Alasdair Scott Bsc (Hons) MBBS Phd

Medicine

Alasdair Scott BSc (Hons) MBBS PhD

2012

[email protected] Table of Contents 1. Cardiology ...... 1 2. Pulmonology ...... 35 3. Endocrinology ...... 59 4. Gastroenterology ...... 78 5. Nephrology ...... 103 6. Haematology ...... 118 7. Infectious Disease ...... 137 8. Neurology ...... 153 9. Rheumatology ...... 198 10. Clinical Chemistry ...... 211 11. Oncology ...... 222 12. Immunology ...... 227 13. Dermatology ...... 232 14. Epidemiology ...... 240 15. Emergencies ...... 246

Cardiology

Contents Cardiac Electrophysiology ...... 2 ECG Analysis ...... 3 ECG Abnormalities ...... 4 Bradycardias ...... 10 Narrow Complex Tachycardias = SVT ...... 11 Atrial Fibrillation ...... 13 Acute Coronary Syndromes ...... 14 MI Complications ...... 15 STEMI Management...... 16 Angina Pectoris ...... 18 Heart Failure: Concepts and Causes ...... 19 Chronic Heart Failure ...... 20 Severe Pulmonary Oedema ...... 21 Cardiogenic Shock ...... 22 Hypertension ...... 23 Aortic Stenosis ...... 24 Aortic Regurgitation ...... 25 Mitral Stenosis ...... 26 Mitral Regurgitation ...... 27 Mitral Valve Prolapse (Barlow Syndrome) ...... 27 Right Heart Valve Disease ...... 28 Infective Endocarditis ...... 29 Pericardial Disease...... 31 Myocardial Disease ...... 32 Congenital Heart Disease ...... 33 Inherited Connective Tissue Disorders ...... 34

View Leads Vessel Inferior II, III, aVF RCA Anterolateral I, aVL, V5 + V6 L circumflex Anteroseptal V2-V4 LAD Anterior V2-V6 Left main stem Posterior V1, V2, V3 (recip) RCA

1. Rate 6. PR interval (120-200ms)  300 / no. of large squares  Start of P wave to start of QRS  6 = 50  Long: heart block  5 = 60  Short  4 = 75 . Accessory conduction: e.g. WPW  3 = 100 . Nodal rhythm  2 = 150 . HOCM  1 = 300  Depressed: pericarditis

2. Rhythm 7. QTc (380-420ms)  Look for P waves followed by QRS complexes  Start of QRS to end of T wave  AF  Bazett’s formula: QTc = actual QT/√R-R . No discernable P waves  Long (>420ms): TIMME . Irregularly irregular QRS . Toxins  Atrial flutter: saw-toothed baseline  Macrolides  Nodal rhythm: regular QRS but no P waves  Anti-arhythmics (Ia/III): quinidine, amiod  TCAs  Histamine antagonists 3. Axis . Inherited: e.g. Romano-Ward, Jervell (c¯ SNHL)  I and II +ve = normal axis (-30 – +90) . Ischaemia  I +ve and II –ve (leaving) = LAD (-30 – -90) . Myocarditis  I –ve and II +ve (reaching) = RAD (+90 – +180) . Mitral valve prolapse . Electrolytes: ↓Mg, ↓K, ↓Ca, ↓ temp  Short (<380ms) RAD (> +90) LAD (<-30) . Digoxin Anterolateral MI Inferior MI . β-B RVH, PE LVH . Phenytoin L post. hemiblock L ant. Hemiblock WPW WPW ASD secundum ASD primum 8. ST Segments  Elevated (limbs: >1mm, chest: >2mm) . Acute MI 4. P Waves . Prinzmetal’s angina . Pericarditis: saddle-shaped  Absent: AF, SAN block, nodal rhythm . Aneurysm: ventricular  Dissociated: complete heart block

 P mitrale: bifid P waves = LA hypertrophy  Depressed (>0.5mm) . HTN, AS, MR, MS . Ischaemia: flat  P pulmonale: peaked P waves= RA hypertrophy . Digoxin: down-sloping . pulmonary HTN, COPD

5. QRS 9. T-waves  Wide QRS (>120ms)  Normally inverted in aVR and V1 . Ventricular initiation . + V2-V3 in blacks . Conduction defect  Abnormal if inverted in: I, II and V4-6 . WPW . Strain  Pathological Q wave . Ischaemia . >1mm wide and > 2mm deep . Ventricular hypertrophy . Full Thickness MI . BBB  RVH: Dominant R wave in V1 + deep S wave in V6 . Digoxin  LVH  Peaked in ↑K+ . R wave in V6 >25mm  Flattened in ↓K+ . R wave in V5/V6 + S wave in V1 > 35mm

10. Extras  U waves . Occur after T waves . Seen in ↓ K  J waves / Osborne wave . Occur between QRS and ST segment . Causes  hypothermia < 32OC  SAH  Hypercalcaemia © Alasdair Scott, 2012 3 ECG Abnormalities

Conduction Defects

Abnormality Features ECG 1st Degree Heart Block PR > 200ms

2nd Degree Heart Block Progressive lengthening of - Wenckebach /Mobitz I PR interval

One non-conducted P wave

Next conducted beat has shorter PR interval 2nd Degree Heart Block Constant PR - Mobitz II Occasional non-conducted P waves

Often wide QRS - block is usually in bundle branches of Purkinje fibres 2nd Degree Heart Block Two P waves per QRS - 2:1 Block Normal consistent PR intervals

3rd Degree Heart Block P waves and QRS @ different rates - dissociation

Abnormally shaped QRS - ventricular origin (40bpm)

Abnormality Features ECG Aetiology Right BBB MaRRoW Infarct – Inferior MI Wide QRS Normal variant RSR pattern in V1 Congenital – ASD, VSD, Fallot’s Hypertrophy – RVH (PE, Cor Pulmonale)

Left BBB WiLLiaM Fibrosis Wide QRS ¯c notched LVH – AS, HTN top Infarct – Inf. MI T wave inversion in lat Coronary HD leads

Bifascicular Block RBBB + LAD RBBB + Left ant. hemiblock Trifascicular Block RBBB + LAFB + 1st degree AV block

Abnormality Features ECG Atrial Escape SAN fails to depolarise

Abnormal P wave

Normal QRS

60-80bpm Junctional Escape Usually no P waves (occasionally after QRS)

Normal QRS

40-60bpm Ventricular Escape Usually result of complete AV block  regular P waves seen (top).

May be SAN failure → no P waves (below).

Wide QRS,

20bpm

Extrasystoles: appear early (before anticipated beat)

Abnormality Features ECG Atrial Extrasystole Abnormal P wave

Normal QRS

Nodal Extrasystole P wave buried in QRS or sometimes immediately before/after QRS. - may be negative

Normal QRS Ventricular No P wave. Extrasystole Wide QRS and abnormal T wave.

Abnormality Features ECG AV Nodal Re- P wave absent or immediately entrant before/after QRS Tachycardia Normal QRS

AVRT P waves usually visible between QRS complexes

QRS may be narrow or wide

Accessory conduction bundle Atrial Tachycardia Abnormally shaped P waves

Normal QRS complexes.

Rate > 150bpm

May be assoc. ¯c AV block.

Atrial Flutter “Saw-toothed” baseline as atria contract @ 300bpm.

AVN can’t conduct > 200bpm  AV block occurs. - 2:1(150), 3:1(100), 4:1(75)

Normal QRS Atrial Fibrillation No P waves – irregular line

Irregularly irregular QRS

Abnormality Features ECG VT No P waves

Regular, wide QRS

No T waves

Torsades

VF Shapeless, rapid oscillations and no organised complexes.

Ventricular tachycardia vs. SVT with bundle branch block

VT more likely if:  Hx: recent infarction  Atrioventricular dissociation  Broad QRS complexes (>140ms)  Concordant QRS direction in V1-V6  Fusion and capture beats

Abnormality Features ECG Aetiology P pulmonale Peaked P wave RAH - pulmonary HTN - tricuspid stenois

P mitrale Broad, bifid P wave LAH - mitral stenois

QRS Abnormalities

Abnormality Features ECG Aetiology RVH Tall R wave in V1 Cor pulmonale Deep S wave in V6 RAD

Normal QRS width

May be T wave inversion in V1-V3 LVH S in V1 + R in V6 >35mm HTN and/or R wave in V6 >25mm AS COA May be LAD H(O)CM

May be T wave inversion in II, aVL, V5, V6

Abnormality Features ECG WPW Accessory conducting bundle.

Short PR interval

Slurred upstroke of QRS called a delta wave (V3/4).

Can establish re-entrant circuit → SVT (antidromic AVRT)

AF + WPW → irregularly irregular broad QRS complexes (below).

Brugada RBBB Syndrome Coved ST elevation in V1-V3

Digoxin Reverse tick - Down-sloping ST depression - T wave inversion

PE SI QIII TIII (rare) - deep S wave in I (RAD) - pathological Q in III - T inversion in III

Right vent strain - RAD (S wave in I) - Dominant R wave and T wave inversion in V1-V3 ↑ K+ Tall tented T waves Widened QRS Absent P waves Sine wave appearance

Fig shows serial ↓ in K+

↓ K+ Small T waves ST depression Prolonged QT interval Prominent U waves

Causes: DIVISIONS Classification  Sinus bradycardia Drugs  First degree heart block: PR > 200ms  Antiarrhythmics (type 1a, amiodarone)  Second degree heart block  β-blockers . Wenkebach / Mobitz I  Ca2+-channel blockers (verapamil) . Mobitz II  Digoxin  Complete heart block . Junctional: narrow QRS @ ~50bpm Ischaemia / Infarction . Ventricular: broad QRS @ ~40bpm  Inferior MI Rx Vagal hypertonia  If asymptomatic and rate >40: no Rx needed  Athletes  Vasovagal syncope  Carotid sinus syndrome Urgent / rate <40bpm 1. Rx underlying cause: e.g. drugs, MI Infection  Viral myocarditis 2. Medical  Rheumatic fever  Atropine 0.6–1.2g (max 3g) IV  Infective endocarditis  Isoprenaline IVI

Sick sinus syndrome 3. Pacing: External  Structural damage or fibrosis of SAN, AVN or conducting tissue  PC Elective . SVT alternating ¯c either sinus bradycardia ± 1. Permanent pacing arrest or SA/AV block  Mobitz II  Rx  Complete AV block . Bradyarrhythmias: pace  Sick sinus . Tachyarrhythmias: amiodarone  AF  Drug-resistant tachyarrhythmias Infiltration: restrictive / dilated cardiomyopathy  Autoimmune  Sarcoid  Haemochromatosis  Amyloid  Muscular dystrophy

O  hypOthyroidism  hypOkalaemia (or ↑)  hypOthermia

Neuro: ↑ ICP

Septal defect: primum ASD

Surgery or catheterisation

Definition: Rate >100bmp, QRS width < 120ms

Differential Principles of Mx 1. Sinus tachycardia  If pt. compromised → sedate + DC cardioversion  Otherwise ID rhythm and Rx accordingly 2. Atrial . Key to ID irregular rhythm = AF = different Rx  AF  Vagal manoeuvres (carotid sinus massage, valsalva) transiently ↑ AV block and  Atrial flutter may unmask underlying atrial rhythm.  Atrial tachycardia  If manoeuvres unsuccessful, give adenosine while recording rhythm strip . → transient AV block, unmasking atrial rhythm 3. AV nodal re-entry tachycardia . → cardioverts AVNRT/AVRT to sinus rhythm  If adenosine fails, choose from: 4. AV re-entry tachycardia . Digoxin . Atenolol . Verapamil (not if on β-blocker) . Amiodarone  If unsuccessful → DC cardioversion

O2 + IV access

Regular rhythm? NO Treat as AF  Control rate ¯c β-B (e.g. metoprolol) or digoxin YES  If onset <48h consider cardioversion ¯c amiodarone (as below) or DC shock  Continuous ECG trace  Consider anticoagulation ¯c heparin and/or warfarin  Vagal manoeuvres  Adenosine 6mg IV bolus NB. Avoid adenosine, CCB, β-B in AF/Flutter with WPW or Hx  Then 12mg, then 12mg of WPW as may → VF. Use Amiodarone or flecainide

YES Adverse Signs? Sedation  BP <90  HF  ↓ consciousness Synchronised cardioversion:  HR >200 100→200→360J

Choose from: Amiodarone:  Digoxin (500ug over 30min)  Amiodarone  300mg over 20-60min  Verapamil  Then 900mg over next 23h  Atenolol

Adenosine Prophylaxis  MOA: temporary AVN block  β-B  SEs: Transient chest tightness, dyspnoea, flushing, headache  AVRT: flecainide  Relative CIs: asthma, 2nd/3rd degree block  AVNRT: verapamil  Interactions . fx ↑d by dipyridimole . fx ↓d by theophylline

Definition: Rate >100bmp, QRS width > 120ms VT Causes: I’M QVICK  Infarction (esp. ¯c ventricular aneurysm) Differential  Myocarditis 1. VT  QT interval↑ 2. Torsades de points  Valve abnormality: mitral prolapse, AS 3. SVT ¯c BBB  Iatrogenic: digoxin, antiarrhythmics, catheter  Cardiomyopathy (esp. dilated)  K↓, Mg↓, O2↓, acidosis

Pulse? CPR NO YES

O2 + IV access

YES Adverse Signs? Sedation  BP <90  HF  Chest pain  ↓ consciousness Synchronised cardioversion:  HR > 150 200→300→360

Correct Electrolyte Problems Amiodarone:  ↓K+: max 60mM KCL @ 20mmol/h  300mg over 20-60min 2+  ↓Mg : 4ml 50% MgSO4 in 30min  Then 900mg over next 23h

Assess Rhythm Regular (i.e. VT):  Amiodarone (see opposite)  Or lignocaine 50mg over 2min

If irregular, Dx is usually:  AF ¯c BBB  Pre-excited AF: flec / amio Recurrent / Paroxysmal VT  TDP: MgSO4 2g IV over 10 min Medical:  Amiodarone Failure  β-B

Synchronised Cardioversion ICD

Pathology Persistent AF  LA loses refractoriness before the end of atrial systole.  >7d, may recur even after cardioversion  → recurrent, uncoordinated contraction @ 300-600bpm  Atrial contraction responsible for ~25% of CO Try rhythm control first-line if: . often triggers heart failure  Symptomatic or CCF  Younger (<65) Causes  Presenting first time ¯c lone AF  Secondary to treated precipitant Common Other  IHD  Alcohol Rhythm Control  Rheumatic heart disease  Pneumonia  TTE first: structural abnormalities  Thyrotoxicosis  PE  Anticoagulate ¯c warfarin for ≥3wks  Hypertension  Post-op . or use TOE to exclude intracardiac thrombus.  Hypokalaemia  Pre-Rx ≥4wks ¯c sotalol or amiodarone if ↑ risk of failure  RA  Electrical or pharmacological cardioversion  ≥ 4 wks anticoagulation afterwards (target INR 2.5) Symptoms  Asympto Maintenance antiarrhythmic  Chest pain  Not needed if successfully treated precipitant  1st: β-B (e.g. bisoprolol, metoprolol).  Palpitations nd  Dyspnoea  2 : amiodarone

 Faintness Other options

Radiofrequency ablation of AV node Signs   Maze procedure  Irregularly irregular pulse  Pacing  Pulse deficit: difference between pulse and HS . Fast AF → loss of diastolic filling → no palpable pulse Rate control (target <90bpm at rest):  1st line: β-B or rate-limiting CCB (NOT both!)  Signs of LVF nd  2 line: add digoxin (don’t use as monotherapy)  3rd line: consider amiodarone Ix  ECG Mx of Permanent AF  FBC, U+E, TFTs, Trop  Failed cardioversion / unlikely to succeed  Consider TTE: structural abnormalities . AF >1yr, valve disease, poor LV function  Pt. doesn’t want cardioversion  → Rate control Acute AF (≤48h)  Haemo unstable → emergency cardioversion Mx of Atrial Flutter nd . (IV amiodarone 2 line)  Manage as for AF  Anti-AF drugs may not work, but try Control ventricular rate . Amiodarone to restore sinus st  1 line: diltiazem or verapamil or metoprolol . Amiodarone or sotalol to maintain it nd  2 line: digoxin or amiodarone  Cavotricuspid isthmus ablation (RA) is Rx of choice.

Start LMWH CHA2-DS2-VAS Score  Determines necessity of anticoagulation in AF Cardioversion: only if acute AF <48hrs  Warfarin CI in AF  Electrical cardioversion or pharmacological st . Bleeding diathesis, ↓plats, BP > 160/90, poor . 1 : Flecainide (if no structural heart disease) compliance . 2nd: Amiodarone  Dabigatran may be cost-effective alternative.  Long-term anticoagulation not needed if sinus restored no RFs (0 CHADSVAS) + low recurrence risk. CHA -DS VAS 2 2  CCF  Vascular disease  HTN  Age: 65-74yrs Paroxysmal AF  Age≥75 (2 points)  Sex: female  Self-limiting, <7d, recurs  DM  Anticoagulate: use CHADSVAS  Stroke or TIA (2 points)  Rx “pill-in-pocket” : flecainide, propafenone  Prevention: β-B, sotalol or amiodarone Score  0: aspirin 300mg  ≥1: Warfarin

Definition Investigations  ACS = unstable angina + evolving MI  Divided into: ECG . ST elevation or new onset LBBB  STEMI Sequence . NSTEMI . Normal . ST elevation + hyperacute (tall) T waves . Q waves: full-thickness infarct Epidemiology . Normalisation of ST segments . T wave inversion  Incidence 5/1000 for STEMI . (New onset LBBB also = STEMI)

 NSTEMI . ST depression Pathophysiology . T wave inversion  Plaque rupture, thrombosis and inflammation.  No Q waves = subendocardial infarct  Rarely due to coronary spasm View Leads Vessel Complication Inferior II, III, aVF RCA Bradyarrhythmias Risk Factors Anterolateral I, aVL, V4-V6 LCx Anteroseptal V2-V4 LAD Modifiable Non-modifiable Anterior V2-V6 LMS LVF  HTN  Age Posterior V1, V2, V3 (recip) RCA  DM  Male  Smoking  FH (MI < 55yrs) Bloods  ↑cholesterol  Troponin T/I  Obesity . Myofibrillar proteins linking actin and myosin . Elevated from 3-12h Symptoms   need 12h trop to exclude MI . Peak 24h  Acute central/left chest pain >20min . Baseline from 5-14d  Radiates to left jaw or arm  FBC, U+E, glucose, lipids, clotting  Nausea

 Sweating CXR  Dyspnoea  Cardiomegaly  Palpitations  Pulmonary oedema

 Widened mediastinum: aortic rupture May get silent MIs in elderly/diabetics

 Syncope  Delirium  Post-op oliguria / hypotension Diagnosis  STEMI / LBBB: Typical symptoms + ST elevation (/LBBB)  NSTEMI: Typical symptoms + no ST elevation + +ve trop Signs  UA: Typical symptoms + no ST elevation + -ve trop

 Anxiety  Pallor Sweating  Pulse ↑/↓ Treatment  BP ↑/↓  STEMI: PCI or thrombolysis  4th heart sound  NSTEMI / UA: medical + elective angio ± PCI/CABG  Signs of LVF (basal creps, ↑ JVP, 3rd HS)  PSM: papillary muscle dysfunction / rupture Prognosis  Varies ¯c pt. factors Differential  STEMI: 30 day mortality ~15%  Angina  NSTEMI: overall mortality 1-2%  Peri / endo / myocarditis  Dissection  PE, pneumothorax, pneumonia  Costochondritis  GI: e.g. GORD, spasm  Anxiety

Death Passing PRAED st. Aneurysm: ventricular Death: VF, LVF, CVA Presentation  4-6wk Pump Failure  LVF  Angina Pericarditis  Recurrent VT Presentation  Systemic emboli.  Occurs early  Mild fever ECG: persistent ST elevation.  Central chest pain / change in pain  Relieved by sitting forward Rx  Pericardial friction rub  Anticoagulate  Consider Excision ECG  Saddle-shaped ST elevation  ± PR depression Embolism  Arise from LV mural thrombus Rx  Consider warfarin for 3mo after large anterior MI  NSAIDs: ibuprofen  Echo to exclude effusion Dressler’s Syndrome: pleuro-pericarditis  Due to auto-antibodies vs. myocyte sarcolemma. Rupture: myomalacia cordis  Cardiac tamponade: Left ventricular free wall rupture Presentation . Beck’s triad (↓BP, ↑JVP, muffled heart sounds)  2-6wks . Pulsus paradoxus  Recurrent pericarditis  Papillary muscle / chordae → MR  Pleural effusions . PSM  Fever . Pulmonary oedema.  Anaemia  Septum  ↑ESR . PSM . ↑JVP Rx . Heart failure  NSAIDs  Steroids if severe

Arrhythmias

Tachycardias  SVT . Sinus tachycardia – give O2 + analgesia . AF or flutter  Compromised → DC cardioversion  Otherwise → rate control: digoxin ± β-B  Ventricular . Frequent PVC common after acute MI: no Rx . Sustained VT  Compromised → DC cardioversion  Else → amiodarone or lignocaine  May need pacing . VF  Early (<48hrs): reperfusion (good prog)  Late (>48hrs): extensive heart damage  Rx: DC shock

Bradycardias  Sinus bradycardia . esp. in inferior MI. . Rx: atropine 0.6 – 1.2mg  AV block . Pace Mobitz II  Ventricular bradycardia . Suggests SA and AV node damage

12 lead ECG Primary Percutaneous Coronary Intervention  Rx of choice if <12h  Angioplasty and stenting  + GP IIb/IIIa antagonist (tirofiban) if high risk

O2 2-4L aim for SpO2 94-98% . Delayed PCI, DM, complex procedure

Complications:  Bleeding IV access  Emboli Bloods for FBC, U+E, glucose, lipids  Arrhythmia

Thrombolysis Brief assessment  CI beyond 24hrs from pain onset  Hx of CVD and risk factors  Thrombolysis CIs ECG Criteria:  CV exam  ST elevation > 1mm in 2+ limbs or > 2mm in 2+ chest leads.  New LBBB  Posterior: Deep ST “depression” and tall “R” waves in V1-V3

Antiplatelet Contraindications: AGAINST  Aspirin 300mg PO (then 75mg/d)  Aortic dissection  Clopidogrel 300mg PO (then 75mg/d)  GI bleeding  Allergic reaction previously  Iatrogenic: recent surgery  Neuro: cerebral neoplasm or CVA Hx Analgesia  Severe HTN (200/120)  Morphine 5-10mg IV  Trauma, inc. CPR  Metoclopramide 10mg IV Agents: 1st: streptokinase, alteplase (rt-PA), tenecteplase

Complications: Anti-ischaemia  Bleeding  GTN 2 puffs or 1 tablet SL  Stroke  β-B atenolol 5mg IV (CI: asthma, LVF)  Arrhythmia  Allergic reaction

Pts. not receiving any form of reperfusion therapy should be given LMWH: e.g. enoxaparin IV then SC fondaparinux.

Continuing Therapy: address risk factors Admit to CCU for monitoring  ACEi: start w/i 24hrs of MI (e.g. lisinopril 2.5mg)  Arrhythmias  β-blocker: e.g. bisoprolol 10mg OD (or, CCB)  Continue meds except CCBs  Cardiac rehabilitation (group exercise and info) / Heart Manual  DVT prophylaxis until fully mobile . Continue for 3mo if large anterior MI  Statin: regardless of basal lipids (e.g. atorvastatin 80mg) Primary PCI or Thrombolysis Advice  Stop smoking  Diet: oily fish, fruit, veg, ↓ sat fats  Exercise: 30min OD  Work: return in 2mo  Sex: avoid for 1mo  Driving :avoid for 1mo

NB. Continue clopidogrel for 1mo following STEMI Continue aspirin indefinitely.

12 lead ECG + Admit to CCU

O2 2-4L aim for SpO2 94-98%

IV access Bloods for FBC, U+E, glucose, lipids, Troponin

Brief Assessment  Hx of CVD and risk factors  CV exam

Antiplatelet  Aspirin 300mg PO (then 75mg/d)  Clopidogrel 300mg PO

Anticoagulate  Fondaparinux 2.5mg SC

Analgesia  Morphine 5-10mg IV  Metoclopramide 10mg IV

Anti-ischaemia  GTN: 2 puffs or 1 tablet SL  β-B: atenolol 50mg/24h PO (CI: asthma, LVF)  IV GTN if pain continues

Assess Cardiovascular Risk: GRACE/TIMI

Intermediate- to High-Risk Low-Risk  Persistent/recurrent ischaemia, ST depression, DM,  No further pain, flat or inverted T waves or normal positive trop. ECG, negative trop.  GPIIb/IIIa antagonist (tirofiban)  May discharge if 12h trop is negative.  Angiography (±PCI) w/i 96hrs  Outpatient tests: angio, perfusion scan, stress echo  Clopidogrel 75mg/d for one year

Continuing Therapy: address risk factors  ACEi (e.g. lisinopril 2.5mg)  β-blocker (e.g. bisoprolol 10mg OD) or (CCB)  Cardiac rehabilitation (group exercise and info) / Heart Manual  Stop antithrombotic therapy when pain free (but give 3-5d)  Statin (e.g. atorvastatin 80mg)

General advice as above NB. Continue clopidogrel for 1yr following NSTEMI Continue aspirin indefinitely.

Pathophysiology Mx  Atherosclerosis → myocardial ischaemia Lifestyle Aetiology  Stop smoking  Mostly atheroma.  Wt. loss and ↑ exercise  Anaemia  Healthy diet: oily fish, fruit, veg, ↓ sat fats  AS Medical  Tachyarrhythmias O  Arteritis  2 Prevention: prevent cardiovascular events . Aspirin 75mg OD . ACEi (esp. if angina + DM) Risk Factors . Statins: simvastatin 40mg Modifiable: Non-modifiable: . Antihypertensives  HTN  Age  DM  Male  Anti-anginals: prevents angina episodes  Smoking  FH (MI < 55yrs) 1. GTN (spray or SL) + either  ↑cholesterol  Genetic: e.g. hyperlipidaemia . 1st: β-B (e.g. Atenolol 50-100mg OD)  Obesity . 2nd: CCB (e.g. Verapamil 80mg TDS) 2. If either β-B or CCB doesn’t control symptoms, Symptoms try the other option.  Central chest tightness or heaviness 3. Can try β-B + dihydropyridine CCB . e.g. amlodipine MR 10mg/24h  Brought on by exertion, relieved by rest 4. If symptoms still not controlled  May radiate to one/both arms, neck, jaw or teeth . ISMN 20-40mg BD (8h washout @ PM) or  Other ppts: emotion, cold weather, heavy meals slow-release nitrate (Imdur 60mg OD)  Ivabradine (esp. if can’t take β-B) Classification . Nicorandil 10-30mg BD  Stable: induced by effort . Ranolazine  Unstable: occurs at rest / minimal exertion  Decubitus: induced by lying down  Prinzmetal’s / variant: occurs during rest Interventional: PCI . Due to coronary spasm  Indications . ST elevation during attack: resolves as pain . Poor response to medical Rx subsides. . Refractory angina but not suitable for CABG . Rx: CCB + long-acting nitrate  Complications  Syndrome X: angina pain + ST elevation on exercise . Re-stenosis (20-30% @ 6mo) test but no evidence of coronary atherosclerosis. . Emergency CABG (<2%) . Probably represents small vessel disease . MI (<2%) . Death (<0.5%) Differential  Clopidogrel ↓s risk of re-stenosis . Bare metal stent: 1mo  AS . Drug-eluting (e.g. sirolimus) stent: 1yr  Aortic aneurysm

 GI: GORD, spasm  Musculoskeletal Surgical: CAGB  Indications Ix . L main stem disease  Bloods: FBC, U+E, lipids, glucose, ESR, TFTs . Triple vessel disease  ECG: usually normal . Refractory angina . May show ST ↓, flat/inverted T waves, past MI . Unsuccessful angioplasty . Consider exercise ECG  Complications  Stress echo . MI  Perfusion scan . Stroke  CT coronary Ca2+ score . Pericardial tamponade or haemothorax  Angiography (gold standard) . Postperfusion syn. . Post-op AF . Nonunion of sternum . Graft stenosis

Definition: CO is inadequate for the body’s requirements despite adequate filling pressures.

Epidemiology RVF  Prev: 2% @ 50yrs → 10% @ 80yrs Causes  LVF Pathophysiology  Cor pulmonale  Tricuspid and pulmonary valve disease Reduced CO initially → compensation  Starling effect dilates heart to enhance contractility Symptoms  Remodelling → hypertrophy  Anorexia and nausea  RAS and ANP/BNP release  Sympathetic activation Signs  ↑JVP + jugular venous distension Progressive ↓ in CO → decompensation  Tender smooth hepatomegaly (may be pulsatile)  Progressive dilatation → impaired contractility +  Pitting oedema functional valve regurgitation  Ascites  Hypertrophy → relative myocardial ischaemia  RAS activation → Na+ and fluid retention → ↑ venous pressure → oedema LVF  Sympathetic excess → ↑ afterload → ↓ CO Causes  1st: IHD nd Low Output: CO ↓ and fails to ↑ c¯ exertion  2: idiopathic dilated cardiomyopathy  3rd: Systemic HTN th 1. Pump failure  4: Mitral and aortic valve disease  Systolic failure → impaired contraction  Specific cardiomyopathies . Ischaemia/MI (commonest cause) . Dilated cardiomyopathy Symptoms . Hypertension  Fatigue . Myocarditis  Exertional dyspnoea  Orthopnoea + PND  Diastolic failure → impaired filling  Nocturnal cough (± pink, frothy sputum) . Pericardial effusion / tamponade / constriction  Wt. loss and muscle wasting . Cardiomyopathy: restrictive, hypertrophic Signs  Arrhythmias  Cold peripheries ± cyanosis . Bradycardia, heart block  Often in AF . Tachycardias  Cardiomegaly ¯c displaced apex . Anti-arrhythmics (e.g. beta-blocker, verapamil)  S3 + tachycardia = gallop rhythm  Wheeze (cardiac asthma) 2. Excessive pre-load  Bibasal creps  AR, MR  Fluid overload

3. Excessive afterload Acute vs. Chronic  AS  Acute  HTN . New onset or decompensation of chronic  HOCM . Peripheral / pulmonary oedema . ± evidence of peripheral hypoperfusion  Chronic . Develops / progresses slowly High Output: ↑ needs → RVF initially, then LVF . Venous congestion common  Anaemia, AVM . Arterial pressure maintained until v. late  Thyrotoxicosis, Thiamine deficiency (beri beri)  Pregnancy, Paget’s

Dx of CCF: Framingham Criteria General Mx  2 major criteria or 1 major + 2 minor 1O/2O Cardiovascular Risk Major Minor  Stop smoking  PND  Bilat ankle oedema  ↓ salt intake  +ve abdominojugular reflux  SOBOE  Optimise wt.: ↑ or ↓ - dietician  Neck vein distension  ↑HR >120  Supervised group exercised based rehab programme  S3  Nocturnal cough  Aspirin  Basal creps  Hepatomegaly  Statins  Cardiomegaly  Pleural effusion  Acute pulmonary oedema  30% ↓ vital capacity Rx Precipitants / Causes  ↑ CVP (>16cmH2O)  Underlying cause  Wt. loss >4.5kg in 5d 2O to Rx . Valve disease . Arrhythmias . Ischaemia Ix  Exacerbating factors  Bloods: FBC, U+E, BNP, TFTs, glucose, lipids . Anaemia .  CXR: ABCDE Infection . Alveolar shadowing . ↑BP . Kerley B lines . Cardiomegaly (cardiothoracic ratio >50%) Specific Mx . Upper lobe Diversion  ACEi, β-B and spiro → ↓ mortality . Effusions st . Fluid in the fissures 1 line: ACEi/ARB + β-B + loop diuretic  ECG  ACEi/ARB: e.g. lisinorpil or candesartan . Ischaemia . Hydralazine + ISDN if not tolerated . Hypertrophy . AF  β-B: e.g. carvedilol or bisoprolol (licensed)  Echo: the key investigation . Start low, go slow . Global systolic and diastolic function . E.g. carvedilol 3.125mg/12h → 25-50mg/24h  Ejection fraction normally ~60% . Wait ≥2wks between increments . Focal / global hypokinesia . Switch stable pts taking a β-B for a comorbidity . Hypertrophy to a β-B licensed for heart failure . Valve lesions . β-B therapy may be particularly good in COPD . Intracardiac shunts  Loop diuretic: frusemide or bumetanide B-type Natriuretic Peptide: BNP or NTproBNP nd  Secreted from ventricles in response to 2 line: get specialist advice . ↑ pressure → stretch  Spironolactone / eplerenone . Tachycardia . Watch K carefully (on ACEi too…) . Glucocorticoids . Thyroid hormones  ACEi + ARB  Actions . ↑ GFR and ↓ renal Na reabsorption  Vasodilators: hydralazine + ISDN . ↓ preload by relaxing smooth muscle . Additional Rx in Blacks  BNP is a biomarker of heart failure rd . ↑ BNP (>100) better than any other variable and 3 line clinical judgement in diagnosing heart failure  Digoxin . BNP correlates ¯c LV dysfunction  Cardiac resynchronisation therapy ± ICD  i.e. ↑ most in decompensated heart failure  ↑ BNP = ↑ mortality Other Considerations . BNP <100 excludes heart failure (96% NPV)  Monitoring . BNP also ↑ in RHF: cor pulmonale, PE . BP: may be v. low . Renal function . Plasma K New York Heart Association Classification . Daily wt. 1. No limitation of activity  Use amlodipine for comorbid HTN or angina 2. Comfortable @ rest, dyspnoea on ordinary activity  Avoid verapamil, diltiazem and nifedipine (short- 3. Marked limitation of ordinary activity acting) 4. Dyspnoea @ rest, all activity → discomfort Invasive Therapies  Cardiac resynchronisation ± ICD  Intra-aortic balloon counterpulsation  LVAD  Heart transplant (70% 5ys) © Alasdair Scott, 2012 20 Severe Pulmonary Oedema

Sit pt. up Causes

Cardiogenic  MI O 2  Arrhythmia  15L/min via reservoir mask  Fluid overload: renal, iatrogenic  Target SpO : 94-98% 2 Non-cardiogenic  ARDS: sepsis, post-op, trauma IV access + monitor ECG  Upper airway obstruction  Bloods for FBC, U+E, troponin, BNP, ABG  Neurogenic: head injury  Rx any arrhythmias (e.g. AF)

Symptoms  Dyspnoea Diamorphine 2.5-5mg IV  Orthopnoea + Metoclopramide 10mg IV  Pink frothy sputum

Frusemide 40-80mg IV Signs  Distressed, sweaty, cyanosed  ↑HR, ↑RR  ↑JVP GTN 2 puffs or 2 x 300ug tabs SL  S3 / gallop rhythm Unless SBP <90mmHg  Bibasal creps  Pleural effusions  Wheeze (cardiac asthma) Hx, Ex, Ix  CXR: ABCDE  ECG: MI, arrhythmias, pulsus alternans Differential  Consider echo  Asthma/COPD  Pneumonia  PE If SBP >100mmHg, start nitrate IVI  ISMN 2-10mg/h IVI  Keep SBP >90 Monitoring Progress  BP  HR and RR If worsening, consider:  JVP  CPAP  Urine Output  More frusemide or ↑ nitrate infusion  ABG  Haemofiltration / dialysis

If SBP <100mmHg: Rx as cardiogenic shock  i.e. consider inotropes

Continuing Therapy  Daily weights  DVT prophylaxis  Repeat CXR  Change to oral frusemide or bumetanide  ACEi + β-B if heart failure  Consider spironolactone  Consider digoxin ± warfarin (esp. if in AF)

Morphine in Pulmonary Oedema  Make pt. more comfortable  Pulm venodilators → ↓ pre-load → optimise position on Starling Curve

O2 Definition  15L/min via reservoir mask  Inadequate tissue perfusion primarily due to  Target SpO2: 94-98% cardiac dysfunction.

Causes: MI HEART IV access + monitor ECG  MI  Bloods for FBC, U+E, troponin, ABG  Hyperkalaemia (inc. electrolytes)  Endocarditis (valve destruction)  Aortic Dissection Diamorphine 2.5-5mg IV (pain/anxiety)  Rhythm disturbance + metoclopramide 10mg IV  Tamponade

Obstructive  Tension pneumo Correct any:  Massive PE  Arrhythmias  Electrolyte disturbance  Acid-base abnormalities Presentation  Unwell: pale, sweaty, cyanosed, distressed  Cold clammy peripheries Hx, Ex, Ix  ↑RR ± ↑HR  CXR  Pulmonary oedema  Echo  Consider CT thorax (dissection/PE)

Monitoring  CVP, BP, ABG, ECG, urine output.

Consider need for dobutamine

Rx underlying cause

Tamponade

Causes: Signs: Ix:  Trauma  Beck’s triad: ↓BP, ↑JVP, muffled heart sounds  Echo: diagnostic  Lung/breast Ca  Kussmaul’s sign: ↑JVP on inspiration  CXR: globular heart  Pericarditis  Pulsus paradoxus (pulse fades on inspiration)  MI  Bacteria (e.g. TB)

Mx:  ABCs  Pericardiocentesis (preferably under echo guidance)

Definitions Management  Stage 1: Clinic BP > 140/90  Do ABPM to confirm Dx before Rx (unless severe HTN)  Stage 2: Clinic BP > 160/100  Severe: Clinic BP > 180/110 Lifestyle interventions  Malignant: BP > 180/110 + papilloedema and/or retinal  ↑ exercise haemorrhage  ↓ smoking, ↓ EtOH, ↓ salt, ↓ caffeine  Isolated SHT: SBP ≥140, DBP <90 Indications for Pharmacological Rx Aetiology: PREDICTION  <80yrs, stage 1 HTN (>140/90) and one of:  Primary: 95% . Target organ damage (e.g. LVH, retinopathy)  Renal: RAS, GN, APKD, PAN . 10yr CV risk ≥20%  Endo: ↑T4, Cushing’s, phaeo, acromegaly, Conn’s . Established CVD  Drugs: cocaine, NSAIDs, OCP . DM  ICP ↑ . Renal disease  CoA  Anyone with stage 2 HTN (>160/100)  Toxaemia of Pregnancy (PET)  Severe / malignant HTN (specialist referral)  Increased viscosity  Consider specialist opinion if <40yrs with stage 1 HTN  Overload with fluid and no end organ damage.

 Neurogenic: diffuse axonal injury, spinal section BP Targets  Under 80yrs: <140/90 (<130/80 in DM) Aetiological clues  Over 80yrs: <150/90  ↑HR: Thyrotoxicosis  RF-delay: CoA CV Risk Mx  Renal bruits: RAS  Statins indicated for 1O prevention if 10yr CVD risk ≥20%  Palpable kidneys: APKD  Aspirin may be indicated: evaluate risk of bleeding  Paroxysmal headache, tachycardia, sweating, palpitations, labile or postural hypotension: phaeo Antihypertensive Rx End-organ damage: CANER < 55 > 55 / Black Cardiac  IHD 1: A C (or D)  LVH → CCF  AR, MR

Aortic 2: A + C (/D)  Aneurysm  Dissection 3: A + C + D Neuro  CVA: ischaemic, haemorrhagic  Encephalopathy (malignant HTN) 4: Resistant HTN

A+C+D+ consider further diuretic (e.g. Eyes: hypertensive retinopathy  spiro) or α-blocker or β-B.  Keith-Wagener Classification: 1. Tortuosity and silver wiring  Seek expert opinion 2. AV nipping 3. Flame haemorrhages and cotton wool spots A: ACEi or ARB 4. Papilloedema  e.g. lisinopril 10mg OD (↑ to 30-40mg)  Grades 3 and 4 = malignant hypertension  e.g. candesartan 8mg OD (max 32mg OD) C: CCB: e.g. nifedipine MR30-60mg OD Renal D: Thiazide-like diuretic: e.g. chlortalidone 25-50mg OD  Proteinuria  CRF In step 2, use ARB over ACEi in blacks. Avoid thiazides + β-B if possible (↑ risk of DM). Ix Only consider β-B if young and ACEi/ARB not tolerated.  24h ABPM  Urine: haematuria, Alb:Cr ratio  Bloods: FBC, U+Es, eGFR, glucose, fasting lipids Malignant HTN  12 lead ECG: LVH, old infarct  Controlled ↓ in BP over days to avoid stroke  Calculate 10yr CV risk  Atenolol or long-acting CCB PO  Encephalopathy/CCF: fruse + nitroprusside / labetalol IV . Aim to ↓ BP to 110 diastolic over ~4h . Nitroprusside requires intra-arterial BP monitoring

Causes Ix  Senile calcification (60yrs +): commonest  Congenital: Bicuspid valve (40-60yrs), William’s syn. Bloods: FBC, U+E, lipids, glucose  Rheumatic fever ECG  LVH Symptoms  LV strain: tall R, ST depression, T inversion in V4-V6  Triad: angina, dyspnoea, syncope (esp. ¯c exercise)  LBBB or complete AV block (septal calcification)  LVF: PND, orthopnoea, frothy sputum . May need pacing

 Arrhythmias CXR  Systemic emboli if endocarditis  Calcified AV (esp. on lateral films)  Sudden death  LVH

 Evidence of failure Signs  Post-stenotic aortic dilatation

 Slow rising pulse ¯c narrow PP Echo + Doppler: diagnostic  Aortic thrill  Thickened, calcified, immobile valve cusps  Apex: Forceful, non-displaced (pressure overload)  Severe AS (AHA / ACC 2006 guidelines):  Heart Sounds . Pressure gradient >40mmHg . Quiet A2 . Jet velocity >4m/s (or ↑ by 0.3m/s in a yr) . Early syst. ejection click if pliable (young) valve . Valve area <1cm2 . S4 (forceful A contraction vs. hypertrophied V)  Murmur Cardiac Catheterisation + Angiography . ESM nd  Can assess valve gradient and LV function . Right 2 ICS  Assess coronaries in all pts. planned for surgery . Sitting forward in end-expiration . Radiates to carotids Exercise Stress Test  Contraindicated if symptomatic AS  May be useful to assess ex capacity in asympto pts. Clinical Indicators of Severe AS  Quiet / absent A2 Mx  S4  Narrow pulse pressure Medical  Decompensation: LVF  Optimise RFs: statins, anti-hypertensives, DM  Monitor: regular f/up ¯c echo

 Angina: β-B Differential  Heart failure: ACEi and diuretics  Coronary artery disease  Avoid nitrates  MR  Aortic sclerosis Surgical . Valve thickening: no pressure gradient  Poor prog. if symptomatic . Turbulence → murmur . Angina/syncope: 2-3yrs . ESM ¯c no radiation and normal pulse . LVF: 1-2yrs  HOCM  Indications for valve replacement . ESM murmur which ↑ in intensity ¯c valsalva (AS↓) . Severe symptomatic AS . Severe asymptomatic AS ¯c ↓ EF (<50%) . Severe AS undergoing CABG or other valve op Aortic Stenosis Aortic Sclerosis  Valve types Valve narrowing due to fusion of Valve thickening . Mechanical valves last longer but need the commissures anticoagulation: young pts. Narrow PP, slow rising pulse . Bioprosthetic don’t require anticoagulation but Forceful apex fail sooner (10-15yrs) ESM radiating → carotids ESM ¯c no radiation ECG: LVF Options for unfit patients  Balloon Valvuloplasty . Limited use in adults as complication rate is high (>10%) and restenosis occurs in 6-12mo  Transcatheter Aortic Valve Implantation (TAVI) . Folded valve deployed in aortic root. . ↑ perioperative stroke risk cf. replacement . ↓ major bleeding . Similar survival @ 1yr . Little Long-term data

Causes Ix

Acute Bloods: FBC, U+E, lipids, glucose  Infective endocarditis  Type A aortic dissection ECG: LVH (R6+S1 > 35mm)

Chronic CXR  Congenital: bicuspid aortic valve  Cardiomegaly  Rheumatic heart disease  Dilated ascending aorta  Connective tissue: Marfan’s, Ehler’s Danlos  Pulmonary oedema

 Autoimmune: Ank spond, RA Echo

 Aortic valve structure and morphology (e.g. bicuspid) Symptoms  Evidence of infective endocarditis (e.g. vegetations)  LVF: Exertional dyspnoea, PND, orthopnoea  Severity  Arrhythmias (esp. AF) → palpitations . Jet width (>65% of outflow tract = severe) . Forceful heart beats . Regurgitant jet volume  Angina . Premature closing of the mitral valve  LV function: ejection fraction, end-systolic dimension Signs  Collapsing pulse (Corrigan’s pulse) Cardiac Catheterisation  Wide PP  Coronary artery disease  Apex: displaced (volume overload)  Assess severity, LV function, root size  Heart Sounds . Soft / absent S2 . ± S3 Mx  Murmur . EDM Medical . URSE + 3rd left IC parasternal  Optimise RFs: statins, anti-hypertensives, DM . Sitting forward in end-expiration  Monitor: regular f/up c echo . ± ejection systolic flow murmur ¯ . ± Austin-Flint murmur  ↓ systolic hypertension: ACEi, CCB  Underlying cause . ↓ afterload → ↓ regurgitation . High-arched palate . Spondyloarthropathy Surgery: aortic valve replacement . Embolic phenomena  Definitive therapy  Indicated in severe AR if: Eponyms . Symptoms of heart failure . Asympto ¯c LV dysfunction: ↓EF/↑ES dimension  Corrigan’s sign: carotid pulsation  De Musset’s: head nodding  Quincke’s: capillary pulsation in nail beds  Traube’s: pistol-shot sound over femorals  Austin-Flint murmur . Rumbling MDM @ apex due to regurgitant jet fluttering the ant. mitral valve cusp. . = severe AR  Duroziez’s . Systolic murmur over the femoral artery ¯c proximal compression. . Diastolic murmur ¯c distal compression

Clinical Indicators of Severe AR  Wide PP and collapsing pulse  S3  Long murmur  Austin Flint murmur  Decompensation: LVF

Causes Ix  Rheumatic fever  Prosthetic valve Bloods: FBC, U+E, LFTs, glucose, lipids  Congenital (rare) ECG  AF  P mitrale (if in sinus) Pathophysiology  RVH ¯c strain: ST depression and T wave inversion in V1-V2 Valve narrowing → ↑ left atrial pressure → loud S1  and atrial hypertrophy → AF CXR → pulmonary oedema and PHT → loud P2, PR   LA enlargement → RVH → left parasternal heave   Pulmonary oedema: ABCDE → TR → large v waves   Mitral valve calcification  → RHF → ↑JVP, oedema, ascites Echo + Doppler  Severe MS (AHA 2006 Criteria) Symptoms . Valve orifice <1cm2  Dyspnoea . Pressure gradient >10mmHg  Fatigue . Pulmonary artery systolic pressure >50mmHg  Chest pain  Use TOE to look for left atrial thrombus if intervention  AF → palpitations + emboli considered.  Haemoptysis: rupture of bronchial veins Cardiac Catheterisation  Assess coronary arteries Signs  Symptoms manifest when orifice <2cm2 (norm 4-6)  AF, low volume pulse Mx  Malar flush (↓CO → backpressure + vasoconstriction)  JVP may be raised late on Medical . Prominent a waves: PTH  Optimise RFs: statins, anti-hypertensives, DM . Large v waves: TR  Monitor: regular f/up ¯c echo . Absent a waves: AF  Consider prophylaxis vs. rheumatic fever: e.g. Pen V  Left parasternal heave (RVH 2O to PHT)  AF: rate control and anticoagulate  Apex: Tapping (palpable S1), non-displaced  Diuretics provide symptom relief  Heart sounds . Loud S1 Surgical . Loud P2 (if PHT)  Indicated in mod–severe MS (asympto and symptomatic) . Early diastolic opening snap  Percutaneous balloon valvuloplasty  Murmur . Rx of choice . Rumbling MDM . Suitability depends on valve characteristics . Apex  Pliable, minimally calcified . Left lateral position in end expiration . CI if left atrial mural thrombus . Radiates to the axilla  Surgical valvotomy / commissurotomy: valve repair . ± Graham Steell murmur (EDM 2O to PR)  Valve replacement if repair not possible

Clinical Indicators of Severe MS  Mitral facies  Longer murmur  Opening snap closer to 2nd heart sound . High LA pressure forcing valve open early  Decompensation: RVF

Complications  Pulmonary HTN  Emboli: TIA, CVA, PVD, ischaemic colitis  Hoarseness: rec laryngeal N. palsy = Ortner’s Syn  Dysphagia (oesophageal compression)  Bronchial obstruction

Causes Ix

Mitral valve prolapse  Bloods: FBC, U+E, glucose, lipids  LV dilatation: AR, AS, HTN  Annular calcification → contraction (elderly) ECG  Post-MI: papillary muscle dysfunction/rupture  AF  Rheumatic fever  P mitrale (unless in AF)  Connective tissue: Marfan’s, Ehlers-Danlos  LVH

Symptoms CXR  Dyspnoea, fatigue  LA and LV hypertrophy  AF → palpitations + emboli  Mitral valve calcification  Pulmonary congestion → HTN + oedema  Pulmonary oedema

Signs Echo  AF  Doppler echo to assess MR severity: multiple criteria  Left parasternal heave (RVH) . Jet width (vena contracta) >0.6cm  Apex: displaced . Systolic pulmonary flow reversal . Volume overload as ventricle has to pump . Regurgitant volume >60ml forward SV and regurgitant volume  TOE to assess severity and suitability of repair cf. . → eccentric hypertrophy replacement.  Heart Sounds . Soft S1 Cardiac Catheterisation . S2 not heard separately from murmur  Confirm Dx . Loud P2 (if PTH)  Assess CAD  Murmur . Blowing PSM Mx . Apex Medical . Left lateral position in end expiration  Optimise RFs: statins, anti-hypertensives, DM . Radiates to the axilla  Monitor: regular f/up ¯c echo  AF: rate control and anticoagulate Clinical Indicators of Severe MR . Also anticoagulate if: Hx of embolism, prosthetic  Larger LV valve, additional MS  Decompensation: LVF  Drugs to ↓ afterload can help ↓ symptoms  AF . ACEi or β-B (esp. carvedilol) . Diuretics Differential  AS Surgical  TR  Valve replacement or repair  VSD  Indications . Severe symptomatic MR . Severe asympto MR ¯c diastolic dysfunction: ↓EF

Mitral Valve Prolapse (Barlow Syndrome)  Commonest valve prob. (~5%)

Causes Complications  Primary: myxomatous degeneration  MR . Often young women  Cerebral emboli  MI  Arrhythmias → sudden death  Marfan’s, ED  Turner’s Mx  β-B may relieve palpitations and chest pain Symptoms  Surgery if severe (commonest reason for MV surgery)  Usually asymptomatic  Autonomic dysfunction: Atypical chest pain, palpitations, anxiety, panic attack  MR: SOB, fatigue

Signs  Mid-systolic click ± late-systolic murmur

Tricuspid Regurgitation Pulmonary Regurgitation

Causes Causes  Functional: RV dilatation  Any cause of pulmonary HTN O  Rheumatic fever  PR 2 to MS = Graham-Steell murmur  Infective endocarditis  Carcinoid syndrome Signs  Murmur: Decrescendo EDM @ ULSE Symptoms  Fatigue  Hepatic pain on exertion  Ascites, oedema Pulmonary Stenosis

Causes Signs  Usually congenital: e.g. Turner’s, Fallot’s  ↑JVP ¯c giant V waves  Rheumatic fever  RV heave  Carcinoid syndrome  Murmur: . PSM Symptoms . LLSE in inspiration (Carvallo’s sign)  Dyspnoea, fatigue  Pulsatile hepatomegaly  Ascites  Jaundice  Oedema

Ix Signs  LFTs  Dysmorphia  Echo  Large A wave  RV heave Mx  Ejection click, soft P2  Rx cause  Murmur  Medical: diuretics, ACEi, digoxin . ESM  Surgical: valve replacement . ULSE → L shoulder

Tricuspid Stenosis  ECG . P pulmonale Causes . RAD  Rheumatic fever (with MV and AV disease) . RBBB  CXR: Symptoms . Prominent pulmonary arteries: post-stenotic  Fatigue dilatation  Ascites  Catheterisation: diagnostic  Oedema  Mx: valvuloplasty or valvotomy

Signs  Large A waves  Opening snap  Murmur: . EDM . LLSE in inspiration

Mx  Medical: diuretics  Surgical: repair, replacement

Definition Ix  Cardiac valves develop vegetations composed of bacteria and platelet-fibrin thrombus. Bloods  N.chromic, N.cytic anaemia Risk Factors  ↑ESR, ↑CRP Cardiac disease → Subacute Normal valves → Acute  +ve IgG RF (immune phenomenon)  Prosthetic valves  Dental caries  Cultures x 3, >12h apart  Degen. valvulopathy  Post-op wounds  Serology for unusual organisms  VSD, PDA, CoA  IVDU (tricuspid valve)  Rheumatic fever  Immunocomp. (inc. DM) Urine: Micro haematuria

Aetiology ECG: AV block

Culture +ve Culture –ve Non-infective Echo  S. viridans (>35%)  Haemophilus  SLE  TTE detects vegetations > 2mm  S. bovis  Actinobacillus  Marantic  TOE is more sensitive (90-100% vs. 50-60%)  S. aureus  Cardiobacterium S. epidermidis   Eikenella  Enterococci  Kingella  Pseudomonas  Coxiella Rx  Chlamydia  Empiric . Acute severe: Fuclox + gent IV Clinical Features . Subacute: Benpen + gent IV

Sepsis Embolic phenomena  Streps: benpen + gent IV  Fever, rigors  Abscesses in brain, heart,  Enterococci: amoxicillin + gent IV  Night sweats kidney, spleen, gut and  Staphs: fluclox ± rifampicin IV  Wt. loss lung (if right-sided)  Fungi: flucytosine IV + fluconazole PO.  Anaemia  Janeway lesions . Amphotericin if flucytosine resistance or  Splenomegaly Immune complex deposition Aspergillus.  Clubbing  Micro haematuria due to Consider surgery if Cardiac GN  Heart failure  New/changing murmur  Vasculitis  Emboli (MR: 85%, AR: 55%)  Roth spots  Valve obstruction  AV block  Splinter haemorrhages  Prosthetic valve  LVF  Osler’s nodes

Roth spots: boat-shaped retinal haemorrhages ¯c pale centre Prophylaxis Janeway lesions: painless palmer macules  Abx prophylaxis solely to prevent IE not recommended Osler’s nodes: painful, purple papules on finger pulps

Dx: Duke Criteria Mortality  30% ¯c staphs Major  14% ¯c bowel flora 1. +ve blood culture  6% ¯c sensitive streps  Typical organism in 2 separate cultures, or  Persistently +ve cultures, e.g. 3, >12h apart 2. Endocardium involved  +ve echo (vegetation, abscess, valve dehiscence) or  New valvular regurgitation

Minor 1. Predisposition: cardiac lesion, IVDU 2. Fever >38 3. Emboli: septic infarcts, splinters, Janeway lesions 4. Immune phenomenon: GN, Osler nodes, Roth spots, RF 5. +ve blood culture not meeting major criteria

Dx if:  2 major  1 major + 3 minor  All 5 minor

Aetiology Ix  Group A β-haemolytic strep. (pyogenes) Bloods Epidemiology  Strep Ag test or ASOT  5-15yrs  FBC, ESR/CRP  Rare in West. Common in developing world. ECG  Only 2% of population susceptible Echo

Pathophysiology  Ab cross-reactivity following S. pyogenes infection → Rx T2 hypersensitivity reaction (molecular mimicry).  Bed rest until CRP normal for 2wks  Abs. vs. M protein in cell wall.  Benpen 0.6-1.2mg IM for 10 days  Cross react c myosin, muscle glycogen and SM cells.  Analgesia for carditis/arthritis: aspirin / NSAIDs ¯ rd  Path: Aschoff bodies and Anitschkow myocytes.  Add oral pred if: CCF, cardiomegaly, 3 degree block  Chorea: Haldol or diazepam Dx: revised Jones Criteria  Evidence of GAS infection plus: . 2 major criteria, or Prognosis . 1 major + 2 minor  Attacks last ~ 3mo.  60% ¯c carditis develop chronic rheumatic heart Evidence of GAS infection disease.  +ve throat culture  Recurrence ppted by  Rapid strep Ag test . Further strep infection  ↑ ASOT or DNase B titre . Pregnancy  Recent scarlet fever . OCP  Valve disease: regurgitation → stenosis Major Criteria . Mitral (70%)  Pancarditis . Aortic (40%)  Arthritis . Tricuspid (10%)  Subcutaneous nodules . Pulmonary (2%)

 Erythema marginatum  Sydenham’s chorea Secondary Prophylaxis Minor criteria  Prevent recurrence  Fever  Pen V 250mg/12h PO  ↑ESR or ↑CRP . Carditis + valve disease: until 40yrs old  Arthralgia (not if arthritis is major) . Carditis w/o valve disease:10yrs . No carditis: 5yrs  Prolonged PR interval (not if carditis is a major)  Prev rheumatic fever

Symptomatology

Pancarditis (60%)

 Pericarditis: chest pain, friction rub  Myocarditis: sinus tachy, AV block, HF, ↑CK, T

inversion  Endocarditis: murmurs . MR, AR, Carey Coombs’ (MDM)

Arthritis (75%)  Migratory polyarthritis of large joints (esp. knees)

Subcutaneous nodules (2-20%)  Small mobile, painless nodules on extensor surfaces (esp. elbows)

Erythema marginatum (2-10%)  Red, raised edges ¯c central clearing.  Trunk, thighs and arms.

Sydenham’s Chorea (10%)  Occurs late  Grimacing, clumsy, hypotonia (stops in sleep)

Acute Pericarditis Pericardial Effusion

Causes Causes  Any cause of pericarditis  Viral: coxsackie, flu, EBV, HIV

 Bacterial: pneumonia, rheumatic fever, TB, staphs Clinical Features Fungi   Dyspnoea MI, Dressler’s   ↑JVP (prominent x descent)  Drugs: penicillin, isoniazid, procainamide, hydralazine  Bronchial breathing @ left base  Other: uraemia, RA, SLE, sarcoid, radiotherapy . Ewart’s sign: large effusion compressing left lower lobe Clinical Features  Signs of cardiac tamponade may be present.  Central / retrosternal chest pain . Sharp Ix . Pleuritic  CXR: enlarged, globular heart . Worse lying down  ECG . Relieved by sitting forward . Low-voltage QRS complexes . Radiates to left shoulder . Alternating QRS amplitude (electrical alterans)  Pericardial friction rub.  Echo: echo-free zone around heart  Fever

 Signs of effusion / tamponade Mx

 Treat cause Ix  Pericardiocentesis may be diagnostic or therapeutic ECG: saddle-shaped ST-elevation ± PR depression  . Culture, ZN stain, cytology  Bloods: FBC, ESR, trop (may be ↑), cultures, virology

Mx  Analgesia: ibuprofen 400mg/8h PO  Rx cause  Consider steroids / immunosuppression

Constrictive Pericarditis  Heart encased in a rigid pericardium. Tamponade  Accumulation of pericardial fluid → ↑ intra-pericardial Causes pressure → poor ventricular filling → ↓ CO  Often unknown  May occur after any pericarditis Causes  Any cause of pericarditis Clinical features  Aortic dissection  RHF ¯c ↑JVP (prominent x and y descents)  Warfarin  Trauma  Kussmaul’s sign: ↑JVP ¯c inspiration

 Quiet heart sounds Signs  S3  Beck’s Triad: ↓ BP, ↑ JVP, quiet heart sounds  Hepatosplenomegaly  Pulsus paradoxus: pulse fades on inspiration  Ascites, oedema  Kussmaul’s sign

Ix Ix  CXR: small heart + pericardial calcification  ECG: low-voltage QRS ± electrical alternans  Echo  CXR: large, globular heart  Cardiac Catheterisation  Echo: diagnostic, echo-free zone around heart

Mx Mx  Surgical excision  Urgent pericardiocentesis . 20ml syringe + long 18G cannula . 45O, just left of xiphisternum, aiming for tip of left scapula. . Aspirate continuously and watch ECG.  Treat cause  Send fluid for cytology, ZN stain and culture

Acute Myocarditis Cardiac Myxoma  Rare, benign cardiac tumour Causes  F>M=2:1  Idiopathic (~50%)  May be familial: e.g. Carney Complex  Viral: coxsackie B, flu, HIV . Cardiac and cutaneous myxoma, skin  Bacterial: S. aureus, syphilis pigmentation, endocrinopathy (e.g. Cushing’s)  Drugs: cyclophosphamide, Herceptin, CBZ, phenytoin  90% in left atrium (fossa ovalis)  Autoimmune: Giant cell myocarditis assoc. ¯c SLE  Features: . Clubbing, fever, ↓wt., ↑ESR Symptoms . Signs similar to MS (MDM, systemic emboli, AF)  Flu-like prodrome: fever, sore throat, myalgia but vary ¯c posture.  Dyspnoea, fatigue  Dx: Echo  Chest pain (may coexist ¯c Bornholm disease)  Rx: Excision  Arrhythmia → palpitations Restrictive Cardiomyopathy Signs  Soft S1 Causes: miSSHAPEN  S4 gallop  Sarcoid  Systemic sclerosis Ix  Haemochromatosis  ECG  Amyloidosis . ST-elevation or depression  Primary: endomyocardial fibrosis . T wave inversion  Eosinophilia (Loffler’s eosinophilic endocarditis) . Transient AV block  Neoplasia: carcinoid (→ TR and PS)  Bloods: +ve trop, ↑CK Clinical Features: as constrictive pericarditis Mx  Supportive Dx: Catheterisation  Rx cause Rx: Rx cause

Hypertrophic Obstructive Cardiomyopathy  LVOT obstruction from asymmetric septal hypertrophy Dilated Cardiomyopathy  AD inheritance (but 50% sporadic)  β-myosin heavy chain mutation commonest Causes: DILATE  Ask re family Hx of sudden death  Dystophy: muscular, myotonic, glycogen storage disease  Infection: complication of myocarditis Symptoms  Late pregnancy: peri-, post-partum  Angina  Autoimmune: SLE  Dyspnoea  Toxins: EtOH, doxorubicin, cyclophosphamide, DXT  Palpitations: AF, WPW, VT  Endocrine: thyrotoxicosis  Exertional syncope or sudden death Presentation Signs  LVF and RVF  Jerky pulse  Arrhythmias  Double apex beat  Harsh ESM @ LLSE ¯c systolic thrill Signs  S4  JVP ↑↑  Displaced apex Ix  S3 gallop  ECG  ↓BP . LVH/LAD/L strain,  MR/TR . Ventricular ectopics, VT, VF  Echo: ASH Ix  Exercise test ± holter monitor to quantify risk  CXR: cardiomegaly, pulmonary oedema  ECG: T inversion, poor progression Mx  Echo: globally dilated, hypokinetic heart + ↓EF  Medical st nd  Catheter + biopsy: myocardial fibre disarray . -ve inotropes: 1 – β-B, 2 –verapamil . Amiodarone: arrhythmias Mx . Anticoagulate if AF or emboli  Bed rest  Non-medical  Medical: diuretics, ACEi, digoxin, anticoagulation . Septal myomectomy (surgical or chemical) if  Non-medical: biventricular pacing, ICD severe symptoms  Surgical: heart Tx  Consider ICD © Alasdair Scott, 2012 32 Congenital Heart Disease

Bicuspid Aortic Valve Ventricular Septal Defect  No problems @ birth  Hole connects ventricles  Most eventually develop stenosis ± regurgitation . Pre-disposes to IE/SBE Causes  Congenital  Acquired: post-MI Atrial Septal Defect  Hole connects the atria Presentation  Secundum defects high in the septum are commonest  Severe HF in infancy or incidental discovery in later life  Often asympto until adulthood . LV compliance ↓ ¯c age → ↑ L→R shunt Signs  Small holes which are haemodynamically less significant Symptoms → louder murmurs  Dyspnoea . Harsh, pansystolic murmur @ left sternal edge  Pulmonary HTN . Systolic thrill . Left parasternal heave  Arrhythmia  Larger holes → PHT  Chest pain

Complications Signs  Infective endocarditis  AF  PHT  ↑ JVP  Eisenmenger’s  Pulmonary ESM

 PHT → TR or PR ECG

 Small: normal Complications  Large: LVH + RVH  Paradoxical emboli

 Eisenmenger’s syndrome CXR . ↑ RA pressure: R→L shunt → cyanosis  Small: mild pulmonary plethora

Ix  Large: cardiomegaly + marked pulmonary plethora

 ECG: Rx . Secundum: RAD  Surgical closure indicated if symptomatic VSD c large  CXR: pulmonary plethora ¯ shunt.  Echo: diagnostic

Rx  Transcatheter closure Fallot’s Tetralogy  Recommended in adults if high pulmonary to systemic  Commonest congenital cyanotic heart defect blood flow ratio (≥1.5:1)  Abnormal separation of truncus arteriosus into aorta and pulmonary arteries.

Coarctation of the Aorta Pathology  Congenital narrowing of the aorta 1. VSD  Usually occurs just distal to origin of left subclavian 2. Pulmonary stenosis  M>F 3. RVH 4. Overriding aorta Associations Associations  Bicuspid aortic valve  Di George: CATCH-22  Turner’s syndrome

Presentation Signs  Infants: hypercyanotic episodes, squatting, clubbing  Radio-femoral delay + weak femoral pulse  Adult  Hypertension . Often asympto  Systolic murmur / bruit heard best over left scapula . Unoperated: cyanosis, ESM of PS

. Repaired: dyspnoea, palpitations, RVF Complications

 Heart failure ECG: RVH + RBBB  IE CXR: Coeur en sabot Echo: anatomy + degree of stenosis Ix  CXR: rib notching Rx: Surgical (usually before 1yr)  ECG: LV strain  Closure of VSD  CT angiogram  Correction of the pulmonary stenosis

Rx: balloon dilatation + stenting © Alasdair Scott, 2012 33 Inherited Connective Tissue Disorders

Marfan’s Syndrome Ehlers-Danlos Syndrome

Epidemiology Pathogenesis  Autosomal dominant  Rare heterogeneous group of collagen disorders.  Spontaneous mutation in 25%  6 subtypes ¯c varying severity  M=F  Commonest types (1 and 2) are autosomal dominant  Prevalence = 1/5000 Presentation Pathophysiology  Hyperelastic skin  Mutation in FBN1 gene on Chr 5  Hypermobile joints . Encodes fibrillin-1 glycoprotein  Cardiac: MVP, AR, MR and aneurysms  Fibrillin-1 is an essential component of elastin  Fragile blood vessels → easy bruising, GI bleeds  Histology: “cystic medial necrosis”  Poor healing

Presentation Differential Diagnosis  Cardiac  Cutis Laxa: loose skin + hypermobile joints . Aortic aneurysm and dissection  Pseudoxanthoma elasticum: skin laxity . Aortic root dilatation → regurgitation  Marfan’s . MV prolapse ± regurgitation  Ocular . Lens dislocation: superotemporal  MSK . High-arched palate . Arachnodactyly . Arm-span > height . Pectus excavatum . Scoliosis . Pes planus . Joint hypermobility

Complications  Ruptured aortic aneurysm  Spontaneous pneumothorax  Diaphragmatic hernia  Hernias

Dx  Two 2/3 organ systems must be involved

Differential Diagnosis  MEN-2b  Homocystinuria  Ehlers-Danlos

Ix  Slit-lamp examination: ectopia lentis  CXR . Widened mediastinum . Scoliosis . Pneumothorax  ECG . Arrhythmias: premature atrial and ventricular ectopics  Echo . Aortic root dilatation → AR . MVP and MR  MRI: dural ectasia (dilation of neural canal)  Genetic testing: FBN-1 mutation

Mx  Refer to ortho, cardio and ophtho  Life-style alteration: ↓ cardiointensive sports  Beta-blockers slow dilatation of the aortic root  Regular cardiac echo . Surgery when aortic root ≥5cm wide

Contents Clubbing ...... 36 Cyanosis ...... 36 Pneumonia ...... 37 Complications of Pneumonia ...... 38 Systemic Inflammatory Response Syndrome ...... 38 Specific Pneumonias ...... 39 Bronchiectasis ...... 40 Cystic Fibrosis ...... 41 Pulmonary Aspergillus Infections ...... 42 Lung Cancer: Presentation ...... 43 Lung Cancer: Investigation and Management ...... 44 ARDS ...... 45 Respiratory Failure ...... 46 Oxygen Therapy ...... 46 Chronic Asthma ...... 47 Acute Severe Asthma ...... 48 COPD ...... 49 Acute Exacerbation of COPD ...... 50 Pulmonary Embolism ...... 51 Pneumothorax ...... 52 Pleural Effusion ...... 53 Sarcoidosis ...... 54 Interstitial Lung Disease ...... 55 Extrinsic Allergic Alveolitis ...... 56 Industrial Lung Disease ...... 56 Idiopathic Pulmonary Fibrosis (CFA) ...... 56 Pulmonary Hypertension ...... 57 Cor Pulmonale ...... 57 Obstructive Sleep Apnoea ...... 58 Smoking Cessation ...... 58

Features and Stages Definition 1. Bogginess / ↑ fluctuance of nail bed  Blue discoloration of mucosal membranes or skin 2. Loss of concave nail fold angle  Deoxygenated Hb >5g/dl 3. ↑ longitudinal and transverse curvature 4. Soft tissue expansion at distal phalanx (drumstick) Classification  Peripheral: cold, blue nails Causes  Central: blue tongue, lips

Respiratory Causes  Carcinoma  Think of O2 cascade . Bronchial . Mesothelioma Respiratory Chronic lung suppuration   Hypoventilation: COPD, MSK . Empyema, abscess  ↓ diffusion: pulm oedema, fibrosing alveolitis . Bronchiectasis, CF  V/Q mismatch: PE, AVM (e.g. HHT)  Fibrosis

. Idiopathic pulmonary fibrosis / CFA Cardiac . TB  Congenital: Fallot’s, TGA

Cardiac  ↓ CO: MS, systolic LVF  Infective Endocarditis  Vascular: Raynaud’s, DVT

 Congenital cyanotic heart disease RBCs  Atrial myxoma  Low affinity Hb, may be hereditary or acquired

GIT  Cirrhosis  Crohn’s, uC  Coeliac  Cancer: GI lymphoma

Other  Familial  Thyroid Acropachy  Upper limb AVMs or aneurysms . Unilateral clubbing

Epidemiology Ix  Incidence: 1/100  Bloods: FBC, U+E, LFT, CRP, culture, ABG (if ↓SpO2)  Mortality: 10% in hospital, 30% in ITU  Urine: Ag tests (Pneumococcal, Legionella)  Sputum: MC&S Anatomic Classification  Imaging: CXR . infiltrates, cavities, effusion Bronchopneumonia  Special  Patchy consolidation of different lobes . Paired sera Abs for atypicals  Mycoplasma, Chlamydia, Legionella Lobar Pneumonia . Immunofluorescence (PCP)  Fibrosuppurative consolidation of a single lobe . BAL  Congestion → red → grey → resolution . Pleural tap

Severity: CURB-65 (only if x-ray changes)  Confusion (AMT ≤ 8) Score  Urea >7mM  0-1 → home Rx  Resp. rate >30/min  2 → hospital Rx  BP <90/60  ≥3 → consider ITU  ≥65

Mx  Abx  O2: PaO2≥8, SpO2 94-98% Aetiological Classification  Fluids  Analgesia Community Acquired Pneumonia  Chest physio  Pneumococcus, mycoplasma, haemophilus  Consider ITU if shock, hypercapnoea, hypoxia  S. aureus, Moraxella, Chlamydia, Legionella  F/up @ 6wks ¯c CXR  Viruses: 15% . Check for underlying Ca

Hospital Acquired Pneumonia Empirical Abx  >48hrs after hospital admission  Gm-ve enterobacteria, S. aureus CAP

Aspiration Mild amoxicillin 500mg TDS PO for 5d or  ↑ Risk: stroke, bulbar palsy, ↓GCS, GORD, achalasia clarithro 500mg BD PO for 7d  Anaerobes Mod amoxicillin 500mg TDS and clarithro 500mg BD PO/IV Immunocompromised (clarithro alone if pen allergy) for 7d  The usual suspects, plus  PCP, TB, fungi, CMV/HSV Sev Co-amoxiclav 1.2g TDS IV / cefuroxime 1.5g TDS IV and clarithro 500mg BD IV for 7-10d Add fluclox if staph suspected.

Symptoms Atyp Chlamydia: tetracycline  Fever, rigors PCP: Co-trimoxazole  Malaise, anorexia Legionella: Clarithro + rifampicin  Dyspnoea  Cough, purulent sputum, haemoptysis HAP  Pleuritic pain  Mild / <5d: Co-amoxiclav 625mg PO TDS for 7d  Severe / >5d: Tazocin ± vanc ± gent for 7d

Signs Aspiration  Co-amoxiclav 625mg PO TDS for 7d ↑RR, ↑ HR   Cyanosis Pneumovax (23 valent)  Confusion  ≥65yrs  Consolidation . ↓ expansion  Chronic HLKP failure or conditions . Dull percussion  DM . Bronchial breathing  Immunosuppression: hyposplenism, chemo, HIV . ↓ air entry  CI: P, B, fever . Crackles . Pleural rub NB. revaccinate every 6yrs . ↑VR © Alasdair Scott, 2012 37 Complications of Pneumonia Systemic Inflammatory Response Syndrome Respiratory failure  Type 1: PaO2 <8kPa + PaCO2 <6kPa Inflammatory response to a variety of insults  Type 2: PaO2 <8kPa + PaCO2 >6kPa manifest by ≥2 of:  Mx: O2 therapy, ventilation  Temperature: >38°C or <36°C Hypotension  Heart rate: >90  Respiratory rate: >20 or PaCO2 <4.6 KPa  Cause: dehydration + septic vasodilatation 9 9  WCC: >12x10 /L or <4 x10 /L or >10% bands  Mx

. If SBP<90 → 250ml fluid challenge over 15min . If no improvement: central line + IV fluids . If refractory: ITU for inotropes Sepsis  SIRS caused by infection AF  Usually resolves ¯c Rx  Mx: Digoxin or β-B for rate control Severe Sepsis  Sepsis ¯c at least 1 organ dysfunction or hypoperfusion Pleural effusion  Exudate  Mx: tap and send for MC+S, cytology and chemistry Septic Shock  Severe sepsis with refractory hypotension Empyema  Pus in the pleural cavity  Anaerobes, Staph, Gm-ve MODS  Assoc. ¯c recurrent aspiration  Impairment of ≥2 organ systems  Pt. ¯c resolving pneumonia develops recurrent fever  Homeostasis cannot be maintained without therapeutic  Tap: turbid, pH<7.2, ↓glucose, ↑LDH intervention.  Mx: US guided chest drain + Abx

Lung Abscess

Causes  Aspiration  Bronchial obstruction: tumour, foreign body  Septic emboli: sepsis, IVDU, RH endocarditis  Pulmonary infarction  Subphrenic / hepatic abscess

Features  Swinging fever  Cough, foul purulent sputum, haemoptysis  Malaise, wt. loss  Pleuritic pain  Clubbing  Empyema

Tests  Blood: FBC, ESR, CRP, cultures  Sputum: micro, culture, cytology  CXR: cavity ¯c fluid level  Consider CT and bronchoscopy

Mx  Abx according to sensitivities  Aspiration  Surgical excision

Other Complications  Sepsis  Pericarditis / myocarditis  Jaundice . Usually cholestatic . Causes: sepsis, drugs (fluclox, Augmentin), Mycoplasma, Legionella

Organism Risk Factors Pulmonary Features Extrapulmonary Mx Pneumococcus Elderly Lobar consolidation Herpes labialis Amoxicillin EtOH Benpen Immunosuppressed Cephalosporins CHF Pulmonary disease S. aureus Influenza infection Bilateral cavitating Fluclox IVDU bronchopneumonia Vanc Co-morbidities Klebsiella Rare Cavitating pneumonia Cefotaxime Elderly Esp. upper lobes EtOH DM Pseudomonas Bronchiectasis Taz CF Mycoplasma Epidemics Dry cough Flu-like prodrome Dx: serology - headache Reticulo-nodular shadowing or - myalgia/arthralgia Clarithro patchy consolidation Cipro Cold agglutinins → AIHA Cryoglobulin Erythema multiforme SJS GBS Hepatitis Legionella Travel Dry cough Flu-like prodrome Lymphopenia Air conditioning Dyspnoea ↓Na+ Anorexia Deranged LFTs Bi-basal consolidation D&V Hepatitis Dx: Urinary Ag or Renal Failure serology Confusion SIADH → ↓Na Clarithro ± rifa Chlam. Pharyngitis, otitis  pneumonia Sinus pain Dx: serology pneumoniae Clarithro Chlam. psittaci Parrots Dry cough Horder’s spots ~ rose spots Dx: serology Patchy consolidation Splenomegaly Epistaxis Clarithro Hepatitis, nephritis Meningo-encephalitis PCP Immunocompromised Dry cough Dx: visualisation Exertional dyspnoea from BAL, Bilateral creps sputum, biopsy

CXR: normal or bilateral perihilar High dose co- interstitial shadowing trimoxazole or pentamidine

Prophylaxis if CD4<200 or after 1st attack

Pathophysiology Complications  Chronic infection of bronchi/bronchioles → permanent  Pneumonia dilatation.  Pleural effusion  Retained inflammatory secretions and microbes →  Pneumothorax airway damage and recurrent infection  Pulmonary HTN  Organisms:  Massive haemoptysis . H. influenza  Cerebral abscess . Pneumococcus  Amyloidosis . S. aureus . Pseudomonas

Ix Causes  Sputum MCS  Blood: Se Ig, Aspergillus precipitins, RF, α1-AT level  Idiopathic in 50% . Test Ig response to pneumococcal vaccine

 CXR: thickened bronchial walls (tramlines and rings) Congenital  Spirometry: obstructive pattern  CF (mainly upper lobe infiltration)  HRCT chest  Kartagener’s / PCD . Dilated and thickened airways  Young’s syn. (azoopermia + bronchiectasis) . Saccular dilatations in clusters c pools of mucus ¯ Post-infectious  Bronchoscopy + mucosal biopsy  Measles . Focal obstruction . PCD  Pertussis  CF sweat test (pilocarpine iontopheresis)  Pneumonia

 TB

 Bronchiolitis Rx Immunodeficiency  Chest physio: expectoration, drainage, pulm. rehab  Hypogammaglobulinaemia  Abx for exacerbations: e.g. cipro for 7-10d . X-linked agammaglobulinaemia: Bruton’s  Bronchodilators: nebulised β agonists . CVID  Treat underlying cause . IgG subclass deficiency . CF: DNAase . IgA deficiency . ABPA: Steroids . Immune deficiency: IVIg Other  Surgery may be indicated in severe localised disease  Bronchial obstruction: LNs, tumour, foreign body  ABPA  RA  UC  Yellow nail syndrome . Yellow nail discoloration and dystrophy . Lymphoedema . Pleural effusions . Bronchiectasis

Symptoms  Persistent cough ¯c purulent sputum  Haemoptysis (may be massive)  Fever, wt. loss

Signs  Clubbing  Coarse inspiratory creps  Wheeze  Purulent sputum  Cause . Situs inversus (+ PCD = Kartagener’s syn.) . Splenomegaly: immune deficiency

Pathogenesis Ix  Auto recessive, 1:2000 live Caucasian births  Bloods: FBC, LFTs, clotting, ADEK levels, glucose TT  Mutation in CFTR gene on Chr 7 (commonly ∆F508)  Sputum MCS  → ↓ luminal Cl secretion and ↑ Na reabsorption →  CXR: bronchiectasis viscous secretions.  Abdo US: fatty liver, cirrhosis, pancreatitis  In sweat glands, ↓ Cl and Na reabsorption → salty sweat  Spirometry: obstructive defect  Aspergillus serology / skin test (20% develop ABPA)

Clinical Features Mx Neonate  FTT General  Meconium ileus  MDT: physician, GP, physio, dietician, specialist nurse  Rectal prolapse Chest Children / Young Adults  Physio: postural drainage, forced expiratory techniques  Nose: nasal polyps, sinusitis  Abx: acute infections and prophylaxis  Resp: cough, wheeze, infections, bronchiectasis,  Mucloytics: DNAse haemoptysis, pneumothorax, cor pulmonale  Bronchodilators  GI:  Vaccinate . Pancreatic insufficiency: DM, steatorrhoea . Distal Intestinal Obstruction Syndrome GI . Gallstones  Pancreatic enzyme replacement: pancreatin (Creon) . Cirrhosis (2O biliary)  ADEK supplements  Other: male infertility, osteoporosis, vasculitis  Insulin

 Ursodeoxycholic acid for impaired hepatic function Signs . Stimulates bile secretion Clubbing ± HPOA   Cyanosis Advanced Lung Disease  Bilateral coarse creps  O2  Diuretics (Cor pulmonale)  NIV Common Respiratory Organisms  Heart/lung transplantation  Early . S. aureus Other . H. influenza  Rx of complications: e.g. DM  Late  Fertility and genetic counselling . P. aeruginosa: 85%  DEXA osteoporosis screen . B. cepacia: 4%

Dx  Sweat test: Na and Cl > 60mM  Genetic screening for common mutations  Faecal elastase (tests pancreatic exocrine function)  Immunoreactive trypsinogen (neonatal screening)

Diseases 1. Asthma: T1HS reaction to spores 2. ABPA 3. Aspergilloma (mycetoma) 4. Invasive aspergillosis 5. Extrinsic allergic alveolitis

Allergic Bronchopulmonary Aspergillosis Invasive Aspergillosis  T1 and T3 HS reaction to Aspergillus fumigatus  Aflatoxins → liver cirrhosis and HCC (especially A.  Bronchoconstriction → bronchiectasis flavus)

Symptoms Risk factors  Wheeze  Immunocompromise: HIV, leukaemia, Wegener’s  Productive cough  Post-broad spectrum Abx  Dyspnoea Ix Ix  CXR: consolidation, abscess  CXR: bronchiectasis  Sputum MCS  Aspergillus in sputum (black on silver stain)  BAL  Aspergillus skin test or IgE RAST  +ve se precipitins  +ve se precipitins  Serial galactomannan  ↑ IgE and ↑ eosinophils Rx Rx  Voriconazole (better cf amphotericin)  Pred 40mg/d + itraconazole for acute attacks  Pred maintenance 5-10mg/d Prog  Bronchodilators for asthma  30% mortality

Aspergilloma (mycetoma) Extrinsic Allergic Alveolitis  Fungus ball within a pre-existing cavity  Sensitivity to Aspergillus clavatus → Malt worker’s lung . e.g. TB or sarcoid

Features  Usually asympto  Can → haemoptysis (may be severe)  Lethargy, ↓wt.

Ix  CXR: round opacity w/i a cavity, usually apical  Sputum culture  +ve se precipitins  Aspergillus skin test / RAST

Rx  Consider excision for solitary lesions / severe haemoptysis

Type Epidemiology Pathology Behaviour SCC 35% Centrally located Locally invasive M>F Histo: Evidence of squamous differentiation Metastasise late (via LN) Smoking - Keratinisation PTHrP → ↑ Ca2+ Radon gas Adeno 25% Peripherally located Extrathoracic mets common and early. Females, Histo: Glandular differentiation - 80% present with mets Non-smokers - Gland formation Far East - Mucin production Large-cell 10% Peripheral or central Poor prognosis Histo: Large, poorly differentiated cells Small-cell 20% Central location, near bronchi 80% present ¯c advanced disease Smoking Histo: Small, poorly differentiated cells V. chemosensitive but v. poor prog Ectopic hormone secretion

Other Lung Tumours: all rare Complications  Adenoma: 90% are carcinoid tumours  Hamartoma Local  Mesothelioma  Recurrent laryngeal N. palsy  Phrenic N. palsy  SVC obstruction Epidemiology  Horner’s (Pancoast’s tumour)  AF  19% of all cancers

 27% of cancer deaths (commonest) Paraneoplastic

 Endo . ADH → SIADH ( euvolaemic ↓Na+) Symptoms . ACTH → Cushing’s syndrome  Cough and haemoptysis . Serotonin → carcinoid (flushing, diarrhoea)  Dyspnoea . PTHrP → 1O HPT (↑Ca2+, bone pain) – SCC  Chest pain  Rheum  Recurrent or slow resolving pneumonia . Dermatomyositis / polymyositis  Anorexia and ↓wt.  Neuro  Hoarseness . Purkinje Cells (CDR2) → cerebellar degeneration . Peripheral neuropathy  Derm Signs . Acanthosis nigricans (hyperpigmented body folds) . Trousseau syndrome: thrombophlebitis migrans

Chest Metastatic  Consolidation  Pathological #  Collapse  Hepatic failure  Pleural effusion  Confusion, fits, focal neuro

 Addison’s General

 Cachexia

 Anaemia  Clubbing and HPOA (painful wrist swelling)  Supraclavicular and/or axillary LNs

Metastasis  Bone tenderness  Hepatomegaly  Confusion, fits, focal neuro  Addison’s

Ix Mx  MDT: pulmonologist, oncologist, radiologist, Bloods: FBC, U+E, Ca2+, LFTs histopathologist, cardiothoracic surgeon, specialist Cytology: sputum, pleural fluid nurses, palliative care, GP  Assess risk of operative mortality: e.g. Thoracoscore Imaging . Cardiorespiratory function  CXR . Co-morbidities . Coin lesion  Advise smoking cessation . Hilar enlargement . Consolidation, collapse NSCLC . Effusion  Surgical Resection . Bony secondaries . Rx of choice for peripheral lesions ¯c no metastatic  Contrast-enhanced Volumetric CT spread = stage I/II (~25%) . Staging: lower neck, chest, upper abdomen . Need good cardiorespiratory function . Consider CT brain . Wedge resection, lobectomy or pneumonectomy  PET-CT: exclude distant mets . ± adjuvant chemo  Radionucleotide bone scan  Curative radiotherapy . If cardiorespiratory reserve is poor Biopsy  Chemo ± radio for more advanced disease  Percutaneous FNA: peripheral lesions and LNs . Platinum-based regimens  Bronchoscopy: biopsy and assess operability . MAbs targeting EGFR (e.g. cetuximab) or TKI  Endoscopic bronchial US biopsy: mediastinal LNS (e.g. erlotinib)  Mediastinoscopy SCLC Lung Function Tests  Typically disseminated @ presentation  Assess treatment fitness  May respond to chemo but invariably relapse

CXR Coin Lesion Differential Palliation  Foreign body  Radio: bronchial obstruction, haemoptysis, bone or CNS  Abscess: Staph, TB, Klebsiella, Mycetoma mets  Neoplasia (1O or 2O)  SVC obstruction: stenting + radio + dexamethasone  Granuloma: RA, Wegener’s, TB, Sarcoid  Endobronchial therapy: stenting, brachytherapy  Structural: AVM  Pleural drainage / pleurodesis  Analgesia

TNM Staging for NSCLC Prognosis Tx Malignant cells in bronchial secretions  NSCLC: 50% 5ys w/o spread; 10% ¯c spread Tis CIS  SCLC: 1-1.5yrs median survival treated; 3mo untreated T0 None evident T1 ≤3cm, in lobar or more distal airway T2 >3cm and >2cm from carina or pleural involvement T3 <2cm from carina or involves chest wall, diaphragm T4 Involves mediastinum or malignant effusion is present

N0 None involved N1 Peribronchial or ipsilateral hilum N2 Ipsilateral mediastinum N3 Contralateral hilum or mediastinum or supraclavicular

Pathogenesis Causes  May result from direct pulmonary insult or be 2O to severe systemic illness. Pulmonary  Inflam mediators → ↑ capillary permeability and non-  Pneumonia cardiogenic pulmonary oedema.  Aspiration  Inhalation injury  Contusion Clinical Features  Tachypnoea Systemic  Cyanosis  Shock  Bilateral fine creps  Sepsis  SIRS  Trauma  Haemorrhage and multiple transfusions  Pancrea0titis Ix  Acute liver failure  Bloods: FBC, U+E, LFTs, clotting, amylase, CRP,  DIC cultures, ABG.  Obs: eclampsia, amniotic embolism  CXR: bilateral perihilar infiltrates  Drugs: aspirin, heroin

Dx Differential Dx of Pulmonary Oedema  Acute onset  CXR shows bilateral infiltrates Tranusdates  No evidence of congestive cardiac failure  ↑ capillary hydrostatic pressure . CCF  PaO :FiO <200 2 2 . Iatrogenic fluid overload

. Renal failure . Relative ↑ in negative pressure pulmonary Mx oedema  Admit to ITU for organ support and Rx underlying cause  ↓ capillary oncotic pressure . Liver failure Ventilation . Nephrotic syndrome  Indications . Malnutrition, malabsorption, protein-losing . PaO2<8KPa despite 60% FiO2 enteropathy . PaCO2>6KPa  ↑ interstitial pressure  Method . ↓lymphatic drainage: e.g. Ca . 6ml/kg + PEEP (e.g. 10cm H2O)  SEs Exudates . VILI  ARDS . VAP . Weaning difficulty

Circulation  Invasive BP monitoring  Maintain CO and DO2 ¯c inotropes . E.g. norad or dobutamine  RF may require haemofiltration

Sepsis  Abx

Other  Nutritional support: enteral (best), TPN

Prognosis  50-75% mortality

Type 1 Clinical Features  PaO2 <8KPa and PaCO2 <6KPa  V/Q mismatch and diffusion failure Hypoxia  Acute . Dyspnoea Type 2 . Agitation . Confusion  PaO2 <8KPa and PaCO2 >6KPa  Alveolar hypoventilation ± V/Q mismatch . Cyanosis  Chronic . Polycythaemia . PHT Causes . cor pulmonale

V/Q Mismatch (↑A-a gradient) Hypercapnoea  Vascular  Headache . PE  Flushing and peripheral vasodilatation . PHT  Bounding pulse . Pulmonary Shunt (R → L)  Flap  Asthma (early)  Confusion → coma  Pneumothorax  Atelectasis Mx: Rx underlying cause

Alveolar Hypoventilation Type 1  Obstructive  Give O to maintain SpO 94-98% . COPD 2 2 . Asthma  Assisted ventilation if PaO2<8KPa despite 60% O2 . Bronchiectasis . Bronchiolitis Type 2 . Intra- and Extra-thoracic (Ca, LN, epiglottitis…)  Controlled O2 therapy @ 24% O2 aiming for SpO2 88-92%  Restrictive and a PaO2 >8kPa . ↓ drive: CNS sedation, trauma, tumour  Check ABG after 20min . NM disease: cervical cord lesion, polio, GBS, . If PaCO2 steady or lower can ↑ FiO2 if necessary MG . If PaCO2 ↑>1.5KPa and pt. still hypoxic, consider . Chest: flail, kyphoscoliosis, obesity NIV or respiratory stimulant (e.g. doxapram) . Fluid and fibrosis

Diffusion Failure (↑A-a gradient) Oxygen Therapy  Fluid . Pulmonary oedema Principles . Pneumonia  Critically ill pts. should receive high conc O2 immediately. . Infarction  O2 should be prescribed to achieve target SpO2 . Blood . 94-98% for most patients  Fibrosis . 88-92% for those at risk or hypercapnic resp failure  In pts. at risk of hypercapnic resp failure: NB. Both fluid and fibrosis also → V/Q mismatch and . Start O2 therapy at 24% and do an ABG alveolar hypoventilation due to ↓ compliance – Blue Venturi @ 2-4L/min . Clinically: ↓ RR ¯c O2 may be useful sign . If PCO2 ≤6kPa: ↑ target SpO2 to 94-98% A-a Gradient . If PCO2 >6kPa: maintain target SpO2  PAO2= (95 x FiO2) – (PaCO2/0.8)  ↑ (PAO2-PaO2) suggests lung pathology Mechanisms Nasal Prongs: 1-4L/min = 24-40% O2

Simple Face Mask

Non-rebreathing Mask  Reservoir bag allows delivery of high concentrations of O2.  60-90% at 10-15L

Venturi Mask  Provide precise O2 concentration at high flow rates . Yellow: 5% . White: 8% . Blue: 24% . Red: 40% . Green: 60% © Alasdair Scott, 2012 46 Chronic Asthma

Definition Differential  Episodic, reversible airway obstruction due to  Pulmonary oedema (cardiac asthma) bronchial hyper-reactivity to a variety of stimuli.  COPD

Epidemiology Ix  Incidence 5-8% (↑ in children vs. adults)  Peaks at 5yrs, most outgrow by adolescence Bloods  FBC (eosinophila) Pathophysiology  ↑IgE  Aspergillus serology Acute (30min)

 Mast cell-Ag interaction → histamine release CXR: hyperinflation  Bronchoconstriction, mucus plugs, mucosal swelling Spirometry Chronic (12h)  Obstructive pattern ¯c FEV1:FVC < 0.75  T2 cells release IL-3,4,5 → mast cell, eosinophil and H  ≥15% improvement in FEV1 c β-agonist B cell recruitment ¯  Airway remodelling PEFR monitoring / diary

 Diurnal variation >20% Causes  Morning dipping

Atopy Atopy: skin-prick, RAST  T1 hypersensitivity to variety of antigens  Dust mites, pollen, food, animals, fungus Mx Stress  Cold air General Measures: TAME  Viral URTI  Technique for inhaler use  Exercise  Avoidance: allergens, smoke (ing), dust  Emotion  Monitor: Peak flow diary (2-4x/d)  Educate Toxins . Liaise ¯c specialist nurse  Smoking, pollution, factory . Need for Rx compliance  Drugs: NSAIDS, β-B . Emergency action plan

Symptoms Drug Ladder  Cough ± sputum (often at night)  Wheeze 1 SABA PRN  Dyspnoea  If use >1/d or nocte symptoms → step 2  Diurnal variation ¯c morning dipping 2 Low-dose inhaled steroid: beclometasone 100-400ug bd Hx 3 LABA: salmeterol 50ug bd  Precipitants  Good response: continue  Diurnal variation  Benefit but control still poor: ↑ steroid to 400ug bd  Exercise tolerance  No benefit: discontinue + ↑ steroid to 400ug bd  Life effects: sleep, work  Other atopy: hay fever, eczema If control is still poor consider trial of:  Home and job environment  Leukotriene receptor antagonist (e.g. monetelukast) . Esp. if exercise- / NSAID-induced asthma Signs  SR Theophylline  Tachypnoea, tachycardia  Widespread polyphonic wheeze 4 Trials of  Hyperinflated chest  ↑ inhaled steroid to up to 1000ug bd  ↓ air entry  Leukotriene receptor antagonist  Signs of steroid use  SR Theophylline  MR β agonist PO

Associated Disease 5 Oral steroids: e.g. prednisolone 5-10mg od  GORD  Use lowest dose necessary for symptom control  Churg-Strauss  Maintain high-dose inhaled steroid  ABPA  Refer to asthma clinic

Presentation Mx  Acute breathlessness and wheeze

O2, Nebs and Steroids Hx 1. Sit-up  Precipitant: infection, travel, exercise? 2. 100% O2 via non-rebreathe mask (aim for 94-98%)  Usual and recent Rx? 3. Nebulised salbutamol (5mg) and ipratropium (0.5mg)  Previous attacks and severity: ICU? 4. Hydrocortisone 100mg IV or pred 50mg PO (or both)  Best PEFR? 5. Write “no sedation” on drug chart

Ix  PEFR If Life Threatening  ABG  Inform ITU . PaO2 usually normal or slightly ↓  MgSO4 2g IVI over 20min . PaCO2 ↓  Nebulised salbutamol every 15min (monitor ECG) . If PaCO2 ↑: send to ITU for ventilation  FBC, U+E, CRP, blood cultures

If Improving Assessment  Monitor: SpO @ 92-94%, PEFR 2  Continue pred 50mg OD for 5 days Severe: any one of  Nebulised salbutamol every 4hrs  PEFR <50%  RR >25  HR >110  Can’t complete sentence in one breath IV Rx if No Improvement in 15-30min:

 Nebulised salbutamol every 15min (monitor ECG) Life Threatening: any one of  Continue ipratropium 0.5mg 4-6hrly  PEFR <33%  MgSO 2g IVI over 20min  SpO <92%, PCO >4.6kPa, PaO <8kPa 4 2 2 2  Salbutamol IVI 3-20ug/min  Cyanosis  Consider aminophylline  Hypotension . Load: 5mg/kg IVI over 20min  Exhaustion, confusion  Unless already on theophylline  Silent chest, poor respiratory effort . Continue: 0.5mg/kg/hr  Tachy-/brady-/arrhythmias . Monitor levels  ITU transfer for invasive ventilation Differential  Pneumothorax  Acute exacerbation of COPD  Pulmonary oedema Monitoring  PEFR every 15-30min Admission Criteria . Pre- and post-β agonist  SpO : keep >92%  Life-threatening attack 2  ABG if initial PaCO normal or ↑  Feature of severe attack persisting despite initial Rx 2  May discharge if PEFR > 75% 1h after initial Rx

Discharge When  Been stable on discharge meds for 24h  PEFR > 75% ¯c diurnal variability < 20%

Discharge Plan  TAME pt.  PO steroids for 5d  GP appointment w/i 1 wk.  Resp clinic appointment w/i 1mo

Definition Ix  Airway obstruction: FEV1 <80%, FEV1:FVC <0.70  BMI  Chronic bronchitis: cough and sputum production on  Bloods: FBC (polycythaemia), α1-AT level, ABG most days for 3mo of 2 successive years.  CXR  Emphysema: histological diagnosis of enlarged air . Hyperinflation (> 6 ribs anteriorly) spaces distal to terminal bronchioles ¯c destruction of . Prominent pulmonary arteries alveolar walls. . Peripheral oligaemia . Bullae Epidemiology  ECG: . R atrial hypertrophy: P pulmonale  Prevalence: 10-20% of >40s . RVH, RAD

 Spirometry: FEV1 <80%, FEV1:FVC <0.70, ↑TLC, ↑RV Causes  Echo: PHT  Smoking  Pollution  α1ATD Chronic Rx

Assess Severity Symptoms  Mild: FEV1 >80% (but FEV/FVC <0.7 and symptomatic)  Cough + sputum  Mod: FEV1 50-79%  Dyspnoea  Severe: FEV1 30-49%  Wheeze  Very Severe: FEV1 < 30%  Wt. loss General Measures Signs  Stop smoking  Tachypnoea . Specialist nurse  Prolonged expiratory phase . Nicotine replacement therapy  Hyperinflation . Bupropion, varenicline (partial nicotinic agonist) . ↓Cricosternal distance (normal = 3 fingers) . Support programme . Loss of cardiac dullness  Pulmonary rehabilitation / exercise . Displaced liver edge  Rx poor nutrition and obesity  Wheeze  Screen and Mx comorbidities  May have early-inspiratory crackles . e.g. cardiovasc, lung Ca, osteoporosis  Cyanosis  Influenza and pneumococcal vaccine  Cor pulmonale: ↑JVP, oedema, loud P2  Review 1-2x/yr  Signs of steroid use  Air travel risky if FEV1<50%

Pink Puffers in emPhysema Mucolytics  ↑ alveolar ventilation → breathless but not cyanosed  Consider if chronic productive cough  Normal or near normal PaO2  E.g. Carbocisteine (CI in PUD)

 Normal or low PaCO2  Progress → T1 respiratory failure Breathlessness and/or exercise limitation  SABA and/or SAMA (ipratropium) PRN Blue Bloaters in chronic Bronchitis  SABA PRN may continue at all stages  ↓ alveolar ventilation → cyanosed but not breathless Exacerbations or persistent breathlessness  ↓PaO2 and ↑ PaCO2: rely on hypoxic drive  Progress → T2 respiratory failure and cor pulmonale  FEV1 ≥50%: LABA or LAMA (tiotropium) (stop SAMA)  FEV1 <50%: LABA+ICS combo or LAMA

Persistent exacerbations or breathlessness mMRC Dyspnoea Score  LABA+LAMA+ICS 1. Dyspnoea only on vigorous exertion  Roflumilast / theophylline (PDIs) may be considered 2. SOB on hurrying or walking up stairs  Consider home nebs 3. Walks slowly or has to stop for breath

4. Stops for breath after <100m / few min LTOT 5. Too breathless to leave house or SOB on dressing  Aim: PaO2 ≥8 for ≥15h / day (↑ survival by 50%)  Clinically stable non-smokers ¯c PaO2 <7.3 (stable on Complications two occasions >3wks apart)  PaO 7.3 – 8 + PHT / cor pulmonale / polycythaemia /  Acute exacerbations ± infection 2 nocturnal hypoxaemia  Polycythaemia  Terminally ill pts.  Pneumothorax (ruptured bullae)

 Cor Pulmonale Surgery  Lung carcinoma  Recurrent pneumothoraces  Isolated bullous disease  Lung volume reduction © Alasdair Scott, 2012 49 Acute Exacerbation of COPD

Causes Management  Viral URTI (30%)  Also bacterial infections Controlled O2 Therapy  Sit-up Presentation  24% O2 via Venturi mask: SpO2 88-92%, Cough + sputum   Vary FiO2 and SpO2 target according to ABG Breathlessness   Aim for PaO2 >8 and ↑ in PCO2 of <1.5kPa  Wheeze

Hx  Smoking status Nebulised Bronchodilators  Exercise capacity  Air driven ¯c nasal specs  Current treatment  Salbutamol 5mg/4h  Previous exacerbations  Ipratropium 0.5mg/6h

Ix  PEFR  Bloods: FBC, U+E, ABG, CRP, cultures Steroids (IV and PO)  Sputum culture  Hydrocortisone 200mg IV  CXR: infection, pneumothorax  Prednisolone 40mg PO for 7-14d  ECG

Differential Abx  Pneumothorax  If evidence of infection  Pulmonary oedema  Doxy 200mg PO STAT then 100mg OD PO for 5d  PE  Asthma

NIV if no response: Discharge  Repeat nebs and consider aminophylline IV  Spirometry  Consider NIV (BiPAP) if pH<7.35 and/or RR >30  Establish optimal maintenance therapy  Consider invasive ventilation if pH<7.26  GP and specialist f/up . Depends on pre-morbid state: exercise capacity,  Prevention using home oral steroids and Abx home O2, comorbidity  Pneumococcal and Flu vaccine  Home assessment

Causes Management  Usually arise from DVTs in proximal leg or iliac veins  Rarely: O . Right ventricle post MI 2  Sit-up . Septic emboli in right sided endocarditis  100% O2 via non-rebreather mask Risk Factors: SPASMODICAL  Sex: F  Pregnancy Analgesia  Age: ↑  Morphine ± metoclopramide if distressed  Surgery (classically 10d post-op straining at stool)  Malignancy  Oestrogen: OCP/HRT If critically ill c¯ massive PE consider thrombolysis  DVT/PE previous Hx Alteplase 50mg bolus stat  Immobility   Colossal size  (Surgical or interventional embolectomy)  Antiphospholipid Abs  Lupus Anti-coagulant LMWH Heparin Presentation e.g. enoxaparin 1.5mg/kg/24h SC  Symptoms and signs depend on size, number and distribution of emboli

Symptoms SBP?  Dyspnoea  Pleuritic pain  Haemoptysis <90 >90  Syncope  500ml colloid  Start Warfarin

 Confirm Dx Signs  Fever  Cyanosis  Tachycardia, tachypnoea Inotropes if BP still ↓  RHF: hypotension, ↑JVP, loud P2  Dobutamine: aim for SBP >90  Evidence of cause: DVT  Consider addition of NORAD  Consider thrombolysis (medical or surgical) Ix  Bloods: FBC, U+E, clotting, D-dimers  ABG: normal or ↓PaO2 and ↓PaCO2, ↑pH On-going Mx  CXR: normal or oligaemia, linear atelectasis  ECG: sinus tachycardia, RBBB, right ventricular strain  TEDS stockings in hospital (inverted T in V1-V4)  Graduated compression stockings for 2yrs if DVT: . S1, Q3, T3 is rare prevent post-phlebitic syndrome (10-30%)  Doppler US: thigh and pelvis (+ve in 60%)  Continue LMWH until INR >2 (at least 5d)  CTPA + venous phase of legs and pelvis  Target INR = 2-3 . 85-95% sensitivity  Duration  V/Q scan no longer used . Remedial cause: 3mo . No identifiable cause: 6mo Dx . On-going cause: indefinite 1. Assess probability using Wells’ Score  VC filter if repeat DVT/PE despite anticoagulation 2. Low-probability → perform D-dimers . Negative → excludes PE . Positive → CTPA 3. High probability → CTPA

NB. –ve D-dimer has 95% NPV for PE

Prevention  Risk assessment for all pts  TEDS  Prophylactic LMWH  Avoid OCP/HRT if @ risk

Definition Mx  Accumulation of air in the pleural space ¯c 2O lung collapse. Tension PTX

 Resuscitate pt. Classification  No CXR  Closed: intact chest wall and air leaks from lung into  Large bore Venflon into 2nd ICS, mid-clavicular line pleural cavity.  Insert ICD  Open: defect in the chest wall allows communication between PTX and exterior: may be sucking.  Tension: air enters pleural cavity through one-way valve Traumatic and cannot escape → mediastinal compression.  Resuscitate pt.  Analgesia: e.g. morphine Causes  3-sided wet dressing if sucking Spontaneous  Insert ICD  1O: no underlying lung disease . Young, thin men (ruptured subpleural bulla) . Smokers O O 1 PTX  2 : underlying lung disease . COPD SOB and/or rim ≥2cm? No Consider d/c . Marfan’s, Ehler’s Danlos Yes . Pulmonary fibrosis, sarcoidosis Yes

Trauma Aspiration successful?  Penetrating  Blunt ± rib #s No

Iatrogenic Insert ICD  Subclavian CVP line insertion  Positive pressure ventilation O  Transbronchial biospy 2 PTX  Liver biopsy SOB and > 50yrs and Yes Insert ICD rim ≥2cm? Presentation No No Symptoms  Sudden onset Aspiration successful?  Dyspnoea  Pleuritic chest pain Yes  Tension: respiratory distress, cardiac arrest Admit for 24h Signs  Chest . ↓ expansion . Resonant percussion . ↓ breath sounds . ↓VR  Tension: ↑JVP, mediastinal shift, ↑HR, ↓BP  Crepitus: surgical emphysema

Ix  ABG  US  CXR (expiratory film may be helpful) . Translucency + collapse (2cm rim = 50% vol loss) . Mediastinal shift (away from PTX) . Surgical emphysema . Cause: rib #s, pulmonary disease (e.g. bullae)

Classification Ix  Effusion protein < 25g/L = transudate  Blood: FBC, U+E, LFT, TFT, Ca, ESR  Effusion protein >35g/L = exudate  CXR  Between 25-35g/L: apply Light’s Criteria . Blunt costophrenic angles . Dense shadow ¯c meniscus Light’s Criteria . Mediastinal shift away  An exudate has one of: . Cause: coin lesion, cardiomegaly . Effusion : serum protein ratio >0.5  US: facilitates tapping . Effusion : serum LDH ratio >0.6  Volumetric CT . Effusion LDH is 0.6 x ULN Diagnostic Tap  Percuss upper boarder and go 1-2 spaces below Causes  Infiltrate down to pleura ¯c lignocaine.  Aspirate ¯c 21G needle Exudates: ↑ capillary permeability  Send for  Infection: pneumonia, TB . Chemistry: protein, LDH, pH, glucose, amylase  Neoplasm: bronchial, lymphoma, mesothelioma . Bacteriology: MCS, auramine stain, TB culture  Inflammation: RA, SLE . Cytology  Infarction . Immunology: SF, ANA, complement

Empyema, Ca, TB, RA and SLE Transudates: ↑ capillary hydrostatic or ↓ oncotic pressure  ↑ protein  CCF  ↓ glucose <3.3mM  Renal failure  ↓ pH <7.2  ↓ albumin: nephrosis, liver failure, enteropathy  ↑ LDH > 0.6 x serum / ULN  Hypothyroidism  Meig’s Syndrome Oesophageal Rupture . Right pleural effusion  ↓ pH <7.2 . Ascites  ↑ amylase (also ↑ in pancreatitis) . Ovarian fibroma Pleural Biopsy  If pleural fluid is inconclusive Presentation  CT-guided ¯c Abrams needle

Symptoms  Asymptomatic Mx  Dyspnoea  Rx underlying cause  Pleuritic chest pain  May use drainage if symptomatic (≤2L/24h)

. Repeated aspiration or ICD Signs  Chemical pleurodesis if recurrent malignant effusion  Chest  Persistent effusions may require surgery . Tracheal deviation away from effusion

. ↓ expansion

. Stony dull percussion . ↓ air entry . Bronchial breathing just above effusion . ↓VR  Associated disease . Ca: cachexia, clubbing, HPOA, LNs, radiation burn, radiation tattoo . Chronic liver disease . Cardiac failure . RA, SLE . Hypothyroidism

Definition Ix  Multisystem granulomatous disorder of unknown cause Bloods Epidemiology  ↑ESR  Age: 20-40yrs  ↑Ca  Sex: F>M  Lymphopenia  Geo: Afro Caribbean  ↑ se ACE  HLA-DRB1 and DQB1 alleles  ↑ Ig  ↑LFTs Clinical Features: GRAULOMAS CXR, CT, MRI  In 20-40% the disease presents incidentally on CXR  Acute sarcoidosis: EN, fever, polyarthralgia, BHL Tuberculin skin test  Negative in 2/3 General  Fever Lung function tests  Anorexia and ↓ wt.  Restrictive pattern ¯c ↓FVC Fatigue   ↓ transfer factor  Lymphadenopathy and HSM Tissue Biopsy Respiratory  Lung, LNs, skin nodules, liver Upper: otitis, sinusitis   Diagnostic: non-caseating granulomas  Lower (seen in 90%) . Dry cough, SOB, chest pain, ↓ lung function Ophthalmology assessment . Stage 1: BHL . Stage 2: BHL + peripheral infiltrates . Stage 3: Peripheral infiltrates alone Rx . Stage 4: Progressive mid-zone fibrosis ¯c bullae  Pts. c asymptomatic BHL do not require Rx. ¯ Arthralgia  Acute sarcoidosis  Polyarthralgia . Usually resolves spontaneously . Bed rest and NSAIDs  Dactylitis  Chronic sarcoidosis Neurological . Steroids: pred 40mg/d for 4-6wks . Additional immunosuppression: methotrexate,  Peripheral and cranial polyneuropathy (esp. Bell’s palsy) ciclosporin, cyclophosphamide  Meningitis, transverse myelitis, SOL

Urine

 ↑Ca → Renal stones, nephrocalcinosis, DI Prognosis Low Hormones  60% ¯c thoracic sarcoidosis resolve over 2yrs  Pituitary dysfunction: e.g. amenorrhoea  20% respond to steroids  20% no improvement despite Rx Ophthalmological  Uveitis  Keratoconjunctivitis BHL Differential  Sicca / Mikulicz / Sjogrens syndrome  Sarcoidosis  Infection: TB, mycoplasma Myocardial  Malignancy: lymphoma, carcinoma  Restrictive cardiomyopathy 2O to granulomas + fibrosis  Interstitial disease: EAA, silicosis  Pericardial effusion

Abdominal Granulomatous Disease Differential  Hepatomegaly + cholestatic LFTs  Infections: TB, leprosy, syphilis, crypto, schisto  Splenomegaly  AI: PBC  Vasculitis: GCA, PAN, Wegener’s, Takayasu’s Skin  Idiopathic: Crohns, Sarcoid  EN: painful erythematous nodules on shins (paniculitis)  Interstitial lung: EAA, silicosis  Lupus pernio: raised, dusky purple plaque on nose, cheek, fingers

Principal Features Cause by Location  Dyspnoea  Dry cough Upper Zone: A PENT  Abnormal CXR / CT  Aspergillosis : ABPA  Restrictive Spirometry  Pneumoconiosis: Coal, Silica  Extrinsic allergic alveolitis  Negative, sero-arthropathy Causes  TB

Known Cause Lower Zone: STAIR  Environmental: asbestosis, silicosis  Sarcoidosis (mid zone)  Drugs: BANS ME  Toxins: BANS ME . Bleomycin, Busulfan  Asbestosis . Amiodarone  Idiopathic pulmonary fibrosis . Nitrofurantoin  Rheum: RA, SLE, Scleroderma, Sjogren’s, PM/DM . Sulfasalazine . MEthotrexate, MEthysergide  Hypersensitivity: EAA  Infection: TB, viral, fungi

Assoc. c¯ systemic disease  Sarcoidosis  RA  SLE, systemic sclerosis, Sjogren’s, MCTD  UC, ankylosing spondylitis

Idiopathic  Idiopathic pulmonary fibrosis (CFA)

© Alasdair Scott, 2012 55 Extrinsic Allergic Alveolitis Idiopathic Pulmonary Fibrosis (CFA)  Acute allergen exposure in sensitised pts. → T3HS  Chronic exposure → granuloma formation and Epidemiology obliterative bronchiolitis (T4HS)  Commonest cause of interstitial lung disease  Middle age Causes  M>F = 2:1  Bird fancier’s lung: proteins in bird droppings  Assoc. ¯c other AI disease in 30%  Farmer’s / mushroom worker’s  Malt worker’s lung: Aspergillus clavatus Presentation

Clinical Features Symptoms  Dry cough 4-6h post-exposure  Dyspnoea  Fever, rigors, malaise  Malaise, wt. loss  Dry cough, dyspnoea  Arthralgia  Crackles (no wheeze)  OSA

Chronic Signs  Increasing dyspnoea  Cyanosis  Wt. loss  Clubbing  T1 respiratory failure  Crackles: fine, end-inspiratory  Cor pulmonale Complications Ix  ↑ risk Ca lung  Bloods  Type 2 respiratory failure and cor pulmonale . Acute: neutrophilia, ↑ESR . +ve se precipitins Ix  CXR . Upper zone reticulonodular opacification or Bloods fibrosis → honeycomb lung  ↑CRP . BHL (rare)  ↑Ig  Spirometry  ANA+ (30%) . Restrictive defect  RF+ (10%) . ↓ transfer factor during acute attacks  ABG: ↓PaO2, ↑PaCO2  BAL . ↑ lymphocytes and mast cells CXR  ↓ lung volume Mx  Bilat lower zone retic-nod shadowing  Avoid exposure  Honeycomb lung  Steroids: acute / long-term  Compensation may be payable HRCT  Shows similar changes to CXR  More sensitive

Industrial Lung Disease Spiro  Restrictive defect

 ↓ transfer factor Coal-workers Pneumoconiosis  CWP → Progressive Massive Fibrosis Other  Presents as progressive dyspnoea and chronic  Lung biopsy: Usual interstitial pneumonia bronchitis  BAL: may indicate disease activity  CXR: upper zone fibrotic masses . ↑ lymphocytes: good prognosis . ↑ PMN or eosinophils: bad prognosis Silicosis  DTPA scan: may reflect disease activity  Quarrying, sand-blasting  Upper zone reticular shadowing and egg shell Mx calcification of hilar nodes → PMF  Supportive care . Stop smoking Asbestosis . Pulmonary rehabilitation  Demolition and ship building . O2 therapy  Basal fibrosis, pleural plaques . Palliation  ↑ risk of mesothelioma . Rx symptoms of heart failure . Chest pain, wt. loss, clubbing, recurrent effusions,  Lung Tx offers only cure dyspnoea. . CXR: pleural effusions, thickening Prognosis . Dx by histology of pleural biopsy  50% 5yr survival . <2yr survival © Alasdair Scott, 2012 56 Pulmonary Hypertension Cor Pulmonale

Definition Definition  PA pressure >25mmHg  RHF due to chronic PHT

Causes Symptoms  Dyspnoea Left Heart Disease  Fatigue  Mitral stenosis  Syncope  Mitral regurgitation  Left ventricular failure  L → R shunt Signs 1. ↑ JVP ¯c prominent a wave Lung Parenchymal Disease 2. Left parasternal heave  Mechanism 3. Loud P2 ± S3 . Chronic hypoxia → hypoxic vasoconstriction 4. Murmurs . Perivascular parenchymal changes  PR: Graham Steell EDM  COPD  TR: PSM  Asthma: severe, chronic 5. Pulsatile hepatomegaly  Interstitial lung disease 6. Fluid: Ascites + Peripheral oedema  CF, bronchiectasis

Pulmonary Vascular Disease Ix  Idiopathic pulmonary hypertension  Bloods: FBC, U+E, LFTs, ESR, ANA, RF  Pulmonary vasculitis: scleroderma, SLE, Wegener’s  ABG: hypoxia ± hypercapnoea  Sickle cell  CXR  Pulmonary embolism: acute or chronic . Enlarged R atrium and ventricle  Portal HTN: portopulmonary HTN . Prominent pulmonary arteries . Peripheral oligaemia Hypoventilation  ECG: P pulmonale + RVH  OSA  Echo: RVH, TR, ↑ PA pressure  Morbid obesity (Pickwickian syn.)  Spirometry  Thoracic cage abnormality: kyphosis, scoliosis  Right heart catheterisation  Neuromuscular: MND, MG, polio

Mx Ix  Rx underlying condition  ECG  ↓ pulmonary vascular resistance . P pulmonale . LTOT . RVH . CCB: e.g. nifedipine . RAD . Sildenafil (PDE-5 inhibitor)  Echo . Prostacycline analogues . Velocity of tricuspid regurgitation jet . Bosentan (endothelin receptor antagonist) . Right atrial or ventricular enlargement  Cardiac failure . Ventricular dysfunction . ACEi + β-B (caution if asthma) . Valve disease . Diuretics  Right heart catheterisation: gold standard  Heart-Lung Tx . Mean pulmonary artery pressure . Pulmonary vascular resistance . CO Prognosis . Vasoreactivity testing to guide Rx  50% 5ys

Definition Very Brief Advice  Intermittent closure/collapse of pharyngeal airway →  Ask: enquire as to smoking status apnoeic episodes during sleep.  Advise: best way to stop is with support and medication  Act: provide details of where to get help . E.g. NHS stop smoking helpline Risk Factors  Obesity  Male Facilitating Quitting  Smoker  Refer to specialist stop smoking service  EtOH  Nicotine replacement  Idiopathic pulmonary fibrosis . Gum  Structural airway pathology: e.g. micrognathia . Patches  NM disease: e.g. MND  Varenicline: selective partial nicotine receptor agonist . Recommended by NICE . 23% abstinence @ 1yr vs. 10% for placebo

. Start while still smoking Ix  Bupropion: also an option  SpO2  Polysomnography is diagnostic

Rx  Wt. loss  Avoid smoking and EtOH  CPAP during sleep

Clinical Features

Nocturnal  Snoring  Choking, gasping, apnoeic episodes

Daytime  Morning headache  Somnolence  ↓ memory and attention  Irritability, depression

Complications  Pulmonary hypertension  Type 2 respiratory failure  Cor pulmonale

Mx  ↓ wt.  Stop smoking  CPAP @ night via a nasal mask  Surgery to relieve pharyngeal obstruction . Tonsillectomy . Uvulopalatpharyngoplasty

Contents DM: Classification, Dx and Causes ...... 60 DM: Conservative Mx ...... 60 DM: Oral Hypoglycaemics ...... 61 Insulin ...... 61 Diabetic Complications ...... 62 Macrovascular ...... 62 Diabetic Feet ...... 62 Diabetic Ketoacidosis ...... 63 Hyperosmolar Non-Ketotic Coma ...... 64 Hypoglycaemia ...... 65 Thyrotoxicosis ...... 66 Hypothyroidism ...... 67 Hyperparathyroidism ...... 70 Hypoparathyroidism...... 70 Cushing’s Syndrome ...... 71 Hyperaldosteronism...... 72 Adrenal Insufficiency ...... 73 Phaeochromocytoma ...... 74 Multiple Endocrine Neoplasia ...... 74 Autoimmune Polyendocrine Syndromes ...... 74 Hypopituitarism ...... 75 Pituitary Tumours ...... 75 Hyperprolactinaemia ...... 76 Acromegaly ...... 76 Diabetes Insipidus ...... 77 Sexual Characteristics ...... 77

Definition MDT  Multisystem disorder due to an absolute or relative lack of  GP, endocrinologist, surgeons, specialist nurses, endogenous insulin → metabolic and vascular dieticians, chiropodists, fellow patients (education complications. groups).

Monitoring: 4Cs Classification Control, glycaemic T1DM  Record of complications: DKA, HONK, hypos  Path: autoimmune destruction of β-cells → absolute  Capillary blood glucose insulin deficiency. . Fasting: 4.5-6.5mM  Age: usually starts before puberty . 2h post-prandial: 4.5-9mM  Presentation: polyuria, polydipsia, ↓wt., DKA  HbA1c  Genetics: concordance only 30% in MZs . Reflects exposure over last 6-8wks  Assoc.: HLA-D3 and –D4, other AI disease . Aim <45 - 50mM (7.5 - 8%)  Abs: anti-islet, anti-GAD  BP, lipids

T2DM Complications  Path: insulin resistance and β-cell dysfunction → relative  Macro insulin deficiency . Pulses  Age: usually older patients . BP  Presentation: polyuria, polydipsia, complications . Cardiac auscultation  Genetics: concordance 80% in MZs  Micro  Assoc.: obesity, ↓exercise, calorie and EtOH excess . Fundoscopy . ACR + U+Es . Sensory testing plus foot inspection Dx Competency  Symptomatic: Polyuria, polydipsia, ↓wt., lethargy  With insulin injections . ↑ plasma venous glucose detected once  Checking injection sites  Fasting ≥7mM  BM monitoring  Random ≥11.1mM

 Asymptomatic Coping . ↑ venous glucose on 2 separate occasions  Psychosocial: e.g. ED, depression . Or, 2h OGTT ≥ 11.1mM Occupation   Domestic Glucose Testing  OGTT only needed if borderline fasting or random Lifestyle Modification: DELAYS

glucose measurements. Diet Normal IFG IGT Diabetes  Same as that considered healthy for everyone Fasting <6.1 6.1 – 6.9 ≥7.0  ↓ total calorie intake 75g OGTT <7.8 7.8 – 11 ≥11.1  ↓ refined CHO, ↑ complex CHO  ↑ soluble fibre  ↓ fat (especially saturated) Secondary Causes of DM  ↓ Na  Avoid binge drinking  Drugs: steroids, anti-HIV, atypical neuroletics, thiazides

 Pancreatic: CF, chronic pancreatitis, HH, pancreatic Ca Exercise Endo: Phaeo, Cushings, Acromegaly, T4   Other: glycogen storage diseases Lipids

 Rx of hyperlipidaemia O  1 prevention ¯c statins if >40yrs (regardless of lipids) Metabolic Syndrome  Central obesity (↑ waist circumference) and two of: ABP . ↑ Triglycerides  ↓ Na intake and EtOH . ↓ HDL  Keep BP <130/80 . HTN  ACEis best (β-B: mask hypos, thiazides: ↑ glucose) . Hyperglycaemia: DM, IGT, IFG

Aspirin  1O prevention if >50yrs or <50 ¯c other CVD RFs

Yearly / 6 monthly check-up: 4Cs

Smoking cessation © Alasdair Scott, 2012 60 DM: Oral Hypoglycaemics Insulin

1. Lifestyle Modification: DELAYS Principles  Ensure pt. education about 2. Start Metformin . Self-adjustment ¯c exercise and calories (if HBA1c >target after lifestyle changes) . Titrate dose  SE: nausea, diarrhoea, abdo pain, lactic acidosis . Family member can abort hypo ¯c sugary drinks  CI: GFR<30, tissue hypoxia (sepsis, MI), morning or GlucoGel before GA and iodinated contrast media  Pre-prandial BM don’t tell you who much glucose is  500mg after evening meal, ↑ing to 2g max. needed  Fasting BM before meal informs re long-acting insulin dose. 3. Metformin + Sulfonylurea  Finger-prick BM after meal informs re short-acting (if HBA1c >target) insulin dose (for that last meal)

 E.g. gliclazide MR 30mg ¯c breakfast

 SE: hypoglycaemia, wt. gain  CI: omit on morning of surgery Common Regimes

Other Options BD Biphasic Regime  Consider adding a rapid-acting insulin  BD insulin mixture 30min before breakfast and dinner secretagogue (e.g. nateglinide) to metformin . Rapid-acting: e.g. actrapid instead of a sulfonylurea. . Intermediate- / long-acting: e.g. insulatard . May be preferable if erratic lifestyle.  T2 or T1 DM ¯c regular lifestyle: children, older pts.  Consider adding pioglitazone to metformin instead  Assoc, ¯c fasting hyperglycaemia of a sulfonylurea Basal-Bolus Regime  Bedtime long-acting (e.g. glargine) + short acting 4. Additional Therapy before each meal (e.g. lispro) . Adjust dose according to meal size . ~50% of insulin given as long-acting 1st line  T1DM allowing flexible lifestyle  Add insulin → insulin + metformin + sulfonylurea  Best outcome

2nd line OD Long-Acting Before Bed  Add sitagliptin or pioglitazone if insulin  Initial regime when switching from tablets in T2DM unacceptable . Employment, social or recreational issues . Obesity Illness  metformin + sulfonylurea + sitagliptin / pio  Insulin requirements usually ↑ (even if food intake ↓)  Maintain calories (e.g. milk) rd 3 line  Check BMs ≥4hrly and test for ketonuria  Add exenatide (SC) if insulin unacceptable or BMI>35  ↑ insulin dose if glucose rising  metformin + sulfonylurea + exenatide

th 4 line Side-Effects  Consider acarbose if unable to use other glucose- lowering drugs  Hypoglycaemia . At risk: EtOH binge, β-B (mask symptoms), elderly . Need to admit sulfonylurea-induced hypo  Lipohypertrophy . Rotate injection site: abdomen, thighs  Wt. gain in T2DM . ↓ wt. gain if insulin given ¯c metformin

Summary Retinopathy, Maculopathy and Cataracts  Hyperglycaemia: DKA, HONK  Hypoglycaemia Pathogenesis  Infection  Microvascular disease → retinal ischaemia → ↑VEGF  Macrovascular: MI, CVA  ↑ VEGF → new vessel formation  Microvascular Presentation Macrovascular  Retinopathy and maculopathy  Cataracts  MI: May be “silent” due to autonomic neuropathy  Rubeosis iris: new vessels on iris → glaucoma  PVD: claudication, foot ulcers  CN palsies  CVA Diabetic Retinopathy and Maculopathy Rx: Manage CV risk factors  Commonest cause of blindness up to 60yrs  BP (aim <130/80)  Refer if pre-proliferative retinopathy / maculopathy  Smoking  Ix: fluorescein angiography  Lipids  Rx: laser photocoagulation  HBA1c Background Retinopathy Prevention . Dots: microaneurysms  Good glycaemic control (e.g. HbA1c <6%) prevents . Blot haemorrhages both macro- and micro-vascular complications. . Hard exudates: yellow lipid patches  Proved by DCCT, EDIC and UKPDS trials Pre-proliferative Retinopathy  Regular screening: fundoscopy, ACR, foot check . Cotton-wool spots (retinal infarcts) . Venous beading Diabetic Feet . Haemorrhages Proliferative Retinopathy

. New vessels Ischaemia . Pre-retinal or vitreous haemorrhage  Critical toes Maculopathy  Absent pulses (do ABPI) . ↓ acuity may be only sign  Ulcers: painful, punched-out, foot margins, pressure . Hard exudates w/i one disc width of macula points

Neuropathy Neuropathy  Loss of protective sensation  Deformity: Charcot’s joints, pes cavus, claw toes Pathophysiology  Injury or infection over pressure points  Metabolic: glycosylation, ROS, sorbitol accumulation  Ulcers: painless, punched-out, metatarsal heads,  Ischaemia: loss of vasa nervorum calcaneum Symmetric sensory polyneuropathy st  Glove and stocking: length-dependent ( feet 1 ) Mx . Loss of all modalities  Conservative  Absent ankle jerks . Daily foot inspection (e.g. ¯c mirror)  Numbness, tingling, pain (worse @ night) . Comfortable / therapeutic shoes  Rx . Regular chiropody (remove callus) . Paracetamol  Medical . Amitriptyline, Gabapentin, SSRI . Rx infection: benpen + fluclox ± metronidazole . Capsaicin cream  Surgical . Baclofen . Abscess or deep infection . Spreading cellulitis Mononeuropathy / Mononeuritis Multiplex . Gangrene  E.g. CN3/6 palsies . Suppurative arthritis Femoral Neuropathy / Amyotrophy  Painful asymmetric weakness and wasting of quads ¯c Nephropathy loss of knee jerks

 Dx: nerve conduction and electromyography Pathophysiology

 Hyperglycaemia → nephron loss and Autonomic Neuropathy glomerulosclerosis  Postural hypotension – Rx: fludrocortisone

 Gastroparesis → early satiety, GORD, bloating Features  Diarrhoea: Rx c codeine phosphate  Microalbuminuria: urine albumin:Cr (ACR) ≥30mg/mM ¯  If present → ACEi / ARA  Urinary retention  Refer if UCR >70  ED

Pathogenesis Management Ketogenesis  ↓ insulin → ↑ stress hormones and ↑ glucagon Fluids  → ↓ glucose utilisation + ↑ fat β-oxidation  0.9% NS infusion via large bore cannula  ↑ fatty acids → ↑ ATP + generation of ketone bodies. . SBP<90 → 1L stat + more until SBP >90 . SBP>90 → 1L over 1h Dehydration  Then: 1L over next 2h, 1L/2h, 1L/4h, 1L/4h, 1L/6h  ↓ insulin → ↓ glucose utilisation + ↑ gluconeogenesis →  Switch to 10% dex 1L/8h when glucose <14mM severe hyperglycaemia  → osmotic diuresis → dehydration Start Potassium Replacement in 2nd Bag of Fluids  Also, ↑ ketones → vomiting  >5.5mM → Nil  3.5-5.5mM → 40mmol/L Acidosis  <3.5mM → consult senior for review  Dehydration → renal perfusion  Hyperkalaemia

Insulin Infusion Precipitants  Actrapid 0.1u/kg/h IVI (6u if no wt., max 15u)  Infection / stress ± stopping insulin  New T1DM

Presentation Assessment  Abdo pain + vomiting  Hx + full examination  Gradual drowsiness  Investigations: capillary, urine, blood, imaging  Sighing “Kussmaul” hyperventilation  Dehydration  Ketotic breath Additional Measures  Urinary catheter (aim: 0.5ml/kg/hr) Dx  NGT if vomiting or ↓GCS  Acidosis (↑AG): pH <7.3 (± HCO3 <15mM)  Thromboprophylaxis ¯c LMWH  Hyperglycaemia: ≥11.1mM (or known DM)  Refer to Specialist Diabetes Team  Ketonaemia: ≥3mM (≥2+ on dipstix)  Find and treat precipitating factors

Ix  Urine: ketones and glucose, MCS Monitoring  Cap glucose and ketones  Hrly capillary glucose and ketones  VBG: acidosis + ↑K  VBG @ 60min, 2h and then 2hrly  Bloods: U+E, FBC, glucose, cultures  Plasma electrolytes 4hrly  CXR: evidence of infection Aims Subtleties  ↓ ketones by ≥0.5mM/h or ↑HCO3 by ≥3mM/h  Hyponatraemia is the norm  ↓ plasma glucose by ≥3mM/h . Osmolar compensation for hyperglycaemia  Maintain K in normal range . ↑/↔ Na indicates severe dehydration  Avoid hypoglycaemia  Avoid rapid ↓ in insulin once glucose normalised . Glucose decreases faster than ketones and insulin is necessary to get rid of them.  Amylase is often ↑ (up to 10x) Resolution  Excretion of ketones → loss of potential bicarbonate →  Ketones <0.3mM + venous pH>7.3 (HCO3 >18mM) hyperchloraemic metabolic acidosis after Rx  Transfer to sliding scale if not eating  Transfer to SC insulin when eating and drinking Complications  Cerebral oedema: excess fluid administration . Commonest cause of mortality Transfer to SC Insulin  Aspiration pneumonia  When biochemically resolved and eating  Hypokalaemia  Start long-acting insulin the night before  Hypophosphataemia → resp and skeletal muscle  Give short-acting insulin before breakfast weakness  Stop IVI 30min after short acting  Thromboembolism

Mx: in HDU  Gastric aspiration Pt. Education  Rehydrate  ID precipitating factors and provide action plan  Insulin infusion  Provision of ketone meter ¯c education on use.  Potassium replacement © Alasdair Scott, 2012 63 Hyperosmolar Non-Ketotic Coma

The Patient  Usually T2DM, often new presentation  Usually older  Long hx (e.g. 1wk)

Metabolic Derangement  Marked dehydration and glucose >35mM  No acidosis (no ketogenesis)  Osmolality >340mosmol/kg

Complications  Occlusive events are common: DVT, stroke . Give LMWH

Mx  Rehydrate ¯c 0.9% NS over 48h . May need ~9L  Wait 1h before starting insulin . It may not be needed . Start low to avoid rapid changes in osmolality  E.g. 1-3u/hr  Look for precipitant . MI . Infection . Bowel infarct

Hypoglycaemia: Whipple’s Triad Mx  Low plasma glucose ≤3mM  Symptoms consistent ¯c hypoglycaemia Alert and Orientated: Oral Carb  Relief of symptoms by glucose administration  Rapid acting: lucozade  Long acting: toast, sandwich Symptoms Drowsy / confused but swallow intact: Buccal Carb Autonomic: 2.5-3 Neuroglycopenic: <2.5  Hypostop / Glucogel  Sweating  Confusion  Consider IV access  Anxiety  Drowsiness  Hunger  Seizures Unconscious or Concerned re Swallow: IV dextrose  Tremor  Personality change  100ml 20% glucose (50ml 50% dextrose: not used)

 Palpitations  Focal neurology (e.g. CN3) Deteriorating / refractory / insulin-induced / no access  Coma (<2.2)  1mg glucagon IM/SC  Won’t work in drunks + short duration of effect (20min) Fasting Hypoglycaemia  Insulin release may → rebound hypoglycaemia

Causes: EXPLAIN  Usually insulin or sulfonylurea Rx in a known diabetic . Exercise, missed meal, OD  Exogenous drugs  Pituitary insufficiency  Liver failure  Addison’s  Islet cell tumours (insulinomas)  Immune (insulin receptor Abs: Hodgkin’s)  Non-pancreatic neoplasms: e.g. fibrosarcomas

Ix  72h fast ¯c monitoring  Sympto: Glucose, insulin, C-peptide, ketones

Dx  Hyperinsulinaemic hypoglycaemia . Drugs  ↑ C-pep: sulfonylurea  Normal C-pep: insulin . Insulinoma  ↓ insulin, no ketones . Non-pancreatic neoplasms . Insulin receptor Abs  ↓ insulin, ↑ ketones . Alcohol binge ¯c no food . Pituitary insufficiency . Addison’s

Insulinoma  Path: 95% benign β-cell tumour usually seen ¯c MEN1  Pres: fasting- / exercise-induced hypoglycaemia  Ix: . Hypoglycaemia + ↑ insulin . Exogenous insulin doesn’t suppress C-pep . MRI, EUS pancreas  Rx: excision

Post-Prandial Hypoglycaemia  Dumping post-gastric bypass

Definition Other Causes  The clinical effect of ↑T4, usually from gland hyperfunction. Toxic Multinodular Goitre = Plummer’s Disease  Autonomous nodule develops on background multinodular Symptoms goitre.  Diarrhoea  Elderly and iodine-deficient areas  ↑ appetite but ↓ wt.  Iodine scan shows hot nodules

 Sweats, heat intolerance Toxic Adenoma  Palpitations  Solitary hot nodule ± producing T3/T4  Tremor  Most nodules are non-functional  Irritability

 Oligomenorrhoea ± infertility Thyrotoxic Phase of Thyroiditis

 Hashimoto’s Signs  de Quervain’s Hands  Subacute lymphocytic  Fast / irregular pulse  Warm, moist skin Drugs  Fine tremor  Thyroxine  Palmer erythema  Amiodarone

Face  Thin hair Rx  Lid lag

 Lid retraction Medical

 Symptomatic: β-B (e.g. propranolol 40mg/6h) Neck  Anti-thyroid: carbimazole (inhibits TPO)  Goitre or nodules . Titrate according to TFTs or block and replace

. In Graves’ Rx for 12-18mo then withdraw Graves’ Specific  ~50% relapse → surgery or radioiodine  Ophthalmopathy . SE: agranulocytosis . Exophthalmos

. Ophthalmoplegia: esp. up-gaze palsy . Eye discomfort and grittiness Radiological: Radio-iodine . Photophobia and ↓ acuity  Most become hypothyroid . Chemosis  CI: pregnancy, lactation  Dermopathy: pre-tibial myxoedema Surgical: Thyroidectomy  Thyroid acropachy  Recurrent laryngeal N. damage → hoarseness Ix  Hypoparathyroidism  Hypothyroidism  ↓TSH, ↑T4/↑T3

 Abs: TSH receptor, TPO

 ↑Ca, ↑LFTs  Isotope scan Thyroid Storm . ↑ in Graves’ . ↓ in thyroiditis Features  Ophthalmopathy: acuity, fields, movements  ↑ temp  Agitation, confusion, coma Graves’ Disease  Tachycardia, AF  Acute abdomen Epidemiology  Heart failure  60% of cases of thyrotoxicosis  Prev: 0.5% Precipitants  Sex: F>>M=9:1  Recent thyroid surgery or radio-iodine  Age: 40-60yrs  Infection  MI Features  Trauma  Diffuse goitre ¯c ↑iodine uptake Rx  Ophthalmopathy and dermopathy 1. Fluid resuscitation + NGT  Triggers: stress, infection, child-birth 2. Bloods: TFTs + cultures if infection suspected

3. Propranolol PO/IV Associations 4. Digoxin may be needed  T1DM 5. Carbimazole then Lugol’s Iodine 4h later to inhibit thyroid  Vitiligo 6. Hydrocortisone  Addison’s 7. Rx cause © Alasdair Scott, 2012 66 Hypothyroidism

Epidemiology Ix  Incidence: 4/1000/yr  ↑TSH, ↓T3/T4  Sex: F>>M=6:1  ↑MCV ± normochromic anaemia  Age: >40yrs  ↑ triglyceride + ↑ cholesterol  Hyponatraemia (SIADH) Symptoms  ↑ CK if assoc. myopathy  Lethargy  Abs: TPO, TSH  Cold intolerance  ↓ appetite but ↑wt. Rx  Constipation  Levothyroxine  Menorrhagia . Titrate to normalise TSH  ↓ mood . Enzyme inducers ↑ thyroxine metabolism . Clinical improvement takes ~2wks Signs  Check for other AI disease: e.g. Addison’s, PA  Cold hands  Bradycardic  Slow-relaxing reflexes Myxoedema Coma  Dry hair and skin  Puffy face Features  Goitre  Looks hypothyroid  Myopathy, neuropathy  Hypothermia  Ascites  Hypoglycaemia  Myxoedema  Heart failure: bradycardia and ↓BP . SC tissue swelling in severe hypothyroidism  Coma and seizures . Typically around eyes and dorsum of hand Precipitants Causes  Radioiodine  Thyroidectomy Primary  Pituitary surgery  Atrophic thyroiditis (commonest UK)  Infection, trauma, MI, stroke  Hashimoto’s thyroiditis  Subacute thyroiditis (e.g. post-partum) Mx  Post De Quervain’s thyroiditis  Bloods: TFTs, FBC, U+E, glucose, cortisol  Iodine deficiency (commonest worldwide)  Correct any hypoglycaemia  Drugs: carbimazole, amiodarone, lithium  T3/T4 IV slowly (may ppt. myocardial ischaemia)  Congenital: thyroid agenesis  Hydrocortisone 100mg IV  Rx hypothermia and heart failure Post-surgical  Thyroidectomy  Radioiodine

Secondary  Hypopituitarism (v. rare cause)

Atrophic Thyroiditis  Thyroid antibodies +ve: anti-TPO, anti-TSH  Lymphocytic infiltrate → atrophy (no goitre)  Associations . Pernicious anaemia . Vitiligo . Endocrinopathies

Hashimoto’s Thyoiditis  TPO +ve  Atrophy + regeneration → goitre  May go through initial thyrotoxicosis phase  May be euthyroid or hypothyoid

Disease Clinical Features Cause Management Simple goitre Diffuse painless goitre Endemic Thyroxine Mass effects: - iodine deficiency - dysphagia Total or subtotal - stridor Sporadic thyroidectomy if pressure - SVC obstruction - autoimmune symptoms. - goitrogens (e.g. sulphonylureas) Usually euthyroid, may → hypothyroid - hereditary (dyshormogenic) Multinodular Evolves from long-standing simple As for simple goitre Thyroxine goitre goitre. Mass effects. Euthyroid (or subclinical hyperthyroid) Total or subtotal thyroidectomy if pressure symptoms. Plummer’s Multinodular goitre Autonomous nodule develops on Anti-thyroid drugs Toxic multinodular Thyrotoxicosis background multinodular goitre goitre Uneven iodine uptake with hot nodule Total or subtotal thyroidectomy. Graves’ Diffuse goitre ¯c bruit Autoimmune (T2 hypersensitivity) Propranolol Ophthalmopathy - anti-TSH Carbimazole Dermopathy Radioiodine Thyrotoxicosis Thyroidectomy Assoc. ¯c other AI disease (T1DM, PA) ↑ uptake on radionucleotide scan Hashimoto’s Diffuse painless goitre Autoimmune (T2 and T4) Levothyroxine thyroiditis May have transient thyrotoxicosis, then - anti-TPO, -Tg hypothyroidism Assoc. ¯c other AI disease (T1DM, PA) de Quervain’s Diffuse painful goitre Viral: Coxsackie common Self-limiting Preceding viral URTI common Thyrotoxicosis → hypo→eu Autoimmune ↓ iodine uptake Subacute Diffuse painless goitre Autoimmune Self-limiting lymphocytic May occur post-partum Thyrotoxicosis → hypo→eu Riedel’s thyoiditis Hard fixed thyroid mass Autoimmune fibrosis Conservative Mass effects Assoc. ¯c retroperitoneal fibrosis Follicular Single thyroid nodule Hemithyroidectomy adenoma ± thyrotoxicosis (majority are cold) May get pressure symptoms Thyroid cysts Solitary thyroid nodule Aspiration or excision Asympto or pressure symptoms Can → localised pain due to cyst bleed

Disease Frequency Age Cell Origin Spread Mx Papillary 80% 20-40 Follicular cells Nodes and lung Total thyroidectomy - JDG node = ± node excision Assoc. ¯c Tg tumour marker lateral aberrant ± radioiodine irradiation thyroid T4 to suppress TSH

>95% 10ys Follicular 10% 40-60 Follicular cells Blood → bone Total thyroidectomy + F>M = 3:1 and lungs T4 suppression + Tg tumour marker Radioiodine

>95% 10ys Medullary 5% Men: young Parafollicular C-cells Do phaeo screen pre-op 30% are familial Sporadic: 40-50 Thyroidectomy + - e.g. MEN2 CEA and calcitonin Node clearance markers Consider radiotherapy Anaplastic Rare >60 Undifferentiated Rapid growth Usually palliative F>M = 3:1 follicular cells Aggressive: local, May try thyroidectomy + LN and blood. radiotherapy

<1% 10ys Lymphoma 5% Lymphocytes Chemo-radiotherapy - MALToma in Hashi’s

Presentation: Complications of Thyroid Surgery  Non-functional (cold)  Painless neck mass Early  Cervical mets  Reactionary haemorrhage → haematoma (<1%)  Compression symptoms . Can → airway obstruction. . Dysphagia . Call anaesthetist and remove wound clips . Stridor . Evacuate haematoma and re-explore wound . SVC obstruction  Laryngeal oedema . Damage during intubation or surgical Risk factors for malignancy in thyroid nodules manipulation  Solitary . Can → airway obstruction  Solid  Recurrent laryngeal nerve palsy (0.5%) . Right RLN more common (oblique ascent)  Younger . Damage to one → hoarse voice  Male . Damage to both → obstruction needing  Cold trachyostomy  Risk factor: e.g. radiation exposure  Hypoparathyroidism (2.5%) 2+ . → ↓ Ca → Chvostek’s and Trousseau’s  Thyroid storm Thyroid Surgery . Severe hyperthyroidism . Rx: propranolol, antithyroid drugs, Lugol’s iodine Indications and hydrocortisone sodium succinate  Pressure symptoms  Relapse hyperthyroidism (>1 failed drug Rx) Late  Cosmesis  Hypothyroidism  Carcinoma  Recurrent hyperthyroidism  Keloid scar Practicalities  Render euthyroid pre-op ¯c antithyroid drugs . Stop 10 days prior to surgery (they ↑ vascularity) . Alternatively just give propronalol  Check for phaeo pre-op in medullary carcinoma  Laryngoscopy: check vocal cords pre- and post-op

Procedure  Collar incision

© Alasdair Scott, 2012 69 Hyperparathyroidism Hypoparathyroidism  ↓PTH due to gland failure Physiology  PTH secreted in response to ↓Ca2+ Presentation: ↓Ca → SPASMODIC . ↑osteoclast activity  Spasms (carpopedal = Trousseau’s sign) 2+ . ↑Ca and ↓PO4 reabsorption in kidney  Perioral paraesthesia . ↑ 1α-hydroxylation of 25OH-Vit D3  Anxious, irritable  Seizures 2+ Presentation: ↑ Ca  Muscle tone ↑→ colic, wheeze, dysphagia  Stones  Orientation impaired (confusion) . Renal stones  Dermatitis . Polyuria and polydipsia (nephrogenic DI)  Impetigo herpetiformis (↓Ca + pustules in pregnancy) . Nephrocalcinosis  Chovsteks, cardiomyopathy (↑ QTc → TdP)  Bones . Bone pain Causes . Pathological #s  Autoimmune  Moans: depression  Congenital: DiGeorge  Groans . Cardiac abnormality: Fallot’s . Abdo pain . Abnormal facies . n/v and constipation . Thymic aplasia . Pancreatitis . Cleft palate . PUD (↑gastrin secretion) . Hypocalcaemia  Other: 2+ . Chr 22 . ↑ BP (check Ca in all with HTN)  Iatrogenic . Surgery Primary Hyperparathyroidism . Radiation

Causes Ix  Solitary adenoma: 80%  ↓Ca, ↑PO4, ↓PTH, normal ALP  Hyperplasia: 20%  Pathyroid Ca: <0.5% Rx

 Ca supplements Ix 2+  Calcitriol  ↑Ca + ↑ or inappropriately normal PTH, ↑ALP, ↓PO4 st  ECG: ↓QTc → bradycardia → 1 degree block Pseudohypoparathyroidism  X-ray: osteitis fibrosa cystica → phalangeal erosions  Failure of target organ response to PTH DEXA: osteoporosis   Symptoms of hypocalcaemia th th  Short 4 and 5 metacarpals, short stature Rx  Ix: ↓Ca, ↑PTH  General  Rx: Ca + calcitriol . ↑ fluid intake 2+ . Avoid dietary Ca and thiazides (↑ serum Ca) Pseudopseudohypoparathyroidism  Surgical: excision of adenoma  Normal (maternal) receptor in kidney → normal . Hypoparathyroidism biochem . Recurrent laryngeal N. palsy  Abnormal (paternal) receptors in body → Secondary Hyperparathyroidism pseudohypoparathyroidsm phenotype

Causes  Vitamin D deficiency  Chronic renal failure

Ix  ↑PTH, ↓Ca, ↑PO4, ↑ALP, ↓vit D

Rx  Correct causes  Phosphate binders . With Ca: calcichew . W/o Ca: sevelamer, lanthanum  Vit D: calcitriol (active), cholecalciferol (innactive)  Cinacalcet: ↑ parathyroid Ca-sensitivity

Tertiary Hyperparathyroidism  Prolonged 2O HPT → autonomous PTH secretion 2+  ↑Ca , ↑PTH, ↓PO4, ↑ALP

Definition ACTH-Independent  Clinical state produced by chronic glucocorticoid excess  ↓ACTH due to –ve FB  No suppression ¯c any dose of dex

Features Causes  Iatrogenic steroids: commonest cause

Adrenal adenoma / Ca: carcinoma often → virilisation Catabolic Effects  Adrenal nodular hyperplasia  Proximal myopathy   Carney complex: LAME Syndrome  Striae  McCune-Albright  Bruising

 Osteoporosis

Glucocorticoid Effects ACTH-Dependent  DM  ↑ ACTH  Obesity Causes Mineralocorticoid Effects  Cushing’s disease  HTN . Bilat adrenal hyperplasia from ACTH-secreting  Hypokalaemia pituitary tumour (basophilic microadenoma) . Cortisol suppression ¯c high-dose dex  Ectopic-ACTH . SCLC Appearance . Carcinoid tumour  Moon face . Skin pigmentation, metabolic alkalosis, wt. loss,  Acne and hirsutism hyperglycaemia  Interscapular and supraclavicular fat pads . No suppression ¯c any dose of dex  Centripetal obesity  Striae  Thin limbs Ix  Bruising  1st: 24h urinary free cortisol  Thin skin  Late night serum or salivary cortisol . Highest @ AM, lowest @ midnight  Dexamethasone suppression tests  ACTH (but ACTH degrades v. quick after venepuncture)  Localisation: CT, MRI  DEXA scan

Rx: Treat Causes  Cushing’s disease: trans-sphenoidal excision  Adrenal adenoma / Ca: adrenelectomy  Ectopic ACTH: tumour excision, metyrapone (inhibits cortisol synthesis)

Nelson’s Syndrome  Rapid enlargement of a pituitary adenoma following bilateral adrenelectomy for Cushing’s syndrome . Not typically performed nowadays  Presentation . Mass effects: bitemporal hemianopia . Hyperpigmentation

Primary Hyperaldosteronism Secondary Hyperaldosteronism  Excess aldosterone, independent of RAS  Due to ↑ renin from ↓ renal perfusion

Features Causes  Hypokalaemia: weakness, hypotonia, hyporeflexia,  RAS cramps  Diuretics  Paraesthesia  CCF  ↑BP  Hepatic failure  Nephrotic syndrome Causes  Bilateral adrenal hyperplasia (70%) Ix  Adrenocortical adenoma (30%): Conn’s syndrome  Aldosterone:renin ratio: normal

Ix Bartter’s Syndrome  U+E: ↑/↔ Na, ↓K, alkalosis  Autosommal recesive . Care ¯c diuretics, hypotensives, laxatives, steroids  Blockage of NaCl reabsorption in loop of Henle (as if  Aldosterone:renin ratio: ↑ ¯c primary taking frusemide)  ECG: flat / inverted T waves, U waves, depressed ST  Congenital salt wasting → RAS activation → segments, prolonged PR and QT intervals hypokalaemia and metabolic alkalosis  Adrenal CT/MRI  Normal BP

Rx  Conn’s: laparoscopic adrenelectomy  Hyperplasia: spironolactone, eplerenone or amiloride

Primary Adrenal Insufficiency: Addison’s Addisonian Crisis  Destruction of adrenal cortex → glucocorticoid and mineralocorticoid deficiency Presentation  Shocked: ↑HR, postural drop, oliguria, confused Causes  Hypoglycaemia  Autoimmune destruction: 80% in the UK  Usually known Addisonian or chronic steroid user  TB: commonest worldwide  Metastasis: lung, breast, kidneys Precipitants  Haemorrhage: Waterhouse-Friedrichson  Infection  Congenital: CAH  Trauma  Surgery Symptoms  Stopping long-term steroids  Wt. loss + anorexia  n/v, abdo pain, diarrhoea/constipation Mx  Lethargy, depression  Bloods: cortisol, ACTH, U+E, cultures  Hyperpigmentation: buccal mucosa, palmer creases  Check CBG: glucose may be needed  Postural hypotension → dizziness, faints  Hydrocortisone 100mg IV 6hrly  Hypoglycaemia  IV crystalloid  Vitiligo  Septic screen  Addisonian crisis  Treat underlying cause

Ix  Bloods . ↓Na/↑K . ↓glucose . ↓Ca . Anaemia  Differential . Short synACTHen test  Cortisol before and after tetracosactide  Exclude Addison’s if ↑ cortisol . ↑ 9am ACTH (usually low)  Other . 21-hydroxylase Abs: +ve in 80% of AI disease . Plasma renin and aldosterone . CXR: evidence of TB . AXR: adrenal calcification

Rx  Replace . Hydrocortisone . Fludrocortisone  Advice . Don’t stop steroids suddenly . ↑ steroids during intercurrent illness, injury . Wear a medic-alert bracelet  F/up . Watch for autoimmune disease

Secondary Adrenal Insufficiency  i.e. hypothalamo or pituitary failure

Causes  Chronic steroid use → suppression of HPA axis  Pituitary apoplexy / Sheehan’s  Pituitary microadenoma

Features  Normal mineralocorticoid production  No pigmentation (ACTH ↓)

Pathology Definition  Catecholamine-producing tumours arising from  Functioning hormone tumours in multiple organs sympathetic paraganglia  All autosomal dominant  Usually found in adrenal medulla  Extra-adrenal phaeo’s found by aortic bifurcation MEN1  Pituitary adenoma: prolactin or GH Rule of 10s  Parathyroid adenoma / hyperplasia  10% malignant  Pancreatic tumours: gastrinoma or insulinoma  10% extra-adrenal  10% bilateral  10% part of hereditary syndromes MEN2  Thyroid medullary carcinoma Associations  Adrenal phaeochromocytoma  10% part of herediatary syndromes . A) Hyperthyroidism . MEN2a and 2b . B) Marfanoid habitus . Neurofibrimatosis . Von Hippel-Lindau: RCC + cerebellar signs Carney Complex / LAME Syndrome Presentation  Lentigenes: spotty skin pigmentation  Triad: episodic headache, sweating and tachycardia . Differential: Peutz-Jehgers  Other adrenergic features  Atrial Myxoma . ↑BP, palpitations  Endocrine tumours: pituitary, adrenal hyperplasia . Headache, tremor, dizziness  Schwannomas . Anxiety . d/v, abdo pain Peutz-Jeghers . Heat intolerance, flushes  Mucocutaneous freckles on lips, oral mucosa and palms /  May have precipitant soles . Straining, abdo palpation  GI hamartomas: obstruction, bleeds . Exercise, stress  Pancreatic endocrine tumours . β-B, IV contrast, TCAs, GA  ↑ risk of cancer: CRC, pancreas, liver, lungs, breast

Ix  Plasma + urine metadrenaline Von Hippel-Lindau . Also vanillylmandelic acid  Renal cysts  Abdo CT/MRI  Bilateral renal cell carcinoma  MIBG (mete-iodobenzylguanidine) scan  Haemangioblastomas . Often in cerebellum → cerebellar signs Rx  Phaeochromocytoma  Pancreatic endocrine tumours

Medical  If malignant Neurofibrimatosis  Chemo or radiolabelled MIGB  Dermal neurofibromas  Café-au-lait spots Surgery: adrenelectomy  Lisch nodules  α-blocker first, then β-blockade pre-op  Axillary freckling . Avoids unopposed α-adrenergic stimulation  Phaeochromocytoma . Phenoxybenzamine = α-blocker  Monitor BP post-op for ↓↓BP

Autoimmune Polyendocrine Hypertensive Crisis Syndromes

Features Type 1  Pallor  Autosomal recessive  Pulsating headache  Addison’s  Feeling of impending doom  Candidiasis  ↑↑BP  Hypoparathyroidism  ↑ ST and cardiogenic shock Type 2: Schmidt’s Syndrome Rx  Polygenic  Phentolamine 2-5mg IV (α-blocker) or labetalol 50mg IV  Addison’s . Repeat to safe BP (e.g. 110 diastolic)  Thyroid disease: hypothyroidism or Graves’  Phenoxybenzaime 10mg/d PO when BP controlled  T1DM  Elective surgery after 4-6wks to allow full α-blockade © andAlasdair volume Scott, expansion2012 74 Hypopituitarism Pituitary Tumours  10% of intracranial tumours Causes  Hypothalamic Classification . Kallmann’s (anosmia + GnRH deficiency) . Tumour Size . Inflam, infection, ischaemia  Microadenoma: <1cm  Pituitary Stalk  Macroadenoma: >1cm . Trauma . Surgery Pathology . Tumour (e.g. craniopharyngioma)  Many are non-secretory  Pituitary  ~50% produce PRL . Irradiation  Others produce GH or ACTH . Tumour . Ischaemia: apoplexy, Sheehan’s . Infiltration: HH, amyloid Features

Commonest causes of panhypopituitarism Mass Effects  Surgery  Headache  Tumour  Visual field defect: bitemporal hemianopia  Irradiation  CN palsies: 3, 4, 5, 6 (pressure on cavernous sinus)  Diabetes insipidus  CSF rhinorrhoea

Features Hormone Effects  PRL → galactorrhoea, ↓libido, amenorrhoea, ED Hormone Deficiency . ↑PRL → ↓GnRH → ↓LH/FSH  GH: central obesity, atherosclerosis, ↓CO, ↓stength  GH → acromegaly  LH/FSH  ACTH → Cushing’s Disease . M: ↓libido, ED, ↓hair . F: ↓libido, amenorrhoea, breast atrophy Ix  TSH: hypothyroidism  MRI  ACTH: 2O adrenal failure  Visual field tests

Cause  Hormones: PRL, IGF, ACTH, cortisol, TFTs, LF/FSH  Mass effects  Suppression tests

 Other hormones: e.g. prolactin excess Rx

Medical Ix  Replace hormones  Basal hormone tests  Treat hormone excess  Dynamic pituitary function test . Insulin → ↑ cortisol + ↑ GH Surgical: Trans-sphenoidal excision . GnRH → ↑ LH/FSH  Pre-op hydrocortisone . TRH → ↑T4 + ↑ PRL  Post-op dynamic pituitary tests  MRI brain Radiotherapy: sterotactic

Rx  Hormone replacement Pituitary Apoplexy  Treat underlying cause  Rapid pituitary enlargement due to bleed into a tumour  Mass effects . Headache, meningism, ↓GCS . Bitemporal hemianopia  Cardiovascular collapse due to acute hypopituitarism  Rx: urgent hydrocortisone 100mg IV

Craniopharyngeoma  Originates from Rathke’s pouch  Commonest childhood intracranial tumour . → growth failure  Calcification seen on CT/MRI

Causes Causes  Excess pituitary production  Pituitary acidophil adenoma in 99% . Pregnancy, breastfeeding  Hyperplasia from GHRH secreting carcinoid tumour . Prolactinoma (PRL >5000)  GH stimulates bone and soft tissue growth through ↑IGF1 . Hypothyroidism (↑TRH)  Disinhibition by compression of pituitary stalk Symptoms . Pituitary adenoma  Acroparaesthesia . Craniopharyngioma  Amenorrhoea, ↓libido  Dopamine antagonsists (commonest cause)  Headache . Antiemetics: metoclopramide  Snoring . Antipsychotics: risperidone, haldol  Sweating

 Arthralgia, back ache

 Carpal tunnel (50%) Symptoms  Amenorrhoea Signs  Infertility

Galactorrhoea  Hands ↓ libido   Spade-like ED   Thenar wasting Mass effects from prolactinoma   Boggy sweaty palms (if active)

 ↑ skin fold thickness

 Carpal tunnel: ↓ sensation + thenar wasting Ix  Basal PRL: >5000 = prolactinoma Face  Pregnancy test, TFTs  Prominent supraorbital ridges  MRI  Scalp folds: cutis verticis gyrata  Coarse face, wide nose and big ears  Prognathism: look from side Rx  Macroglossia st  1 line: Cabergoline or bromocroptine  Widely-spaced teeth . Da agonist  Goitre . ↓ PRL secretion and ↓ tumour size . SE: nausea, postural hypotension, fibrosis (lung Other and heart) nd  Puffy, oily, darkened skin skin  2 line: Trans-sphenoidal excision  Proximal weakness + arthropathy . If visual or pressure symptoms don’t response to  Pituitary mass effects: bitemporal hemianopia medical Rx

Complications  Endocrine . Impaired glucose tolerance (40%) . DM (15%)  Cardiovascular . ↑BP . LVH . Cardiomyopathy . ↑ IHD and ↑ stroke  Neoplasia . ↑ risk of CRC

Ix  ↑IGF1  ↑ glucose, ↑Ca, ↑PO4  Glucose tolerance test . GH fails to suppress ¯c glucose in acromegaly  Visual fields and acuity  MRI brain

Rx  1st line: trans-sphenoidal excision  2nd line: somatostatin analogues – octreotide  3rd line: GH antagonist – pegvisomant  4th line: radiotherapy

Symptoms Hirsutism  Polyuria  Polydipsia Causes  Dehydration  Familial  Hypernatraemia: lethargy, thirst, confusion, coma  Idiopathic  ↑ androgens: . Ovary: PCOS Causes . Adrenals: Cushing’s, adrenal Ca . Drugs: steroids Cranial  Idiopathic: 50% PCOS  Features  Congenital: DIDMOAD / Wolfram Syndrome O  Tumours . 2 oligo-/amenorrhoea → infertility . Obesity  Trauma . Acene, hirsutism  Vascular: haemorrhage (Sheehan’s syn.)  US: bilateral polycystic ovaries  Infection: meningoencephalitis  Hormones: ↑ testosterone, ↓ SHBG, ↑LH:FSH ratio  Infiltration: sarcoidosis  Mx . Metformin

. COCP Nephrogenic . Clomifene for infertility  Congenital

 Metabolic: ↓K, ↑Ca

 Drugs: Li, demecleocycline, vaptans Gynaecomastia  Post-obstructive uropathy  Abnormal amount of breast tissue in men  May occur in normal puberty Ix Causes  Bloods: U+E, Ca, glucose  Cirrhosis  Urine and plasma osmolality  Hypogonadism . Exclude DI if U:P osmolality >2  Hyperthyroidism

Oestrogen- or HCG-producing tumours: e.g. testicular   Drugs: spiro, digoxin, oestrogen Dx  Water deprivation test ¯c desmopressin trial ED

Differential Organic Causes  DM  Smoking  Diuretics or Lithium  EtOH  Primary polydipsia  DM  Endo: hypogonadism, hyperthyroidism, ↑Prl  Neuro: MS, autonomic neuropathy, cord lesion Rx  Pelvic surgery: bladder, prostate  Penile abnormalities: Peyronie’s disease Cranial  Find cause: MRI brain  Desmopressin PO

Nephrogenic  Treat cause

Contents Diarrhoea ...... 79 C. diff Diarrhoea ...... 79 Constipation ...... 80 IBS ...... 80 Dysphagia ...... 81 Dyspepsia ...... 82 Peptic Ulcer Disease ...... 83 GORD ...... 84 Hiatus Hernia ...... 84 Haematemesis Differential ...... 85 Rectal Bleeding Differential ...... 85 Upper GI Bleeding ...... 86 Jaundice ...... 87 Liver Failure ...... 88 Cirrhosis ...... 89 Portal Hypertension ...... 90 Alcoholism ...... 91 Alcoholic Hepatitis ...... 91 Viral Hepatitis ...... 92 Non-alcoholic Fatty Liver Disease (NAFLD) ...... 92 Budd-Chiari Syndrome ...... 92 Hereditary Haemochromatosis ...... 93 α1-Antitrypsin Deficiency ...... 93 Wilson’s Disease ...... 94 Autoimmune Hepatitis ...... 94 Primary Biliary Cirrhosis ...... 95 Primary Sclerosing Cholangitis ...... 95 Liver Tumours ...... 96 Liver Transplant in CLD ...... 96 Inflammatory Bowel Disease: Pathology and Presentation ...... 97 Ulcerative Colitis: Management ...... 98 Crohn’s Disease: Management ...... 99 Coeliac Disease ...... 100 Malabsorption ...... 100 Pancreatic Cancer ...... 101 Chronic Pancreatitis ...... 101 Carcinoid Tumours ...... 102 Nutritional Deficiencies ...... 102

Definitions Pathogen  Diarrhoea = ↑ stool water → ↑ stool frequency  Gm+ve spore-forming anaerobe  Steatorrhoea = ↑ stool fat → pale, float, smelly  Release enterotoxins A and B  Faecal urgency = suggests rectal pathology  Spores are v. robust and can survive for >40d

Clinical Features and Causes Epidemiology  Commonest cause (25%) of Abx assoc. diarrhoea Acute . 100% of Abx assoc. pseudomembranous colitis  Suspect gastroenteritis  Stool carriage in 3% of healthy adults and 15-30% of  Travel, diet, contacts? hospital pts.

Chronic Risk Factors  Diarrhoea alternating ¯c constipation: IBS  Abx: e.g. clindamycin, cefs, augmentin, quinolones  Anorexia, ↓wt., nocturnal diarrhoea: organic cause  ↑ age  In hospital: ↑ ¯c length of stay, ↑ ¯c C. diff +ve contact Bloody  PPIs  Vascular: ischaemic colitis  Infective: campylobacter, shigella, salmonella, E. coli, Clinical Presentations amoeba, pseudomembranous colitis  Asymptomatic  Inflammatory: UC, Crohn’s  Mild diarrhoea  Neoplastic: CRC, polyps  Colitis w/o pseudomembranes

 Pseudomembranous colitis Mucus  Fulminant colitis  IBS, CRC, polyps May occur up to 2mo after discontinuation of Abx  Pus  IBD, diverticulitis, abscess Pseudomembranous Colitis  Severe systemic symptoms: fever, dehydration Assoc. c¯ medical disease  Abdominal pain, bloody diarrhoea, mucus PR  ↑ T4  Pseudomembranes (yellow plaques) on flexi sig  Autonomic neuropathy (e.g. DM)  Complications  Carcinoid . Paralytic ileus . Toxic dilatation → perforation Assoc. c¯ drugs . Multi-organ failure

 Abx  PPI, cimetidine Ix  NSAIDs  Bloods: ↑↑CRP, ↑↑WCC, ↓albumin, dehydration  Digoxin  CDT ELISA  Stool culture

Ix Severe Disease: ≥1 of  WCC >15 Bloods  Cr >50% above baseline  FBC: ↑ WCC, anaemia  Temp >38.5  U+E: ↓K+, dehydration  Clinical / radiological evidence of severe colitis  ↑ESR: IBD, Ca  ↑CRP: IBD, infection Rx  Coeliac serology: anti-TTG or anti-endomysial Abs General  Stop causative Abx Stool  Avoid antidiarrhoeals and opiates  MCS and C. diff toxin  Enteric precautions Specific  1st line: Metronidazole 400mg TDS PO x 10-14d nd Rx  2 line: Vanc 125mg QDS PO x 10-14d . Failed metro  Treat cause  Severe: Vanc 1st (may add metro IV)  Oral or IV rehydration . ↑ to 250mg QDS if no response (max 500mg)  Codeine phosphate or loperamide after each loose . Urgent colectomy may be needed if stool  Toxic megacolon  Anti-emetic if assoc. c n/v: e.g. prochlorperazine ¯  ↑ LDH  Abx (e.g. cipro) in infective diarrhoea → systemic illness  Deteriorating condition

 Recurrence (15-30%) . Reinfection or residual spores . Repeat course of metro x 10-14d . Vanc if further relapse (25%) © Alasdair Scott, 2012 79 Constipation IBS

Definition Definition  Infrequent BMs (≤3/wk) or passing BMs less often than  Disorders of enhanced visceral perception → bowel normal or ¯c difficulty, straining or pain. symptoms for which no organic cause can be found.

Causes: OPENED IT Dx: ROME Criteria Obstruction  Abdo discomfort / pain for ≥ 12wks which has 2 of:  Mechanical: adhesions, hernia, Ca, inflamatory . Relieved by defecation strictures, pelvic mass . Change in stool frequency (D or C)  Pseudo-obstruction: post-op ileus . Change in stool form: pellets, mucus  + 2 of: Pain . Urgency  Anal fissure . Incomplete evacuation  Proctalgia fugax . Abdo bloating / distension . Mucous PR Endocrine / Electrolytes . Worsening symptoms after food  Endo: ↓T4  Exclusion criteria  Electrolytes: ↓Ca, ↓K, uraemia . >40yrs . Bloody stool Neuro . Anorexia  MS . Wt. loss  Myelopathy . Diarrhoea at night  Cauda equina syndrome Ix Elderly  Bloods: FBC, ESR, LFT, coeliac serology, TSH Diet / Dehydration  Colonoscopy: if >60yrs or any features of organic IBS disease Toxins  Opioids Rx  Anti-mACh  Exclusion diets can be tried  Bulking agents for constipation and diarrhoea (e.g. Mx fybogel). General  Antispasmodics for colic/bloating (e.g. mebeverine)  Drink more  Amitriptyline may be helpful  ↑ dietary fibre  CBT

Bulking: ↑ faecal mass → ↑ peristalsis  CI: obstruction and faecal impaction  Bran  Ispaghula husk (Fybogel)  Methylcellulose

Osmotic: retain fluid in the bowel  Lactulose  MgSO4 (rapid)

Stimulant: ↑ intestinal motility and secretion  CI: obstruction, acute colitis  SE: abdo cramps  Bisacodyl PO or PR  Senna  Docusate sodium  Sodium picosulphate (rapid)

Softeners  Useful when managing painful anal conditions  Liquid paraffin

Enemas  Phosphate enema (osmotic)

Suppositories  Glycerol (stimulant)

Definition Achalasia  Difficulty swallowing  Pathophysiology . Degeneration of myenteric plexus (Auerbach’s) Causes . ↓ peristalsis . LOS fails to relax  Cause Inflammatory O  Tonsillitis, pharyngitis . 1 / idiopathic: commonest . 2O: oesophageal Ca, Chagas’ disease (T. cruzii)  Oesophagitis: GORD, candida  Presentation  Oral candidiasis . Dysphagia: liquids and solids at same time  Aphthous ulcers . Regurgitation

. Substernal cramps Mechanical Block . Wt. loss  Luminal  Comps: Chronic achalasia → oesophageal SCC . FB  Ix . Large food bolus . Ba swallow: dilated tapering oesophagus (Bird’s  Mural beak) . Benign stricture . Manometry: failure of relaxation + ↓ peristalsis  Web (e.g. Plummer-Vinson) . CXR: may show widended mediastinum  Oesophagitis . OGD: exclude malignancy  Trauma (e.g. OGD)  Rx: . Malignant stricture . Med: CCBs, nitrates  Pharynx, oesophagus, gastric . Int: endoscopic balloon dilatation, botulinum toxin . Pharyngeal pouch injection  Extra-mural . Surg: Heller’s cardiomyotomy (open or endo) . Lung Ca . Rolling hiatus hernia . Mediastinal LNs (e.g. lymphoma) Pharyngeal Pouch: Zenker’s Diverticulum . Retrosternal goitre  Outpouching of oesophagus between upper boarder of . Thoracic aortic aneurysm cricopharyngeus muscle and lower boarder of inferior

constrictor of pharynx Motility Disorders . Weak area called Killian’s dehiscence.  Local  Defect usually occurs posteriorly but swelling usually . Achalasia bulges to left side of neck. . Diffuse oesophageal spasm  Food debris → pouch expansion → oesophageal . Nutcracker oesophagus compression → dysphagia. . Bulbar / pseudobulbar palsy (CVA, MND)  Pres: regurgitation, halitosis, gurgling sounds  Systemic . Systemic sclerosis / CREST  Rx: excision, endoscopic stapling . MG

Presentation Diffuse Oesophageal Spasm  Dysphagia for liquids and solids at start  Intermittent dysphagia ± chest pain . Yes: motility disorder  Ba swallow shows corkscrew oesophagus . No, solids > liquids: stricture  Difficulty making swallowing movement: bulbar palsy  Odonophagia: Ca, oesophageal ulcer, spasm Nutcracker Oesophagus  Intermittent: oesophageal spasm  ↑ contraction pressure ¯c normal peristalsis  Constant and worsening: malignant stricture  Neck bulges or gurgles on drinking: pharyngeal pouch

Signs  Cachexia  Anaemia  Virchow’s node (+ve = Troisier’s sign)  Neurology  Signs of systemic disease (e.g. scleroderma)

Ix  Bloods: FBC, U+E  CXR  OGD  Barium swallow ± video fluoroscopy  Oesophageal manometrry

Definition Eradication Therapy  Non-specific group of symptoms  7 days Rx 13  Epigastric pain  NB. PPIs and cimetidine → false –ve C breath tests  Bloating and antigen tests  stop >2wks before.  Heartburn PAC 500 ALARM Symptoms  PPI: lansoprazole 30mg BD  Anaemia  Amoxicillin 1g BD  Loss of wt.  Clarithromycin 500mg BD

 Anorexia PMC 250  Recent onset progressive symptoms  PPI: lansoprazole 30mg BD  Melaena or haematemesis  Metronidazole 400mg BD  Swallowing difficulty  Clarithromycin 250mg BD

Failure Causes  95% success  Inflammation: GORD, gastritis, PUD  Mostly due to poor compliance  Ca: oesophageal, gastric  Add bismuth  Functional: non-ulcer dyspepsia . Stools become tarry black

Mx of New Onset Dyspepsia

 OGD if >55 or ALARMS

 Try conservative measures for 4 wks . Stop drugs: NSAIDs, CCBs (relax LOS) . Lose wt., stop smoking, ↓ EtOH . Avoid hot drinks and spicy food . OTC  Antacids: magnesium trisilicate  Alginates: gaviscon advance

 Test for H. pylori if no improvement: breath or serology . +ve → eradication therapy  Consider OGD if no improvement . -ve → PPI trial for 4wks  Consider OGD if no improvement  PPIs can be used intermittently to control symptoms.

 Proven GORD . Full dose PPI for 1-2mo . Then, low-dose PPI PRN

 Proven PUD . Full dose PPI for 1-2mo . H. pylori eradication if positive . Endoscopy to check for resolution if GU . Then, low-dose PPI PRN

Classification  Acute: usually due to drugs (NSAIDs, steroids) or “stress”  Chronic: drugs, H. pylori, ↑Ca, Zollinger-Ellison

Features

Duodenal Ulcers Gastric Ulcers Pathology  4x commoner cf. GU  Lesser curve of gastric antrum  1st part of duodenum (cap)  Beware ulcers elsewhere (often malignant)  M>F

Risk Factors  H. pylori (90%)  H. pylori (80%)  Drugs: NSAIDs, steroids  Smoking  Smoking  Drugs  EtOH  Delayed gastric emptying  ↑ gastric emptying  Stress  Blood group O . Cushing’s: intracranial disease . Curling’s: burns, sepsis, trauma

Presentation  Epigastric pain:  Epigastric pain: . Before meals and at night . Worse on eating . Relieved by eating or milk . Relieved by antacids  Wt. loss

Complications Surgery for PUD Haemorrhage  Haematemeis or melaena Concepts  Fe deficiency anaemia  No acid → no ulcer Perforation  Secretion stimulated by gastrin and vagus N.  Peritonitis Gastric Outflow Obstruction Vagotomy  Vomiting, colic, distension  Truncal: ↓ acid secretion but prevents pyloric sphincter Malignancy relaxation  must be combined ¯c pyloroplasty or  ↑ risk ¯c H. pylori gastroenterostomy.  Selective: vagus nerve only denervated where it supplies lower oesophagus and stomach Ix . Nerves of Laterjet (supply pylorus) left intact  Bloods: FBC, urea (↑ in haemorrhage) 13  C breath test Antrectomy ¯c vagotomy  OGD (stop PPIs >2wks before)  Distal half of stomach removed + anastomosis: . CLO / urease test for H. pylori . Directly to duodenum: Billroth 1 . Always take biopsies of ulcers to check for Ca . To small bowel loop ¯c duodenal stump oversewn:  Gastrin levels if Zollinger-Ellison suspected Billroth 2 or Polya

Subtotal gastrectomy c¯ Roux-en-Y Mx  Occasionally performed for Zollinger-Ellison

Conservative Complications  Lose wt. Physical  Stop smoking and ↓ EtOH  Stump leakage  Avoid hot drinks and spicy food  Abdominal fullness  Stop drugs: NSAIDs, steroids  Reflux or bilious vomiting (improves ¯c time)  OTC antacids  Stricture

Medical Metabolic  OTC antacids: Gaviscon, Mg trisilicate  Dumping syndrome  H. pylori eradication: PAC500 or PMC250 . Abdo distension, flushing, n/v  Full-dose acid suppression for 1-2mo . Early: osmotic hypovolaemia . PPIs: lansoprazole 30mg OD . Late: reactive hypoglycaemia . H2RAs: ranitidine 300mg nocte  Blind loop syndrome → malabsorption, diarrhoea  Low-dose acid suppression PRN . Overgrowth of bacteria in duodenal stump . Anaemia: Fe + B12 . Osteoporosis  Wt. loss: malabsorption of ↓ calories intake © Alasdair Scott, 2012 83 GORD

Pathophysiology Rx  LOS dysfunction → reflux of gastric contents → oesophagitis. Conservative  Lose wt. Risk Factors  Raise head of bed  Hiatus hernia  Small regular meals ≥ 3h before bed  Smoking  Stop smoking and ↓ EtOH  EtOH  Avoid hot drinks and spicy food  Obesity  Stop drugs: NSAIDs, steroids, CCBs, nitrates  Pregnancy  Drugs: anti-AChM, nitrates, CCB, TCAs Medical  Iatrogenic: Heller’s myotomy  OTC antacids: Gaviscon, Mg trisilicate  1: Full-dose PPI for 1-2mo Symptoms . Lansoprazole 30mg OD  2: No response → double dose PPI BD Oesophageal  3: No response: add an H2RA  Heartburn . Ranitidine 300mg nocte . Related to meals  Control: low-dose acid suppression PRN . Worse lying down / stooping . Relieved by antacids Surgical: Nissen Fundoplication  Belching  Indications: all 3 of:  Acid brash, water brash . Severe symptoms  Odonophagia . Refractory to medical therapy . Confirmed reflux (pH monitoring) Extra-oesophageal  Nocturnal asthma Nissen Fundoplication  Chronic cough  Aim: prevent reflux, repair diaphragm  Laryngitis, sinusitis  Usually laparoscopic approach  Mobilise gastric fundus and wrap around lower Complications oesophagus  Oesophagitis: heartburn  Close any diaphragmatic hiatus  Ulceration: rarely → haematemesis, melaena, ↓Fe  Complications: . Gas-bloat syn.: inability to belch / vomit  Benign stricture: dysphagia . Dysphagia if wrap too tight  Barrett’s oesophagus . Intestinal metaplasia of squamous epithelium . Metaplasia → dysplasia → adenocarcinoma Hiatus Hernia  Oesophageal adenocarcinoma Classification Differential Dx  Oesophagitis Sliding (80%) . Infection: CMV, candida  Gastro-oesophageal junction slides up into chest . IBD  Often assoc. ¯c GORD . Caustic substances / burns  PUD Rolling (15%)  Oesophageal Ca  Gastro-oesophageal junction remains in abdomen but a bulge of stomach rolls into chest alongside the Ix oesophagus  Isolated symptoms don’t need Ix  LOS remains intact so GORD uncommon  Bloods: FBC  Can → strangulation  CXR: hiatus hernia may be seen  OGD if: Mixed (5%) . >55yrs . Symptoms >4wks Ix . Dysphagia  CXR: gas bubble and fluid level in chest . Persistent symptoms despite Rx  Ba swallow: diagnostic . Wt. loss  OGD: visualises the mucosa but can’t exclude hernia . OGD allows grading by Los Angeles  24h pH + manometry: exclude dysmotility or achalsia Classification  Ba swallow: hiatus hernia, dysmotility Rx  24h pH testing ± manometry  Lose wt. . pH <4 for >4hrs  Rx reflux

 Surgery if intractable symptoms despite medical Rx. . Should repair rolling hernia (even if asympto) as it may strangulate. © Alasdair Scott, 2012 84 Haematemesis Differential Rectal Bleeding Differential

VINTAGE DRIPING Arse

Varices Diverticulae

Inflammation Rectal  Oesophago-gastro-duodenitis  Haemorrhoids  PUD: DU is commonest cause Infection Neoplasia  Campylobacter, shigella, E. coli, C. diff, amoebic  Oesophageal or gastric Ca dysentery

Trauma Polyps  Mallory-Weiss Tear . Mucosal tear due to vomiting Inflammation  Boerhaave’s Syndrome  UC, Crohn’s . Full-thickness tear . 2cm proximal to LOS Neoplasia

Angiodysplasia + other vascular anomalies Gastic-upper bowel bleeding  Angiodysplasia  HHT Angio  Dieulafoy lesion: rupture of large arteriole in stomach or  Ischaemic colitis other bowel  HHT  Angiodysplasia Generalised bleeding diathesis  Warfarin, thrombolytics  CRF

Epistaxis

© Alasdair Scott, 2012 85 Upper GI Bleeding Hx  Previous bleeds Management  Dyspepsia, known ulcers  Liver disease or oesophageal varices Resuscitate  Dysphagia, wt. loss  Head-down.  Drugs and EtOH  100% O2, protect airway  Co-morbidities  2 x 14G cannulae + IV crystalloid infusion up to 1L.  Bloods: FBC, U+E (↑ urea), LFTs, clotting, x-match o/e 6u, ABG, glucose  Signs of CLD  PR:melaena  Shock? Blood if remains shocked . Cool, clammy, CRT>2s  Group specific or O- until X-matched . ↓BP (<100) or postural hypotension (>20 drop) . ↓ urine output (<30ml/h) . Tachycardia . ↓GCS Variceal Bleed  Terlipressin IV (splanchnic vasopressor) Common Causes  Prophylactic Abx: e.g. ciprofloxacin 1g/24h  PUD: 40% (DU commonly)  Acute erosions / gastritis:20%  Mallory-Weiss tear: 10% Maintenance  Varices: 5%  Crystalloid IVI, transfuse if necessary (keep Hb≥10)  Oesophagitis: 5%  Catheter + consider CVP (aim for >5cm H2O)  Ca Stomach / oesophagus:<3%  Correct coagulopathy: vit K, FFP, platelets  Thiamine if EtOH Rockall Score: (Prof T Rockall, St. Mary’s)  Notify surgeons of severe bleeds  Prediction of re-bleeding and mortality  40% of re-bleeders die  Initial score pre-endoscopy Urgent Endoscopy . Age Haemostasis of vessel or ulcer: . Shock: BP, pulse  Adrenaline injection . Comorbidities  Thermal / laser coagulation  Final score post-endoscopy . Final Dx + evidence of recent haemorrhage  Fibrin glue  Active bleeding  Endoclips

 Visible vessel Variceal bleeding:  Adherent clot  2 of: banding, sclerotherapy, adrenaline,  Initial score ≥3 or final >6 are indications for surgery coagulation

 Balloon tamponade ¯c Sengstaken-Blakemore tube Oesophageal Varices . Only used if exsanguinating haemorrhage or  Portal HTN → dilated veins @ sites of porto-systemic failure of endoscopic therapy anastomosis: L. gastric and inferior oesophageal veins  TIPSS if bleeding can’t be stopped endoscopically  30-50% ¯c portal HTN will bleed from varices  Overall mortality 25%: ↑ ¯c severity of liver disease.

Causes of portal HTN After endoscopy  Pre-hepatic: portal vein thrombosis  Omeprazole IV + continuation PO (↓s re-bleeding)  Hepatic: cirrhosis (80% in UK), schisto (commonest  Keep NBM for 24h → clear fluids → light diet @ 48h worldwide), sarcoidosis.  Daily bloods: FBC, U+E, LFT, clotting  Post-hepatic: Budd-Chiari, RHF, constrict pericarditis  H. pylori testing and eradication  Stop NSAIDs, steroids et.c. Bleed Prevention  1O: β-B, repeat endoscopic banding O  2 : β-B, repeat banding, TIPSS Indications for Surgery  Re-bleeding Transjugular Intrahepatic Porto-Systemic Shunt (TIPSS)  Bleeding despite transfusing 6u  IR creates artificial channel between hepatic vein and  Uncontrollable bleeding at endoscopy portal vein → ↓ portal pressure.  Initial Rockall score ≥3, or final >6.  Colapinto needle creates tract through liver Open stomach, find bleeder and underrun vessel. parenchyma which is expand using a balloon and maintained by placement of a stent.  Used prophylactically or acutely if endoscopic therapy NB. Avoid 0.9% NS in uncompensated liver disease (worsens fails to control variceal bleeding. ascites). Use blood or albumin for resus and 5% dex for maintenance. © Alasdair Scott, 2012 86 Jaundice

Physiology  Normal BR = 3-17uM  Jaundice visible @ 50uM (3 x ULN)  Hb → unconjugated to BR by splenic macrophages  uBR → cBR by BR-UDP-glucuronyl transferase in liver  Secreted in bile then cBR → urobilinogen (colourless) . Some urobilinogen is reabsorbed, returned to liver and re-excreted into bile. . Some reabsorbed urobilinogen is excreted into the urine . The urobilinogen that remains in the GIT is converted to stercobilin (brown) and excreted.

Causes

Pre-Hepatic Hepatic Post-Hepatic Unconjugated Conjugated Excess BR production ↓ BR Uptake Hepatocellular Dysfunction Obstruction  Haemolytic anaemia  Drugs: contrast, RMP  Congen: HH, Wilson’s, α1ATD  Stones  Ineffective erythropoiesis  CCF  Infection: Hep A/B/C, CMV, EBV  Ca pancreas . e.g. thalassaemia  Toxin: EtOH, drugs  Drugs ↓ BR Conjugation  AI: AIH  PBC  Hypothyroidism  Neoplasia: HCC, mets  PSC  Gilbert’s (AD)  Vasc: Budd-Chiari  Biliary atresia  Crigler-Najjar (AR)  Choledochal cyst ↓ Hepatic BR Excretion  Cholangio Ca Neonatal jaundice is both  Dubin-Johnson ↑ production + ↓ conjug.  Rotor’s

Drug-induced Jaundice Gilbert’s  Auto dom partial UDP-GT deficiency Mechanism Drug  2% of the population Haemolysis  Antimalarials (e.g. dapsone)  Jaundice occurs during intercurrent illness  Dx: ↑ uBR on fasting, normal LFTs Hepatitis  Paracetamol OD  RMP, INH, PZA Crigler-Najjar  Valproate  Rare auto rec total UDP-GT deficiency  Statins  Severe neonatal jaundice and kernicterus  Halothane  Rx: liver Tx  MOAIs

Cholestasis  Fluclox (may be wks after Rx)  Co-amoxiclav  OCP  Sulfonylureas  Chlopromazine, prochlorperazine

Pre-Hepatic Hepatic Post-Hepatic Urine  No BR (acholuric)  ↑BR  ↑↑ BR  ↑ urobilinogen  ↑ urobilinogen  No urobilinogen  ↑Hb if intravascular haemolysis LFTs  ↑ uBR  ↑ cBR (usually)  ↑↑ cBR  ↑ AST  ↑AST:↑ALT  ↑ AST, ↑ ALT  ↑ LDH . > 2 = EtOH  ↑↑ ALP . < 1 = Viral  ↑ GGT  ↑ GGT (EtOH, obstruction)  ↑ ALP  Function: ↓ albumin, ↑ PT Other  FBC and film  FBC: anaemia  Abdo US: ducts >6mm  Coombs Test  Anti- SMA, LKM, SLA, ANA  ERCP, MRCP  Hb electrophoresis  α1AT, ferritin, caeruloplasmin  Anti- AMA, ANCA, ANA  Liver biopsy

Causes Mx  Cirrhosis (see below)  Manage in ITU  Acute  Rx underlying cause: e.g. NAC in paracetamol OD . Infection: Hep A/B, CMV, EBV, leptospirosis  Good nutrition: e.g. via NGT ¯c high carbs . Toxin: EtOH, paracetamol, isoniazid, halothane  Thiamine supplements . Vasc: Budd-Chiari  Prophylactic PPIs vs. stress ulcers . Other: Wilson’s, AIH . Obs: eclampsia, acute fatty liver of pregnancy Monitoring  Fluids: urinary and central venous catheters Signs  Bloods: daily FBC, U+E, LFT, INR  Jaundice  Glucose: 1-4hrly + 10% dextrose IV 1L/12h  Oedema + ascites  Bruising Complications  Encephalopathy  Bleeding: Vit K, platelets, FFP, blood . Aterixis  Sepsis: tazocin (avoid gent: nephrotoxicity) . Constructional apraxia (5-pointed star)  Ascites: fluid and salt restrict, spiro, fruse, tap, daily wt  Fetor hepaticus  Hypoglycaemia: regular BMs, IV glucose if <2mM  Signs of cirrhosis / chronic liver disease  Encephalopathy: avoid sedatives, lactulose ± enemas, rifaximin Ix  Seizures: lorazepam Blood  Cerebral oedema: mannitol  FBC: infection, GI bleed, ↓ MCV (EtOH)  U+E Prescribing in Liver Failure . ↓U, ↑Cr: hepatorenal syndrome  Avoid: opiates, oral hypoglycaemics, Na-containing IVI . Urea synth in liver  poor test of renal function  Warfarin effects ↑  LFT  Hepatotoxic drugs: paracetamol, methotrexate, . AST:ALT > 2 = EtOH isoniazid, salicylates, tetracycline . AST:ALT < 1 = Viral . Albumin: ↓ in chronic liver failure Poor Prognostic Factors . PT: ↑ in acute liver failure  Grade 3/4 hepatic encephalopathy  Clotting: ↑INR  Age >40yrs  Glucose  Albumin <30g/L  ABG: metabolic acidosis  ↑INR  Cause: Ferritin, α1AT, caeruloplasmin, Abs,  Drug-induced liver failure paracetamol levels

Microbiology  Hep, CMV, EBV serology Liver Transplant

 Blood and urine culture Types  Ascites MCS + SAAG Cadaveric: heart-beating or non-heart beating  Radiology  Live: right lobe  CXR Kings College Hospital Criteria in Acute Failure  Abdo US + portal vein duplex

Paracetamol-induced Non-paracetamol Hepatorenal Syndrome pH< 7.3 24h after ingestion PT > 100s  Renal failure in pts. ¯c advanced CLF Or all of: Or 3 out of 5 of:  Dx of exclusion PT > 100s Drug-induced Cr > 300uM Age <10 or >40 Pathophysiology: “Underfill theory” Grade 3/4 encephalopathy >1wk from jaundice to  Cirrhosis → splanchnic arterial vasodilatation → encephalopathy effective circulatory volume → RAS activation → renal PT > 50s arterial vasoconstriction. BR ≥ 300uM  Persistent underfilling of renal circulation → failure

Classification  Type 1: rapidly progressive deterioration (survival <2wks)  Type 2: steady deterioration (survival ~6mo)

Rx  IV albumin + splanchnic vasoconstrictors (terlipressin)  Haemodialysis as supportive Rx  Liver Tx is Rx of choice

Causes Ix  Common Bloods . Chronic EtOH  FBC: ↓WCC and ↓ plats indicate hypersplenism . Chronic HCV (and HBV)  ↑LFTs . NAFLD / NASH  ↑INR  Other  ↓Albumin . Genetic: Wilson’s, α1ATD, HH, CF . AI: AH, PBC, PSC Find Cause . Drugs: Methotrexate, amiodarone, methyldopa,  EtOH: ↑MCV, ↑GGT INH  NASH: hyperlipidaemia, ↑ glucose . Neoplasm: HCC, mets  Infection: Hep, CMV, EBV serology . Vasc: Budd-Chiari, RHF, constrict. pericarditis  Genetic: Ferritin, α1AT, caeruloplasmin (↓ in Wilson’s)  Autoimmune: Abs (there is lots of cross-over) Signs . AIH: SMA, SLA, LKM, ANA . PBC: AMA Hands . PSC: ANCA, ANA  Clubbing (± periostitis) . Ig: ↑IgG – AIH, ↑IgM – PBC  Leuconychia (↓ albumin)  Ca: α-fetoprotein  Terry’s nails (white proximally, red distally)  Palmer erythema Abdo US + PV Duplex  Dupuytron’s contracture  Small / large liver  Focal lesions Face  Reversed portal vein flow  Pallor: ACD  Ascites  Xanthelasma: PBC  Parotid enlargement (esp. ¯c EtOH) Ascitic Tap + MCS  PMN >250mm3 indicates SBP Trunk  Spider naevi (>5, fill from centre) Liver biopsy  Gynaecomastia  Loss of 2O sexual hair Mx General Abdo  Good nutrition  Striae  EtOH abstinence: baclofen helps ↓ cravings  Hepatomegaly (may be small in late disease)  Colestyramine for pruritus  Splenomegaly  Screening  Dilated superficial veins (Caput medusa) . HCC: US and AFP  Testicular atrophy . Oesophageal varices: endoscopy

Specific Complications  HCV: Interferon-α  PBC: Ursodeoxycholic acid 1. Decompensation → Hepatic Failure  Wilson’s: Penicillamine  Jaundice (conjugated)  Encephalopathy Complications  Hypoalbuminaemia → oedema + ascites  Varices: OGD screening + banding  Coagulopathy → bruising  HCC: US + AFP every 3-6mo  Hypoglycaemia Decompensation 2. SBP  Ascites: fluid and salt restrict, spiro, fruse, tap, daily wt  Coagulopathy: Vit K, platelets, FFP, blood 3. Portal Hypertension: SAVE  Encephalopathy: avoid sedatives, lactulose ± enemas,  Splenomegaly rifaximin  Ascites  Sepsis / SBP: tazocin (avoid gent: nephrotoxicity)  Varices  Hepatorenal syndrome: IV albumin + terlipressin . Oesophageal varices (90% of cirrhotics) . Caput medusa Child-Pugh Grading of Cirrhosis . Worsens existing piles  Predicts risk of bleeding, mortality and need for Tx  Encephalopathy  Graded A-C using severity of 5 factors . Albumin 4. ↑ risk of HCC . Bilirubin . Clotting . Distension: Ascites . Encephalopathy  Score >8 = significant risk of variceal bleeding © Alasdair Scott, 2012 89 Portal Hypertension

Causes Sequelae: SAVE  Pre-hepatic: portal vein thrombosis (e.g. pancreatitis)  Splenomegaly  Hepatic: cirrhosis (80% in UK), schisto (commonest  Ascites worldwide), sarcoidosis.  Varices  Post-hepatic: Budd-Chiari, RHF, constrictive  Encephalopathy pericarditis, TR

Portosystemic Anastomoses Ascites

Effect Portal Systemic Pathophysiology Oesophageal Left and short Inf. oesophageal  Back-pressure → fluid exudation varices gastric veins veins  ↓ effective circulating volume → RAS activation Caput medusae Peri-umbilical Superficial abdo wall  (In cirrhosis: ↓ albumin → ↓ plasma oncotic pressure veins veins and aldosterone metabolism impaired) Haemorrhoids Sup. rectal veins Inf. and mid. Rectal (worsened veins Symptoms  Distension → abdominal discomfort and anorexia Prominent Abdominal Veins  Dyspnoea  A lot more common than caput medusa  ↓ venous return  Blood flow down below the umbilicus: portal HTN  Blood flow up below the umbilicus: IVC obstruction Differential: Serum Ascites Albumin Gradient (SAGG)  SAAG ≥1.1g/dL = Portal HTN (97% accuracy) Encephalopathy . Pre-, hepatic and post . Cirrhosis in 80% Pathophysiology  SAAG <1.1g/dL = Other Causes  ↓ hepatic metabolic function . Neoplasia: peritoneal or visceral (e.g. ovarian)  Diversion of toxins from liver directly into systemic . Inflammation: e.g. pancreatitis system. . Nephrotic Syndrome . Infection: TB peritonitis  Ammonia accumulates and pass to brain where

astrocytes clear it causing glutamate → glutamine Ix  ↑ glutamine → osmotic imbalance → cerebral oedema. Bloods: FBC, U+E, LFTs, INR, chronic hepatitis screen  Classification  US: confirm ascites, liver echogenicity, PV duplex  1: Confused – irritable, mild confusion, sleep inversion  Ascitic tap . MCS and AFB  2: Drowsy – ↑ disorientated, slurred speech, asterixis . Cytology  3: Stupor – rousable, incoherence . Chemistry: albumin, LDH, glucose, protein  4: Coma – unrousable, ± extensor plantars . SAAG = serum albumin – ascites albumin

 Liver biopsy Presentation

 Asterixis, ataxia Rx  Confusion  Daily wt. aiming for ≤0.5kg/d reduction  Dysarthria  Fluid restrict <1.5L/d and low Na diet  Constructional apraxia  Spironolactone + frusemide (if response poor)  Seizures  Therapeutic paracentesis ¯c albumin infusion (100ml

20% albumin /L drained) Precipitants → HEPATICS . Respiratory compromise  Haemorrhage: e.g. varices . Pain / discomfort  Electrolytes: ↓K, ↓Na . Renal impairment  Poisons: diuretics, sedatives, anaesthetics  Refractory: TIPSS  Alcohol  Tumour: HCC SBP  Infection: SBP, pneumonia, UTI, HDV  Pt. ¯c ascites and peritonitic abdomen  Constipation (commonest cause)  E. coli, Klebsiella, Streps  Sugar (glucose) ↓: e.g. low calorie diet  Complicated by hepatorenal syn. in 30% 3  Ix: ascitic PMN > 250mm + MC+S Ix  Rx: Tazocin or cefotaxime until sensitivities known  ↑ plasma NH 4  Prophylaxis: high recurrence  cipro long-term

Rx  Nurse 20O head up Splenomegaly  Correct any precipitants  Splenic congestion  Avoid sedatives  Hypersplenism: ↓ WCC, ↓ plats

 Lactulose ± PO4 enemas to ↓ nitrogen-forming bowel bacteria → 2-4 soft stools/d  Consider rifaximin PO to kill intestinal microflora © Alasdair Scott, 2012 90 Alcoholism Alcoholic Hepatitis

Effects Presentation  Anorexia Hepatic  D/V  Fatty liver → hepatitits → cirrhosis  Tender hepatomegaly  AST:ALT >2, ↑ GGT  Ascites  Severe: Jaundice, bleeding, encephalopathy GIT  Gastritis, erosions Ix  PUD  Bloods: ↑MCV, ↑GGT, AST:ALT>2  Varices  Ascitic tap  Pancreatitis  Abdo US + PV duplex  Carcinoma Rx CNS  Stop EtOH  Poor memory / cognition  Rx withdrawal  Peripheral polyneuropathy (mainly sensory)  High dose B vitamins: Pabrinex  Wernicke’s encephalopathy  Optimise nutrition . Confusion . Ophthalmoplegia (nystagmus, LR palsy)  Daily wt., LFT, U+E, INR . Ataxia  Mx complications of failure  Korsakoff’s: amnesia → confabulation  Fits, falls Prognosis  Maddrey score predicts mortality Heart . Mild: 0-5% 30d mortality  Arrhythmias: e.g. AF . Severe: 50% 30d mortality  Dilated cardiomyopathy . 1yr after admission: 40% mortality  ↑BP

Blood  ↑ MCV  Folate deficiency → anaemia

Dx: CAGE  Cut down?  Annoyed by people’s criticisms  Guilty about drinking  Eye opener?

Withdrawal  10-72h after last drink  Consider in new ward pt (≤3d) ¯c acute confusion  Signs . ↑HR, ↓BP, tremor . Confusion, fits, hallucinations: esp formication (DTs)  Rx . Tapering regimen of chlordiazepoxide PO / lorazepam IM . Thiamine

Mx  Group therapy or self-help (e.g. AA)  Baclofen: ↓ cravings  Acamprosate: ↓ cravings  Disulfiram: aversion therapy

insulin resistance and the metabolic syndrome. Type Spread Cause  Non-alcoholic steatohepatitis (NASH) is most extreme A FO Seafood, especially abroad form and → cirrhosis in 10% B IV Blood, body fluids, babies (vertical) C IV Mainly blood. Less vertical cf. HCV Risk Factors D IV Dependent on prior HBV infection  Obesity E FO Developing world  HTN

 T2DM Presentation  Hyperlipidaemia

Prodromal Phase  Seen particularly in HAV and BV Presentation  Flu-like, malaise, arthralgia, nausea  Mostly asymptomatic  Distaste for cigarettes in Hep A  Hepatomegaly and RUQ discomfort may be present.

Icteric Phase Metabolic Syndrome Central obesity (↑ waist circumference) and two of:  Acute jaundice in A>B>C (99, 75 and 25%)  . ↑ Triglycerides  Hepatitis . ↓ HDL . Abdo pain . HTN . Hepatomegaly . Hyperglycaemia: DM, IGT, IFG . Cholestasis: dark urine, pale stools

 Extrahepatic features due to complexes (esp. Hep B) . Urticaria or vasculitic rash Ix . Cryoglobulinaemia  BMI . PAN  Glucose, fasting lipids . GN  ↑ transaminases: AST:ALT <1 . Arthritis  Liver biopsy

Chronic Phase Mx  Mainly HCV and childhood HBV  Lose wt.  Cirrhosis → ↑ risk of HCC  Control HTN, DM and lipids

Hep B  Carrier: 10% . HBsAg +ve > 6mo Budd-Chiari Syndrome  Chronic hepatitis: 10%  Hepatic vein obstruction → ischaemia and hepatocyte  Cirrhosis: 5% damage → liver failure or insidious cirrhosis.

Hep C  Carrier: 80% Causes . HCV RNA+ve >6mo  Hypercoagulable states: myeloproliferative disorders  Chronic hepatitis: 80% (PV = commonest cause), PNH, anti-phospholipid, OCP  Cirrhosis: 20%  Local Tumour: HCC  Congenital: membranous obstruction of IVC Ix  FBC, LFTs, clotting Presentation  Hep A/B/C serology  RUQ pain: stretching of Glisson’s capsule  Hepatomegaly Rx  Ascites: SAAG ≥1.1g/dL  Supportive  Jaundice (and other features of liver failure) . No EtOH . Avoid hepatotoxic drugs (e.g. aspirin) Ix  Anti-viral  Bloods: FBC, clotting, LFTs . Indicated in chronic disease  US + hepatic vein Doppler . HBV: PEGinterferon  Ascitic tap: ↑↑ protein (>2.5g/dL) ¯c ↑SAAG (≥1.1g/dL) . HCV: PEGinterferon + ribavarin  Other: JAK2 mutation analysis, RBC CD55 and CD59 . Seroconversion: HBV – 40%, HCV – 10% Rx  Anticoagulate unless there are varices  Ascites: fluid and salt restrict, spiro, fruse, tap, daily wt  Other options: thrombolysis, angioplasty, TIPSS  Transplant if fulminant hepatic failure or cirrhosis  Rx underlying cause

Epidemiology Epidemiology  Prevalence: 1/3000, 10% are carriers.  Prevalence: 1/4000, 10% are carriers  Age of onset: 40-60yrs (women later due to menses)  Genetics: AR, Chr 14  Genetics: AR, HFE gene (High FE) on Chr6 (C282Y) . Homozygotes have PiZZ phenootype

Pathophysiology Pathophysiology  Inherited, multisystem disorder resulting from abnormal  α1AT is a serpin involved in control of the inflammatory iron metabolism. cascade by inhibiting neutrophil elastase.  ↑ intestinal Fe absorption (↑ enterocyte DMT + ↓  α1AT is synthesised in the liver and comprises 90% of hepatocyte hepcidin) → deposition in multiple organs. se α1-globulin on electrophoresis.

Clinical Features: iron MEALS Presentation  Variable presentation Myocardial . Neonatal and childhood hepatitis  Dilated cardiomyopathy . 15% of adults develop cirrhosis by 50yrs  Arrhythmias . 75% of adults have emphysema (esp. smokers)

Endocrine Ix  Pancreas: DM  Blood: ↓ se α1AT levels  Pituitary: hypogonadism → amenorrhoea, infertility  Liver biopsy: PAS+ve, diastase-resistant globules  Parathyroid: hypocalcaemia, osteoporosis  CXR: emphysematous changes  Spirometry: obstructive defect Arthritis  Prenatal Dx: possible by CVS nd rd  2 and 3 MCP joints, knees and shoulders

Liver Mx  Chronic liver disease → cirrhosis → HCC  Mostly supportive for pulmonary and hepatic  Hepatomegaly complications.  Quit smoking Skin  Can consider α1AT therapy from pooled donors.  Slate grey discolouration

Ix  Bloods: ↑LFT, ↑ ferritin, ↑Fe, ↓TIBC, glucose, genotype  X-ray: chondrocalcinosis  ECG, ECHO  Liver biopsy: Pearl’s stain to quantify Fe and severity  MRI: can estimate iron loading

Rx  Iron removal . Venesection: aim for Hct <0.5 . Desferrioxamine is 2nd line  General . Monitor DM . Low Fe diet  Screening . Se ferritin and genotype . Screen 1st degree relatives  Transplant in cirrhosis

Prognosis  Venesection returns life expectancy to normal if non- cirrhotic and non-diabetic.  Cirrhotic patients have >10% chance of HCC

Epidemiology Pathophysiology  Prevalence: 3/100,000  Inflammatory disease of unknown cause characterised  Age: presents between childhood and 30 (never >56) by Abs directed vs. hepatocyte surface antigens  Genetics: AR, ATP7B gene on Chr 13  Predominantly young and middle-aged women  Classified according to Abs . T1: Adult, SMA+ (80%), ANA+ (10%), ↑IgG Pathophysiology . T2: Young, LKM+ . T3: Adult, SLA+  Mutation of Cu transporting ATPase

 Impaired hepatocyte incorporation of Cu into caeruloplasmin and excretion into bile. Presentation  Cu accumulation in liver and, later, other organs  Teens and early 20s (25%) . Constitutional: fatigue, fever, malaise . Cushingoid: hirsute, acne, striae . Hepatitis Clinical Features: CLANKAH . HSM . Fever Cornea . Amenorrhoea  Kayser-Fleischer rings (70%, may need slit-lamp) . Polyarthritis . Pulmonary infiltration Liver Disease . Pleurisy  Children usually present ¯c acute hepatitis.  Post-/peri-menopausal  Fulminant necrosis may occur . Present insidiously ¯c chronic liver disease  → cirrhosis

Arthritis Associated Diseases  Chondrocalcinosis  Autoimmune thyroiditis  Osteoporosis  DM  Pernicious anaemia Neurology  PSC  Parkinsonism: bradykinesia, tremor, chorea, tics  UC  Spasticity, dysarthria, dysphagia  GN  Ataxia  AIHA (Coombs +ve)  Depression, dementia, psychosis

Kidney Ix  Fanconi’s syn. (T2 RTA) → osteomalacia  ↑LFTs

Abortions  ↑IgG  Auto Abs: SMA, LKM, SLA, ANA Haemolytic anaemia  ↓WCC and ↓plats = hypersplenism  Coombs’ negative  Liver biopsy

Ix Mx  Bloods: ↓Cu, ↓ caeruloplasmin  Immunosuppression . Prednisolone NB. Caeruloplasmin is an acute-phase protein and may . Azathioprine as steroid-sparer be high during infection. It may also be low protein-  Liver transplant (disease may recur) deficient states: nephrotic syndrome, malabsorption

 ↑ 24h urinary Cu Prognosis  Liver biopsy: ↑ hepatic Cu  Remission in 80% of patients  MRI: basal-ganglia degeneration  10yr survival 80%

Rx  Diet: avoid high Cu foods: liver, chocolate, nuts  Penicillamine lifelong (Cu chelator) . SE: nausea, rash, ↓WCC, ↓Hb, ↓plats, lupus, haematuria . Monitor FBC and urinary Cu excretion  Liver Tx if severe liver disease  Screen siblings

Epidemiology Pathophysiology  Prev: ≤4/100,000  Inflammation, fibrosis and strictures and intra- and  Sex: F>>M = 9:1 extra-hepatic ducts.  Age: 50s  Chronic biliary obstruction → 2O biliary cirrhosis → liver failure

Pathology  Intrahepatic bile duct destruction by chronic Epidemiology granulomatous inflammation → cirrhosis  Age: 30-50yrs  Sex: M>F = 2:1

Presentation: PPBBCCS Presentation  Often asympto and Dx incidentally (↑ALP)  May be asypmto and Dx incidentally (↑ALP)  Jaundice occurs late

 Pruritus and fatigue Symptoms  Pigmentation of face  Jaundice  Bones: osteoporosis, osteomalacia (↓ vit D)  Pruritus and fatigue  Big organs: HSM  Abdo pain  Cirrhosis and coagulopathy (↓ vit K)  Cholesterol ↑: xanthelasma, xanthomata Signs  Steatorrhoea  Jaundice: dark urine, pale stools  HSM

Associated Diseases Complications  Thyroid disease  Bacterial cholangitis  RA, Sjogrens, scleroderma  ↑ Cholangiocarcinoma  Coeliac disease  ↑ CRC  RTA  Membranous GN Associated Diseases  UC Ix . 3% of those ¯c UC have PSC  LFTs: ↑↑ALP, ↑↑GGT, ↑AST/ALT . 80-100% of those ¯c PSC have UC/Crohn’s . Late: ↑BR, ↑PT, ↓albumin  Crohn’s (much rarer)  Abs: AMA+ (98%)  AIH  ↑IgM  HIV  ↑ cholesterol  ± ↑ TSH  US to exclude extra-hepatic cholestasis Ix  Liver biopsy: non-caseating granulomatous inflam  LFTs: ↑ALP initially, then ↑BR  Abs: pANCA (80%), ANA and SMA may be +ve  ERCP/MRCP: “beaded” appearance of ducts Rx  Biopsy: fibrous, obliterative cholangitis  Symptomatic . Pruritus: colestyramine, naltrexone . Diarrhoea: codeine phosphate Rx . Osteoporosis: bisphosphonates  No curative medical therapy: transplant needed  Specific  Symptomatic . ADEK vitamins . Pruritus: colestyramine, naltrexone . Ursodeoxcholic acid: ↓LFTs but no effect on . Diarrhoea: codeine phosphate mortality or need for transplant  Specific  Liver transplant . ADEK vitamins . End-stage disease or intractable pruritus . Ursodeoxycholic acid improves cholestasis only . Recurrence occurs in ~20% but doesn’t usually . Abx for cholangitis → graft failure. . Endoscopic stenting for dominant strictures  Screening . Cholangiocarcinoma: US + Ca19-9 Prognosis . CRC: colonoscopy  Once jaundice develops survival is <2yrs  Transplant . Recurrence occurs in 30%

Pathology Types  90% of liver tumours are 2O metastases  Cadaveric: heart-beating or non-heart beating . 1O in men: stomach, lung, colon  Live: right lobe . 1O in women: breast, colon, stomach, uterus . Less common: pancreas, leukaemia, lymphoma Indications  90% of primary tumours are HCC.  Advanced cirrhosis  Benign tumours: haemangiomas, adenomas, cysts  HCC

Symptoms Contraindications  Benign tumours are usually asymptomatic  Extra-hepatic malignancy  Systemic: fever, malaise, wt. loss, anorexia  Severe cardiorespiratory disease  RUQ pain: stretching of Glisson’s capsule  Systemic sepsis  Jaundice is often late, except in cholangiocarcinoma  HIV infection  May rupture → intraperitoneal haemorrhage  Non-compliance ¯c drug therapy

Signs Post-op  Hepatomegaly: smooth or hard and irregular  12-24h on ITU  Signs of chronic liver disease  Immunosuppression  Abdominal mass . Ciclosporin / Tacrolimus +  Hepatic bruit (HCC) . Azathioprine / Mycophenolate Mofetil + . Prednisolone Ix  Bloods: LFTs, hepatitis serology, AFP Complications  Imaging:  Acute rejection (T-cell mediated) . US or CT / MRI ± guided diagnostic biopsy . 50% @ 5-10 days . ERCP + biopsy in suspected cholangiocarcinoma . Pyrexia, tender hepatomegaly  Biopsy (seeding may occur along tract) . ↑ or change immunosuppressants  Find primary: e.g. colonoscopy, mammography  Sepsis  Hepatic artery thrombosis Liver Mets  CMV infection  Rx and prognosis vary ¯c type and extent of 1O  Chronic rejection (6-9mo): shrinking bile ducts  Small, solitary CRC mets may be resectable  Disease recurrence (e.g. HBV)  Advanced disease  prognosis: < 6mo Prognosis HCC  Depends on disease aetiology  Rare in West, common in China and sub-Saharan Africa  60-90% 5ys

Causes  Viral hepatitis  Cirrhosis: EtOH, HH, PBC  Aflatoxins (produced by Aspergillus)

Mx  Resection of solitary tumours improves prognosis (13 → 59%), but 50% have recurrence.  Also: chemo, percutaneous ablation and embolization

Cholangiocarcinoma  Biliary tree malignancy (10% of liver 1O tumours)

Causes  Flukes (Clonorchis)  PSC  Congenital biliary cysts  UC

Presentation  Fever, malaise  Abdominal pain, ascites, jaundice  ↑BR, ↑↑ALP

Mx  30% resectable  © PalliativeAlasdair Scott, stenting: 2012 percutaneous or ERCP 96 Inflammatory Bowel Disease: Pathology and Presentation

Epidemiology Pathology

UC Crohn’s UC Crohn’s

Prev 100-200 /100,000 50-100 /100,000 Macroscopic Age 30s 20s Location Rectum + colon Mouth to anus Sex F>M (just) ± backwash ileitis esp. terminal ileum Aet Concordance = 10% Concordance = 70% Distribution Contiguous Skip lesions Smoking protective Smoking ↑ risk Strictures No Yes TH2-mediated TH1/TH17-mediated Microscopic Inflammation Mucosal Transmural Crypt Abscesses Ulceration Shallow, broad Deep, thin, serpiginous → cobblestone mucosa Fibrosis None Marked Granulomas None Present Pseudoplyps Marked Minimal Fistulae No Yes Presentation

UC Crohn’s

Symptoms Systemic Fever, malaise, anorexia, wt. loss in active disease Abdominal  Diarrhoea  Diarrhoea (not usually bloody)  Blood ± mucus PR  Abdominal pain  Abdominal discomfort  Wt. loss  Tenesmus, faecal urgency

Signs Abdominal  Fever  Aphthous ulcers, glossitis  Tender, distended abdomen  Abdominal tenderness  RIF mass  Perianal abscesses, fistulae, tags  Anal / rectal strictures Extra-abdominal Skin Joints  Clubbing  Arthritis (non-deforming, asymm)  Erythema nodosum  Sacroiliitis  Pyoderma gang (esp. UC)  Ank spond HPB Eyes  PSC + cholangiocarcinoma (esp. UC)  Iritis  Gallstones (esp. Crohn’s)  Episcleritis  Fatty liver  Conjunctivitis Other  Amyloidosis  Oxalate renal stones (esp. Crohns)

Complications  Toxic megacolon  Fistulae . Diameter >6cm . Entero-enteric/colonic → diarrhoea . Risk of perforation . Enterovesical → frequency, UTI  Bleeding . Enterovaginal  Malignancy . Perianal → “pepperpot” anus . CRC in 15% ¯c pancolitis for 20yrs  Strictures → obstruction . Cholangiocarcinoma  Abscesses  Strictures → obstruction . Abdominal  Venous thrombosis . Anorectal  Malabsorption . Fat → Steatorrhoea, gallstones . B12 → megaloblastic anaemia . Vit D → osteomalacia . Protein → oedema  Toxic megacolon and Ca may occur (< cf. UC) © Alasdair Scott, 2012 97 Ulcerative Colitis: Management

Ix Inducing Remission in Mild / Mod Disease  Bloods:  OPD-based . FBC: ↓Hb, ↑WCC . LFT: ↓albumin Oral Therapy . ↑CRP/ESR  1st line: 5-ASAs . Blood cultures  2nd line: prednisolone  Stool . MCS: exclude Campy, Shigella, Salmonella… Topical Therapy: mainly left-sided disease . CDT: C. diff may complicate or mimic  Proctitis: suppositories  Imaging  More proximal disease: enemas or foams . AXR: megacolon (>6cm), wall thickening  5-ASAs ± steroids (prednisolone or budesonide) . CXR: perforation . CT Additional Therapy: steroid sparing . Ba / gastrograffin enema  Azathioprine or mercaptopurine  Lead-pipe: no haustra  Infliximab: steroid-dependent pts  Thumbprinting: mucosal thickening  Pseudopolyps: regenerating mucosal island Maintaining Remission  Ileocolonoscopy + regional biopsy: Baron Score  1st line: 5-ASAs PO – sulfasalazine or mesalazine . Topical Rx may be used in proctitis Severity  2nd line: Azathioprine or 6-mercaptopurine . Relapsed on ASA or are steroid-dependent Truelove and Witts Criteria . Use 6-mercaptopurine if azathioprine intolerant  3rd line: Infliximab / adalimumab Mild Moderate Severe Motions <4 4-6 >6 Emergency Surgery PR bleed small moderate large  20% require surgery at some stage Temp Apyrexic 37.1-37.8 >37.8  30% c colitis require surgery w/i 5yrs HR <70 70-90 >90 ¯ Hb >11 10.5-11 <10.5 Indications ESR <30 >30  Toxic megacolon

 Perforation  Massive haemorrhage Acute Severe UC  Failure to respond to medical Rx  Resus: Admit, IV hydration, NBM  Hydrocortisone: IV 100mg QDS + PR Procedures  Transfuse if required  Total / subtotal colectomy ¯c end ileostomy ± mucus  Thromboprophylaxis: LMWH fistula  Monitoring  Followed after ~3mo by either . Bloods: FBC, ESR, CRP, U+E . Completion proctectomy + Ileal-pouch anal . Vitals + stool chart anastomosis (IPAA) or end ileostomy . Twice daily examination . Ileorectal anastomosis (IRA) . ± AXR  Panproctocolectomy + permanent end ileostomy  Acute colitis op mortality: 7% (30% if perforated) NB. RCTs show no benefit of Abx: not routinely recommended . May use: megacolon, perforation, uncertain Dx Elective Surgery Acute Complications  Perforation Indications  Bleeding  Chronic symptoms despite medical therapy  Toxic megacolon (>6cm)  Carcinoma or high-grade dysplasia  VTE Procedures Improvement → oral therapy  Panproctocolectomy ¯c end ileostomy or IPAA  Switch to oral pred + a 5-ASA  Total colectomy ¯c IRA  Taper pred after full remission Surgical Complications No Improvement → rescue therapy  Abdominal  On day 3: stool freq >8 or CRP >45 . SBO . Predicts 85% chance of needing a colectomy during . Anastomotic stricture the admission . Pelvic abscess  Discussion between pt, physician and surgeon  Stoma: retraction, stenosis, prolapse, dermatitis  Medical: ciclosporin, infliximab or visilizumab (anti-T cell)  Pouch  Surgical . Pouchitis (50%): metronidazole + cipro . ↓ female fertility . Faecal leakage © Alasdair Scott, 2012 98 Crohn’s Disease: Management

Ix Inducing Remission in Mild / Mod Disease  Bloods: (top 3 are severity markers)  OPD treatment . FBC: ↓Hb, ↑WCC . LFT: ↓albumin Supportive . ↑CRP/ESR  High fibre diet . Haematinics: Fe, B12, Folate  Vitamin supplements . Blood cultures  Stool Oral Therapy st . MCS: exclude Campy, Shigella, Salmonella…  1 line . CDT: C. diff may complicate or mimic . Ileocaecal: budesonide  Imaging . Colitis: sulfasalazine . AXR: obstruction, sacroileitis  2nd line: prednisolone (tapering) . CXR: perforation  3rd line: methotrexate . MRI  4th line: infliximab or adalimumab  Assess pelvic disease and fistula  Assess disease severity Perianal Disease . Small bowel follow-through or enteroclysis  Occurs in ~50%  Skip lesions  Ix: MRI + EUA  Rose-thorn ulcers  Rx  Cobblestoning: ulceration + mural oedema . Oral Abx: metronidazole  String sign of Kantor: narrow terminal ileum . Immunosuppression ± infliximab  Endoscopy . Local surgery ± seton insertion . Ileocolonoscopy + regional biopsy: Ix of choice . Wireless capsule endoscopy Maintaining Remission . Small bowel enteroscopy  1st line: azathioprine or mercaptopurine  2nd line: methotrexate  3rd line: Infliximab / adalimumab Severe Attack

Assessment Surgery  ↑temp, ↑HR, ↑ESR, ↑CRP, ↑WCC, ↓albumin  50-80% need ≥1 operation in their life  Never curative Management  Should be as conservative as possible  Resus: Admit, NBM, IV hydration  Hydrocortisone: IV + PR if rectal disease Indications  Abx: metronidazole PO or IV  Emergency . Failure to respond to medical Rx  Thromboprophylaxis: LMWH . Intestinal obstruction or perforation  Dietician Review . Massive haemorrhage . Elemental diet  Elective  Liquid prep of amino acids, glucose and fatty . Abscess or fistula acids . Perianal disease . Consider parenteral nutrition . Chronic ill health  Monitoring . Carcinoma . Vitals + stool chart . Daily examination Procedures

 Limited resection: e.g. ileocaecal Improvement → oral therapy  Stricturoplasty  Switch to oral pred (40mg/d)  Defunction distal disease c temporary loop ileostomy ¯ No Improvement → rescue therapy Complications  Discussion between pt, physician and surgeon  Stoma complications  Medical: methotrexate ± infliximab  Enterocutaneous fistulae  Surgical  Anastomotic leak or stricture

Short gut  <1-2m small bowel  Features . Steatorrhoea . ADEK and B12 malabsorption . Bile acid depletion → gallstones . Hyperoxaluria → renal stones  Rx . Dietician . Supplements or TPN . Loperamide © Alasdair Scott, 2012 99 Coeliac Disease

Epidemiology Ix  Prev: 0.5 – 1%  Bloods: FBC, LFTs (↓alb), INR, Vit D and bone, red cell  Age: Any, bimodal: infancy and 50-60yrs folate, serum B12  Sex: F>M  Abs  Geo: ↑ in Ireland and N. Africa . Anti-endomysial IgA (95% specificity) . Anti-TTG IgA Pathophysiology  Both above ↓ ¯c exclusion diet  HLA-DQ2 (95%) and DQ8 . Anti-gliadin IgG persist ¯c exclusion diet)  CD8+ mediated response to gliadin in gluten . IgA ↑ in most but may have IgA deficiency  Stools Presentation: GLIAD . Stool cysts and antibody: exclude Giardia  OGD and duodenal biopsy GI Malabsorption: fatigue, weakness . Subtotal villous atrophy  Carb . Crypt hyperplasia . N/V/D . Intra-epithelial lymphocytes . Abdo distension + colic . Flatus Rx . Wt. ↓  Lifelong gluten-free diet  Fat . Avoid: barley, rye, oats, wheat . Steatorrhoea . OK: Maize, soya, rice . Hyperoxaluria → renal stones . Verify diet by endomysial Ab tests  Protein  Pneumovax as hyposplenic . Protein-losing enteropathy if severe  Dermatitis herpetiformis: dapsone  Haematinics . ↓ Folate and Fe → anaemia  Vitamins . Vit D and Ca → bone pain, osteoporosis Malabsorption . Vit K → petechiae and ↑INR . B2 (riboflavin) → angular stomatitis Presentation . B1 and B6 → polyneuropathy  Diarrhoea / Steatorrhoea  Wt. loss Lymphoma and Carcinoma  Lethargy  Enteropathy-associated T-cell lymphoma  Adenocarcinoma of small bowel Causes  Other Ca: breast, bladder, breast  Common in UK: Coeliac, Chronic pancreatitis, Crohn’s  Rarer Immune Associations . ↓Bile: PBC, ileal resection, colestyramine  IgA deficiency . Pancreatic insufficiency: Ca, CF, chronic panc  T1DM . Small bowel: resection, tropical sprue, metformin  PBC . Bacterial overgrowth: spontaneous, post-op blind loops, DM, PPIs Anaemia . Infection: Giardia, Strongyloides, Crypto parvum  ↑ or ↓ MCV . Hurry: post-gastrectomy dumping  Hyposplenism: Howell-Jolly bodies, target cells Ix Dermatological  Coeliac tests  Dermatitis herpetiformis: 15-20%  Stool microscopy . Symmetrical vesicles, extensor surfaces  Faecal elastase  Esp. elbows  Hydrogen breath test . Very itchy  MRI / CT . Responds to gluten-free diet or dapsone  ERCP (chronic pancreatitis) . Biopsy: granular deposition of IgA  Small bowel endoscopy  Aphthous ulcers

Risk Factors: SINED Causes: AGITS  Smoking  Alcohol  Inflammation: chronic pancreatitis  Genetic  Nutrition: ↑fat diet . CF  EtOH . HH  DM . Hereditary pancreatitis  Immune Pathology . Lymphoplasmacytic sclerosing pancreatitis (↑IgG4)  Mostly ductal adenocarcinoma  Triglycerides ↑  Metastasis early, present late  Structural  60% head . Obstruction by tumour . Pancreas divisum  25% body

 15% tail  Endocrine tumours are rare Presentation  Epigastric pain Presentation . Bores through to back . Relieved by sitting back or hot water bottle →  Typically male >60yrs erythema ab igne  Head: painless obstructive jaundice . Exacerbated by fatty food or EtOH . c dark urine + pale stools ¯  Steatorrhoea  Body / Tail: epigastric pain  Wt. loss . Radiates to back, relieved sitting forward  DM  Anorexia and wt. loss  Epigastric mass: pseudocyst  Acute pancreatitis  Sudden onset DM in the elderly Ix Signs  ↑ glucose  ↓ faecal elastase  Epigastric mass  US: pseudocyst  Jaundice  AXR: speckled pancreatic calcifications  Palpable gallbladder  CT: pancreatic calcifications  Thrombophlebitis migrans (Trousseau Sign)

 Splenomegaly: PV thrombosis → portal HTN  Ascites Rx  Drugs Ix . Analgesia: may need coeliac plexus block . Creon  Bloods: cholestatic LFTs, ↑Ca19-9, ↑Ca . ADEK vitamins  Imaging . DM Rx . US: pancreatic mass, dilated ducts, hepatic mets,  Diet allows biopsy . No EtOH . EUS: better than CT/MRI for staging . ↓ fat, ↑ carb  ERCP  Surgery . Shows anatomy . Ind: unremitting pain, wt. loss . Allows stenting . Pancreatectomy

Rx Complications  Surgery  Pseudocyst . Fit, no mets, tumour ≤3cm (≤10% of pts)  DM . Whipple’s pancreatoduodenectomy Pancreatic Ca . Post-op chemo delays progression  . 5ys = 5-14%  Biliary obstruction  Palliation  Splenic vein thrombosis → splenomegaly . Endoscopic / percutaneous stenting of CBD . Palliative bypass surgery . Pain relief: may need coeliac plexus block

Prognosis  Mean survival <6mo Whipple’s Procedure  5ys = <2%

Pathology Vitamin A → Xerophthalmia  Diverse group of neuroendocrine tumours of  Dry conjunctivae, develop spots (Bitots spots) enterochromaffin cell origin capable of producing 5HT  Corneas become cloudy then ulcerate  May secrete: 5-HT, VIP, gastrin, glucagon, insulin, ACTH  Night blindness → total blindness  Carcinoid syndrome suggest bypass of first-pass metabolism and is strongly assoc. ¯c metastatic disease. Thiamine (B1) → Beri Beri  10% part of MEN1  Wet: heart failure + oedema  Sites  Dry: polyneuropathy . Appendix: 45%  Wernicke’s: ophthalmoplegia, ataxia, confusion . Ileum: 30% . Colorectum: 20% Niacin / Nicotinic acid (B3) → Pellagra . Stomach: 10%  Diarrhoea, Dermatitis, Dementia . Elsewhere in GIT and bronchus  Also: neuropathy, depression, ataxia  Consider all as malignant  Causes: dietary, isoniazid, carcinoid syndrome

Pyridoxine (B6) Presentation  Peripheral sensory neuropathy  Cause: PZA Local  Appendicitis Cyanocobalamin (B12)  Intussusception or obstruction  Glossitis → sore tongue  Abdominal pain  Peripheral neuropathy

. Paraesthesia Carcinoid Syndrome: FIVE HT . Early loss of vibration and proprioception  Flushing: paroxysmal, upper body ± wheals . → ataxia  Intestinal: diarrhoea  SCDC  Valve fibrosis: tricuspid regurg and pulmonary stenosis . Dorsal and corticospinal tracts  whEEze: bronchoconstriction . Sensory loss and UMN weakness  Hepatic involvement: bypassed 1st pass metabolism  Overall mixed UMN and LMN signs ¯c sensory  Tryptophan deficiency → pellagra (3Ds) disturbance . Extensor plantars + absent knee and ankle jerks Ix  ↑ urine 5-hydroxyindoleacetic acid Vitamin C → Scurvy  ↑ plasma chromogranin A  Gingivitis  CT/MRI: find primary  Bleeding: gums, nose, hair follicles (petechial)  Muscle pain / weakness  Oedema Rx  Corkscrew hairs  Symptoms: octreotide or loperamide  Curative Vitamin D → Osteomalacia . Resection: tumours are v. yellow  Bone pain . Give octreotide to avoid carcinoid crisis  #s

Carcinoid Crisis Vitamin K  Tumour outgrows blood supply or is handled too  ↓ factors: 2, 7, 9, 10, C and S much → massive mediator release  Bruising, petechiae  Vasodilatation, hypotension, bronchoconstriction,  Bleeding: e.g. epistaxis, menorrhagia hyperglycaemia  Rx: high-dose octreotide

Prognosis  Median survival is 5-8yrs (~3yrs if mets present)

Contents Renal Physiology ...... 104 Urine ...... 105 Urea and Creatinine ...... 105 Causes of Renal Disease ...... 106 Presentation of Renal Failure ...... 106 Urinary Tract Infection ...... 107 Glomerulonephritis ...... 108 Asymptomatic Haematuria ...... 108 Nephritic Syndrome / Acute GN ...... 109 Nephrotic Syndrome ...... 109 Acute Kidney Injury...... 110 Management of Acute Renal Failure ...... 111 Interstitial Nephritidies ...... 112 Nephrotoxins ...... 112 Chronic Renal Failure ...... 113 Renal Transplant ...... 114 Renal Complications of Systemic Disease ...... 115 Renal Vascular Disease ...... 116 Renal Tubular Disease ...... 116 Renal Cystic Diseases ...... 117

The Glomerulus Diuretics  Epithelial pouch invaginated by capillary tuft  Semi-permeable filter Carbonic Anhydrase Inhibitors (acetazolamide) . Endothelium  MOA: inhibit carbonic anhydrase in PCT . Basement membrane  Effect: ↓ HCO3 reabsorption → small ↑ Na loss . Epithelium  Use: glaucoma  Mesangial cells are specialised smooth muscle cells that  SE: drowsiness, renal stones, metabolic acidosis support the glomerulus and regulate blood flow and GFR

Loop Diuretics (fursemide, bumetanide) Filtration  MOA: inhibit Na/K/2Cl symporter in thick ascending limb  Receive 25% of CO (1200ml/min)  Effect: massive NaCl excretion, Ca and K excretion  20% of blood volume is filtered (~250ml/min)  Use: Rx of oedema – CCF, nephrotic syndrome,  GBM is –vely charged → retention of anionic proteins hypercalcaemia such as albumin which are small enough to pass.  SE: hypokalaemic met alkalosis, ototoxic, Hypovolaemia  Filtration is key to excretion of waste and remains constant over a range of pressures (80-200mmHg).  Flow will depend on Na and water reabsorption. Thiazide Diuretics (bendroflumethazide)

 MOA: inhibit NaCl co-transporter in DCT

 Effect: moderate NaCl excretion, ↑ Ca reabsorption Na Reabsorption  Use: HTN, ↓ renal stones, mild oedema  Main factor determining extracellular volume  SE: ↓K, hyperglycaemia, ↑ urate (CI in gout)  ↓BP and ↓NaCl @ macula densa (DCT) → renin release → aldosterone release → more Na/K pumps.

K-Sparing Diuretics (spironolactone, amiloride)

 MOA Water Reabsorption . Spiro: aldosterone antagonist  Determines ECF osmolality . Amiloride: blocks DCT/CD luminal Na channel  ↑osmolality or ↓BP → ADH release  Effect: ↑ Na excretion, ↓K and H excretion

 Use: used ¯c loop or thiazide diuretics to control K loss,

spiro has long-term benefits in aldosteronsim (LF, HF) The Nephron  SE: ↑K, anti-androgenic (e.g. gynaecomastia)

PCT: Reabsorption of filtrate +  70% of total Na reabsorption Osmotic Diuretics (mannitol)  Reabsorption of amino acids, glucose, cations  MOA: freely filtered and poorly reabsorbed  Bicarbonate reabsorbed using carbonic anhydrase  Effect: ↓ brain volume and ↓ ICP

 Use: glaucoma, ↑ICP, rhabdomyolysis Thick Ascending Limb: Creation of osmolality gradient  SE: ↓Na, pulmonary oedema, n/v  20% of Na reabsorption  Na/K/2Cl triple symporter

DCT: pH and Ca reabsorption  5% of Na reabsorption  Apical NaCl co-transporter  Ca2+ reabsorption under control of PTH

Medullary CD: pH and K regulation  Na reabsorption coupled to K or H excretion  Basolateral aldosterone-sensitive Na/K pump

Cortical CD: Regulation of water reabsorption  Water reabsorption controlled by aquaporin-2 channels

Endocrine Function  Secretion of renin by juxtaglomerular apparatus  EPO synthesis  1α-hydroxylation of vitamin D (controlled by PTH)

Haematuria Creatinine Renal  Creatinine is synthesised during muscle turnover.  Congenital: PCK  Freely filtered and small proportion secreted by PCT  Trauma  ↑ muscle → ↑ creatinine: age, sex, race  Infection: pyelonephritis  Plasma Cr doesn’t ↑ above normal until 50% ↓ in GFR  Neoplasm  Immune: GN, TIN Urea Extra-renal  Produced from ammonia by liver in ornithine cycle  Trauma: stones, catheter  ↑ ¯c protein meal (e.g. upper GI bleed, supplements)  Infection: cystitis, prostatitis, urethritis  ↓ ¯c hepatic impairment  Neoplasm: bladder, prostate  10-70% is reabsorbed: depends on urine flow.  Bleeding diathesis  ↓ flow → ↑ urea reabsorption (e.g. in dehydration)  Drugs: NSAIDs, frusemide, cipro, cephalosporins

NB. False +ve: myoglobin, porphyria Interpretation

 Isolated ↑ urea = ↓ flow (i.e. hypoperfusion / dehydration)  ↑ U and ↑ Cr = ↓ filtration (i.e. renal failure) Proteinuria  30mg/dL = 1+  300mg/dL = 3+ Creatinine Clearance  PCR < 20mg/mM is normal, >300 = nephrotic  Vol of blood that can be cleared of a substance in 1min  CrC roughly approximates GFR as it is freely filtered and Causes only a small proportion secreted (~10%)  Commonest . Slightly overestimates GFR . DM  Requires urine concentration from 24h collection . Minimal change  Can use radiolabelled EDTA: very rarely done . Membranous . Amyloidosis . SLE eGFR  Other . HTN (inc. PET)  Modifiation of Diet in Renal Disease (MDRD) equation . ATN  Serum Cr, sex, age, race . TIN  Obviates need for urine collection . UTI . Fever, orthostatic Problems . Validated for patients ¯c established renal failure: NB. False –ve: Bence-Jones protein ?applicable to general population. . Most elderly people are in ≥ stage 3 CRF by eGFR: Microalbuminuria may not progress or impinge on their health.  Albumin 30-300mg/24h . eGFR is too pessimistic in mild renal impairment  Causes: DM, ↑BP, minimal change GN

Casts  RBC: glomerular haematuria  WBC: interstitial nephritis or pyelonephritis  Tubular: ATN

Differential

Pathology Urine Glomerular Haematuria, proteinuria, red cells / casts Tubular White cell casts, small protein, leukocyturia Pre-renal Nothing CRF Depends on cause

Pre-renal Uraemia (need GFR <15ml/min)  Shock  Renal Vascular Symptoms Signs . RAS . Toxins: NSAIDs, ACEi Pruritus Pale, sallow skin . Thrombosis n/v, anorexia, wt. loss Striae . Hepatorenal syn. Lethargy Pericardial or plueral rub Confusion Fits Restless legs Coma Renal Metallic taste  Glomerulonephritis Paraesthesia: neuropathy  Acute Tubular Necrosis Bleeding  Interstitial disease Chest pain: serositis Hiccoughs

Post-renal +  Diseases of renal papillae, pelvis, ureters, bladder or Protein loss and Na retention urethra. Symptoms Signs  SNIPPIN . Stone . Neoplasm Polyuria, polydipsia Oedema . Inflammation: stricture Oliguria, anuria ↑ JVP . Prostatic hypertrophy Breathlessness HTN (or ↓BP) . Posterior urethral valves . Infection: TB, schisto . Neuro: post-op, neuropathy Acidosis

Symptoms Signs

Breathlessness Kussmaul respiration Confusion

Hyperkalaemia

Symptoms Signs

Palpitations Peaked T waves Chest pain Flattened P waves Weakness ↑ PR interval Widened QRS Sine-wave pattern → VF

Anaemia

Symptoms Signs

Breathlessness Pallor Lethargy Tachycardia Faintness Flow mumurs (ESM @ apex) Tinnitus

Vitamin D Deficiency

Symptoms Signs

Bone pain Osteomalacia #s - Looser’s zones (pseudo#s) - Cupped mataphyses

Definitions Risk Factors  Bacteriuria: bacteria in urine, symptomatic or asympto  Female  UTI: symptomatic ¯c +ve culture or dipstick  Sex  Urethral Syndrome: symptomatic but no bacteriuria  Pregnancy  Menopause Classification  DM  Uncomplicated: normal GU tract and function  Abnormal tract: stone, obstruction, catheter,  Complicated: abnormal GU tract, outflow obstruction, ↓ malformation renal function, impaired host defence, virulent organism  Recurrent: further infection ¯c new organism  Relapse: further infection ¯c same organism Organisms  E. coli  Staphylococcus saprophyticus Presentation  Proteus (alkaline urine → struvite renal stones)  Klebsiella Pyelonephritis  Fever, rigors  Loin pain and tenderness Ix  Vomiting  Dipstick  Oliguria if ARF  MSU for MCS  Bloods: FBC, U+E, blood cultures (if systemic signs) Cystitis  US: children, men, recurrence, pyelonephritis  Frequency and urgency  Polyuria Positive Culture 4  Haematuria  >10 CFU/ml pure growth 3  Dysuria  >10 CFU/ml pure growth of E. coli or S. saprophyticus 5  Suprapubic tenderness  >10 CFU/ml mixed growth ¯c one predominant organism  Foul smelling urine

Prostatitis Rx  Flu-like symptoms  Low backache General  Dysuria  Drink plenty, urinate often  Tender swollen prostate on PR Cystitis  Rx for 3-6d Sterile Pyuria  Trimethoprim 200mg BD  TB  Nitrofurantoin 50mg QDS (not in RF)  Treated UTI  Cefalexin 500mg BD (good in RF)  Appendicitis  Co-amoxiclav 625mg TDS  Calculi  TIN Pyelonephritis  Papillary necrosis  Cefotaxime 1g IV BD for 10d  Polycystic Kidney  No response: Augmentin 1.2g IV TDS + gentamicin  Chemical cystitis (e.g. cyclophosphamide)

Prevention  Drink more  Abx prophylaxis  ? cranberry juice

Features Causes 1. IgA Nephropathy  Group of disorders resulting from glomerular damage 2. Thin BM  Can → proteinuria ± haematuria 3. Alport’s  Can → AKI or ESRF

1. IgA Nephropathy / Berger’s Disease Presentations  Commonest GN in developed world  Asymptomatic haematuria  Nephrotic syndrome Features  Nephritic syndrome  Young male ¯c episodic macroscopic haematuria

occurring a few days after URTI.  Rapid recovery between attacks Causes  ↑IgA  Idiopathic  Can occasionally → nephritic syndrome  Immune: SLE, Goodpastures, vasculitis  Infection: HBV, HCV, Strep, HIV Biopsy: IgA deposition in mesangium  Drugs: penicillamine, gold  Amyloid Rx: Steroids or cyclophosphamide if ↓renal function

Prognosis: 20% ESRF after 20yrs Ix

Blood 2. Thin BM Disease  Basic: FBC, U+E, ESR  Autosomal dominant  Complement (C3 and C4)  Commonest cause of asymptomatic haematuria  Abs: ANA, dsDNA, ANCA, GBM  Serum protein electrophoresis and Ig Features  Infection: ASOT, HBC and HCV serology  Persistent, asymptomatic microscopic haematuria  V. small risk of ESRF Urine  Dipstick: proteinuria ± haematuria  Spot PCR 3. Alport’s Syndrome  MCS  85% X-linked inheritance  Bence-Jones protein Features Imaging  Haematuria, proteinuria → progressive renal failure  CXR: infiltrates (Goodpasture’s, Wegener’s)  Sensorineural deafness  Renal US ± biopsy  Lens dislocation and cataracts  Retinal “flecks”  Females: haematuria only General Mx  Refer to nephrologist  Rx HTN aggressively (≤130/80)  Include and ACEi / ARA

© Alasdair Scott, 2012 108 Nephritic Syndrome / Acute GN Nephrotic Syndrome  Haematuria (macro / micro) + red cell casts  Proteinuria: PCR >300mg/mM or >3g/24h  Proteinuria → oedema (esp. periorbital)  Hypoalbuminaemia: <35g/L  Hypertension  Oedema: periorbital, genital, ascites, peripheral  Oliguria and progressive renal impairment . Often intravascularly depleted ¯c ↓ JVP (cf. CCF)

Causes Complications 1. Proliferative / post-streptococcal  Infection: ↓ Ig, ↓ complement activity 2. Crescentic / RPGN  VTE: up to 40%  Hyperlipidaemia: ↑ cholesterol and triglycerides

1. Proliferative / Post-streptococcal Ix

 As for GN, check lipids Features  Biopsy  Young child develops malaise and nephritic syndrome c ¯ . All adults smoky urine 1-2wks after sore throat or skin infection. st . Steroids 1 ¯c children: mostly minimal change ↑ ASOT   ↓C3 Secondary to Systemic Disease Biopsy: IgG and C3 deposition  DM: glomerulosclerosis  SLE: membranous Rx: Supportive  Amyloidosis

Prognosis 1. Minimal Change Glomerulonephritis  95% of children recover fully  Commonest cause of nephrotic syndrome in children  Minority develop RPGN  Assoc.: URTI  Biopsy: normal light micro, fusion of podocytes on EM  Rx: steroids 2. Crescentic / RPGN  Prog: 1% → ESRF  Most aggressive GN which can → ESRF in days 2. Membranous Nephropathy Type 1: Anti-GBM (Goodpasture’s) – 5%  20-30% of adult nephrotic syndrome  Ab to NC domain of collagen 4  Associations  Haematuria and haemoptysis . Ca: lung, colon, breast  CXR shows infiltrates . AI: SLE, thyroid disease  Rx: Plasmapheresis and immunosuppression . Infections: HBV . Drugs: Penicillamine, gold Type 2: Immune Complex Deposition – 45%  Biopsy: subepithelial immune complex deposits  Complication of any immune complex deposition  Rx: immunosuppression if renal function declines . Berger’s, post-strep, endocarditis, SLE  Prog: 40% spontaneous remission

Type 3: Pauci Immune – 50% 3. FSGS cANCA: Wegener’s   Commoner in Afro-Caribs  pANCA: microscopic polyangiitis, Churg-Strauss  Idiopathic or Secondary: VUR, Berger’s, SCD, HIV Even if ANCA+ve, may still be idiopathic   Biopsy: focal scarring, IgM deposition . i.e. no features of systemic vasculitis  Rx: steroids or cyclophosphamide/ciclosporin

 Prog: 30-50% → ESRF (may recur in transplants)

5. Membranoproliferative / Mesangiocapillary GN  Rare  May → nephrotic (60%) or nephritic (30%) syndrome  Asooc. ¯c HBV, HCV, endocarditis  Prog: 50% → ESRF

Mx  Monitor U+E, BP, fluid balance, wt.  Treat underlying cause  Symptomatic / Complication Rx: . Oedema: salt and fluid restrict + frusemide . Proteinuria: ACEi / ARA ↓ proteinuria . ↑ Lipids: Statin . VTE: Tinzaparin . Rx HTN

Definition RIFLE Classification  Significant decline in renal function over hrs or days  3 grades of AKI and 2 outcomes manifesting as an abrupt and sustained ↑ in Se U and Cr  Classification determined by worst criteria

Causes (Pre-renal and ATN account for ~80%) Classification GFR UO Risk ↑Cr x1.5 <0.5ml/kg/h x 6h Pre-renal: commonest cause ↓GFR >25%  Shock or renovascular compromise (e.g. NSAIDs, ACEi) Injury ↑Cr x 2 <0.5ml/kg/h x 12h ↓GFR >50% Renal Failure ↑Cr x 3 <0.3ml/kg/h x 24h, or  ATN: ↓GFR >75% anuria x12h . Ischaemia: shock, HTN, HUS, TTP Loss Persistent ARF = complete LOF >1mo . Direct nephrotoxins: drugs, contrast, Hb ESKD complete LOF >3mo  Acute TIN: drug hypersensitivity  Nephritic syndrome Rx Post-renal: SNIPPIN General  Identify and Rx pre-renal or post-renal causes Presentation  Urgent US  Uraemia / Azotaemia  Rx exacerbating factors: e.g. sepsis  Acidosis  Give PPIs  Hyperkalaemia  Stop nephrotoxins: NSAIDs, ACEi, gent, vanc  Fluid overload  Stop metformin if Cr > 150mM . Oedema, inc. pulmonary . ↑ BP (or ↓) Monitor . S3 gallop  Catheterise and monitor UO . ↑ JVP  Consider CVP  Fluid balance Clinical Assessment  Wt. 1. Acute or chronic?  Can’t tell for sure: Rx as acute Hyperkalaemia  Chronic features  ECG Features (in order) . Hx of comorbidity: DM, HTN . Peaked T waves . Long duration of symptoms . Flattened P waves . Previously abnormal bloods (GP records) . ↑ PR interval . Widened QRS 2. Volume depleted? . Sine-wave pattern → VF  Postural hypotension  Mx  ↓ JVP . 10ml 10% calcium gluconate  ↑ pulse . 100ml 20% glucose + 10u insulin (Actrapid)  Poor skin turgor, dry mucus membranes . Salbutamol 5mg nebulizer . Calcium resonium 15g PO or 30g PR 3. GU tract obstruction? . Haemofiltration (usually needed if anuric)  Suprapubic discomfort  Palpable bladder Pulmonary Oedema  Enlarged prostate  Sit up and give high-flow O2  Catheter  Morphine 2.5mg IV (± metoclopramide 10mg IV)  Complete anuria (rare in ARF)  Frusemide 120-250mg IV over 1h  GTN spray ± ISMN IVI (unless SBP <100) 4. Rare cause?  If no response consider:  Assoc. ¯c proteinuria ± haematuria . CPAP  Vasculitis: rash, arthralgia, nosebleed . Haemofiltration / haemodialysis ± venesection

Ix Bleeding  ↑ urea impairs haemostasis  Bloods: FBC, U+E, LFT, glucose, clotting, Ca, ESR  FFP + plats as needed  ABG: hypoxia (oedema), acidosis, ↑K+  Transfuse to maintain Hb >10  GN screen: if cause unclear

 Urine: dip, MCS, chemistry (U+E, PCR, osmolality, BJP) Indications for Acute Dialysis (AEIOU)  ECG: hyperkalaemia 1. Persistent hyperkalaemia (>7mM)  CXR: pulmonary oedema 2. Refractory pulmonary oedema  Renal US: Renal size, hydronephrosis 3. Symptomatic uraemia: encephalopathy, pericarditis 4. Severe metabolic acidosis (pH <7.2) NB. in pre-renal failure, urine is concentrated and Na is 5. Poisoning (e.g. aspirin) reabsorbed → ↑osmolality, Na <20mM © Alasdair Scott, 2012 110 Management of Acute Renal Failure

Common Causes  Pre-renal: shock (e.g. sepsis, hypovolaemia), HRS Resuscitate and Assess Fluid Status  Renal: ATN, TIN, GN  A: ↓GCS may need airway Mx  Post-renal: Stone, neoplasm, catheter  B: pulmonary oedema – sit up, high flow O2  C: Assess fluid status:

CV Tissues End-organ Presentation Postural BP CRT Mental state  Usually presents in the context of critical illness JVP Cold / warm hands Urine output  Uraemia HR Skin turgor  Hyperkalaemia Mucus membranes  Acidosis  Oedema and ↑BP

Rx Life-Threatening Complications Ix  Hyperkalaemia  Bloods: FBC, U+E, LFT, glucose, clotting, Ca, ESR  Pulmonary oedema  ABG: hypoxia (oedema), acidosis, ↑K+  Consider need for rapid dialysis  GN screen: if cause unclear  Urine: dip, MCS, chemistry (U+E, CRP, osmolality, BJP)  ECG: hyperkalaemia Rx Shock or Dehydration  CXR: pulmonary oedema  Fluid challenge 250-500ml over 30min  Renal US: Renal size, hydronephrosis  Repeat as necessary: aim for CVP of 5-10cm  Once replete, continue @ 20ml+UO/h

Hyperkalaemia  ECG Features (in order) . Peaked T waves Monitor . Flattened P waves  Cardiac monitor . ↑ PR interval  Urinary catheter . Widened QRS  Consider CVP . Sine-wave pattern → VF  Start fluid balance chart  Mx . 10ml 10% calcium gluconate . 50ml 50% glucose + 10u insulin (Actrapid) . Salbutamol 5mg nebulizer Look for Evidence of Post-Renal Causes . Calcium resonium 15g PO or 30g PR  Palpable ± tender bladder . Haemofiltration (usually needed if anuric)  Enlarged prostate  Catheter in situ  Complete anuria Pulmonary Oedema  Sit up and give high-flow O2  Morphine 2.5mg IV (± metoclopramide 10mg IV) Hx and Ix  Frusemide 120-250mg IV over 1h Hx: Evidence of Acute vs. Chronic RF  GTN spray ± ISMN IVI (unless SBP <90)  Duration of symptoms  If no response consider:  Co-morbidities . CPAP . Haemofiltration / haemodialysis ± venesection  Previous blood results

Ix Indications for Acute Dialysis (AEIOU)  Bloods, ABG  Urine dip + MCS + chem 1. Persistent hyperkalaemia (>7mM) 2. Refractory pulmonary oedema  ECG 3. Symptomatic uraemia: encephalopathy, pericarditis  CXR and Renal US 4. Severe metabolic acidosis (pH <7.2) 5. Poisoning (e.g. aspirin) Rx Sepsis  Blood cultures and empirical Abx

Further Mx  Call urologists if obstructed despite catheter  Care with nephrotoxic drugs: e.g. gentamicin

© Alasdair Scott, 2012 111 Interstitial Nephritidies Nephrotoxins  Either directly toxic → ATN Acute Interstitial / Tubulointerstitial Nephritis  Or cause hypersensitivity → TIN  Immune-mediated hypersensitivity ¯c either drugs or other Ag acting as haptans Exogenous  NSAIDs Causes  Antimicrobials: AVASTA  Drug hypersensitivity in 70% . Aminoglycosides . NSAIDs . Vancomycin . Abx: Cephs, penicillins, rifampicin, sulphonamide . Aciclovir . Diuretics: frusemide, thiazides . Sulphonamides . Allopurinol . Tetracycline . Cimetidine . Amphotericin  Infections in 15%  ACEi . Staphs, streps  Immunosuppressants  Immune disorders . Ciclosporin . SLE, Sjogren’s . Tacrolimus  Contrast media Presentation  Anaesthetics: enflurane  Fever, arthralgia, rashes  AKI → olig/anuria  Uveitis Endogenous  Haemoglobin, myoglobin Ix  Urate  ↑IgE, eosinophilia  Ig: e.g. light chains in myeloma  Dip: haematuria, proteinuria, sterile pyuria

Rx  Stop offending drug Rhabdomyolysis  Prednisolone Pathogenesis  Skeletal muscle breakdown → release of: Prognosis: Most recover renal function + . K, PO4, urate Chronic TIN . Myoglobin, CK  Fibrosis and tubular loss  ↑K and AKI

 Commonly caused by: Causes . Reflux and chronic pyelonephritis . DM  Ischaemia: embolism, surgery . SCD or trait  Trauma: immobilisation, crush, burns, seizures, compartment syndrome Analgesic Nephropathy  Toxins: statins, fibrates, ecstasy, neuroleptics

Prolonged heavy ingestion of compound analgesics  Clinical Often a Hx of chronic pain: headaches, muscle pain   Muscle pain, swelling

 Red/brown urine Features  AKI occurs 10-12h later  Sterile pyuria ± mild proteinuria

Slowly progressive CRF  Ix Sloughed papilla can → obstruction and renal colic   Dipstick: +ve Hb, -ve RBCs

 Blood: ↑CK, ↑K, ↑PO , ↑urate Ix: CT w/o contrast (papillary calcifications) 4

Rx: stop analgesics Rx

 Rx hyperkalaemia Acute Urate Crystal Nephropathy  IV rehydration: 300ml/h  AKI due to urate precipitation  CVP monitoring if oliguric  Usually after chemo-induced cell lysis  IV NaHCO3 may be used to alkalinize urine and stabilise  Rx: hydration, urinary alkalinisation a less toxic form of myoglobin.

Nephrocalcinosis  Diffuse renal parenchymal calcification  Progressive renal impairment  Causes . Malignancy . ↑PTH . Myeloma . Sarcoidosis . Vit D intoxification . RTA © Alasdair Scott, 2012 112 Chronic Renal Failure

Features Renal Osteodystrophy  Kidney damage ≥3mo indicated by ↓ function  Symptoms usually only occur by stage 4 (GFR<30) Features  ESRF is stage 5 or need for RRT  Osteoporosis: ↓ bone density  Osteomalacia: ↓ mineralisation of osteoid (matrix) Classification  2O/3O HPT → osteitis fibrosa cystica . Subperiosteal bone resorption Stage GFR . Acral osteolysis: short stubby fingers 1 >90 . Pepperpot skull 2 60-89  May get spinal osteosclerosis → Rugger Jersey spine 3a 45-59 . Sclerotic vertebral end-plate ¯c lucent centre 3b 30-44 4 16-29 Mechanism 5 <15  ↓ 1α-hydroxylase → ↓ vit D activation → ↓ Ca → ↑ PTH  Phosphate retention → ↓ Ca and ↑ PTH (directly) Causes  ↑ PTH → activation of osteoclasts ± osteoblasts Also acidosis → bone resorption  Common  . DM . HTN Mx  Other . RAS General . GN  Rx reversible causes . Polycystic disease  Stop nephrotoxic drugs . Drugs: e.g. analgesic nephropathy . Pyelonephritis: usually 2O to VUR Lifestyle . SLE  Exercise . Myeloma and amyloidosis  Healthy wt.  Stop smoking Hx  Na, fluid and PO4 restriction  Past UTI  HTN, DM CV Risk  FH  Statins (irrespective of lipids)  DH  Low-dose aspirin  Symptoms  Rx DM

Ix Hypertension Blood  Target <140/90 (<130/80 if DM)  ↓Hb, U+E, ESR, glucose, ↓Ca/↑PO , ↑ALP, ↑PTH  In DM kidney disease give ACEi/ARB (inc. if normal BP) 4  Immune: ANA, dsDNA, ANCA, GBM, C3, C4, Ig, Hep Oedema  Film: burr cells  Frusemide

Urine: dip, MCS, PCR, BJP Bone Disease

Imaging  Phosphate binders: sevelamer, calcichew  CXR: cardiomegaly, pleural/pericardial effusion, oedema  Vit D analogues: alfacalcidol (1 OH-Vit D3)  AXR: calcification from stones  Ca supplements  Renal US  Cinacalcet: Ca mimetic . Usually small (<9cm) . May be large: polycystic, amyloid Anaemia  Bone X-rays: renal osteodystrophy (pseudofractures)  Exclude IDA and ACD  CT KUB: e.g. cortical scarring from pyelonephritis  EPO to raise Hb to 11g/dL (higher = thrombosis risk)

Renal biopsy: if cause unclear and size normal Restless Legs  Clonazepam Complications: CRF HEALS  Cardiovascular disease  Renal osteodystrophy  Fluid (oedema)  HTN  Electrolyte disturbances: K, H  Anaemia  Leg restlessness  Sensory neuropathy

Treatment of choice for ESRF Complications

Assessment Post-op  Virology status: CMV, HCV, HBV, HIV, VZV, EBV  Bleeding  CVD  Graft thrombosis  TB  Infection  ABO and HLA haplotype  Urinary leaks

Hyperacute rejection (minutes) Contraindications  ABO incompatibility  Active infection  Thrombosis and SIRS  Cancer  Severe HD or other co-morbidity Acute Rejection (<6mo)  ↑ing Cr (± fever and graft pain)  Cell-mediated response Types of Graft  Responsive to immunosuppression  Cadaveric: brainstem death ¯c CV support  Non-heart beating donor: no active circulation Chronic Rejection (>6mo)  Live-related  Interstitial fibrosis + tubular atrophy . Optimal surgical timing  Gradual ↑ in Cr and proteinuria . HLA-matched  Not responsive to immunosuppression . Improved graft survival  Live unrelated Ciclosporin / tacrolimus nephrotoxicity  Acute: reversible afferent arteriole constriction → ↓GFR  Chronic: tubular atrophy and fibrosis Immunosuppression  Pre-op: campath / alemtuzumab (anti-CD52) ↓ Immune Function  Post-op: prednisolone short-term and tacro/ciclo long-  ↑ risk of infection: opportunists, fungi, warts term  ↑ risk of malignancy: BCC, SCC, lymphoma (EBV)

Cardiovascular Disease Prognosis  Hypertension and atherosclerosis  t½ for cadaveric grafts: 15yrs

Differential of Rising Cr in Tx pt.  Rejection  Obstruction  ATN  Drug toxicity

Diabetic Nephropathy Myeloma  Causes ~20% of ESRF  Advanced / ESRF occurs in 40% of T1 and T2 DM Pathology  Excess production of monoclonal Ab ± light chains Pathology (excreted and detected in 60% as urinary BJP).  Diabetic nephropathy describes conglomerate of lesions  Light chains block tubules and have direct toxic effects occurring concurrently. → ATN. 2+  Hyperglycaemia → renal hyperperfusion → hypertrophy  Myeloma also assoc. ¯c ↑↑Ca and ↑ renal size  Hypertrophy and metabolic defects inc. ROS production Presentation → glomerulosclerosis and nephron loss  ARF / CRF  Nephron loss → RAS activation → HTN  Amyloidosis

Clinically Rx  Microalbuminuria (30-300mg/d or albumin:creatinine >3)  Ensure fluid intake of 3L/d to prevent further impairment . Strong independent RF for CV disease  Dialysis may be required in ARF  Progresses to proteinuria (albuminuria >300mg/d)  Diabetic retinopathy usually co-exists and HTN is common Rheumatological Disease

Screening RA  T2DMs should be screened for microalbuminuria 6moly  NSAIDs → ATN  Penicillamine and gold → membranous GN Rx  AA amyloidosis occurs in 15%  Good glycaemic control delays onset and progression  BP target 130/80 SLE  Start ACEi/ARB even if normotensive  Involves glomerulus in 40-60% → ARF/CRF  Stop smoking  Proteinuria and ↑BP common  Combined kidney pancreas Tx possible in selected pts  Rx . Proteinuria: ACEi . Aggressive GN: immunosuppression Amyloidosis  Renal involvement usually caused by AL/AA amyloid Diffuse Systemic Sclerosis  Features:  Renal crisis: malignant HTN + ARF . Proteinuria . Commonest cause of death . Nephrotic syndrome  Rx: ACEi if ↑BP or renal crisis . Progressive renal failure  Dx . Large kidneys on US . Biopsy

Infection  GN: post-strep, HCV, HBV, HIV, SBE/IE, visceral abscess  Vasculitis: HBV, HCV, post-strep  TIN: bacterial pyelonephritis, CMV, HBV, toxo

Malignancy  Direct . Renal infiltration: leukaemia, lymphoma . Obstruction: pelvic tumour . Mets  Nephrotoxicity . Toxic chemo . Analgesics . Tumour lysis syndrome

Hyperparathyroidism  → hypercalcaemia

Sarcoidosis  ↑ Ca and TIN

Hypertension Renal Tubular Acidosis  HTN can be both the cause and effect of renal damage.  Impaired acid excretion → hyperchloraemic met acidosis  Renal diseases are commonest causes of 2O HTN  Both → RAS activation → K+ wasting and hypokalaemia . Activation of RAS . Retention of Na and water due to ↓ excretion Type 1 (Distal)  Inability to excrete H+, even when acidotic Renovascular Disease: RAS  May complicate other renal disorders  Causes Cause . Hereditary: Marfan’s, Ehler’s Danlos  Atherosclerosis in 80% . AI: Sjogren’s, SLE, thyroiditis  Fibromuscular dysplasia . Drugs  Thromboembolism  Features  External mass compression . Rickets / osteomalacia (bone buffering) . Renal stones and UTIs Features . Nephrocalcinosis → ESRF  Refractory hypertension  Dx  Worsening renal function after ACEi/ARB . Failure to acidify urine (pH >5.5) despite acid load  Flash pulmonary oedema (no LV impairment on echo) Type 2 (Proximal) Ix  Defect in HCO3 reabsorption in PCT  US + doppler: small kidney + ↓ flow  Tubules can reabsorb some HCO3 so can acidify urine in  CT/MR angio systemic acidosis when HCO3 ↓  Renal angiography: gold standard  Usually assoc. ¯c Fanconi syndrome  Dx Rx . Urine will acidify ¯c acid load (pH <5.5)  Rx medical CV risk factors  Angioplasty and stenting Fanconi Syndrome  Disturbance of PCT function → generalised impaired reabsorption + Haemolytic Uraemic Syndrome (HUS) . amino acids, K , HCO3, phosphate, glucose  E. coli O157:H7: verotoxin → endothelial dysfunction  Causes . Idiopathic Features . Inherited: inborn errors, Wilson’s  Young children eating undercooked meat (burgers) . Acquired: tubule damage (drugs, myeloma…)  Bloody diarrhoea and abdominal pain precedes:  Features . MAHA . Polyuria (osmotic diuresis) . Thrombocytopenia . Hypophosphataemic rickets (Vit D resistant) . Renal failure . Acidosis, ↓K

Ix Hereditary Hypokalaemic Tubulopathies  Schistocytes, ↓ plats  Bartter’s Syndrome . Blockage of NaCl reabsorption in loop of Henle  ↓Hb (as if taking frusemide)  Normal clotting . Congenital salt wasting → RAS activation →

hypokalaemia and metabolic alkalosis Rx . Normal BP  Usually resolves spontaneously  Gitelman Syndrome  Dialysis or plasma exchange may be needed . Blockage of NaCl reabsorption in DCT (as if taking thiazides) . Congenital salt wasting → RAS activation → Thrombotic Thrombocytopenia Purpura (TTP) hypokalaemia and metabolic alkalosis +  Genetic or acquired deficiency of ADAMTS13 → giant hypocalciuria vWF multimers . Normal BP

Features  Adult females  Pentad . Fever . CNS signs: confusion, seizures . MAHA . Thrombocytopenia . Renal failure

Ix: As HUS

Rx: Plasmapheresis, immunosuppression, splenectomy © Alasdair Scott, 2012 116 Renal Cystic Diseases

Auto Dom Polycystic Kidney Disease  Prev: 1:1000 Auto Rec Polycystic Kidney Disease  Age: Adults 40-60yrs  Prev: 1:40,000  Genetics  Infancy . PKD1 on Chr16, polycystin 1 (80%): cell-cell and cell-  Renal cysts and congenital hepatic fibrosis matrix membrane receptor 2+ . PKD2 on Chr4, polycystin 2: Ca channel that interacts ¯c polycystin 1 Medullary Sponge Kidney  Path  Multiple cystic dilatations of the CDs in the medulla . Large cysts arising from all parts of nephron . Progressive decline in renal function  Typically presents in 20-30s . 70% ESRF by 70yrs  Commoner in females  Often asymptomatic, but predisposes to Presentation: MISSHAPES . Hypercalciuria and nephrolithiasis  Mass: abdo mass and flank pain . Recurrent UTIs and pyelonephritis .  Infected cyst Haematuria Renal function is usually normal  Stones 

 SBP ↑  Haematuria or haemorrhage into cyst  Aneurysms: berry → SAH Tuberous Sclerosis (Bourneville’s Disease)  Polyuria + nocturia  AD condition ¯c hamartomas in skin, brain, eye,  Extra-renal cysts: liver kidney  Systolic murmur: mitral valve prolapse  Skin: nasolabial adenoma sebaceum, ash-leaf macules, peri-ungual fibromas Rx  Neuro: ↓IQ, epilepsy  General  Renal: cysts, angiomyolipomas . ↑ water intake, ↓ Na, ↓ caffeine (may ↓ cyst formation) . Monitor U+E and BP . Genetic counselling Renal Enlargement Differential: PHONOS . MRA screen for Berry aneurysms  Polycystic kidneys: ADPKD, ARPKD, TS  Medical  Hypertrophy 2O to contralateral renal agenesis . Rx HTN aggressively: <130/80 (ACEi best)  Obstruction (hydronephrosis) . Rx infections  Neoplasia: RCC, myeloma, amyloidosis  Surgical  Occlusion (renal vein thrombosis) . Pain may be helped by laparoscopic cyst removal or  Systemic: early DM, amyloid nephrectomy.  ESRF in 70% by 70yrs . Dialysis or transplant

Contents Anaemia Classification and Causes ...... 119 Microcytic Anaemia ...... 120 Macrocytic Anaemia ...... 121 Haemolytic Anaemias ...... 122 Sickle Cell Disease ...... 123 Bleeding Diatheses...... 124 Thrombophilia ...... 125 Blood Transfusion ...... 126 Bone Marrow Failure ...... 127 Myelodysplastic Syndromes ...... 127 Chronic Myeloproliferative Disorders ...... 128 Acute Lymphoblastic Leukaemia ...... 129 Acute Myeloid Leukaemia ...... 129 Chronic Lymphocytic Leukaemia ...... 130 Chronic Myeloid Leukaemia ...... 130 Non-Hodgkin’s Lymphoma ...... 131 Hodgkin’s Lymphoma ...... 131 Multiple Myeloma ...... 132 Other Paraproteinaemias ...... 133 Amyloidosis ...... 133 Complications of Haematological Malignancies ...... 134 Spleen and Splenectomy ...... 135 The Lab ...... 136

Low Hb Haemolytic Anaemia  Men: <13.5g/dl  Women: <11.5g/dl ↑ red cell breakdown 1. Anaemia ¯c ↑ MCV + polychromasia = reticulocytosis 2. ↑ unconjugated bilirubin Symptoms 3. ↑ urinary urobilinogen 4. ↑ se LDH  Fatigue 5. Bile pigment stones  Dyspnoea

 Faintness Intravascular  Palpitations 1. Haemoglobinaemia  Headache 2. Haemoglobinuria  Tinnitus 3. ↓ se haptoglobins 4. ↑ urine haemosiderin 5. Methaemalbuminaemia Signs  Pallor Extravascular  Hyperdynamic circulation 1. Splenomegaly . Tachycardia . Flow murmur: apical ESM Acquired . Cardiac enlargement  Immune-mediated DAT+ve  Ankle swelling ¯c heart failure . AIHA: warm, cold, PCH . Drugs: penicillin, quinine, methyldopa . Allo-immune: acute transfusion reaction, HDFN Microcytic  PNH  Mechanical:  Haem Defect . MAHA: DIC, HUS, TTP . IDA . Heart valve . ACD  Infection: malaria . Sideroblastic / lead poisoning  Burns  Globin Defect

. Thalassaemia Hereditary

 Enzyme: G6PD and pyruvate kinase deficiency Normocytic  Membrane: HS, HE  Haemoglobinopathy: SCD, thalassaemia  Recent blood loss  Bone marrow failure  Renal failure  Early ACD  Pregnancy (↑ plasma volume)

Macrocytic  Megaloblastic . Vit B12 or folate deficiency . Anti-folate drugs: phenytoin, methotrexate . Cytotoxics: hydroxycarbamide  Non-megaloblastic . Reticulocytosis . Alcohol or liver disease . Hypothyroidism . Myelodysplasia

IDA Thalassaemia

Signs Pathophysiology  Koilonychia  Point mutations (β) / deletions (α) → unbalanced  Angular stomatitis / cheilosis production of globin chains  Post-cricoid Web: Plummer-Vinson  → precipitation of unmatched globin  → membrane damage → haemolysis while still in BM Causes and removal by the spleen

Mechanism Examples Epidemiology ↑ Loss Menorrhagia  Common in Mediterranean and Far East GI bleeding Hookworms β Thalassaemia Trait / Heterozygosity + O  β / β (↓ production) or β / β (no production) ↓ Intake Poor diet  Mild anaemia which is usually harmless  ↓ MCV (“too low for the anaemia”): e.g. <75 Malabsorption Coeliac  ↑ HbA2 (α2δ 2) and ↑HbF (α2γ2) Crohn’s β Thalassaemia Major O O O + + + Ix  β / β or β / β or β / β  Haematinics: ↓ferritin, ↑TIBC, ↓ transferrin saturation  Features develop from 3-6mo  Film: Anisocytosis, poikilocytosis, pencil cells . Severe anaemia  Upper and lower GI endoscopy . Jaundice . FTT Rx . Extramedullary erythropoiesis  Ferrous sulphate 200mg PO TDS  Frontal bossing . SE: GI upset  Maxillary overgrowth  HSM . Haemochromatosis after 10yrs (transfusions) Sideroblastic Anaemia  Ix  Ineffective erythropoiesis . ↓Hb, ↓MCV, ↑↑HbF, ↑HbA2 variable . ↑ iron absorption . Film: Target cells and nucleated RBCs . Iron loading in BM → ringed sideroblasts  Rx . Haemosiderosis: endo, liver and cardiac damage . Life-long transfusions . SC desferrioxamine Fe chelation Causes . BM transplant may be curative  Congenital  Acquired α Thalassaemia . Myelodysplastic / myeloproliferative disease  Trait . Drugs: chemo, anti-TB, lead . --/αα or α-/α- . Asymptomatic Ix . Hypochromic microcytes  Microcytic anaemia not responsive to oral iron  HbH Disease  ↑Ferritin, ↑ se Fe, ↔TIBC . --/-α . Moderate anaemia: may need transfusions Rx . Haemolysis: HSM, jaundice  Remove cause  Hb Barts  Pyridoxine may help . --/-- . Hydrops fetalis → death in utero

Ix B12 Deficiency

Film Vit B12  B12/Folate  Source: meat, fish and dairy (vegans get deficient) . Hypersegmented PMN  Stores: 4yrs . Oval macrocytes  Absorption: terminal ileum bound to intrinsic factor  EtOH/Liver (released from gastric parietal cells) . Target cells  Role: DNA and myelin synthesis

Blood Causes  LFT: mild ↑ bilirubin in B12/folate deficiency  TFT Mechanism Examples  Se B12 ↓ Intake Vegan  Red cell folate: reflects body stores over 2-3mo ↓ intrinsic factor Pernicious anaemia BM biopsy: if cause not revealed by above tests Post-gastrectomy  Megaloblastic erythropoiesis  Giant metamyelocytes Terminal ileum Crohn’s Ileal resection Bacterial overgrowth Folate Deficiency Features

 General Folate . Symptoms of anaemia  Source: Green veg, nuts, liver . Lemon tinge: pallor + mild jaundice  Stores: 4mo . Glossitis (beefy, red tongue)  Absorption: proximal jejunum  Neuro . Paraesthesia Causes . Peripheral neuropathy . Optic atrophy Mechanism Examples . SACD ↓ Intake Poor diet Subacute Combined Degeneration of the Cord ↑ Demand Pregnancy  Usually only caused by pernicious anaemia Haemolysis  Combined symmetrical dorsal column loss and Malignancy corticospinal tract loss.

 → distal sensory loss: esp. joint position and vibration Malabsorption Coeliac . → ataxia c wide-gait and +ve Romberg’s test Crohn’s ¯  Mixed UMN and LMN signs Drugs EtOH . Spastic paraparesis Phenytoin . Brisk knee jerks Methotrexate . Absent ankle jerks . Upgoing plantars Rx  Pain and temperature remain intact  Assess for underlying cause  Give B12 first unless B12 level known to be normal Ix . May precipitate or worsen SACD  ↓ WCC and plats if severe  Folate 5mg/d PO  Intrinsic factor Abs: specific but lower sensitivity  Parietal cell Abs: 90% +ve in PA but ↓ specificity

Rx  Malabsorption → parenteral B12 (hydroxocobalamin) . Replenish: 1mg/48h IM . Maintain: 1mg IM every 3mo  Dietary → oral B12 (cyanocobalamin)  Parenteral B12 reverses neuropathy but not SACD

Pernicious Anaemia  Autoimmune atrophic gastritis caused by autoAbs vs. parietal cells or IF → achlorhydria and ↓ IF.  Usually >40yrs, ↑ incidence ¯c blood group A  Associations: . AI: thyroid disease, Vitiligo, Addison’s, ↓HPT . Ca: 3x risk of gastric adenocarcinoma

© Alasdair Scott, 2012 121 Haemolytic Anaemias AIHA Hereditary Spherocytosis Warm  Commonest inherited haemolytic anaemia in N. Europe  IgG-mediated, bind @ 37OC  Extravascular haemolysis and spherocytes Pathophysiology  Ix: DAT+ve  Autosomal dominant defect in RBC membrane  Causes: idiopathic, SLE, RA, Evan’s  Spherocytes get trapped in spleen → extravascular  Rx: immunosuppression, splenectomy haemolysis

Cold Features  IgM-mediated, bind @ <4OC  Splenomegaly  Often fix complement → intravascular haemolysis  Pigment gallstones  May cause agglutination → acrocyanosis or Raynaud’s  Jaundice  Ix: DAT+ve for complement alone  Causes: idiopathic, mycoplasma Complications  Rx: avoid cold, rituximab  Aplastic crisis  Megaloblastic crisis Paroxysmal Cold Haemoglobinuria  Rare: assoc. ¯c measles, mumps, chickenpox Ix  IgG “Donath-Landsteiner” Abs bind RBCs in the cold and  ↑ osmotic fragility → complement-mediated lysis on rewarming  Spherocytes  DAT-ve PNH Rx  Absence of RBC anchor molecule (GPI) → ↓ cell-surface complement degradation proteins → IV lysis  Folate and splenectomy (after childhood)

 Affects stem cells and  may also → ↓plats + ↓PMN

Features Hereditary Eliptocytosis  Visceral venous thrombosis (hepatic, mesenteric, CNS)  Autosomal dominant defect → elliptical RBCs  IV haemolysis and haemoglobinuria  Most pts. are asymptomatic  Rx: folate, rarely splenectomy Ix  Anaemia ± thrombocytopenia ± neutropenia  FACS: ↓CD55 and ↓CD59 G6PD deficiency

Rx Pathophysiology  Chronic disorder  long-term anticoagulation  X-linked disorder of pentose phosphate shunt  Eculizumab (prevents complement MAC formation)  ↓ NADPH production → RBC oxidative damage  Affects mainly Mediterranean and Mid / Far East Haemolytic Uraemic Syndrome (HUS) Features Haemolysis Triggers  E. coli O157:H7 from undercooked meat  Broad (Fava) beans  Bloody diarrhoea and abdominal pain precedes:  Mothballs (naphthalene) . MAHA  Infection . Thrombocytopenia  Drugs: antimalarials, henna, dapsone, sulphonamides . Renal failure Ix Ix: schistocytes, ↓ plats, normal clotting  Film Rx . Irregularly contracted cells  Usually resolves spontaneously . Bite cells, ghost cells and blister cells  Exchange transfusion or dialysis may be needed . Heinz bodies  G6PD assay after 8wks (reticulocytes have high G6PD) Thrombotic Thrombocytopenia Purpura (TTP)  Genetic or acquired deficiency of ADAMTS13 Rx Features  Treat underlying infection  Adult females  Stop and avoid precipitants  Pentad  Transfusion may be needed . Fever . CNS signs: confusion, seizures . MAHA Pyruvate Kinase Deficiency . Thrombocytopenia  Autosomal recessive defect in ATP synthesis . Renal failure  → rigid red cells phagocytosed in the spleen  Features: splenomegaly, anaemia ± jaundice Ix: schistocytes, ↓ plats, normal clotting  Ix: PK enzyme assay Rx: Plasmapheresis, immunosuppression, splenectomy  Rx: often not needed or transfusion ± splenectomy © Alasdair Scott, 2012 122 Sickle Cell Disease

Epidemiology Mx Chronic Disease  Africa, Caribbean’s, Middle-East  Pen V BD + immunisations  UK prevalence = 1/2000  Folate  Hydroxycarbamide if frequent crises

Pathogenesis  Point mutation in β globin gene: glu→val Mx Acute Crises . SCA: HbSS . Trait: HbAS General  HbS insoluble when deoxygenated → sickling  Analgesia: opioids IV  Sickle cells have ↓ life-span → haemolysis  Good hydration  Sickle cells get trapped in microvasc → thrombosis  O2  Keep warm

Ix Ix  Hb 6-9, ↑ retics, ↑ bilirubin  FBC, U+E, reticulocytes, cultures  Film: sickle cells and target cells  Urine dip  Hb electrophoresis  CXR . Dx at birth ¯c neonatal screening Rx  Blind Abx: e.g. ceftriaxone Presentation  Transfusion: exchange if severe  Clinical features manifest from 3-6mo due to ↓HbF  Triggers . Infection . Cold . Hypoxia . Dehydration

 Splenomegaly: may → sequestration crisis  Infarction: stroke, spleen, AVN, leg ulcers, BM  Crises: pulmonary, mesenteric, pain  Kidney disease  Liver, Lung disease  Erection  Dactylitis

Complications  Sequestration crisis . Splenic pooling → shock + severe anaemia  Splenic infarction: atrophy and hyposplenism  ↑ infection: osteomyelitis  Aplastic crisis: parvovirus B19 infection  Gallstones

Coagulation Tests Platelet Disorders

APTT Thrombocytopenia  Intrinsic: 12, 11, 9, 8  ↓ production  Common: 10, 5, 2, 1 . BM failure: aplastic, infiltration, drugs (EtOH, cyto)  Increased . Megaloblastic anaemia . Lupus anti-coagulant  ↑ destruction . Haemophilia A or B . Immune: ITP, SLE, CLL, heparin, viruses . vWD (carries factor 8) . Non-immune: DIC, TTP, HUS, PNH, anti- . Unfractionated heparin phospholipid . DIC  Splenic pooling . Hepatic failure . Portal hypertension . SCD PT  Extrinsic: 7 ITP  Common: 10, 5, 2, 1 . Children: commonly post-URTI, self-limiting  Increased . Adults: F>M, long-term . Warfarin / Vit K deficiency . Ix: Anti-platelet Abs present . Hepatic failure . Rx: conservative, steroids, IVIg, splenectomy . DIC Functional Defects Bleeding Time / PFA-100  Drugs: aspirin, clopidogrel O  Platelet function  2 : paraproteinaemias, uraemia  Increased  Hereditary . ↓ plats number or function . Bernard-Soulier: GpIb deficiency . vWD . Glanzmann’s: GpIIb/IIIa deficiency . Aspirin . DIC Coagulation Disorders Thrombin Time  Fibrinogen function Acquired  Increased  Severe liver disease . Quantitative/ qualitative fibrinogen defect  Anticoagulants  DIC, dysfibrinogenaemia  Vitamin K deficiency . Heparin Haemophilia A: F8 Deficiency Clinical Features  X-linked, affects 1/5000 males  Pres: haemoarthroses, bleeding after surgery/extraction Vascular or Platelet Disorder  Ix: ↑APTT, normal PT, ↓F8 assay  Bleeding into skin: petechiae, purpura, echymoses  Mx  Bleeding mucus mems: epistaxis, menorrhagia, gums . Avoid NSAIDs and IM injections  Immediate, prolonged bleeding from cuts . Minor bleeds: desmopressin + tranexamic acid . Major bleeds: rhF8 Coagulation Disorder  Deep bleeding: muscles, joints, tissues Haemophilia B: F9 deficiency  Delayed but severe bleeding after injury  X-linked, 1/20,000 males

VWD Vascular Disorders  Commonest inherited clotting disorder (mostly AD)  vWF Congenital . Stabilises F8  HHT . Binds plats via GpIb to damaged endothelium  Ehler’s Danlos (easy bruising)  Ix  Pseudoxanthoma elasticum . If mild, APTT and bleeding time may be normal . ↑ APTT, ↑ bleeding time, normal plat, ↓ vWF AG Acquired  Rx: desmopressin + tranexamic acid  Senile purpura  Vitamin C deficiency DIC  Infection: e.g. meningococcus  ↑PT, ↑APTT, ↑TT, ↓plats, ↓fibrinogen, ↑FDPs  Steroids  Schistocytes  Vasculitis: e.g. HSP  Thrombosis and bleeding  Causes: sepsis, malignancy (esp. APML), trauma, obs  Rx: FFP, plats, heparin

Definition Thrombophilia Screen  Coagulopathy predisposing to thrombosis, usually venous. Indications  Arterial thrombosis <50yrs (?APL) Inherited  Venous thrombosis <40yrs ¯c no RFs  Familial VTE Factor V Leiden / APC resistance  Unexplained recurrent VTE  Protein C deactivates F5 and F8  Unusual site: portal, mesenteric . ¯c protein S and thrombomodulin cofactors  Recurrent foetal loss  Degradation resistance present in 5% of population  Neonatal . Most don’t develop thrombosis  Heterozygotes: 5x ↑VTE Investigations  Homozygotes: 50x ↑ VTE  FBC, clotting, fibrinogen concentration  Factor V Leiden / APC resistance Prothrombin Gene Mutation  Lupus anticoagulant and anti-cardiolipin Abs  ↑ prothrombin levels  Assays for AT, protein C and S deficiencies  ↑ thrombosis due to ↓ fibrinolysis by thrombin-activated  PCR for prothrombin gene mutation fibrinolysis inhibitor Rx Protein C and S Deficiency  Rx acute thrombosis as per normal  Heterozygotes for either have ↑ risk of thrombosis.  Anticoagulate to INR 2-3 . Skin necrosis occurs – esp. ¯c warfarin  Consider lifelong warfarin  Heterozygotes → neonatal purpura fulminans  If recurrence occurs on warfarin ↑INR to 3-4

Antithrombin III Deficiency  AT is heparin co-factor → thrombin inhibition Prevention  Deficiency affects 1/500  Lifelong anticoagulation not needed if asymptomatic  Heterozygotes have ↑↑ thrombosis risk  ↑ VTE risk ¯c OCP or HRT  Homozygosity is incompatible ¯c life  Prophylaxis in high risk situations . Surgery Acquired . Pregnancy

 Progesterones in OCPs  Anti-phospholipid syndrome . CLOTs: venous and arterial  Coagulation defect: ↑APTT  Livido reticularis  Obstetric complications: recurrent 1st trimester abortion  Thrombocyotpenia

Products FFP O  Stored @ -18 C Packed red cells  Should be X-matched  Stored @ 4OC in SAGM  Uses: DIC, liver disease, TTP, massive haemorrhage  Hct ~70%  Use to correct anaemia or blood loss Human Albumin Solution  1u → ↑Hb by 1-1.5g/dL  Protein replacement . After abdominal paracentesis Platelets . Liver failure, nephrotic syndrome  Stored @ RT under agitation  Not needed if count >20 or not actively bleeding  Should be x-matched

Immediate Transfusion Reactions

Reaction Time Clinical Features Mechanism Rx Haemolytic Minutes Agitation ABO incompatibility Stop transfusion Fever → IV haemolysis Tell lab Abdo/chest pain Keep IV line open ¯c NS ↓ BP → shock Treat DIC DIC → haemorrhage Renal failure Bacterial <24h ↑↑ temp + rigors Bacterial proliferation Stop transfusion Contamination ↓BP → Shock Esp. plats Send unit to lab (Transfuse blood w/i 5h) Abx: Taz+gent Febrile non- <24h Fever, rigors, chills Recipient anti-HLA Abs Slow transfusion Haemolytic Paracetamol 1g Allergic Immediate Urticaria, itch Recipient IgA deficiency Slow Angioedoema Anti-IgA IgE Chlorphenamine 10mg IV/IM Anaphylaxis TRALI <6h ARDS: SOB, cough Anti-WBC Abs in donor plasma Stop transfusion Bilat infiltrates on CXR Rx ARDS Fluid <6h CCF Slow transfusion Overload O2 + frusemide 40mg IV Massive 24h ↑K Whole blood vol in 24h Massive Transfusion Protocol Transfusion ↓ Ca (citrate chelation) (5L = 10units) - 1:1:1 ratio of PRBC:FFP:PLT ↓ F5 and F8 - → ↑ survival ↓ plats Hypothermia Warm the blood

Delayed Transfusion Reactions

Reaction Time Clinical Features Mechanism Rx Delayed 1-7d Jaundice Recipient anti-Rh Abs Haemolytic Anaemia / ↓ing Hb Extravasc haemolysis Fever ± Haemoglobinuria Fe Overload Chronic SCA or Thal Major Chronic transfusions Desferrioxamine SC Haemochromatosis Post-transfusion 7-10d Thrombocytopenia AlloAbs attack recipient + donor plats IvIg Purpura Purpura Plat transfusions GvHD 4-30d Diarrhoea Viable lymphocytes transfused into Skin rash immunocompromised host Liver Failure → ↑ LFTs Pancytopaenia Irradiate blood for vulnerable hosts

Pancytopenia Pathophysiology  Heterogeneous group of disorders → BM failure Congenital  Clone of stem cells ¯c abnormal development  Fanconi’s anaemia: aplastic anaemia . → functional defects . → quantitative defects Acquired  May be primary or secondary  Idiopathic aplastic anaemia . Chemo or radiotherapy  BM infiltration  Haematological Characteristics . Leukaemia  Cytopenias . Lymphoma  Hypercellular BM . Myelofibrosis  Defective cells: e.g. ringed sideroblasts . Myelodysplasia  30% → AML . Megaloblastic anaemia

 Infection: HIV Clinical Features  Radiation  Elderly  Drugs . Cytotoxic: cyclophos, azathioprine, methotrexate  BM failure: anaemia, infection, bleeding, bruising . Abx: chloramphenicol, sulphonamides  Splenomegaly . Diuretic: thiazides . Anti-thyroid: carbimazole Ix . Anti-psychotic: clozapine  Film: blasts, Pelger-Huet anomaly, dimorphic . Anti-epileptic: phenytoin  BM: Hypercellular, blasts, ringed sideroblasts

Mx Aplastic Anaemia  Supportive: transfusions, EPO, G-CSF  Rare stem cell disorder  Immunosuppression  Allogeneic BMT: may be curative Key Features  Pancytopenia  Hypocellular marrow

Presentation: Pancytopenia  Age: 15-24yrs and >60yrs  Anaemia  Infections  Bleeding

Causes  Inherited . Fanconi’s anaemia: Ashkenazi, short, pigmented . Dyskeratosis congenita: premature ageing . Swachman-Diamond syn.: pancreatic exocrine dysfunction  Acquired . Drugs . Viruses: parvovirus, hepatitis . Autoimmune: SLE

Ix  BM: Hypocellular marrow

Mx  Supportive: transfusion  Immunosuppression: anti-thymocyte globulin  Allogeneic BMT: may be curative

Classification Essential Thrombocythaemia  RBC → Polycythaemia Vera  WBC → CML Features  Platelets → Essential thrombocythaemia  Thrombosis  Megakaryocytes → Myelofibrosis . Arterial: strokes, TIA, peripheral emboli . Venous: DVT, PE, Budd-Chiari Polycythaemia Vera  Bleeding (abnormal plat function) . E.g. mucus membranes

 Erythromelagia Features

 Hyperviscosity Ix . Headaches  Plats >600 (often >1000) . Visual disturbances . Tinnitus  BM: ↑ megakaryocytes . Thrombosis  50% JAK2+ve  Arterial: strokes, TIA, peripheral emboli Rx  Venous: DVT, PE, Budd-Chiari  Plats 400-1000: aspirin alone  Histamine Release . Aquagenic pruritus  Thrombosis or plats >1000: hydroxycarbamide  Erythromelalgia  Anagralide may be used . Inhibits platelet maturation . Sudden, severe burning in hands and feet ¯c . ↓ plat count and function redness of the skin

 Splenomegaly: 75% Prognosis  Hepatomegaly: 30%  5% → AML/MF over 10yrs  Gout

Ix Thrombocythaemia Differential  99% JAK2+ve  Primary: ET  ↑RBC, Hb and Hct  Secondary:  ↑WCC and ↑plats . Bleeding  BM: hypercellular c erythroid marrow ¯ . Infection  ↓EPO . Chronic inflammation: RA, IBD  ↑ red cell mass ¯c isotope studies . Trauma / surgery . Hyposplenism / splenectomy Rx  Aim to keep Hct <0.45 to ↓thrombosis . Aspirin 75mg OD Primary Myelofibrosis . Venesection if young  Clonal proliferation of megakaryocytes → ↑ PDGF → . Hydroxycarbamide if older / higher risk Myelofibrosis

 Extramedullary haematopoiesis: liver and spleen Prognosis  Thrombosis and haemorrhage are main complications Features  30% → MF  Elderly  5% → AML  Massive HSM

 Hypermetabolism: wt. loss, fever, night sweats  BM failure: anaemia, infections, bleeding Polycythaemia Differential Ix True Polycythaemia: ↑ total volume of red cells  Film: leukoerythroblastic ¯c teardrop poikilocytes  Primary: PV  Cytopenias  Secondary  BM: dry tap (need trephine biopsy) . Hypoxia: altitude, COPD, smoking  50% JAK2+ve . EPO: renal cysts/tumours Rx Pseudopolycythaemia: ↓ plasma volume  Supportive: blood products  Acute  Splenectomy . Dehydration  Allogeneic BMT may be curative in younger pts. . Shock . Burns Prognosis  Chronic  5yr median survival . Diuretics . Smoking

Epidemiology Epidemiology  Children 2-5yrs (commonest childhood Ca)  ↑ risk ¯c age: mean 65-70  Rare in adults  Commonest acute leukaemia of adults

Aetiology Aetiology  Arrest of maturation and proliferation of lymphoblasts  Neoplastic proliferation of myeloblasts  80% B lineage, 20% T lineage Risk Factors Risk Factors  Chromosomal abnormalities  Genetic susceptibility (often Chr translocations)  Radiation  Environmental trigger  Down’s . Radiation (e.g. during pregnancy)  Chemotherapy: e.g. for lymphoma . Down’s  Myelodysplastic and myeloproliferative syndromes

Features FAB Classification (based on cell type)  M2: granulocyte maturation BM Failure  M3: acute promyelocytic leukaemia – t(15;17)  Anaemia  M4: acute myelomonocytic leukaemia  Thrombocytopenia → bleeding  M7: megakaryoblastic leukaemia – trisomy 21  Leukopenia → infection Features Infiltration

 Lymphadenopathy BM Failure  Orchidomegaly  Cytopenias  Thymic enlargement  HSM Infiltration  CNS: CN palsies, meningism  Gum infiltration → hypertrophy and bleeding (M4)  Bone pain  HSM  Skin involvement Ix  Bone pain  ↑WCC: lymphoblasts  ↓RBC, ↓PMN, ↓plats Blood  BM aspirate  DIC: APML (M3) . ≥20% blasts  Hyperviscosity: ↑↑WCC may → thrombi . Cytogenetic and molecular analysis  CXR+CT: mediastinal + abdominal LNs Ix  LP: CNS involvement  ↑ WCC blasts (occasionally normal)  Anaemia and ↓ plats Mx  BM aspirate . ≥20% blasts Supportive . Auer rods are diagnostic  Blood products  Allopurinol Dx  Hickman line or Portacath  Made by immunological and molecular phenotyping . Flow cytometry Infections  Cytogenetic analysis affects Rx and guides prognosis  Gentamicin + tazocin  Prophylaxis: e.g. co-timoxazole, ciprofloxacin Mx

Chemotherapy (recruited into national trials) Supportive: as for ALL 1. Remission induction Infections: as for ALL 2. Consolidation + CNS Rx 3. Maintenance for 2-3yrs Chemotherapy

 V. intensive → long periods of neutropenia and ↓ plats BMT  ATRA for APML  Best option for younger adults

BMT

 Allogeneic if poor prognosis Prognosis . Destroy BM and leukemic cells ¯c chemotherapy  85% survival in children and total body irradiation.  Worse in adults . Repopulate marrow ¯c HLA-matched donor HSCs  Autologous if intermediate prognosis . HSCs taken from pt.

Epidemiology Epidemiology  Commonest leukaemia in Western World  15% of leukaemia  M>F=2:1  Middle-aged: 60-60yrs  Elderly: 70s Aetiology Aetiology  Myeloproliferative disorder: clonal proliferation of  Clone of mature B cells (memory cells) myeloid cells.

Features Features  Often asymptomatic incidental finding  Systemic: wt. loss, fever, night sweats, lethargy  Symmetrical painless lymphadenopathy  Massive HSM → abdo discomfort  HSM  Bruising / bleeding (platelet dysfunction)  Anaemia  Gout  B symptoms: wt. loss, fever, night sweats  Hyperviscosity

Complications Philadelphia Chromosome  Autoimmune haemolysis  Reciprocal translocation: t(9;22) . Evan’s = AIHA and ITP  Formation of BCR-ABL fusion gene  Infection (↓Ig): bacterial, zoster . Constitutive tyrosine kinase activity  Marrow failure / infiltration  Present in >80% of CML  Discovered by Nowell and Hungerford in 1960 Ix  ↑ WCC, lymphocytosis Ix  Smear cells  ↑↑WBC  ↓ se Ig . PMN and basophils  +ve DAT . Myelocytes  Rai or Binet staging  ± ↓Hb and ↓plat (accelerated or blast phase)  ↑urate Dx  BM cytogenetic analysis: Ph+ve  Immunophenotyping to distinguish from NHL Natural Hx Natural Hx  Chronic phase: <5% blasts in blood or DM  Some remain stable for years  Accelerated phase: 10-19% blasts  Nodes usually enlarge slowly (± lymphatic obstruction)  Blast crisis: usually AML, ≥20% blasts  Death often due to infection: e.g. encapsulates, fungi  Richter Transformation: CLL → large B cell lymphoma Rx  Imatinib: tyrosine kinase inhibitor Rx . → >90% haematological response  Indications . 80% 5ys . Symptomatic  Allogeneic SCT . Ig genes un-mutated (bad prognostic indicator) . Indicated if blast crisis or TK-refractory . 17p deletions (bad prognostic indicator)  Supportive care  Chemotherapy . Cylophosphamide . Fludarabine . Rituximab  Radiotherapy . Relieve LN or splenomegaly

Prognosis  1/3 never progress  1/3 progress ¯c time  1/3 are actively progressing

Features Epidemiology  M>F=2:1 (esp. in paeds) Lymphadenopathy: 75% @ presentation  Bimodal age incidence: 20-29yrs and >60yrs  Painless  May be assoc. ¯c EBV  Symmetric  Multiple sites Features  Spreads discontinuously Lymphadenopathy Extranodal  Painless  Skin: esp. T cell lymphomas  Asymmetric  CNS  Spreads contiguously to adjacent LNs  Oropharynx and GIT  Cervical nodes in 70% (also axillary and inguinal)  Splenomegaly  May be alcohol-induced LN pain  Mediastinal LN may → mass effects B Symptoms . SVC obstruction  Fever . Bronchial obstruction  Night sweats  Wt. loss (>10% over 6mo) B Symptoms  Fever Blood  Night sweats  Pancytopenia  Wt. loss (>10% over 6mo)  Hyperviscosity Other Ix  Itch  FBC, U+E, LFT, LDH  Pel Ebstein Fever: cyclical fever . ↑ LDH = worse prognosis  Hepato- and/or spleno-megaly  Film . Normal or circulating lymphoma cells Ix . ± pancytopenias  FBC, film, ESR, LFT, LDH, Ca  Classification: LN and BM biopsy . ↑ESR or ↓Hb = worse prognosis  Staging: CT/MRI chest, abdomen, pelvis  LN excision biopsy or FNA . Stage ¯c Ann Arbor System . Reed-Sternberg Cells (owl’s eye nucleus)  Staging: CT/MRI chest, abdomen, pelvis Classification  BM biopsy if B symptoms or Stage 3/4 disease

B Cell (commonest) Staging: Ann Arbor System  Low Grade: usually indolent but often incurable 1. Single LN region . Follicular 2. ≥2 nodal area on same side of diaphragm . Small cell lymphocytic (=CLL) 3. Nodes on both sides of diaphragm . Marginal Zone (inc. MALTomas) 4. Spread byond nodes: e.g. liver, BM . Lymphoplamsacytoid (e.g. Waldenstrom’s)  + B if constitutional symptoms  High Grade: aggressive but may be curable . Diffuse large B cell (commonest NHL) . Burkitt’s Mx

 Chemo, radio or both T Cell  ABVD regimen  Adult T cell lymphoma: Caribs and Japs – HTLV-1  BMT for relapse  Enteropathy-assoc. T cell lymphoma: chronic coeliac

 Cutaneous T cell lymphoma: e.g. Sezary syn.

 Anaplastic large cell Prognosis Mx  Depends on stage and grade . 1A: >95% 5ys  Diagnosis and management in an MDT . 4B: <40% 5ys

High Grade (e.g. DLBCL)  R-CHOP regimen  BMT for relapse  ~30% 5ys

Low Grade (e.g. follicular)  Rx when clinically indicated (e.g. chloambucil)  >50% 5ys

Epidemiology Dx  M=F  Clonal BM plasma cells ≥10%  Blacks>White=2:1  Presence of se and/or urinary monoclonal protein  ~70yrs  End-organ Damage: CRAB (1 or more) . Ca ↑ (>2.6mM) Pathogenesis . Renal insufficiency  Clonal proliferation of plasma cells → monoclonal ↑↑Ig . Anaemia (<10g/dL) . Usually IgG or IgA . Bone lesions  Clones may also produce free light chain (λ or κ): ~2/3 . Excreted by kidney → urinary BJP Mx . Light chains only seen in plasma in renal failure  Clones produce IL-6 which inhibits osteoblasts (↔ ALP) Supportive and activates osteoclasts.  Bone pain: Analgesia (avoid NSAIDs) + bisphosphonates Symptoms  Anaemia: Transfusions and EPO  Renal impairment: ensure good hydration ± dialysis Osteolytic Bone Lesions  Infections: broad spectrum Abx ± IVIg if recurrent  Backache and bone pain  Pathological #s Complications  Vertebral collapse  ↑Ca: aggressive hydration, frusemide, bisphosphonates  Cord compression: MRI, dexamethasone + local radio BM Infiltration  Hyperviscosity: Plasmapheresis (remove light chains)  Anaemia, neutropenia or thrombocytopenia  AKI: rehydration ± dialysis

Recurrent Bacterial Infections Specific  Neutropenia  Fit pts.  Immunoparesis (= ↓Ig) . Induction chemo: lenalidomide + low-dose dex  Chemotherapy . Then allogeneic BMT  Unfit pts. Renal Impairment . Chemo only: melphalan + pred + lenalidomide  Light chains . Bortezomib for relapse  ↑Ca  AL-amyloid Prognosis  Mean survival: 3-5yrs Complications  Poor prognostic indicators  Hypercalcaemia . ↑ β2-microglobulin  Neurological: ↑Ca, compression, amyloid . ↓ albumin  AKI  Hyperviscosity  AL-amyloid (15%)

NB. Do ESR and Se electrophoresis if >50 ¯c back pain

Bloods  FBC: normocytic normochromic anaemia  Film: rouleaux ± plasma cells ± cytopenias  ↑↑ESR/PV, ↑U+Cr, ↑Ca, normal ALP  Se electrophoresis and β2-microglobulin

Urine  Stix: ↑ specific gravity (BJP doesn’t show)  Electrophoresis: BJP

BM trephine biopsy

X-ray: Skeletal Survey  Punched-out lytic lesions  Pepper-pot skull  Vertebral collapse  Fractures

Smouldering / Asymptomatic Myeloma Definition  Se monoclonal protein and/or BM plasma cells ≥10%  Group of disorders characterised by extracellular  No CRAB deposits of a protein in an abnormal fibrillar form that is resistant to degradation. MGUS  Se monoclonal protein <30g/L  Clonal BM plasma cells <10% AL Amyloidosis  No CRAB  Clonal proliferation of plasma cells ¯c production of amyloidogenic light chains. Solitary Plasmacytoma  1O: occult plasma cell proliferation  Solitary bone/soft tissue plasma cell lesion  2O: myeloma, Waldenstrom’s, MGUS, lymphoma  Se or urinary monoclonal protein  Normal BM and normal skeletal survey (except lesion) Features  No CRAB  Renal: proteinuria and nephrotic syndrome  Heart: restrictive cardiomyopathy, arrhythmias, echo Waldenstrom’s Macroglobulinaemia . “Sparkling” appearance on echo  Lymphoplasmacytoid lymphoma→ monoclonal IgM  Nerves: peripheral and autonomic neuropathy, carpal band tunnel.  Features:  GIT: macroglossia, malabsorption, perforation, . Hyperviscosity: CNS and ocular symptoms haemorrhage, hepatomegaly, obstruction. . Lymphadenopathy + splenomegaly  Vascular: periorbital purpura (characteristic)  Ix: ↑ESR, IgM paraprotein

Primary AL Amyloid AA Amyloidosis  Occult proliferation of plasma cells → production of  Amyloid derived from serum amyloid A amyloidogenic monoclonal protein. . SAA is an acute phase protein  Se or urinary light chains  Chronic inflammation . RA Paraproteinaemia in lymphoma or leukaemia . IBD  E.g. seen in 5% of CLL . Chronic infection: TB, bronchiectasis

Features  Renal: proteinuria and nephrotic syndrome  Hepatosplenomegaly

Familial Amyloidosis  Group of AD disorders caused by mutations in transthyretin (produced by liver)  Features: sensory or autonomic neuropathy

Others: non-Systemic Amyloidosis  β-amyloid: Alzheimer’s  β2 microglobulin: chronic dialysis  Amylin: T2DM

Dx  Biopsy of affected tissue . Rectum or subcut fat is relatively non-invasive  Apple-green birefringence ¯c Congo Red stain under polarized light.

Rx  AA amyloid may improve ¯c underlying condition  AL amyloid may respond to therapy for myeloma  Liver Tx may be curative for familial amyloidosis

Prognosis  Median survival: 1-2yrs

Neutropenic Sepsis DIC  Widespread activation of coagulation from release of pro- General Precautions coagulants into the circulation.  Barrier nursing in a side room  Clotting factors and plats are consumed → bleeding  Avoid IM injections (may → infected haematoma)  Fibrin strands → haemolysis  Swabs + septic screen  TPR 4hrly Causes  Malignancy: e.g. APML Antimicrobials  Sepsis  Start broad spectrum Abx: check local guidelines  Trauma  Consider G-CSF  Obstetric events: e.g. PET

Signs Hyperviscosity Syndrome  Bruising  Bleeding Causes  Renal failure  ↑↑RBC / Hct >0.5: e.g. PV  ↑↑WCC > 100: e.g. leukaemia Ix  ↑↑ plasma proteins: Myeloma, Waldenstrom’s  ↓plats, ↓Hb, ↑APTT, ↑PT, ↑FDPs, ↓fibrinogen (↑TT)

Features Rx  CNS: headache, confusion, seizures, faints  Rx cause  Visual: retinopathy → visual disturbance  Replace: cryoprecipitate, FFP  Bleeding: mucus membranes, GI, GU  Consider heparin and APC  Thrombosis

Ix Tumour Lysis Syndrome  ↑ plasma viscosity (PV)  Massive cell destruction  FBC, film, clotting . High count leukaemia or bulky lymphoma  Se + urinary protein electrophoresis  ↑K, ↑urate → renal failure  Prevention: ↑ fluid intake + allopurinol Rx  Polycythaemia: venesection  Leukopheresis: leukaemia . Avoid transfusing before lowering WCC  Plasmapheresis: myeloma and Waldenstrom’s

Anatomy Splenectomy → Hyposplenism  Intraperitoneal structure lying in the LUQ  Measures 1x3x5 inches Indications  Weighs ~7oz  Trauma  Lies anterior to ribs 9-11  Rupture (e.g. EBV infection)  AIHA Features  ITP 1. Dull to percussion  HS 2. Enlarges to RIF  Hypersplenism 3. Moves inferiorly on respiration 4. Can’t get above it Complications 5. Medial notch  Redistributive thrombocytosis → early VTE  Gastric dilatation (ileus) Function: part of the mononuclear phagocytic system  Left lower lobe atelectasis: v. common  Phagocytosis of old RBCs, WBCs and opsonised bugs  ↑ susceptibility to infections  Antibody production . Encapsulates: haemophilus, pneumo, meningo  Haematopoiesis  Sequestration of formed blood elements Film  Howell-Jolly bodies  Pappenheimer bodies Causes of Massive Splenomegaly: >20cm  Target cells  CML  Myelofibrosis Mx  Malaria  Immunisation: pneumovax, HiB, Men C, yrly flu  LeishManiasis  Daily Abx: Pen V or erythromycin  Gaucher’s (AR, glucocerebrosidase deficiency)  Warning: Alert Card and/or Bracelet

Other Causes of Hyposplenism

 SCD All Causes of Splenomegaly  Coeliac disease  Haematological  IBD . Haemolysis: HS . Myelproliferative disease: CML, MF, PV . Leukaemia, lymphoma  Infective . EBV, CMV, hepatitis, HIV, . TB, infective endocarditis . Malaria, leishmanias, hydatid disease  Portal HTN: cirrhosis, Budd-Chiari  Connective tissue: RA, SLE, Sjogrens  Other . Sarcoid . Amyloidosis . Gaucher’s . 1O Ab deficiency (e.g. CVID)

Splenomegaly may → Hypersplenism  Pancytopenia as cells are sequestrated

ESR The Peripheral Film  How far RBCs fall through anti-coagulated blood in 1h  Normal: ~20mm/h (M: age/2, F: (age+10)/2 Feature Causes  ↑ se proteins cover RBCs → clumping → rouleaux → Acanthocytes Abetaliproteinaemia faster settling → ↑ESR. Alcoholic lever disease Basophilic stippling Lead poisoning ↑ ESR Thalassaemia  Plasma factors Blasts Leukaemia . ↑ fibrinogen: inflammation Burr cels Uraemia . ↑ globulins: e.g. myeloma Dimorphic picture Myelodysplasia  Red cell factors Howell-Jolly bodies Hyposplenism . Anaemia → ↑ESR Heinz bodies G6PD deficiency Irregularly contracted cells G6PD deficiency ∆∆ of ESR >100 Leukoerythroblastic film BM infiltration  Myeloma Pappenheimer bodies Hyposplenism  SLE Pencil cells IDA  GCA Reticulocytes Haemolysis  AAA Haemorrhage  Ca prostate Spherocytes AIHA Hereditary spherocytosis Differential White Count Schistocytes MAHA Prosthetic valve Neutrophilia Target cells Hyposplenism  Bacterial infection Thalassaemia . Left shift Liver disease . Toxic granulation Tear-drop cells / Dacrocytes BM infiltration . Vacuolation  Stress: trauma, surgery, burns, haemorrhage  Steroids Cytochemistry  Inflammation: MI, PAN  Myeloblasts  Myeloproliferative disorders: e.g. CML . Sudan black B . MPO Neutropenia  Hairy cell leukaemia: tartrate resistant acid phosphatase  Viral infection  Leukocyte alkaline phosphatase  Drugs: chemo, cytotoxics, carbimazole, sulphonamides . ↑: PV, ET, MF  Severe sepsis . ↓: CML, PNH  Hypersplenism: e.g. Felty’s

Lymphocytosis  Viral infections: EBV, CMV  Chronic infections: TB, Brucella, Hepatitis, Toxo  Leukaemia, lymphoma: esp. CLL

Lymphopenia  Drugs: steroids, chemo  HIV

Monocytosis  Chronic infection: TB, Brucella, Typhoid  AML

Eosinophilia  Parasitic infection  Drug reactions: e.g. ¯c EM  Allergies: asthma, atopy, Churg-Strauss  Skin disease: eczema, psoriasis, pemphigus

Basophilia  Parasitic infection  IgE-mediated hypersensitivity: urticarial, asthma  CML

Contents

Tuberculosis ...... 138 Other Mycobacterial Disease ...... 139 Influenza ...... 139 HIV ...... 140 Complications of HIV Infection ...... 141 Herpes Infections ...... 142 Viral Hepatitis ...... 144 Gastrointestinal Infections 1 ...... 145 Gastrointestinal Infections 2 ...... 146 Sexually Transmitted Infections ...... 147 Syphilis ...... 148 Zoonoses ...... 149 Malaria ...... 150 Other Tropical Diseases ...... 151 Miscellaneous Infections ...... 152 Approach to Nosocomial Fever ...... 152

Pathophysiology Dx

Primary TB Latent TB  Childhood or naïve TB infection  Tuberculin Skin Test  Organism multiplies @ pleural surface → Ghon Focus  If +ve → IGRA  Macros take TB to LNs . Nodes + lung lesion = Ghon complex Active TB  Mostly asympto: may → fever and effusion  CXR  Cell mediated immunity / DTH controls infection in 95% . Mainly upper lobes. . Fibrosis of Ghon complex → calcified nodule . Consolidation, cavitation, fibrosis, calcification (Ranke complex)  If suggestive CXR take ≥3 sputum samples (one AM)  Rarely may → 1O progressive TB (immunocomp) . May use BAL if can’t induce sputum . Microscopy for AFB: Ziehl-Neelsen stain Primary Progressive TB . Culture: Lowenstein-Jensen media (Gold stand)  Resembles acute bacterial pneumonia  Mid and lower zone consolidation, effusions, hilar LNs PCR Can Dx rifampicin resistance  Lymphohaematogenous spread → extra-pulmonary and  milliary TB  May be used for sterile specimens

Latent TB Tuberculin Skin Test  Infected but no clinical or x-ray signs of active TB  Intradermal injection of purified protein derivative  Non-infectious  Induration measured @ 48-72h . Had BCG: +ve = ≥15mm  May persist for years . No BCG: +ve = ≥6mm  Weakened host resistance → reactivation  False +ve: BCG, other mycobacteria, prev exposure Secondary TB  False –ve: HIV, sarcoid, lymphoma

 Usually reactivation of latent TB due to ↓ host immunity Interferon Gamma Release Assays (IGRAs)  May be due to reinfection  Pt. lymphocytes incubated c M. tb specific antigens →  Typically develops in the upper lobes ¯ IFN-γ production if previous exposure.  Hypersensitivity → tissue destruction → cavitation and formation of caseating granulomas.  Will not be positive if just BCG (uses M. bovis)  E.g. Quantiferon Gold and T-spot-TB Clinical Features

Pulmonary Mx  Cough, sputum  Rx w/o culture if clinical picture is consistent ¯c TB  Malaise . Continue even if culture results are negative  Fever, night sweats, wt. loss  Stress importance of compliance  Haemoptysis  Check FBC, liver and renal function  Pleurisy . CrCl 10-50ml/min → ↓ R dose by 50%, avoid E  Pleural effusion  Test visual acuity and colour vision  Aspergilloma / mycetoma may form in TB cavities  Give pyridoxine throughout Rx

Meningitis Initial Phase (RHZE): 2mos  Headache, drowsiness  RMP: hepatitis, orange urine, enzyme induction  Fever  INH: hepatitis, peripheral sensory neuropathy, ↓PMN  Vomiting  PZA: hepatitis, arthralgia (CI: gout, porphyria)  Meningism  EMB: optic neuritis  Worsening over 1-3wks  CNS signs Continuation Phase (RH): 4mos . Papilloedema  RMP . CN palsies  INH

Lymph Nodes TB Meningitis  Cervical lymphadenitis: scrofula  RHZE: 2mos  Painless neck mass: no signs of infection (cold)  RH: 10mos  ± dexamethasone GU TB  Frequency, dysuria, loin/back pain, haematuria Chemoprophylaxis in latent TB  Sterile pyuria  RH for 3mo or H alone for 6mo

Bone TB: vertebral collapse and Pott’s vertebra Skin: Lupus vulgaris (jelly-like nodules) Peritoneal TB: abdominal pain, GI upset, ascites Adrenal: Addison’s disease © Alasdair Scott, 2012 138 Other Mycobacterial Disease Influenza

Leprosy / Hansen’s Disease Pathophysiology  Spread: droplet Pathogenesis  Incubation: 1-4d  Transmitted via nasal secretions  Infectivity: 1d before symptoms start to 7d after . Not very infectious  Immunity: only strains which have already attacked pt  M. leprae Presentation Classification  Fever  Tuberculoid  Headache . Less severe  Malaise . T1-mediated control of bacteria → paucibacillary H  Myalgia . Anaesthetic hypopigmented macules  n/v  Lepromatous  Conjunctivitis . Weak T 1/2 → multibacillary H . Skin nodules . Nerve damage (esp. ulnar and peroneal) Complications  Bronchitis Clinical Features  Pneumonia: esp. Staph  Hypopigmented, insensate plaques  Sinusitis  Trophic ulcers  Encephalitis  Thickened nerves  Pericarditis  Keratitis  Reyes: rash, vomiting, ↑LFTs in children give aspirin

Rx Ix  Tuberculoid: 6mo Rx  Bloods: paired sera (takes 14d), lymphopenia, . Rifampicin monthly thrombocytopenia . Clofazamine daily  Culture: 1wk from nasal swabs  Lepromatous: 2yrs  PCR: takes 36h, 94% sensitivity, 100% specificity . Rifampicin monthly . Clofazamine + dapsone daily Rx  Bed rest + paracetamol  If severe MAI . Mx in ITU  Complicates HIV infection . Cipro and co-amoxiclav: prevent Staph and Strep  Widely disseminated: lungs / GIT  Oseltamivir  Fever, night sweats, wt. loss . Neuraminidase inhibitor active vs. flu A and B  Diarrhoea . May be indicated if >1yr ¯c symptoms of <48hr  Hepatomegaly  Zanamivir . Inhaled NA inhibitor active vs. influenza A and B . >5yrs ¯c symptoms <48h Buruli Ulcer  M. ulcerans Prevention  Australia and the Tropics  Good hygiene  Transmitted by insects  Trivalent Vaccine  Nodule → ulcer . >65yrs . DM, COPD, heart, renal, liver failure . Immunosuppression: splenectomy, steroids . Medical staff Fish Tank Granuloma  Oseltamivir  M. marinum . Prophylactic use if influenza A/B is circulating  Skin lesion appearing ~3wks after exposure and >1yr old and <48hr since exposure.

Immunology Ix  HIV binds via gp120 to CD4  HIV diagnostic tests . TH cells, monocytes, macrophages, neural cells  Drug resistance studies  CD4+ cells migrate to lymphoid tissue where virus . e.g. genotyping for reverse transcriptase or replicates → infection of new CD4+ cells protease mutations  Depletion and impaired function of CD4+ cells →  Mantoux test immune dysfunction.  Serology: toxo, CMV, HBV, HCV, syphilis

Monitoring Virology  CD4 count  RNA retrovirus  Viral load (HIV RNA)  After entry, viral reverse transcriptase makes DNA  FBC, U+E, LFTs, lipids, glucose copy of viral RNA genome.  Viral integrase enzyme integrates this ¯c host DNA  Core viral proteins synthesised by host and then HAART cleaved by viral protease into mature subunits.  Completed virions released by budding Indications  CD4 ≤350  AIDS-defining illness Natural Hx  Pregnancy  HIVAN Acute Infection: usually asympto  Co-infected ¯c HBV when Rx is indicated for HBV

Seroconversion Regimens  Transient illness 2-6wks after exposure  1 NNRTI + 2 NRTIs  Fever, malaise, myalgia, pharyngitis, macpap rash . NNRTI = Efavirenz  Rarely meningoencephalitis . NRTI = emtricitabine + tenofovir (Truvada) . Atripla = efavirenz + emtricitabine + tenofovir Asymptomatic Infection  PI + 2 NRTIs  But 30% will have PGL . PI = lopinavir (+ low dose ritonavir = Kaletra) . Nodes >1cm in diameter . ≥2 extra-inguinal sites Aim . ≥3mo  Undetectable VL after 4mo  If VL remains high despite good compliance AIDS-related Complex (ARC) . Change to a new drug combination  AIDS prodrome . Request resistance studies  Constitutional symptoms: fever, night sweats, wt. loss  Minor opportunistic infections . Oral candida Prophylaxis . Oral hairy leukoplakia (EBV)  CD4 <200: PCP – co-trimoxazole . Recurrent HSV  CD4 <100: Toxo – co-trimoxazole . Seborrhoeic dermatitis  CD4 <50: MAC – azithromycin

AIDS  Defining illness  CD4 usually <200 HIV Exposure  Seroconversion post-needle-stick = ~0.3% (1/300) Other Effects of HIV  Report to occupational health  Osteoporosis  Immunise against hep B (active + passive)  Dementia  Test blood from both parties: HIV, HBC, HCV  Neuropathy  Repeat recipient testing @ 3 and 6mo  Nephropathy PEP  Start PEP in high-risk exposure from HIV+ or unknown Dx source.  Start ASAP as possible.  ELISA: detect serum (or salivary) anti-HIV Abs  Continue for at least 28d  Western Blot: for confirmation  E.g. Truvada + Kaletra If recent exposure, may be window period  . Usually 1-3wks

. Can be 3-6mo  PCR: can detect HIV virions in the window period  Rapid Antibody Tests: false positives are a problem and results should be confirmed by Western Blot

Major AIDS-Defining Illnesses Candidiasis  Candidiasis: oesophageal or pulmonary  Oral: nystatin suspension  Cryptococcal meningitis  Oesophageal  Cryptosporidiosis . Dysphagia  CMV retinitis . Retrosternal pain  Kapsosi sarcoma . Rx: itraconazole PO  Lymphoma: Burkitt’s, 1O brain  MAC  PCP Cryptococcal Meningitis  PML  Presentation  Toxo . Chronic Hx  TB . Headache . Confusion . Papilloedema TB and HIV . CN lesions  Ix  ↑ reactivation of latent TB . India ink CSF stain  ↑ risk of disseminated TB . ↑↑ CSF pressure  Higher bacterial loads but ↑ false –ve smears . CrAg in blood and CSF . Fewer bacteria in sputum  Rx  False –ve skin tests (T cell anergy) . Amphotericin B + flucytosine for 2wks then  Absence of characteristic granulomas fluconazole for for 6mo / until CD4 >200  ↑ toxicity combining anti-TB and anti-HIV drugs  IRIS: HAART → ↑ CD4 → paradoxical worsening of TB symptoms PML

 Progressive multifocal leukoencephalopathy

 Demyelinating inflammation of brain white matter PCP caused by JC virus.  P. jiroveci: fungus  Presentation  Presentation . Weakness . Dry cough . Paralysis . Exertional dyspnoea . Visual loss . Fever . Cognitive decline  CXR: bilat perihilar interstitial shadowing  Ix: JC viral PCR  Dx: visualisation from sputum, BAL or lung biopsy  Rx: HAART, mefloquine may halt progression  Rx . High-dose co-trimoxazole IV . Or, pentamidine IVI Kaposi’s Sarcoma . Prednisolone if severe hypoxaemia  Neoplasm derived from capillary endothelial cells or  Prophylaxis fibrous tissue. . Co-trimoxazole if CD4 <200 or after 1st attack  Caused by HHV8 infection

Presentation  . Purple papules CMV . May have visceral involvement  Mainly → retinitis  Rx . ↓ acuity . HAART . Eye pain, photophobia . Radiotherapy or chemotherapy . “Pizza” sign on Fundoscopy . Rx: ganciclovir eye implant  Also: pneumonitis, colitis, hepatitis Other Presentations

 Pulmonary

. MAI Toxoplasmosis . Fungi: aspergillus, crypto, histoplasma  Presentation . CMV . Posterior uveitis  ↑ LFT and Hepatomegaly . Encephalitis . Drugs . Focal neurology . Viral hepatitis  Dx . AIDS sclerosing cholangitis . Toxoplasma serology . MAI . Toxo isoloation from LN or CNS biopsy  Chronic Diarrhoea . CT/MRI: ring-shaped contrast enhancing lesions . Bacteria: Salmonella, shigella, campylobacter  Rx: pyrimethamine + sulfadiazine + folate . Protozoa: cryptosporidium, microsporidium  Prophylaxis . Virus: CMV . Co-trimoxazole if CD4 <100 O  Neuro . Lifelong 2 prophylaxis . CMV encephalitis . Lymphoma © Alasdair Scott, 2012 141 Herpes Infections

Herpes Simplex

Virology Disease Features Diagnosis Treatment α-neurotrophic Oropharyngeal / primary HSV-1 Topical Aciclovir stomatitis Severe painful ulceration Persists in DRG Fever + Submandibular lymphadenopathy Encephalitis 90% HSV-1, 10% HSV-2 CSF: ↑lympho, normal gluc Aciclovir IV Mucocutaneous spread Flu-like prodrome CSF PCR Headache, focal neuro, fits, odd behaviour, ↓GCS MRI Haemorrhagic necrosis of temporal lobes Mollaret’s Meningitis HSV-2 mostly Aciclovir IV Benign recurrent aseptic meningitis Herpes Gladiatorum Rugby players, wrestlers Aciclovir PO Painful vesicular rash, lymphadenopathy, fever Herpetic Whitlow Healthcare workers, children Topical Aciclovir Painful red finger Eczema Herpeticum Herpes infection at the site of skin damage Aciclovir Genital Herpes HSV-2 Urinary PCR Aciclovir PO Flu-like prodrome Dysuria, inguinal LNs, painful ulcers Sacral radiculomyelitis → urinary retention + sacral sensory loss (Elsberg syndrome) Herpes meningitis in 4-8% primary genital herpes Herpetic Keratitis Unilat/bilat conjunctivitis + pre-auricular LNs May cause a corneal ulcer = dendritic ulcer

Varicella Zoster

Virology Disease Features Diagnosis Treatment α-neurotrophic Chickenpox Flu-like prodrome followed by vesicular rash that crops DIF of scrapings Calamine lotion = varicella zoster Not contagious after lesions scab Aciclovir Droplet or contact spread Droplet spread Tzanck cells - adults - immunocomp Replication in LN, then liver Complications: pneumonitis, haemorrhage, encephalitis - pregnant and spleen - ↑ risk in immunocompromised and adults VZIg if contact Shingles Zoster reactivation due to ↓ immunity/stress Aciclovir PO/IV = herpes zoster Lifetime prevalence = 20% Famciclovir Painful vesicular rash in dermatomal distribution Valaciclovir - Thoracic and ophthalmic most commonly - Multidermatomal / disseminated in immunocomp Rx may ↓ progression to post-herpetic neuralgia

Post-Herpetic neuralgia = severe dermatomal pain Ramsay Hunt = ear zoster, facial palsy, ↓ taste, ↓ hearing © Alasdair Scott, 2012 142 EBV

Virology Disease Features Diagnosis Treatment γ-lymphotrophic Glandular fever Saliva or droplet spread Lymphocytosis Infectious mononucleosis Fever, malaise, sore throat, cervical LNs +++ Atypical Lymphocytes Infects B-cells Splenomegaly, hepatitis (→ hepatomegaly and jaundice) +ve Heterophile Abs Complications: splenic rupture, CN lesion (e.g. 7), ataxia GBS, - Monospot pancytopenia with megaloblastic marrow, meningoencephalitis, - Paul Bunnell chronic fatigue ↑LFTs Blood: serology, PCR Burkitt’s lymphoma Jaw or abdo mass Starry-sky appearance Endemic: Africa, malaria CD10, BCL6 Sporadic: non-African, impaired immunity t(8;14) Immunodeficiency: HIV or post-Tx PTLD Lymphoma following solid organ TX Viral load > 105c/ml Rituximab Oral hairy leukoplakia HIV+ Aciclovir Painless shaggy white plaque along lateral tongue border Primary brain lymphoma HIV+ CT/MRI: Ring-enhancing lesion Mass effects + systemic symptoms Nasopharyngeal Ca Especially in Asia

False +ve Heterophile Abs: hepatitis, parvovirus, leukaemia, lymphoma, SLE, pancreatic Ca

CMV

Virology Disease Features Diagnosis Treatment β-epitheliotropic Primary Infection 80% asymptomatic Flu-like illness can occur (±hepatitis) Mucocutaneous spread Reactivation Immunocompromise Blood: PCR, serology 1 = Ganciclovir 2 = Foscarnet Infected cells become swollen HIV: retinitis > colitis > CNS disease Owl’s Eye intranuclear 3 = Cidofovir Transplant: pneumonitis > colitis > hepatitis> > retinitis inclusions

Atypical Lymphocytes

Congenital Petechiae at birth + hepatosplenomegaly

BMT Prevention  Do weekly PCR for first 100d  If viraemia +ve → ganciclovir IV  Use CMV-ve irradiated blood products

Solid Organ Transplant Prevention  Greatest risk = seroneg recipient and seropos donor  Renal Tx prophylaxis = valganciclovir © Alasdair Scott, 2012 143 Viral Hepatitis

Types Hep C  Mainly spread by blood. Type Spread Cause  Thousands of UK cases due to transfusion (eligible for A FO Seafood, especially abroad compensation from Skipton fund) B IV Blood, body fluids, babies (vertical) C IV Mainly blood. Less vertical cf. HCV Presentation D IV Dependent on prior HBV infection  Initial infection is usually asymptomatic E FO Developing world  25% have acute icteric phase  85% → chronic infection Hepatitis A  20-30% → cirrhosis w/i 20yrs  ↑↑ risk of HCC Presentation  Prodromal Phase Ix . Fever, malaise, arthralgia, nausea, anorexia  Anti-HCV Abs . Distaste for cigarettes  HCV-PCR  Icteric Phase  Liver biopsy if PCR+ve to assess liver damage and . Jaundice, HSM, lymphadenopathy, cholestasis need for Rx  HCV genotype Ix  ↑↑ALT, ↑AST (AST:ALT <2) Rx  IgM+ ~25d after exposure  Indications . = recent infection . Chronic haepatitis  IgG+ for life . ↑ ALT . Fibrosis Rx  PEGinterferon α2b + ribavirin  Supportive  ↓ efficacy if  Avoid alcohol . Genotype 1, 4, 5 or 6  IFN-α for fulminant hepatitis (rare) . ↑ VL . Older Prevention . Black  Passive Ig → <3mo protection (e.g. travellers) . Male

 Can give active vaccine Hep D Hep B  Incomplete RNA virus that can only exist ¯c HBV  ↑ risk of acute hepatic failure and cirrhosis Incubation: 1-6mo  Ix: anti-HDV Ab

Presentation Hep E  Prodromal phase and icteric phase as for Hep A  Similar to HAV  Extra-hepatic features due to immune complexes  Common in Indochina . Urticaria or vasculitic rash . Cryoglobulinaemia Differential . PAN . GN Acute . Arthritis  Infection: CMV, EBV, leptospirosis  Toxin: EtOH, paracetamol, isoniazid, halothane Ix  Vasc: Budd-Chiari  HBsAg +ve = current infection  Obs: eclampsia, acute fatty liver of pregnancy . +ve >6mo = chronic disease  Other: Wilson’s, AIH  HBeAg +ve = high infectivity  Anti-HBc IgM = recent infection Cirrhosis  Anti-HBc IgG = past infection  Common:  Anti-HBs = cleared infection or vaccinated . Chronic EtOH  HBV PCR: monitoring response to Rx . NAFLD / NASH  Other: Rx . Genetic: Wilson’s, α1ATD, HH, CF  Supportive . AI: AH, PBC, PSC  Avoid EtOH . Drugs: Methotrexate, amiodarone, isoniazid  Chronic disease: PEGinterferon α2b . Neoplasm: HCC, mets . Vasc: Budd-Chiari, RHF, constrict. pericarditis Complications  Fulminant hepatic failure (rare)  Chronic hepatitis (5-10%) → cirrhosis in 5%  HCC

Organism Aetiology Inc Clinical Features Dx Mx Staph aureus Meat 1-6h Diarrhoea, vomiting, abdo pain, ↓BP Rapid resolution Bacilus cereus Reheated rice 1-6h Watery diarrhoea and vomiting E. coli ETEC Travelling Watery diarrhoea Cipro E. coli EHEC Undercooked minced beef 12-72h Dysentery Stool MC+S Dialysis if necessary (O157:H7) - e.g. burgers HUS Campylobacter Unpasteurised milk 2-5d Commonest bacterial diarrhoea Stool MC+S Cipro jejuni Animal faeces (cats, dogs) Bloody diarrhoea, fever - 250-750mg BD PO Guillain-Barre - 200-400mg BD IVI over 30min – 1h Reactive arthritis Shigella 1-7d Bloody diarrhoea, abdo pain, fever Stool MC+S Cipro Reactive arthritis Salmonella Poultry, eggs, meat 12-48h Diarrhoea, vomiting, fever, abdo pain Cipro or ceftriaxone enteritidis Listeria Refrigerated food Watery diarrhoea, cramps, flu-like Blood culture Ampicillin monocytogenes - cold enhancement Pneumonia Pates, soft cheeses Meningoencephalitis Miscarriage Clostridium Antibiotic use 1-7d Bloody diarrhoea, abdo pain, fever Stool MC+S Stop causative Abx difficle - cephs, cipro, clinda - foul smelling CDT ELISA 1st: Metronidazole 400mg TDS PO for 10d Pseudomembranous colitis 2nd: Vanc 125mg QDS PO FO spread Toxic megacolon Colectomy may be needed Environment: spores GI perforation Clostridium Canned / vac-packed food 12-36h Afebrile Toxin in blood samples Antitoxin botulinum Kids=honey Descending symmetric flaccid paralysis Benpen + metro Students=beans No sensory signs Autonomic: dry mouth, fixed dilated pupils Clostridium Reheated meat 8-24h Watery diarrhoea + cramps Stool MC+S Benpen + metro perfringes Vibrio cholera FO spread Hrs-5d Rice-water stools Stool MC+S Rehydrate Dirty water Shock, acidosis, renal failure - Cooked rice powder solution - Hartmann’s ¯c K+ supplements Cipro Zn supplement Vibrio Raw/undercooked seafood Profuse diarrhoea, abdo pain, vomiting Doxy 100-200mg/d PO parahaemolyticus - Japan Norovirus 12-48h Commonest cause in adults 50% of all gastroenteritis worldwide Fever, diarrhoea, projectile vomiting Rotavirus 1-7d Commonest cause in children Secretory diarrhoea and vomiting

Organism Aetiology Inc Features Dx Mx Salmonella FO spread 3-21d Malaise, headache, cough, constipation Leukopenia Cefotaxime or cipro typhi/paratyphi Tropics High fever ¯c relative bradycardia Blood culture Rose spots: patchy red macules Urine or stool culture Epistaxis, splenomegaly Diarrhoea after 1st wk Yersinia Food contaminated by 24-36h Abdo pain, fever, diarrhoea Serology Cipro enterocolitica domestic animal faeces Mesenteric adenitis Reactive arthritis, pharyngitis, pericarditis Erythema Nodosum Entamaeoba MSM 1-4wk Dysentery, wind, tenesmus Stool micro Metro histolytica Travelling Wt. loss if chronic - Motile trophozoite ¯c 4 nuclei Liver abscess Tinidazole if severe or - RUQ pain, swinging fever, sweats Stool Ag abscess - Mass in R lobe Flask-shaped ulcer on histo Giardia lamblia MSM 1-4wk Bloating, explosive diarrhoea, offensive gas Direct fluorescent Ab assay Tinidazole Hikers Stool micro Travellers Malabsorption → steatorrhoea and wt. loss - Pear-shaped trophozoites ¯c 2 nuceli Duodenal fluid analysis on swallowed string Crypto parvum Waterborne 4-12d Severe acute watery diarrhoea in HIV Stool micro Paromomycin - protozoan Strongyloides Endemic in sub-tropics Migrating urticarial rash on trunk and legs Stool MC+S Ivermectin stercoralis Hyperinfestation in AIDS Pneumonitis, enteritis Serology Malabsorption → chronic diarrhoea

Secretory Diarrhoea  Bacteria only found in lumen: don’t activate innate immunity  No / low fever  No faecal leukocytes  Caused by bacterial toxins: Cholera, E. coli (except EIEC), S. aureus  Toxin → ↑cAMP→ open CFTR channel → Cl loss followed by HCO3, Na and H2O loss → secretory diarrhoea

Inflammatory Diarrhoea  Bacteria invade lamina propria: activate innate immunity  Fever  PMN in stool  Campylobacter, shigella, non-typhoidal salmonella, EIEC

Enteric Fever  Abdo pain, fever, mononuclear cells in stool  Typhoidal salmonella, Yersinia enterocolitica, Brucella

Disease Risk Factors Clinical Features Diagnosis Management Complications Gonorrhoea Young, Black M Men: Urine NAATs Cefixime PO Prostatitis - Purulent urethral d/c, dysuria, prostatitis Ceftriaxone IM Epididymitis Culture is gold standard Salpingitis / PID Women: - Intracellular Gm- diplococci + Azithro for C Reactive Arthritis - Usually asympto, dysuria, d/c - Transport in Stuart’s Medium Ophthalmia neonatorum

Chlamydia 10% <25 Asympto in 50% men and 80% women NAATs Azithromycin / Prostatitis - D-K Men: - Urine doxycycline Epididymitis - Urethritis Salpingitis / PID Culture Reactive Arthritis Women: - Endocervical swab Opthalmia neonatorum - Cervicitis, urethritis, salpingitis - Discharge LGV Tropical STI Primary Stage: Chlamydia serovars L1, L2, L3 Azithromycin / Genital elephantiasis Outbreak in MSM - painless genital ulcer, heals fast doxycycline Rectal strictures - balanitis, proctitis, cervicitis NAATs Inguinal Syndrome: - Painful inguinal buboes - Fever, malaise → gential elephantiasis Anogenitorectal syndrome: - Proctocolitis → Rectal strictures → Abscesses and fistulae HPV 6, 11 Often asympto Podophyllotoxin Cauliflower warts Cryotherapy HSV 2 (/1) Flu-like prodrome PCR Analgesia Meningitis Inguinal LNs Serology Aciclovir Elsberg Syndrome Painful grouped vesicles → ulcers - sacral radiculomyelitis Dysuria → retention + saddle paraesthesia Syphilis MSM Painless, indurated ulcer Dark ground microscopy Benzathine Pen Jarisch-Herxheimer Reaction Mac pap rash: soles, palms RPR/VDRL: cardiolipin Abs - Hrs after 1st Pen dose Aortic aneurysms - not treponeme specific - Fever, ↑HR, vasodilation Tabes dorsalis - indicate active disease

TPHA/FTA - treponeme-specific Chancroid Mainly Africa Papule → Painful soft genital ulcer Culture Azithromycin H. ducreyi - base covered in yellow/grey PCR Progressing to inguinal buboes Granuloma Africa Painless, beefy-red ulcer Donovan bodies Erythromycin inguinale India Subcutaneous inguinal granulomas - Giemsa stain (Donovanosis) - Pseudobuboes Klebsiella Possible elephantiasis granulomatis © Alasdair Scott, 2012 147 Syphilis

Stages Dx

Stage Features: due to endarteritis obliterans Cardiolipin antibody Primary  Mac→pap→indurated, painless ulcer = Chancre  E.g. VDRL, RPR  Regional LNs  Not treponeme specific  Heals in 1-3wks . False +ve: pregnancy, pneumonia, SLE, malaria, TB +ve in 1O and 2O syphilis (wanes in late disease) Secondary  6wks -6mo wks after chancre  Reflects disease activity: -ve after Rx  Systemic bacteraemia → fever, malaise 

 Skin rash: Treponeme-specific Ab . Symmetrical, non-itchy, mac pap / pustular O O . Palms, soles, face, trunk  +ve in 1 and 2 syphilis Remains +ve despite Rx  Buccal snail-track ulcers  THPA and FTA  Warty lesions: condylomata lata 

Treponemes Tertiary  2-20yrs latency  Seen by dark ground microscopy of chancre fluid  Gummas O . Granulomas in skin, mucosa, bones, joints  Seen in lesions of 2 syphilis  May not be seen in late syphilis

Quaternary  Syphilitic aortitis . Aortic aneurysm . Aortic regurg Rx  Neurosyphilis  2-3 doses (1wk apart of benzathine penicillin . Paralytic dementia  Or, doxycycline for 28d . Meningovascular: CN palsies, stroke . Tabes dorsalis Jarisch-Herxheimer Reaction  Degeneration of sensory neurones,  Fever, ↑HR, vasodilatation hrs after first Rx esp. legs  ? sudden release of endotoxin  Ataxia and +ve Romberg’s  Rx: steroids  Areflexia  Plantars ↑↑  Charcot’s joints . Argyll-Robertson pupil  accommodates, doesn’t react

Disease Risk Factors Presentation Diagnosis Management Leptospirosis Infected rat urine High fever, headache, myalgia / myositis Blood culture Doxycycline Weil’s Disease - swimming Cough, chest pain ± haemoptysis Serology - canoeing ± hepatitis ¯c jaundice ± meningitis Brucellosis Middle and Far East, Malta Undulant fever (PUO): peak PM, normal AM Pancytopenia Doxy + RMP + gent

Melitensis Unpasteurised milk / cheeses Sweats, malaise, anorexia Positive Rose Bengal Test - goats, commonest - esp. goat Arthritis, spinal tenderness Anti-O-polysaccharide Ag Abortus: cattle LN, HSM Suis: pigs Vets, farmers, abattoir workers Rash, jaundice Lyme disease Ixodes tick bite Early localised: Biopsy ECM edge + Ab Rash: Doxy Walkers, hikers - Erythema migrans (target lesions) ELISA Borrelia burgdorferi Early disseminated: Complications: IV benpen - Malaise, LN, migratory arthritis, hepatitis Late persistent : - Arthritis, focal neuro (Bell’s palsy), heart block, myocarditis - Lymphocytoma: blue/red ear lobe Cat-Scratch Disease Hx of cat scratch Tender regional LNs +ve cat scratch skin Ag test Azithro Bartonella henselae Toxoplasmosis Cats are definitive hosts Mostly asympto CT/MRI: ring-shaped Pyrimethamine + sulfadiazine Sheep / pig intermediate hosts Reactivated in immunodeficiency contrast enhancing CNS - Encephalitis: confusion, seizures, focal lesions Septrin prohylaxis in HIV - SOL/↑ICP - Posterior uveitis Serology Rabies Animal bites Prodrome “Bullet-shaped” RNA virus Immunised - Bats, dogs, foxes - Headache, malaise, bite - diploid vaccine itch, odd behaviour Negri bodies Furious Rabies Unimmunised - Hydrophobia - vaccine + rabies Ig - Muscle spasms Dumb Rabies - flaccid limb paralysis Anthrax Spread by infected carcasses or hides Cutaneous Microscopy Cipro + clindamycin - abattoir workers, farmers - ulcer with BLACK centre - Gm+ spore forming rod - rim of oedema Inhalational - massive lymphadenopathy - mediastinal haemorrhage - resp failure GI - severe bloody diarrhoea

Species

Species Inc Liver stage? Rhythm Rx Falciparum 7-10d No Tertian: 48h Artemether-lumefantrine (Riamet) (Quinine + Doxy) Vivax 10-17d Chronic liver stage Tertian: 48h Chloroquine then primaquine Ovale 10-17d Chronic liver stage Tertian: 48h Chloroquine then primaquine Malariae 18-40d No Quartan: 72h Chloroquine then primaquine

Biology Mx  Plasmodium sporozoites injected by females Anopheles mosquito. Uncomplicated Ovale, Vivax, Malariae  Sporozoites migrate to liver, infect hepatocytes and multiply  Chloroquine base asymptomatically (incubation period) → merozoites  Then primaquine  Merozoites released from liver and infect RBCs  Multiply in RBCs Uncomplicated Falciparum . Haemolysis  Artemether-lumefantrine . RBC sequestration → splenomegaly . Cytokine release Severe Falciparum Malaria  Need ITU Mx  IV antimalarials Falciparum Malaria Prophylaxis  90% present w/i 1mo  No resistance: proguanil + chloroquine

 Resistance: mefloquine or malarone Flu-like Prodrome . Malarone: atovaquone + proguanil  Headache, malaise, myalgia, anorexia

Fever Paroxysms  Shivering ≤1h Antimalarial SEs  Hot stage for 2-6h: ~41OC  Chloroquine: retinopathy . Flushed, dry skin, headache, n/v  Fansidar: SJS, ↑LFTs, blood dyscrasias  Sweating for 2-4h as temp falls  Primaquine: haemolysis if G6PD deficient  Malarone: abdo pain, nausea, headache Signs  Mefloquine: dysphoria, neuropsychiatric signs  Anaemia  Jaundice  HSM  No rash, no LNs

Complications  Cerebral malaria: confusion, coma, fits  Lactic acidosis → Kussmaul respiration  Hypoglycaemia  Acute renal failure: 2O to ATN  ARDS

Dx  Serial thick and thin blood films  Parasitaemia level  FBC: anaemia, thrombocytopenia  Clotting: DIC  Glucose  ABG: lactic acidosis  U+E: renal failure  Urinalysis: haemoglobionuria

Disease Aetiolgy Presentation Diagnosis African Tsetse fly Tender subcut nodule @ site of infection Thick and thin films Trypanosomiasis - flagellated protozoa Haemolymphatic Stage “Sleeping sickness” - rash, fever, rigors, headaches Serology - LNs and HSM - Posterior cervical nodes (Winterbottom’s sign)

Miningoencephalitic Stage - Wks – Mos after original infection - Convulsions, agitation confusion - Apathy, depression, hypersomnolence, coma

T. gambiense: West Africa T. rhodesiense: East Africa - More severe than gambiense American Reduviids T. cruzi Trypanosomiasis - Latin America - Erythematous nodule, fever, LN, HSM “Chagas Disease” - Swelling of eyelid (Romana’s Sign) - Cardiac disease Leishmaniasis Sandflies Cutaneous (L. major, L. tropica) Visceral: - Skin ulcer @ bite → depigmented scar - Leucopaenia South + Central Am Diffuse cutaneous - ↑Ig Asia - Widespread nodules (fail to ulcerate) - Pancytopaenia Africa - Serology Mucocutaneous (L. braziliensis) - South America Visualisation of - Ulcer in mucous mems of mouth and nose Leishman-Donovan bodies Visceral = Kala Azar (L. donovani) - Dry, warty hyperpigmented skin lesions (dark face and hands) - Prolonged fever - Massive splenomegaly, LNs, abdo pain Filariasis Asia Lymphatic Filariasis Nemotodes Africa - Wuchereria bancrofti South America - elephantiasis Microfilariae in the blood Eosinophilia Dengue Fever Aedes mosquito Flushes: facem neck, chest Serology Central macpap rash Tourniquet test RNA virus South + Central Am Headache, arthralgia Asia HSM Africa Jaundice Haemorrhage: petechial, GI, gums or nose, GU

NB. can exclude if fever starts >2wks after leaving endemic area. Schistosomiasis Tremotode (Fluke) Itchy papular rash at site of penetration Snail vector - Swimmer’s Itch

Mansoni - abdo pain D&V - later hepatic fibrosis and portal HTN - HSM

Haematobium - frequency, dysuria, haematuria - may → hydronephrosis and renal failure - ↑ risk of bladder SCC

Tetanus Epidemiology  2-30% of hospital inpatients Pathophysiology  Mostly due to bacterial infection  Clostridium tetani spores live in faeces, dust, soil and medical instruments. Definition . Mucosal breach admits spores  Oral temp ≥38 that occurs ≥48hrs after admission and . Spores germinate and produce exotoxin is recorded on at least two separate occasions over 48h  Exotoxin prevents the release of inhibitory transmitters . GABA and glycine Causes  → generalised muscle over-activity  Infection (commonest cause)  Inflammation Presentation  Ischaemia  Prodrome: fever, malaise, headache  Malignancy  Trismus  Drug-induced  Risus sardonicus  Opisthotonus Mx  Spasms: may → respiratory arrest  Careful Hx and examination  Autonomic dysfunction: arrhythmias, fluctuating BP  Study drug list

 Basic Ix Rx . Urinalysis  Mx on ITU: may need intubation . FBC, LFT, ESR, cultures  Human tetanus Ig . Swabs  Metronidazole, benpen . CXR

Prevention  Active immunisation ¯c tetanus toxoid  Clean minor wounds . Uncertain Hx / <3 doses: give vaccine . ≥3 doses: only vaccinate if >10yrs since last dose  Heavily contaminated wounds . Uncertain Hx / <3 doses: vaccine + TIg . ≥3 doses: vaccinate if ≥5yrs since last dose

Actinomycosis  Actinomyces israelii  Subcut infections: esp. on jaw  Forms sinuses which discharge pus containing sulphur granules.  Rx: ampicillin for 30d, then pen V for 100d

Contents Basic Neuroscience ...... 155 Motor and Sensory Patterns ...... 158 Specific Neurological Patterns and Causes ...... 159 Muscle Weakness Differential ...... 160 Hand Wasting Differential ...... 160 Gait Disturbance Differential ...... 160 Blackouts ...... 161 Vertigo and Dizziness ...... 162 Causes of Hearing Loss ...... 162 Abnormal Involuntary Movements – Dyskinesias ...... 163 Dementia ...... 164 Delirium / ACS ...... 164 Headache: Differential and Investigation ...... 165 Headaches: Key Features ...... 166 Migraine ...... 167 Subarachnoid Haemorrhage ...... 168 Stroke: Causes and Investigation ...... 169 Stroke: Presentation ...... 170 Stroke: Management ...... 171 Transient Ischaemic Attack ...... 172 Subdural Haemorrhage ...... 173 Extradural Haemorrhage ...... 173 Intracranial Venous Thrombosis ...... 174 Meningitis ...... 175 Encephalitis ...... 176 Cerebral Abscess ...... 176 Epilepsy: Features ...... 177 Epilepsy: Investigation and Management ...... 178 Status Epilepticus ...... 179 Head Injury ...... 180 Space Occupying Lesions ...... 181 Idiopathic Intracranial Hypertension ...... 181 Raised ICP ...... 182 Signs and Symptoms ...... 182 Parkinsonism ...... 183 Parkinson’s Disease ...... 184 Multiple Sclerosis ...... 185 Cord Compression ...... 186 Cervical and Lumbar Degeneration ...... 187 Facial Nerve Palsy...... 188 Mononeuropathies ...... 189 Polyneuropathies ...... 190 Autonomic Neuropathy ...... 190 Guillain-Barré Syndrome ...... 191 © Alasdair Scott, 2012 153 Charcot-Marie-Tooth Syndrome ...... 191 Motor Neurone Disease ...... 192 Polio ...... 192 Myopathies ...... 193 Myasthenia Gravis ...... 194 Lambert-Eaton Myasthenic Syndrome (LEMS) ...... 194 Botulism ...... 194 Neurofibromatosis 1 – von Recklinghausen’s ...... 195 Neurofibromatosis 2 ...... 195 Intrinsic Cord Disease ...... 196 Syringomyelia ...... 196 Brown-Sequard Syndrome ...... 196 Miscellaneous Conditions ...... 197

The Spinal Cord Cerebellum and Basal Ganglia  Output to cortex via thalamus Gross Anatomy  Regulation of posture, locomotion, coordination and  Foramen magnum to L1 movement.  Terminates as conus medullaris  Spinal nerves continue inferiorly as corda equina  Denticulate ligament and filum terminale are pial Internal Capsule extensions that suspend cord in subarachnoid space.  White matter carrying axonal fibres from motor cortex to pyramids of medulla.  Infarction → contralateral hemiparesis Blood Supply  3 longitudinal vessels . 2 posterior spinal arteries: dorsal 1/3 . 1 anterior spinal artery: ventral 2/3 Brain Lobar Function  Reinforced by segmental feeder arteries . E.g. artery of Adamkiewicz Frontal  Longitudinal veins drain into extradural vertebral plexus  Cognition and memory  Executive function  Motor cortex Organisation  Dominant hemisphere: motor speech (Broca’s area)

Parietal  Sensory cortex  Body orientation

Temporal  Memory  Dom hemisphere: receptive language (Wernicke’s)

Occipital  Visual cortex

Homunculus

Dorsal Columns (FG + FC)  Mode: fine touch, vibration and proprioception  Cell body: DRG  Decussation: in medulla forming medial lemniscus

Lateral Spinothalamic Tract  Mode: pain and temperature  Cell body: DRG  Decussation: in cord, at entry level

Lateral Corticospinal Tract  Mode: motor (body)  Cell body: 1O motor cortex Brain Blood Supply  Decussation: pyramidal decussation in ventral medulla

Thalamic Nucelei  VPL: somoatosensory body  VPM: somatosensory head  LGN: visual  MGN: auditory

Motor Pathway

Sensory Pathway

Transmission Vestibulo-occular reflex (VOR) 1. Presynaptic voltage-gated Ca2+ channels open → Ca2+  Axons from vestibular neurones project via MLF to influx abducens and occulomotor nuclei 2. ACh vesicles released from presynaptic terminal  Head turns L → eyes turn R 3. ACh diffuses across cleft  Absent Doll’s Eye sign = brainstem death 4. ACh binds to nicotinic receptors on post-synaptic terminal Caloric Tests + 2+ 5. → Na influx → depolarisation → Ca release from SR  Warm → ↑ firing of vestibular N. → eyes turn to → muscle contraction contralateral side ¯c nystagmus to ipsilateral side 6. ACh is degraded by acetylcholinesterase and choline is  Remember fast direction of nystagmus – COWS taken up into presynaptic terminal. . Cold: Opposite . Warm: Same Blockade  Absence of eye movements = brainstem damage on 1. Block presynaptic choline uptake: hemicholinium side being tested. 2. Block ACh vesicle fusion: botulinum, LEMS

3. Block nicotinic ACh receptors . Non-depolarising: atracurium, vecuronium Visual Field Defects . Depolarising: suxamethonium

Dopamine Pathways  Mesocorticolimbic: SCZ  Nigrostriatal: Parkinsonism  Tuberoinfundibular: Hyperprolactinaemia

Sympathetic NS  Cell bodies from T1-L2  GVE preganglionic fibres synapse @ either: . Paravertebral ganglia . Prevertebral ganglia . Chromaffin cells of adrenal medulla  Preganglionic fibres are myelinated and release ACh @ nicotinic receptors Pupillary Light Reflex  Postganglionic fibres are unmyelinated and release NA @ adrenergic receptors . Except @ sweat glands where they release ACh for muscarinic receptors.

Parasympathetic NS  Cranial: CN 3, 7, 9, 10 . Ciliary: ciliary muscle and sphincter pupillae . Pterygopalatine: mucus mems of nose and palate, lacrimal gland . Submandibular: submandibular and sublingual glands . Otic: parotid gland . Vagus supplies thoracic and abdo viscera  Sacral: pelvic splanchnic nerves (S2-4) innervate pelvic viscera  Preganglionic fibres release ACh @ nicotinic receptors  Postganglionic fibres release ACh @ muscarinic receptors

CN Nuclei  Midbrain: 3, 4, (5)  Pons: 5, 6, 7, 8  Medulla: (5), 9, 10, 11, 12

NB. All nuclei except 4, innervate ipsilateral side. Fibres from trochlear nucleus decussate in medulla and supply contralateral SOB muscle.

Patterns of Motor Deficits

Cortical Lesions  Hyperreflexia proximally in arm or leg  Unexpected patterns: e.g. all movements in hand/foot

Internal Capsule and Corticospinal Lesions  Contralateral hemiparesis ¯c pyramidal distribution.  Lesion ¯c epilepsy, ↓ cognition or homonymous hemianopia = in a cerebral hemisphere  Lesion ¯c contralateral CN palsy = brainstem lesion on the side of the palsy (E.g. Miilard-Gubler syn.)

Cord Lesions  Quadriparesis / paraparesis  Motor and reflex level: LMN signs at level of lesion and UMN signs below

Peripheral Neuropathies  Usually distal weakness  In GBS weakness is proximal (root involvement)  Single nerve = mononeuropathy: trauma or entrapment  Several nerves = mononeuritis multiplex: vasculitis or DM

UMN Lesions LMN Lesions  Motor cells in pre-central gyrus to anterior horn cells  Anterior horn cells to peripheral nerves in the cord  Wasting  Pyramidal weakness: extensors in UL, flexors in LL  Fasciculation  No wasting  Flaccidity: ↓ tone  Spasticity: ↑ tone ± clonus  Hyporeflexia  Hyperreflexia  Down-going plantars  Up-going plantars

Primary Muscle Lesions  Symmetrical loss  Reflexes lost later vs. neuropathies  No sensory loss  Fatiguability in myasthenia

Patterns of Sensory Deficits  Pain and temp travel in small fibres in peripheral nerves and in anterolateral spinothalamic tracts  Touch, joint position and vibrations travel in large fibres peripherally and in dorsal columns centrally

Distal Sensory Loss  Suggests a neuropathy

Sensory Level  Hallmark of cord lesion  Hemi-cord lesion → Brown-Sequard syndrome . Ipsilateral loss of proprioception / vibration and UMN weakness with contralateral loss of pain

Dissociated Sensory Loss  Selective loss of pain and temp ¯c conservation of proprioception and vibration  Occurs in cervical cord lesions: e.g. syringomyelia

Cerebellar Syndrome Vertebrobasilar Circulation Effects: DANISH  Supplies cerebellum, brainstem and occipital lobes  Dysdiadochokinesia  Combination of symptoms  Dysmetria: past-pointing . Visual: hemianopia, cortical blindness  Ataxia: limb / trunkal . Cerebellar: DANISH  Nystagmus: horizontal = ipsilateral hemisphere . CN lesions  Intention tremor . Hemi- / quadriplegia  Speech: slurred, staccato, scanning dysarthria . Uni- / bi-lateral sensory symptoms  Hypotonia

Common Causes: PASTRIES Lateral Medullary Syn. / Wallenberg’s Syn.  Paraneoplastic: e.g. from bronchial Ca  Occlusion of one vertebral A. or PICA  Alcohol: thiamine and B12 deficiency  Features: DANVAH  Sclerosis . Dysphagia  Tumor: e.g. CPA lesion . Ataxia (ipsilateral)  Rare: MSA, Friedrich’s, Ataxia Telangiectasia . Nystagmus (ipsilateral)  Iatrogenic: phenytoin . Vertigo  Endo: hypothyroidism . Anaesthesia  Stroke: vertebrobasilar  Ipsilat facial numbness + absent corneal reflex  Contralateral pain loss . Horner’s syndrome (ipsilateral) Anterior Cerebral Artery  Supplies frontal and medial part of cerebrum  Contralateral motor / sensory loss in the legs > arms Millard-Gubler Syndrome: crossed hemiplegia  Face is spared  Pontine lesions (e.g. infarct)  Abulia (pathological laziness)  Effects: 6th and 7th CN palsy + contralateral hemiplegia

Middle Cerebral Artery Locked-in Syndrome  Supplies lateral / external part of hemisphere  Pt. is aware and cognitively intact but completely  Contralateral motor / sensory loss in face and arms > paralysed except for the eye muscles. legs.  Causes  Contralateral homonymous hemianopia due to . Ventral pons infarction: basilar artery involvement of optic radiation . Central potine myelinolysis: rapid correction of  Cognitive changes hyponatraemia . Dominant (L): aphasia . Non-dominant (R): neglect, apraxia Cerebellopontine Angle Syndrome

 Causes: acoustic neuroma, meningioma, cerebellar astrocytoma, metastasis (e.g. breast) Posterior Cerebral Artery  Effects: ipsilat CN 5, 6, 7, 8 palsies + cerebellar signs  Supplies occipital lobe . Absent corneal reflex  Contralateral homonymous hemianopia ¯c macula . LMN facial palsy sparing. . LR palsy . Sensorineural deafness, vertigo, tinnitus . DANISH

Subclavian Steal Syndrome  Subclavian A. stenosis proximal to origin of vertebral A. may → blood being stolen from this vertebral artery by retrograde flow.  Syncope / presyncope or focal neurology on using the arm.  BP difference of >20mmHg between arms

Anterior Spinal Artery / Beck’s Syndrome  Infarction of spinal cord in distribution of anterior spinal artery: ventral 2/3 or cord.  Causes: Aortic aneurysm dissection or repair  Effects . Para- / quadri-paresis . Impaired pain and temperature sensation . Preserved touch and proprioception © Alasdair Scott, 2012 159 Muscle Weakness Differential Hand Wasting Differential

1. Cerebrum / Brainstem 1. Cord  Vascular: infarct, haemorrhage  Anterior Horn: MND, polio  Inflammation: MS  Syringomyelia  SOL  Infection: encephalitis, abscess 2. Roots (C8 T1)  Compression: spondylosis, neurofibroma 2. Cord  Vascular: anterior spinal artery infarction 3. Brachial Plexus  Inflammation: MS  Compression  Injury . Cervical rib . Tumour: Pancoast’s, breast 3. Anterior Horn  Avulsion: Klumpke’s palsy  MND, polio 4. Neuropathy 4. Roots / Plexus  Generalised: CMT  Spondylosis  Mononeuritis multiplex: DM  Cauda equina syndrome  Compressive mononeuropathy  Carcinoma . Median: thenar wasting . Ulnar: hypothenar and interossei wasting 5. Motor Nerves  Mononeuropathy: e.g. compression 5. Muscle  Polyneuropathy: e.g. GBS, CMT  Disuse: RA  Compartment syndrome: Volkman’s ischaemic 6. NMJ contracture  GB, LEMS, botulism  Distal myopathy: myotonic dystophy  Cachexia 7. Muscle

 Toxins: steroids  Poly- / Dermato-myositis  Inherited: DMD, BMD, FSH

Gait Disturbance Differential

Motor Sensory

Basal Ganglia: festinating / shuffling Vestibular (Romberg’s +ve)  PD  Meniere’s  Parkinsonism: MSA, PSP, Lewy body dementia, CBD  Viral labyrinthitis  Brainstem lesion UMN Bilateral: spastic, scissoring  Cord: compression, trauma, hereditary spastic Cerebellar: ataxic paraparesis, syringomyelia, transverse myelitis  EtOH  Bihemispheric: CP, MS  Infarct

UMN Unilateral: spastic circumducting Proprioceptive Loss (Romberg’s +ve)  Hemisphere lesion: CVS, MS, SOL  Dorsal columns: B12 deficiency  Hemicord: MS, tumour  Peripheral neuropathy: DM, EtOH, uraemia

LMN Bilateral: bilat foot drop Visual Loss  Polyneuropathy: CMT, GBS  Corda equina Other LMN Unilateral: foot drop → high stepping gait  Myopathy, MG/LEMS  Ant horn: polio  Medical: postural hypotension, Stokes-Adams, arthritis  Radicular: L5 root lesion  Sciatic / common peroneal nerve: trauma, DM

Mixed UMN and LMN: MAST  MND  Ataxia: Friedrich’s  SACD  Taboparesis © Alasdair Scott, 2012 160 Blackouts

Causes: CRASH Presentation and Investigation

Cardiac: Stokes-Adams Attacks Cardiogenic Syncope  Brady: heart block, sick sinus, long-QT  Trigger: exertion, drug, unknown  Tachy: SVT, VT  Before: palpitations, chest pain, dyspnoea  Structural  During: pale, slow/absent pulse, clonic jerks may occur . Weak heart: LVF, tamponade  After: rapid recovery . Block: AS, HOCM, PE  Ix: ECG, 24hr ECG, Echo

Reflexes 1. Vagal overactivity Reflex: Vasovagal  Vasovagal syncope  Trigger: prolonged standing, heat, fatigue, stress  Situational: cough, effort, micturition  Before  Carotid sinus syncope . Gradual onset: secs→mins . Nausea, pallor, sweating, tunnel vision, tinnitus 2. Sympathetic underactivity = Post. Hypotension . Cannot occur lying down  Salt deficiency: hypovolaemia, Addison’s  During  Toxins . Pale, grey, clammy, brady . Cardiac: ACEi, diuretics, nitrates, α-B . Clonic jerks and incontinence can occur, but no . Neuro: TCAs, benzos, antipsychotics, L- tongue biting DOPA  After: rapid recovery  Autonomic Neuropathy: DM, Parkinson’s, GBS  Ix: Tilt-table testing  Dialysis  Unwell: chronic bed-rest  Pooling, venous: varicose veins, prolonged Reflex: Postural Hypotension standing  Trigger: Standing up  Before, During and After as for vagal above Arterial  Ix: Tilt-table testing  Vertebrobasilar insufficiency: migraine, TIA, CVA, subclavian steal  Shock Arterial  Hypertension: phaeochromocytoma  Trigger: Arm elevation (subclavian steal), migraine  Before, During and After as for vasovagal ± brainstem Systemic Sx (diplopia, nausea, dysarthria)  Metabolic: ↓glucose  Ix: MRA, duplex vertebrobasilar circulation  Resp: hypoxia, hypercapnoea (e.g. anxiety)  Blood: anaemia, hyperviscosity Systemic Head  Hypoglycaemia: tremor, hunger, sweating, light-  Epilepsy headedness → LOC  Drop attacks

Head: Epileptic  Trigger: flashing lights, fatigue, fasting Examination  Before: e.g. aura in complex partial seizures – feeling  Postural hypotension: difference of >20/10 after strange, epigastric rising, deja/jamias vu, smells, lights, standing for 3min vs. lying down automatisms  Cardiovascular  During: Tongue biting, incontinence, stiffness→jerking,  Neurological eyes open, cyanosis, ↓SpO2  After: headache, confusion, sleeps, Todd’s palsy  Ix: EEG, ↑ se prolactin at 10-20min

Ix  ECG ± 24hr ECG Head: Drop Attacks  U+E, FBC, Glucose  Trigger: nil  Tilt table  Before: no warning  EEG, sleep EEG  During: sudden weakness of legs causes older woman  Echo, CT, MRI brain to fall to the ground.  After: no post-ictal phase

Vertigo Conductive: WIDENING  The illusion of movement: usually rotatory  Wax or foreign body  Of patient or surroundings  Infection: otitis media, OME  Worse on movement  Drum perforation  Extra: ossicle discontinuity – otosclerosis, trauma Not Vertigo  Neoplasia: carcinoma  Faintness  INjury: e.g. barotrauma  Light-headedness  Granulomatous: Wegener’s, Sarcoid  Lost awareness

Dizziness Sensorineural: DIVINITY  ¯c Impaired consciousness = blackout  w/o impaired consciousness Developmental . Vertigo: vestibular  Genetic: Alport’s, Waardenburgs . Imbalance: vestibular, cerebellar, extrapyramidal  Congenital: TORCH  Perinatal: anoxia

Causes of Vertigo: IMBALANCE Degenerative  Presbyacusis  Infection / Injury . Labyrinthitis: post-viral severe vertigo, n/v Infection . Ramsay Hunt  VZV, measles, mumps, influenza . Trauma: to petrous temporal bone  Meningitis  Meniere’s . Recurrent vertigo (~20min) ± n/v Vascular . Fluctuating SNHL  Ischaemia: Internal Auditory Artery (AICA) → sudden . Tinnitus hearing loss and vertigo . Aural fullness  Stroke  Benign Positional Vertigo . Sudden vertigo provoked by head rotation Inflammation  Aminoglycosides / frusemide  Vasculitis  Lymph, Peri-, fistula  Sarcoidosis . Path: Connection between inner and middle ears . Causes: Congenital, trauma Neoplasia . PC: vertigo, SNHL  CPA tumours: acoustic neuroma (commonest cause . o/e: Tullio’s phen – nystagmus evoked by loud of unilateral SNHL) sound  Arterial Injury . Migraine  Noise . TIA / stroke  Head trauma  Nerve . Acoustic neuroma / vestibular schwannoma Toxins  Central lesions  Gentamicin . Demyelination, tumour, infarct (e.g. LMS)  Frusemide  Epilepsy  Aspirin . Complex partial lYmph  Endolymphatic Hydrops = Meniere’s  Perilymphatic fistula: ruptured round window

Tremor Dystonia  Regular, rhythmic oscillation  Prolonged muscle contracture → unusual joint posture  NB. Asterixis = rhythmic myoclonus or repetitive movements

Types and Causes: RAPID Idiopathic generalised dystonia  Often autosomal dominant Resting  Childhood onset: starts in one leg and spreads on that  Features side of the body over 5-10yrs . 4-6Hz, pill-rolling . Abolished on voluntary movement Idiopathic focal dystonia . ↑ ¯c distraction (e.g. counting backwards)  Commonest form of dystonia  Causes: Parkinsonism  Confined to one part of the body  Rx: Da agonists, antimuscarinic (e.g. procyclidine)  Worsened by stress  Types: Action / Postural . Spasmodic torticollis  Features . Blepharospasm . 6-12Hz . Oromandibular . Absent at rest . Writer’s / Muscician’s cramp . Worse ¯c outstretched hands or movement . Equally bad at all stages of movement Acute Dystonia  Causes: BEATS  Torticollis, trismus and/or occulogyric crisis . Benign essential tremor  Typically a drug reaction: . Endocrine: thyroxicosis, ↓glucose, phaeo . Neuroleptics . Alcohol withdrawal (or caffeine, opioids…) . Metoclopramide . Toxins: β-agonists, theophylline, valproate, PHE . L-DOPA . Sympathetic: physiological tremor may be  Rx: procyclidine (antimuscarinic) enhanced: e.g. in anxiety Chorea Intention  Non-rhythmic, purposeless, jerky, flitting movements  Features  E.g. facial grimacing, flexing / extending the fingers . >6Hz, irregular, large amplitude  Causes . Worse at end of movement . Huntington’s . E.g. past-pointing . Sydenham’s  Causes: cerebellar damage . Wilson’s . L-DOPA Dystonic  Features: variable Athetosis  Causes: mostly idiopathic, as for dystonia  Slow, sinuous, writhing movements

 Causes Benign Essential Tremor . Cerebral palsy  Autosomal dominant . Kernitcterus  Occur ¯c action and worse ¯c anxiety, emotion, caffeine  Arms, neck, voice Hemiballismus  Doesn’t occur during sleep  Large amplitude, flinging hemichorea  Better ¯c EtOH  Contralateral to a vascular lesion in the subthalamic nucleus: often elderly diabetics  Recovers spontaneously over months Myoclonus  Sudden, involuntary jerks Tardive Syndromes  Delayed onset following chronic exposure to Da Causes agonists (e.g. antipsychotics, antiemetics, L-DOPA)  Metabolic = Asterixis (L, R, ↑CO2)  Neurodegenerative diseases (LSDs) Classification  CJD  Dyskinesia: orobuccolingual, truncal or choreifirm  Myoclonic epilepsies (e.g. infantile spasms) movements  Dystonia: sustained, stereotyped muscle spasms of Benign Essential Myoclonus twitching or turning  Auto dom  Akathisia: unpleasant sense of inner restlessness ±  Childhood onset frequent generalised myoclonus w/o repetitive movements (e.g. pacing) progression.  May respond to valproate Rx  Change (e.g. to atypical) or slowly withdraw drug  Dyskinesia: Da antagonist (tetrabenazine)  Akathisia: β-B

Definition Definition  Chronically impaired cognition that affects multiple  Globally impaired cognition and impaired consciousness domains: memory, attention, language  No impairment of consciousness Features  Acquired and progressive (cf. LD)  Disorientation to person, time and place  Reversal of sleep-wake cycle (hyperactive at night) Alzheimer’s Disease  Labile mood  Epi: 50%  Illusions, delusions and hallucinations  Path: neurofibrillary tangles and β amyloid plaques  Cognitive impairment: mem, language, concentration…  PC: progressive, global cognitive decline  RFs: ApoE4 allele, presenillin 1/2 mutations, Down’s Causes: DELIRIUMS  Ix: MRI – medial temporal lobe atrophy  Rx: cholinesterase inhibitors (donepezil, rivastigmine) if  Drugs: opioids, sedatives, L-DOPA MMSE is 10-20  Eyes, ears and other sensory deficits  Low O2 states: MI, stroke, PE Vascular Dementia  Infection  Epi: 20%  Retention: stool or urine  Path: multiple infarcts  Ictal  PC: sudden onset, stepwise deterioration, patchy  Under- hydration / -nutrition deficits, vascular RFs  Metabolic: DM, post-op, sodium, uraemia  Ix: MRI – extensive infarcts or small vessel disease  Subdural haemorrhage or other intracranial pathology  Rx: manage predisposing factors Ix Lewy Body Dementia  Bloods: FBC, U+E, LFTs, glucose, ABG  Epi: 20%  Urine dip  Path: Lewy Bodies in occipito-parital cortex  Septic screen  PC: Fluctuating cognitive dysfunction, visual  ECG, LP hallucinations, parkinsonism  Rx: cholinesterase inhibitors Mx  ID and Rx underlying cause Frontotemporal Dementia (Pick’s)  Surround ¯c familiar people  Epi: <5%  Nurse in moderately lit, quiet room  Path: Pick Bodies  Find glasses, hearing aids…  PC: disinhibition, personality change, early memory  Avoid sedatives if possible, but if disruptive: preservation, progressive aphasia . Haldol 0.5-2mg PO/IM  Ix: MRI – frontal or temporal atrophy . Chlorpromazine 50-100mg PO/IM (avoid in elderly)

Ameliorable Causes

Infection  Viral: HIV, HSV, PML  Helminth: cysticercosis, toxo

Vascular  Chronic subdural haematoma

Inflammation  SLE  Sarcoid

Neoplasia

Nutritional  Thiamine deficiency  B12 and folate deficiency  Pellagra (B3 / niacin deficiency)

Hypothyroid Hypoadrenalism Hypercalcaemia Hydrocephalus (normal pressure)

Acute: VICIOUS Chronic: MCD TINGS

Vascular Migraine  Haemorrhage: SAH, intracranial, intracerebral  Infarction: esp. posterior circulation Cluster headaches  Venous: Sinus / cortical thrombosis Drugs Infection/Inflammation  Analgesics  Meningitis  Caffeine 2+  Encephalitis  Vasodilators: Ca antagonists, nitrates  Abscess Tension headaches Compression  Obstructive hydrocephalus: tumour ICP ↑/↓  Pituitary enlargement: apoplexy  ↑: tumour, aneurysm, AVM, benign intracranial HTN  ↓: spontaneous intracranial hypotension ICP  Spontaneous intracranial hypotension Neuralgia (trigeminal) . Acute dural CSF leak . Worse on standing initially. Giant cell arteritis

Ophthalmic Systemic  Acute glaucoma  HTN  Organ failure: e.g. uraemia Unknown  Situational: cough, exertion, coitus

Systemic  HTN: Phaeo, PET  Infection: sinusitis, tonsillitis, atypical pneumonia  Toxins: CO

Investigations:

Bloods Urine Micro  Blood cultures  Serology: enterovirus (common cause of viral meningitis), HSV, HIV, syphilis, crypto  CSF

Radiology  Non-contrast CT . SAH: blood in sulci, cisterns (white). 90% sensitivity in first 24h  MRI . MRA: aneurysm . MRV: sinus thrombosis

Special: CSF  Opening pressure (norm = 5-20cm H2O): . ↑: SAH, meningitis . ↓: spontaneous intracranial hypotension  Xanthochromia: yellow appearance of CSF due to bilirubin. Detect by spectrophotometry.

Findings Bacterial TB Viral Appearance Turbid Fibrin web Clear Cells PMN Lympho / mononuc Lympho / mononuc Count 100-1000 10-1000 50-1000 Glucose ↓ (< ½ plasma) ↓ (< ½ plasma) > ½ plasma Protein (g/L) ↑↑ (>1.5) ↑↑↑ (1-5) mild ↑ (<1)

SAH Hemicrania  Sudden onset, worst ever, occipital headache.  Paroxysmal hemicranias: cluster-like headache lasting  Meningism, focal signs, ↓consciousness 5-45min, 5-30x/day  SUNCT: short-lasting unilateral neuralgia with Venous Sinus Thrombosis conjunctival injection and tearing, attacks last 15-60s,  Sagittal: headache, vomiting, seizures, ↓vision, recur 5-30x/hr papilloedema  Hemicrania continua: continuous cluster-like headache  Transverse: headache ± mastoid pain, focal CNS  Rx: all respond well to indomethacin signs, seizures, papilloedema Trigeminal neuralgia Cortical Vein Thrombosis  Paroxysms of unilateral intense stabbing pain in  Thunderclap headache trigeminal distribution (usually V2/3)  Stroke-like focal symptoms over days  Triggers: washing area, shaving, eating, talking  Focal seizures are common  Male > 50yrs  2O in 14%: compression of CNV, MS, Zoster, Chiari Meningitis malformation O  Fever, photophobia, neck stiffness, kernig’s +ve  Ix: exclude 2 cause by MRI.  Purpuric rash  Rx Med: CBZ, lamotrigine, gabapentin  ↓consciousness  Rx Surg: microvascular decompression

Encephalitis Analgesia Overuse  Fever, odd behaviour, fits, focal neuro, ↓consciousness  Episodic headache becomes daily chronic headache  Use OTC analgesia on 6 days/month max Acute Glaucoma  Constant unilat eye pain, radiating to forehead ICP  ↓ acuity, haloes, n/v  ↑: worse in AM, stooping, visual probs (papilloedema),  Red eye, cloudy cornea. obese women  Dilated, non-responsive pupil  ↓: worse sitting or standing

Tension Headache TMJ Dysfunction  Bilateral / vertex-bitemporal, non-pulsatile, band-like  Preauricular pain on chewing  Assoc. ¯c crepitus Migraine  Earache, headache  Prodrome → aura → headache  Unilat, throbbing Giant Cell Arteritis (>60yrs, ESR>60, pred 60mg)  n/v, phono/photophobia  Unilateral temple/scalp pain and tenderness.  Thickened, pulseless temporal artery Cluster  Jaw claudication, amaurosis fugax, sudden blindness  Rapid onset very severe pain around/behind one eye.  Assoc. ¯c PMR in 50%  Red, watery eye, nasal congestion  Ix: ESR↑↑↑, plats↑, ALP↑, Hb↓, temporal artery biopsy  Miosis, ptosis  Rx  Attacks last 15min–3hrs, 1-2x/day, mostly nocturnal . High dose pred (60mg/d PO) for 5-7d  Clusters last 4-12wks, remission lasts 3mo-3yrs. Can . Guided by symptoms and ESR. be chronic vs. episodic. . Give PPI+bisphosphonate.  Rx: 100% O2 via non-rebreathe mask, Sumitriptan  Prog: 2yr course then complete remission  Prevention: verapamil, topiramate, Li

Epidemiology Diagnostic Criteria  8% prev  Typical aura + headache, or  F:M = 2:1  ≥ 5 headaches lasting 4-72h with either n/v or photo/phonophobia + ≥2 of: Risk Factors . Unilat  Obesity . Pulsating  PFO . Interferes with normal life . Worsened by routine activity Pathophysiology  Vascular: cerebrovascular constriction → aura, dilatation → headache. Differential  Brain: spreading cortical depression  Cluster / tension headache  Inflammation: activation of CN V nerve terminals in  Cervical spondylosis meninges and cerebral vessels.  HTN  Intracranial pathology Triggers  Epilepsy  CHOCOLATE  CHeese  OCP Treatment  Caffeine  alcohOL Acute episode  Anxiety  1st: Paracetamol + metoclopramide / domperidone  Travel  2nd: NSAID (e.g. ketoprofen) + M/D  Exercise  3rd: Rizatriptan . CI: IHD, uncontrolled HTN, SSRIs Symptoms  4th: ergotamine

Headache Prophylaxis  Aura lasting 15-30min then unilat, throbbing  Avoid triggers headache  1st: Propanolol, topiramate  Phono/photophobia  2nd: Valproate, pizotifen (↑ wt.), gabapentin  n/v  Allodynia  Often premenstrual

Prodrome (50%): precede migraine by hrs - days  Yawning  Food cravings  Changes in sleep, appetite or mood

Aura (20%): precedes migraine by mins and may persist  Visual: distortion, lines, dots, zig-zags, scotoma, hemianopia  Sensory: paraesthesia (fingers → face)  Motor: dysarthria, ataxia, ophthalmoplegia, hemiparesis (hemiplegic migraine)  Speech: dysphasia, paraphasia Classification  Migraine ¯c aura (classical migraine)  Migraine w/o aura (common migraine)

Epidemiology Investigations  9/100,000  35-65yrs CT  Detects >90% of SAH w/i first 48hrs Causes  Rupture of saccular aneurysms (80%) LP  AVMs (15%)  If CT-ve and no CIs >12h after start of headache  Xanthochromia due to breakdown of bilirubin Risk Factors  Smoking Mx  HTN  Frequent neuro obs: pupils, GCS, BP  EtOH  Maintain CPP: keep SBP >160  Bleeding diathesis  Nimodipine for 3wks → ↓ cerebral vasospasm  Mycotic aneurysms (SBE)  Endovascular coiling (preferable to surgical clipping)  FH (close relatives have 3-5x risk)

Berry Aneurysms Complications

Sites Rebleeding: 20%  Junction of post. communicating ¯c IC  Commonest cause of mortality  Junction of ant. communicating ¯c ACA Cerebral Ischaemia  Bifurcation of MCA  Due to vasospasm Associations  Commonest cause of morbidity  Adult polycystic kidneys Hydrocephalus  CoA  Due to blockage of arachnoid granulations  Ehlers Danlos  May require ventricular or lumbar drain

Symptoms Hyponatraemia  Sudden, severe occipital headache  Common  Collapse  Don’t Mx ¯c fluid restriction  Meningism: neck stiffness, n/v, photophobia  Seizures  Drowsiness → coma Mx of Unruptured Aneurysms

 Young pts. c aneurysms >7mm in diameter may Signs ¯ benefit from surgery.  Kernig’s  Retinal or subhyaloid haemorrhage  Focal neuro . @ presentation suggests aneurysm location . Later deficits suggests complications

Sentinel Headache  ~6% of pts. experience sentinel headache from small warning bleed.

Differential  In 1O care, 25% of those ¯c thunderclap headache have SAH  50-60% no cause found  Rest: meningitis, intracerebral bleeds, cortical vein thrombosis

Pathogenesis Ix  Infarction due ischaemia (80%) or intracerebral  ID risk factors for further strokes haemorrhage (20%). HTN Ischaemia (80%)  Retinopathy  Atheroma  Nephropathy . Large (e.g. MCA)  Big heart on CXR . Small vessel perforators (lacunar)  (Don’t treat acutely)  Embolism . Cardiac (30% of strokes):AF, endocarditis, MI Cardiac emboli . Atherothromboembolism: e.g. from carotids  ECG ± 24hr tape: AF  Echo: mural thrombus, hypokinesis, valve lesions, ASD, Haemorrhage (20%) VSD (paradoxical emboli)  ↑BP  Trauma Carotid artery stenosis  Aneurysm rupture  Doppler US ± angio  Anticoagulation  Endarterectomy beneficial if ≥ 70% symptomatic  Thrombolysis stenosis

Rarer Causes Bleeding / thrombotic tendency  Watershed stroke: sudden ↓ in BP (e.g. in sepsis)  Thrombophilia screen  Carotid artery dissection  Thrombocytopenia  Vasculitis: PAN, HIV  Cerebral vasospasm 2O to SAH Hyperviscosity  Venous sinus thrombosis  Polycythaemia  Anti-phospholipid syndrome, thrombophilia  SCD  Myeloma

Risk Factors Metabolic  HYPERTENSION  ↑↓ glucose  Smoking, DM, ↑ lipids, FH  ↑ lipids  Cardiac: AF, valve disease  Hyperhomocystinaemia

 Peripheral vascular disease Vasculitis  Previous history  ↑ESR  Ethnicity: ↑ in Blacks and Asians  ANA  ↑ PCV/Hct

 OCP

Cardiac Causes of Stroke  AF: 4.5% /yr  External cardioversion: 1-3%  Prosthetic valves  Acute MI: esp. large anterior  Paradoxical systemic emboli  Cardiac surgery  Valve vegetations

Oxford / Bamford Classification Brainstem Infarcts  Based on clinical localisation of infarct  Complex signs depending on relationship of infarct to  S=syndrome: prior to imaging CN nuclei, long tracts and brainstem connections  I=infarct: after imaging when atheroembolic infarct confirmed Features

Feature Structure Total Anterior Circulation Stroke (TACS) Hemi- / quadr-paresis Corticospinal tracts  Highest mortality (60% @ 1yr) + poor independence Conjugate gaze palsy Oculomotor system  Large infarct in carotid / MCA, ACA territory  All 3 of: Horner’s syndrome Sympathetic fibres 1. Hemiparesis (contralateral) and/or sensory deficit Facial weakness (LMN) CN7 nucleus (≥2 of face, arm and leg) 2. Homonymous hemianopia (contralateral) Nystagmus, vertigo CN8 nucleus 3. Higher cortical dysfunction Dysphagia, dysarthria CN9 and CN10 nuclei  Dominant (L usually): dysphasia Dysarthria, ataxia Cerebellar connections  Non-dominant: hemispatial neglect ↓ GCS Reticular activating syndrome

Partial Anterior Circulation Stroke (PACS)

 Carotid / MCA and ACA territory Lateral Medullary Syndrome / Wallenberg’s Syndrome  2/3 of TACS criteria, usually:  PICA or vertebral artery 1. Hemiparesis (contralateral) and/or sensory deficit  Features: DANVAH (≥2 of face, arm and leg) . Dysphagia 2. Higher cortical dysfunction . Ataxia (ipsilateral)  Dominant: dysphasia . Nystagmus (ipsilateral)  Non-dom: neglect, constructional apraxia . Vertigo  Deficit is less dense and/or incomplete . Anaesthesia  Ipsilat facial numbness + absent corneal reflex Posterior Circulation Stroke (POCS)  Contralateral pain loss  Infarct in vertebrobasilar territory . Horner’s syndrome (ipsilateral)  Any of 1. Cerebellar syndrome 2. Brainstem syndrome Millard-Gubler Syndrome 3. Contralateral homonymous hemianopia  Pontine infarct  6th and 7th CN nuclei + corticospinal tracts . Diplopia Lacunar Stroke (LACS) . LMN facial palsy + loss of corneal reflex  Small infarcts around basal ganglia, internal capsule, . Contralateral hemiplegia thalamus and pons.  Absence of

. Higher cortical dysfunction Locked-in Syndrome . Homonymous hemianopia  Pt. is aware and cognitively intact but completely . Drowsiness paralysed except for the eye muscles. . Brainstem signs  Causes  5 syndromes . Ventral pons infarction: basilar artery . Pure motor: post. limb of internal capsule . Central potine myelinolysis: rapid correction of  Commonest hyponatraemia . Pure sensory: post. thalamus (VPL)

. Mixed sensorimotor: internal capsule

. Dysarthria / clumsy hand . Ataxic hemiparesis: ant. limb of internal capsule Stroke Differential  Weakness + dysmetria  Head injury ± haemorrhage  ↑↓ glucose  SOL Other Signs  Hemiplegic migraine  Ischaemic pointers  Todd’s palsy . Carotid bruit  Infections: encephalitis, abscesses, Toxo, HIV, HTLV . AF  Drugs: e.g. opiate overdose . Past TIA . IHD  Haemorrhagic pointers . Meningism . Severe headache . Coma © Alasdair Scott, 2012 170 Stroke: Management

Acute Management Primary Prevention  Control RFs: HTN, ↑ lipids, DM, smoking, cardiac Resuscitate disease  Ensure patent airway: consider NGT  Consider life-long anticoagulation in AF (use CHADS2)  NBM until swallowing assessed by SALT  Carotid endarterectomy if symptomatic 70% stenosis  Don’t overhydrate: risk of cerebral oedema  Exercise

Monitor  Glucose: 4-11mM: sliding scale if DM Secondary Prevention  BP: <185/110 (for thrombolysis)  Risk factor control as above . Rx of HTN can → ↓ cerebral perfusion . Start a statin after 48h  Neuro obs  Aspirin / clopi 300mg for 2wks after stroke then either . Clopidogrel 75mg OD (preferred option) Imaging . Aspirin 75mg OD + dipyridamole MR 200mg BD  Urgent CT/MRI  Warfarin instead of aspirin/clopidogrel if  Diffusion-weighted MRI is most sensitive for acute infarct . Cardioembolic stroke or chronic AF  CT will exclude primary haemorrhage . Start from 2wks post-stroke (INR 2-3) . Don’t use aspirin and warfarin together. Medical  Carotid endarterectomy if good recovery + ipsilat  Consider thrombolysis if 18-80yrs and <4.5hrs since stenosis ≥70% onset of symptoms . Alteplase (rh-tPA) . → ↓ death and dependency (OR 0.64) Rehabilitation: MENDS . CT 24h post-thrombolysis to look for haemorrhage  MDT: physio, SALT, dietician, OT, specialist nurses,  Aspirin 300mg PO/PR once haemorrhagic stroke neurologist, family excluded ± PPI  Eating . Clopidogrel if aspirin sensitive . Screen swallowing: refer to specialist  NG/PEG if unable to take oral nutrition Surgery . Screen for malnutrition (MUST tool)  Neurosurgical opinion if intracranial haemorrhage  Supplements if necessary  May coil bleeding aneurysms  Neurorehab: physio and speech therapy  Decompressive hemicraniectomy for some forms of MCA . Botulinum can help spasticity infarction.  DVT Prophylaxis

 Sores: must be avoided @ all costs Stroke Unit

 Specialist nursing and physio  Early mobilisation Occupational Therapy  DVT prophylaxis  Impairment: e.g. paralysed arm

Secondary Prevention  Disability: e.g. inability to write  Handicap: e.g. can’t work as accountant Rehabilitation  OT aims to minimise disability and abolish handicap

Prognosis @ 1yr  10% recurrence  PACS . 20% mortality . 1/3 of survivors independent . 2/3 of survivors dependent  TACS is much worse . 60% mortality . 5% independence

Definition Mx: ACAS  Sudden onset focal neurology lasting <24h due to  Time to intervention is crucial. temporary occlusion of part of the cerebral circulation. . Intervention w/i 72hrs → 2% strokes @ 90d  ~15% of 1st strokes are preceded by TIAs. . Intervention w/i 3wks → 10% strokes @ 90d  Avoid driving for 1mo Signs  Symptoms usually brief  Global events (e.g. syncope, dizziness) are not typical 1. Antiplatelet Therapy / Anticoagulate  Signs mimic those of CVA in the same arterial territory . Aspirin/clopi 300mg/d for 2wks then 75mg/d  Add dipyridamole MR to aspirin Signs of Causes . Warfarin if cardiac emboli: AF, MI, MS  After 2wks  Carotid bruits

 ↑BP 2. Cardiac Risk Factor Control  Heart murmur . BP, lipids, DM, smoking  AF . Exercise . Diet: ↓ salt Causes  Atherothromboembolism from carotids is main cause 3. Assess risk of subsequent stroke  Cardioembolism: post-MI, AF, valve disease . ABCD2 score  Hyperviscosity: polycythaemia, SCD, myeloma 4. Specialist referral to TIA clinic Differential . ABCD2 ≥4: w/i 24hrs  Vascular: CVA, migraine, GCA . ABCD2 <4: w/i 1wk  Epilepsy Carotid Endarterectomy  Hyperventilation  Beneficial if ≥70% symptomatic stenosis  Hypoglycaemia  50-70% stenosis may benefit if operative risk is <3% Ix  Surgery should be performed w/i 2wks.  Endovascular stenting is an alternative, but safety and  Aim to find cause and define vascular risk long-term benefits (in-stent restenosis is common) are  Bloods: FBC, U&E, ESR glucose, lipids still under Ix.  CXR  Major complications are stroke and death.  ECG  Echo  Carotid doppler ± angiography  Consider brain imaging Prognosis . Diffusion weighted MRI is best  Combined risk of stroke and MI is ~9%/yr  3x ↑ in mortality cf TIA-free populations

ABCD2 Score  Predicts stroke risk following TIA  Score ≥6 = 8% risk w/i 2d, 35% risk w/i 1wk  Score ≥4 = pt. assessment by specialist w/i 24hrs  All pts with suspected TIA should be seen by specialist w/i 7d.

1. Age ≥ 60 2. BP ≥ 140/90 3. Clinical features a. Unilateral weakness (2 points) b. Speech disturbance w/o weakness 4. Duration a. ≥ 1h (2 points) b. 10-59min 5. DM

NB. 7 points max.

© Alasdair Scott, 2012 172 Subdural Haemorrhage Extradural Haemorrhage  Bleeding from bridging veins between cortex and  Often due to # temporal or parietal bone → laceration of sinuses middle meningeal artery and vein.  Haematoma between dura and arachnoid  Blood between bone and dura  Often due to minor trauma that occurred a long time  Suspect if after head injury GCS falls, is slow to previously – especially deceleration injuries improve or there is a lucid interval.

Risk Factors Presentation  Elderly: brain atrophy  Falls: epileptics, alcoholics Lucid Interval  Anticoagulation  Deterioration of GCS after head injury that caused no LOC, or following initial improvement in GCS.  Lucid interval may be hrs or days Symptoms  Headache ↑ ICP  Fluctuating GCS, sleepiness  Headache  Gradual physical or mental slowing  Vomiting  Unsteadiness  Confusion → coma  Fits rd  Ipsilateral blown pupil (3 nerve palsy) Signs  ± hemiparesis ¯c upgoing plantars and ↑ reflexes  ↑ ICP (can → tentorial herniation)  Localising signs occur late Brainstem Compression  Deep irregular breathing (brainstem compression)  Cushing response (↑BP, ↓HR) is late Imaging: CT / MRI  Death by cardiorespiratory arrest

 Crescentic haematoma over one hemisphere

 Clot goes from white → grey c time ¯ Imaging: CT  Mid-line shift  Lens-shaped haematoma  Skull # (↑↑ risk of extradural haemorrhage) Mx

 1st line: irrigation/evacuation via burr-hole craniostomy nd Mx  2 line: craniotomy  Neuroprotective ventilation (O >100, CO 35-40)  Address causes of trauma 2 2  Consider mannitol (1g/kg IV via central line)  Craniectomy for clot evacuation and vessel ligation Differential  Stroke  Dementia  SOL

Dural Venous sinus Thrombosis Common Causes  Symptoms come one gradually over days-wks  Pregnancy / puerperium  Sinus thrombosis may extend to cortical veins  OCP  Head injury Sagittal Sinus  Dehydration  45% of IVT  Intracranial / extracranial malignancy  Often co-exists if other sinuses are thrombosed  Thrombophilia  Headache, vomiting, seizures, ↓ vision, papilloedema

Transverse Sinus Ix  35% of IVT  Exclude SAH and meningitis  Headache ± mastoid pain, focal neuro, seizures,  CT/MRI venography: absence of a sinus papilloedema  LP: ↑ pressure, may show RBCs and xanthochromia

Sigmoid Sinus  Cerebellar signs, lower CN palsies Mx Inferior Petrosal Sinus  LMWH → warfarin (INR 2-3)  5th and 6th CN palsies (Gradenigo’s syn.)  Fibrinolytics (e.g. streptokinase) can be used via selective catheterisation. Cavernous sinus  Thrombophilia screen  Spread from facial pustules or folliculitis  Headache, chemosis, eyelid oedema, proptosis, painful ophthalmoplegia, fever

Cortical Vein Thrombosis  Often → venous infarcts ¯c stroke-like focal symptoms that evolve over days  Thunderclap headache  Focal-seizures

Differential  SAH  Meningitis  Encephalitis  Intracranial abscess  Arterial stroke

Features Abx Therapy  Community: benpen 1.2g IV/IM Meningitic  <50: ceftriaxone 2g IVI/IM BD  Headache  >50: ceftriaxone + ampicillin 2g IVI /4h  Neck stiffness  If viral suspected: aciclovir O . Kernig’s: Straightening leg ¯c hip @ 90 . Brudzinski’s: lifting head → lifting of legs Organisms  Photophobia  Viruses: enteroviruses (Coxsackie, echovirus), HSV2  n/v  Meningococcus

 Pneumococcus Neurological  Listeria  ↓ GCS → coma  Haemophilus  Seizures (20%)  TB  Focal neuro (20%): e.g. CN palsies  Cryptococcus

Septic  Fever Ix  ↓BP, ↑HR  Bloods: FBC, U+Es, clotting, glucose, ABG  ↑CRT  Blood cultures  Purpuric rash  LP: MCS, glucose, virology/PCR, lactate  DIC

Acute Management

ABC  O2 15L – SpO2 94-98%  IVI fluid resus ¯c crystalloid

Mainly Septicaemic Mainly Meningitic  Don’t attempt LP  If no shock or CIs do LP  Ceftriaxone 2g IVI  Dexamethasone 0.15mg/kg IV QDS  Consider ITU if shocked  Ceftriaxone 2g IVI post-LP

Continuing Management  Ceftriaxone 2g BD IVI . Meningococcus: 7d IV then review . Pneumococcus: 14d IV then review  Maintenance fluids . UO 30ml/h . SBP >80mmHg  If response is poor, consider intubation ± inotropic support  Rifampicin prophylaxis for household contacts.

CIs to LP: Try LP Unless ContraINdicated CSF Findings  Thrombocytopenia Findings Bacterial TB Viral  Lateness (delay in antibiotic admin) Appearance Turbid Fibrin web Clear  Pressure (signs of raised ICP) Cells PMN Lympho / Lympho /  Unstable (Cardio + resp systems) mononuc mononuc  Coagulation disorder Count 100-1000 10-1000 50-1000  Infection at LP site Glucose ↓ (< ½ ↓ (< ½ > ½ plasma  Neurology (focal neurological signs) plasma) plasma) Protein (g/L) ↑↑ (>1.5) ↑↑↑ (1-5) mild ↑ (<1)

Presentation Pre-disposing Factors  Infectious prodrome: fever, rash, LNs, cold sores,  Infection: ear, sinus, dental or periodontal conjunctivitis, meningeal signs.  Skull #  Bizarre behaviour or personality change  Congenital heart disease  Confusion  Endocarditis  ↓ GCS → coma  Bronchiectasis  Fever  Immunosuppression  Headache  Focal neuro Organisms  Seizures  Frontal sinus/teeth: strep. Milleri, oropharyngeal  Hx of travel or animal bite anaerobes  Ear: Bacteroides, other anaerobes Causes Signs Usually viral  Seizures  HSV1/2  Fever  CMV, EBV, VZV  Localizing signs  Arboviruses  Signs of ↑ ICP  HIV  Signs of infection elsewhere

Non-viral Ix  Any bacterial meningitis  CT/MRI: ring-enhancing lesion  TB  ↑WCC, ↑ESR  Malaria  Lyme disease Rx

 Neurosurgical referral Ix  Abx: e.g. ceftriaxone  Bloods: cultures, viral PCR, malaria film  Treat ↑ ICP  Contrast CT: focal bilat temporal involvement suggests HSV  LP: ↑ CSF protein, lymphocytes, PCR  EEG: shows diffuse abnormalities, may confirm Dx

Mx  Aciclovir STAT: 10mg/kg/8h IVI over 1h for 14/7  Supportive measures in HDU/ITU  Phenytoin for seizures

Prognosis  70% mortality if untreated

w/o fever, consider encephalopathy  ↓ glucose  Hepatic  DKA  Drugs  SLE  Uraemia  Hypoxic brain injury  Beri-Beri

Definition Presenting Features  Recurrent tendency to spontaneous, intermittent, abnormal electrical activity in part of the brain, manifest Simple Partial as seizures.  Focal motor, sensory, autonomic or psychic symptoms

Causes Complex Partial: 5As  2/3 are idiopathic (often familial)  Aura  Congenital  Autonomic: change in skin colour, temperature, palps . NF  Awareness lost: motor arrest, motionless stare . Tuberous Sclerosis  Automatisms: lip-smacking, fumbling, chewing, . TORCH swallowing . Perinatal anoxia  Amnesia  Acquired . Vascular: CVA NB. Usually arise from temporal lobe . Cortical scarring: trauma, infection . SOL Absences (Petit mal) . Other: SLE, PAN, MS, sarcoidosis  ABrupt onset and offset  Non-epileptic / provoked seizures  Short: <10s . Withdrawal: EtOH, opiates, benzos  Eyes: glazed, blank-stare . Metabolic: glucose, Na, Ca, urea, NH3  Normal: intelligence, examination, brain-scan . ↑ICP: trauma, haemorrhage, cortical venous  Clonus or automatisms may occur thrombosis  EEG: 3Hz spike and wave . Infection: meningitis, encephalitis, cycticerosis,  Stimulated by hyperventilation and photics HIV . Eclampsia Tonic-Clonic (Grand mal) . Pseudoseizures  LOC  Tonic: limbs stiffen NB. 3-10% of provoked seizures tend to recur, cf 30-50% of  Clonic: rhythmic jerking of limbs unprovoked seizures  ± cyanosis, incontinence, tongue biting (lateral)  Post-ictal confusion and drowsiness Seizure Terms  Prodrome Myoclonic Seizure . pt. or others may notice change in mood or  Sudden jerk of limb, face or trunk. behaviour lasting hrs – days. . Not part of seizure. Atonic (akinetic seizures)  Aura  Sudden loss of muscle tone → fall . A simple partial seizure (usually temporal) which  No LOC may precede other manifestations. . Experienced as a strange feeling: West Syndrome / Infantile Spasms  Epigastric rising  Clusters of head nodding and arm jerks  Deja/jamias vu,  EEG shows hypsarrhythmia  Automatisms,  Smells, lights, sounds  Partial (focal) Localising Features . Features referable to part of one hemisphere

 Primary Generalised Temporal . No warning / aura  Automatisms: lip smacking, chewing, fumbling . Discharge throughout cortex w/o localising  Deja/jamias vu features  Delusional behaviour  Simple: awareness unimpaired  Abdominal: rising, n/v  Complex: awareness impaired  Emotional disturbance: terror, panic, anger, elation  Secondary Generalised  Tastes, smells . Focal seizure → generalised

. E.g. aura → tonic-clonic Frontal

 Motor features: arrest, Jacksonian march, Todd’s palsy

Diagnostic Pointers Parietal  Aura  Sensory disturbance: tingling, numbness  Specific trigger: e.g. flashing lights  Lateral tongue biting (> incontinence) Occipital  Typical movements: e.g. tonic-clonic  Visual phenomena: spots, lines, flashes  Cyanosis  Post-ictal phase

General Principles Side Effects of Common AEDs  After any seizure advise against driving, swimming, et.c. until a Dx is established Enzyme Effects  Don’t diagnose epilepsy from a single seizure  Inducers: CBZ, PHE and barbiturates  Diagnosis should be made by a specialist  Inhibitors: Valproate  After Dx, cannot drive until seizure-free for >1yr . 10yrs for HGV (no meds) Lamotrigine  Skin rash → SJS: occurs w/i 1st 8wks  Rash may be assoc. ¯c hypersensitivity → fever, ↑LFTs, Investigations DIC.  Basic bloods: FBC, U+Es, glucose  Diplopia, blurred vision  Se ↑ Prl 10min after fit (relative to baseline)  Levels affected by enzyme inhibitors/inducers  Se AED levels  Urine toxicology Valproate  Appetite ↑ → ↑wt.  ECG st  Liver failure: monitor LFTs over 1 6mo EEG  Pancreatitis  Use to support Dx (cannot exclude or prove)  Reversible hair loss  Helps classification and prognosis  Oedema  Use ¯c hyperventilation and photic stimulation  Ataxia  Teratogenicity, Tremor, Thrombocytopaenia Neuroimaging: typically MRI  Encephalopathy: due to ↑ ammonia  Not routine for idiopathic generalised epilepsy  Indications Carbamazepine . Developed epilepsy as an adult  Leukopenia . Any evidence of focal onset  Skin reactions . Seizures continue despite 1st-line Rx  Diplopia, blurred vision  SIADH → hyponatraemia

Drug Therapy Phenytoin  Gingival hypertrophy Seizure Type 1st line 2nd line  Hirsutism Tonic-Clonic Valproate Lamotrigine  Cerebellar syn. Absences Valproate Lamotrigine . Ataxia Ethosuximide . Nystagmus Tonic, atonic or Valproate Levetiracetam . Dysarthria myoclonic  Peripheral sensory neuropathy Focal ± 2O gen Lamotrigine CBZ  Diplopia  Tremor

In Women / Pregnancy  Avoid valproate: take lamotrigine (or CBZ)  5mg folic acid daily if child-bearing age  CBZ and PHE are enzyme inducers and ↓ the effectiveness of the OCP

Other Options  Neurosurgical resection can be an option if a single epileptogenic focus is identified  Vagal nerve stimulation can ↓ seizure frequency and severity in ~33%

Definition Drugs  Seizure lasting >30min, or  Repeated seizures w/o intervening consciousness Lorazepam  2-4mg IV bolus over 30s Ix  2nd dose if no response w/i 2min  BM  Alternatives:  Bloods: glucose, ABG, U+E, FBC, Ca2+ . Diazepam 10mg IV/PR (20mg max)  ECG, EEG . Midazolam 10mg buccal  Consider: AED levels, tox screen, LP, βhCG, CT Phenytoin  18mg/kg IVI @ 50mg/min  100mg/6-8h maintenance  Monitor ECG and BP  CI: bradycardia or heart block

Diazepam Infusion  100mg in 500ml 5% dex @ 40ml/hr (3mg/kg/24h)

Dexamethasone  10mg IV if vasculitis / cerebral oedema (tumour) possible

Acute Management

ABC  Oral / nasal airway, intubate  Suction  100% O2  Capillary blood glucose

IV Access + Bloods  U+E, LFT, FBC, Glucose, Ca2+  AED levels  Tox screen

Reverse Potential Causes  Thiamine 250mg IV if EtOH  100ml 20% glucose unless glucose known to be normal

Slow IV Bolus Phase  Lorazepam 2-4mg IV  2nd dose if no response w/i 2min

IV Infusion Phase  Phenytoin 18mg/kg IVI (then 100mg/6-8h)  Or, diazepam 100mg in 500ml 5% dex IVI

RSI Phase Never spend >20min ¯c someone in status w/o getting an anaesthetist

Initial Mx Intubate  GCS ≤ 8 O 1 Survey  PaO2 <9KPa on air / <13KPa on O2 or PCO2 >6KPa  A: ? intubation, immobilise C-spine  Spontaneous hyperventilation: PCO2 <4KPa  B: 100% O2, RR  Respiratory irregularity  C: IV access, BP, HR  D: GCS, pupils CT head guidelines: BANGS LOC  Treat seizures  Break: open, depressed or base of skull . Lorazepam 2-4mg IV  Amnesia >30min retrograde . Phenytoin18mg/kg IVI then 100mg/6-8h  Neuro deficit or seizure  E: expose pt. and look for other obvious injuries  GCS: <13 @ any time or <15 2h after injury  Sickness: vomited > once O Survey 2  LOC or any amnesia and any of:  Look for: . Dangerous mechanism: RTA, great height . Lacerations . Age ≥ 65 . Obvious facial/skull deformity . Coagulopathy (inc. warfarin) . CSF leak from nose or ears . Battle’s sign, Racoon eyes . Blood behind TM Risk of Intracranial Haematoma in Adults: . C-spine tenderness ± deformity  Fully conscious, no skull # = <1:1000  Head-to-toe examination for other injuries  Confused, no skull # = 1:100  Log role  Fully conscious, skull # = 1:30  Confused, skull # = 1:4 Hx if possible  How and when? GCS  GCS and other vitals immediately after injury  Headache, fits, vomiting, amnesia, EtOH Eyes: 4 4 – Spontaneous eye opening Ix 3 – Open to voice  Bloods: FBC, U+E, glucose, clotting, EtOH level, ABG 2 – Open to pain  ? CT head + c-spine 1 – No opening

Verbal: 5 Rx 5 – Orientated conversation  Neurosurgical opinion if signs of ↑ICP, CT evidence of 4 – Confused conversation intracranial bleed significant skull # 3 – Inappropriate speech  Admit if: 2 – Incomprehensible sounds . Abnormalities on imaging 1 – No speech . Difficult to assess: EtOH, post-ictal . Not returned to GCS 15 after imaging Motor: 6 . CNS signs: vomiting, severe headache 6 – Obeys commands  Neuro-obs half-hrly until GCS 15 5 – Localises pain . GCS 4 – Withdraws to pain . Pupils 3 – Decorticate posturing to pain (flexor) . HR, BP 2 – Decerebrate posturing to pain (extensor) . RR, SpO2 1 – No movement . Temperature

Discharge Advice  Stay with someone for first 48hrs  Give advice card advising return on: . Confusion, drowsiness, unconsciousness . Visual problems . Weakness . Deafness . V. painful headache that won’t go away . Vomiting . Fits

Presentation Presentation  Typically obese females ↑ ICP  As if SOL  Headache: worse on waking, lying down, bending . ↑ ICP forward, coughing, straining. . Headache  Vomiting . Papilloedema  Papilloedema  Visual  ↓GCS . Blurred vision . 6th CN palsy Seizures . Enlarged blind spot  Exclude SOL in adult-onset seizures, especially ¯c localising aura or post-ictal weakness (Todd’s) Cause  Usually idiopathic Evolving Focal Neurology  May be 2O to venous sinus thrombosis or drugs  May be false-localising (esp. CN6 palsy) Mx Subtle Personality Change  Wt. loss

 Acetazolamide  Loop diuretics Causes  Prednisolone  Vascular: chronic subdural haematoma, AVM,  Lumbar-peritoneal shunt may be necessary if drugs fail aneurysm and visual loss deteriorates.  Infection: abscess, cyst (cysticercosis)  Neoplasm: primary or secondary Prognosis  Granuloma: TB, sarcoid  Usually self-limiting  Permanent visual loss in 10%. Tumours  30% metastatic: breast, lung, melanoma  Astrocytoma  Glioblastoma multiforme  Ependyoma  Meningiomas  Cerebellar haemangioblastoma  CNS lymphoma

Differential  Vasc: stroke, venous sinus thrombosis  Traumatic head injury  Infection: encephalitis  Inflam: vasculitis, MS  Metabolic disturbance  Idiopathic intracranial hypertension

Ix  CT or MRI (better for post. cranial fossa)  Consider biopsy

Types of Cerebral Oedema 1. Vasogenic (↑ cap permeability): trauma, tumour, ischaemia, infection 2. Cytotoxic: e.g. from hypoxia 3. Interstitial: e.g. obstructive hydrocephalus, ↓Na+

Causes Acute Management  Haemorrhage ABC  Tumours  Infection: meningitis, encephalitis, abscess  Hydrocephalus  Status Treat seizures and correct hypotension  Cerebral oedema

Signs and Symptoms Elevate bed to 40O  Headache  n/v  Seizures Neuroprotective Ventilation  Drowsiness → coma  PaO2: >13KPa (100mmHg)  Cushing’s reflex: ↑BP, ↓HR, irregular breathing th  PCO2: 4.5kPa  6 CN palsy (may be false localising)  Good sedation ± NM blockade  Cheyne-Stokes respiration  Pupils: constriction → dilatation  Papilloedema, loss of venous pulsation @ disc Mannitol or Hypertonic Saline  ↓ICP short-term, but may → rebound ↑ICP later  Mannitol 1g/kg (20% @ 5ml/kg)

Herniation Syndromes

Tonsillar (Coning)  ↑ pressure in posterior fossa → displacement of cerebellar tonsils through foramen magnum  → compression of brainstem and cardioresp centres in medulla  CN6 palsy, upgoing plantars → irregular breathing → apnoea

Transtentorial / Uncal  Lateral supratentorial mass → compression of ipsilateral inferomedial temporal lobe (uncus) against free margin of tentorium cerebelli.  Ipsilateral CN3 palsy: mydriasis (dilation) then down-and-out  Ipsilateral corticospinal tract: contralateral hemiparesis  May → compression of contralateral corticospinal tracts → ipsilateral hemiparesis (Kernohan’s Notch: False Localising)

Subfalcine  Frontal mass  Displacement of cingulate gyrus (medial frontal lobe) under falx cerebri  Compression of ACA → stroke . Contralateral motor/sensory loss in legs>arms . Abulia (pathological laziness)

Causes

Degenerative 1. Parkinson’s disease

2. Parkinson’s-plus syndromes (basal ganglia degeneration + other system)

a. Multiple Systems Atrophy / Shy-Drager  Autonomic dysfunction: post hypotension, bladder dysfunction  Cerebellar + pyramidal signs  Rigidity > Tremor

b. Progressive Supranuclear Palsy  Postural instability → falls  Speech disturbance (+ dementia)  Palsy: vertical gaze

c. Corticobasilar Degeneration:  Aphasia, dysarthria, apraxia  Akinetic rigidity in one limb  Astereognosis (cortical sensory loss)  Alien limb phenomenon

d. Lewy Body Dementia:  Fluctuating cognition  Visual hallucinations

Infection  Syphilis  HIV  CJD

Vascular: Multiple infarcts in SN

Drugs: Antipsychotics, metoclopramide

Trauma: dementia pugilistica

Genetic: Wilson’s disease

Symptoms

Tremor  Worse at rest  Exacerbated by distraction  4-6hz, pill-rolling

Rigidity  ↑ tone in all muscle groups: lead-pipe rigidity  Rigidity + tremor → cog-wheel rigidity

Bradykinesia  Slow initiation of movement ¯c reduction of amplitude on repetition  Expressionless face  Monotonous voice  Micrografia

Gait  ↓ arm swing  Festinance  Freezing (esp. in doorways)

Epidemiology Ix  Mean onset 65yrs  DaTSCAN  2% prevalence

Mx Pathophysiology  MDT: neurologist, PD nurse, physio, OT, social worker,  Destruction of dopaminergic neurones in pars compacta GP and carers of substantia nigra.  Assess disability  β-amyloid plaques . e.g. UPDRS: Unified Parkinson’s Disease Rating Scale  Neurofibrillary tangles: hyperphosphorlated tau  Physiotherapy: postural exercises  Depression screening

Features: TRAPPS PD Medical  Asymmetric onset: side of onset remains worst  Young onset ± biologically fit 1. Da agonists: ropinirole, pramipexole 2. MOA-B inhibitors: rasagiline, selegiline  Tremor: ↑ by stress, ↓ by sleep 3. L-DOPA: co-careldopa or co-beneldopa  Rigidity: lead-pipe, cog-wheel

 Akinesia: slow initiation, difficulty c repetitive movement, ¯  Biologically frail ± comorbidities micrographia, monotonous voice, mask-like face 1. L-DOPA  Postural instability: stooped gait ¯c festination 2. MOA-B inhibitors  Postural hypotension: + other autonomic dysfunction  Sleep disorders: insomnia, EDS, OSA, RBD  Other therapies  Psychosis: esp. visual hallucinations . COMT inhibitor: tolcapone, entacapone  Depression / Dementia / Drug SEs  Lessen end-of-dose effect . Apomorphine: potent Da agonist Sleep Disorder  SC rescue pen for sudden “off” freezing  Affects ~90% of PD pts. . Amantidine: weak Da agonist  Insomnia + frequent waking → EDS  Rx of drug-induced dyskinesias . Inability to turn . Atypical antipsychotics: e.g. quetiapine . Restless legs  Disease-induced psychosis . Early morning dystonia (drugs wearing off) . SSRIs: citalopram, sertraline . Nocturia  Depression . OSA  REM Behavioural sleep Disorder Surgical . Loss of muscle atonia during REM sleep  Interrupt basal ganglia . Violent enactment of dreams  Deep brain stimulation  Da SEs: insomnia, drowsiness, EDS

Autonomic Dysfunction  Combined effects of drugs and neurodegeneration Prognosis  Postural hypotension  ↑ mortality  Constipation  Loss of response to L-DOPA w/i 2-5yrs  Hypersalivation → dribbling (↓ ability to swallow saliva)  Urgency, frequency, Nocturia  ED Differential  Hyperhidrosis  Parkinson plus syndromes  Multiple infarcts L-DOPA SEs: DOPAMINE  Drugs: neuroleptics  Dyskinesia  Inherited: Wilson’s  On-Off phenomena = Motor fluctuations  Infection: HIV, syphilis, CJD  Psychosis  Dementia pugilistica  ABP↓  Mouth dryness  Insomnia  N/V  EDS (excessive daytime sleepiness)

Motor Fluctuations  End-of-dose: deterioration as dose wears off ¯c progressively shorter benefit.  On-Off effect: unpredictable fluctuations in motor performance unrelated to timing of dose.

Definition  A chronic inflammatory condition of the CNS characterised by multiple plaques of demyelination disseminated in time and space.

Epidemiology Ix  Lifetime risk: 1/1000  MRI: Gd-enhancing or T2 hyper-intense plaques  Age: mean @ onset = 30yrs . Gd-enhancing = active inflammation  Sex: F>M = 3:1 . Typically located in periventricular white matter  Race: rarer in blacks  LP: IgG oligoclonal bands (not present in serum)  Abs Aetiology . Anti-MBP  Genetic (HLA-DRB1), environmental, viral . NMO-IgG: highly specific for Devic’s syn.  Evoked potentials: delayed auditory, visual and sensory Pathophysiology  CD4 cell-mediated destruction of oligodendrocytes → Diagnosis: clinical demyelination and eventual neuronal death.  Demonstration of lesions disseminated in time and space  Initial viral inflam primes humoral Ab responses vs. MBP  May use McDonald Criteria  Plaques of demyelination are hallmark Differential Classification: Inflammatory conditions may mimic MS plaques:  Relapsing-remitting: 80%  CNS sarcoidosis  Secondary progressive  SLE  Primary progressive: 10%  Devic’s: Neuromyelitis optica (NMO)  Progressive relapsing . MS variant ¯c transverse myelitis and optic atrophy . Distinguished by presence of NMO-IgG Abs Presentation: TEAM  Tingling Mx  Eye: optic neuritis (↓ central vision + eye move pain)  MDT: neurologist, radiologist, physio, OT, specialist  Ataxia + other cerebellar signs nurses, GP, family  Motor: usually spastic paraparesis Acute Attack Clinical features  Methylpred 1g IV/PO /24h for 3d Sensory: Motor . Doesn’t influence long-term outcome  Dys/paraesthesia  Spastic weakness . ↓ duration and severity of attacks  ↓ vibration sense  Transverse myelitis Preventing Relapse: DMARDs  Trigeminal neuralgia  IFN-β: ↓ relapses by 30% in relapsing remitting MS Eye: Cerebellum:  Glatiramer: similar efficacy to IFN-β  Diplopia  Trunk and limb ataxia  Visual phenomena  Scanning dysarthria Preventing Relapse: Biologicals  Bilateral INO  Falls  Natalizumab: anti-VLA-4 Ab . ↓ Relapses by 2/3 in RRMS  Optic neuritis → atrophy  Alemtuzumab (Campath): anti-CD52 nd GI: Sexual/GU: . 2 line in RRMS  Swallowing disorders  ED + anorgasmia Symptomatic  Constipation  Retention  Fatigue: modafinil  Incontinence  Depression: SSRI (citalopram) Lhermitte’s Sign  Pain: amitryptylline, gabapentin  Neck flexion → electric shocks in trunk/limbs  Spasticity: physio, baclofen, dantrolene, botulinum  Urgency / frequency: oxybutynin, tolterodine Optic Neuritis  ED: sildenafil  PC: pain on eye movement, rapid ↓ central vision  Tremor: clonazepam  Uhthoff’s: vision ↓ ¯c heat: hot bath, hot meal, exercise  o/e: ↓ acuity, ↓ colour vision, white disc, central scotoma, Prognosis RAPD Poor Prognostic Signs Better Prognostic Signs INO / ataxic nystagmus / conjugate gaze palsy  Older  Female  Disruption of MLF connecting CN6 to CN3  Male  <25  Weak adduction of ipsilateral eye  Motor signs @ onset  Sensory signs @ onset  Nystagmus of contralateral eye  Many relapses early on  Long interval between  Convergence preserved  Many MRI lesions relapses  Axonal loss  Few MRI lesions

Symptoms Cauda Equina and Conus Medullaris Lesions  Deep, local spinal pain  Spinal cord tapers to its end at L1  Stabbing, radicular pain in a dermatomal distribution  Compared ¯c lesions higher up the cord, these lesions and LMN weakness @ lesion level are flaccid and areflexic (cf, spastic and hyperreflexic)  Progressive UMN weakness and sensory loss below lesion Conus Medullaris Lesions  Bladder hesitancy, frequency → painless retention  Mixed UMN/LMN weakness  Faecal incontinence or constipation  Early constipation and retention  Back pain Signs  Sacral sensory disturbance  Look for motor, reflex and sensory level  ED  Shooting, radicular pain @ level, anaesthesia below  LMN signs @ level, UMN signs below level Cauda Equina Lesions  Tone and reflexes are usually reduced in acute cord  Saddle anaesthesia compression  Back pain  Radicular pain down legs Causes  Bilateral flaccid, areflexic lower limb weakness  Trauma  Incontinence / retention of faeces / urine  Infection: epidural abscess, TB  Poor anal tone  2O to malignancy: breast, thyroid, bronchus, kidney, prostate Mx  Disc prolapse  As for cord compression  Haematoma: warfarin  These are neurosurgical emergencies and require  Intrinsic cord tumour urgent imaging and surgical decompression

 Myeloma

Ix  MRI is definitive modality  CXR for primaries

Rx  This is a neurosurgical emergency  Malignancy . Dexamethasone IV . Consider chemo, radio and decompressive laminectomy  Abscess: abx and surgical decompression

Differential  Transverse myelitis  MS  Cord vasculitis  Spinal artery thrombosis  Aortic dissection

Spondylosis Lumbosacral Spondylosis  Degeneration due to trauma or ageing  IV disc / vertebral collapse Presentation  Osteophytes  L5 and S1 roots most commonly compressed by  May → central (myelopathy) and/or lateral prolapse of L4/5, L5/S1 discs. (radiculopathy) pathology  May present as severe pain on sneezing/coughing, a few days after low back strain  Lumbago – low back pain Cervical Spondylosis  Sciatica – shooting radicular pain down buttock and  90% of men > 60 and women > 50 thigh

Presentation Signs  Usually asympto  Limited spinal flexion  Neck stiffness ± crepitus  Pain on straight-leg raise  Stabbing / dull arm pain (brachialgia)  Upper limb motor and sensory disturbances according L4/5 → L5 Root Compression to compression level (often C7)  Weak hallux extension ± foot drop  Can → myelopathy ¯c quadraparesis and sphincter . In foot drop due to L5 radiculopathy, weak dysfunction inversion (tib. post.) helps distinguish from peroneal N. palsy. Specific Signs  ↓ sensation on inner dorsum of foot  Lhermitte’s sign: neck flexion → tingling down spine  Hoffman reflex: flick to middle finger pulp → brief pincer L5/S1 → S1 Root Compression flexion of thumb and index finger  Weak foot plantarflexion and eversion  Loss of ankle-jerk Typical Deficits  Calf pain  ↓ sensation over sole of foot and back of calf Root Disc Motor Weakness Sensory C5 C4/5 Deltoid Numb elbow Central Compression Supraspinatus  Cauda equina syndrome ↓ supinator jerk C6 C5/6 Biceps Numb thumb and index Ix Brachioradialis finger  MRI is definitive (emergency if cauda-equina syndrome) ↓ biceps jerk C7 C6/7 Triceps Numb middle finger Rx Finger extension  Conservative: rest, analgesia, mobilisation/physio ↓ triceps jerk  Medical: transforaminal steroid injection C8 C7/T1 Finger flexors Number ring and little  Surgical: discectomy or laminectomy may be Intrinsic hand fingers considered in cauda-equina syndrome, continuing pain or muscle weakness. Ix  MRI Spinal Stenosis Rx  Developmental predisposition ± facet joint osteoarthritis  Conservative: stiff collar, analgesia → generalized narrowing of lumbar spinal canal.  Medical: transforaminal steroid injection  Surgical: decompression: laminectomy or laminoplasty Presentation  Spinal claudication Differential . Aching or heavy buttock and lower limb pain on  MS walking  Nerve root neurofibroma . Rapid onset  SACD . May c/o paraesthesiae/numbness . Pain eased by leaning forward (e.g. on bike)  Pain on spine extension  Negative straight leg raise

Ix  MRI

Rx  Corsets  NSAIDs  Epidural steroid injection  Canal decompression surgery

Bell’s Palsy Other Causes of Facial Palsy  Inflammatory oedema from entrapment of CNVII in narrow facial canal May be suggested by  Probably of viral origin (HSV1)  Bilat symptoms: Lyme, GBS, leukaemia, sarcoid, MG  75% of facial palsy  UMN signs: sparing of frontalis and orbicularis oculi . Due to bilateral cortical representation Features  Other CN palsies (but seen in 8% of Bell’s)  Sudden onset: e.g. overnight  Limb weakness  Complete, unilateral facial weakness in 24-72h  Rashes . Failure of eye closure → dryness . Bell’s sign: eyeball rolls up on attempted closure Intracranial . Drooling, speech difficulty  Vascular, MS, SOL  Numbness or pain around ear . Motor cortex → UMN  ↓ taste (ageusia)  Assoc. ¯c ipsilateral hemiplegia  Hyperacusis: stapedius palsy . Brainstem nuclei → LMN  Usually assoc. ¯c CN6 palsy + contralateral Ix hemiplegia  Serology: Borrelia or VZV Abs  Cerebello-pontine angle: acoustic neuroma, meningioma  MRI: SOL, stroke, MS . Both may be accompanied by 5th, 6th and 8th CN  LP palsies and cerebellar signs  Loss of corneal reflex Mx  Sensorineural deafness, tinnitus, vertigo  Give prednisolone w/i 72hrs  DANISH . 60mg/d PO for 5/7 followed by tapering  Valaciclovir if zoster suspected Intra-temporal . Otherwise antivirals don’t help  Cholesteatoma  Protect eye  Ramsay Hunt . Dark glasses  Otitis media . Artificial tears  Trauma . Tape closed @ night  Plastic surgery may help if no recovery Infra-temporal  Parotid tumours Prognosis  Trauma  Incomplete paralysis: recovers completely w/i wks  Complete: 80% get full recovery Systemic . Remainder have delayed recovery or permanent  Peripheral neuropathy neurological / cosmetic abnormalities. . Demyelinating: GBS . Axonal: DM, Lyme, HIV, Sarcoid Complications: Aberrant Neural Connections  Pseudopalsy: MG, botulism  Synkinesis: e.g. blinking causes up-turning of mouth  Crocodile tears: eating stimulates unilateral lacrimation, not salivation

Ramsay Hunt Syndrome  American neurologist James Ramsay Hunt in 1907  Reactivation of VZV in geniculate ganglion of CNVII

Features  Preceding ear pain or stiff neck  Vesicular rash in auditory canal ± TM, pinna, tongue, hard palate (no rash = zoster sine herpete)  Ipsilateral facial weakness, ageusia, hyperacusis,  May affect CN8 → vertigo, tinnitus, deafness

Mx  If Dx suspected give valaciclovir and prednisolone w/i first 72h

Prognosis  Rxed w/i 72h: 75% recovery  Otherwise: 1/3 full recovery, 1/3 partial, 1/3 poor

 Lesions of individual peripheral or cranial nerves . Usually local cause: trauma, entrapment  Mononeuritis multiplex: 2 or more peripheral nerves affects . Usually systemic cause: DM most commonly . WAARDS PLC: Wegener’s, AIDS, Amyloid, RA, DM, Sarcoidosis, PAN, Leprosy, Carcinomatosis  Electromyography (EMG) helps define site of lesion

Nerve Location / Cause Motor Features Sensory Loss/ Features Median: C6-T1 Wrist: carpal tunnel, trauma LLOAF muscles Radial 3½ fingers and palm Thenar wasting Aching pain in hand ↓ 2-point discrimination Tinel’s and Phalen’s +ve Ulnar: C7-T1 Elbow trauma Partial claw hand Ulnar 1½ fingers - e.g. supracondylar # Hypothenar wasting Can’t do good luck sign Weakness and wasting of 1st dorsal interosseous Froment’s +ve Radial: C5-T1 Low: wrist Low: finger drop Dorsal thumb root (snuff box) High: humerus High: wrist drop V. high: Axilla V. high: triceps paralysis, wrist drop Brachial plexus Trauma High (C5-6): Erb’s palsy → waiter’s tip High: C5-6 dermatome Radiotherapy (e.g. breast) Low (C8-T1): Klumpke’s → claw hand Low: C8-T1 dermatome Phrenic: C3-5 Neoplastic: Orthopnoea + raised hemidiaphragm Lung Ca Myeloma Thymoma Mechanical: Cervical spondylosis Big left atrium Infective: C3-5 zoster HIV Lyme TB Lat. cut. N. Entrapment under inguinal Meralgia paraesthetica – thigh: L2-3 ligament anterolat. burning thigh pain Sciatic: L4-S3 Pelvic tumours Hamstrings Below knee laterally and foot Pelvic or femur #s All muscles below knee Common Fibular head: trauma, sitting Foot drop: can’t walk on heals Below knee laterally peroneal: L4-S1 cross legged Weak ankle dorsiflexion, eversion NB. inversion intact! Tibial: L4-S3 Can’t plantar flex → can’t stand on tiptoe Sole of foot Foot inversion Toe flexion

Features Sensory Neuropathy  Generalised disorders of peripheral or cranial nerves  Distribution is symmetrical and widespread Main Causes  Distal weakness and sensory loss (glove + stocking)  Alcohol  Classification  B12 . Time-course: acute, chronic  CRF and Ca (paraneoplastic) . Function: motor, sensory, autonomic, mixed  DM . Path: demyelination, axonal degeneration, both  Every vasculitis

General Features Causes  Glove and stocking distribution: length dependent  Deep tendon reflexes may be ↓ or absent Metabolic (mostly axonal) Vasculitis . E.g. loss of ankle jerks in diabetic neuropathy  DM  PAN  Signs of trauma or joint deformity (Charcot’s joints)  Renal failure / uraemia  RA  Diabetic and alcoholic neuropathies are painful  Hypothyroid  Wegener’s  Some aetiologies favour loss of particular fibres  ↓B1 or ↓B12 (EtOH) Large Myelinated Fibres (Aα): e.g. B12 Inflammatory Infection  Loss of proprioception → ataxia  GBS  HIV  Pins and needles  Sarcoidosis  Syphilis  Leprosy Small Unmyelinated Fibres (C): e.g. EtOH  Lyme  Loss of pain and temperature sensation  Painful dysesthesia: e.g. burning, hyperalgesia Inherited Toxins  CMT  Lead  Refsum’s syndrome Motor Neuropathy

Main Causes Drugs Other  GBS (+ botulism)  Isoniazid  Amyloid  HMSN / CMT  EtOH  Paraproteinaemias  Paraneoplastic  Phenytoin  Lead poisoning  Vincristine Features  Weakness/clumsiness of hands, difficulty walking History  LMN signs  Time-course  CN: diplopia, dysarthria, dysphagia  Precise symptoms  Involvement of respiratory muscles → ↓FVC  Assoc. events . D&V: GBS . ↓wt: Ca . Arthralgia: connective tissue Autonomic Neuropathy  Travel, EtOH, drugs Causes  DM Ix  HIV  SLE  LFTs, U+E, glucose, ESR, B12  GBS, LEMS  TFTs B1, ANA, ANCA

 Genetic tests: e.g. PMP22 in CMT Features Nerve conduction studies   Postural hypotension EMG   ED, ejaculatory failure  ↓ sweating  Constipation / Nocturnal diarrhoea  Urinary retention  Horner’s

Autonomic Function Tests  BP: Postural drop > 20/10mmHg  ECG: variation >10bpm ¯c respiration

Primary Autonomic Failure  Idiopathic or part of MSA or PD

© Alasdair Scott, 2012 190 Guillain-Barré Syndrome Charcot-Marie-Tooth Syndrome = Peroneal Muscular Atrophy Classification = Hereditary Motor and Sensory Neuropathy  AIDP: Acute autoimmune demyelinating polyneuropathy  AMAN: Acute motor (± sensory) axonal neuropathy Pathophysiology  Miller-Fisher: Ophthalmoplegia + ataxia + areflexia  Group of inherited motor and sensory neuropathies

Causes HMSN1  Abs cross-react to gangliosides  Commonest form  No precipitant identified in 40%  Demyelinating  Bacteria: C. jejuni, mycoplasma  AD mutation in the peripheral myelin protein 22 gene  Viruses: CMV, EBV, HSV, HIV, flu  Vaccines: esp. rabies HMSN2  Second commonest form Features and Ix: GBS=AIDP  Axonal degeneration (near normal conduction velocity)

Growing Weakness Clinical Features  Symmetrical, ascending flaccid weakness / paralysis  Onset at puberty  LMN signs: areflexia, fasciculations may occur  Proximal > distal (trunk, respiratory, CNs [esp. 7]) Nerves Thickened, enlarged nerves: esp. common peroneal  Progressive phase lasts ≤ 4wks 

Breathing and Bulbar Problems Motor  Foot drop → high stepping gait Back Pain  Weak ankle dorsiflexion and toe extension  Back / limb pain is common  Absent ankle jerks  Symmetrical muscle atrophy: mainly distal Sensory disturbance . Peroneal muscles → “Champagne Bottle”  Paraesthesia in extremities . Hand and arm muscles → “Claw Hand”  Sensory ataxia in Miller-Fisher  Pes cavus (high-arched feet)

Autonomic Neuropathy Sensory  Arrhythmias, ↑ HR  Variable loss of sensation in a stocking distribution  Labile BP  Neuropathic pain in some  Sweating  Urinary retention Ix  Genetic tests: PMP22 gene mutation Immune  Nerve conduction studies: ↓ conduction speed in CMT1  Serology for anti-ganglioside Abs  Evidence of infection: e.g. stool sample Mx  Supportive Demyelinating Nerve Conduction Studies . Physio  Slow conduction velocities . Podiatry . Orthoses: e.g. ankle braces Protein in CSF  Protein often > 5.5g/L  Normal white cell count

Mx Supportive  Airway / ventilation: ITU if FVC < 1.5L  Analgesia: NSAIDs, gabapentin  Autonomic: may need inotropes, catheter  Antithrombotic: TEDS, LMWH

Immunosuppression  IVIg  Plasma exchange

Physiotherapy  Prevent flexion contractures

Prognosis  85% complete recovery  10% unable to walk alone at 1yr  5% mortality © Alasdair Scott, 2012 191 Motor Neurone Disease

Characteristics Classification  Cluster of degenerative disease characterised by axonal degeneration of neurones in the motor cortex, Amyotrophic Lateral Sclerosis: 50% CN nuclei and anterior horn cells.  Loss of motor neurones in cortex and anterior horn →  UM and LM neurones affected (cf. polyneuropathy) UMN signs and LMN wasting + fasciculation  No sensory loss or sphincter disturbance (cf. MS)  Never affects eye movements (cf. MG) Progressive Bulbar Palsy: 10%  Only affects CN 9-12 → bulbar palsy Epidemiology  Prevalence: 6/100,000 Progressive Muscular Atrophy: 10%  Sex: M>F=3:2  Anterior horn cell lesion → LMN signs only  Median age @ onset = 60yrs  Distal to proximal  Often fatal in 2-4yrs  Better prognosis cf. ALS

Causes Primary Lateral Sclerosis  Loss of Betz cells in motor cortex → mainly UMN signs  Unknown  Marked spastic leg weakness and pseudobulbar palsy  ~10% familial: SOD1 mutation in 20% of those  No cognitive decline

Ix  Brain/cord MRI: exclude structural cause . Cervical cord compression → myelopathy Bulbar Palsy . Brainstem lesions  Diseases of nuclei of CN 9-12 in the medulla  LP: exclude inflammatory cause  LMN lesions of tongue, talking and swallowing  EMG: shows denervation  Signs . Flaccid, fasciculating tongue Features . Speech: quiet or nasal (“Donald Duck” speech) . Normal / absent jaw jerk  UMN: spasticity, ↑ reflexes, ↑ plantars . Loss of gag reflex LMN: wasting, fasciculation of tongue / abdo / thigh   Causes  Speech or swallowing impairment . MND  Fronto-temporal dementia . GBS . MG Diagnosis . Central pontine myelinolysis (CPM)  MRI to exclude structural lesions  LP to exclude inflammation  EMG shows acute denervation Pseudobulbar / Corticobulbar Palsy  Use Revised El Escorial Diagnostic Criteria  Commoner than bulbar palsy  Bilateral lesions above mid-pons (e.g. corticobulbar Mx tracts) → UMN lesions of swallowing and talking  MDT: neurologist, physio, OT, dietician, specialist . CN motor nuclei have bilateral cortical nurse, GP, family representation except lower half of CN7  Discussion of end-of-life decisions  Signs . E.g. Advanced directive . Spastic tongue . DNAR . Slow tongue movements ¯c slow deliberate speech: “hot-potato” speech Specific . Brisk jaw jerk  Riluzole: antiglutamatergic that prolongs life by ~3mo . Emotional incontinence  Causes Supportive . MS  Drooling: propantheline or amitriptyline . MND  Dysphagia: NG or PEG feeding . Stroke  Respiratory failure: NIV . CPM  Pain: analgesic ladder  Spasticity: baclofen, botulinum

Prognosis Polio  Most die w/i 3yrs  RNA virus . Bronchopneumonia and respiratory failure  Affects anterior horn cells  Worse prog: elderly, female, bulbar involvement  Fever, sore throat, myalgia  0.1% develop paralytic polio . Asymmetric LMN paralysis . No sensory involvement . May be confined to upper or lower limbs or both . Respiratory muscle paralysis can → death

Myopathy vs. Neuropathy Myotonic Dystrophy Myopathy  AD Cl- channelopathy  Gradual onset  Onset in 20s  Symmetrical, proximal weakness: difficulty combing  Tonic muscle spasm (myotonia) hair, climbing stairs, getting up from chairs  Dystrophies usually affect specific muscle groups Presentation  Preserved tendon reflexes  Face . Myopathic facies: long, thin, expressionless Neuropathy . Wasting of facial muscles and SCM  Paraesthesia, bladder problems . Bilateral ptosis  Distal weakness . Dysarthria: myotonia of tongue and pharynx  Hands Other Pointers . Myotonia: slow relaxation  Rapid onset: neuropathy, or drug, toxic or metabolic  E.g. inability to release hand after shake myopathy . Wasting and weakness of distal muscles +  Fatiguability: MG, LEMS areflexia → wrist drop  Spontaneous pain and tenderness @ rest: inflam . Percussion myotonia: percuss thenar eminence myopathy → involuntary thumb flexion  Pain on exercise: ischaemia or metabolic myopathy  Other  Oddly firm muscles: pseudohypertrophy in muscular . Frontal balding dystrophies . Cataracts  Fasciculation: anterior horn cell or root disease . DM . Cardiomyopathy, tachy- / brad-arrhythmias Ix . Dysphagia . Testicular atrophy  ESR, CK, AST, LDH

 EMG Rx

 No Rx for weakness

 Phenytoin may improve myotonia Muscular Dystrophies  Caution ¯c GA: high risk of anaesthetic complications  Group of genetic disease ¯c progressive degeneration and weakness of specific muscle groups. Prognosis  Most die in middle-age of intercurrent illness DMD  Commonest: 3/1000 male births  X-linked recessive, 30% spontaneous → non-functional Acquired myopathies of late onset dystrophin  Usually part of systemic disease  Presentation 2+  Hyperthyroidism, Cushing’s, ↑/↓Ca . ~4yrs old . Difficulty standing  Drugs: steroids, statins, EtOH . Calf pseudohypertrophy

. Respiratory failure  Ix: ↑↑CK Inflammatory Myopathies  Prog: some survive > 20yrs  Inclusion body myositis  Polymyositis BMD  Dermatomyositis  0.3/1000 male births  X-linked recessive Inclusion Body Myositis  Partially functioning dystrophin  Asymmetric weakness affecting distal and prox muscles  Presents later, is less severe and has better prognosis . Early involvement of quads, ankle dorsiflexors and wrist/finger flexors Facioscapulohumeral MD (Landouzy-Dejerine)  → loss of grip strength and ↓dexterity  Almost as common as DMD  Dysphagia is very common  AD inheritance  Myalgia is relatively uncommon  Presentation . Onset @ 12-14yrs . Difficulty puffing cheeks and raising arms above head  Signs . Weakness of face, shoulders and upper arms (often asymmetric ¯c deltoids spared) . Winging of scapula . Foot drop.  Prog: <20% need wheelchair by 20yrs

Pathophysiology Associations  Autoimmune disease mediated by Abs vs. nicotinic Ach  <50yrs MG is commoner in women and assoc. ¯c other receptors. AI disease (DM, RA, Graves) and thymic hyperplasia.  Interferes ¯c NM transmission via depletion of working  >50yrs MG is commoner in men and assoc. ¯c thymic post-synaptic receptor sites atrophy or thymic tumour.

Presentation Treatment  ↑ing muscular fatigue . Extra-ocular: bilateral ptosis, diplopia Symptom Control . Bulbar: voice deteriorates on counting to 50  Anticholinesterase: e.g. pyridostigmine. . Face: myasthenic snarl on attempting to smile . Cholinergic SEs = SLUDGEM . Neck: head droop . Limb: asymmetric, prox. weakness Immunosuppression  Normal tendon reflexes  Rx relapses ¯c pred  Weakness worsened by pregnancy, infection, emotion,  Steroids may be combined ¯c azathioprine or drugs (β-B, gent, opiates, tetracyclines) methotrexate

Investigations Thymectomy  Tensilon Test  Consider if young onset and disease not control by . Give edrophonium IV anticholinesterases . +ve if power improves w/i 1min  Remission in 25%, benefit in further 50%.  Anti-AChR Abs: ↑ in 90%, MuSK Abs  EMG: ↓ response to a train of impulses Complications  Respiratory function: ↓FVC  Thymus CT Myasthenic Crisis  TFTs  Weakness of respiratory muscles during relapse may be lethal. Differential of Muscle Fatigability  Monitor FVC: vent support if <20ml/kg  Polymyositis  Plasmapheresis or IVIg  SLE  Rx trigger for relapse (drugs, infection…)  Botulism Prognosis  Relapsing or slow progression

Lambert-Eaton Myasthenic Syndrome (LEMS)

Pathophysiology  Abs to VGCC ↓ influx of Ca2+ during presynaptic excitation → ↓ presynaptic ACh-vesicle fusion.

Causes  Paraneoplastic: e.g SCLC  Autoimmune

Presentation  As for MG except: LEMS . Leg weakness early (before eyes) . Extra: Autonomic and areflexia . Movement improves symptoms . Small response to edrophonium  Anti-VGCC Abs

Mx  3,4-diaminopyridine or IVIg  Do regular CXRs / HRCTs as symptoms my precede Ca by 4yrs

Botulism  Botulinum toxin prevents ACh vesicle release  Descending flaccid paralysis ¯c no sensory signs  Anti-cholinergic effects: mydriasis, cycloplegia, n/v, dry mouth, constipation  Rx: benpen + antiserum © Alasdair Scott, 2012 194 Neurofibromatosis 1 – von Neurofibromatosis 2 Recklinghausen’s Epidemiology Epidemiology  AD inheritance (Chr 22), but 50% are de novo  Prev: 1/35,000  AD Chr 17

 Variable expression  Prev: 1/2500 Signs

Features: CAFÉ NOIR Café-au-lait spots  Rare

 Fewer cf. NF1 Café-au-lait spots st  1 yr of life Bilateral Vestibular Schwannomas  ↑ in size and no. c age ¯  Characteristic  Adults: >6, >15mm across  Symptomatic by 20yrs

 SNHL is first sign, then tinnitus, vertigo Axillary Freckling

 in skin folds Juvenile Posterior Subcapsular Lenticular Opacity

 Form of cataract Fibromas, neuro-:  Bilateral  Subcutaneous  Occur before other manifestations and may be useful . Small, gelatinous, violaceous nodules for screening those @ risk . Appear @ puberty

. May itch . Nos. ↑ ¯c age Complications  Plexiform  Tender schwannomas of cranial and peripheral nerves . Overgrowth of nerve trunk and overlying tissue and spinal nerve roots. . Large cutaneous mass  Meningiomas: often multiple  Complications  Gliomas . Sarcomatous change . Compression: Mx  Nerve roots: weakness, pain, paraesthesia  Hearing tests from puberty in affected families  GI: bleeds and obstruction  MRI brain if abnormality detected

Eye Prognosis  Lisch nodules  Mean survival from Dx is 15yrs . Brown/translucent iris hamartomas . Use a slit lamp  Optic N. glioma

Neoplasia  CNS: meningioma, ependyoma, astrocytoma  Phaeochromocytoma  Chronic or acute myeloid leukaemia

Orthopaedic  Kyphoscoliosis  Sphenoid dysplasia

IQ↓ and Epilepsy

Renal  RAS → ↑ BP

Mx  MDT orchestrated by GP  Yearly BP and cutaneous review  Excise some neurofibromas  Genetic counselling

Café-au-Lait Spots Differential  NF  McCune-Albright  Multiple Lentigenes  Urticaria Pigmentosa

Presentation Characteristics  Painless  Syrinx: tubular cavity in central canal of the cervical cord.  Early sphincter / erectile dysfunction  Onset @ 30yrs  Bilateral motor and sensory disturbance below  Symptoms may be static for yrs but then worsen fast lesion . e.g. on coughing, sneezing as ↑ pressure → extension  Commonly located in cervical cord Causes: DIVINITY  Syrinx expands ventrally affecting: . Decussating spinothalamic neurones Degenerative . Anterior horn cells  MND . Corticospinal tracts

Developmental Causes  Friedrich’s Ataxia  Blocked CSF circulation ¯c ↓ flow from posterior fossa  Hereditary spastic paraparesis . Arnold-Chiari malformation (cerebellum herniates through foramen magnum) Infection . Masses  Viral: HIV, HTLV-1  Spina bifida  Syphilis: Tabes Dorsalis  2O to cord trauma, myelitis, cord tumours and AVMs

Vascular Infarction Cardinal Signs  Aortic dissection/aneurysm 1. Dissociated Sensory Loss  Thromboembolism . Absent pain and temperature → scars from burns  Atheroma . Preserved touch, proprioception and vibration.  Vasculitis: esp. PAN . Root distribution reflects syrinx location  Usually upper limbs and chest: “cape” NB. ant. spinal A. infarction → spinothalamic and 2. Wasting/weakness of hands ± Claw hand corticospinal tract loss → bilat loss of pain/temp and 3. Loss of reflexes in upper limb spastic paresis 4. Charcot Joints: shoulder and elbow . = Beck’s Syndrome Other Signs Inflammation  UMN weakness in lower limbs ¯c upgoing plantars  Demyelination: MS  Horner’s syndrome  Transverse myelitis  Syringobulbia: cerebellar and lower CN signs

 Kyphoscoliosis Neoplasia

 Glioma  Ependymoma Ix  MRI spine Injury Surgery Toxin / Nutrition  Decompression at the foramen magnum for Chiari mal  B12 deficiency sYringomyelia

Brown-Sequard Syndrome  Hemi-cord lesion  Ipsilateral loss of proprioception and vibration sense  Ipsilateral UMN weakness  Contralateral loss of pain sensation

Friedrich’s Ataxia  Auto recessive progressive degeneration of DRGs, spinocerebellar and corticospinal tracts and cerebellar cells  Mitochondrial disorder  Onset in teenage years  Assoc. ¯c HOCM and mild dementia

Presentation  Pes cavus and scoliosis  Bilateral cerebellar signs . Ataxia . Dysarthria . Nystagmus  Leg wasting + areflexia but extensor plantars  Loss of lower limb proprioception and vibration sense  Optic atrophy  Cardiac: HOCM → ESM + 4th heart sound  DM → hyperglycaemia

Hereditary Spastic Paraparesis  Lower limb spasticity  Ataxia  Extrapyramidal signs

Human T-lymphotropic Virus-1  Retrovirus  ↑ prevalence in Japan and Caribbean

Features  Adult T cell leukaemia / lymphoma  Tropical spastic paraplegia / HTLV myelopathy . Slowly progressing spastic paraplegia . Sensory loss and paraesthesia . Bladder dysfunction

Contents Patterns of Presentation ...... 199 Rheumatological Investigations ...... 199 Back Pain ...... 200 Osteoarthritis ...... 201 Septic Arthritis ...... 201 Rheumatoid Arthritis ...... 202 Gout ...... 203 Ca Pyrophosphate Dehydrate Arthropathy ...... 203 Seronegative Spondyloarthropathies ...... 204 Autoimmune Connective Tissue Disease ...... 205 Systemic Sclerosis ...... 206 Polymyositis and Dermatomyositis ...... 206 Systemic Lupus Erythematosus ...... 207 Vasculitis ...... 208 ANCA Positive Vasculitidies ...... 209 ANCA Negative Vasculitidies ...... 209 Fibromyalgia ...... 210

Monoarthritis Joint Aspiration  Septic arthritis  The key investigation in a monoarthritis  Crystal arthritis: gout, CPPD  Appearance  Osteoarthritis  Send for  Trauma: haemarthrosis . WCC . Gram stain and culture Oligoarthritis (≤5 joints) . Polarized light microscopy  Crystal arthritis  Psoriatic arthritis  Reactive arthritis Bloods  Ankylosing spondylitis  Basic: FBC, U+E, ESR, CRP, urate  Osteoarthritis  Culture: septic arthritis  Abs: RF, ANA, others Polyarthritis (>5 joints)  HLA-B27  Viral serology, urine chlamydia PCR: reactive arthritis Symmetrical  RA  Osteoarthritis Radiology  Viruses: Hep A,B,C, mumps  CXR: RA, SLE, Vasculitis, TB, Sarcoid  US/MRI: more sensitive for synovitis, enthesitis, infection Asymmetrical  Reactive arthritis Osteoarthritis  Psoriatic arthritis  Loss of joint space  Osteophytes Either  Subchondral cysts  Systemic disease: SLE, sarcoid, endocarditis  Subchondral sclerosis

Rheumatoid Arthritis  Loss of joint space  Soft tissue swelling  Peri-articular osteopenia  Deformity  Subluxation

Gout  Normal joint space  Soft tissue swelling  Periarticular erosions

Red Flags Ix  Age <20 or >55yrs  Usually only necessary if red flags present  Neurological disturbance (inc. sciatica)  FBC, ESR, CRP, ALP, se electrophoresis, PSA  Sphincter disturbance  MRI  Bilateral or alternating leg pain  Current or recent infection Mx  Fever, wt. loss, night sweats  Neurosurgical referral if neurology  History of malignancy  Conservative  Thoracic back pain . Max 2d bed rest  Morning stiffness . Education: keep active, how to lift / stoop  Acute onset in elderly people . Physiotherapy  Constant or progressive pain . Psychosocial issues re. chronic pain and disability  Nocturnal pain . Warmth  Medical . Analgesia: paracetamol ± NSAIDs ± codeine Causes . Muscle relaxant: low-dose diazepam (short-term) . Facet joint injections  Mechanical  Surgical . Strain/idiopathic . Decompression . Trauma . Prolapse surgery: e.g. microdiscectomy . Pregnancy

. Disc prolapse . Spondylolisthesis (forward shift of one vertebra)  Degenerative: spondylosis, vertebral collapse, stenosis Neurosurgical Emergencies  Inflammatory: Ank spond, Paget’s  Neoplasm: Mets, myeloma Acute Cord Compression  Infection: TB, abscess  Bilateral pain: back and radicular  LMN signs at compression level  UMN signs and sensory level below compression Nerve Root Lesions  Sphincter disturbance

Acute Cauda Equina Compression Root Weakness Reflex  Alternating or bilateral radicular pain in the legs L2 Hip flexion + adduction  Saddle anaesthesia L3 Knee extension Knee Jerk  Loss of anal tone Hip adduction  Bladder ± bowel incontinence L4 Foot inversion + dorsiflexion Knee Jerk

Knee extension Rx L5 Great toe dorsiflexion  Large prolapse: laminectomy / discectomy Foot inversion + dorsiflexion Knee Flexion  Tumours: radiotherapy and steroids Hip extension + abduction  Abscesses: decompression S1 Foot eversion Ankle Jerk Foot and toe plantarflexion Knee flexion

Definition Pathophysiology  Degenerative joint disorder in which there is  Source: local or haematogenous. progressive loss of hyaline cartilage.  Organisms . Staph: commonest overall (60%) Aetiology / Risk Factors . Gonococcus: commonest in young sexually active  Age (80% > 75yrs) . Streps  Obesity . Gm-ve bacilli  Joint abnormality  RFs . Joint disease (e.g. RA) Classification . CRF . Immunosuppression (e.g. DM)  Primary: no underlying cause . Prosthetic joints Secondary: obesity, joint abnormality  Symptoms Symptoms  Acutely inflamed tender, swollen joint  Affects: knees, hips, DIPs, PIPs, thumb CMC  ↓ROM  Pain: worse c movement, background rest/night pain, ¯  Systemically unwell worse @ end of day.  Stiffness: especially after rest, lasts ~30min (e.g. AM) Investigations  Deformity  Joint aspiration for MCS  ↓ ROM 3 . ↑↑ WCC (e.g. >50,000/mm ): mostly PMN  ↑ESR/CRP, ↑WCC, Blood cultures Signs  X-ray  Bouchard’s (prox), Heberden’s (dist.) nodes  Thumb CMC squaring Management  Fixed flexion deformity  IV Abx: vanc + cefotaxime  Consider joint washout under GA Hx and Ix  Splint joint  Focus on ADLs and social circumstances  Physiotherapy after infection resolved  X-ray Complications Differential  Osteomyelitis  Septic  Arthritis  Crystal  Ankylosis: fusion  Trauma Differential Mx  Crystal arthropathy

 Reactive arthritis Conservative

 ↓ wt.  Alter activities: ↑ rest, ↓ sport  Physio: muscle strengthening  Walking aids, supportive footwear, home mods

Medical  Analgesia . Paracetamol . NSAIDs: e.g. arthrotec (diclofenac + misoprostol)  But misoprostol → diarrhoea . Tramol  Joint injection: local anaesthetic and steroids

Surgical  Arthroscopic washout: esp. knee. . Trim cartilage, remove foreign bodies.  Arthroplasty: replacement (or excision)  Osteotomy: small area of bone cut out.  Arthrodesis: last resort for pain management  Novel Techniques . Microfracture: stem cell release → fibro-cartilage formation . Autologous chondrocyte implantation

Definition Ix  Chronic systemic inflammatory disease characterised by  Bloods: FBC (anaemia, ↓PMN, ↑plat), ↑ESR, ↑CRP a symmetrical, deforming, peripheral polyarthritis.  RF +ve in 70% . High titre assoc. ¯c severe disease, erosions and Epidemiology extra-articular disease  Prev: 1% (↑ in smokers) . -ve = “seronegative rheumatoid”  Sex: F>M=2:1  Anti-CCP: 98% specific (Ag derived from collagen)  Age: 5th-6th decade  ANA: +ve in 30%  Genetics: HLA-DR4/DR1 linked  Radiography, US, MRI

Features: ANTI CCP Or RF Mx Conservative Arthritis  Refer to rheumatologist  Symmetrical, polyarthritis of MCPs, PIPs of hands and  Regular exercise feet → pain, swelling, deformity  PT 1. Swan neck  OT: aids, splints 2. Boutonniere Medical 3. Z-thumb  DAS28: Monitor disease activity 4. Ulnar deviation of the fingers  DMARDs and biologicals: use early 5. Dorsal subluxation of ulnar styloid  Steroids: IM, PO or intra-articular for exacerbations  Morning stiffness >1h . Avoid giving until seen by rheumatologist  Improves ¯c exercise  NSAIDs: good for symptom relief  Larger joints may become involved  Mx CV risk: RA accelerates atherosclerosis  Prevent osteoporosis and gastric ulcers Nodules Surgical  Commonly elbows also fingers, feet, heal  Ulna stylectomy . Firm, non-tender, mobile or fixed  Joint prosthesis  Lungs DMARDs Tenosynovitis  1st line for treating RA  De Quervain’s  Early DMARD use assoc. ¯c better long-term outcome  Atlanto-axial subluxation  All DMARDs can → myelosuppression → pancytopenia

Immune Main agents  AIHA  Methorexate: hepatotoxic, pulmonary fibrosis  Vasculitis  Sulfasalazine: hepatotoxic, SJS, ↓ sperm count  Amyloid  Hydroxychloroquine: retinopathy, seizures Lymphadenopathy  Other Agents

 Leflunomide: ↑ risk of infection and malignancy Cardiac: pericarditis + pericardial effusion  Gold: nephrotic syndrome

Carpal Tunnel Syndrome  Penicillamine: drug-induced lupus, taste change

Pulmonary Biologicals  Fibrosing alveolitis (lower zones) Anti-TNF  Pleural effusions (exudates)  Severe RA not responding to DMARDs  Screen and Rx TB first Ophthalmic  Infliximab: chimeric anti-TNF Ab  Epi-/scleritis  Etanercept: TNF-receptor  2O Sjogren’s Syndrome  Adalimumab: human anti-TNF Ab  SEs: ↑ infection (sepsis, TB), ↑ AI disease, ↑ Ca Raynaud’s Rituximab (anti-CD20 mAb) Felty’s Syndrome  severe RA not responding to anti-TNF therapy  RA + splenomegaly + neutropenia  Splenomegaly alone in 5%, Felty’s in 1% Anatomy of Rheumatoid Hands  Boutonierre’s: rupture of central slip of extensor Dx – 4/7 of: expansion → PIPJ prolapse through “button-hole” 1. Morning stiffness >1h (lasting >6wks) created by the two lateral slips. 2. Arthritis ≥3 joints  Swan: rupture of lateral slips → PIPJ hyper-extension 3. Arthritis of hand joints 4. Symmetrical Differential of Rheumatoid Hands 5. Rheumatoid nodules  Psoriatic arthritis: nail changes and plaques 6. +ve RF  Jaccoud’s arthropathy: reducible in extension 7. Radiographic changes  Chronic crystal arthritis © Alasdair Scott, 2012 202 Gout Ca Pyrophosphate Dehydrate Arthropathy Pathophysiology  Pseudogout / Chondrocalcinosis  Deposition of monosodium urate crystals in and around joints → erosive arthritis  May be ppted by surgery, infection, fasting or diuretics Acute CPPD

 Presents as acute monoarthropathy Presentation . Usually knee, wrist or hip  M>F=5:1  Usually spontaneous and self-limiting  Acute monoarthritis ¯c severe joint inflammation . ~60% occur @ great toe MTP = Podagra . Also: ankle, foot, hand joints, wrist, elbow, knee Chronic CPPD  Also: asymmetric oligoarthritis  Destructive changes like OA  Urate deposits in pinna and tendons = Tophi  Can present as poly-arthritis (pseudo-rheumatoid)  Renal disease: radiolucent stones and interstitial nephritis Risk Factors Differential  ↑ age  Septic arthritis  OA  Pseudogout  DM  Haemarthrosis  Hypothyroidism  Hyperparathyroidism Causes  Hereditary haemochromatosis  Hereditary  Wilson’s disease  Drugs: diuretics, NSAIDs, cytotoxics, pyrazinamide  ↓ excretion: 1O gout, renal impairment  ↑ cell turnover: lymphoma, leukaemia, psoriasis, Ix haemolysis, tumour lysis syndrome  Polarized light microscopy  EtOH excess . Positively birefringent rhomboid-shaped crystals  Purine rich foods: beef, pork, lamb, seafood  X-ray may show chondrocalcinosis . Soft-tissue Ca deposition (e.g. knee cartilage) Associations  Check for: . HTN Rx . IHD  Analgesia . Metabolic syndrome  NSAIDs  May try steroids: PO, IM or intra-articular Ix  Polarised light microscopy . Negatively birefringent needle-shaped crystals  ↑ serum urate (may be normal)  X-ray changes occur late . Punched-out erosions in juxta-articular bone . ↓ joint space

Acute Rx  NSAID: diclofenac or indomethacin  Colchicine . NSAIDs CI: warfarin, PUD, HF, CRF . SE: diarrhoea  In renal impairment: NSAIDs and colchicine are CI . → Use steroids

Prevention  Conservative . Lose wt. . Avoid prolonged fasts and EtOH excess  Xanthine Oxidase Inhibitors: Allopurinol . Use if recurrent attacks, tophi or renal stones . Introduce ¯c NSAID or colchicine cover for 3/12 . SE: rash, fever, ↓WCC (c¯ azathioprine) . Use febuxostat (XO inhibitor) if hypersensitivity  Uricosuric drugs: e.g. probenecid, losartan . Rarely used  Recombinant urate oxidase: rasburicase . May be used pre-cytotoxic therapy © Alasdair Scott, 2012 203 Seronegative Spondyloarthropathies

Definition Psoriatic Arthritis  Group of inflammatory arthritidies affecting the spine and  Develops in 10-40% and may predate skin disease peripheral joints w/o production of RFs and associated ¯c HLA-B27 allele. Patterns of joint involvement  Asymmetrical oligoarthritis: 60% (commonest)  Distal arthritis of the DIP joints: 15% (classical) Common Features  Symmetrical polyarthritis: 15% (like RA but ¯c DIPJs)  Axial arthritis and sacroiliitis  Arthritis mutilans (rare, ~3%)  Asymmetrical large-joint oligoarthritis or monoarthritis  Spinal (like AS)  Enthesitis  Dactylitis Other Features  Extra-articular: iritis, psoriaform rashes, oral ulcers,  Psoriatic plaques aortic regurg, IBD  Nail changes . Pitting . Subungual hyperkeratosis Ankylosing Spondylitis . Onchyolysis  Chronic disease of unknown aetiology characterised by  Enthesitis: Achilles tendonitis, plantar fasciitis stiffening and inflammation of the spine and sacroiliac  Dactylitis joints. X-Ray Epidemiology  Erosion → “pencil-in-cup” deformity  Sex: M>F=6:1  Age: men present earlier – late teens, early 20s Rx  Genetics: 95% are HLA-B27+ve  NSAIDs  Sulfasalazine, methotrexate, ciclosporin Presentation  Anti-TNF  Gradual onset back pain . Radiates from SI joints to hips and buttocks . Worse @ night ¯c morning stiffness Reactive Arthritis . Relieved by exercise.  Sterile arthritis 1-4wks after urethritis or dysentery  Progressive loss of all spinal movements . Urethritis: chlamydia, ureaplasma . Schober’s test <5cm . Dysentery: campy, salmonella, shigella, yersinia  Some develop thoracic kyphosis and neck hyperextension = question mark posture Presentation  Enthesitis: Achilles tendonitis, plantar fasciitis  Asymmetrical lower limb oligoarthritis: esp. knee  Costochondritis  Iritis, conjunctivitis  Keratoderma blenorrhagica: plaques on soles/palms Extra-articular manifestations  Circinate balanitis: painless serpiginous penile ulceration  Osteoporosis: 60%  Enthesitis  Acute iritis / anterior uveitis: 30%  Mouth ulcers  Aortic valve incompetence: <3%  Apical pulmonary fibrosis Ix  ↑ESR, ↑CRP Ix  Stool culture if diarrhoea  Clinical Dx as radiological changes appear late  Urine chlamydia PCR . Sacroliliitis: irregularities, sclerosis, erosions . Vertebra: corner erosions, squaring Mx syndesmophytes (bony proliferations)  NSAIDs and local steroids . Bamboo spine: calcification of ligaments,  Relapse may need sulfasalazine or methotrexate periosteal bone formation  FBC (anaemia), ↑ESR, ↑CRP, HLA-B27  DEXA scan and CXR Enteropathic Arthritis

Mx  Occurs in 15% of pts. ¯c UC or Crohn’s  Conservative . Exercise Presentation . Physio  Asymmetrical large joint oligoarthritis mainly affecting  Medical the lower limbs. . NSAIDs: e.g. indomethacin  Sacroiliitis may occur . Anti-TNF: if severe . Local steroid injections Rx . Bisphosphonates  Treat the IBD  Surgical  NSAIDs or articular steroids for arthritis . Hip replacement to ↓ pain and ↑ mobility  Colectomy → remission in UC

Types Sjogren’s Syndrome (= Keratoconjunctivitis Sicca)  SLE  Systemic Sclerosis Classification  1O Sjogren’s  Primary  Myositis . F>>M=9:1 th th  Mixed Connective Tissue Disease . Onset 4 -5 decade  Relapsing Polychondritis  Secondary  Behcet’s Disease . RA . SLE Autoantibodies . Systemic Sclerosis

Features RF  ↓ tear production → dry eyes  Sjogren’s 100%  ↓ salivation → xerostomia  Felty’s 100%  Bilateral parotid swelling  RA 70% Vaginal dryness → dyspareunia  ANA  Systemic . Polyarthritis  SLE >95% . Raynaud’s  AIH 75% . Bibasal pulmonary fibrosis  Sjogren’s 70% . Vasculitis

. Myositis dsDNA SLE

Histone Drug-induced lupus Associations Centromere CREST Syndrome  AI: thyroid disease, AIH, PBC ENAs Marginal zone MALT lymphoma - Ro SLE, Sjogren’s, heart block  - La SLE, Sjogren’s - Sm SLE Ix - RNP SLE, MCTD  Schirmer tear test - Jo-1 Polymyositis, Dermatomyositis  Abs: ANA – Ro and La, RF - Scl70 Diffuse Systemic Sclerosis  Hypergammaglobulinaemia - RNA pol 1/2/3 Diffuse Systemic Sclerosis  Parotid biopsy

Relapsing Polychondritis Rx  Rare inflammatory disease of cartilage  Artificial tears  Saliva replacement solutions Presentation  NSAIDs and hydroxychloroquine for arthralgia  Tenderness, inflammation and destruction of cartilage  Immunosuppression for severe systemic disease  Ear → floppy ears  Nose → saddle-nose deformity  Larynx → stridor Raynaud’s Phenomenon  Peripheral digital ischaemia precipitated by cold or Associations emotion.  Aortic valve disease Classification  Polyarthritis O  Vasculitis  Idiopathic / 1 : Raynaud’s Disease  Secondary: Raynaud’s Syndrome Rx . Systemic sclerosis, SLE, RA, Sjogren’s  Immunosuppression . Thrombocytosis, PV . β-blockers Behcet’s Disease Presentation  Systemic vasculitis of unknown cause  Digit pain + triphasic colour change: WBC

. White, Blue, Crimson Presentation  Digital ulceration and gangrene  Turks, Mediterraneans and Japanese

 Recurrent oral and genital ulceration Rx Eyes: ant/post uveitis   Wear gloves  Skin lesions: EN  CCBs: nifedipine  Vasculitis  ACEi  Joints: non-erosive large joint oligoarthropathy  IV prostacyclin  Neuro: CN palsies  GI: diarrhoea, colitis MCTD / UCTD Ix: skin pathergy test (needle prick → papule formation)  Combined features of SLE, PM, RA, SS Rx: immunosuppression  Ab: RNP © Alasdair Scott, 2012 205 Systemic Sclerosis Polymyositis and Dermatomyositis  Striated muscle inflammation Epidemiology  F>M=3:1 Principal Features  30-50yrs  Progressive symmetrical proximal muscle weakness. . Wasting of shoulder and pelvic girdle Limited Systemic Sclerosis: 70% . Dysphagia, dysphonia, respiratory weakness (includes CREST syndrome)  Assoc. myalgia and arthralgia  Calcinosis  Commoner in females  Raynaud’s  Often a paraneoplastic phenomenon  Esophageal and gut dysmotility → GOR . Lung, pancreas, ovarian, bowel  Sclerodactyly  Telangiectasia Dermatomyositis = myositis + skin signs  Skin involvement limited to face, hands and feet  Heliotrope rash on eyelids ± oedema . Beak nose  Macular rash (shawl sign +ve: over back and shoulders) . Microstomia  Nailfold erythema  Pulmonary HTN in 15%  Gottron’s papules: knuckles, elbows, knees  Mechanics hands: painful, rough skin cracking of finger Diffuse Systemic Sclerosis: 30% tips  Diffuse skin involvement  Retinopathy: haemorrhages and cotton wool spots  Organ fibrosis  Subcutaneous calcifications . GI: GOR, aspiration, dysphagia, anal incontinence . Lung: fibrosis and PHT Extra-Muscular Features . Cardiac: arrhythmias and conduction defects  Fever . Renal: acute hypertensive crisis (commonest  Arthritis cause of death)  Bibasal pulmonary fibrosis  Raynaud’s phenomenon Ix  Myocardial involvement: myocarditis, arrhythmias  Bloods: FBC (anaemia), U+E (renal impairment)  Abs Ix . Centromere: limited  Muscle enzymes: ↑CK, ↑AST, ↑ALT, ↑LDH . Scl70 / topoisomerase: diffuse  Abs: Anti-Jo1 (assoc. ¯c extra-muscular features) . RNA pol 1,2,3: diffuse  EMG  Urine: stix, PCR  Muscle biopsy  Imaging  Screen for malignancy . CXR: cardiomegaly, bibasal fibrosis . Tumour markers . Hands: calcinosis . CXR . Ba swallow: impaired oesophageal motility . Mammogram . HiRes CT . Pelvic/abdo US . Echo . CT ECG + Echo: evidence of pulmonary HTN 

Differential Mx  Inclusion body myositis  Conservative  Muscular dystrophy . Exercise and skin lubricants: ↓ contractures  Polymyalgia rheumatica . Hand warmers: Raynaud’s  Endocrine / metabolic myopathy  Medical . Immunosuppression  Drugs: steroids, statins, colchicine, fibrates . Raynaud’s: CCBs, ACEi, IV prostacyclin . Renal: intensive BP control – ACEi 1st line Mx . Oesophageal: PPIs, prokinetics (metoclopramide)  Screen for malignancy . PHT: sildenafil, bosentan  Immunosuppression . Steroids . Cytotoxics: azathioprine, methotrexate

Definition Drug-Induced Lupus  Multisystemic autoimmune inflammatory disease in  Causes: procainamide, phenytoin, hydralazine, isoniazid which autoAbs to a variety of autoantigens result in the  Anti-histone Abs in 100% formation and deposition of immune complexes.  Mostly skin and lung signs  Disease remits if drug stopped

Epidemiology  Prev: 0.2% Anti-Phospholipid Syndrome  Sex: F>>M=9:1  Age: child-bearing age Classification  Genetic: ↑ in Afro-Caribs and Asians  Primary: 70%  Secondary to SLE: 30%

Features Pathology  Relapsing, remitting history  Anti-phospholipid Abs: anti-cardiolipin and lupus  Constitutional symptoms: fatigue, wt. loss, fever, myalgia anticoagulant

A RASH POINts an MD Features  Arthritis  CLOTs: venous (e.g. DVT) and arterial (e.g. stroke) . Non-erosive, involving peripheral joints  Coagulation defect: ↑APTT . Jaccoud’s: reducible deforming arthropathy  Livido reticularis st  Renal  Obstetric complications: recurrent 1 trimester abortion . proteinuria and ↑BP  Thrombocyotpenia  ANA (+ve in 95%)  Serositis Rx . Pleuritis: pleuritic pain, dyspnoea, effusion  Low-dose aspirin . Pericarditis: chest pain relieved by sitting forwards  Warfarin if recurrent thromboses: INR 3.5  Haematological . AIHA . ↓WCC Mx . ↓Plats  In specialist SLE and lupus nephritis clinics  Photosensitivity  Oral ulcers Severe Flares: Acute SLE  Immune phenomenon  AIHA, nephritis, pericarditis or CNS disease . Anti-dsDNA  High-dose prednisolone + IV cyclophosphamide . Anti-Sm . Anti-phospholipid Cutaneous Symptoms  Neurological  Treat ¯c topical steroids and prevent ¯c sun cream . Seizures, psychosis  Malar Rash Maintenance . Facial erythema sparing the nasolabial folds  For joint and skin symptoms  Discoid Rash  NSAIDs and hydroxychloroquine ± low-dose steroids . Erythema → pigmented hyperkeratotic papules → atrophic depressed lesions Lupus Nephritis . Mainly affects face and chest  Proteinuria: ACEi  Aggressive GN: immunosuppression

Immunology Rx Complications  95% ANA+ve  ↑ risk of osteoporosis and CV disease  dsDNA is very specific (sensitivity 60%)  30% ENA+ve: Ro, La, Sm, RNP  Anticardiolipin Abs → false +ve syphilis serology Prognosis  80% survival @ 15yrs

Monitoring Disease Activity  Anti-dsDNA titres  Complement: ↓C3, ↓C4  ↑ESR

Other Ix  Bloods: FBC, U+E, CRP, clotting (usually normal)  Urine: stix, PCR

Classification Takayasu’s Arteritis = Pulseless Disease

Large Vessel Epidemiology  Giant Cell Arteritis  Geo: Rare outside Japan  Takayasu’s Arteritis  Sex: F>M  Age: 20-40yrs Medium Vessel  Polyarteritis Nodosa Features  Kawasaki Disease  Constitutional symptoms: fever, fatigue, wt. loss  Weak pulses in upper extremities Small Vessel  Visual disturbance  pANCA  HTN . Churg-Straus . Microscopic Polyangiitis  cANCA: Wegener’s Granulomatosis Polyarteritis Nodosa  ANCA –ve . Henoch-Schonlein Purpura Epidemiology . Goodpasture’s Disease  Prev: rare in UK . Cryoglobulinaemia  Sex: M>F=2:1 . Cutaneous Leukocytoclastic Vasculitis Age: young adults 

Giant Cell Arteritis / Temporal Arteritis Features  Common in elderly (rare <55)  Assoc. ¯c Hep B  Assoc. c PMR in 50% ¯  Constitutional symptoms

 Rash Features  Renal → HTN  Systemic signs: fever, malaise, fatigue  GIT → melaena and abdo pain Headache   Temporal artery and scalp tenderness Rx  Jaw claudication  Pred + cyclophosphamide  Amaurosis fugax  Prominent temporal arteries ± pulsation

Mx and Ix Kawasaki’s Disease  If suspect GCA: Do ESR and start pred 40-60mg/d PO  Childhood PAN variant  ↑↑ESR and CRP Features  ↑ALP  5-day fever  ↓Hb (normo normo), ↑Plats  Bilat non-purulent conjunctivitis  Temporal artery biopsy w/i 3d: but skip lesion occur  Oral mucositis Continuing Rx  Cervical lymphadenopathy  Taper steroids gradually, guided by symptoms and ESR  Polymorphic rash (esp. trunk)  PPI and alendronate cover (~2yr course usually)  Extremity changes (erythema + desquamation)  Coronary artery aneurysms PMR Rx

Presentation  IVIg + aspirin  >50yrs old  Severe pain and stiffness in shoulders, neck and hips . Sudden / subacute onset . Symmetrical . Worse in the morning: stops pt. getting out of bed . No weakness (cf. myopathy or myositis)  ± mild polyarthritis, tenosynovitis and carpal tunnel syn.  Systemic signs: fatigue, fever, wt. loss  15% develop GCA

Ix  ↑↑ESR and CRP (+ ↑plasma viscosity)  ↑ALP  Normal CK

Rx  Pred 15mg/d PO: taper according to symptoms and ESR  PPI and alendronate cover (~2yr course usually) © Alasdair Scott, 2012 208 ANCA Positive Vasculitidies ANCA Negative Vasculitidies

Wegener’s Granulomatosis HSP (Childhood IgA nephropathy variant)  Necrotizing granulomatous inflammation and small vessel  Children 3-8yrs vasculitis ¯c a predilection for URT, LRT and Kidneys  Post-URTI  Palpable purpura on buttocks Features  Colicky abdo pain URT  Arthralgia  Chronic sinusitis  Haematuria  Epistaxis  Saddle-nose deformity Goodpastures LRT  Anti-GBM Abs  Cough  RPGN  Haemoptysis  Haemoptysis  Pleuritis  CXR: Bilat lower zone infiltrates (haemorrhage)

Renal Rx  RPGN  Immunosuppresion + plasmapheresis  Haematuria and proteinuria

Other  Palpable purpura Cryoglobulinaemia  Ocular: conjunctivitis, keratitis, uveitis Simple Ix  Monoclonal IgM O  cANCA  2 to myeloma / CLL / Waldenstroms  Dipstick: haematuria and proteinuria  → Hyperviscosity  CXR: bilat nodular and cavity infiltrates . Visual disturbance . Bleeding from mucus mems . Thrombosis Churg-Strauss . Headache, seizures

 Late-onset asthma Mixed (80%)  Eosinophilia  Polyclonal IgM  Granulomatous small-vessel vasculitis O  2 to SLE, Sjog, HCV, Mycoplasma . RPGN  → Immune complex disease . Palpable purpura . GN . GIT bleeding . Palpable purpura  pANCA . Arthralgia  May be ssoc. ¯c montelukast . Peripheral neuropathy

Microscopic Polyangiitis Cutaneous Leukocytoclastic Vasculitis  RPGN  Palpable purpuric rash  Haemoptysis  ± arthralgia ± GN  Palpable purpura  Causes  pANCA . HCV . Drugs: sulphonamides, penicillin

Epidemiology  10% of new rheum referrals  Prev: 0.5-4%  Sex: F>>M=10:1

Risk Factors  Neurosis: depression, anxiety, stress  Dissatisfaction at work  Overprotective family or lack of support  Middle age  Low income  Divorced  Low educational status

Associations  Chronic fatigue syndrome  Irritable bowel syndrome  Chronic headache syndromes

Features  Chronic, widespread musculoskeletal pain and tenderness  Morning stiffness  Fatigue  Poor concentration  Sleep disturbance  Low mood

Ix  All normal  Rule out organic cause: FBC, ESR, CRP, CK, TFTs, Ca

Mx  Educate pt.  CBT  Graded exercise programs  Amitriptyline or pregabalin  Venlafaxine

Contents Major Disease Patterns ...... 212 Hyponatraemia ...... 213 Hypernatraemia ...... 213 Hypokalaemia ...... 214 Hyperkalaemia ...... 214

Ca and PO4 Physiology ...... 215 Hypocalcaemia ...... 215 Hypercalcaemia ...... 216 Osteoporosis ...... 216 Osteomalacia ...... 217 Paget’s Disease / Osteitis Deformans ...... 217 Metabolic Bone Disease Summary ...... 218 Hyperlipidaemia ...... 219 Porphyrias ...... 220 Acute Intermittent Porphyria ...... 220 Rare Inherited Metabolic Disorder ...... 221

Disease Biochemistry Dehydration ↑↑ U, ↑Cr ↑albumin ↑HCT Low GFR ↑U, ↑Cr, ↑H, ↑K, ↑urate ↑PO4, ↓Ca Tubular Dysfunction Normal U and Cr ↓K, ↓urate, ↓PO4, ↓HCO3 Thiazide and Loop Diuretics ↓Na, ↓K, ↑HCO3, ↑U Hepatocellular Disease EtOH: AST:ALT>2, ↑GGT Viral: AST:ALT<2 ↑bilirubin, ↑ALP, ↓albumin, ↑PT (↑APTT if end-stage) Cholestasis ↑↑ALP, ↑↑GGT, ↑Bilirubin, ↑AST Excess EtOH intake ↑GGT, ↑MCV, evidence of hepatocellular disease Addison’s ↑K, ↓Na Cushing’s May show: ↓K, ↑Na, ↑HCO3 Conn’s ↓K, ↑Na, ↑HCO3 DM ↑glucose DI ↑Na, ↑ serum osmolality, ↓ urine osmolality SIADH ↓Na, ↓ serum osmolality, ↑ urine osmolality (>500), ↑ urine Na

Presentation Presentation  <135: n/v, anorexia, malaise  Thirst  <130: headache, confusion, irritability  Lethargy  <125: seizures, non-cardiogenic pulmonary oedema  Weakness  <115: coma and death  Irritability  Confusion, fits, coma Causes  Signs of dehydration

Hypovolaemic Causes  U Na >20mM (= renal loss)  Usually caused by dehydration (↓ intake or ↑ loss) . Diuretics . Addison’s Hypovolaemic . Osmolar diueresis (e.g. glucose)  GI loss: diarrhoea, vomiting . Renal failure (diuretic phase)  Renal loss: diuretics, osmotic diuresis (e.g. DM)  U Na >20mM (= extra-renal loss)  Skin: sweating, burns . Diarrhoea . Vomiting Euvolaemic . Fistula  ↓ fluid intake . SBO  DI . Burns  Fever

Hypervolaemic Hypervolaemic  Cadiac failure  Hyperaldosteronism (↑BP, ↓K, alkalosis)  Nephrotic syndrome  Hypertonic saline  Cirrhosis  Renal failure Mx

 Give water PO if possible Euvolaemic  Otherwise, 5% dextrose IV slowly  U osmolality >500 . SIADH  Use 0.9% NS if hypovolaemic or Na >170mM . Causes less marked fluid shifts  U osmolality <500 . Water overload  Aim for Na ↓ ≤12mM/d . Severe hypothyroidism . Too fast → cerebral oedema . Glucocorticoid insufficiency Free Water Deficit Mx  TBW (L) = coeff x wt. . Coeff = men:0.6, women:0.5  Correct the underlying cause  Def (L) = TBW x (1-[140/Na])  Replace Na and water at the same rate they were lost . Too fast → central pontine myelinolysis . Chronic: 10mM/d Diabetes Insipidus . Acute: 1mM/hr  Polyuria  Asymptomatic chronic hyponatraemia  Polydipsia . Fluid restrict  Dehydration  Symptomatic / acute hyponatraemia / dehydrated . Cautious rehydration with 0.9% NS Causes  If hypervolaemic consider frusemide  Nephrogenic  Emergency: seizures, coma . Inherited . Consider hypertonic saline (e.g. 1.8%) . ↑Ca . Drugs: Li, demeclocycline SIADH . Post-obstructive uropathy  Cranial  Concentrated urine: Na >20mM, osmolality >500 . Idiopathic  Hyponatraemia or plasma osmolality <275 . Congenital: DIDMOAD  Absence of hypovolaemia, oedema or diuretics . Tumor . Trauma Causes . Vascular: haemorrhage  Resp: SCLC, pneumonia, TB . Infection: meningoencephalitis  CNS: meningoencephalitis, head injury, SAH  Endo: hypothyroidism Ix  Drugs: cyclophosphamide, SSRIs, CBZ  ↑Na  Dilute urine Rx  Dx: Water deprivation test  Rx cause and fluid restrict  Vasopressin receptor antagonists Rx . Demeclocycline  Treat cause . Vaptans  Desmopressin if cranial © Alasdair Scott, 2012 213 Hypokalaemia Hyperkalaemia

Symptoms Symptoms  Muscle weakness  Fast, irregular pulse  Hypotonia  Palpitations  Hyporeflexia  Chest pain  Cramps  Weakness  Tetany  Palpitations  Arrhythmias ECG  Tall tented T waves NB. ↓K exacerbates digoxin toxicity  Flattened P waves  ↑ PR interval  Widened QRS ECG  Sine-wave pattern → VF  Result from delayed ventricular repolarisation  Flattened / inverted T waves  Prominent U waves (after T waves) Causes  ST depression  Long PR interval Artefact  Long QT interval  Haemolysis

 K2EDTA contamination from FBC bottle  Leucocytosis, thrombocytosis Causes  Drip arm

Internal Distribution Internal Distribution  Alkalosis  Acidosis  ↑ insulin  ↓ insulin  β-agonists  Cell death / tissue trauma / burns  Digoxin poisoning ↑ Excretion  Suxamethonium  GI: vomiting, diarrhoea, rectal villous adenoma  Renal: RTA (esp. type 2), Bartter syn. ↓ Excretion  Drugs: diuretics, steroids  Oliguric renal failure  Endo: Conn’s syn., Cushing’s syn.  Addison’s  Drugs: ACEi, NSAIDs, K+-sparing diuretics ↓ Input  Inappropriate IV fluid management ↑ Input  Excessive K therapy  Massive transfusion Mx  1mM K ↓ = ~200-300mmol total deficit  Don’t give K if oliguric Mx  Never give STAT fast bolus Non-urgent Mild: K >2.5  Treat cause: review meds  Oral K supplements  Polystyrene sulphonate resin (Calcium Resonium)  ≥80mmol/d . Binds K in the GIT and ↓K over days

Severe: K <2.5 and/or dangerous symptoms Emergency: evidence of myocardial instability or K >6.5  IV KCl cautiously  10ml 10% calcium gluconate  10mmol/h (20mmol/h max)  100ml 20% glucose + 10u insulin (Actrapid)  Best to give centrally (burning sensation peripherally)  Salbutamol 5mg nebulizer . Max central conc: 60mM  Haemofiltration (usually needed if anuric) . Max peripheral conc: 40mM  Calcium resonium 15g PO or 30g PR

Mg Replacement  Pts. are often Mg deplete too  Until Mg is replaced the K will not return to normal levels despite K replacement  Give empiric Mg replacement

PTH Presentation: SPASMODIC  Overall: ↑Ca and ↓PO4  Spasms (carpopedal = Trousseau’s sign)  ↓ ionised Ca → PTH release  Perioral paraesthesia  Anxious, irritable Renal  Seizures  ↑ Ca reabsorption  Muscle tone ↑: colic, wheeze, dysphagia  ↓ PO4 reabsorption  Orientation impaired (confusion)  ↑ 1α-hydroxylation of 25-OH-Vit D3 in kidney  Dermatitis: atopic, exfoliative  ↑ HCO3 excretion (may → mild met acidosis)  Impetigo herpetiformis (↓Ca + pustules in cyesis)  Chovsteks, Cardiomyopathy (↑ QTc  TdP) Bone . ↑ Ca → ↑threshold for action potential  ↑ osteoclast activity → ↑Ca, ↑PO4 Causes  Commonest cause is CRF Vitamin D and Calcitriol  Hepatic 25 hydroxylation → 25-OH-Vit D3 (Calcidiol) With ↑ PO4  Renal 1α-hydroxylation in kidney → 1,25(OH)2 Vit D3  CKD (Calcitriol)  Hypoparathyroidism / pseudoyhpoparathyroidism . ↑ by ↑PTH, ↓Ca or ↓PO4  ↓ Mg  Acute rhabdomyolysis (muscle Ca deposition) GIT  ↑Ca and ↑PO4 absorption With normal or ↓ PO4  Inhibition of PTH release  Osteomalacia  Active pancreatitis Renal  Respiratory alkalosis  ↑Ca and ↑PO4 reabsorption Rx

Magnesium Mild  ↓Mg prevents PTH release  Ca 5mmol QDS PO . May → ↓Ca  Daily Ca levels

CKD Plasma Binding  Alfacalcidol (1-OH-Vit D3)  2.2-2.6mM  50% albumin bound ( ↓Alb →↓Ca) Severe . Labs measure total Ca  10ml 10% Ca gluconate IV (2.25mmol) over 30min . cCa: ↑ Ca by 0.1mM for every 4g/L albumin↓  Repeat as necessary below 40g/L  Alkalosis → ↓albumin protonation → ↑Ca binding → ↓[Ca]

NB. Prolonged tourniquet application → ↑ albumin → ↑ Ca . Take uncuffed specimen if concerned

Presentation Definition  Stones  ↓ bone mass . Renal stones  1O: age-related . Polyuria and polydipsia (nephrogenic DI)  2O: drugs or other condition . Nephrocalcinosis  Bones Risk Factors: SHATTERED . Bone pain  Steroids . Pathological #s  Hyperthyroidism, HPT, HIV  Moans: depression, confusion  Alcohol and Cigarettes  Groans  Thin (BMI <22) . Abdo pain  Testosterone Low . n/v and constipation  Early Menopause . Pancreatitis  Renal / liver failure . PUD (↑gastrin secretion)  Erosive / inflam bone disease (e.g. RA, myeloma)  Other: . ↑ BP (check Ca2+ in all with HTN)  Dietary Ca low / malabsorption . ↓ QT interval Presentation  Vertebral crush #s Causes  # NOF and other long bone #s

 Most commonly malignancy or 1O HPT Ix: Bone profile, FBC, U+E

With ↑ PO4  ↑ ALP (e.g. ↑ bone turnover) DEXA Scan . Bone mets  Indications  thyroid, breast, lung, kidney, prostate, colon . Low-trauma # . Sarcoidosis . Women ≥65yrs ¯c one or more risk factors . Thyrotoxicosis . Before giving long-term steroids (>3mo) . Lithium . Parathyroid disorders, myeloma, HIV  Normal ALP  Interpretation . Myeloma . T: no. of SDs away from youthful average . Hypervitaminosis D . Z: no. of SDs away from matched average . Sarcoidosis . T > -1 = normal . Milk alkali syn. . T -1 - -2.5 = osteopenia . T <-2.5 = osteoporosis

With normal or ↓ PO4  1O or 3O HPT Rx  Familial benign hypercalciuria  Decision to instigate pharmacological Rx is based . AD upon age, RFs, and BMD. . ↑ Ca-sensing receptor set-point . FRAX can estimate 10yr # risk  Paraneoplastic: PTHrP (but ↓PTH) Conservative  Stop smoking, ↓ EtOH Ix  Wt. bearing or balancing exercise (e.g. Tai Chi)  ↑PTH = 1O or 3O HPT  Ca and vit-D rich diet  ↓PTH: most likely Ca  Home-based fall-prevention program ¯c visual  FBC, protein electrophoresis, CXR, bone scan assessment.

Primary and secondary prevention of #s  Bisphosphonates: alendronate is 1st line Mx  Ca and Vit D supplement’s: e.g Calcium D Forte  Dx and Rx underlying cause 3  Strontium ranelate: bisphosphonate alternative

Rehydrate O Alternative for 2 prevention of osteoporotic #s  1L 0.9% NS / 4h  Raloxifene: SERM, ↓ breast Ca risk cf. HRT  Monitor pts. hydration state  Teriparetide: PTH analogue → new bone formation

 Denosumab: anti-RANKL → ↓ osteoclast activation Frusemide

 Only start once pt. is volume replete Bisphosphonate SEs  Calciuric + makes room for more fluids  GI upset

 Oesophageal ulceration / erosion Bisphosphonates . Take ¯c plenty of water on an empty stomach  Ca bisphosphonate can’t be resorbed by osteoclasts and refrain from lying and don’t eat for 30min.  Only used in hypercalcaemia of malignancy  Diffuse musculoskeletal pain . Can obscure Dx as → ↓Ca, ↓PO and ↑PTH 4  Osteonecrosis of the jaw  E.g. Pamidronate, Zoledronate (IV)

Definition Pathophysiology  ↓ bone mineral content  Affects 3% over 55yrs . Excess uncalcified osteoid and cartilage  ↑ bone turnover → bone remodelling, enlargement, weakness and deformity. Presentation . ↑ bone mass but disordered and weak  Commoner in temperate climes and Anglo-Saxons Rickets: children  Knock-kneed / bow-legged 3 Phases  Bone pain  Osteolytic  Craniotabes  Mixed Osteolytic-osteoblastic  Osteochondral swelling: rachitic rosary  Quiescent osteosclerotic stage  Harrison’s sulcus Presentation Osteomalacia: adults (after epiphyseal fusion)  Asymptomatic in 70%  Bone pain and tenderness  Predominantly affects the axial skeleton  #s: esp. NOF . Pelvis, lumbar spine, skull, femur and tibia  Proximal myopathy due to ↓PO4 . Polyostotic in 85%  Bone pain Causes  Pathological #  Vitamin D deficiency: malabsorption, poor diet, ↓sunlight  Deformity  Renal osteodystrophy: ↓ 1α hydroxylation . Sabre tibia  Drugs: AEDs → ↑ hepatic vit D metabolism . Head enlargement  Vit D resistance: inherited conditions . Type 1: ↓ renal hydroxylation Complications . Type 2: end-organ resistance  Nerve compression: deafness, radiculopathy  Hepatic disease: malabsorption and ↓ 25 hydroxylation  High output CCF  Malignancy: oncogenic hypophosphataemia  Osteosarcoma (<1% after 10yrs) . ↑ fibroblast growth factor-23 → hyperphosphaturia . Sudden onset or worsening of bone pain

Ix Ix  ↑↑ALP, (Ca and PO normal)  ↓Ca, ↓PO4, ↑ALP, ↑PTH, ↓25-OH Vit D3 (unless resistance) 4  X-ray  Bone scan: hot spots . Loss of cortical bone  X-ray . Looser’s zones: pseudofractures . Bone enlargement . Cupped metaphyses in Rickets . Sclerosis . Patchy cortical thickening Rx . Deformity . Wedge-shaped lytic lesions  Dietary: Calcium D Forte 3 . Osteoporosis circumscripta  Malabsorption or hepatic disease  Well-defined lytic skull lesions . Vit D (ergocalciferol) PO 2 . Parenteral calcitriol  Renal disease or vit D resistance Mx  Analgesia . 1α-OH-Vit D3 (alfacalcidol) . ↓1,25-(OH)2 Vit D3 (calcitriol)  Alendronate: ↓ pain and/or deformity  Monitor plasma Ca

Disease Aetiology Characteristics Symptoms Risk Factors Biochemistry Ca PO4 ALP PTH Osteoporosis 1o: age, post-menopausal Normal bone quality, ↓ bone density: Back pain SHATTERED N N N N 2o: drugs, systemic disease T -1 - -2.5 = osteopenia Fractures T <-2.5 = osteoporosis Osteomalacia Vit D or PO4 deficiency Defective bone mineralisation Bone pain Vegan ↓ ↓ ↑ ↑ - ↑ osteoid #s Breast milk - widened osteoid seams Proximal weakness Malabsorption Bone deformity ↓ sun ↓ Ca  SPASMODIC CLD Rickets Looser’s zones on X-ray Craniotabes CRD ↓/N ↓ ↑ ↑ - pseudofractures Frontal bossing Rachitic rosary Bowed legs Cupped metaphysis @ wrist 1o HPT 80% parathyroid adenomas Osteitis fibrosa cystica Stones, bones, moans, groans ↑ ↓ ↑ ↑ /N 20% gland hyperplasia - Subperiosteal erosions <0.5% parathyroid Ca - Acral osteolysis 2o HPT Chronic renal failure - Cysts ↓ ↑ ↑ ↑ Vit D deficiency - Brown tumours (fibrous, vascular) Malabsorption - Pepperpot skull 3o HPT Parathyroid hyperplasia due to Stones, bones, moans, groans Post-renal Tx ↑ ↑/N ↑ ↑ prolonged 2o HPT Hypo-PTH Surgical Spasmodic ↓ ↑ N ↓/N Autoimmune Congen – Di George Paget’s Unknown Disorder of bone turnover → ↑ bone Bone pain N N ↑↑↑ N mass but bone is disordered + weak Sabre tibia - disorganised mosaic pattern of Chalkstick # lamellar bone Nerve compression - sclerosis + cortical thickening - deafness Heart failure Axial skeleton, esp. skull, pelvis ↑ risk of osteosarcoma

Wedge-shaped lytic lesions Osteoporosis circumscripta Renal PO4 retention + ↓vit D →↓Ca ↑ bone resorption → osteitis fibrosa Bone pain ↓ ↑ ↑ /N ↑ osteodystrophy → ↑PTH Osteomalacia #s Osteosclerosis: rugger jersey spine Uraemia Met acidosis of RF → release of Osteoporosis hydroxyapataite

Biology Presentation  Chylomicrons  CVD . Mainly TG  Xanthomata . Carry dietary TG tissues . Eruptive: itchy nodules in crops (↑TG)  VLDL . Tuberous: plaques on elbows, knees . Mainly TG . Planar: ornage streaks in palmer creases . Take endogenous TG from liver → tissue  Remnant hyperlipidaemia  LDL . Xanthelasma: eyelids . Mainly cholesterol . Arcus: cornea . Carry cholesterol from liver to tissues  Pancreatitis (↑TG)  HDL . Mainly phospholipid . Take cholesterol from tissues → liver for excretion Ix  Apolipoproteins . Contained in lipoproteins and control transport and  Plasma cholesterol uptake.  Plasma HDL . ApoB contained in LDL and binds to cell receptors  Fasting TGs → uptake  TC:HDL ratio is best predictor of CV risk

Classification Mx  Common 1O hyperlipidaemia . 70% Aims . Dietary and genetic factors  TC <4 . ↑ LDL only  TC:HDL ratio <4.5  Familial primary hyperlipidaemia . Multiple phenotypes Lifestyle . ↑↑ risk of CVD  Lose wt.  2O hyperlipidaemia  ↓ saturated fat, ↑ fibre, ↑ fruit and veg . ↑ LDL  ↑ exercise  Nephrotic syn.  Cholestasis: lipoprotein x Treatment Priorities  Hypothyroidism  Known CVD  Cushing’s  Those ¯c DM  Drugs: thiazides, steroids  Those ¯c 10yr CVD risk >20% . Mixed: ↑LDL and ↑TG . Irrespective of baseline lipids  T2DM st  EtOH 1 -line: Statins  CRF  E.g. simvastatin 40mg PO nocte  HMG-CoA reductase inhibitors → ↓ cholesterol synth.

nd Familial Primary Hyperlipidaemias 2 -line:  Fibrates: PPARα antagonists, ↓ TGs 1O Hypercholesterolaemia  Ezetimibe: inhibits cholesterol absorption  Commonest  Niacin / nicotinic acid: ↑HDL, ↓LDL  ApoB (LDL receptor) defect → ↑↑ LDL-C

Combined Hyperlipidaemia  2nd commonest  ↑LDL-C + ↑TG

Lipoprotein Lipase Deficiency  ↑↑ chylomicrons

Hypertriglyceridaemia Remnant Particle Disease

Pathogenesis Porphyria Cutanea Tarda  Deficiencies of enzymes in haem biosynthesis  Commonest porphyria  → overproduction of toxic haem precursors  Cutaneous manifestations only . Porphyrins: induce photosensitivity  Uropophyrinogen decarboxylase deficiency . Porphyrin precursors: neurotoxic  Genetic or acquired Presentation . EtOH, lead and Fe → abnormal porphyrin  Photosensitivity: blistering skin lesions metabolism  Facial hyperpigmentation and hypertrichosis

Acute Intermittent Porphyria Precipitants  Sunlight  The Madness of King George nd  EtOH  2 commonest porphyria Ix Pathophysiology  ↑ urine and se porphyrins  AD c partial penetrance ¯  ↑ se ferritin  Porphyrobilinogen deaminase deficiency  F>M = 2:1 Rx  Presents @ 20-40yrs  Avoid sun  Phlebotomy / iron chelators Presentation  Chloroquine  GI: Abdo pain, n/v, constipation  CV: ↑HR, ↑BP (sympathetic overactivity)  Neuropsych: peripheral motor neuropathy, seizures, psychosis  Other: Red urine, fever, ↑WCC

NB. Can mimic surgical abdomen (anaesthesia = disaster)

Precipitants  P450 inducers: AEDs, EtOH, OCP/HRT  Infection / stress  Fasting  Pre-menstrual

Ix  ↑ urine PBG and ALA

Rx  Supportive . Analgesia: opiate (avoid oxycodone) . IV fluids . Carbohydrate . Rx ↑HR and ↑BP ¯c β-B  Specific . IV haematin

Homocystinuria  Auto recessive  Cystathione β-synthetase deficiency  Accumulation of homocystine

Presentation  Marfanoid habitus  Downward lens dislocation  Mental retardation  Heart rarely affected  Recurrent thrombosis

Rx  Some response to high-dose pyridoxine

Gaucher’s Disease  Commonest lysosomal storage disease  Autosomal recessive glucocerebrosidase deficiency . → accumulation of glucosylceramide in the lysosomes of the reticuloendothelial system.  Liver  BM  Spleen  High incidence in Ashkenazi Jews (1/450)

Presentation  3 clinical types: type 1 is commonest . Presents in adulthood . Gross HSM . Brown skin pigmentation: forehead, hands . Pancytopenia . Pathological fractures

Mx  Most have normal life expectancy in type 1  Can give recombinant enzyme replacement

Contents Genetic Oncology ...... 223 Epidemiology ...... 223 Oncological Emergencies ...... 224 Cancer Therapy ...... 225 Tumour Markers ...... 226

© Alasdair Scott, 2012 222 Genetic Oncology Epidemiology  Cancer affects 30% of the population Familial Breast and Ovarian Ca  20% of people die from cancer  ~10% of breast Ca is familial  ~5% is caused by BRCA1 or BRCA2 mutations . Both TSGs Commonest Incidence . BRCA1: Breast Ca – 80%, Ovarian Ca – 40% 1. Skin cancers . BRCA2: Breast Ca – 80%, male breast Ca 2. Breast / Prostate  May opt for prophylactic mastectomy and oophrectomy. 3. Lung 4. CRC

Familial Prostate Ca  ~5% of those ¯c prostate Ca have +ve fam Hx Commonest Mortality  Multifactorial inheritance  Lung  BRCA1/2 → moderately ↑ risk  Breast / Prostate  CRC

Familial CRC  ~20% of those ¯c CRC have +ve fam Hx  Relative risk of CRC for individual ¯c FH related to . Closeness of relative . Age of relative when Dx.

Familial Adenomatous Polyposis  Mutation in APC gene on Chr 5 . TSG . Promotes β-catenin degredation . β-catenin is an oncogene which → cell proliferation  Cells then acquire another mutation to become Ca . p53 . kRAS  AD transmission  ~100% risk of CRC by 50yrs

HNPCC  Familial clustering of cancers . Lynch 1: CRC . Lynch 2: CRC + other Ca  Ovarian  Endometrial  Pancreas  Small Bowel  Renal pelvis  Mutations in DNA mismatch repair genes  AD transmission (variable penetrance)  Often Right-sided CRC  Present @ young age: <50yrs

Peutz-Jehgers  AD transmission  Multiple GI hamartomatous polyps  Mucocutaneous hyperpigmentation . Lips . Palms  10-20% lifetime risk of CRC  Also ↑ risk of other Ca . Pancreas . Lung . Breast . Ovaries and uterus . Testes

Febrile Neutropenia Hypercalcaemia  PMN <1x109/L  Affects 10-20% of those ¯c Ca  Isolation + barrier nursing  Affects 40% of those ¯c myeloma  Meticulous antisepsis  Broad-spectrum Abx, anti-fungals, anti-virals Causes  Prophylaxis: co-trimoxazole  Lytic bone metastases  Production of PTHrP

Spinal Cord Compression Symptoms  Confusion Presentation  Renal stones  Back pain, radicular pain  Polyuria and polydipsia → dehydration  Motor, reflex and sensory level  Abdominal pain, constipation  Bladder and bowel dysfunction  Depression  Lethargy Causes  Anorexia  Usually extradural metastasis  Crush fracture Ix  ↑ Ca (often >3mM) Ix  ↓ PTH (key to exclude 1O HPT)  Urgent MRI spine  CXR  Isotope bone scan Mx  Dexamethasone Rx  Discuss ¯c neurosurgeon and oncologist  Aggressive hydration  Consider radiotherapy or surgery . 0.9% NS (e.g. 1L/4h) . Monitor volume status . Frusemide when full to make room for more fluid  If 1O HPT excluded, give maintenance therapy c SVCO ¯c Airway Compromise ¯ bisphosphonate: zoledronate is good  SVCO not an emergency unless there’s tracheal compression ¯c airway compromise.

Causes Raised ICP  Usually lung Ca  Thymus malignancy Presentation  LNs  Headache: worse AM and bending over  SVC thrombosis: central lines, nephrotic syndrome  n/v  Fibrotic bands: lung fibrosis after chemo  Focal neuro and fits  Papilloedema Presentation  Headache Ix  Dyspnoea and orthopneoa  CT/MRI

 Plethora + thread veins in SVC distribution Rx  Swollen face and arms  Dexamethasone  Engorged neck veins  Radio- / chemo-therapy

Pemberton’s Sign

 Lifting arms above head for >1min → facial plethora, ↑JVP and inspiratory stridor Tumour Lysis Syndrome  Due to narrowing of the thoracic inlet  Massive cell destruction . High count leukaemia or bulky lymphoma Ix  ↑K, ↑urate, ↑PO4, ↓Ca  Sputum cytology  → renal failure  CXR  Prevention  CT . ↑ fluid intake + allopurinol 24h before chemo  Venography . Rasburicase is an option

Mx  Dexamethasone  Consider balloon venoplasty + SVC stenting  Radical or palliative chemo / radio

Cancer must be managed in an MDT Radiotherapy

Chemotherapy Mechanism  Neoadjuvant  Ionising radiation → free radicals which damage DNA . Shrink tumour to ↓ need for major surgery  Normal cells better at repairing damage cf. Ca cells. . Control early micrometastases  Radiation dose: gray (Gy)  Primary Therapy  Given in daily fractions . E.g. sole Rx in haematological Ca  India ink tattoo for reproducible targeting  Adjuvant . ↓ chance of relapse: e.g. breast and GI Ca Radical Rx  Palliative  Curative intent . Provide relief from symptoms  40-70Gy . Prolong survival  15-30 daily fractions

Important Cytotoxic Classes Palliation  Symptom relief Alkylating agents . Bone pain, haemoptysis, cough, dyspnoea,  Cyclophosphamide, chlorambucil, busulfan bleeding.  8-30Gy Antimetabolites: methotrexate, 5-FU  1-10 fractions

Vinca alkaloids: vincristine, vinblastine Early Reactions  Tiredness Cytotoxic Abx: doxorubicin, bleomycin, actinomycin D  Skin reactions: erythema → ulceration  Mucositis Taxanes: paclitaxel  n/v: occur ¯c stomach, liver or brain Rx

 Diarrhoea: pelvic or abdo Rx Immune Modulators: thalidomide, lenalidomide  Cystitis MAbs  BM suppression  Trastuzumab (anti-Her2): breast Ca Late Reactions (months or yrs)  Bevacizumab (anti-VEGF): RCC, CRC, lung  Brachial plexopathy  Cetuximab (anti-EGFR): CRC . Follows axillary radiotherapy  Rituximab (anti-CD20): NHL . Numb, weak, painful arm

 Lymphoedema Tyrosine Kinase Inhibitors  Pneumonitis  Erlotinib: lung Ca . Dry cough ± dyspnoea  Imatinib: CML . Rx: prednisolone

 Xerostomia Endocrine Modulators: tamoxifen, anastrazole  Benign strictures Common Side Effects  Fistulae  ↓ fertility  n/v: prophylactic granisetron + dexamethasone  Panhypopituitarism  Alopecia

 Neutropenia: 10-14d after chemo  Extravasation of chemo agent Surgery . Pain, burning, bruising @ infusion site . Stop infusion, give steroids, apply cold pack  Diagnostics: tissue biopsy or complete removal Excision: GI, soft-tissue sarcomas, gynae . Liaise early ¯c plastics  . Often with neo-/adjunctive chemo or radiotherapy

 Palliation: e.g. bypass procedures, stenting Specific Problems

Drug Problems Analgesia Cyclophosphamide Haemorrhagic cystitis: give mesna Hair loss  Oral where possible BM suppression  Fixed interval to give continuous relief Doxorubicin Cardiomyopathy  Stepwise approach Bleomycin Pulmonary fibrosis Vincristine Peripheral neuropathy (don’t give IT) Carboplatin Peripheral neuropathy n/v Nephrotoxic Paclitaxel Hypersenstivity 5-FU Mucositis

Marker Malignant Non-malignant AFP HCC Hepatitis Teratoma Cirrhosis Pregnancy CA 125 Ovary Cirrhosis Uterus Pregnancy Breast CA 15-3 Breast Benign breast disease CA 19-9 Pancreas Cholestasis Cholangiocarcinoma Pancreatitis CRC CA 27-29 Breast Neuron-specific SCLC enolase CEA CRC Pancreatitis Cirrhosis βHCG Germ cell tumour Pregnancy PSA Prostate BPH Mono Ig Multiple myeloma S-100 Melanoma Sarcoma PLAP Seminoma Acid phosphatases Prostate Ca Thyroglobulin Thyroid Ca

Contents Phagocyte Deficiencies ...... 228 T Cell Deficiency ...... 228 B Cell Deficiency ...... 229 Complement Dysfunction ...... 230 Infections Associated With Immune Deficiencies ...... 231

Condition Mechanisms Presentation PMN Adhesion Mol NBT/DHR Pus Reticular dysgenesis HSC defect Deficiency of PMN, lymphos, monos Type of SCID Kostmann’s Syndrome Congenital neutropenia Rx: G-CSF or BMT Absent Normal Absent No Auto Recessive Cyclic neutropenia Episodic neutropenia every 4-6 wks Rx: G-CSF Auto Dominant Mutation in ELA2 gene LAD CD18 (β2-integrin) deficiency Delayed umbilical cord separation ↑↑ Absent Normal No Neonatal bacterial infections CGD NADPH oxidase deficiency Recurrent pneumonias and abscesses Normal Normal Abnormal Yes X-linked recessive Granulomas Can resist catalase negative bacteria Lymphadenopathy HSM Rx: gamma-IFN therapy Cytokine Failure gIFN / gIFN-R and Susceptible to mycobacteria and salmonella IL-12 / IL-12-R deficiency BCG infection after vaccination No granulomas

T Cell Deficiencies

Condition Mechanisms Presentation CD4 CD8 B Cell IgM IgG IgA Reticular dysgenesis HSC defect Deficiency of PMN, lymphos, monos ↓ ↓ ↓ Type of SCID SCID X-linked: (common) IL2R gamma chain mutation Unwell by 3mo - T-/B+ Infections ↓ ↓ N/↓ N/↓ ↓ ↓ FTT ADA deficiency: auto recessive Persistent diarrhoea - T-/B- Unusual skin disease FH of early infant death Di George Defect of 3rd/4th pharyngeal arches Immune function improves with age. Thymic aplasia Rx: Thymus transplant ↓ ↓ N N ↓ ↓ CATCH-22 BLS-II Absent MHC-II Unwell by 3mo FTT ↓ N N N ↓ ↓ Assoc. with sclerosing cholangitis FH of early infant death Cytokine Failure gIFN / gIFN-R and Susceptible to mycobacteria and salmonella IL-12 / IL-12-R deficiency BCG infection after vaccination No granulomas

Condition Mechanisms Clinical CD4 CD8 B Cell IgM IgG IgA SCID X-linked: (common) IL2R gamma chain mutation Unwell by 3mo - T-/B+ Infections ↓ ↓ N/↓ N/↓ ↓ ↓ FTT ADA deficiency: auto recessive Persistent diarrhoea - T-/B- Unusual skin disease FH of early infant death Bruton’s X-linked No Ig after ~3mo B-cell tyrosine kinase deficiency Recurrent childhood infections N N ↓ ↓ ↓ ↓ Pre-B cells cannot mature - bacterial - enterovirus Hyper IgM X-linked Boys present in first few yrs CD40L (CD154) mutation (T cells) Recurrent bacterial infections N N N ↑↑ ↓ ↓ No germinal centre development in LN/spleen FTT Failure of isotype switching PCP, autoimmune disease, Ca IgA deficiency Assoc. with coeliac disease Recurrent GIT and RT infections N N N N N ↓ Not severe Common variable ID Recurrent bacterial infections - bronchiectasis N N N N ↓ ↓ - sinusitis Autoimmune disease Granulomatous disease Wiskott-Aldrich WASP gene mutation Immunodeficiency X-linked Thrombocytopenia ↓ ↕ ↑ Eczema Malignant Lymphoma ↑ IgE

Pathway Deficiency Outcome Classical C1, C2, C4 SLE C2 deficiency = commonest MBL MBL deficiency ↑ infection is patient’s with other cause of immune impairment - prems, chemo, HIV, Ab deficiency Alternative B, I, P deficiency Infection (esp. with encapsulates) Terminal pathway C5-9 deficiency - Meningococcus - Pneumococcus Inability to make MAC - H. influenzae - Hib FH of infection C3 deficiency C3 deficiency Infections as above + SLE Acquired C3 deficiency due to C3 nephritic factor – assoc. with membranoproliferative (mesangiocapillary) GN

Ix Hereditary Angioedema / C1 Esterase Deficiency  C3, C4 level  Auto dominant: commoner than complement deficiencies  CH50: classical pathway  Acquired form may be caused by splenic marginal zone lymphoma  AP50: alternative pathway  If CH50 and AP50 both abnormal with normal C3, C4 = final common pathway Pathophysiology deficiency (C5-9)  Serpin that inhibits . C1 . F12 of coag cascade . Kallikrein (Cleaves HMWK → Bradykinin)  Deficiency → ↑ bradykinin → symptoms

Presentation  Attacks may be ppted by EtOH, emotional stress, exercise.  Angioedema but NO rash and NOT itchy . Skin . Oropharynx – asphyxia . GIT – nausea, vomiting diarrhoea  ↓ C2 and ↓C4 (normal C1 and C3)

Antibody Deficiency Cellular Deficiency Combined Deficiency Phagocyte (PMN) Complement B cell T cell B+T cell Deficiency Deficiency Viruses Enterovirus CMV, VAZ, HSV, EBV, measles, All resp viruses Bacteria Encapsulates: Pneumococcus Mycobacteria As for Ab deficiency S. aureus Encapsulates Meningococcus Salmonella S. typhi Other Gm+ and Gm- Esp. Meningococcus Haemophilus Listeria Listeria Mycobacteria Enterics Staph. aureus Pseudomonas Fungi Candida Candida Candida Candida Aspergillus Aspergillus Aspergillus Histoplasma Histoplasma Crypto Crypto PCP PCP Protozoa Giardia lamblia Toxoplasma Toxoplasma Clinical Respiratory and GI sepsis Systemic viral / fungal infections Systemic viral/fungal Lymphadenitis, skin/mouth Systemic bacterial infections and infections, liver and lung infections Early malignancy gastroenteritis abscesses, granulomas Autoimmune disease

Dx of Immune Deficiency

Infections  2 major or 1 major + recurrent minor infections in 1 year  Unusual organisms  Unusual sites  Unresponsive to oral Abx  Chronic infections  Early structural damage

Other  FTT  Skin disease  Chronic diarrhoea  Mouth ulceration  Family Hx

Contents Malignant and Pre-malignant Skin Lesions ...... 233 Psoriasis ...... 234 Eczema ...... 235 Pruritus ...... 235 Skin Infections ...... 236 Miscellaneous Skin Disorders ...... 237 Acne Vulgaris ...... 237 Acne Rosacea ...... 237 Drug Eruptions ...... 238 Infestations ...... 238 Skin Manifestations of Systemic Disease...... 239

Malignant Melanoma Squamous Cell Carcinoma  Ulcerated lesion ¯c hard, raised everted edges Epidemiology  Sun exposed areas  F>M = 1.5:1  UK incidence = 10 000/yr and 2000 deaths/yr Causes . ↑80% in 20yrs  Sun exposure: scalp, face, ears, lower leg  May arise in chronic ulcers: Marjolin’s Ulcer Features  Xeroderma pigmentosa  Asymmetry  Boarder: irregular Evolution  Colour: non-uniform  Solar/actinic keratosis → Bowen’s → SCC  Diameter > 6mm  Lymph node spread is rare  Evolving / Elevation Rx Risk Factors  Excision + radiotherapy to affected nodes  Sunlight: esp. intense exposure in early years.  Fair skinned (Low Fitzpatrick Skin Type)  ↑ no. of common moles Actinic Keratoses  +ve FH  Irregular, crusty warty lesions.  ↑ age  Pre-malignant (~1%/yr)  Immunosuppression Rx Classification  Cautery  Superficial Spreading: 80%  Cryo . Irregular boarders, colour variation  5-FU . Commonest in Caucasians  Imiquimod . Grow slowly, metastasise late = better prognosis  Photodynamic phototherapy  Lentigo Maligna Melanoma

. Often elderly pts.

. Face or scalp  Acral Lentiginous Bowen’s Disease . Asians/blacks  Red/brown scaly plaques . Palms, soles, subungual (c¯ Hutchinson’s sign)  SCC in situ  Nodular Melanoma . All sites Rx . Younger age, new lesion  As for AKs . Invade deeply and metastasis early = poor prog  Amelanotic . Atypical appearance → delayed Dx Keratoacanthoma  A well differentiated SCC that arises in a hair follicle. Staging and Prognosis  Fast-growing, dome-shaped ¯c a keratin plug.  Breslow Depth  Usually regress but may be excised . Thickness of tumour to deepest point of dermal invasion . <1mm = 95-100% 5ys Basal Cell Carcinoma . >4mm = 50% 5ys  Commonest cancer  Clark’s Staging  Pearly nodule ¯c rolled telangiectactic edge . Stratifies depth by 5 anatomical levels  May ulcerate . Stage 1: Epidermis  Typically on face in sun-exposed area . Stage 5: sc fat . Above line from tragus → angle of mouth

Metastasis Behaviour  Liver  Low-grade malignancy → very rarely metastasise  Eye  Locally invasive

Mx  Excision + 2O margin excision depending on Bres depth Rx  ± lymphadenectomy  Excision . Mohs: complete circumferential margin  ± adjuvant chemo (may use isolated limb perfusion) assessment using frozen section histology

Poor prognostic indicators  Cryo/radio may be used.  Male sex (more tumours on trunk cf females)  ↑ mitoses  Satellite lesions (lymphatic spread)  Ulceration

Epidemiology Mx  Prevalence: 2% of Caucasians  Age: peaks in 20s and 50s Education  Sex: F=M  Avoid triggers  Genetics: 30% have FH . Genetic predisposition Soap Substitute  Aqueous cream Pathology  Dermol cream  TIV hypersensitivity reaction  Epaderm ointment  Epidermal proliferation  T-cell driven inflammatory infiltration Emollients  Histo  Epaderm . Acanthosis: thickening of the epidermis  Dermol . Parakeratosis: nuclei in stratum corneum  Diprobase . Munro’s microabscesses: neutrophils Topical Therapy Triggers  Vit D3 analogue: e.g. calcipotriol  Stress  Steroids: e.g. betamethasone . Dovobet = Calcipotriol + betamethasone  Infections: esp. streps  Tar: mainly reserved for in-patient use  Skin trauma: Kobner phenomenon  Dithranol  Drugs: β-B, Li, anti-malarials, EtOH  Retinoids: e.g. tazarotene  Smoking

UV Phototherapy Signs  Causes local immunosuppression

 Narrow band UVB Plaques  Psoralen + UVA: PUVA  Symmetrical well-defined red plaques c silvery scale ¯ . Psoralen is a photsensitising agent and can be  Extensors: elbows, knees topical or oral  Flexures (no scales): axillae, groins, submammary  PUVA is more effective but ↑ skin Ca risk  Scalp, behind ears, navel, sacrum Non-Biologicals Nail Changes (in 50%)  Methotrexate  Pitting  Ciclosporin  Onycholysis  Acetretin (oral retinoid / vit A analogue)  Subungual hyperkeratosis . SE: ↑ lipids, ↑ glucose

10-40% Develop Seronegative Arthritis Biologicals  Mono-/oligo-arthritis: DIPs commonly involved  Infliximab  Rheumatoid-like  Etanercept  Asymmetrical polyarthritis  Adalimumab  Psoriatic spondylitis  Arthritis mutilans  May → dactylitis

Variants

Guttate  Drop-like salmon-pink papules ¯c fine scale  Mainly on trunk  Occurs in children assoc. ¯c strep infection

Pustular  Sterile pustules  May be localised to palms and soles

Erythroderma and Generalised Pustular  Generalised exfoliative dermatitis  Severe systemic upset: fever, ↑WCC, dehydration  May be triggered by rapid steroid withdrawal

Presentation Mx of Atopic Eczema  Extremely itchy  Poorly demarcated rash Education . Acute: oozing papules and vesicles  Avoid triggers: e.g. soap . Subacute: red and scaly  Chronic eczema → lichenification Soap Substitute . Skin thickening ¯c exaggeration of skin markings  Aqueous cream  Dermol cream  Epaderm ointment Pathology Emollients  Epidermal spongiosus  Epaderm  Dermol  Diprobase Atopic Eczema  Oilatum (bath oil)  TH2 driven inflammation ¯c ↑IgE production  Affects 2% of infants Topical Therapy  Most children grow-out of it by 13yrs  Steroids . 1% Hydrocortisone: face, groins Cause . Eumovate: can use briefly (<1wk) on face  FH of atopy common . Betnovate  Specific allergens . Dermovate: very strong, brief use on thick skin . House dust mite  Palms, soles . Animal dander  Diet: e.g. dairy products 2nd line Therapies  Topical tacrolimus Presentation  Phototherapy  Face: esp. around eyes, cheeks  Ciclosporin or azathioprine  Flexures: knees, elbows  May become 2O infected . Staph → fluclox . HSV → aciclovir Pruritus

Associations Generalised  Asthma  CRF  Hay fever  Cholestasis

Ix  Haematological . Polycythaemia  ↑ IgE . Hodgkin’s  RAST testing: identify specific Ag . Leukaemia

. Iron deficiency  Endocrine Irritant Contact Dermatitis . DM  Everyone is susceptible to irritants . Hyper- / hypo-thyroidism  Causes: detergents, soaps, oils, solvents, venous stasis . Pregnancy

Very Itchy Dermatological Diseases Allergic Contact Dermatitis  Eczema  Type IV hypersensitivity reaction  Urticaria  Common allergens  Scabies . Nickel: jewellery, watches, coins  Dermatitis herpetiformis . Chromates: leather . Lanolin: creams, cosmetics  Location: correlates sharply ¯c allergen exposure  Ix: Patch testing

Adult Seborrhoeic Dermatitis  Red, scaly, rash  Cause: overgrowth of skin yeasts (e.g. malassezia)  Location: scalp (dandruff), eyebrows, cheeks, nasolabial folds  Rx: mild topical steroids / antifungal . Daktacort: miconazole + hydrocortisone

Tinea Erysipelas  A superficial mycosis caused by dermatophytes  Sharply defined superficial infection by S. pyogenes . Microsporum  Often affects the face . Epidermophyton  High fever + ↑ WCC . Trichophyton  Rx . Benpen IV Presentation . Pen V and fluclox PO  Round scaly lesion  Itchy Cellulitis  Central clearing  Acute infection of skin and soft tissues  Scalp, body, foot, groin, nails Cause: β-haemolytic Strep + staph. aureus Rx  Skin: terbinafine or topical ketoconazole / miconazole Presentation  Scalp: griseofulvin or terbinafine  Deeper and less well defined than erysipelas  Nails: terbinafine  Pain, swelling, erythema and warmth  Systemic upset  ± lymphadenopathy Candida  Common Rx  RFs: immunosuppression, Abx, steroid inhalers  Empiric: fluclox IV  Confirmed Strep: Benpen or Pen V Presentation  Pen allergic: clindamycin  Pink + white patches  Moist Warts  Satellite lesions  Caused by HPV infection  Mouth, vagina, skin folds, toe web Rx Rx  Expectant  Mouth: nystatin  Destructive  Vagina: clotrimazole cream and pessary . Topical salicylic acid . Cryotherapy . Podophyllin . Imiquimod Pityriasis versicolor  Caused by Malassezia furfur Molluscum

 Pox virus Presentation  Pink papules c umbilicated central punctum  Common in hot and humid environments ¯  Circular hypo-/hyper-pigmented patches  Resolve spontaneaously

 Fine white scale  Itchy Herpes Zoster / Shingles  Back of neck and trunk  Recurrent VZV infection  Dermatomal distribution of cropping vesicles and crust Ix . Thoracic: 50%  “Spaghetti and meatballs” appearance ¯c KOH stain . Ophthalmic: 20%  Cornea affected in 50% → keratitis, iritis Rx  May → post-herpetic neuralgia  Selenium sulphate or ketoconazole shampoos  Rx: aciclovir or famciclovir PO if severe

Herpes Simplex Impetigo  Gingivostomatitis or recurrent genital or oral infections  Triggered by infection (e.g. CAP), sunlight and  Contagious superficial skin rash caused by S. aureus immunosuppression

 May complicate eczema: eczema herpeticum Presentation  Grouped painful vesicles on an erythematous base  Age: peak @ 2-5yrs  Rx: acyclovir or famciclovir indicated if  Honey-coloured crusts on erythematous base immunosuppressed or recurrent genital herpes.  Common on face

Rx Pityriasis Rosea  Mild: topical Abx (fusidic acid, mupirocin)  HHV-6/-7  More severe: fluclox PO  Herald patch precedes rash, mainly on the trunk

Lichen Planus Pathophysiology  ↑ sebum production: androgens and CRH Skin Presentation  P. acnes is a skin commensal that flourishes in the  Flexors: wrists, forearms, ankles, legs anaerobic environment of the blocked follicle  Display Kobner phenomenon . → inflammation  Purple  Pruritic Presentation  Polygonal  Inflammation of pilosebaceus follicles  Planar  Comedones (white- or black-heads), papules, pustules  Papules nodules, cysts  Lacy white marks: Wickham’s Striae  Face, neck, upper chest and back

Lesions Elsewhere Mx  Scalp: scarring alopecia  Pt. education  Nails: longitudinal ridges  Remember that topical therapy is difficult to apply to the  Mouth: lacy white plaques on inner cheeks back.  Genitals Mild: topical therapy Rx  Benzoyl peroxide  Mild: topical steroids  Erythromycin, Clindamycin  Severe: systemic steroids  Tretinoin / Isotretinoin

Moderate Bullous Pemphigoid  Topical benzoyl peroxide + oral Abx (doxy or erythro)  Autoimmune blistering disease due to auto-abs against hemidesmosomes Severe  Isotretinoin (vitamin A analogue) Presentation . 60-70% have no further recurrence  Mainly affects the elderly . SE: teratogenic, hepatitis, ↑lipids, depression, dry  Tense bullae on erythematous base skin, myalgia  Can be itchy . Monitor: LFTs, lipids, FBC  May try Dianette in women Ix  Biopsy shows linear IgG along the BM and subepidermal bullae Acne Rosacea  Chronic relapsing remitting disorder affecting the face Rx  Clobetasol (Dermavate) Presentation  Chronic flushing ppted. by alcohol or spicy foods.  Fixed erythema: chin, nose, cheeks, forehead Pemphigus Vulgaris  Telangiectasia, papules, pustules (no comedones)  Autoimmune blistering disease due to auto-abs against desmosomes. Associations  May be ppted by drugs  Rhinophyma: swelling and soft tissue overgrowth of the . NSAIDs nose in males . ACEi  Blepharitis: scaling and irritation at the eyelashes . L-dopa Rx Presentation  Avoid sun exposure  Younger pts.  Topical azelaic acid  Large flaccid bullae which rupture easily  Oral doxycycline or azithromycin  Nikolsky’s sign +ve  Mucosa is often affected

Ix  Intraepidermal bullae

Rx  Prednisolone  Rituximab  IVIg

Maculopapular Scabies  Commonest type  Sarcoptes scabei  Generalized erythematous macules and papules  Highly contagious: spread by direct contact  ± fever and ↑ eosinophils  Female mite digs burrows and lays eggs  Develops w/i two weeks of onset of drug  Penicillins, cephalosporins, AEDs Presentation  Burrows: short, serpiginous grey line, block dot  Hypersensitivity rash: eczematous, vesicles  Extremely itchy → escoriation Urticaria st  Wheals ± angioedema and anaphylaxis  Particularly affects the finger web spaces (esp. 1 )  Rapid onset after taking drug  Also: axillae, groin, umbilicus  Immune (IgE) . Penicillins Mx . Cephalosporins  Permethrin cream: applied from neck down for  Non-immune (direct mast cell degranulation) 24hrs  2nd line: Malathion . Morphine rd . Codeine  3 line: oral ivermectin . NSAIDs  Treat all members of the household . Contrast

Headlice Erythema Multiforme  Pediculus humanus capitis  Symmetrical target lesions on palms, soles and limbs  Spread by head to head contact  Occurs 1-2wks after insult  Nits = empty eggs  Infections are commoner cause of EM Presentation Causes  Itch  Idiopathic  Papular rash @ the nape of the neck  Infections: HSV, mycoplasma Rx  Drugs . Sulphonamides, NSAIDs, allopurinol, penicillin  Malathion phenytoin  Combing

Stevens-Johnson Syndrome  More severe variant of EM,  Blistering mucosa: conjunctiva, oral, genital

Toxic Epidermal Necrolysis  Extreme form of SJS  Nearly always a drug reaction  Features . Severe mucosal ulceration . Widespread erythema followed by epidermal necrosis ¯c loss of large sheets of epidermis . → dehydration  ↑↑↑ risk in HIV+  Rx: dexamethasone, IVIg  Mortality: 30%

Skin Conditions Diseases

Erythema Nodosum Disease Skin Manifestation  Painful blue-red lesions on anterior shins Rheumatic fever Erythema marginatum  3 S’s: sarcoid, strep infections and sulfonamides Lyme Erythema chronicum migrans  Also: OCP, IBD and TB, Behcet’s (Borrelia burgdorferi) Crohn’s Perianal ulcers and fistulae Erythema Multiforme EN  Symmetrical target lesions on palms, soles and limbs Pyoderma gangrenosum  Possibly mediated by IgM deposition Dermatomyositis Heliotrope rash on eyelids  Usually 2O to infection Shawl sign (macular rash)  Infections: HSV (70%), mycoplasma Gottron’s Papules  Drugs: SNAPP Mechanic’s hands Nailfold erythema, telangiectasia Stevens-Johnson Syndrome and TEN DM Ulcers  Severe variants of EM Candida  Nearly always drug-induced Kyrle disease  Fever, mucosal and skin ulceration and necrosis Acanthosis nigricans Necrobiosis lipoidica (shins) Pyoderma Gangrenosum Granuloma annulare (hands, feet) Sarcoidosis Erythema nodosum  Wide (10cm), deep ulceration ¯c violaceous border Erythema multiforme  Purulent surface Lupus pernio  Undermined edge Hypopigmented areas  Commonly occurs on legs Red/violet plaques  Heal ¯c cribriform (pitted) scars Coeliac Dermatitis herpetiformis (elbows)  Assocs.: IBD, AIH, Wegener’s, RA, leukaemia Graves’ Pre-tibial myxoedema (lat mal)  Rx: High-dose systemic steroids RA Rheumatoid nodules Vasculitis (palpable purpura) Vitiligo SLE Facial butterfly rash  Chalky white patches ¯c hyperpigmented borders Systemic sclerosis Calcinosis  Itch in sunlight Raynaud’s  Assocs.: autoimmune disorders Sclerodactyly Telangiectasia Livedo Reticularis Generalised skin thickening  Persistent mottled red/blue lesions that don’t blanch Liver disease Palmar erythema  Commonly found on the legs Spider naevi  Triggered by cold Gynaecomastia O  Causes ↓ 2 sexual hair . Idiopathic Jaundice . Vasculitis: RA, SLE, PAN Bruising . Obstruction: anti-phos, cryoglobulinaemia Excoriations . Sneddon’s syn.: LR + CVAs ESRD Assoc. c¯ Cause - DM, vasculitis, sclero, RA, SLE Assoc. c¯ ESRD - Pruritus, xerosis, pigment change Bullous disease Assoc. c¯ Transplant - Cushingoid, gingival hyperplasia, Infections, BCC, SCC, melanoma Kaposi’s

Neoplasia Acanthosis nigricans Dermatomyositis Thrombophlebitis migrans Acquired ichthyosis

Contents Health Information ...... 241 Public Health Issues ...... 242 Clinical Evidence ...... 243 Epidemiological Concepts ...... 244 Disease Prevention ...... 245 Likelihood Ratios ...... 245

Routine Data Clinical Governance  Data that are routinely collected and recorded in an on- going systematic way, often for administrative purposes. Definition  A transparent system for the continual maintenance and Advantages improvement of healthcare standards both on an  Relatively cheap individual and organisational level within the NHS.  Already collected and available  Standardised collection procedures Elements  Education and Training Disadvantages  Clinical audit  May not answer the question  Clinical effectiveness  Variable quality  Research and Development  Not every case captured  Openness  Risk Management Sources  Demographics: census Agencies  Health: births, deaths, admissions, prescriptions, hospital  The Care Quality Commission episode statistics, cancer . Independently inspect healthcare services  Exposures: smoking, air pollution, crime against standards set by the Department of  Disease prevention: screening, immunisation uptake Health. . Investigate serious failures in healthcare services. . Publish regular ratings of NHS trusts. Hospital Episode Statistics  Electronic record of every inpatient or day-case episode of patient care in every NHS hospital. Clinical Audit  300 fields of information, including:  Are pts. given the best care? . Pt demographics . Diagnosis using ICD-10 Definition . Procedures using OPCS4  A quality improvement process that seeks to improve pt. care and outcomes through the systematic review of Advantages care against explicit criteria and the implementation of  Comprehensive change.  Unbiased  Based on case notes

Disadvantages Outcome Measures  Data may not be complete  Are pts. better and do they feel better?  In-hospital death only Patient Reported Outcomes (PROMs)  Calculate the health gain from the pts. perspective after surgical Rx using pre- and post-operative surveys. Mortality . Arthroplasty, hernia repairs, varicose veins . Hip replacement gives largest improvement in UK specific condition and general health. 1. Heart and Circulatatory disorders: 33% a. IHD (23%) Quality and Outcomes Framework (QOF) b. Stroke (10%)  Voluntary annual reward and incentive programme for 2. Cancer: 30% all GP surgeries in England, detailing practice a. Trachea, bronchus, lung achievement results. b. Breast, prostate c. Colorectum 3. Respiratory disorders: 13% a. Pneumonia b. COPD

Worldwide 1. IHD 2. Stroke and other cerebrovascular disease 3. LRTI 4. COPD 5. Diarrhoeal diseases

Major Contributions to Health Smoking  Drugs and medical intervention  Commonest cause of preventable death in the UK  Obstetric and perinatal care  2nd hand smoking  Immunisation . Respiratory infections  Screening . Asthma  Chronic disease Mx . SIDS . ↑ lung Ca and CHD risk  Social gradient in mortality is partially explained by Major Mortality Risk Factors social gradient in smoking.

 Heart and Circulatory Disorders Some Strategies . Smoking  Health education . ↓ exercise  Restrict advertising . Diet: ↑fat, ↑calorie, ↑salt, EtOH . ?Stress  Remove from display in shops  Neoplasms  ↑ price . Smoking  Smoking ban in public places . ↓ exercise  Very brief advice . Diet: ↓fruit and veg, ↓fibre, ↑fat  Pulmonary Disease . Smoking Alcohol . ↓ exercise  5% of men and 2% of women report problems . Occupation: asbestos, dust exposure  Recommended . Men: 21u/wk or 3-4u/d . Women: 14u/wk or 2-3u/d Major Public Health Issues . NB. 1u = 10ml EtOH

 Smoking Some Strategies  Obesity / unhealthy diet  National Alcohol Harm Reduction Strategy  ↓ Exercise  ↑ minimum price / unit  EtOH abuse

 Sexual health  Mental health Mental Health  Common: ~15% lifetime risk  Depression and anxiety disorders most commonly Obesity  20% obese Some Strategies  50% of females overweight or obese  GPs get rewarded for depression screening  Expansion of psychological therapies (e.g. CBT) Nurses’ Health Study  Overwt. → ↓3yrs of life  Obese → ↓7yrs of life  Active lifestyle (30min walk/d) prevents 30% of obesity and 45% of new DM.

Evidence for Changing Nutrition  Mediterranean diet can ↓ cardiac death post-MI  Low Na diet → ↓ BP

Sexual Health  10% of 16-24yr olds have ≥1 STI  ↑ in urban areas and amongst Blacks and Minorities  → infertility, ectopics, Cervical Ca, HIV

Some Strategies  Improving access to sexual health services  Chlamydia screening

Hierarchy of Evidence Cohort Study 1. Systematic reviews and meta-analyses  Prospective study comparing development of disease in 2. RCTs exposed and non-exposed grps. 3. Cohort or case-control studies  Incidence of disease in each grp → relative risk 4. Descriptive studies 5. Case reports Examples  Million Women study Study Types  Framingham Heart Study  Nurses’ Health Study Observational  Analytical / Aetiological Advantages . Studies determinants of disease by judging  Good for evaluation of rare exposures whether exposure causes or prevents disease  Can examine multiple effects of a single exposure  Descriptive  Can elucidate temporal relationship . Studies distribution of disease  Direct incidence calculation . Person, place and time Disadvantages Experimental  Inefficient for evaluation of rare diseases  RCTs  Expensive and time-consuming  Loss to f/up affects results

Descriptive Studies  Can be used to generate hypotheses RCTs  Provide frequency data  Planned experiment designed to assess the efficacy of . Incidence an intervention. . Point prevalence  Randomisation: ↓ selection bias.  Can’t determine causation  Blinding: ↓ measurement bias

Examples Advantages  Cross-sectional Surveys  Most reliable demonstration of causality . Household interview surveys asking questions regarding illness, social circumstances and Disadvantages demographics.  Non-compliance  Cross-sectional Census  Loss to f/up  Ecological studies  Validity depends on quality of study . Use populations rather than individual as unit of  Ethical issues observation.  Selection criteria may limit generalisability . Subject to significant confounding: age, sex, SES  Other routine data

Meta-Analyses

 Observational study of evidence Case-Control Studies  Systematic identification of relevant trials and  Retrospective study of exposure in a case grp ¯c the assessment of their quality disease and a control grp w/o the disease.  Allow accurate interpretation of multiple RCTs  Proportion of exposed in each group → odds ratio Forest plots Advantages  Square = OR  Quick and cheep . Size = size of study  Well-suited for diseases ¯c long latent periods  Line = 95% CI of OR  Good for evaluation of rare diseases  Diamond = combined odds ratio  Can examine multiple aetiological factors for a single . Width = 95% CI disease.

Disadvantages  Inefficient for evaluating rare exposures  Cannot calculate incidence rates  Temporal relationship between exposure and disease can be difficult to establish  Recall bias . E.g. testicular cancer sufferers more likely to report preceding trauma  Selection bias . E.g. non-random selection of study grps.

5 Steps of EBM Odds Ratio 1. Question 2. Search OR = odds of exposure in cases / odds of exposure in controls 3. Appraise = (A/C) / (B/D) = AD/BC 4. Apply 5. Evaluate Case Control Exposed A B Association and Causation Not Exposed C D  Association: a relationship between two factors  Causation: X → Y OR = ~RR if disease is rare (<10%)

Bradford Hill Causation Criteria Relative Risk  Strong association: i.e ↑↑ RR or OR  ↑/↓ in probability of disease given a particular RF  Consistency ¯c other investigations  Specificity RR = incidence in exposed / incidence in unexposed  Temporal relationship = (A/A+B) / (C/C+D)

 Dose response relationship  Plausibility Risk Estimates  Coherence  Absolute risk: probability of disease occurrence  Experimental evidence  Relative risk: ↑/↓ in probability of disease given a RF  Analogy  Attributable risk: measure of excess risk due a factor

Chance Number Needed To Treat  Studies are based on estimates from samples and are  NNT = (1 / Absolute risk reduction) x 100 therefore subject to random variation.  Absolute risk reduction = 1- hazard ratio  Random variation can be minimised by ↑ sample size.  The role of chance is assessed by statistical significance Screening tests and by calculating confidence intervals. Modified Wilson Criteria Bias  Disease  Inaccurate data due to systematic error in selection, . Important health problem measurement or analysis. . Well recognised pre-clinical stage . Natural Hx well understood Selection Bias  Test  Systematic difference between the characteristics of . Valid and reliable those selected for a study and those who were not or . Simple and cheap differences between study grps. . Safe and acceptable  E.g. self-selection, healthy worker effect  Dx and Rx . Adequate facilities Measurement Bias . Acceptable Rx . Early intervention is of more benefit than later Rx  Occurs when measurements or classifications of disease or exposure are inaccurate.  Cost effective

 E.g. inaccuracies of the instruments, expectations of observers or participants. Validity  Sensitivity: detect true positives Analysis Bias  Specificity: exclude true negatives  Error caused by participants being lost to f/up or  PPV: how likely to have disease if positive switching treatment groups.  NPV: how likely not to have disease if negative  Take into account using an intention to treat analysis. . PPV and NPV depend on disease frequency

Confounding Disease No Disease Positive A B PPV  Error in the interpretation of an accurate measurement. A/(A+B)  Any factor which is prognostically linked to the outcome Negative C D NPV and is unevenly distributed between study groups. C/(C+D)  Not a confounder if it lies on the causal pathway Sensitivity Specificity between the variables of interest. A/(A+C) B/(B+D)  Common confounders: age, sex, SES

Effectiveness Reducing Confounding  Selection bias: healthiest come for screening  Randomisation  Lead-time bias: disease Dx earlier → ↑ survival time  Stratification: e.g. stratify by age  Length-time bias: outcome appears better because  Standardisation: e.g. SMR more disease ¯c good outcome detected. . Ratio of observed:expected deaths . Expected deaths derived from larger population  Regression © Alasdair Scott, 2012 244 Disease Prevention Likelihood Ratios

Primordial Prevention Pre- and Post-test Probability  Prevention of factors promoting the emergence of risk  Pre-: estimate of probability that pt. has a certain factors: lifestyle, behaviours, exposure patterns disease based on presentation or epidemiology.  Test: diagnostic test or sign or symptom that you elicit Examples  Post-: new probability taking into account the “test”  Healthy eating programmes in schools result  Social policies to ↓ poverty and inequality  Likelihood ratio: measure of how much the test alters  Programmes that promote walking, cycling and public your probability of the disease. transport.  Encouragement of positive health behaviour. Calculation

Odds = probability / (1- probability) Primary Prevention  i.e. the ratio of the probability something will happen to the probability that it won’t.  Prevention of disease onset

Probability = odds / (odds +1) Examples

 Vaccination LR = p [test result if disease present] / p [test result if disease  Smoking cessation absent]  Healthy diet  Condom use LR for positive test result = sensitivity / (1- specificity)  Detection and Rx of hyperlipidaemia LR for negative test result = (1- sensitivity) / specificity

Secondary Prevention Post-test odds = pre-test odds x likelihood ratio  Halting progression of established disease  Early detection followed by prompt, effective Rx Example  Pre-test probability could be disease incidence in that Examples population.  Screening for Ca  Convert pre-test probability to odds.  Smoking cessation after MI  Calculate likelihood ratio based on the result of your test.  Apply likelihood ratio to get post-test odds.  Convert post-test odds to post-test probability Tertiary Prevention  Rehabilitation of people ¯c established disease to minimise residual disability and complications.

Examples  Rapid Rx of MI or stroke to ↓ disability  HAART

Disease Prevention in General Practice  General advice for a healthy lifestyle  Identifying and facilitating reduction of risk factors  Ensuring availability of preventative interventions  Identifying early disease and offering treatment

Prevention Paradox  Many people exposed to a small risk may generate more disease than a few exposed to a large risk.   when many people receive a small benefit the total benefit may be large.  However, individual inconvenience may be high to the many while benefit may only be to a few.

Health Promotion  Process of enabling people to increase control over, and to improve, their health. . Public policy, supportive environments…  Health promotion is specific requirement of the GMC Good Medical Practice guidelines.

Contents Shock ...... 247 Anaphylactic Shock ...... 248 Narrow Complex Tachycardias = SVT ...... 249 Broad Complex Tachycardias ...... 250 STEMI ...... 251 NSTEMI + UA ...... 252 Severe Pulmonary Oedema ...... 253 Cardiogenic Shock ...... 254 Meningitis ...... 255 Encephalitis ...... 256 Cerebral Abscess ...... 256 Status Epilepticus ...... 257 Head Injury ...... 258 Raised ICP ...... 259 Signs and Symptoms ...... 259 Acute Severe Asthma ...... 260 Acute Exacerbation of COPD ...... 261 Pulmonary Embolism...... 262 Pneumothorax ...... 263 Upper GI Bleeding ...... 264 Acute Renal Failure ...... 265 Poisoning: Recognition and Management ...... 266 Diabetic Ketoacidosis ...... 267 Hyperosmolar Non-Ketotic Coma ...... 268 Hypoglycaemia ...... 268 Thyroid Storm ...... 269 Myxoedema Coma ...... 269 Addisonian Crisis ...... 270 Hypertensive Crisis...... 270 Burns ...... 271 Hypothermia ...... 272 ALS Algorithm ...... 272 Tachycardia Algorithm ...... 272 Bradycardia Algorithm ...... 272

If ECG unrecordable, Rx as cardiac arrest Causes : CHOD

Cardiogenic ABCDE  MI  Arrhythmia

Hypovolaemic Raise foot of bed  Haemorrhage: internal and external (unless cardiogenic)  Endocrine: Addisonion crisis, DKA  Excess loss: burns, diarrhoea  Third-spacing: pancreatitis IV Access:  2 wide bore (14g) cannula in each ACF Obstructive  PE  Tension pneumothorax

Fast infusion of crystalloid to raise BP Distributive (unless cardiogenic)  Sepsis  Anaphylaxis  Neurogenic

Assessment Appearance History  Cold, clammy: cardiogenic or hypovolaemic  Chest pain: MI, PE, dissection, anaphylaxis  Warm, well perfused: septic  Abdo pain: AAA, DKA, peritonitis, ruptured ectopic  Urticaria, angioedema, wheeze: anaphylaxis  Back pain: AAA

Hands JVP  ↑CRT: hypovolaemia, cardiogenic  ↑: cardiogenic  ↓: hypovolaemic, distributive Pulse  Tachy (unless β-B or bradyarrhythmia) Abdomen  Small, thread: hypovolaemia  Tender, guarding: trauma, aneurysm, peritonitis.  Bounding: sepsis  Melaena: GI bleed ABP  ↓PP: hypovolaemia  R-L differential > 20mmHg: dissection

Ix Specific Measures  FBC, U+E, glucose, ABG, CRP, trop Anaphylaxis:  X-match, clotting  Adrenaline (0.5mg), hydrocortisone (200mg), chlorphenamine  Blood cultures, urine MCS (10mg), salbutamol  ECG, CXR, USS, Echo, CT Cardiogenic:  Rx arrhythmias/MI. Consider dobutamine.

Septic shock: Monitoring  IV Abx (e.g. meropenem 1g/8h IV + tazocin 4.5g/8h IV)  Catheter (>30ml/hr)  Fluids, vasopressors (e.g. norad)  Art line  CVP line Hypovolaemic  Fluid replacement: crystalloid, colloid, blood (grp specific/O neg)  Titrate to: urine output, CVP, BP  Haemodialysis if ATN

Pathogenesis Mx  Type 1 IgE mediated hypersensitivity reaction O  TH2 driven IgE production following 1 allergen exposure Secure Airway and give 100% O2  Re-exposure → biphasic inflammatory response  Intubate if respiratory obstruction

 Elevate the feet Early phase: w/i minutes  IgE cross-linking →mast cell degranulation  Vasoactive mediator release . Histamine Adrenaline 0.5mg IM . Tryptase  0.5ml of adrenaline 1:1000 Lipid mediator synthesis   Repeat every 5min if needed . Leukotrienes: ↑ vasc perm + → bronchial  Guided by cardiorespiratory function constriction . Prostacyclin  Chemokines: e.g. eotaxin . Promote leukocyte recruitment (esp. eosinophils) Secure IV Access Late Phase: 2-24hrs  Blood for mast cell tryptase  Eosinophils recruited in early phase.  IVI 0.9% NS may be needed  Release enzymes and stimulate mast cells.  E.g. 500ml over 15-30min  Amplify and sustain the initial response  Titrate against BP

Common Precipitants Chlorphenamine 10mg IV  Drugs: penicillin, contrast media +  Food: peanuts, eggs, fish, semen Hydrocortisone 200mg IV  Latex  Stings

Salbutamol Nebs if wheeze Presentation  5mg salbutamol + 0.5mg ipratropium  Sweating, d/v  Urticaria, itching, oedema  Wheeze, laryngeal obstruction, cyanosis Further Mx  Tachycardia, hypotension  Monitor closely for second deterioration.  Possible improvement and then deterioration as late

phase initiates. Discharge

 Teach adrenaline self-injection and ensure pt. has ≥2 0.3mg Epipens.  Advise wearing of medic alert bracelet  Advice re recognition and avoidance  Arrange OPD f/up

OPD f/up  Skin prick tests may help ID antigens  RAST may be preferable

Definition: Rate >100bmp, QRS width < 120ms Principles of Mx  If pt. compromised → sedate + DC cardioversion Differential  Otherwise ID rhythm and Rx accordingly 1. Sinus tachycardia . Key to ID irregular rhythm = AF = different Rx  Vagal manoeuvres (carotid sinus massage, valsalva) transiently ↑ 2. Atrial AV block and may unmask underlying atrial rhythm.  AF  If manoeuvres unsuccessful, give adenosine while recording  Atrial flutter rhythm strip  Atrial tachycardia . → transient AV block, unmasking atrial rhythm . → cardioverts AVNRT/AVRT to sinus rhythm 3. AV nodal re-entry tachycardia  If adenosine fails, choose from: 4. AV re-entry tachycardia . Digoxin . Atenolol . Verapamil (not if on β-blocker) . Amiodarone  If unsuccessful → DC cardioversion

Mx Flowchart

O2 + IV access

Regular rhythm? NO Treat as AF  Control rate ¯c β-B (e.g. metoprolol) or digoxin YES  If onset <48h consider cardioversion ¯c amiodarone (as below) or DC shock  Continuous ECG trace  Consider anticoagulation ¯c heparin and/or warfarin  Vagal manoeuvres  Adenosine 6mg IV bolus NB. Avoid adenosine, CCB, β-B in AF/Flutter with WPW or Hx of  Then 12mg, then 12mg WPW as may → VF. Use Amiodarone or flecainide.

YES Adverse Signs? Sedation  BP <90  HF  ↓ consciousness Synchronised cardioversion:  HR >200 100→200→360J

Choose from: Amiodarone:  Digoxin (500ug over 30min)  Amiodarone  300mg over 20-60min  Verapamil  Then 900mg over next 23h  Atenolol

Mx Flowchart

Pulse? CPR NO YES

O2 + IV access

YES Adverse Signs? Sedation  BP<90  HF  Chest pain  ↓ consciousness Synchronised cardioversion:  HR > 150 200→300→360

Correct Electrolyte Problems Amiodarone:  ↓K+: max 60mM KCL @ 20mmol/h  300mg over 20-60min 2+  ↓Mg : 4ml 50% MgSO4 in 30min  Then 900mg over next 23h

Assess Rhythm Regular (i.e. VT):  Amiodarone (see opposite)  Or lignocaine 50mg over 2min

If irregular, Dx is usually:  AF ¯c BBB  Pre-excited AF: flec / amio Recurrent / Paroxysmal VT  TDP: MgSO4 2g IV over 10 min Medical:  Amiodarone Failure  β-B

Synchronised Cardioversion ICD

12 lead ECG Primary Percutaneous Coronary Intervention  Rx of choice if <12h  Angioplasty and stenting  + GP IIb/IIIa antagonist (tirofiban) if high risk

O2 2-4L aim for SpO2 94-98% . Delayed PCI, DM, complex procedure

Complications:  Bleeding IV access  Emboli Bloods for FBC, U+E, glucose, lipids  Arrhythmia

Antiplatelet Contraindications: AGAINST  Aspirin 300mg PO (then 75mg/d)  Aortic dissection  Clopidogrel 300mg PO (then 75mg/d)  GI bleeding  Allergic reaction previously  Iatrogenic: major surgery <14d  Neuro: cerebral neoplasm or CVA Hx Analgesia  Severe HTN (200/120)  Morphine 5-10mg IV  Trauma, inc. CPR  Metoclopramide 10mg IV Agents: 1st: streptokinase, alteplase (rt-PA), tenecteplase

Complications: Anti-ischaemia  Bleeding  GTN 2 puffs or 1 tablet SL  Stroke  β-B atenolol 5mg IV (CI: asthma, LVF)  Arrhythmia  Allergic reaction

DVT Prophylaxis Pts. not receiving any form of reperfusion therapy should be given Enoxaparin 40mg SC OD fondaparinux.

Continuing Therapy: address risk factors Admit to CCU for monitoring  ACEi: start w/i 24hrs of MI (e.g. lisinopril 2.5mg)  Arrhythmias  β-blocker: e.g. bisoprolol 1.25mg OD (or, CCB)  Continue meds except CCBs  Cardiac rehabilitation (group exercise and info) / Heart Manual  DVT prophylaxis until fully mobile . Continue for 3mo if large anterior MI  Statin: regardless of basal lipids (e.g. atorvastatin 80mg) Primary PCI or Thrombolysis Advice  Stop smoking  Diet: oily fish, fruit, veg, ↓ sat fats  Exercise: 30min OD  Work: return in 2mo  Sex: avoid for 1mo  Driving :avoid for 1mo

NB. Continue clopidogrel for 1mo following STEMI Continue aspirin indefinitely.

12 lead ECG + Admit to CCU

O2 2-4L aim for SpO2 94-98%

IV access Bloods for FBC, U+E, glucose, lipids, Troponin

Brief Assessment  Hx of CVD and risk factors  CV exam

Antiplatelet  Aspirin 300mg PO (then 75mg/d)  Clopidogrel 300mg PO

Anti-coagulate  Fondaparinux 2.5mg SC

Analgesia  Morphine 5-10mg IV  Metoclopramide 10mg IV

Anti-ischaemia  GTN: 2 puffs or 1 tablet SL  β-B: atenolol 50mg/24h PO (CI: asthma, LVF)  IV GTN if pain continues

Assess Cardiovascular Risk: GRACE/TIMI

Continuing Therapy: address risk factors  ACEi (e.g. lisinopril 2.5mg)  β-blocker (e.g. bisoprolol 1.25mg OD) or,  CCB (diltiazem or verapamil)  Stop antithrombotic therapy when pain free (but give 3-5d)  Statin (e.g. atorvastatin 80mg)

Advice as above NB. Continue clopidogrel for 1yr following NSTEMI Continue aspirin indefinitely.

Sit pt. up Causes

Symptoms  Dyspnoea Diamorphine 2.5-5mg IV  Orthopnea + Metoclopramide 10mg IV  Pink frothy sputum

Frusemide 40-80mg IV Signs  Distressed, pale, sweaty, cyanosed  ↑HR, ↑RR  ↑JVP GTN 2 puffs or 2 x 300ug tabs SL  S3 / gallop rhythm Unless SBP <90mmHg  Bibasal creps  Pleural effusions  Wheeze (cardiac asthma) Hx, Ex, Ix  CXR: ABCDE  ECG: MI, arrhythmias, pulsus alternans Differential  Consider echo  Asthma/COPD  Pneumonia  PE If SBP >100mmHg, start nitrate IVI  ISMN 2-10mg/h IVI  Keep SBP >90 Monitoring Progress  BP  HR and RR If worsening, consider:  JVP  CPAP  Urine Output  More frusemide or ↑ nitrate infusion  ABG  Haemofiltration / dialysis

If SBP <100mmHg: Rx as cardiogenic shock  i.e. consider inotropes

Morphine in Pulmonary Oedema  Make pt. more comfortable  Pulm venodilators → ↓ pre-load → optimise position on Starling Curve

O2 Definition  15L/min via reservoir mask  Inadequate tissue perfusion primarily due to  Target SpO2: 94-98% cardiac dysfunction.

Causes: MI HEART: IV access + monitor ECG  MI  Bloods for FBC, U+E, troponin, ABG  Hyperkalaemia (inc. electrolytes)  Endocarditis (valve destruction)  Aortic Dissection Diamorphine 2.5-5mg IV (pain/anxiety)  Rhythm disturbance + metoclopramide 10mg IV  Tamponade

Monitoring  CVP, BP, ABG, ECG, urine output.

Consider need for dobutamine

Rx underlying cause

Tamponade

Mx:  ABCs  Pericardiocentesis (preferably under echo guidance)

© Alasdair Scott, 2012 254 Meningitis Features Abx Therapy Meningitic  Community: benpen 1.2g IV/IM  Headache  <50: ceftriaxone 2g IVI/IM BD  Neck stiffness  >50: ceftriaxone + ampicillin 2g IVI /4h O . Kernig’s: Straightening leg ¯c hip @ 90  If viral suspected: aciclovir . Brudzinski’s: lifting head → lifting of legs  Photophobia Organisms  n/v  Viruses: enteroviruses (Coxsackie, echovirus), HSV2  Meningococcus Neurological  Pneumococcus  ↓ GCS → coma  Listeria  Seizures (20%)  Haemophilus  Focal neuro (20%): e.g. CN palsies  TB

 Cryptococcus Septic

 Fever  ↓BP, ↑HR Ix  ↑CRT  Bloods: FBC, U+Es, clotting, glucose, ABG  Purpuric rash  Blood cultures  DIC  LP: MCS, glucose, virology/PCR, lactate

Acute Management

ABC  O2 15L – SpO2 94-98%  IVI fluid resus ¯c crystalloid

Presentation Pre-disposing Factors  Infectious prodrome: fever, rash, LNs, cold sores,  Infection: ear, sinus, dental or periodontal conjunctivitis, meningeal signs.  Skull #  Bizarre behaviour or personality change  Congenital heart disease  Confusion  Endocarditis  ↓ GCS → coma  Bronchiectasis  Fever  Immunosuppression  Headache  Focal neuro Organisms  Seizures  Frontal sinus/teeth – strep. Milleri, oropharyngeal  Hx of travel or animal bite anaerobes  Ear – Bacteroides, other anaerobes Causes Signs Usually viral  Seizures  HSV1/2  Fever  CMV, EBV, VZV  Localizing signs  Arboviruses  Signs of ↑ ICP  HIV  Signs of infection elsewhere

Non-viral Ix  Any bacterial meningitis  CT/MRI – ring-enhancing lesion  TB  ↑WCC, ↑ESR  Malaria  Lyme disease Rx

 Neurosurgical referral Ix  Abx – e.g. ceftriaxone  Bloods: cultures, viral PCR, malaria film  Treat ↑ ICP  Contrast CT: focal bilat temporal involvement suggests HSV  LP: ↑ CSF protein, lymphocytes, PCR  EEG: shows diffuse abnormalities, may confirm Dx

Mx  Aciclovir STAT: 10mg/kg/8h IVI over 1h for 14/7  Supportive measures in HDU/ITU  Phenytoin for seizures

Prognosis  70% mortality if untreated

w/o fever, consider encephalopathy  ↓ glucose  Hepatic  DKA  Drugs  SLE  Uraemia  Hypoxic brain injury  Beri-Beri

Definition Drugs  Seizure lasting >30min, or  Repeated seizures w/o intervening consciousness Lorazepam  2-4mg IV bolus over 30s nd Ix  2 dose if no response w/i 2min  BM  Alternatives: 2+ . Diazepam 10mg IV/PR (20mg max)  Bloods: glucose, ABG, U+E, FBC, Ca . Midazolam 10mg buccal  ECG, EEG

 Consider: AED levels, tox screen, LP, βhCG, CT Phenytoin

 18mg/kg IVI @ 50mg/min  100mg/6-8h maintenance  Monitor ECG and BP  CI: bradycardia or heart block

Diazepam Infusion  100mg in 500ml 5% dex @ 40ml/hr (3mg/kg/24h)

Dexamethasone  10mg IV if vasculitis / cerebral oedema (tumour) possible

Acute Management

ABC  Oral / nasal airway, intubate  Suction  100% O2  Capillary blood glucose

IV Access + Bloods  U+E, LFT, FBC, Glucose, Ca2+  AED levels  Tox screen

Reverse Potential Causes  Thiamine 250mg IV if EtOH  100ml 20% glucose unless glucose known to be normal

Slow IV Bolus Phase  Lorazepam 2-4mg IV  2nd dose if no response w/i 2min

IV Infusion Phase  Phenytoin 18mg/kg IVI (then 100mg/6-8h)  Or, diazepam 100mg in 500ml 5% dex IVI

RSI Phase Never spend >20min ¯c someone in status w/o getting an anaesthetist

Initial Mx Intubate  GCS ≤ 8 O 1 Survey  PaO2 <9KPa on air / <13KPa on O2 or PCO2 >6KPa  A: ? intubation, immobilise C-spine  Spontaneous hyperventilation: PCO2 <4KPa  B: 100% O2, RR  Respiratory irregularity  C: IV access, BP, HR  D: GCS, pupils CT head guidelines: BANGS LOC  Treat seizures  Break: open, depressed or base of skull . Lorazepam 2-4mg IV  Amnesia > 30min retrograde . Phenytoin18mg/kg IVI then 100mg/6-8h  Neuro deficit or seizure  E: expose pt. and look for other obvious injuries  GCS: <13 @ any time or <15 2h after injury  Sickness: vomited > once O Survey 2  LOC or any amnesia and any of:  Look for: . Dangerous mechanism: RTA, great height . Lacerations . Age ≥ 65 . Obvious facial/skull deformity . Coagulopathy (inc. warfarin) . CSF leak from nose or ears . Battle’s sign, Racoon eyes . Blood behind TM Risk of Intracranial Haematoma in Adults: . C-spine tenderness ± deformity  Fully conscious, no skull # = <1:1000  Head-to-toe examination for other injuries  Confused, no skull # = 1:100  Log role  Fully conscious, skull # = 1:30  Confused, skull # = 1:4 Hx if possible  How and when? GCS  GCS and other vitals immediately after injury  Headache, fits, vomiting, amnesia, EtOH Eyes: 4 4 – Spontaneous eye opening Ix 3 – Open to voice  Bloods: FBC, U+E, glucose, clotting, EtOH level, ABG 2 – Open to pain  ? CT head + c-spine 1 – No opening

Types of Cerebral Oedema 1. Vasogenic (↑ cap permeability): trauma, tumour, ischaemia, infection 2. Cytotoxic: e.g. from hypoxia 3. Interstitial: e.g. obstructive hydrocephalus, ↓Na+

Causes Acute Management  Haemorrhage ABC  Tumours  Infection: meningitis, encephalitis, abscess  Hydrocephalus  Status Treat seizures and correct hypotension  Cerebral oedema

Signs and Symptoms Elevate bed to 40O  Headache  n/v  Seizures Neuroprotective Ventilation  Drowsiness → coma  PaO2: >13kPa (100mmHg)  Cushing’s reflex: ↑BP, ↓HR, irregular breathing th  PCO2: 4.5kPa  6 CN palsy (may be false localising)  Good sedation ± NM blockade  Cheyne-Stokes respiration  Pupils – constriction → dilatation  Papilloedema, loss of venous pulsation @ disc Mannitol or Hypertonic Saline  ↓ICP short-term, but may → rebound ↑ICP later  Mannitol 1g/kg (20% @ 5ml/kg)

Herniation Syndromes

Transtentorial / uncal  Lateral supratentorial mass → compression of ipsilateral inferomedial temporal lobe (uncus) against free margin of tentorium cerebelli.  Ipsilateral CN3 palsy: mydriasis (dilation) then down-and-out  Contralateral hemiparesis  Compression of contralateral corticospinal tracts → ipsilateral hemiparesis (Kernohan’s Notch)

Presentation Mx  Acute breathlessness and wheeze

If Improving Assessment  Monitor: SpO @ 92-94%, PEFR 2  Continue pred 50mg OD for 5 days Severe  Nebulised salbutamol every 4hrs  PEFR <50%  RR >25  HR >110  Can’t complete sentence in one breath IV Rx if No Improvement in 15-30min:  Nebulised salbutamol every 15min (monitor ECG) Life Threatening  Continue ipratropium 0.5mg 4-6hrly  PEFR <33%  MgSO4 2g IVI over 20min  SpO2 <92%, PCO2 >4.6kPa, PaO2 <8kPa  Salbutamol IVI 3-20ug/min  Cyanosis  Consider Aminophylline  Hypotension . Load: 5mg/kg IVI over 20min  Exhaustion, confusion  Unless already on theophylline  Silent chest, poor respiratory effort . Continue: 0.5mg/kg/hr  Tachy-/brady-/arrhythmias . Monitor levels  ITU transfer for invasive ventilation Differential  Acute exacerbation of COPD  Pneumothorax  Pulmonary oedema Monitoring  PEFR every 15-30min Admission Criteria . Pre- and post-β agonist  SpO : keep >92%  Life-threatening attack 2  ABG if initial PaCO normal or ↑  Feature of severe attack persisting despite initial Rx 2  May discharge if PEFR > 75% 1h after initial Rx

Discharge When  Been stable on discharge meds for 24h  PEFR > 75% ¯c diurnal variability < 25%

Discharge Plan  TAME pt.  PO steroids for 5d  GP appointment w/i 1 wk.  Resp clinic appointment w/i 1mo

Causes  Viral URTI (30%) Management  Also bacterial infections

Controlled O2 Therapy Presentation  Sit-up  Cough + sputum  24% O2 via Venturi mask: Target SpO2 88-92%,  Breathlessness  Vary FiO2 and SpO2 target according to ABG  Wheeze  Aim for PaO2 >8 and ↑ in PCO2 of <1.5kPa

Hx  Smoking status  Exercise capacity Nebulised Bronchodilators  Current treatment  Air driven ¯c nasal specs  Previous exacerbations  Salbutamol 5mg/4h  Ipratropium 0.5mg/6h Ix  PEFR  Bloods: FBC, U+E, ABG, CRP, cultures  Sputum culture Steroids (IV and PO)  CXR: infection, pneumothorax  Hydrocortisone 200mg IV  ECG  Prednisolone 40mg PO for 7-14d

Differential  Pneumothorax Abx  Pulmonary oedema  If evidence of infection  PE  Doxy 200mg PO STAT then 100mg OD PO for 5d  Asthma

Discharge NIV if no response:  Spirometry  Repeat nebs and consider aminophylline IV  Establish optimal maintenance therapy  Consider NIV (BiPAP) if pH<7.35 and/or RR >30  GP and specialist f/up  Consider invasive ventilation if pH<7.26  Prevention using home oral steroids and Abx . Depends on pre-morbid state: exercise capacity,  Pneumococcal and Flu vaccine home O2, comorbidity  Home assessment

Causes Mx  Usually arise from DVTs in proximal leg or iliac veins  Rarely: O . Right ventricle post MI 2  Sit-up . Septic emboli in right sided endocarditis  100% O2 via non-rebreather mask Risk Factors: SPASMODICAL  Sex: F  Pregnancy Analgesia  Age: ↑  Morphine ± metoclopramide if distressed  Surgery (classically 10d post-op straining at stool)  Malignancy  Oestrogen: OCP/HRT If critically ill c¯ massive PE consider thrombolysis  DVT/PE previous Hx Alteplase 50mg bolus stat  Immobility   Colossal size  (Surgical or interventional embolectomy)  Antiphospholipid Abs  Lupus Anti-coagulant LMWH Heparin Presentation e.g. enoxaparin 1.5mg/kg/24h SC  Symptoms and signs depend on size, number and distribution of emboli

Symptoms SBP?  Dyspnoea  Pleuritic pain  Haemoptysis <90 >90  Syncope  500ml colloid  Start Warfarin

NB. –ve D-dimer has 95% NPV for PE

Prevention  Risk assessment for all pts  TEDS  Prophylactic LMWH  Avoid OCP/HRT if @ risk

Definition Mx  Accumulation of air in the pleural space ¯c 2O lung collapse. Tension PTX

 Resuscitate pt. Classification  No CXR  Closed: intact chest wall and air leaks from lung into  Large bore Venflon into 2nd ICS, mid-clavicular line pleural cavity.  Insert ICD  Open: defect in the chest wall allows communication between PTX and exterior: may be sucking.  Tension: air enters pleural cavity through one-way Traumatic valve and cannot escape → mediastinal compression.  Resuscitate pt.  Analgesia: e.g. morphine Causes  3-sided wet dressing if sucking Spontaneous  Insert ICD  1O: no underlying lung disease . Young, thin men (ruptured subpleural bulla) . Smokers O O 1 PTX  2 : underlying lung disease . COPD SOB and/or rim ≥2cm? No Consider d/c . Marfan’s, Ehler’s Danlos Yes . Pulmonary fibrosis, sarcoidosis Yes

Trauma Aspiration successful?  Penetrating  Blunt ± rib #s No

Hx Management  Previous bleeds  Dyspepsia, known ulcers Resuscitate  Liver disease or oesophageal varices  Head-down.  Dysphagia, wt. loss  100% O2, protect airway  Drugs and EtOH  2 x 14G cannulae + IV crystalloid infusion up to 1L.  Co-morbidities  Bloods: FBC, U+E (↑ urea), LFTs, clotting, x-match 6u, ABG, glucose o/e  Signs of CLD  PR:melaena Blood if remains shocked  Shock?  Group specific or O- until X-matched . Cool, clammy, CRT>2s . ↓BP (<100) or postural hypotension (>20 drop) . ↓ urine output (<30ml/h) . Tachycardia Variceal Bleed . ↓GCS  Terlipressin IV (splanchnic vasopressor)  Prophylactic Abx: e.g. ciprofloxacin 1g/24h Common Causes  PUD: 40% (DU commonly)  Acute erosions / gastritis:20% Maintenance  Mallory-Weiss tear: 10%  Crystalloid IVI, transfuse if necessary (keep Hb≥10) Varices: 5%   Catheter + consider CVP (aim for >5cm H2O)  Oesophagitis: 5%  Correct coagulopathy: vit K, FFP, platelets  Ca Stomach / oesophagus:<3%  Thiamine if EtOH  Notify surgeons of severe bleeds Rockall Score: (Prof T Rockall, St. Mary’s)  Prediction of re-bleeding and mortality  40% of re-bleeders die Urgent Endoscopy  Initial score pre-endoscopy Haemostasis of vessel or ulcer: . Age  Adrenaline injection . Shock: BP, pulse . Comorbidities  Thermal / laser coagulation  Final score post-endoscopy  Fibrin glue . Final Dx + evidence of recent haemorrhage  Endoclips  Active bleeding Variceal bleeding:  Visible vessel  2 of: banding, sclerotherapy, adrenaline,  Adherent clot coagulation  Initial score ≥3 or final >6 are indications for surgery  Balloon tamponade c Sengstaken-Blakemore tube ¯ . Only used if exsanguinating haemorrhage or Oesophageal Varices failure of endoscopic therapy  Portal HTN → dilated veins @ sites of porto-systemic  TIPSS if bleeding can’t be stopped endoscopically anastomosis: L. gastric and inferior oesophageal veins  30-50% ¯c portal HTN will bleed from varices  Overall mortality 25%: ↑ ¯c severity of liver disease. After endoscopy Causes of portal HTN  Omeprazole IV + continuation PO (↓s re-bleeding)  Pre-hepatic: portal vein thrombosis  Keep NBM for 24h → clear fluids → light diet @ 48h  Hepatic: cirrhosis (80% in UK), schisto (commonest  Daily bloods: FBC, U+E, LFT, clotting worldwide), sarcoidosis.  H. pylori testing and eradication  Post-hepatic: Budd-Chiari, RHF, constrict pericarditis  Stop NSAIDs, steroids et.c.

Bleed Prevention  1O: β-B, repeat endoscopic banding O Indications for Surgery  2 : β-B, repeat banding, TIPSS  Re-bleeding  Bleeding despite transfusing 6u Transjuglar Intrahepatic Porto-Systemic Shunt (TIPSS)  Uncontrollable bleeding at endoscopy  IR creates artificial channel between hepatic vein and  Initial Rockall score ≥3, or final >6. portal vein → ↓ portal pressure. Open stomach, find bleeder and underrun vessel.  Colapinto needle creates tract through liver parenchyma which is expand using a balloon and maintained by placement of a stent. NB. Avoid 0.9% NS in uncompensated liver disease (worsens  Used prophylactically or acutely if endoscopic therapy ascites). Use blood or albumin for resus and 5% dex for fails to control variceal bleeding. maintenance. © Alasdair Scott, 2012 264 Acute Renal Failure

Rx Life-Threatening Complications Ix  Hyperkalaemia  Bloods: FBC, U+E, LFT, glucose, clotting, Ca, ESR  Pulmonary oedema  ABG: hypoxia (oedema), acidosis, ↑K+  Consider need for rapid dialysis  GN screen: if cause unclear  Urine: dip, MCS, chemistry (U+E, CRP, osmolality, BJP) Rx Shock or Dehydration  ECG: hyperkalaemia  Fluid challenge 250-500ml over 30min  CXR: pulmonary oedema  Repeat as necessary: aim for CVP of 5-10cm  Renal US: Renal size, hydronephrosis  Once replete, continue @ 20ml+UO/h

Hyperkalaemia  ECG Features (in order) Monitor . Peaked T waves  Cardiac monitor . Flattened P waves  Urinary catheter . ↑ PR interval  Consider CVP . Widened QRS  Start fluid balance chart . Sine-wave pattern → VF  Mx . 10ml 10% calcium gluconate . 50ml 50% glucose + 10u insulin (Actrapid) Look for Evidence of Post-Renal Causes . Salbutamol 5mg nebulizer  Palpable ± tender bladder . Calcium resonium 15g PO or 30g PR  Enlarged prostate . Haemofiltration (usually needed if anuric)  Catheter in situ  Complete anuria

Pulmonary Oedema  Sit up and give high-flow O2  Morphine 2.5mg IV (± metoclopramide 10mg IV) Hx and Ix Hx: Evidence of Acute vs. Chronic RF  Frusemide 120-250mg IV over 1h  Duration of symptoms  GTN spray ± ISMN IVI (unless SBP <90)  Co-morbidities  If no response consider: . CPAP  Previous blood results . Haemofiltration / haemodialysis ± venesection Ix  Bloods, ABG Indications for Acute Dialysis (AEIOU)  Urine dip + MCS + chem 1. Persistent hyperkalaemia (>7mM)  ECG 2. Refractory pulmonary oedema  CXR and Renal US 3. Symptomatic uraemia: encephalopathy, pericarditis 4. Severe metabolic acidosis (pH <7.2) 5. Poisoning (e.g. aspirin) Rx Sepsis  Blood cultures and empirical Abx

Further Mx  Call urologists if obstructed despite catheter  Care with nephrotoxic drugs: e.g. gentamicin

Drug Features Mx Benzodiazepines ↓ GCS Flumazenil Respiratory depression β-Blockers Severe bradycardia or hypotension Atropine Cyanide Inhibits the cytochrome system Dicobalt edentate Almond smell Phase 1: Anxiety ± confusion Phase 2: ↓/↑ pulse Phase 3: Fits, coma Carbon monoxide Headache, dizziness, nausea Hyperbaric O2 Hypoxaemia (SpO2 may be normal) Metabolic acidosis Digoxin ↓ GCS Anti-digoxin antibodies Yellow-green visual halos Arrhythmias Ethanol ↓ GCS Respiratory depression Ethylene glycol ↑ AG metabolic acidosis with ↑ OG Ethanol Intoxication with no visual disturbance Haemodialysis Found in antifreeze Heparin Bleeding Protamine Iron Nausea, vomiting, abdo pain Desferrioxamine Lithium n/v Saline Ataxia, coarse tremor Confusion Polyuria and renal failure Methanol ↑ AG metabolic acidosis with ↑ OG Ethanol Intoxication with visual disturbance Haemodialysis Opiates Respiratory depression Naloxone ↓GCS Pin-point pupils Organophosphates SLUDGEM Atropine + Pralidoxime e.g. malathion Tricyclics ↑ QTc → Torsade de pointes Activated charcoal Metabolic acidosis NaHCO3 IV Anticholinergic effects Warfarin Major bleed Vit K IV Prothrombin complex or (FFP)

Aspirin Paracetamol

Effects Effects  Respiratory stimulant → respiratory alkalosis  Normal metabolism overloaded and paracetamol  Uncouples oxidative phosphorylation → met acidosis converted to highly toxic NAPQI by CyP450.  NAPQI can be detoxified by glutathione conjugation Presentation . Overwhelmed in OD  Vomiting and dehydration  Hyperventilation Presentation  Tinnitus, vertigo  Vomiting, RUQ pain  Hyper- or hypo-glycaemia  Jaundice and encephalopathy ± liver failure  Respiratory alkalosis initially then lactic acidosis  Cerebral oedema → ↑ ICP . Mixed picture usually . ↓HR, decerebrate posture, poor pupil responses

Mx Mx  Activated charcoal if <1h since ingestion  Activated charcoal if <1h since ingestion  Bloods  Bloods . Paracetamol and salicylate levels . Paracetamol level 4h post ingestion . Glucose, U+E, LFTs, INR, ABG . Glucose, U+E, LFTs, INR, ABG  Alkalinise urine: NaHCO3 ± KCl  NAC: if levels above treatment line on graph  Haemodialysis may be needed

Pathogenesis Management Ketogenesis  ↓ insulin → ↑ stress hormones and ↑ glucagon Fluids  → ↓ glucose utilisation + ↑ fat β-oxidation  0.9% NS infusion via large bore cannula  ↑ fatty acids → ↑ ATP + generation of ketone bodies. . SBP<90 → 1L stat + more until SBP >90 . SBP>90 → 1L over 1h Dehydration  Then: 1L over next 2h, 1L/2h, 1L/4h, 1L/4h, 1L/6h  ↓ insulin → ↓ glucose utilisation + ↑ gluconeogenesis →  Add 10% dextrose 1L/8h when glucose <14mM severe hyperglycaemia  → osmotic diuresis → dehydration Start Potassium Replacement in 2nd Bag of Fluids  Also, ↑ ketones → vomiting  >5.5mM → Nil  3.5-5.5mM → 40mM/L Acidosis  <3.5mM → consult senior for review  Dehydration → renal perfusion  Hyperkalaemia

Insulin Infusion Precipitants  0.1u/kg/h Actrapid (6u if no wt., max 15u)  Infection / stress ± stopping insulin  New T1DM

The Patient Symptoms  Usually T2DM, often new presentation  Usually older Autonomic Neuroglycopenic  Long hx (e.g. 1wk)  Sweating  Confusion  Anxiety  Drowsiness Metabolic Derangement  Hunger  Seizures  Marked dehydration and glucose >35mM  Tremor  Coma  No acidosis (no ketogenesis)  Palpitations  Personality change  Osmolality >340mosmol/kg

Complications Cause  Occlusive events are common: DVT, stroke  Usually Exogenous: insulin, gliclazide . Give LMWH  Pituitary insufficiency  Liver failure Mx  Addison’s  Rehydrate ¯c 0.9% NS over 48h  Insulinomas . May need ~9L  Wait 1h before starting insulin . It may not be needed Mx . Start low to avoid rapid changes in osmolality  E.g. 1-3u/hr Alert and Orientated: Oral Carb  Look for precipitant  Rapid acting: lucozade . MI  Long acting: toast, sandwich . Infection . Bowel infarct Drowsy / confused but swallow intact: Buccal Carb  LMWH  Hypostop / Glucogel  Consider IV access

Unconscious or Concerned re Swallow: IV dextrose  50ml 50% or 100ml 20% glucose

Deteriorating / refractory / insulin-induced / no access  1mg glucagon IM/SC  Won’t work in drunks + short duration of effect (20min)  Insulin release may → rebound hypoglycaemia

Presentation Presentation  ↑ temp  Looks hypothyroid  Agitation, confusion, coma  Hypothermia  Tachycardia, AF  Hypoglycaemia  Acute abdomen  Heart failure: bradycardia and ↓BP  Heart failure  Coma and seizures

Precipitants Precipitants  Recent thyroid surgery or radio-iodine  Radioiodine  Infection  Thyroidectomy  MI  Pituitary surgery  Trauma  Infection, trauma, MI, stroke

Mx Mx 1. Fluid resuscitation + NGT  Bloods: TFTs, FBC, U+E, glucose, cortisol 2. Bloods: TFTs + cultures if infection suspected  Correct any hypoglycaemia 3. Propranolol PO/IV  T3/T4 IV slowly (may ppt. myocardial ischaemia) 4. Digoxin may be needed  Hydrocortisone 100mg IV 5. Carbimazole then Lugol’s Iodine 4h later to inhibit  Rx hypothermia and heart failure thyroid 6. Hydrocortisone 7. Rx cause

Presentation Cause  Shocked: ↑HR, postural drop, oliguria, confused  Phaeochromocytoma  Hypoglycaemia  Usually known Addisonian or chronic steroid user Presentation  Pallor Precipitants  Pulsating headache  Infection  Feeling of impending doom  Trauma  ↑↑BP  Surgery  ↑ ST and cardiogenic shock  Stopping long-term steroids Precipitants Mx  Stress  Bloods: cortisol, ACTH, U+E  Abdominal palpation  Check CBG: glucose may be needed  General anaesthetic  Hydrocortisone 100mg IV 6hrly  Parturition  IV crystalloid  Contrast media  Septic screen  Treat underlying cause Rx  Phentolamine 2-5mg IV (α-blocker) or labetalol 50mg IV . Repeat to safe BP (e.g. 110 diastolic)  Phenoxybenzamine 10mg/d PO when BP controlled  May now give β-B to control tachycardia / arrhythmias  Elective surgery after 4-6wks to allow full α-blockade and volume expansion

NB. Never give β-B alone first

Risk Factors Mx  Age: children and elderly  Based on ATLS principals  Co-morbidities: epilepsy, CVA, dementia, mental illness  Specific concerns ¯c burns  Occupation . Secure airway . Manage fluid loss Classification . Prevent infection

Superficial Airway  Erythema  Examine for respiratory burns  Painful . Soot in oral or nasal cavity  E.g. sunburn . Burnt nasal hairs . Hoarse voice, stridor Partial Thickness  Flexible laryngoscopy can be helpful  Heal w/i 2-3wks if not complicated  Consider early intubation + dexamethasone (↓ inflam)  Superficial . No loss of dermis Breathing . Painful  100% O2 . Blisters  Exclude constricting burns  Deep  Signs of CO poisoning . Loss of dermis but adnexae remain . Headache . Healing from adnexae: e.g. follicles . n/v . V. painful . Confusion . Cherry red appearance Full Thickness  ABG  Complete loss of dermis . COHb level  Charred, waxy, white, skin . SpO2 unreliable if CO poisoning  Anaesthetic  Heal from the edges → scar Circulation  Fluid losses may be huge  2x large-bore cannulae in each ACF Complications  Bloods: FBC, U+E, G+S/XM  Start 2L warmed Hartmann’s immediately

Early st Parkland Formula to guide replacement in 1 24hrs  Infection: loss of barrier function, necrotic tissue, SIRS,  4 x wt. (kg) x % burn = mL of Hartmann’s in 24h hospital  Replace fluid from time of burn  Hypovolaemia: loss of fluid in skin + ↑ cap permeability  Give half in 1st 8h  Metabolic disturbance: ↑↑K, ↑↑myoglobin, ↑Hb → AKI  Best guide is UO: 30-50mL/h  Compartment syndrome: circumferential burns

 Peptic ulcers: Curling’s ulcers Muir and Barclay Formula to guide fluid replacement  Pulmonary: CO poisoning, ARDS  (wt. x % burn)/2 = mL of Colloid per unit time

 Time units: 4, 4, 4, 6, 6, 12 = 36hrs total Intermediate  May need to use blood  VTE

 Pressure sores Burn Treatments

 Analgesia: morphine Late  Dress partial thickness burns  Scarring . Biological: e.g. cadaveric skin  Contractures . Synthetic  Psychological problems . Cream: e.g. Flamazine (silver sulfadiazine) + sterile film.  Full thickness burns Assessment . Tangential excision debridement . Split-thickness skin grafts Wallace rule of 9s: % BSA burnt  Circumferential burns may require escharotomy to  Head and neck: 9% prevent compartment syndrome.  Arms: 9% each  Anti-tetanus toxoid (o.5ml ATT)  Torso: 18% front and back  Consider prophylactic Abx: esp. anti-pseudommonal  Legs: 18% each  Perineum: 1%  (Palm: 1%)

NB. may also use Lund and Browder charts

Definition Ix  Core (rectal) temperature <35OC  Rectal / ear temperature  FBC, U+E, glucose  TFTs, blood gas Pathophysiology  ECG  Body heat is lost via 4 mechanisms . J waves: between QRS and T wave . Arrhythmias 1. Radiation: 60%  Infra-red emissions Mx  Cardiac monitor 2. Conduction: 15%  Warm IVI 0.9% NS  Direct contact  Urinary catheter  1O means in cold water immersion  Consider Abx for prevention of pneumonia . Routine if temp <32 and >65yrs 3. Convection: 15%  Removes warmed air from around the body Slowly Rewarm  ↑d in windy environments  Reheating too quickly → peripheral vasodilatation and shock. 4. Evaporation: 10%  Aim for 0.5OC /hr  Removal of warmed water  Passive external: blankets, warm drinks  ↑ in dry, windy environments  Active external: warm water or warmed air  Active internal: mediastinal lavage and CPB . Severe hypothermia only Aetiological Classification  Primary: environmental exposure  Secondary: change in temperature set-point Complications . E.g.: age-related, hypothyroidism, autonomic  Arrhythmias neuropathy  Pneumonia  Coagulopathy Presentation  Acute renal failure

Mild: 32.2 – 35OC  Shivering  Tachycardia  Vasoconstriction  Apathy

Moderate: 28 – 32.2OC  Dysrhythmia, bradycardia, hypotension  J waves  ↓ reflexes, dilated pupils, ↓ GCS

Severe: <28OC  VT → VF → Cardiogenic shock  Apnoea  Non-reactive pupils  Coagulopathy  Oliguria  Pulmonary oedema

Adult Advanced Life Support

Unresponsive? Not breathing or only occasional gasps

Call resuscitation team

CPR 30:2 Attach de brillator / monitor Minimise interruptions

Assess rhythm

Shockable Non-Shockable (VF / Pulseless VT) (PEA / Asystole)

1 Shock Return of 150J Biphasic spontaneous 360J Monophasic circulation

Immediately resume Immediate post cardiac Immediately resume CPR for 2 min arrest treatment CPR for 2 min Use ABCDE approach Adrenaline 1mg Controlled oxygenation and Adrenaline 1mg as soon + amiodarone 300mg ventilation as IV access obtained after 3rd shock 12-lead ECG Treat precipitating cause Repeat adrenaline every Repeat adrenaline every Temperature control / other cycle therapeutic hypothermia other cycle

During CPR Reversible Causes Ensure high-quality CPR: 100/min, 4cm deep Hypoxia Plan actions before interrupting CPR Hypovolaemia

Give oxygen Hypo- / hyperkalaemia / metabolic Consider advanced airway and capnography Hypothermia Continuous chest compressions when advanced airway in place Thrombosis - coronary or pulmonary Vascular access (intravenous, intraosseous) Tamponade - cardiac Give adrenaline every 3-5 min Toxins Correct reversible causes Tension pneumothorax

 Assess using the ABCDE approach Adult tachycardia (with pulse)  Give oxygen if appropriate and obtain IV access algorithm  Monitor ECG, BP, SpO2 , record 12-lead ECG  Identify and treat reversible causes (e.g. electrolyte abnormalities)

Adverse features? Synchronised DC Shock Yes / Unstable  Shock Up to 3 attempts  Syncope  Myocardial ischaemia  Heart failure  Amiodarone 300 mg IV over 10-20 min

and repeat shock; followed by: No / Stable  Amiodarone 900 mg over 24 h Broad Is QRS narrow (< 0.12 s)? Narrow

Irregular Broad QRS Regular Regular Narrow QRS Irregular Is rhythm regular? Is rhythm regular?

 Use vagal manoeuvres Irregular Narrow Complex  Adenosine 6 mg rapid IV bolus; Tachycardia if unsuccessful give 12 mg; Probable atrial fibrillation Seek expert help if unsuccessful give further 12 mg.  Monitor ECG continuously Control rate with: !  -Blocker or diltiazem  Consider digoxin or amiodarone Sinus rhythm restored? if evidence of heart failure Possibilities include: If ventricular tachycardia Yes No AF with bundle branch block (or uncertain rhythm): treat as for narrow complex  Amiodarone 300 mg IV Seek expert help over 20-60 min; Pre-excited AF then 900 mg over 24 h Probable re-entry paroxysmal SVT: ! consider amiodarone  Record 12-lead ECG in sinus Polymorphic VT If previously confirmed rhythm (e.g. torsade de pointes - SVT with bundle branch block:  If recurs, give adenosine again & give magnesium 2 g over 10 min)  Give adenosine as for regular consider choice of anti-arrhythmic Possible atrial flutter narrow complex tachycardia prophylaxis  Control rate (e.g. -Blocker)

Adult bradycardia algorithm

 Assess using the ABCDE approach  Give oxygen if appropriate and obtain IV access  Monitor ECG, BP, SpO2, record 12-lead ECG  Identify and treat reversible causes (e.g. electrolyte abnormalities)

Adverse features? YES  Shock NO  Syncope  Myocardial ischaemia  Heart failure

Atropine 500 mcg IV

Satisfactory YES response? NO

Interim measures: Risk of asystole? Atropine 500 mcg IV Recent asystole repeat to maximum of 3 mg Mobitz II AV block -1 YES Isoprenaline 5 mcg min IV Complete heart block Adrenaline 2-10 mcg min-1 IV with broad QRS Alternative drugs * Ventricular pause > 3 s OR NO Transcutaneous pacing

Seek expert help ! Observe Arrange transvenous pacing

* Alternatives include:  Aminophylline  Dopamine  Glucagon (if beta-blocker or calcium channel blocker overdose)  Glycopyrrolate can be used instead of atropine