck or chest surgery, shoulder or neck pain, Neck or chest surgery, shoulder or neck pain, neck neck injury, neuromuscular disease, cervical injury, neuromuscular disease, manipulation of the spine manipulation cervical spine Presentation Asymptomatic, exercise limitation, unexplained Exercise limitation, unexplained dyspnea, orthopnea, dyspnea, incidental radiographic finding dyspnea at rest, dyspnea when bending, respiratory failure, prolonged mechanical ventilation, constitutional symptoms Examination No abdominal paradox Abdominal paradox Laboratory tests Vital capacity >70 <50 (% of predicted value) Decline in supine vital capacity 10–30 30–50 (%) Fluoroscopy Sniff test positive Not helpful Thickening of diaphragm on No change No change inspiration Complications Ocassional hypoventilation during sleep, Frequent hypoventilation during sleep, pneumonia, atelectasis atelectasis, respiratory failure Treatment Observation period for 1.5–3 1.5–3 recovery (yr) Treatment for coexisting Yes Yes conditions Reversal of metabolic Yes Yes disturbance Noninvasive positive pressure Usually not indicated Often indicated ventilation (NIPPV) Plication of diaphragm May be helpful Not indicated Phrenic pacing No Yes, in patients with high spinal cord injury (SCI)

„„ Arterial blood gas analysis: Alteration of ABG is a late „„ Diaphragm pacemakers can be used in case of sign indicating severe functional impairment. functioning phrenic nerves such as patients with „„ Computed tomography scan of the abdomen, chest or trauma to spinal cord or motor neuron disease both. „„ Surgical procedure in the form of diaphragmatic „„ Magnetic resonance imaging (MRI) to detect any plication pathology involving nerve roots or spinal column. „„ Tracheostomy and mechanical ventilation in patients with a severe life threatening disease or in case of high cervical cord lesion causing quadriplegia Therapeutic Management The comparison between unilateral and bilateral „„ Observation and supportive management paralysis of diaphragm regarding the diagnosis and „„ Treatment of concurrent medical conditions management has been described in Table 3. ‘Diagnosis and „„ Inspiratory muscle training (IMT) therapeutic algorithm for unilateral and bilateral diaphragm „„ Noninvasive ventilatory support weakness have been depicted in Flowcharts 1 and 2.

MU-120.indd 758 29-01-2021 14:54:15 Clinical Signs of Diaphragm Dysfunction CHAPTER 120 759 TF, thickening fraction of the diaphragm; VC, vital capacity thickening fraction of the diaphragm; TF, Diagnostic and therapeutic algorithm for unilateral diaphragm weakness diaphragm unilateral algorithm for and therapeutic 1: Diagnostic Flowchart CPAP, continuous positive airway pressure; CT, computed tomography; MIP, maximal inspiratory pressure; PSG, polysomnography; PSG, polysomnography; maximal inspiratory pressure; MIP, tomography; computed CT, airway positive pressure; continuous CPAP,

MU-120.indd 759 29-01-2021 14:54:16 760 SECTION 9 Clinical Medicine Diagnostic and therapeutic algorithm for bilateral diaphragm weakness diaphragm bilateral algorithm for and therapeutic Diagnostic Flowchart 2: Flowchart MIP, maximal inspiratory pressure; NPPV, noninvasive positive pressure ventilation; TF, thickening fraction of the diaphragm; VC, vital capacity thickening fraction of the diaphragm; TF, ventilation; pressure positive noninvasive NPPV, maximal inspiratory pressure; MIP,

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Conclusion 10. Singh R, Verma D, Garg RK, et al. Assessment of respiratory functions by spirometry and phrenic nerve studies in patients of amyotrophic Diaphragmatic weakness has been seen to be associated lateral. Sclerosis J Neurol Sci. 2011;306(1-2):76-81. with poor clinical outcome in most instances. A detailed 11. Murciano D, Rigaud D, Pligleton S, et al. Diaphragmatic function in severely malnourished patients with anorexia nervosa. Am J Respir evaluation is often needed to find out the exact origin, to Crit Care Med. 1994;150(6.1):1569-74. assess and plan to manage its impact on symptoms, exercise 12. Aslam F, Kolpakchi A, Musher D, et al. Unilateral diaphragmatic capacity, and sleep homeostasis. Diagnosis of bilateral or paralysis in a diabetic patient: a case of trepopnea. J Gen Intern unilateral diaphragmatic dysfunction and management Med. 2010;26:555-8. may be challenging for the physician as this is relatively 13. Manning PB, Thompson NW. Bilateral phrenic nerve palsy associated rare, associated with subtle clinical features and difficulties with benign thyroid goiter. Acta Chir Scand. 1989;155(8):429-31. faced in establishing the exact anatomical location and 14. Chan CK, Mohsenin V, Loke J, et al. Diaphragmatic dysfunction in physiological alterations. Diaphragmatic dysfunction is often siblings with hereditary motor and sensory neuropathy (Charcot- Marie-Tooth disease). Chest. 1987;91(4):567-70. underdiagnosed but should never be neglected because 15. Derniaka TA, Younis WGY, Carlile PY, et al. Spontaneous recovery it can be a very good prognostic indicator and this is often in idiopathic unilateral diaphragmatic paralysis. Respir Care. associated with a poor quality of life. Referral to a higher center 2008;53(3):351-4. with experience and expertise in this disease and access to 16. Benditt JO, Boitano LJ. Pulmonary issues in patients with phrenic nerve stimulation or pacing, diaphragm ultrasound chronic neuromuscular disease. Am J Respir Crit Care Med. and surgical expertise in diaphragm plication should be 2013;187(10):1046-55. considered, where necessary. 17. Witoonpanich R, Vichayanrat E, Tantisiriwit E, et al. Survival analysis for respiratory failure in patients with foodborne botulism. Clin Toxicol (Phila). 2010;48:177-83. 18. Mier-Jedrzejowicz A, Brophy C, Moxham J, et al. Assessment of References diaphragm weakness. Am Rev Respir Dis. 1988;137(4):877-83. . 1 Nason LK, Walker CM, McNeeley MF, et al. Godwin: imaging of 19. Boentert M, Prigent H, Várdi K, et al. Practical recommendations for the diaphragm: anatomy and function. Radiographics. 2012;32(2): diagnosis and management of respiratory muscle weakness in late- 51-70. onset Pompe disease. Int J Mol Sci. 2016;17(10):1735. 20. Dot I, Pérez-Teran P, Samper MA, et al. Diaphragm dysfunction . 2 Roberts HC. Imaging the diaphragm. Thorac Surg Clin. in mechanically ventilated patients. Arch Bronconeumol. 2009;19(4):431-50. 2017;53(3):150-6. . 3 Merav AD, Attai LA, Condit DD, et al. Successful repair of a 21. Ridyard JB, Stewart RM. Regional lung function in unilateral transected phrenic nerve with restoration of diaphragmatic diaphragmatic paralysis. Thorax. 1976;31(4):438-42. function. Chest. 1983;84(5):642-4. 22. Gibson GJ. Diaphragmatic paresis: pathophysiology, clinical 4. Willison HJ, Jacobs BC, van Doorn PA, et al. Guillain-Barré syndrome. features, and investigation. Thorax. 1989;44:960-70. Lancet. 2016;388:717-27. 23. Kaufman MR, Elkwood AI, Colicchio AR, et al. Functional 5. Zifko UA, Lahrmann H, Schmmidt G, et al. Wild, isolated, unilateral restoration of diaphragm paralysis: an evaluation of phrenic nerve paresis of the phrenic nerve after pneumonia and pleurisy. reconstruction. Ann Thorac Surg. 2014;97(1):260-6. Nervenarzt. 2002;73(8):770-3. 24. Billings ME, Aitken MD, Bendit JO, et al. Bilateral diaphragm 6. Diukic M, Larsen J, Lingor P, et al. Unilateral phrenic nerve lesion in paralysis: a challenging diagnosis. Respir Care. 2008;53:1368-71. Lyme neuroborreliosis. BMC Pulm Med. 2013;13:4. 25. McCool FD, Tzelepis GE. Dysfunction of the diaphragm. N Engl J Med. 2012;366(10):932-42. . 7 Melero MJ, Mazzei ME, Bergroth B, et al. Bilateral diaphragmatic 26. Lisboa C, Pare PD, Pertuze J, et al. Inspiratory muscle function paralysis in a HIV patient: second reported case and literature in unilateral diaphragmatic paralysis. Am Rev Respir Dis. review. Lung India. 2014;31(2):149-51. 1986;134(3):488-92. . 8 Blanco-Aparicio M, Montero-Martínez C, Couto-Fernández C, 27. Laroche CM, Mier AK, Moxham J, et al. Diaphragm strength et al. Unilateral painful diaphragm paralysis as the only sign of in patients with recent hemidiaphragm paralysis. Thorax. amyotrophic neuralgia. Arch Bronconeumol. 2014;46(7):390-2. 1988;43(3):170-4. . 9 Gaissert H, Wilcox SR. Diaphragmatic dysfunction after thoracic 28. American Thoracic Society. ATS/ERS statement on respiratory operations. Thorac Cardiovasc Surg. 2016;64:621-30. muscle testing. Am J Respir Crit Care Med. 2002;166(4):518-624.

MU-120.indd 761 29-01-2021 14:54:17 CHAPTER

Approach to Chest 121 Pain in Emergency

Partha Sarkar, Adrija Chatterjee

Abstract Chest pain is one of the most common problems faced in the emergency room. The challenge is to develop a strategy to identify more serious pathology from non serious ones, found in majority of patients. Assessment of patient history, physical examination, 12 lead ECG, and cardiac biomarkers form the basis of assessment of chest pain. First and foremost serious life threatening causes of chest pain such as acute coronary syndrome, aortic , pulmonary embolism, tension pneumothorax, and cardiac tamponade have to be ruled out. History of characteristics chest pain have to be taken as per the pneumonic SOCRATES (site, onset, character, radiation, aggravating and relieving factors and severity) helps to differentiate the different causes of chest pain, cardiac versus non cardiac. Subsequently, for acute coronary syndrome, a 12-lead ECG will help to differentiate STEMI from non STEMI. Further the cardiac biomarkers such as highly sensitive cardiac specific troponin will help to identify unstable angina from NSTEMI.

Introduction „„ Minimize cost and hospitalization in patient with chest Chest pain is one of most frequent causes of attending the pain of benign etiology. emergency department. It is also one of the most difficult Diagnostic assessment and triage based on the diagnostic challenges which presents in an emergency following etiologies: room. „„ Myocardial ischemia The differential diagnosis of chest pain syndrome is „„ Other cardiopulmonary causes—pericardial diseases, broad and disparate including disease processes that aortic emergencies, pulmonary conditions range from non urgent to life threatening. Furthermore „„ Non-cardiopulmonary causes within the consideration of life threatening causes patients may be suffering from coronary causes as well as Differential Diagnosis pulmonary embolism, , aortic rupture, pneumothorax or even esophageal rupture. There are „„ Cardiac: Myocaridal ischemia, pericarditis, aortic many other diagnoses, which are much less critical stenosis, hypertrophic obstructive cardiomyopathy but as widely as musculoskeletal pain, zoster, pleurisy, (HOCM) 1 pneumonia, or gastroesophageal reflux. „„ Vascular: , pulmonary embo­ lism, pulmonary hypertension Goals „„ Pulmonary: Pneumonia, pleuritis, pneumothorax „„ Early diagnosis of acute coronary syndrome (ACS). „„ Gastrointestinal: Esophageal reflux, esophageal spasm, „„ Recognition of other life threatening causes. esophageal rupture, peptic ulcer, gallbladder disease

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„„ Neuromuscular: Costochondritis, cervical disc disease, arms. Inferior wall AMI typically produces substernal or trauma, Herpes zoster epigastric discomfort. „„ Psychiatric conditions Chest pain of pericarditis can mimic AMI but can radiate to trapezius, which does not occur with angina. Rule Out Deadly Causes Chest pain due to myocardial ischemia is poorly ACS, pericarditis, acute aortic syndrome, pulmonary localized and diffuse while pleuritic chest pain is localized. embolism, pneumothorax, esophageal rupture. Ascending and descending aortic dissection differ These are the serious causes of chest pain not to be in their location of pain with anterior aortic dissection missed. producing midline anterior chest pain and descending aortic dissection producing back pain. How to Approach a Patient of Chest Pain? Gastrointestinal conditions usually produce abdominal or epigastric discomfort exception being esophageal pain, History which is retrosternal in location. Evaluating clinicians should assess the quality, location, Chest pain of Herpes zoster has dermatomal pattern, provoking and alleviating factors, associated distribution. symptoms, past medical history. Pattern Quality of Pain Chest pain of myocardial ischemia develops over minutes Angina pain of myocardial ischemia is described as and is precipitated by activity and relieved by rest. Pain of tightness, squeezing, or heaviness. Whereas pain of stable angina lasts for 2–10 minutes and subsides on rest pericarditis is described as sharp stabbing in nature. whereas pain of unstable angina persists even on rest. In Pericarditis of an infectious etiology causes case of myocardial infarction pain lasts for more than 30 simultaneous involvement of the adjoining pleura so minutes. patients experience pleuritic chest pain characterized by Chest pain in pericarditis is episodic in nature. Chest a localized sharp lancinating pain, which aggravates on pain in aortic dissection, pneumothorax is of sudden inhalation, coughing. Pain of infectious pericarditis felt in onset. shoulders and neck as central diaphragm attains sensory Pain of constant intensity over a prolonged period of supply from phrenic nerve. However, a more lateral time is more likely to represent peptic ulcer disease than diaphragmatic movement may lead upper abdominal myocardial ischemia. pain. Involvement of pleura as in pneumothorax may Aggravating and Relieving Factors produce pleuritic chest pain similar to infectious Pain of myocardial ischemia is usually relieved by rest. pericarditis. However, one should be aware of the phenomenon of Massive pulmonary embolism can present as “warm up angina” in which pain seems to get relieved by heaviness. continuing at same or greater level of exertion. Acute aortic dissection leads to excruciating ripping Administration of nitroglycerin may relieve both pain or “tearing” pain. myocardial ischemia pain as well as pain produced by Epigastric burning pain like sensation suggests acid esophageal spasm. reflux or peptic ulcer disease. Esophageal spasm can be Pain of musculoskeletal etiology changes in intensity severe squeezing identical to angina. Gallbladder disease with positional change of upper extremities and neck. produces a colicky pain. Pain of pericarditis worsened by supine position and Musculoskeletal disorders produce an aching pain relieved by sitting upright and leaning forward. whereas herpes zoster produces a sharp burning pain. Pain due to gastroesophageal reflux may be exacerbated by alcohol, some foods or reclining position. Localization of Pain Worsening of pain with food suggestive of peptic Myocardial ischemia typically produces retrosternal ulcer disease or cholecystitis, which may be relieved discomfort with radiation to neck, jaw, shoulders, or by acid reducing therapies. However, in setting of a

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severe coronary atherosclerosis redistribution of blood Tachypnea and tachycardia with hypoxemia point flow to splanchnic vasculature after eating can trigger toward a pulmonary cause. postprandial angina. Cardiac Associated Symptoms Search for characteristic pattern of JVP in cardiac Symptoms associated with myocardial ischemia may tamponade or right ventricular dysfunction. include sweating, dyspnea, nausea, vomiting, and S4 in case of myocardial ischemia and S3 in case of faintness. infarction can be found. Pulmonary embolism and pneumothorax should be Murmur of mitral regurgitation is found in case of considered in the background of sudden onset respiratory complications of AMI. Murmur of aortic dissection distress. indicates complications of aortic dissection. Hemoptysis usually points toward pneumonia. Blood Pericardial friction rub suggests pericarditis. tinged frothy sputum can be found in heart failure. Syncope should prompt consideration of Pulmonary hemodynamically unstable conditions in pulmonary Decreased breath sound, hyper-resonant percussion embolism and aortic dissection. note in case of pneumothorax or localized crepitation in Although nausea and vomiting suggest a pneumonia. gastrointestinal disorder, these symptoms may occur in Esophageal rupture or “Boerhaave syndrome” is the setting of myocardial infarction, especially inferior associated with subcutaneous emphysema and on being wall AMI because of activation of vagal reflex. auscultated crackling sound is heard (Hamman’s crunch). Oesophageal rupture usually associated with forceful vomiting. Abdominal Localized tenderness can be found in gastrointestinal Past Medical History conditions such as gallbladder stone or pancreatitis. Assess for risk factors of coronary atherosclerosis and Abdominal findings such as hepatic congestion can be venous thromboembolism. found in right ventricular dysfunction. History of connective tissue disorder such as Marfan’s syndrome should increase the suspicion of acute aortic Musculoskeletal syndrome or spontaneous pneumothorax. Localized swelling, tenderness are useful clinical sign for costochondritis (Tietze’s syndrome). Vesicular rash is Physical Examination found in the area of discomfort suggests Herpes zoster. General Battery of Tests Patients with AMI often appear anxious, pale, cyanotic, or diaphoretic. ECG Patients with AMI may describe their pain by clenched ECG is essential for identification of patients with ongoing fist against sternum termed as “levine’s sign.” ischemia as well as secondary cardiac complications Often body habitus is helpful. Like patients with of other disorders. ST segment elevation, ST segment Marfan’s syndrome have young tall thin built. depression, and symmetric T wave inversions are useful for detecting myocardial ischemia.2 Serial evaluation of Vital Signs ECG every 30–60 minutes is recommended in emergency Tachycardia and hypotension are suggestive of hemo­ for evaluation of suspected ACS.3 dynamic instability should prompt a rapid survey Hyperventilation associated with panic disorder can for AMI, massive pulmonary embolism, pericarditis also lead to nonspecific ST and T wave abnormalities. with tamponade, tension pneumothorax, acute aortic Pulmonary embolism produces rightward shift of ECG dissection. axis manifesting as S wave in lead I, Q wave, and T wave in

MU-121.indd 764 29-01-2021 14:54:10 Approach to Chest Pain in Emergency CHAPTER 121 765

Flowchart 1: How to approach a case of chest pain

ACS, acute coronary syndrome; STEMI, ST-elevation myocardial infarction; UA, unstable angina: CXR, chest X-ray; CT, computed tomgraphy, UA, unstable angina; ECG, electrocardiographic; TEE, transesophageal echocardiography; AoD, aortic dissection; c/w, consistent; hx, history; NSTEMI, non–ST-segment myocardial infraction; PE, pulmonary embolism; MRI, magnetic resonance imaging; V/Q, ventilation-perfusion; STE, stimulated echo.

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lead III (S1Q3T3 pattern of acute cor pulmonale is classic, Recent Advances termed as McGinn-White sign). CT angiography has emerged as a sensitive technique for ST elevation with diffuse lead involvement and PR detection of obstructive coronary disease particularly in segment depression distinguishes pericarditis from AMI. proximal third of major epicardial coronary arteries.6 CECT is useful for detection focal areas of myocardial CXR injury.3 CXR is most useful for detection of lung causes such as CT angiography can be used for exclusion of aortic pneumonia, pneumothorax. dissection, pericardial effusion, and pulmonary embolism. CXR findings commonly associated with pulmonary Cardiac MRI is an emerging technique for structural embolism include Hampton’s hump or Westermark sign and functional evaluation of heart. Gadolinium enhanced or Palla’s sign. MRI can provide early detection of MI and can define CXR showing subcutaneous emphysema suggests areas of myocardial necrosis accurately. “Boerhaave syndrome.” Early myocardial perfusion imaging can be performed for evaluating patients with low or intermediate risk of Cardiac Biomarkers ACS.7 Circulatory proteins released from damaged myocardial Flowchart 1 depicts the approach towards chest pain cells are indicative of myocardial injury. Initially in the emergency room. biomarkers may be normal even in patients with STEMI. Cardiac troponin [cardiac specific troponin T (cTnT)] Don’t Forget the Rare One and cardiac specific troponin I (cTnI) are preferred biomarkers over creatine kinase MB and should be Takotsubo cardiomyopathy characterized by abrupt repeated in 3–6 hours in suspected ACS patients. onset chest pain and shortness of breath, triggered by an Serial changes in cardiac troponin are useful in emotionally stressful event. It mimics AMI because it is discriminating acute causes of myocardial injury from associated with ECG abnormalities and elevated cardiac chronic elevation due to underlying structural heart biomarkers. But surprisingly coronary angiography is disease or end stage renal disease.4 normal. It has predilection for women above 50 years. Assessment of D-dimer test to aid in exclusion of pulmonary embolism. Conclusion Both B-type natriuretic peptide (BNP) and N terminal Chest pain is one of the most common causes for admission to pro BNP (NT-probnp) is useful in diagnosis of heart failure. emergency departments. Emergency clinicians have a difficult task identifying, which patients to admit and which patients to Echocardiography discharge home. Patients with mechanical complications of MI or pericardial Evaluation of acute chest pain in emergency is time tamponade diagnosed easily with echocardiography. consuming and expensive and often results in uncertain Transesophageal echo is more sensitive of aortic diagnosis. A very small percentage of evaluated patients are dissection than transthoracic echo. eventually diagnosed with ACS. Most common diagnoses are gastrointestinal causes. Few of patients with chest discomfort Provocative Tests discharged on the presumption of non-ischemic etiology from Exercise electrocardiography (“stress testing”) is used for emergency are later deemed to have had a missed myocardial patients with low to intermediate risk of ACS who have infarction. not revealed a specific cause of chest discomfort on initial So, rapid and precise identification, triage, and treatment evaluation.5 of high-risk cardiopulmonary conditions are necessary, while low-risk patients can be safely observed with less intensive Patients with ongoing chest pain should not be monitoring. subjected to these stress tests.

MU-121.indd 766 29-01-2021 14:54:11 Approach to Chest Pain in Emergency CHAPTER 121 767

References 5. Amsterdam EA, Kirck JD, Diercks DB, et al. Exercise testing in chest pain units: rationale, implementation and result. Cardiol Clin. 1. Harrison’s Principles of Internal Medicine, 20th edition. volume 1. 2018. 2005;23(4):503-16. . 2 Approach to the Patient with Chest Pain, Marc S. Sabatine and . 6 Hoffmann U, Bamberg F, Chae CU, et al. Coronary CT for early Christopher P. cannon, Braunwald’s Heart Disease. . 3 Ekelund U, Forberg JL. New methods for improved evaluation triage of patients with acute chest pain—The Rule Out Myocardial of patients with suspected acute coronary syndrome in the Infarction Using Computer Assisted Tomography (ROMICAT) Trial. J emergency department. Emerg Med J. 2007;24(12):811-4. Am Coll Cardiol. 2009;53(18):1642-50. 4. Marrow DA. Clinical application of sensitive troponin assays. N Engl . 7 Blomkalns AL, Gibler WB. Chest pain unit concept: rationale and J Med. 2009;361(9):913-5. diagnostic strategies. Cardiology Clinic. 2005;23(4):411-21.

MU-121.indd 767 29-01-2021 14:54:11 CHAPTER

Approach to a 122 Case of Anemia

Manoj Kumar Srivastava

Abstract Anemia is the most common symptom present in most of the clinics of tropical country and it is usually a common symptom in females and during pregnancy! Anemia, which is a symptom and not a disease, is defined as a decrease in the circulating red blood cell mass to below age specific and gender specific limit. Evaluation for anemia is one of the most common clinical problems seen in the present hospital settings. The evaluation of anemia may be straightforward in an otherwise healthy individual with a single cause of anemia, but in many cases the cause is not readily apparent and multiple conditions may be contributing. The first step in diagnosis of anemia is detection with reliable and accurate tests, so that the important clue to underlying causes are not overlooked and patients are not subjected to unwanted laboratory tests.

Introduction for different groups depending on sex, age, and race. lt is important to reach the exact diagnosis of anemia to give Anemia, which is a symptom and not a disease, is defined the proper treatment. The common traditional ways to as a decrease in the circulating red blood cell mass to classify the anemia depend on below age specific and gender specific limit. lt is difficult „„ Red cell morphology and indices to directly measure RBC mass, so the hematocrit or the „„ Pathogenesis hemoglobin level in the blood are usually used instead to 4,5 indirectly estimate the value.1,2 „„ Clinical presentation of anemia Evaluation for anemia is one of the most common clinical problems seen in the present hospital settings. Classification Based on RBC The evaluation of anemia may be straightforward in Morphology and Indices an otherwise healthy individual with a single cause of anemia, but in many cases th cause is not readily apparent The classification of anemia based on the red cell and multiple conditions may be contributing. predominantly depends on the mean corpuscular volume ln clinical practice, the use of proper standard method (MCV) of RBCs. On the basis of MCV the anemia is of history taking and clinical examination supported by classified as: 3 laboratory investigations still form the best approach. „„ Microcytic hypochromic anemia (MCV: <80 fL) There are many ways to classify anemia, but none of them „„ Normocytic normochromic anemia (MCV: 80–100 fL) is perfect. The approach to find the cause of anemia differs „„ Macrocytic anemia (MCV: >100 fL)

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Classification Based on the „„ Excessive destruction of RBS (hemolysis) Clinical Presentation „„ Bleeding—acute or chronic „„ Acute: Due to hemolysis or bleeding Microcytic Anemia (MCV <80 fL) „„ Chronic Anemia: Due to various chronic diseases or due to bone marrow suppression Microcytic anemia is defined as the presence of small, Flowchart 1 shows different types of anemia. often hypochromic, red blood cell in a general blood picture as depicted in Figure 1 (GBP and is characterized Classification Based on by a low MCV (<80 fL) (Flowchart 2). lron deficiency Pathogenesis of Anemia anemia is the most common cause of microcytosis. Overall, 50% of anemia is attributable to iron deficiency „„ Inadequate production: These disorders may be due and accounts for approximately 8,41,000 deaths annually to: worldwide.6,7 —— Nutritional deficiency (vitamin B 12/folic acid deficiency, iron deficiency) Other causes of microcytic anemia are— —— Stem cell disorders „„ Anemia of chronic disease —— Bone marrow infiltration „„ Thalassemia —— Defective bone marrow function of ineffective „„ Lead poisoning erythropoisis „„ Sideroblastic anemia

Flowchart 1: Lab diagnosis cell morphology and type of anemia

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Fig. 1: Microcytic hypochromic anemia

Flowchart 2: Lab diagnosis cell morphology and bloodsmear

Table 1 and Flowchart 3 show the different parameters absence of megaloblasts and instead, the presence of large to differentiate the discussed causes of microcytic anemia. but mature red blood cells. For megaloblastic macrocytic anemia refer Figure 2. Causes of non megaloblastic macrocytosis includes— „„ Chronic alcoholism Non-megaloblastic Macrocytic Anemia „„ Liver disease Causes of non-megaloblastic anemia are not related to „„ Hypothyroidism defective DNA synthesis and it is characterized by the „„ Renal diseases

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TABLE 1 Classification based on RBC morphology and indices

Parameters IDA BT Lead poisening SA Cl

Hgb ↓ N (or ↓) N (or ↓) — ↓

Se Ferritin ↓ N N N (or ↑) N (or ↑)

Serum iron ↓ N N N (or ↑) ↓

FEP ↑ N ↑ — ↑

MCV ↓ ↓ N or ↓ N ↓

RDW ↑ N N — N

Reticulocyte ↓ — — — N or ↓

MCV: RBC (mentzer ↑ ↓ — — — index)

Lead — — ↑ — — BT, beta thalassemia; CI, chronic inflammation or infection; IDA, iron deficiency anemia; N, normal; SA, sideroblastic anemia

Flowchart 3: Lab diagnosis and cell morphology

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Fig. 2: Hypersegmented neutrophils and macroovulocytes (megaloblastic anemia)

Flowchart 4: Lab diagnosis cell morphology and peripheral smear

„„ Reticulocytosis Normocytic Anemia (MCV 80–100 fL) „„ Blood disorders like red-cell aplasia, aplastic anemia A mild normochromic, normocytic anemia is a frequent myelodysplastic syndromes, and myeloid leukemia, finding and mostly due to a consequence of other diseases, PNH including: „„ Drugs such as azathioprine „„ anemia of chronic disorders associated with chronic „„ Pregnancy infection, malignant disease, all forms of inflammatory

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diseases. The exact mechanism is unknown, but References likely to involve multiple factors, which leads to a . 1 Polin RA, Abman SH, Rowitch. Fetal and Neonatal Physiology, 5 reduction in the serum iron concentration along with edition. Elsevier Health Sciences; 2016. p. 1085. concurrent reduction in the level of transferring. That’s . 2 Uthman, Ed. Understanding Anaemia, Univ Press of Mississippi why saturation of the iron binding capacity is usually 2009. P 23. ISBN 9781604737011. 3. Roshan M, Rao AP. A study of relative contributions of the history, normal or only slightly reduced. physical examination and investigations in making medical „„ Other disorders including renal failure, hypothyroidism, diagnosis. J Assoc Physicians India. 2000;48:771-5. marrow failure (aplastic anemia, pure red-cell aplasia, . 4 Bessman JD, Gilmer PR, Gardner FH. Improved classification of infiltration), acute blood loss (Flowchart 4).8,9 anemia by MCV and RDW. Am J Clin Pathol. 1983;80:322-6. 5. Adamson JW, Longo DL. Anemia polycythemia. Harrison’s Principles of lnternal Medicine,15th edition. New York, New York: McGraw-Hill; Conclusion 2001. pp. 348-54. 6. Stoltzfus RJ. Iron deficiency: global prevalence and consequences. A good clinician diagnoses the type of anemia but a excellent Food Nutr Bull. 2003;(4S):S99-103. clinician always tries to search out the cause of the disorder. So, . 7 Ford J. Red blood cell morphology. Int J Lab Hematol. 2013;35(3): to manage a patient of anemia, every effort should be given in 351-7. searching the etiology of anemia. The first step in diagnosis of 8. Kaferle J, Strzoda CE. Evaluation of macrocytosis. Am Fam Physician. anemia is detection with reliable and accurate tests, so that the 2009 Feb 1;79(3):203-8. important clue to underlying causes are not overlooked and 9. Aslinia F, Mazza JJ, Yale SH. Megaloblistic anemia and other causes patients are not subjected to unwanted laboratory tests. of macrocytosis. Clin Med Res. 2006;4(3):236-41.

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123 Approach to Aphasia

Jyotirmoy Pal, Tarun Kumar Paria, Purbasha Biswas, Manisankar Bhattarcharya

Abstract Aphasia refers to a disorder of language processing caused by a dysfunction in specific regions of the brain. It is common after stroke and associated with relevant disability and higher mortality. Evaluation of language function (spontaneous speech, auditory comprehension, naming, repetition, reading, and writing) allows classification of aphasia. Most patients present some degree of recovery. Speech and language therapy is an effective treatment for aphasia following stroke. Other approaches, e.g., pharmacotherapy, transcranial magnetic stimulation, are being investigated.

Introduction expression of thoughts by any means, whereas in speech disorders thoughts can be properly expressed by the While assessing a patient in a neurological ward or agency of nonverbal ways of communication, for instance outpatient department, one has to frequently come across writing (Fig. 1). cases with communication disorders. It is important to distinguish among different types of communication zz Dysarthia: It is a disorder of the motor production or articulation of speech mainly of neurologic origin. problems which may range from language disorder to zz Dysphonia: It is a term that describes voice disorders, for speech production at different levels. example, involuntary tightening or constriction of vocal cords Broadly, communication disorders are divided into causing interruptions of speech and voice quality. two basic groups: zz Aphasia/Dysphasia: It is an acquired disorder with loss or defective language content of speech resulting from damage „„ Speech defect: consisting of Dysarthia and Dysphonia to speech centers of dominant hemisphere (usually left in 97%). „„ Language dysfunction: consisting of Dysphasia/ Aphasia Language has two parts: The fundamental difference between a speech defect „„ Expression and aphasia remains as follows: if one transcribes the „„ Understanding patient’s verbal expression into writing, it will read as combination of normal and grammatically correct Expression sentences in speech defect which is not the case for Expression has got three components: aphasic participants. Thus, a language defect can simply „„ Emotional component: This component of expression be considered a more fundamental disturbance in does not require any learning and is an expression of communication machinery, which hinders appropriate inner suppressed emotions

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Flowchart 1: Pathway of understanding

Flowchart 2: Effects of incomplete Broca’s area damage

Fig. 1: Language areas of brain

„„ Automatic component: This component of expression occurs automatically and is generally acquired through learning „„ Proposition: This is the actual speech component

Understanding This occurs through a series of steps (Flowchart 1). Example 1: “Tarun” → “Arun” : single letter substitution Example 2: “Harry” is a bad boy. → “Tom” is a bad boy : entire word substitution Examination „„ NEOLOGISMS: New words without any meaning Examination of speech consists of testing of the following „„ CIRCUMLOCUTION: The patient can name an object components: but uses different descriptions to describe a particular „„ Spontaneous speech object „„ Comprehension (auditory) Example: A cell phone when put infront of the patient, „„ Naming he can’t name the object but says “this is an object „„ Repetition used to call someone” „„ Writing „„ Reading Tests for Spontaneous Speech „„ Fluency: Normal fluency is 100–150 words per minute Spontaneous Speech or more than 7 words in a sentence, while non fluency Generally motor speech defect (damage of Broca’s area) refers to less than 10–15 words per minute manifests as loss of spontaneous speech. „„ Pronunciation „„ Types: „„ Capability of words/sentence formation —— Complete loss : Mutism (no speech) „„ Speech disorder like paraphasia —— Incomplete Broca’s area damage: This manifests in four forms (Flowchart 2): Comprehension „„ MONOPHASIA: Repetition of the same word The patient’s responses to verbal requests and commands „„ PARAPHASIA: Single letter of a word or the entire word and to everyday questions and comments give information is substituted with similar sounding words about his ability to understand speech.

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Comprehension may be tested by having the patient Flowchart 3: Pathway of writing follow verbal commands (“show me your teeth”, “stick out your tongue”). Comprehension can be judged to be reasonably intact if the patient follows a complicated multistep command. However, failure to follow a command does not necessarily prove that comprehension is impaired. A patient may not comply because of apraxia. Patients with left hemisphere lesion may even have apraxia for functions of their nonparietic left hand. When the patient doesnot follow simple commands, establish whether he can say or shake his head yes or no.

Naming Some caution is necessary while testing for naming, as there are influences of age, culture, and education. Naming is the function of parietal lobe. abnormalities of spoken language, or separately. Patients who are aphasic in speech are also aphasic in writing, but Test for Naming writing may be preserved in patients with dysarthria or verbal apraxia. The ability to write to dictation is analogous While testing naming, always use common object. Naming to the ability to repeat verbal material. Copying written is said to be intact when patient is given several objects to material also assesses the ability to transfer information identify and can name 12 items in 1 minute. from visual system to language area. Having the patient If the patient says less than 12 items, there are three copy written material may also test the connections possibilities: between the receptive language areas and Exner’s writing „„ Can’t say name center (Flowchart 3). „„ Can recognize the item, but can’t say the function „„ Can say only 4 out of 12 items Reading Repetition The patient’s ability to comprehend written language Repetition is the function of lower parietal lobe (arcuate symbols can be tested by having him read. Written fibers). The ability to repeat may be selectively involved or language is perceived by the visual system and the paradoxically preserved in certain aphasic syndromes. A information is conveyed to the perisylvian language patient’s repetition span (i.e., the number of words he can centers. Dysfunctions of the language centers or repeat) is usually two more than his digit span. interruption of the connections with visual system may cause inability to read (alexia). Types of repetition disorders include: „„ Can’t repeat „„ Can repeat only a part Pathway of Reading „„ Can substitute with a new syllable or word Visual association area → Angular gyrus Repetition is preserved in anomic, transcortical, and some cases of subcortical aphasia. Alexia (Fig. 2) Writing „„ Alexia with lesion in Wernicke’s area: Reading and understanding impaired, can’t write dictation. Pathway of Writing „„ Alexia without lesion in Wernicke’s area: Reading The patient’s ability to use written language should also impaired but auditory understanding preserved. This be assessed. It may be disturbed in conjunction with is called PURE WORD BLINDNESS.

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Motor and sensory areas of brain and their TABLE 1 connection

Wernicke’s area Arcuate fasciculus Broca’s area (area 22) (area 44) Decoding of sounds Communication Responsible for into language between the Broca’s spontaneous information and Wernicke’s area. speech output, i.e., (Comprehension) Needed for speech fluency repetition

—— Damage to Auditory Association Area—WORD DEAFNESS —— Damage to Angular Gyrus—WORD BLINDNESS —— Fluency preserved Fig. 2: Pathway of pathology of alexia —— No appropriate response to any command (increased spoken words—HYPERLABIA) —— Repetition lost Types of Aphasia „„ Sylvian aphasia: repetition will be lost Conduction Aphasia —— Broca’s aphasia „„ Lesion involves the Arcuate fibers —— Wernicke’s aphasia „„ Characteristics: —— Conduction aphasia —— Repetition lost —— Global aphasia —— Fluency preserved „„ Perisylvian aphasia: repetition is preserved —— Comprehension is unaffected —— Anomic aphasia —— Reading is lost —— Transcortical aphasia —— Writing is lost —— Subcortical aphasia —— Mixed aphasia Global Aphasia

„„ Sylvian Aphasia (Table 1) Features of above three aphasias „„ Associated with hemianopia, hemisensory loss, Broca’s Aphasia hemiparesis „„ Fluency lost, patient will be frustrated but aware „„ Communicate with small sentences with few words Perisylvian Aphasia and with gestures Anomic Aphasia „„ Reading will be lost „„ Naming difficulty „„ Writing preserved „„ All other modalities preserved „„ If there is combined damage of Broca’s area and „„ Circumlocution will be present Exner’s area, then both reading and writing will be lost „„ Associated with corticospinal tract sign (Faciobrachial) Subcortical Aphasia Wernicke’s Aphasia „„ Repetition preserved „„ Lesion involves: „„ Lesion involves: —— Angular gyrus —— Caudate nucleus: Features of Broca’s aphasia with —— Supramarginal gyrus preserved repetition —— Wernicke’s area —— Thalamus: Features like Wernicke’s aphasia with „„ Characteristics: preserved repetition

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Fig. 3: Areas of transcortical aphasia Fig. 4: Language areas of the brain

Transcortical Aphasia „„ Spoken speech processing: Heschl’s gyrus (bilateral superior temporal gyrus) This is of two types (Fig. 3): „„ Decoding of sounds into language information: „„ Transcortical sensory aphasia: Wernicke’s area (area 22), in left superior temporal —— Features like that of Wernicke’s aphasia with gyrus in its posterior part, as well as posterior parts of preserved repetition middle and inferior temporal gyri. —— Lesion involves the area posterior to central sulcus „„ Phoneme processing: Inferior parietal lobule, especially „„ Transcortical motor aphasia: the supramarginal gyrus. —— Features like that of Broca’s aphasia „„ Readind comprehension: Parieto-occipital cortex, —— Lesion involves the area anterior to the central especially the angular gyrus. sulcus „„ Spontaneous speech output: Broca’s area in the posterior inferior frontal gyrus (areas 44, 45), and the Anatomy of Speech Areas premotor cortex which program the motor cortex to produce sounds. The classical model proposed by Wernicke consists of the „„ Speech repitition: Communication between the following parts (Fig. 4): posterior and anterior speech regions via the arcuate „„ Primary auditory area fasciculus and uncinate fasciculus. „„ Secondary auditory area „„ Alerting the language network: Anterior thalamus, „„ Wernicke’s area (Sensory speech area) basal ganglia. „„ Broca’s area (Motor speech area) „„ Arcuate fasciculus Auditory Pathway and Speech „„ Primary visual cortex „„ The auditory pathway conveys the special sense of „„ Primary somatic sensory cortex hearing. Information travels from the receptors in „„ Primary motor cortex the Organ of Corti of the inner ear (cochlear hair „„ Angular gyrus cells) to the central nervous system carried by the „„ Exner’s area vestibulocochlear nerve. However, this classical model has been expanded „„ This pathway ultimately reaches the primary and modified by recent reviews and are now part of auditory cortex for conscious perception. In addition, Dual Stream Model of Hickok and Poeppel. Some of its unconscious processing of auditory information components include: occurs in parallel (Figs. 5 and 6).

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Fig. 5: Genesis of speech

Aphasia Aphasia as mentioned earlier is a loss or impairment of language production and/or comprehension, often accompanied by a loss of ability to read and/or write resulting from damage to speech centers within the dominant (usually left in 97%) hemisphere (Fig. 7). A language disturbance occurring after a right hemisphere lesion in a right-handed person is known as Crossed aphasia. Aphasia can be categorized according to whether the speech output is fluent or nonfluent: „„ Fluent aphasia (receptive aphasia): It is the impairment mostly due to the input or reception of language with difficulties either in auditory verbal comprehension or in the repetition of words, phrases, or sentences spoken by others. For example, Wernicke’s aphasia. „„ Nonfluent aphasia (receptive aphasia): These are difficulties in articulating with relatively good auditory, verbal comprehension. For example, Broca’s aphasia.

Normal fluency: Between 100–150 words/min, sentence Fig. 6: Auditory pathway length >7 words.

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Fig. 7: Schematic representation of aphasias and associated lesions

TABLE 2 Domains of speech

Domains Methodology Observations Spontaneous zz Observe the speech and language during routine zz Initiation difficulty speech conversation zz Articulation zz Ask open ended questions. Example: zz Fluency —— Why have you come to the hospital? zz Prosody (the melodic intonation) —— Describe the nature of your job zz Grammatical correctness (agrammatic speech zz If the patient is not communicative try recitation list. sounds like telegraphic language) Example: zz Paraphasias:1 If present, literal2 or semantic3? 4 —— List the days of a week zz Neologisms —— List the months of the year zz Word finding pauses, circumlocution Naming Show different categories like objects, body parts, colors, zz Impaired naming, in spite of recognition of the pictures of animals object or the person Example: pen, watch, key hand, thumb, dog , cat, red/blue/ zz Impaired naming restricted to certain category yellow colors, names of familiar people zz Confabulation zz Word finding difficulty, pauses, circumlocution Auditory zz One step commands (beware of apraxias) zz Impaired comprehension to spoken commands comprehension —— Stick out your tongue zz If apraxia/body part agnosia interferes with —— Point to your nose body part commands, impaired “yes/no” —— Open your mouth responses zz Two steps commands (beware of body part agnosias, right left disorientation) —— With your right hand, point to your left ear —— Point to the ceiling and then to the floor —— Raise your hand and close your eyes zz Yes or no responses (inform that patient should say yes or no) —— Is your name xxx? (use a wrong name) —— Is your name zzz? (use correct name) —— Do you live in xxx? (use wrong place) —— Do you live in zzz? (use correct place) —— Does Sunday come after Saturday?

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Contd... Domains Methodology Observations Repetition zz Single words: zz Impaired for difficult consonants in dysarthria —— Brown zz Impaired for complex grammatical sentences —— Chair in aphasia —— Five hundred and fifty-five zz Sentence repetition (there should be no errors of omission or commission) —— It is 4 o’clock —— He locked the doors —— He searched for keys in his pocket —— No ifs, ands, or buts —— He opened the sports page of the newspaper for cricket score Reading zz Simple letters and words: zz Impaired letter formation —— Alphabets (G, C, K, M) zz Spelling errors (most useful in mild Wernicke’s —— Numbers (3, 8, 6, 9) aphasia) —— Simple words (ear, ant, car, etc.) zz Impaired grammar zz Obeying written commands (carry cards with these zz Impaired reading comprehension, in spite of commands written) good speech comprehension in Broca’s aphasia —— Make a fist zz Relatively preserved reading comprehension —— Open your mouth in spite of impaired auditory comprehension in —— Point to the floor then point to the ceiling Wernicke’s aphasia —— With your right hand point to the left knee zz Reading aloud with comprehension —— Ask patient to read a newspaper item and ask him relevant questions Writing zz Ask patient to write few sentences about why he has come to the hospital zz Ask him to write about his job/business zz Show him a picture and ask him to write a few sentences about it zz If the patient has right sided hemiparesis, ask him to use left hand 1Paraphasia: It is a phenomenon of substitutions in speech components. 2Literal paraphasia (Substitution of one phoneme for another; e.g., foon for spoon) 3Semantic paraphasia (Substitution of one word for another; e.g., pan for spoon) 4Neologisms: Use of non-existent words

TABLE 3 Interpretation of language assessment

C-Comprehension (requires intact Wernicke’s and transcortical sensory area) R-Repetition (requires intact Wernicke’s, arcuate fibres, and Broca’s areas) F-Fluency (requires intact Broca’s and transcortical motor area) Aphasia Site of lesion C R F Reading Writing Associated signs Wernicke’s-sensory/ Involvement of _ _ + Impaired, but Impaired, good Visual field defect receptive/posterior inferior division sometimes relatively letter formation, of middle preserved (opposite spelling errors, and cerebral artery of Broca’s aphasia) poor grammars Broca’s-motor/expressive/ Involvement of + _ _ Impaired with Impaired with poor Right sided anterior superior frontal preserved speech letter formation and hemiparesis, apraxia of branch of middle comprehension, poor grammar left limbs cerebral artery especially for syntax (“third alexia”) Contd...

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Contd... Conduction/arcuate Arcuate fasciculus + _ + Inability to read Impaired variably Mild right hemiparesis, aloud, reading apraxia of left limbs, comprehension usually right hemisensory loss, intact visual field defect Transcortical sensory Posterior _ + + Impaired Impaired ------watershed zone Transcortical motor Anterior + + _ May or may not be May or may not be ------watershed zone intact intact Isolation aphasia (mixed Both anterior _ + _ Impaired Impaired ------transcortical aphasia) and posterior watershed zone Global aphasia Dominant frontal, _ _ _ Impaired Impaired Right hemiparesis, parietal, and hemisensory loss, superior temporal hemianopia lobe, left MCA involved

Once the comprehension, repetition, and fluency are intact, we look for Reading, Writing, and Naming disorders associated with reading, writing, and naming. R-Reading W-Writing N-Naming R W N Alexia without agraphia Occipitotemporal region _ + + Alexia with agraphia Left angular gyrus _ _ + Nominal/anomic/amnesic Temporoparietal + + _

TABLE 4 Lesion localization

Aphasia Site of lesion Transcortical motor aphasia zz Left frontal lobe anterior to Broca’s area zz Frontal deep white matter zz Medial frontal region neat SMA (in the anterior cerebral artery territory) Transcortical sensory aphasia Left temporo-occipital region Transcortical mixed aphasia Large watershed infarctions in the left hemisphere, sparing the perisylvian cortex, but disconnecting them from other cortical regions Conduction aphasia Lesion involving either the arcuate fasciculus or the superior temporal gyrus or the inferior parietal region (supramarginal gyrus) Wernicke’s aphasia Lesion involving Wernicke’s area and adjacent temporoparietal region (inferior parietal lobule, superior temporal gyrus) Single word comprehension defect Lesion limited to Wernicke’s area Broca’s aphasia Lesion involving the Broca’s area and adjacent cortex and subcortical white matter Isolated speech initiation defect Lesion limited Broca’s area Global aphasia Large lesion involving the left frontal, temporal, and parietal lobes Anomic aphasia Non-localizing left hemispheric disease. Usually superior temporal gyrus, but also frontal or parietal lobe near angular gyrus Alexia with agraphia Left angular gyrus lesions Alexia without agraphia Disconnection (of language areas from right occipital cortex) by splenial lesion plus left occipital lesion. Patient has intact left hemifield, but written information presented in that hemifield is not conveyed from right occipital cortex to the language areas Third alexia Impaired reading comprehension in Broca’s aphasia Speech alexia Left frontal or insular lesion

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Domains of Language (Table 2) Suggested Readings Language has to be assessed in six domains, which are as . 1 Anderson A. Speech Therapy Aphasia Rehabilitation STAR follows: Workbook. Createspace Independent Pub; 2014. . 2 Berkowitz A. Lange Clinical Neurology and Neuroanatomy: A „„ Spontaneous speech Localization-Based Approach. Mc Graw Hill Education; 2017. „„ Naming . 3 Daroff RB, Jankovic J, Mazziotta JC, et al. Bradley’s Neurology in „„ Auditory comprehension Clinical Practice. Elsevier; 2016. „„ Repitition 4. Ganzfried E, Greenfield M. The Word Escapes Me: Voices of Aphasia. „„ Reading Balboa Press; 2016. . 5 Jameson JL, Fauci AS, Kasper DL, et al. Harrison’s Principles of „„ Writing Internal Medicine. Mc Graw Hill Education; 2018. 6. Kandel E, Schwartz JH, Jessell T, et al. Principles of Neural Science. Interpretation of Language Assessment Mc Graw Hill Education; 2021. See Table 3. 7. Mayans DR, Jordan JT, Soileau MJ, et al. Neurology Self-Assessment: A Companion to Bradley’s Neurology in Clinical Practice E-Book. Elsevier; 2016. Lesion Localization . 8 Ropper A, Brown RH. Adams and Victor’s Principles of Neurology. Mc Graw Hill Medical; 2019. See Table 4. . 9 Ryan Splittgerber. Snell’s Clinical Neuroanatomy. Lippincott Williams and Wilkins; 2018. Conclusion A social approach of language assessment that prioritizes subjectivity is possible when we use a fourth-generation method (Campos and Furtado, 2011), which goes beyond individual evaluation and rehabilitation, providing a more effective improvement. The plasticity of the human brain and training-induced learning improve the quality-of-life due to interference in the process of cognition of individuals with dysgraphia. Although their learning tends to be specific to the trained function and not transferred to similar tasks, there are no obstacles that prevent the discussion of new training schemes. These trainings can lead to the acquisition of new knowledge and to the development of new strategies so that they are used flexibly in various tasks and contexts. These challenges are responsible for increasing learning, for progressing the task difficulty, for the motivational state of the individual, and also for reflecting on the type of feedback that the training provides.

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