Medicine

Cardiology •

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Tricuspid regurgitation - Pulsatile Hepatomegaly - +ve abdominojugular reflux sign - Large systolic v wave with earlobe movement - PSM the left lower sternal border Pulmonary stenosis - Left parasternal heave - Large a wave - Soft wide splitting P2 - ESM in left upper sternal border, 2nd ICS Pulmonary Hypertension - Large a wave - Loud P2 Pulmonary Embolism - Sinus tachycardia (>100bpm) - RAD - V1-V3 T inversion (RVH) - SIQIIITIII - Deep SI, Pathological QIII, Inverted TIII - Low voltage QRS (<5mm) Mitral stenosis - Tapping apex beat (Palpable S1 ) - Mid-Diastolic murmur at the apex accentuated in the left lateral position best heard with the bell (low pitch murmur) - CXR findings; i) LAE manifested by a density behind the right atrial border (double atrial shadow) ii) Elevation of the left main stem bronchus iii) Pulmonary oedema - Redistribution of blood flow to the upper lung fields is frequent, and Kerley Blines (short peripheral lines, perpendicular to the pleura); Kerley A-lines (long, dense lines radiating from the hilum) are seen in patients with severe, chronic mitral stenosis. iv) Mitral valve calcification - Significant stenosis exists if the valve orifice is <1cm²/m² body surface area Mitral regurgitation - Heaving apex beat - PSM at the apex radiating to the left axilla if the posterior valve is involved or towards the tricuspid area if the anterior valve is involved. - Soft S1; Wide splitting S2; Loud S3 Aortic stenosis - Small volume anacrotic (slow rising) pulse/ Pulsus alternans - Narrow pulse pressure - Thrusting apex beat - Soft A2; Reversed splitting of P2 - ESM at the right upper sternal border, 2nd ICS, radiating to the carotids Aortic regurgitation - Quincke's sign - marked capillary pulsation in the nail bed - Collapsing pulse - Wide pulse pressure - Heaving apex beat - EDM in the right upper sternal edge, 2nd ICS, when patient is seated; leaning forwards accentuates the murmur on expiration

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PDA The aortic end of the ductus is just distal to the origin of the left subclavian artery, and the ductus enters the pulmonary artery at its bifurcation. Commonly associated with maternal rubella infection during early pregnancy and preterms as a result of hypoxia and immaturity. Closes in the 1st weeks of life failure to which there is ↑ blood flow to the lungs → pulmonary plethora & congestion → fibrosis of the vessels with narrowing & reduced blood flow to the lungs leading to cyanosis. C/P: - Persistent apnoea for unexplained reasons in an infant recovering from Hyaline Membrane Disease; - CVS * Collapsing pulse * 'Pistol shot' pulse in the femorals (Traube's Sign) * Wide pulse pressures * Reversed splitting of P2 * An active heaving praecordium, a continuous systolic or to-and-fro murmur that may be localized to the 2nd left ICS or radiate down the left sternal border or to the left clavicle - Carbon dioxide retention - Cyanosis - Increasing oxygen dependency - Hepatomegaly CXR - Cardiomegaly and increased pulmonary vascular markings Echocardiographic visualization of a PDA with Doppler flow evidence of left-to-right shunting. Rx: - Supportive measures, including diuretics and fluid restriction. - If spontaneous closure does not occur within a few weeks post partum; * Indomethacin IV, 0.2 mg/kg BD/OD - 3 doses; induces pharmacologic closure by inhibiting prostaglandin synthesis. OR 0.1 mg/kg/d for 6 days. Contraindications to indomethacin: - Thrombocytopenia (<50,000/mm3), - Bleeding disorders - Oliguria (<0.5ml/kg/d) - Elevated plasma creatinine level (>80µmol/L) - Necrotizing enterocolitis (NEC) - Indications for surgical closure are failure to close the ductus following indomethacin therapy with persistent heart failure and ventilator dependence.

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RAE - P pulmonale - Peaked P waves LAE - P mitrale - Bifid P waves ASD - Left parasternal heave - Wide fixed splitting of P2 Atrial fibrillation - Irregularly irregular pulse - Absent a wave - Absent P wave with Irregularly irregular QRS complexes Atrial flutter - Regularly Irregular pulse - 'Canon' a waves - Saw tooth baseline (300/s) with Regular QRS complexes RVH - Left parasternal heave - Dominant RV1 - Deep SV6 - T wave inversion in V1-V3/4 - RAD - QRS enlargement

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Right Ventricular Failure - Raised JVP - normal wave form LVH - RV6 >25mm or SV1+RV6= >35mm - QRS enlargement - T inversion in V4-V6, I & aVL Left Ventricular Failure - Diffuse apex beat - Pulses alternans Ventricular fibrillation - 'Canon' a wave - Irregular rhythm - No QRS complexes VSD - Heaving apex beat - PSM in left lower sternal edge - Single S2; Loud S3 Myocardial Ischemia - Prolonged QT interval (in Anterior MI) - ST depression >0.5mm - T inversion in V4-V6 & aVL Myocardial Infarction - Acute * Hrs ▫ Peaked T waves ▫ ST elevation >1mm * 24hrs ▫ T wave inversion ▫ ST resolution * Days ▫ T wave inversion or normal ▫ ST normal ▫ Pathological Q waves (Normal Q waves - <0.04s/<2mm) - Posterior (V1, V2) * Tall R * ST depression - Anteroseptal (V1-V4) - Anterolateral (V4-V6, I, aVL) * RAD - Non Q wave infarcts (Subendocardial) (V2-V5) * No pathological Q waves - Inferior (II, III, aVF) * Sinus bradycardia (<60bpm) * LAD Myocarditis - Prolonged QT - Low voltage QRS complex Pericardial effusion - Small volume pulses - Low voltage QRS complex Pericarditis - High plateau JVP which increases on inspiration (Kussmaul's sign) with deep x & y descents - Pulsus paradoxicus (systolic pressure weakens in inspiration by >10mmHg) - ST elevation (saddle shaped) - Low voltage QRS complex

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HOCM - Jerky pulses - Double impulse apex beat DCM - Diffuse apex beat HyperK+ - Absent P waves - Increased P-R interval - Widened QRS - Tall, tented T wave HypoK+ - Pseudo-P pulmonale - Prolonged QT - ST depression - Prominent U waves Digoxin effect (V5-V6) - ST depression (downward sloping) - Inverted T wave HyperCa2+ - Short QT interval HypoCa2+ - Long QT interval - Small T waves Cardiomegaly - Normal CTR; - Adults - 0.5 - Children - 0.55 Rate abnormalities; - Paroxysmal tachycardia - 150-250 bpm - Flutter - 250-350 bpm - Fibrillation - >350 bpm Complete Heart Block - 'Canon' a waves - When the atrium contracts against a closed tricuspid valve - There is dissociation between P waves & QRS complexes 1st Degree Heart block - Prolonged P-R interval 2nd Degree Heart block - Regularly irregular pulse RBBB e.g. Pulmonary embolism, Cor pulmonale - Widened QRS - M (RSR) pattern in V1 & W pattern in V5 - Dominant RV1 - Inverted T waves in V1-V3/4 LBBB - Widened QRS - W pattern in V1 & M (RSR) pattern in V6 - No septal Q waves - Inverted T waves in V4-V6, I, aVL Pressures in various chambers of the heart; - RA - 5-10mmHg - RV - 25mmHg - LA - 8-12mmHg - LV - 120mmHg

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Heart failure Definition Cardiac output and BP are inadequate for the body's requirements.

Classification • • • •

LVF RVF CCF - LVF + RVF Low-output cardiac failure - The heart's output is inadequate (e.g. ejection fraction < 0.5), or is only inadequate with high filling pressures. Causes; - Diastolic heart failure (2° to reduced filling of the heart in diastole)- Ischemic scarring , Hypertension, Hypertrophic cardiomyopathy, Amyloidosis - Valve disorders - ↑ Alcohol use

Causes Pump failure due to: • Heart muscle disease; - IHD - Cardiomyopathy • Restricted filling: - Constrictive pericarditis - Tamponade - Restrictive cardiomyopathy This may be the mechanism of action of fluid overload: an expanding right heart impinges on the LV, so filling is restricted by the ungiving pericardium (the mechanism invoking a 'hump in the Starling curve' is now said to be an error based on the artefact) • Inadequate heart rate: - β-blockers - Heart block - Post MI • Negative ionotropic drugs: e.g. most antiarrhythmic agents Excessive preload: • Mitral regurgitation • Fluid overload (e.g. NSAIDS causing fluid retention) - Fluid retention may cause LVF in a normal heart if renal excretion is impaired or big volumes are involved (e.g. IVI running too fast). More commonly if there is simultaneous compromise of cardiac function and in the elderly. Chronic excessive afterload - Here, output is normal or increased in the face of much increased needs. Initially there are features of RVF and later LVF - AS - Hypertension - Heart disease with anaemia or pregnancy - Hyperthyroidism - Paget's disease - Arteriovenous malformations - Beriberi

Causes of Refractory Heart Failure • • • • • • • • • • •

Infective Endocarditis Infections Hypertension Thyrotoxicosis Anaemia Silent AS/MS Arrhythmias Emboli Digoxin toxicity Hypovolaemia Electrolyte Imbalance

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Symptoms LVF - Dyspnoea - Orthopnoea - Paroxysmal nocturnal dyspnoea - Nocturnal cough ( ± pink frothy sputum) - Wheeze (Cardiac 'asthma') 2° to peribronchial cuffing 2° to pulmonary oedema - Poor exercise tolerance - Nocturia - Cold peripheries - Muscle wasting & Weight loss (Cardiac cachexia) - Fatigue RVF - Nausea - Anorexia - Epistaxis - Facial engorgement - Pulsation in the neck & face (tricuspid regurgitation) - Abdominal distension (ascites) - Peripheral oedema (up to thighs, sacrum, abdominal wall) Depression Drug-related side effects

Signs Cardinal i) Tachypnoea ii) Cardiomegaly iii) Tender Hepatomegaly iv) Oedema General - Ill & exhausted - Cool peripheries - Peripheral cyanosis - Peripheral oedema

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CVS -

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Pulse ƒ Resting tachycardia ƒ Pulsus alternans - alternating strong & weak beats ƒ Systolic BP ↓ ƒ Narrow pulse pressure Raised JVP Praecordium ƒ Displaced apex (LV dilatation) ƒ RV heave (Pulmonary hypertension) Auscultation ƒ S3 gallop (LV dysfunction) ƒ Murmurs of mitral and aortic valve disease

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Tachypnoea Bibasilar end inspiratory crackles Wheeze (cardiac 'asthma') Pleural effusions

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Hepatomegaly (pulsatile in tricuspid regurgitation) Ascites Cardiac cachexia (loss of lean tissue ≥10%). The failing heart produces TNF-α which is a key cytokine in the development of catabolism and possibly of cardiac cachexia. Also mesenteric oedema & immobility

P/A

Investigations CXR - ABCDE - Alveolar oedema - Classical perihilar 'bat's wing' shadowing - Kerley B lines - short peripheral lines, perpendicular to the pleura - interstitial oedema - Cardiomegaly (CTR >50%) - Dilated prominent upper lobe veins (Upper lobe diversion) - Pleural Effusion - Peribronchial cuffing ECG

New York Heart Association classification of heart failure I II III IV

Heart disease present, but no undue dyspnoea from ordinary activity Dyspnoea on ordinary activities; Comfortable at rest Dyspnoea on less than ordinary activity which is limiting Dyspnoea present at rest; all activity cause discomfort

Management Treat the cause (e.g. if arrhythmias; valve disease) Treat exacerbating factors (anaemia, thyroid disease, infection, HTN) Avoid exacerbating factors, e.g. NSAIDS (cause fluid retention), & verapamil (negative inotrope) Stop smoking. Eat less salt. Maintain optimal weight & nutrition. Exercise Drugs - Diuretics: Loop diuretics e.g. furosemide 40-80mg/d PO; increase dose as necessary. SE: ↓K+, renal impairment. Monitor U&E & add K+ sparing diuretic (e.g. spironolactone) if K+ < 3.2mmol/l, predisposition to arrhythmias, concurrent digoxin therapy ( ↓K+ increases the risk of digoxin toxicity), or pre-existing K+ losing conditions. Spironolactone (aldosterone antagonist; also elprenelone): Improves endothelial dysfunction (↑ nitric oxide bio-activity) & inhibits vascular angiotensin I→II conversion. If refractory oedema, consider adding metolazone - ACE-i: Especially in LVF; if cough & angioedema is a problem due to blockage of inactivation of bradykinin leading to increased production of prostaglandins, an angiotensin receptor antagonist may be substituted (e.g. lorsatan). Also 1st dose hypotension, postural hypotension. Use long acting ACE-i e.g. Lisinopril in the elderly

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β-blockers reduce mortality (25%) in heart failure especially in LVF e.g. Carvedilol (inhibits α1, β1,2 & has arteriolar vasodilating actions) Digoxin improves symptoms - 0.125-0.25mg/d PO. Monitor U&E & maintain K+ at 4-5 mmol/L SE; CVS (arrhythmias, heart block), GIT (anorexia, nausea, vomiting, diarrhoea, abdominal pain. Also not drug related vomiting; Oedema of the mesentery & Hepatomegaly), CNS (visual disturbances, headache, fatigue, drowsiness, confusion, delirium, hallucinations, depression), gynaecomastia on long term use Vasodilators: Long acting Nitrates ↓ preload by causing venodilatation, e.g. isosorbide mononitrate; 2nd line agents include arterial vasodilators, which ↓ afterload (e.g. Hydralazine SE: drug-induced lupus, tachycardia unless given with a β-blocker) or α-blockers, which are combined arterial & venous vasodilators, e.g. Prazosin - improve arterial haemodynamics & ↓ mortality especially if ACE-I is C/I

Sympathomimmetics (Dopamine, Dobutamine) are indicated in patients with intractable heart failure especially with an irreversible component e.g. MI, Shock, Pulmonary oedema, Surgery; ▪ Dopamine; - Dilates renal & mesenteric blood vessels - Stimulates myocardial β1 receptors with little tachycardia ▪ Dobutamine; - ↓ Peripheral vascular resistance thus ↑ CO - Used in severe heart failure without hypotension

Prognosis Prognosis is poor with 82% of patients dying within 6 yrs of diagnosis.

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Hypertension Major risk factor for; - Stroke - MI

Definition Raised BP on ≥ 2 readings on 2 different visits seated for at least 5mins, feet on the floor, arms at the level of the heart with 80% arm covering of the cuff & caffeine, exercise, vomiting avoided for at least 30mins before reading * 24-H ambulatory BP monitoring may be helpful in some cases e.g. white coat HTN, borderline HTN, episodic HTN, Autonomic dysfunction. Definition - Daytime >135/85mmHg &/or Night time >120/75mmHg (BP falls by 10-20% at night)

Classification i) Essential Hypertension - 1° cause unknown; 95% of cases ii) Secondary Hypertension - 5% of cases Causes; ▪ Renal Disease - Intrinsic renal disease (¾) * Glomerulonephritis * PAN * Systemic sclerosis * Chronic pyelonephritis * Polycystic kidneys - Renovascular disease (¼) * Atheromatous - elderly male cigarette smokers e.g. with peripheral vascular disease * Fibromascular dysplasias - young females ▪ Endocrine disease - Hyperthyroidism - Cushing's syndrome - Conn's syndrome - Pheochromocytoma - Acromegaly ▪ Others - Coarctation of the aorta (radiofemoral delay or weak femoral pulses) - Pregnancy - NSAIDS - Cause fluid retention & Papillary necrosis - Steroids - Cause fluid retention - MAO-i - 'The Pill' - Sleep apnoea iii) Malignant Hypertension Diagnostic criteria; • Severe hypertension (>200/130mmHg) • Bilateral retinal haemorrhages & exudates ± Papilloedema May precipitate; • HF • ARF • Encephalopathy (headache, focal CNS signs, seizures, coma) Pathological Hallmark - Fibrinoid necrosis S/S - Headache ± visual disturbance Mx (controlled reduction in BP over days NOT Hrs) - Oral therapy except in encephalopathy - Loop + thiazide diuretic - Encephalopathy - Reduce DBP to 110 mmHg over 4hrs * Loop diuretic * β-blocker/Na+ Nitroprusside (SE: cyanide poisoning) Prognosis - Untreated - 90% die in 1yr; Treated - 70% survive 5yrs

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Signs & Symptoms Usually asymptomatic but may have features of the underlying cause Signs of end-organ damage which are indications of severity & duration of hypertension & poor prognosis; - CVS * LVH/MI/Angina * HF * Peripheral vascular disease * Hypertensive retinopathy - Keith, Wagener, and Barker Classification (PEAS) I. Tortuous arteries with thick shiny walls (Silver or copper wiring) II. I + A-V nipping (narrowing where arteries cross veins) III. II + Exudates; * Flame haemorrhages (Superficial) * Cotton wool spots - due to ischemia - look like talc powder particles seen in IV drug abusers * Hard exudates - lipid exudates from leaking vessels IV. III + Papilloedema - Brain * Stroke/TIA * Charcot-Bouchard/Miliary aneurysm - dilatation of small arteries and arterioles secondary to lipohyalinosis from long-standing hypertension associated with intracerebral haematomas. - Kidneys * Progressive RF & Proteinuria - Fibrinoid necrosis

Management

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CHD + Stroke risk Factors considered; - Age - Sex - Diabetes - Smoking - SBP - Risk doubles with every increase in BP by 20/10mmHg - Total serum cholesterol to HDL cholesterol ratio High risk diseases; - CHD or other major atherosclerotic disease - Familial hypercholesterolemia or other inherited dyslipidaemias - Stage II Hypertension or associated target organ damage

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Stage II Hypertension or associated target organ damage Diabetes mellitus with associated target organ damage Renal dysfunction

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Look for & treat underlying causes In isolated pre-hypertension, aim for <120/80 mmHg In non-diabetics, the treatment goal is 140/85 mmHg In diabetes mellitus & nephrotic syndrome, aim for <130/80 mmHg (<125/75 if proteinuria >1gm/d) Lifestyle changes - ↓ concomitant risk factors; - Stop smoking - Reduce alcohol & salt intake - Reduce weight if obese - Increase exercise - DASH diet - A diet rich in fruits, vegetables, and low-fat dairy foods and low in saturated and total fats (↓Na+, ↑K+, ↑Ca2+)

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Drugs (ABCD) ` * * * *

Thiazide diuretics - Bendroflumethiazide; SE: HypoK+, HypoNa+, postural hypotension, impotence, hyperlipidaemia, hyperuricaemia + ACE-i - 1st choice if coexisting LVF, or in Diabetics with microalbuminuria or proteinuria. SE: cough, K+ ↑, renal failure, angioedema, 1st dose hypotension; C/I: renal artery stenosis, AS β-blockers - SE: bronchospasm, heart failure, cold peripheries, lethargy, impotence; C/I: Asthma, caution in heart failure CCB - SE: flushing, fatigue, gum hyperplasia, ankle oedema. Avoid short acting drugs.; Never use sublingual nifedipine to reduce BP as it can cause an uncontrollable drop in BP & subsequently stroke as cerebral auto regulation is poor. SE; Headache & dizziness Others - ARBs (e.g. lorsatan), Methyldopa (used in pregnancy), α-blocker (doxazosin). For refractory cases: clonidine, minoxidil, or hydralazine

Stage I - Thiazide diuretic (± A/B/C) Stage II - Thiazide diuretic + A/B/C * Most drugs take 4-8 wks to produce their maximum effect * 'ABCD rule' - If one drug fails, switch between groups combining A or B with C or D •

Aspirin Prophylaxis (75mg OD) Reduces the risk of Cerebrovascular events & MI; however an increased risk of bleeding need to be considered. Indications; • 1° Prophylaxis; * Age >50yrs * Controlled HTN (<150/90mmHg) with end organ damage * Type 2 diabetes * A CHD risk ≥15% over 10yrs • 2° Prophylaxis; * Patients with cardiovascular complications; - MI - Angina - Non-haemorrhagic cerebrovascular disease - Peripheral vascular disease - Atherosclerotic renovascular disease

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Hypertensive encephalopathy An acute or sub-acute potentially reversible cerebral disorder confined to severe cases of hypertension marked by; - Headache - Obtundation - Confusion - Stupor - ± Convulsions

Pathogenesis Involves a breakthrough phenomenon in cerebral auto regulation of blood flow, in which the very high BP is transmitted directly to the capillary bed with transudation and exudation of plasma into the substance of the brain, causing cerebral oedema. The pathologic findings include fibrinoid necrosis, thrombosis of arterioles, micro infarcts, and petechial haemorrhages especially in the brainstem.

C/P •

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Rapidly changing neurological abnormalities occur, including; - Transient cortical blindness - Hemiparesis - Hemisensory defects DBP > 140mmHg Grade III or IV retinopathy Elevated CSF pressures

Rx - Reduce DBP to 110mmHg over 4-6hrs • •

Loop diuretic β-blocker/Na+ Nitroprusside (SE: cyanide poisoning)

Primary Pulmonary Hypertension Pulmonary arterial hypertension of unknown cause, where secondary causes have been ruled out.

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Unknown; possible pulmonary arteriolar hyperactivity and vasoconstriction; occult thromboembolism; possible autoimmune (high frequency antinuclear antibodies) Familial or Sporadic Associated with an underlying cause; - HIV infection - Underlying connective tissue disease, particularly limited cutaneous systemic sclerosis - Anorectic agents (fenfluramine and dexfenfluramine) & Amphetamines

Pathologic subtypes: i) Thrombotic ii) Veno-occlusive iii) Plexogenic pulmonary arteriopathy - Laminar "onion skin" intimal proliferation, focal medial disruption leading to aneurismal dilatation

Ix • • • • • •

CXR & BGAs ECG - RVH + RAD Pulmonary function testing - arterial hypoxemia, hypocapnoea & reduced diffusion capacity. V/Q scan - must rule out proximal pulmonary artery emboli Pulmonary angiography - should be done if segmental or larger defect on V/Q scan. Cardiac catheterization - right heart catheterization is necessary to measure pulmonary artery pressures and haemodynamics; rule out underlying cardiac disease and response to vasodilator therapy

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Epoprostenol (prostacyclin) or iloprost therapy, given either as a continuous IVI through a central venous catheter or via the nebulized route Sildenafil (Phosphodiesterase type 5 inhibitor) Anticoagulation with warfarin improves prognosis

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Hypertensive Crises Hypertensive emergencies are those rare situations requiring immediate blood pressure reduction (not necessarily to normal ranges) to prevent or limit target organ damage e.g. • Hypertensive encephalopathy • Intracranial haemorrhage • Acute LVF with pulmonary oedema • Acute dissecting aortic aneurysm • Severe hypertension accompanying Unstable angina or Acute MI • Eclampsia

Causes; • •

Pheochromocytomas MAOIs interaction with sympathomimetic drugs or food containing tyramine or dopamine

S/S; • • • • • •

DBP >140mmHg. Grade IV retinopathy Encephalopathy - Pulsating headache, confusion, somnolence, stupor, visual loss, focal defects, seizures, or coma. Cardiac findings include a hyperdynamic sustained left ventricular impulse, cardiac enlargement, and pulmonary venous hypertension. Oliguria and azotemia are usually present Nausea and vomiting.

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PO β-Blocker (atenolol or labetalol) or a long acting CCB (e.g. amlodipine or modified-release nifedipine) Within the first 24hrs, the DBP should be reduced to 100-110 mmHg & over the next 2-3 days blood pressure should be normalised by using β-Blockers, CCBs, diuretics, vasodilators, or ACE-i. If parenteral treatment is necessary - Sodium Nitroprusside

S/E Very rapid reduction in BP can reduce organ perfusion leading to; • Cerebral infarction & blindness • Myocardial ischemia. • Deterioration in renal function

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Rheumatic fever Epidemiology

Peak incidence: 5-15yrs

Pathogenesis

Pharyngeal infection with Lancefield Group A β-haemolytic streptococci triggers rheumatic fever 2-4 wks later, in susceptible 2% of the population. A few of the "pharyngeal" serotypes but none of the "skin" strains have been associated with acute rheumatic fever. An antibody to the carbohydrate cell wall of the streptococcus cross-reacts with cardiac myosin & sarcolemmal membrane protein (antigenic mimicry) and may cause permanent damage to the heart valves. Fibrinoid degeneration can be seen in the collagen of connective tissues of involved organs. Acute attacks last an average of 3months

Revised Jones criteria

A. Major criteria

i) Carditis (45-70%) Pancarditis. The Aschoff nodule is pathognomonic & is composed of multinucleated giant cells surrounded by macrophages & T lymphocytes - Breathlessness (due to heart failure or pericardial effusion) - Palpitations or chest pain (due to pericarditis or pancarditis) - Tachycardia - New or changed Murmurs (MR or AR) * PSM to MR * Carey Coombs murmur - Soft Mid-Diastolic MS murmur due to valvulitis, with nodules forming on the mitral valve leaflets causing thickening. - Pericarditis (Chest pain, Pericardial friction rub & Praecordial tenderness) - CCF 2° to myocardial dysfunction &/or M/AR - Cardiomegaly - T wave inversion; ↓ in QRS voltage; Conduction defects Cardiac sequelae affect the following valves, giving incompetent lesions during the attack & stenosis years later; * Mitral (70%) * Aortic (40%) * Tricuspid (10%) * Pulmonary (2%) ii) Arthritis (75%) - Early feature characterised by acute, painful, red, swollen, tender, asymmetric & migratory, 'flitting' polyarthritis usually of the large joints (typically the knees, ankles, elbows & wrists) iii) Subcutaneous nodules (2-20%) - small, mobile painless nodules on extensor surfaces of joints and spine. Appear >3 wks after the onset of other manifestations & are therefore a feature that helps to confirm rather than make the diagnosis iv) Erythema marginatum (2-10%) - Geographical type rash with red, raised edges and clear centre; occurs mainly on trunk, arms, thighs. v) Sydenham's Chorea (St Vitus' dance) (10%) - Late (3 months after the episode of acute rheumatic fever) unilateral/bilateral involuntary semi-purposeful movements of the hands, feet or face. Speech may be explosive & halting. More common in women. May be preceded by emotional labiality and uncharacterised behaviour. Spontaneous recovery usually occurs within a few months.

B. Minor criteria i) ii) iii) iv) v)

Previous rheumatic fever Fever ↑ ESR/CRP Arthralgia (but not if arthritis is one of the major criteria) ↑ P-R interval (but not if carditis is a major criterion) in V4 -V6, aVL

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Diagnosis a)

Evidence of recent strep infection * History of Scarlet fever - "Streptococcal sore throat with a rash." A childhood disease characterized by high fever, pharyngitis, and rash caused by Group A β-haemolytic streptococci pyogenes that produce erythrogenic toxin. Incubation period 1-7 days, duration of illness 4-10 days. * Positive throat swab * Rising or ↑ ASOT >200U/mL (>300U/mL in children) * ↑ Dnase B titre

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≥2 major criteria OR 1 major + ≥2 minor

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Leukocytosis; ↑ ESR, ↑ CRP Throat swab culture ASOT CXR - Cardiomegaly, pulmonary congestion ECG - T wave inversion; ↓ in QRS voltages

Management • • •

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Bed rest until CRP normal for 2-6 wks (maybe 3 months) - lessens joint pains & ↓ cardiac workload Immobilize joints in severe arthritis (Benzyl penicillin 0.6-1.2 mg IM/Vancomycin 1gm BD IV/Erythromycin) stat then Penicillin V 250 mg QID PO for 10 days Analgesia for carditis/arthritis - Aspirin for 6wks; SE: tinnitus, hyperventilation, metabolic acidosis Steroids have no major impact on the sequelae but improve the symptoms of carditis or severe arthritis Haloperidol or diazepam for the chorea

Secondary prophylaxis • Penicillin V 250mg BD PO/Sulfadiazine until no longer at risk (30yrs). Thereafter give (Amoxicillin/Vancomycin) + Gentamicin prophylaxis for dental or other surgery

Prognosis • •

60% carditis develop Chronic rheumatic heart disease Recurrence may be precipitated by; - Further streptococcal infections (Reactivated rheumatic heart disease - Causes a more fulminant infection due to the presence of memory B-cells) - Pregnancy - Use of the pill

Chronic Rheumatic Heart Disease Develops in at least 50-60% of those affected by rheumatic fever with carditis from single or repeated attacks of rheumatic fever. • 25% MS • 40% MS + MR Pathogenesis In contrast to the destructive lytic process of acute rheumatic fever, the main pathological process in chronic rheumatic heart disease is progressive fibrosis. The heart valves are predominantly affected but involvement of the pericardium & myocardium may contribute to heat failure & conduction disorders. Fusion of the mitral valve commissures & shortening of the chordae tendinae may lead to MS ± MR

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Infective Endocarditis Classification A.

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According to areas involved; - Native valve endocarditis - Prosthetic valve endocarditis - Endocarditis in IV drug users - Tricuspid valve According to course of the disease; i) Acute infective endocarditis (50%) Occur on normal valves Follows an acute course & presents with acute heart failure; rapidly fatal without treatment (6wks) Bacteria involved; * Staph. Aureus ▪ Skin infections ▪ Abscesses ▪ Vascular access sites (e.g. IV & central lines) ▪ IV drug misuse (predisposed to right sided IE) * Strep pneumoniae * Neisseria gonorrhoea * Coagulase negative Staph epidermidis, a normal skin contaminant (especially post-op) ii) Sub-acute infective endocarditis Occur on abnormal valves. Predisposing cardiac lesions; ▪ Aortic or Mitral valve disease ▪ Tricuspid valves in IV drug users ▪ Prosthetic valves - may be 'early' (acquired at the time of surgery, poor prognosis) or 'late' (acquired haematogenously) ▪ Coarctation of the aorta ▪ PDA ▪ VSD Bacteria involved; * Streptococcus viridans (35-50%) - Strep mitis, Strep sanguis, α-haemolytic streptococci; Commensals in the upper respiratory tract that may enter the blood stream on chewing, teethbrushing or at the time of dental treatment * Enterococcus faecalis * Enterococcus faecium * Strep bovis - from bowel or urinary tract; associated with large bowel neoplasms * Strep milleri " " " " * Rarely: HACEK group of Gram -ve bacteria (Haemophilus-Actinobacillus-CardiobacteriumEikenella-Kingella) Others; - SLE (Libman-Sacks endocarditis) - Malignancy - Fungi

Pathogenesis Any cause of bacteraemia exposes valves to the risk of bacterial colonization. Vegetations may cause valve destruction, & severe regurgitation, or valve obstruction. An aortic root abscess causes prolongation of the P-R interval, & may lead to complete AV block. LVF is a common cause of death.

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Clinical features Fever + new murmur = endocarditis until proven otherwise • Signs of infection - Fever, Rigors, Night sweats - Malaise - Weight loss - Anaemia - Splenomegaly - Tipped smooth tender spleen (DDx - SCD, Salmonellosis, Sepsis) - Finger clubbing • Cardiac lesions - Any new murmur, or a change in the nature of a pre-existing murmur • Immune complex deposition - Roth spots (boat-shaped retinal haemorrhages with pale centres) - Janeway lesions (painless palmar or plantar macules) - Splinter haemorrhages (on finger or toe nails) - Osler's nodes (painful pulp infarcts in fingers or toes) • Vascular signs - Vasculitis may affect any vessel - Microscopic haematuria is common; Type 1 mesangiocapillary glomerulonephritis 2° to embolic immune complex deposition and ARF may occur • Embolic phenomena - Abscess formation in the relevant organs, e.g. brain, heart, kidney, spleen, GI tract & pulmonary abscess (in right-sided endocarditis)

Ix • •

• • • •

Blood cultures: take 3 sets at different times & from different sites at peak fever. 85-90% are diagnosed from the 1st 2 sets; 10% are culture negative Blood tests - High ESR/CRP - Neutrophil Leukocytosis - Normochromic, normocytic anaemia Urinalysis - microscopic haematuria CXR - Cardiomegaly ECG - prolonged P-R intervals Echo - Trans-Oesophageal Echo - more sensitive - mitral lesions & aortic root abscess - Trans-Thoracic Echo - may show vegetations but only if > 2mm

Duke criteria for infective endocarditis A.

Major criteria i) Positive blood culture: - Typical organism in 2 separate cultures taken at - different times & from different sites at peak fever

or ii)

- Persistently +ve blood cultures, e.g. 3, >12hrs apart (or majority if ≥ 4) Endocardium involved: - Positive Echocardiogram (vegetation, abscess, dehiscence of prosthetic valve)

or B.

- New valvular regurgitation (change in murmur not sufficient) Minor criteria i) Predisposition (cardiac lesion; IV drug abuse) ii) Fever >38°C iii) Vascular/immunological signs iv) +ve blood culture that do not meet major criteria v) +ve Echocardiogram that does not meet major criteria

Diagnosis - 2 major / 1 major + 3 minor / all 5 minor

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Management •

•

Antibiotics - Empirical therapy - Benzyl penicillin 1.2gm/4hrs IV + Gentamicin 80mg BD IV; If acute add flucloxacillin 2gm QID to cover for Staph. - Prophylaxis - Amoxicillin 3gm PO before procedure followed by amoxicillin 500mg PO 6hrs later * Acquired valve disease * Prosthetic valve(s) * Previous endocarditis * Septal defects * Dental procedures * Upper respiratory tract surgery * Oesophageal dilatation * Sclerotherapy for varices * Surgery/instrumentation of lower bowel, gall bladder, or GUT - Streptococci - Benzyl penicillin IV for 2-4 wks then amoxicillin 1gm TDS PO for 2 wks; add gentamicin if resistant - Enterococci - Amoxicillin + Gentamicin - Staphylococci - Flucloxacillin + Gentamicin; Treat for 6-8 wks; stop Gentamicin after 1wk - Fungi - (Flucytosine 3gm QID IVI over 30 mins/Amphotericin B) + Fluconazole 50mg/24hrs PO Surgery if; - Heart failure - Valvular obstruction - Repeated embolic fungal endocarditis - Persistent bacteraemia - Myocardial abscess - Unstable infected prosthetic valve

Prognosis • • •

30% mortality with Staph. 14% with bowel organisms 6% with sensitive streptococci

Infective Endocarditis ⋅ Fever ⋅ Splenomegaly - Tipped smooth tender spleen (DDx - SCD, Salmonellosis, Sepsis) ⋅ Immunological indicators (Roth spots, splinter haemorrhages, Osler’s nodes, Janeway lesions) ⋅ Microscopic haematuria

Rheumatic Heart Disease ⋅ CCF

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Tetralogy Of Fallot (TOF) Major: 1. 2.

Obstruction to right ventricular outflow (pulmonary stenosis) at both the right ventricular infundibulum (subpulmonic area) and pulmonary valve. Ventricular septal defect (VSD) that is non-restrictive and large, located just below the aortic valve, and related to the posterior and right aortic cusps.

Minor: 3. Dextroposition of the aorta with septal override 4. RVH The main pulmonary artery is often smaller than usual, and there may be various degrees of branch pulmonary artery stenosis. Pulmonary atresia with VSD is also classified as an extreme form of TOF. When the right ventricle contracts in the presence of marked pulmonary stenosis, blood is shunted across the VSD into the aorta. Persistent arterial desaturation and cyanosis result. The pulmonary blood flow, when severely restricted by the obstruction to right ventricular outflow, may be supplemented by the bronchial collateral circulation (major aortopulmonary collateral arteries (MAPCAs)) and, especially in the immediate newborn period, by a PDA. When obstruction to right ventricular outflow is mild to moderate and there is a balanced shunt across the VSD, the patient may not be visibly cyanotic (Acyanotic or "Pink" TOF).

a)

b) c)

Clinical manifestations

Often cyanosis is not present at birth, but with increasing hypertrophy of the right ventricular infundibulum and growth, cyanosis occurs later in the 1st yr of life. It is most prominent in the mucous membranes of the lips and mouth, and in the fingernails and toenails. In these infants pulmonary blood flow may be dependent on flow through the ductus arteriosus. When the ductus begins to close in the 1st few hours or days of life, severe cyanosis and circulatory collapse may occur. Older children with long-standing cyanosis may have extreme cyanosis, with a dusky blue skin surface, grey sclera with engorged blood vessels (suggesting mild conjunctivitis), and clubbing of the fingers and toes. Dyspnoea on exertion. Characteristically, children assume a squatting position for the relief of dyspnoea and to increase systemic resistance to facilitate reversal of the Right to Left shunt in the heart especially in patients with significant cyanosis at rest. Spontaneous and unpredictable Paroxysmal hypercyanotic attacks (Hypoxic, "Blue," or "Tet" spells) which are associated with a reduction of an already compromised pulmonary blood flow, which when prolonged results in severe systemic hypoxia and metabolic acidosis are a particular problem during the first 2yrs of life and occur most frequently: * In the morning upon first awakening * Following episodes of vigorous crying * Defecation * Increase in systemic vascular resistance And may last from a few minutes to a few hours but are rarely fatal. Infants who are only mildly cyanotic at rest are often more prone to develop hypoxic spells because they have not developed the homeostatic mechanisms to tolerate rapid lowering of arterial oxygen saturation, for example, polycythemia which is as a result of hypoxic stimulation of the renal system to produce erythropoietin which increases erythropoiesis. S/S ⋅ Hyperpnoea and restlessness ⋅ Cyanosis increases ⋅ Gasping respirations ensue ⋅ Syncope may follow ⋅ Temporary disappearance or decrease in intensity of the ESM is usual as flow across the right ventricular outflow tract diminishes. ⋅ Short episodes are followed by generalized weakness and sleep. ⋅ Severe spells may progress to unconsciousness and, occasionally, to convulsions or hemiparesis. Rx i) Remove aggravating factors ii) Placement of the infant on the abdomen in the knee-chest position to increase systemic resistance to facilitate reversal of the Right to Left shunt, making certain that there is no constricting clothing; Calming the infant, while holding the child in a knee-chest position, may abort progression of an early spell. iii) Administration of oxygen iv) Injection of morphine up to 0.2 mg/kg IV/IM/SC. Reduces anxiety and depresses the respiratory centers. Also Domical (Amitriptyline) and diazepam. v) Since metabolic acidosis develops when the arterial PO2 is <5.3 KPa, rapid correction (within several minutes) with IV sodium bicarbonate 1-2 mEq/kg Stat is necessary if the spell is unusually severe and there is lack of Medicine Page 20

response to the foregoing therapy. β-Adrenergic blockade by IV propranolol 0.15 - 0.25 mg/kg PRN has been used successfully in some patients with severe spells, especially spells accompanied by tachycardia. It reduces the right outflow obstruction and tachycardia. vii) Sedate the patient with Ketamine that also depresses the respiration. viii) Reduce vascular resistance with Phenylephrine. ix) Put patient under general anesthesia and provide mechanical ventilation. vi)

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d) e) f) g)

Growth and development may be delayed in patients with severe untreated TOF. BP & Pulse are normal The left anterior hemithorax may bulge anteriorly due to RVH. The heart is usually normal in size, and there is a substernal right ventricular impulse. In 50% of cases a systolic thrill is felt along the left sternal border in the 2nd ICS - Pulmonary stenosis. The ESM is frequently loud and harsh; it may be transmitted widely, especially to the lungs, but is most intense at the left sternal border. The murmur may be either ejection or holosystolic and may be preceded by a click. The murmur is caused by turbulence through the right ventricular outflow tract -Pulmonary stenosis. It tends to become louder, longer, and harsher as the severity of pulmonary stenosis increases from mild to moderate; however, it can actually become less prominent with severe obstruction, especially during a hypercyanotic spell. The 2nd heart sound is either single or the pulmonic component is soft. Infrequently a continuous murmur may be audible (PDA).

h) Anemia: Hypoxia stimulates erythropoietin production in the kidneys that leads to increased erythropoiesis in the bone marrow that depletes iron stores leading to IDA.

Presenting complications •

•

•

• • • •

Ix

• • • •

• •

•

•

Cerebral thromboses, usually occurring in the cerebral veins or dural sinuses and occasionally in the cerebral arteries, are more common in the presence of extreme polycythemia (PCV >65%) and may also be precipitated by dehydration. Thromboses occur most often in patients <2yrs old. These patients may have IDA. Therapy consists of adequate hydration and phlebotomy and volume replacement with fresh frozen plasma are indicated in the extremely polycythemic patient. Bacterial endocarditis occurs in unoperated patients in the right ventricular infundibulum or on the pulmonic, aortic, or, rarely, tricuspid valves. Endocarditis may complicate palliative shunts or, among patients with corrective surgery, any residual pulmonic stenosis or residual VSD. Antibiotic prophylaxis is essential prior to and after dental and certain surgical procedures associated with a high incidence of bacteraemia CCF is NOT a usual feature of patients with TOF. It may occur, however, in the young infant with "pink" or acyanotic TOF (when obstruction to right ventricular outflow is mild to moderate and there is a balanced shunt across the VSD). As the degree of pulmonary obstruction worsens with age, the symptoms of heart failure resolve and eventually the patient develops cyanosis, often by 6–12mo of age. These patients are at increased risk for hypercyanotic spells at this time. Convulsions due to frequent hypercyanotic spells. Renal infarcts and other infarcts secondary to polycythemia. Coagulation disorders Arrhythmias and death BGAs FBC + ESR: Hb and Hct are raised but MCV is low (IDA) U/E/C CXR: The cardiac shadow consists of a narrow base, concavity of the left heart border in the area usually occupied by the pulmonary artery, and normal heart size. The hypertrophied right ventricle causes the rounded apical shadow to be up tilted so that it is situated higher above the diaphragm than normal. The cardiac silhouette has been likened to that of a boot or wooden shoe - Coeur en sabot (DDx Tricuspid atresia) ECG: Demonstrates RAD and evidence of RVH. Two-dimensional echocardiography provides information as to the extent of aortic over-ride of the septum, the location and degree of the right ventricular outflow tract obstruction, the size of the proximal branch pulmonary arteries, the side of the aortic arch and determining whether a PDA is supplying a portion of the pulmonary blood flow. Cardiac catheterization demonstrates systolic pressure in the right ventricle equal to systemic pressure, with a marked decrease in pressure as the catheter enters the pulmonary artery or, in some cases, the infundibular chamber beyond the obstruction. The mean pulmonary arterial pressure is reduced, the right atrial pressure is usually normal (5-10mmHg). The level of arterial oxygen saturation depends on the magnitude of the right-to-left shunt; in a moderately cyanotic patient at rest it is usually 75–85%. In the absence of a left-to-right shunt, samples of blood from the venae cavae, right atrium, right ventricle, and pulmonary artery will be similar in oxygen content.

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Treatment •

• • • •

•

Oxygenation and Normal body temperature maintenance. Prolonged, severe hypoxia may lead to shock, respiratory failure, and intractable acidosis and will significantly reduce the chances of survival. Cold increases oxygen consumption and causes vasoconstriction, which places a further stress on the cyanotic infant, whose oxygen delivery is already limited. Blood glucose levels monitoring, as infants with cyanotic heart disease are more likely to develop hypoglycaemia. Prevention or prompt treatment of dehydration is important to avoid haemoconcentration and possible thrombotic episodes. Paroxysmal dyspnoeic attacks in infancy may be precipitated by a relative iron deficiency; iron therapy may decrease their frequency and also improve exercise tolerance and general well-being. Red blood cell indices should be maintained in the normocytic range. Infants with marked right ventricular outflow tract obstruction may deteriorate rapidly because as the ductus arteriosus begins to close pulmonary blood flow is further compromised. Administration of prostaglandin E1 (0.05–0.20 µg/kg/min), a potent and specific relaxant of ductal smooth muscle, causes dilatation of the ductus arteriosus and provides adequate pulmonary blood flow until and after surgery. Oral propranolol (1 mg/kg/d QID) is used to decrease the frequency and severity of hypercyanotic spells.

a) Conservative The modified Blalock-Taussig (BT) shunt, a systemic–to–pulmonary artery shunt, consists of a Gore-Tex conduit anastomosed side to side from the left subclavian artery to the homolateral branch of the pulmonary artery and is performed to augment pulmonary artery blood flow to decrease the amount of hypoxia and to improve linear growth as well as to augment the growth of the branch pulmonary arteries. After a successful shunt procedure, cyanosis diminishes. The development of a continuous murmur over the lung fields after the operation indicates a functioning anastomoses. However, a good shunt murmur may not be heard until several days after surgery. Complications; • Congestive heart failure due to a large shunt • Brain abscess especially in patients with a BT shunt. This is due to the blood not being slowed down in the lungs and thus is at elevated pressures in the brain, polycythemia and also due to bypassing of the lung protective alveolar macrophages.

b) Definitive Total correction is done before 2yrs of age for better healing, to reduce damage to the heart and to enable pulmonary alveolar growth that is complete at 2yrs. In several centres, corrective open-heart surgery in early infancy is being performed in critically ill patients as long as they have normal coronary artery anatomy. For infants who can be maintained until 6–12mo of age, full correction is a reasonable primary alternative when the pulmonary arteries are of sufficient size and no other complicating great vessel abnormalities are present. It consists of; i) When there is a previously established systemic to pulmonary shunt, it must be obliterated prior to cardiotomy. ii) Relief of the obstruction of the right ventricular outflow tract by removing obstructive muscle bundles. If the pulmonary valve is stenotic, a valvotomy is performed. If the pulmonary valve annulus is very small or the valve is extremely thickened, a valvectomy may be performed and a transannular patch placed across the pulmonary valve ring. iii) Patch closure of the VSD. iv) Right ventriculotomy is performed in most patients, although in some centres a transatrialtranspulmonary approach reduces the long-term risks of a ventriculotomy. Post-op Complications Cardiac; ⋅ Right ventricular failure (particularly in patients with a transannular outflow patch) requires a positive ionotropic agent such as digoxin. ⋅ Transient heart block ⋅ Residual VSD with left-to-right shunting ⋅ MI from interruption of an aberrant coronary artery ⋅ Disproportionately increased left atrial pressure due to residual collaterals. Complications following a lateral thoracotomy; ⋅ Chylothorax may require repeated thoracocentesis and, on occasion, reoperation in order to ligate the thoracic duct. ⋅ Diaphragmatic paralysis due to injury to the phrenic nerve may result in a more difficult postoperative course. Prolonged ventilator support and vigorous physical therapy may be required, but diaphragmatic function will usually return in 6wks unless the nerve was completely di id d S l l f h d h b i di d Medicine Page 23

divided. Surgical plication of the diaphragm may be indicated. ⋅ Horner syndrome due to lesions affecting the sympathetic fibres of T1 is usually temporary and does not require treatment. The surgical risk of total correction is currently under 5%.

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Portal Hypertension Classification of Portal Hypertension

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i)

Portal-Systemic Communications (Portacaval Anastomoses)

Lower end of the oesophagus - Oesophageal tributaries of the left gastric vein (portal) anastomose with the oesophageal tributaries of the accessory hemiazygous vein (systemic) ii) Umbilicus - The left branch of the portal vein (portal) anastomoses with paraumbilical veins (systemic) of the anterior abdominal wall - Caput Medusae iii) Anal canal - The superior rectal vein (portal) anastomoses with the middle & inferior rectal veins (systemic) iv) Bare area of the liver - Hepatic venules (portal) anastomose with the phrenic & intercostal veins (systemic) v) Posterior abdominal wall - Veins of the retroperitoneal organs (portal) anastomose with the retroperitoneal veins of the posterior abdominal wall & of the renal capsule (systemic). The splenic vein (portal) anastomoses with the left renal & azygous veins (systemic) vi) Liver - rarely ductus venosus remains patent & connects the left branch of the portal vein (portal) directly to the IVC (systemic)

Mx

a) Devascularization of the lower oesophagus b) Surgical Shunts • • • •

TIPS - Transjugular Intrahepatic Portosystemic stent Shunt - A stent is placed between the portal vein and the hepatic vein in the liver Warren shunt - involves anastomosing the distal (splenic) end of the transected splenic vein to the side of the left renal vein Total shunts - The portal vein is transected near its bifurcation in the liver hilum and anastomosed to the side of the IVC. The Mesocaval stent shunt interposes a segment of prosthetic graft or internal jugular vein between the superior mesenteric vein and the IVC

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Liver Abscesses (& Amoebiasis) Liver Abscesses DDx i) ii) iii) iv) v)

Amoebic Pyogenic Hydatid Choledochal cysts Necrotic colorectal metastases

C/P -

-

PUO - High swinging fever sometimes rigors & sweating RUQ pain ± radiation to the right shoulder - Tender hepatomegaly on percussion; raised diaphragm, with diminished movement on the right side Jaundice - mild or severe (only when large abscesses cause biliary obstruction) Durban sign +ve- Pressure in the 6th ICS elicits tenderness 2° to stretching of the liver capsule A large abscess may penetrate the diaphragm & rupture into the lung, from where it's contents may be coughed up. Abscesses may occur on the left lobe that may rupture into the pericardium → pericarditis Cough ± pleuritic pain

-

Abdominal U/S or CT scan U/S guided Needle Aspiration CXR - A raised right hemi diaphragm & lung collapse or an effusion at the base of the right lung

-

Aspirate if; * The abscess is large * The abscess threatens to burst * There is no response to chemotherapy within 72h - aids penetration of antibiotics & may reduce the period of disability Hepatic resection may be indicated for a chronic persistent abscess or 'pseudotumor'

-

Ix

Mx

-

i) Amoebiasis (Entamoeba histolytica) Life cycle

* *

A localised granuloma (amoeboma), presenting as a palpable mass in the caecum or a filling defect in the sigmoid colon on radiography, is a rare complication. Cutaneous amoebiasis causes progressive genital, perianal or peri-abdominal surgical wound ulceration

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a) Amoebic dysentery Incubation - 2wks to years High fever, colic & tenesmus are rare Chronic course; * Grumbling abdominal pains & ≥2 unformed stools/d * Diarrhoea alternating with constipation ± mucous sometimes streaked with blood; Stools may have offensive odour * ± Tenderness along the line of the colon especially over the caecum (DDx acute appendicitis) & sigmoid colon * ± Superadded pyogenic infection of the ulcers in the aged Ix • • • •

Stool m/c/s for Trophozoites containing RBCs or Cysts in Chronic amoebiasis * In endemic areas, ⅓ of the population are symptomless passers of amoebic cysts. A warm saline wet mount of stool may reveal Charcot-Leyden crystals, which, although not specific for amoebic colitis, raise suspicion for amoebiasis (50%). Sigmoidoscopy - flask-shaped ulcers which may cause severe haemorrhage but rarely perforate the bowel wall. Immunofluorescence - indicates previous/current infection in 60% cases & may be unhelpful in acute infection

Mx •

•

•

Metronidazole 800mg PO TDS 5d - Active against Trophozoites (vegetative amoeba) - then the luminal amoebicide Diloxanide furoate 500mg TDS for 10d after treatment to eliminate luminal Cysts. (SE of metronidazole: Nauseating, metallic taste, reacts with alcohol; use Tinidazole, Flagantel or Secnidazole instead) Diloxanide furoate is also best for Chronic diseases when Cysts, NOT trophozoites, are in stools. Other luminal agents; - Iodoquinol - Paromomycin 2nd line agents; - Tetracycline - Erythromycin - Dehydroemetine or Emetine (toxic)

b) Amoebic liver abscess Up to 50% do not have a previous history of intestinal disease Pathogenesis ` Amoebic trophozoites emerge from the vegetative cyst form in the colon & invade the bowel mucosa, enter a portal venous radicle & carried to the liver where they multiply rapidly & destroy the parenchyma causing a large, single abscess located in the right lobe (due to a rich blood supply), although multiple abscesses may occur in advanced diseases. Ix • Neutrophil leucocytosis • Cyst aspiration - The liquid contents at first may have a characteristic pinkish colour which may later change to the classic anchovy sauce (chocolate brown) appearance of the cyst fluid but only rarely contains free amoebic trophozoites • Immunofluorescence- Antibodies are detectable in 95% of patients with hepatic amoebiasis • LFTs may be normal or ↑(cholestatic) Mx - Metronidazole 400mg IV TDS 10d; repeat at 2wks as needed; then the luminal amoebicide Diloxanide furoate 500mg TDS for 10d after treatment to eliminate luminal cysts; it is not effective against hepatic amoebiasis - 2nd line agents; * Chloroquine

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ii) Pyogenic Abscess

Most common in elderly patients (especially 2° to the first 2 causes below) Common organisms - E. coli, Streptococci especially S. milleri Causes • Biliary obstruction (cholangitis) - common cause of multiple abscesses • Contiguous spread from an empyema of the gallbladder • Haematogenous * Portal vein (mesenteric infections) - anaerobes including Streptococci & Bacteroides * Hepatic artery (bacteraemia) • Direct extension • Trauma - Penetrating or non-penetrating • Infection of liver tumour or cyst Dx • Weight loss • Leucocytosis • LFTs -↑ ALP, ↓ Albumin • Blood m/c/s Mx • Ampicillin + Gentamicin + Metronidazole

iii) Hydatid Cysts (OHCM 616) iv) Choledochal Cysts - Surgery v) Necrotic colorectal metastases

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Liver failure Definition a) Acute Hepatic failure - Occurs suddenly in a previously health liver b) Acute-on-chronic Hepatic failure - Occurs as a result of decompensation of chronic liver disease i) Fulminant hepatic failure - Encephalopathy occurring within 8 wks of symptoms of liver disease ii) Late-onset hepatic failure - Encephalopathy occurring within 9-26wks of symptoms of liver disease

Causes •

•

•

•

• • • •

Genetic disorders; - α1-antitrypsin deficiency - Haemochromatosis - Wilson's disease - Presents with hepatolenticular degeneration of the cornea - Kayser-Fleischer rings characterized by greenish-brown discolouration of the corneal margin appearing first at the upper periphery & disappear with treatment. Infections - Viral hepatitis - Yellow fever - Leptospirosis Drugs - Paracetamol overdose - Halothane - Isoniazid Toxins - Amanita phalloides mushrooms - Carbon tetrachloride - Bush tea - Aflatoxins - Aflatoxins have been incriminated, mainly on weak evidence, in Hepatocellular carcinoma, acute hepatic failure, and Reye's syndrome. Kwashiorkor may be associated with ingestion of aflatoxins by infants. They cause steatosis, necrosis, cirrhosis & HCC. Acute fatal aflatoxin poisoning may appear as "hepatitis." Vascular - Budd-Chiari syndrome - Veno-occlusive disease Autoimmune disorders; - AIH - PBC Malignancy Others e.g. Fatty liver of pregnancy

Clinical features • • • • •

•

•

Fetor hepaticus - musty sweet odour Jaundice Ascites Hypoglycaemia Bleeding; - Reduced Vitamin K - Reduced clotting factors II, VII, IX & X - Oesophageal varices - Gastropathy - Thrombocytopenia 2° to Hypersplenism Infection; - Spontaneous bacterial peritonitis - UTI - Pneumonia Signs of chronic liver disease (suggest acute-on-chronic hepatic failure) i) Finger Clubbing ii) Leuconychia - white nails with lunulae undemarcated, from hypoalbuminaemia iii) Terry's nails - white proximally but distal 30% reddened by telangiectasias (Dilation of the previously existing small or terminal vessels of a part) Medicine Page 31

iv) v) vi) vii) viii) ix) x) xi)

previously existing small or terminal vessels of a part) Palmar erythema (hyperdynamic circulation) Dupuytren's contracture Parotids enlarged Spider naevi Gynaecomastia Patchy loss of pubic hair Testicular atrophy Hepatomegaly, or small liver in late disease

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• Hepatic encephalopathy Neuropsychiatric syndrome caused by liver disease - cirrhosis mainly or acute liver failure Aetiology; i) An imbalance of excitatory and inhibitory amino acid neurotransmitters consisting of; a) ↓Excitatory neurotransmitters (glutamate and aspartate) - 2° to ↑ ammonia metabolism b) ↑GABA tone (an inhibitory effect) due to the presence of a benzodiazepine-like substance that modulates the GABA receptor NOT due to greater influx of GABA into the brain (as originally proposed). This receptor (part of a supramolecular complex that also binds benzodiazepines and barbiturates) may also explain, at least partly, the cerebral sensitivity of patients with chronic liver disease to such sedatives. ii) Biochemical 'neurotoxins' - ? Nitrogenous substances (Ammonia) produced in the gut, at least in part by bacterial action, which are normally metabolised by the healthy liver so that they do not enter the systemic circulation iii) False neurotransmitters e.g. amino acids (↑aromatic > branched chain), octopamine, mercaptans & fatty acids Precipitating factors; - Alcohol - Infection - Drugs - sedatives, antidepressants, hypnotics - Increased protein in circulation - Gastrointestinal bleeding, Excess dietary proteins, Constipation - HypoK+ - Uraemia - spontaneous or diuretic induced - Paracentesis (volumes >3-5L) - Trauma (including surgery) - Portosystemic shunts - surgical or systemic (large) - Malignancy Clinical features; - Asterixis - Involuntary jerking movements, especially in the hands, best elicited by having the patient extend the arms, dorsiflex the wrists, and spread the fingers; due to arrhythmic lapses of sustained posture thought to be due to improper integration of peripheral afferent information to the brainstem reticular formation. - Constructional apraxia (ask the patient to draw a five-pointed star) - Hyperreflexia & bilateral extensor plantar responses - In Chronic hepatic encephalopathy - Cerebellar dysfunction; Parkinsonian syndromes, Spastic paraplegia & Dementia Staging I. Altered mood & behaviour II. Increasing drowsiness, confusion, slurred speech III. Stupor, incoherence, restlessness, significant confusion IV. Coma Ix - EEG - Diffuse slowing of the normal α waves with eventual development of δ waves DDx - Hypoglycaemia - Drug or alcohol intoxication - Delirium tremens - Wernicke's encephalopathy - Subdural haematoma - Neurological Wilson's disease - Primary psychiatric disorders

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Investigations •

• • • •

Blood tests - FHG; * ? Infection - leucocytosis need not mean a secondary infection; hepatitis may itself be the cause * ? GI bleed - anaemia - U/E/C - as urea is synthesized in the liver, its a poor test of renal function in liver failure; use creatinine instead - ? Renal failure (HRS) - LFTs; * ↑Bilirubin * ↓ Albumin * ↑AST & ALT; ↑ γ-GT is an indication of cholestasis - Coagulation profile; * ↑PTI/INR - R/O DDx; * RBS - ? Hypoglycaemia * Hepatitis serology * Paracetamol level * Ferritin * α1-antitrypsin * Caeruloplasmin Abdominal U/S Microbiology - Ascitic neutrophils >250/mm3 indicates spontaneous bacterial peritonitis CXR EEG - high-voltage slow wave forms

Management & Treating the complications of Acute hepatic failure • • • • • •

` `

` `

`

Attempts to correct acid-base balance are often harmful Treat cause if known Monitor vitals, pupils, urine output hourly Daily FHG, U/E/Cs, LFTs & INR (best measure of liver synthetic function) If malnourished, give diet rich in carbohydrate- & protein-derived calories, preferably orally. Give thiamine & folate supplements as needed. Reduce acid secretion & risk of gastric stress ulcers, e.g. Ranitidine (Zantac®) or a PPI to reduce the amount of bleeding & thus the amount of blood converted to ammonia in the GIT Hypoglycaemia: • Give 1L 10% dextrose IVI, BD to avoid hypoglycaemia. Give 50mL 50% dextrose if blood glucose <3.5mmol/L (do every 1-4h in acute liver failure). Watch plasma K+ Bleeding • Vit. K 10mg/d IV for 3d (Vitamin K is not given IM as it may cause haemolysis & haematoma formation at site) • Platelet transfusions may be required if thrombocytopenic & bleeding • Consider N-acetylcystein to improve oxygenation & clotting profiles • Avoid FFP unless bleeding or undergoing a surgical procedure. Infection: • Ceftriaxone 1-2gm/d IV. Avoid Gentamicin (↑ risk of renal failure) Ascites: • Fluid restriction • Low-salt diet • Diuretics • Daily weights Cerebral Oedema • Especially in acute fulminant liver failure • Give 20% mannitol IV • Hyperventilate

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`

Encephalopathy • Nurse with a 20° head-up tilt • Protect the airway - to avoid aspiration • Insert an NG tube to; * Decompress stomach to avoid aspiration * Remove any blood from the stomach (bleeding varices) • Treat or remove precipitating factors • Reduce protein intake; * The patient should be bed ridden to reduce creatinine production which increases the total protein * Dietary protein is ↓ to <20g/d & glucose (300g/d) is given orally or parenterally in severe cases. As it improves, dietary protein is ↑ by 10-20g/d every 48hrs to an intake of 40-60g/d the limit in cirrhotic patients * Administration of branched chain amino acids to achieve a positive nitrogen balance - N. Hepa®, Hepamass® (Ornithine + Aspartate) • Suppress production of neurotoxins by bacteria in the bowel; * Emptying the bowel with lactulose (15-30 mL PO TDS) - It reaches the colon intact to be metabolized by colonic bacteria producing; ▫ Lactose - An osmotic laxative effect ▫ Converted to lactic acid reducing the pH of the colonic content, thereby limiting colonic ammonia absorption ▫ Promotes incorporation of Nitrogen into bacteria thus reducing ammonia in the GIT Also Lactitol or magnesium sulphate enemas. Aim for 2 soft stools/d * Consider Metronidazole (Flagyl®) (neomycin is too toxic) to reduce number of bowel organisms • Avoid sedatives (but diazepam is used for seizures) or other drugs with hepatic metabolism • Flumazenil may be used to block the Benzo-diazepine like substance that modulates the GABA receptor • Chronic or refractory hepatic encephalopathy is an indication for liver transplant

`

Hepatorenal syndrome (HRS) An acute, functional and progressive reduction in renal blood flow and GFR 2° to intense renal cortical vasoconstriction in the setting of decompensated cirrhosis with ascites & normal renal histology. Occurs in 18% of cirrhotic patients ↑ levels of neuropeptide Y, a renal vasoconstrictor peptide released on stimulation of sympathetic nervous system, occurs in HRS, worsening renal vasoconstriction. Liver-kidney interactions; * In cirrhosis, ↓ hepatic clearance of immune complexes leads to their trapping in the kidney (therefore IgA nephropathy ± hepatic glomerulosclerosis) * Viruses - HBV may cause membranous nephropathy & PAN - HCV can cause cryoglobulinaemia & MPGN * α1-antitrypsin deficiency can cause MPGN Types; I - is due to a relative hypovolaemia, a poorly understood portorenal reflex in which the kidney is avidly conserving salt and water despite adequate levels of these constituents. II - Cardiac index is increased owing to arteriovenous shunting, and perfusion of the kidney falls to ineffective levels. A useful diagnostic test is the infusion of dopamine, norepinephrine, or phenylephrine, which increases peripheral vascular resistance and temporarily increases urine output. These agents can subsequently be used therapeutically. Rx - Albumin IV ± haemodialysis

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King's College Hospital criteria for Orthotopic liver transplantation •

•

Paracetamol liver failure - Arterial pH <7.3 24h after ingestion or - ALL of the following * PTI >100s * Creatinine >300μmol/L * Grade III/IV encephalopathy Non-paracetamol liver failure - PTI >100s or - 3/5 of the following * Drug-induced liver failure * Age <10 or >40yrs old * >1wk between onset of jaundice & encephalopathy * PTI >50s * Bilirubin >300μmol/L

Prognosis Poor prognostic factors: - Grade III/IV encephalopathy - Age >40yrs - Albumin <30g/L - Drug induced liver failure - Late onset > fulminant failure 65% survival post-transplantation

Prescribing in liver failure Avoid - Opiates - Diuretics (↑ risk of encephalopathy) - increases BUN and serum creatinine - Oral hypoglycaemics - Saline containing IVIs - Warfarin (effects are enhanced) Hepatotoxic drugs; - Azathioprine - Paracetamol - 6-mercaptopurine - Salicylates - Tetracycline - INH - Mitomycin - Oestrogen - Amiodarone - Phenothiazines - Methyldopa - MTX

Liver span In the newborn infant extension of the liver edge > 3.5 cm below the right costal margin in the midclavicular line suggests hepatic enlargement. In children, the normal liver edge can be felt up to 2 cm below the right costal margin. The span ranges from about; ` 1wk of age - 4.5–5 cm ` Adults (>12yrs); - ♂ 7-8 cm - ♀ 6–6.5cm

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Ascites Definition Free fluid in peritoneal cavity

Classification a)

Transudative ascites - Ascites protein concentration - <25g/L - Serum-ascites albumin gradient - >1.1 - Causes; ▫ Liver pathology; * Cirrhosis * Portal Hypertension * IVC or portal vein thrombosis * Portal nodes ▫ Cardiac pathology; * RHF * CCF * Pericarditis Hypoproteinaemia ▫ * Nephrotic syndrome * Protein-losing enteropathy * Malnutrition ▫ Myxoedema b) Exudative ascites - Ascites protein concentration - >25g/L - Serum-ascites albumin gradient - < 1.1 - Causes; ▫ Malignancy (any intra-abdominal organ, e.g. colon, stomach, pancreas, liver, kidney) ▫ Infections - especially TB ▫ Pancreatitis (Ascites amylase activity >1000U/L) ▫ Budd-Chiari syndrome ▫ Hypothyroidism

Pathogenesis • •

Overflow theory - 1° renal retention of sodium & water Underfilling theory - Compensatory renal retention of sodium & water 2° to splanchnic vasodilatation

Signs (only if ascites fluid >1L) • • • • • • • • • • •

Abdominal distension Fullness in the flanks Shifting dullness Fluid thrill Distortion or eversion of the umbilicus Abdominal striae Divarication / Diastasis of the recti (separation of rectus abdominis muscles away from the midline) Meralgia paraesthetica - tingling, formication, itching, and other forms of paresthesia in the outer side of the lower part of the thigh in the area of distribution of the lateral femoral cutaneous nerve; there may be pain, but the skin is usually hypaesthesic to the touch Hernia Scrotal oedema Right sided pleural effusion (10%)

Grades III III -

Shifting dullness Fluid thrill Gross ascites

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Investigations • • •

Ascitic tap (paracentesis) with a 21G needle on a 20mL syringe in the RIF - for M/C/S + protein levels * Ascitic neutrophils >250/mm3 indicates spontaneous bacterial peritonitis Abdominal U/S Laparoscopy

Management • • • • • •

• •

Bed rest Fluid restriction (<1.5L/d) Low-salt diet (40-100mmol/d) Spironolactone 100mg/d PO; ↑ dose every 48h, to 400mg/d SE: painful gynaecomastia, HyperK+; if response is poor + furosemide ≤120mg/d PO - normally S:F - 5:2 Daily weight; aim for weight loss of ≤1/2kg/d - No more than 900ml can be mobilised from the peritoneum daily so the body weight should not fall by >1Kg/d if fluid depletion in the rest of the body is to be avoided Therapeutic paracentesis up to 3-5 litres over 1-2h/d with concomitant albumin infusion - 6-8g/L fluid removed may be tried * Excess tap without concomitant albumin infusion results in the return of the ascites that then leads to hypovolaemia LeVeen Shunt - Non-return valve running subcutaneously from the peritoneum to the internal jugular vein in the neck TIPPS - Transjugular intrahepatic portosystemic stent shunt - Placed between the portal vein and the hepatic vein in the liver

Prognosis Ascites is a serious development in cirrhosis as only 10-20% of patients survive 5yrs from its appearance.

Spontaneous Bacterial Peritonitis Infection of ascitic fluid usually by E.coli. Finding multiple organisms on culture should arouse suspicion of perforated viscus.

Pathogenesis; Occurs especially when the ascitic albumin is < 10g/L thus; * There is hypogammaglobulinaemia * Neutrophil dysfunction * Opsonizing capacity is reduced

C/P * * * * *

Fever Sudden abdominal pain Rebound tenderness Absent bowel sounds Hepatic encephalopathy & Fever may be the only presenting symptoms in patients with cirrhosis

*

Diagnostic paracentesis - Cloudy fluid with an ascitic neutrophil count >250/mm3 indicates infection

* * *

Cefotaxime 2g BD for 5d + Metronidazole; Also other cephalosporins or Augmentin Recurrence may be reduced by Norfloxacin 400mg/d; also Ciprofloxacillin or Septrin Pyeloascites - Flucloxacillin

Ix Rx

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Alcoholism Healthy Drinking • ♂ - <20U/wk (<80gm/d) • ♀ - <15U/wk (<40gm/d) Taken regularly, not in binges, alcohol inhibits platelet aggregation & is an antioxidant (thus cardioprotective); Benefit accrues only those with LDL cholesterol >5.25mmol/L CAGE questions (≥2 +ve answers suggest an alcohol problem) • Have you ever felt you ought to Cut down on your drinking? • Have people Annoyed you by criticizing your drinking? • Ever felt bad or Guilty bout your drinking? • Ever had an Eye-opener to steady nerves in the morning? TWEAK (≥2 points suggest an alcohol problem) Used in Pregnant women • Have you an increased Tolerance of alcohol? - +2 • Do you Worry about your drinking? - +2 • Ever had an Eye-opener to steady nerves in the morning? - +1 • Do you ever get Amnesia after drinking alcohol? - +1 • Have you ever felt you ought to c(K)ut down on your drinking? - +1 Organs affected by Alcohol

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The Liver • Normal in 50% alcoholics • Stages of alcoholic liver disease; i) Alcoholic steatosis (Fatty liver) - Acute & reversible, but may progress to cirrhosis if drinking continues (also seen in Obesity, DM, Amiodarone). Hypertriglyceridemia tends to occur with alcoholism, probably largely due to an increase in serum VLDL. At times, this can result in lactescent (milky) serum, with abdominal pain and mild haemolytic anaemia (Zieve's syndrome). ii) Alcoholic Hepatitis; Develops acutely following a bout of heavy drinking - Coagulation profile; - ↑ T, PR, RR * Bleeding, ↓ INR - Anorexia, Nausea, diarrhoea & vomiting * ↑ MCV - Tender hepatomegaly ± jaundice ↑ WCC - Ascites - ↑ Urea (Hepatorenal syndrome) - LFTs; * ↑↑ AST - Twice as high as ALT * ↑ ALT * ↑ γ-GT iii) Alcoholic/Micronodular/Laennec's Cirrhosis - Peri-portal fibrosis * Biopsy - Mallory bodies ± neutrophil infiltrate 20% progress through the 3 stages through 10yrs (hepatic failure in 10%) CNS • Poor memory/cognition - multiple high potency vitamins IM may reverse it • Cortical atrophy, enlarged ventricles • Retrobulbar neuropathy • Fits • Cerebellar degeneration leads to Falls & Wide-based gait neuropathy • Wernicke's encephalopathy constitutes the acute phase of two distinct disorders - Wernicke's syndrome and Korsakoff's syndrome - both of which are caused by thiamine deficiency. a) Korsakoff's syndrome - The hallmark and sine qua non of Korsakoff's syndrome is a dissociation between immediate recall and recent recall/recent memory/short-term memory. In addition to significant problems registering new information, these patients demonstrate long-term memory problems (retrograde amnesia). One can think of this long-term memory deficit as a reflection of the difficulty these patients had registering new information at earlier times (anterograde amnesia). He will confabulate to fill in the gaps in his memory. Petechial hemorrhagic lesions stretch from the 3rd-4th ventricle in the midline along the cerebral aqueduct. Lesions in the mamillary bodies and in the dorsomedial nucleus of the thalamus are also predictable findings. b) Wernicke's syndrome Thiamine (Vitamin B1) deficiency, often occurring in alcoholics, with a classical triad of; i) Eye signs - Nystagmus (horizontal) or Ophthalmoplegia (external recti commonly) ii) Ataxia iii) Confusion ± Other signs; - Ptosis - Abnormal pupillary reactions - Altered consciousness - Headache - Anorexia, Nausea, Vomiting Causes; • Alcoholism • Glucose administration to a thiamine deficient patient • Eating disorders • Malnutrition • Prolonged vomiting associated with chemotherapy Ix; - ↓ Red cell transketolase - ↑ Plasma pyruvate

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•

GIT • • • • • •

Alcoholic Pellagra Encephalopathy - Alcoholic patients who have received thiamine and pyridoxine but not niacin may develop a secondary pellagra consisting of confusion or an altered state of consciousness, oppositional hypertonia, and myoclonus. Stimulation of metabolic pathways by pyridoxine and thiamine may increase the relative deficit of niacin.

Obesity Varices Gastric mucosa: inflammation, ulceration Peptic ulcers Pancreatitis (acute & chronic) - inflammation, liquefaction necrosis Intestine: flattening of villi, loss of enzymes leading to diarrhoea

Blood • Macrocytosis - MCV (>96fl) usually without any accompanying anaemia • Anaemia from; - Marrow depression - GI bleeds - Alcoholism associated folate deficiency - Haemolysis • Sideroblastic anaemia Heart • • • •

Arrhythmia Hypertension Dilated Cardiomyopathy - interstitial fibrosis and myofibril atrophy Sudden death in binge drinkers

Immune system • Depression of granulocyte production, lymphocyte proliferation response, and cell-mediated immunity Endocrine organs • Elevated plasma cortisol levels (can influence Cushing's syndrome screening tests) • Testicular atrophy • Suppression of reproductive hormones in women Pellagra Clinical deficiency syndrome characterized by; • Dermatitis - Skin lesions appear in area exposed to light and/or trauma due to lack of formation of NAD • Diarrhoea - 2° to Inflammation of mucus membranes. • Dementia - Mental symptoms include depression, irritability, anxiety, confusion, disorientation, delusions and hallucinations. • Delirium • Death Causes; · Nicotinic acid deficiency · Tryptophan deficiency · Folic acid deficiency · Carcinoma · Isoniazid Rx; · Nicotinic acid

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Withdrawal signs Occurs 2-5d post admission; • The mild withdrawal syndrome includes tremor, weakness, sweating, hyperreflexia, and GI symptoms. Some patients have generalized tonic-clonic seizures, usually not more than two in short succession (alcoholic epilepsy or rum fits). • Hallucinations (delirium tremens) - may be visual or tactile e.g. of animals crawling all over one • Anxiety, Insomnia • Craving - Alcoholics have more glutamate binding sites - so taking alcohol facilitates dopamine neurotransmission in the mid-brain, which, in the tegmental area mediates alcohol's rewarding effect. Topiramate facilitates GABA function & antagonizes glutamate activity at kainate receptors - & has been found to ↓ cravings in alcoholism • Pulse ↑, BP ↓ • ↑ LFTs • ↑ MCV Mx • • • • • • • •

Mx hypotension Vitals + investigations daily; RFTs to monitor for HRS. HypoNa+ is common, but water restriction may make matters worse Give chlordiazepoxide PO for 1st 3 days, weaning over 7-14d; Alternative, diazepam, lorazepam - DO NOT use chlorpromazine High dose B vitamins IV before glucose Glucose Optimize nutrition - Prevents encephalopathy, sepsis, death Culture ascites & provide necessary antibiotics Prednisolone 40mg/d for 5d tapered off over 3wks

Alcohol poisoning S/S - CNS; Ataxia, Dysarthria, Nystagmus, Drowsiness, Coma - CVS; Vasodilatation, Tachycardia - GIT irritation - Methanol - visual disturbance, frequently described as "like being in a snowstorm.". A complaint of blurred vision with a relatively clear sensorium should strongly suggest the diagnosis of methanol poisoning. * Since much of the toxicity is due to metabolites of methanol, there is often a delay of up to 30 hours before development of visual disturbances and other signs of severe intoxication. * In severe cases, the odour of formaldehyde may be present on the breath or in the urine. * Changes in the retina may sometimes be detected on examination, but these are usually late. Complications - Aspiration of vomit - Hypoglycaemia - Resistant acidosis Mx - Supportive - Thiamine then Glucose - Methanol poisoning; * Suppression of metabolism by alcohol dehydrogenase to toxic products -Give ethanol ± fomepizole (an alcohol DH inhibitor) * Dialysis to enhance removal of methanol and its toxic products * Alkalinization to counteract metabolic acidosis - HCO3* Folic acid

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Pyelonephritis Bacteria-induced inflammation of the renal pelvis, calyces & parenchyma. It can occur in acute & chronic forms & can affect one or both kidneys.

Causes; • •

Ascending infection (mostly faecal flora) often in association with VUR Septicaemia

Acute Pyelonephritis Predisposing conditions; • • • • • •

UTO - PUVs, neurogenic bladder VUR Instrumentation of the renal tract Pregnancy Immunosuppression e.g. DM (general susceptibility to infection) Pre-existing or acquired renal lesions which may cause intra-renal scarring & obstruction, e.g. gout, interstitial nephritis

Pathological changes Acute inflammation of the pelves, calyces & renal parenchyma especially in the upper & lower poles which in severe cases, may progress to suppuration which may be discrete & focal, involving one or both kidneys. Pale linear streaks of pus may extend radially from the tip of the papillae to the surface of the cortex, where adjacent lesions may fuse to produce extensive abscesses. There may be much destruction of the cortex, although there may be remarkable sparing of glomeruli & blood vessels. When there is virtually total or complete obstruction, pus may accumulate in the pelves & calyces to produce pyonephrosis. Extension through the renal capsule may produce a perinephric abscess.

C/P • • • •

Loin pain & tenderness High fever often with rigors Vomiting ± Symptoms of cystitis (frequency, dysuria, urgency, strangury, haematuria, suprapubic pain)

Chronic Pyelonephritis Predisposed individuals; • • •

Reflux nephropathy - Those with bacteriuria + ureteric reflux in infancy in whom chronic pyelonephritis manifests itself in late childhood or early adult life Anatomical (PUV) or functional (neurogenic bladder) abnormalities of the urinary tract Xanthogranulomatous pyelonephritis - Unilateral chronic pyelonephritis commonly in females associated with chronic infection (Proteus spp. in 60% of the cases) & obstruction to urinary flow, often 2° to staghorn calculus. The kidney is enlarged & dilated calyces contain yellowish friable material which histologically contains numerous lipid-laden macrophages.

C/P • • •

History of recurrent UTIs History of failure to thrive in early childhood or of nocturnal enuresis * In Bilateral cases, the condition usually presents with features of CRF or HTN (15-20% malignant hypertension)

• •

Leucocytes >10/mm3 IVP - Asymmetrical shrinkage of the kidneys, irregularity of renal outline due to cortical scarring & dilatation or disturbances of the calyces opposite the scarred area. In contrast to CGN, the renal parenchyma shows irregular asymmetrical scarring & shrinkage, these scars being in close relationship to deformed calyces & being found mainly at the upper & lower poles of the kidney Heavy proteinuria almost nephrotic & such patients show focal segmental glomerulosclerosis

Ix

•

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CGN Vs CPN Chronic Glomerulonephritis Involves both kidneys Involves the whole kidney Both kidneys are uniformly & equally reduced in size The calyces & renal pelvis are not distorted

The capsule is firmly adherent & the subcapsular surface uniformly & finely irregular (‘granular contracted kidney’) No history of recurrent urinary tract infection

Chronic pyelonephritis Involves one or both kidneys Involves mainly the upper & lower poles of the kidney There is irregular asymmetrical scarring & shrinkage of the kidneys The pelvic & calyceal walls are thickened & distorted, their mucosa is granular or atrophic, with also scarring of the pyramids & usually calyceal dilatation Surface is smooth History of recurrent urinary infection

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Nephrotic Syndrome Definition i) ii) iii) iv)

Proteinuria (Albuminuria) (>3g/24h) Hypoalbuminaemia (albumin <25g/L) Oedema EMU Protein : creatinine ratio (>200mg/mmol) * more accurate

Pathogenesis Develops secondary to selective protein loss in the kidneys 2° to damage of the GBM resulting in ↓ albumin, → ↓ plasma oncotic pressure though patients may have a normal or ↑ plasma volume.

Causes 1° Nephrotic Syndrome GN (nephritic nephrosis); - Minimal change GN - Children (2.5yrs) & young adults - Focal segmental GN - Children (6yrs) - +ve IgM, C3 - Membranous GN - Adults - +ve IgG, C3 * In KNH the most common cause is Proliferative GN (PSAGN) - +ve IgG, ↓C3, ↑ ASOT 2° Nephrotic Syndrome - Infections; * Streptococcus Group A - A few of the "pharyngeal" strains (e.g., M type 12) have been associated with proliferative glomerulonephritis, but far more of the "skin" strains (e.g., M types 1, 4, 25, 49, 55, 57, & 60) have been considered nephritogenic. * Tropical nephropathy; 9 Plasmodium malariae 9 HBV * HIV * Syphilis - DM - Amyloidosis - SLE - +ve ANA, RF - HSP - +ve IgA, C3 - Heavy metal poisoning e.g. mercury - Hodgkin's disease

Clinical features Symptoms - History of acute or chronic infections, drugs, allergies, systemic symptoms (vasculitis, malignancy) Signs - Facial swelling/peripheral oedema (Anasarca - ↑ fluid in organs & cavities with severe oedema (+ tissue hardening); it is also seen in; * CCF * Liver failure * Protein-losing enteropathy * Foetal hydrops * Capillary leak syndrome with monoclonal gammopathy - Pleural effusions - Ascites - Hepatomegaly - Hypertension - Xanthelasma - Xanthomata - Widespread yellow nodules or plaques, especially of the skin, composed of lipid-laden histiocytes, especially on the elbows and knees

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Complications i) ↑ susceptibility to infection (peritonitis, pneumococcus, e.g. in children) - Stretched skin & oedematous tissue - Urinary loss of immunoglobulins - Nephrotic plasma impairs lymphocytic function - Steroids are immunosuppressive ii) Thromboembolism (DVT, PE, renal vein thrombosis, CNS vessels) - ↑ fibrinogen concentration 2° to ↑ protein synthesis due to hypoalbuminaemia - Urinary loss of Anti-thrombin III iii) ARF 2° to Hypovolaemia iv) Hyperlipidaemia 2° to increased liver synthetic functioning v) Proteinuria - loss of LMWT binding proteins in urine

DDx • • • • • • •

Nephritic syndrome - haematuria, proteinuria, oliguria, HTN Kwashiorkor - oedema, hypoalbuminaemia but NO proteinuria Allergic reactions - NO proteinuria CCF - NO proteinuria, NO hypoalbuminaemia Beriberi Liver disease - hypoalbuminaemia ARF/CRF

Investigations •

•

• •

Urine Blood -

Dipstick (microscopic haematuria, proteinuria - 3+ or 4+) - False +ve in ↑SGA >1.030 & ↑pH >8 m/c/s (RBC, casts) 24h collection (protein excretion >3g; creatinine clearance)

Cholesterol - ↑ Immunoglobulins - ↓ Serum electrophoresis Complement (C3, C4); About ½ of patients who develop immunologically mediated renal disease associated predominantly with C3 deposition have a serum protein that can directly cleave C3 to active C3b,C3 nephritic factor, is a heat-stable IgG autoantibody that may be deposited in the phagocytic mesangium of the glomerulus; * Normal in idiopathic nephrotic syndrome * ↓ in SLE, PSAGN, MPGN - Autoantibodies (ANA, ANCA, anti-dsDNA, anti-GBM) - SLE - HBV serology - HIV - ASOT - PSAGN - RBS - Steroids are diabetogenic Imaging - CXR - for PTB as treatment involves chronic steroid therapy which may reactivate TB - Abdominopelvic U/S Renal biopsy - Indications; - In all adults - Steroid non-responding children - Onset before 6mo age - ↓ complements - 2° Nephrotic syndrome - Persistent hypertension & microscopic haematuria - Macroscopic haematuria - Renal failure not attributable to hypovolaemia

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Treatment • • • •

•

• • • • •

Monitor U&E, BP, fluid balance, weight Active mobilisation due to hypercoagulable state Diet - Normal protein diet as the patient is losing proteins Diuresis; - 0-7/14d - Manage oedema by; * Fluid restriction - 1-1.5L/d; salt restriction (50mmol/d) * If NO hypovolaemia - Furosemide ± metolazone / spironolactone; If hypovolaemic (abdominal pain 2° to mesenchymal ischemia, hypotension, tachycardia, RF) - Furosemide ± metolazone / spironolactone + IV salt-poor albumin - aim for a loss of 1Kg/d - By day 7-14, proteinuria resolves due to use of steroids which cause diuresis Prednisolone 2mg/Kg/d PO for 4wks then 1.5mg/Kg on alternate days for 4wks then taper SE; - Peptic ulceration (cover with Ranitidine (Zantac®)) - Cushingoid habitus - Hypertension - Diabetes - Osteoporosis & avascular necrosis of bone - Growth failure - Cataract - Pseudotumor cerebri - Mood & behaviour change - Reactivation of latent infections e.g. TB Hypertension - ABCD In chronic nephrotic syndrome - consider drugs to reduce proteinuria e.g. Nifedipine or hydralazine or cyclosporine (also reduce GFR) Prompt treatment of infections - Prophylactic penicillin in children & pneumococcal vaccine (during remission) Prophylactic heparin 5000U SC BD if immobile; warfarin for symptomatic thrombosis Hyperlipidaemia usually improves with resolution of nephrotic syndrome. If prolonged, consider treatment with a statin

Outcome • • • •

•

Remission - Proteinuria 0/trace on 3 consecutive days Relapse - Proteinuria ≥ 2+ on 3 consecutive days having been previously in remission Continue 2mg/kg/d till remission then 1.5mg/Kg on alternate days for 4wks Frequent relapser - ≥ 2 relapses within 6mo or ≥4 relapses in a year Steroid dependent - 2 consecutive relapses during steroid treatment or within 14d of stopping treatment Maintain steroids for 6-12mo on 0.5-1mg/Kg on alternate days Alternate therapy; - Levamisole - Cyclophosphamide - Cyclosporine Steroid resistant - Failure to achieve remission despite 4wks of prednisolone 2mg/Kg/d

Prognosis Disease goes up to puberty & ESRF is rare - Prognosis is good

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Renal vein thrombosis Causes; - 6-8% Membranous GN nephrotics - 1-3% others C/P - Loin pain (e.g. acute) - Haematuria - Proteinuria - Renal enlargement - Deteriorating renal function Dx - Doppler U/S - Renal angiography (venous phase) - Spiral CT - MRI Rx - Warfarin for 3-6mo (or until albumin >25g/L)

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ARF Definition A significant deterioration in renal function (↓ GFR by 50% - equivalent to the functioning of 1 kidney) occurring over hours or days

Causes i)

Pre-renal renal failure - Renal hypoperfusion * Diarrhoea, vomiting, dehydration * Salt wasting/adrenal causes * Burns * Diabetes insipidus * 3rd space loss - pleural effusion, ascites 2° to sepsis, nephrotic syndrome * CCF - Hypoxia - interferes with synthesis of ATP * Pneumonia * ARDS - Reperfusion of kidney - There is release of reactive oxygen molecules leading to renal injury ii) Renal/Intrinsic renal failure - Acute Tubular Necrosis - Shock - Nephrotoxins; * Drugs e.g. Aminoglycosides, amphotericin B, tetracyclines, NSAIDS, ACE-i * Contrast especially in myeloma & DM * Haemoglobinuria * Rhabdomyolysis - ribena coloured urine with haemoglobinuria in dipstick but no RBC on microscopy - Vascular (acute cortical necrosis, large/small vessel obstruction) - Glomerulonephritis - MPGN, SLE - Vasculitis - Petechial rash, nosebleeds, haematuria, ↑ESR, ↑CRP - Interstitial nephritis - Penicillin, Rifampicin, NSAIDS, Sulphonamides, Herbals * History of drug use in the last 44d; C/P - Rash, fever, eosinophilia, eosinophiluria - Haematological (myeloma, HUS, TTP) - Hepatorenal syndrome - Renal vein thrombosis - Kidney infiltrating tumours Na+

Urine (mmol/L) Fractional Na+ excretion (%) Urine osmolality Urine/plasma urea Urine/plasma creatinine

Pre-renal <20 <1 >500 >8 >40

ATN >40 >2 <350 <3 <20

Creatinine is filtered at the glomerulus and is not reabsorbed. Therefore under conditions of avid water reabsorption, the urine creatinine concentration will rise, but its serum value will remain relatively constant, resulting in a high urine/plasma creatinine ratio. Urea, on the other hand, is both filtered and reabsorbed. Its reabsorption is flow dependent; thus during low flow conditions e.g. dehydration, more urea is reabsorbed, resulting in a high plasma urea/creatinine ratio. Water is, however, reabsorbed in excess of urea in this setting, and the urine/plasma ratio will still rise normal ratio is 8-10 iii) Post-renal renal failure - Urinary obstruction; consider; - Patients with a single functioning kidney - History of renal stones, anuria, prostatism or previous pelvic/retroperitoneal surgery - PUVs - Tumours - Bilateral obstruction of the ureters - Neurogenic bladder

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C/P • • •

• • • •

Oliguria (<400mL/24h) Or Non-oliguric renal failure - In cytotoxic therapy (tumour lysis syndrome) - Prevent by proper hydration (150% maintenance fluid) + Allopurinol In ATN; i) Oliguric phase - lasts 7-10d; Urine output (<400mL/24h) with resultant accumulation of waste products of protein metabolism in the blood → uraemia, metabolic acidosis, hyperK+, hyperNa+ & hypervolaemia ii) Diuretic phase - 2° to osmotic diuretic effect of Urea & creatinine with tubular recovery iii) Recovery phase Oedema Hypertension Uraemic encephalopathy - vomiting, lethargy, confusion, convulsions, pericardial rub ABSENCE of anaemia, ↓ Ca2+, ↑ PO43-

Ix • •

•

•

Full workup U/E/C - Rising plasma urea & creatinine - Na+ ↓ - K+ ↑ - Ca2+ ↓ - PO43- ↑ Urinalysis; - Urinary specific gravity or osmolality reflects the activity of ADH and the sensitivity of the collecting tubule to its effects, except in situations in which abnormal solutes are excreted by the kidney, resulting in an osmotic diuresis. - Proteinuria - DDX Orthostatic proteinuria, fever, or after exercise - Haematuria - DDx Postural haematuria in normal persons, pregnancy & athletes during training - Eosinophiluria - in interstitial nephritis Also; - Autoantibodies (ANA, ANCA, anti-dsDNA, anti-GBM) - ASOT - Bence Jones proteins - CXR - pulmonary oedema? - ECG - HyperK+ - Renal U/S

Management • •

Monitor & treat cause & fluid & electrolyte balance accordingly * Give fluids at the rate of (500mls + previous days output)/d Dialysis; * Persistent HyperK+ (K+ >7mmol/L) * Severe or worsening metabolic acidosis (pH <7.2 or base excess <-10) * Refractory pulmonary oedema * Uraemic encephalopathy * Uraemic pericarditis

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Complications • •

•

• •

Metabolic acidosis * Aim for a pH of 7.2 & a HCO3- of 12 * Deficit HCO3- * wt (Kg) * volume of distribution (0.6) = HCO3- over 30mins HyperK+ - may cause arrhythmias or cardiac arrest - ECG changes; * Tall 'tented' T waves * Small or absent P wave * ↑ P-R interval * Widened QRS complex * 'sine wave' pattern * Asystole - Rx; * 10mL 10% calcium gluconate IV over 2 min - This is cardio-protective * 0.2U IV insulin + 10mls 10% Glucose (1:5) over 10mins; Insulin stimulates the intracellular uptake of K+, lowering serum K+ by 1-2mmol/L over 30-60min * β-agonists e.g. nebulized salbutamol * Consider calcium resonium PO/PR to bind K+ in the GIT; SE: Constipation Pulmonary oedema - C/P - gallop rhythm, ↑BP,↑JVP, basal crepitations, peripheral oedema - Mx * Sit up & give high flow oxygen by mask * Venous vasodilator, e.g. morphine (+ metoclopromide) * IV diuretic e.g. furosemide over 1hr * If no response, urgent haemodialysis or haemofiltration * CPAP therapy * Venesection (100-200mL) if the patient is in extremis * ± IV nitrates GIT bleeding 2° to stress ulcers - Ranitidine or Omeprazole Coma

Prognosis Complete recovery of renal function usually occurs within days/weeks. Worse is oliguric

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CRF Definition Substantial, irreversible, & usually long standing loss of renal function

Classification (Normal GFR 80-120mL/min) • • • •

Mild (GFR 30-50mL/min) Moderate (GFR 10-29mL/min) Severe (GFR <10mL/min) ESRF (GFR <5mL/min)

Causes • • • • • • •

Glomerulonephritis - IgA nephropathy Pyelonephritis Interstitial nephritis - Penicillin, Rifampicin, NSAIDS, Sulphonamides, Herbals DM HTN Prostatic hypertrophy Others (rare); - Nephrocalcinosis - Myeloma - Oxalosis - Amyloidosis - Cystinosis - SLE - Alport's syndrome - Gout - Scleroderma - Vasculitis - Fabry's disease - HUS - Renal tumour

Diagnosis Suspect CRF if; - History of chronic ill-health or signs of CRF - Oliguria/Anuria - Previously abnormal blood tests - Granular contracted kidneys on U/S - (Normal kidney size - (9-12*6*3)cm; 130-150gm)

Signs/symptoms (uraemia); •

•

•

Anaemia - Causes; - Relative deficiency of erythropoietin - Reduced dietary intake & absorption of iron & other haematinics - Diminished erythropoiesis due to toxic effects of uraemia on marrow precursor cells - Reduced red blood cell survival - Increased blood loss due to capillary fragility & poor platelet function Renal osteodystrophy; i) Osteomalacia - ↓ activity of renal 1-α-hydroxylase → diminished intestinal absorption of Ca2+→ HypoCa2+ → reduction in the calcification of osteoid particularly in the spine, pelvis, and lower extremities; the fibrous lamellae become visible on x-rays, and incomplete ribbon like areas of demineralization (Pseudofractures, Looser's lines, Milkman's syndrome) ii) Osteitis fibrosa cystica (Hyperparathyroid bone disease) - 2° hyperparathyroidism 2° to HypoCa2+ & HyperPO43-; - A disease of bone that is characterized by fibrous degeneration of bone & the formation of cystic cavities & results in deformities of the affected bone & sometimes in fractures; also 3° or autonomous hyperparathyroidism with HyperCa2+ iii) Osteoporosis - 2° to malnutrition iv) Osteosclerosis - idiopathic reaction in the base of skull, vertebrae & sacral area Proximal myopathy; - 2° to poor nutrition, hyperparathyroidism, vitamin D deficiency & disorders of electrolyte metabolism C/P; - Muscle cramps - give quinine sulphate - Restless leg syndrome - give clonazepam

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•

•

•

• • • •

• •

Neuropathy - 2° to demyelination of medullated fibres with the longer fibres being involved at an earlier stage - Sensory neuropathy - Paraesthesia - Motor neuropathy - Foot drop - Uraemic autonomic neuropathy - Delayed gastric emptying, diarrhoea, postural hypotension Endocrine function - Hyperprolactinaemia & galactorrhoea- amenorrhoea, loss of libido & sexual function - give bromocriptine - Hyperparathyroidism - ↑ insulin half life due to ↓ tubular metabolism; Post-receptor defect in insulin action leading to resistance Cardiovascular disorders; - Hypertension * Na+ retention * Hypersecretion of renin - exaggerated by renal vascular disease leading to hypoperfusion - Pericarditis 2° to uraemia that may lead to pericardial tamponade & constrictive pericarditis - Cardiomegaly - Pleural effusion - Pulmonary or peripheral oedema - Atherosclerosis - may be accelerated by hypertension - Vascular calcification that may lead to limb ischemia Metabolic acidosis - if sustained may result in protons being buffered in bone in place of calcium, thus aggravating metabolic bone disease Infection due to impaired immunity - 2nd most common cause of death in dialysis patients after cardiovascular disease Bleeding due to impaired platelet function & prolonged bleeding time 2° to capillary fragility Uraemia * Uraemic fetor is the characteristic fishy odour of the breath due to the conversion of urea to ammonia in the saliva. * The skin may appear yellow-brown; occasionally, urea from sweat may crystallize on the skin as uraemic frost * Pruritus; Excoriation * Brown nails * Hiccoughs DDx • Chest disease • Diaphragmatic disease • Occlusion of the vertebrobasilar circulation (cerebellum, brain stem, occipital lobes) Rx - Chlorpromazine * Pericarditis * Encephalopathy - especially if levels are >50-60mmmol/L PUD - due to increased H. pylori infestations ESRF; - Anorexia, nausea, vomiting - Pruritus - Na+ & water depletion - Kussmaul's respiration (unusually deep respiration related to metabolic acidosis) - Hiccoughs - Anaemia - Arrhythmia - Muscle twitching - Encephalopathy; Seizures; Coma

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Tests •

•

• • •

•

Full workup; - Normochromic normocytic anaemia - ↑ Urea, ↑ creatinine - Urate ↑ - Glucose (DM) - ↓ Ca2+, ↑ PO43- ↑ Alkaline phosphate (renal osteodystrophy) - Serum alkaline phosphatase is directly related to the amount of osteoid in the skeleton (regardless of the type) thus indicates the severity but not the quality of the bone disease. - ↑ PTH (hyperparathyroidism) Renal U/S - Small granular contracted kidney with thinning of the cortex & loss of the corticomedullary junction May be normal or large in; i) DM ii) PCKD iii) Amyloidosis iv) Myeloma v) Systemic sclerosis vi) Asymmetrical renal vascular disease IVU/DTPA scan - The latter is only indicative of CRF if renal scarring is still noted 6mo after original diagnosis CXR - Cardiomegaly, pleural/pericardial effusion or pulmonary oedema Bone x-rays - renal osteodystrophy - The erosion of cortical bone by osteoclastic resorption accounts for the roentgenologic finding of subperiosteal resorption, periosteal and endosteal resorption cavities, cortical striation, and cortical thinning in the following areas; i) Erosive cortical defects in the skull ("pepper pot skull") ii) A "rugger jersey" appearance of the spine iii) Acro-osteolysis of the clavicle iv) Erosion of the terminal finger phalanges v) A ground-glass appearance of the skull, ribs, pelvis, and metaphysis of tubular bones reflect cancellous changes Renal biopsy - in patients with normal size kidneys

Management • • • • • • •

Treat reversible causes - relieve obstruction, stop nephrotoxic drugs Hypertension - ACE-i; Aim for a BP of <130/80 (especially if >3g proteinuria/d) - In non-diabetic patients with hypertension, CRF & proteinuria, ACE-i (& ARBs) reduce proteinuria & slow the rate of loss of renal function Oedema - Loop diuretics + metolazone Dietary advice - Na+ restriction may help control BP & prevent oedema. K+ restriction is only required in hyperK+ & acidosis; treat with HCO3- supplements Anaemia - Erythropoietin to maintain Hb 10-12g/dL + Ferrous sulphate 200-300mg TDS Renal bone disease (osteodystrophy) - treat as soon as ↑ PTH; ↓ dietary PO43- (less milk, cheese, eggs); phosphate binders (CaCO3, Al(OH)3); 1-α-hydroxylated Vitamin D analogues & Ca2+ supplements to ↓ risk bone disease, & risk of hyperparathyroidism (2° & 3°) Hyperlipidaemia - This may contribute to renal damage & increases the risk of cardiovascular disease. Treat with statins.

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02 February 2005 21:57

HUS Most common cause of acute renal failure in young children

Etiology •

•

Infection associated HUS - The disease most frequently follows an episode of gastroenteritis caused by an enteropathogenic strain of Escherichia coli (0157:H7) transmitted by undercooked meat and unpasteurized milk. The organism elaborates a toxin, called verotoxin, which is apparently absorbed from the intestines and initiates endothelial cell injury. Also Shigella dysenteriae, Streptococcus pneumoniae, coxsackievirus, echovirus, adenovirus Sporadic HUS - Idiopathic - Drugs - the Pill, cyclosporine, mitomycin C, 5-fluorouracil, ticlopidine - Pregnancy - SLE - HIV - Tumours

Characteristics i) The microangiopathic haemolytic anemia results from mechanical damage to the red blood cells as they pass through the altered vasculature. ii) Thrombocytopenia - Damaged red cells and platelets are removed from circulation by the liver and spleen iii) Acute Renal Failure is due to intrarenal platelet adhesion or damage.

Pathogenesis (HUS & TTP) The key feature may be the formation of platelet aggregates, stimulated by endothelial damage, causing release of ultra-large multimers of Von Willebrand factor, so activating platelets.

C/P ⋅ The syndrome is most common in children < 4 yr ⋅ The onset is usually preceded by gastroenteritis (fever, vomiting, abdominal pain, and diarrhea, which is often bloody) or, less commonly, by an upper respiratory tract infection. This is followed in 5–10 days by the sudden onset of; ⋅ Pallor ⋅ Irritability ⋅ Weakness, lethargy ⋅ Oliguria ⋅ Dehydration ⋅ Edema ⋅ Petechiae ⋅ Hepatosplenomegaly

DDx Other causes of acute renal failure, especially those that can be associated with a microangiopathic anemia; ⋅ Lupus ⋅ Malignant hypertension Bilateral renal vein thrombosis - Both disorders may be preceded by gastroenteritis, and in both the children may present with dehydration, pallor, and evidence of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The marked enlargement of kidneys of the child with renal vein thrombosis helps to distinguish the disorders.

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Ix The diagnosis of the syndrome is supported by the findings of; a) microangiopathic hemolytic anemia ⋅ ↓ Hemoglobin ⋅ PBF - helmet cells, burr cells, and fragmented red blood cells ⋅ ↑ Reticulocyte count ⋅ Coombs test is negative ⋅ ↑ White blood cell count b) thrombocytopenia ⋅ Thrombocytopenia ⋅ = Partial thromboplastin time ⋅ = Prothrombin time (Their prolongation is more commonly due to vitamin K deficiency than to disseminated intravascular coagulation) c) acute renal failure ⋅ On urinalysis - microscopic haematuria and proteinuria. ⋅ ↓ Na+ ⋅ ↑ Creatinine ⋅ ↑ Urate LFTs - ↑ Bilirubin - ↑ LDH - ↓ Haptoglobulin

Management -

Treat hypovolaemia & hypertension Dialysis, steroids or plasma exchange may be required

Complications ⋅ Anemia ⋅ Acidosis ⋅ Hyperkalemia ⋅ Fluid overload ⋅ Congestive heart failure ⋅ Hypertension ⋅ Uremia Extrarenal involvement may include; ⋅ Central nervous system manifestations (irritability, seizures, coma) ⋅ Colitis (melena, perforation) ⋅ Diabetes mellitus ⋅ Rhabdomyolysis

Prognosis and Rx Peritoneal dialysis - Controls the manifestations of the uraemic state and promotes recovery by removing an inhibitor of fibrinolysis (plasminogen activates inhibitor-1) from the circulation, thus allowing endogenous fibrinolytic mechanisms to dissolve vascular thrombi. Long-term observation is necessary to watch for late development of hypertension or chronic kidney disease.

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TTP

02 February 2005 22:11

Incidence Affects adult females

Causes & Pathogenesis * See HUS

C/P i) ii) iii) iv) v) •

Fever Fluctuating CNS signs (microthrombi, e.g. causing fits, hemiparesis, ↓ consciousness, ↓ vision) MAHA Thrombocytopenia Renal failure Others; - Purpura - GI or intracerebral bleeds - Haematuria - Proteinuria - ↑ U&E

Ix •

• • •

FBC; - Anaemia - Reticulocytosis and occasional circulating nucleated red blood cells - The hallmark is a microangiopathic blood picture with fragmented red blood cells (schistocytes, helmet cells, triangle forms) on the smear. One cannot make the diagnosis without significant red blood cell fragmentation. - Thrombocytopenia - White blood cells may show increased band neutrophils. Haemolysis may be manifested by increasing indirect bilirubin and occasionally hemoglobinemia and haemoglobinuria; methaemalbuminemia may impart a brown colour to the plasma. The LDH is markedly elevated in proportion to the severity of haemolysis; the Coombs test is negative. Coagulation tests (prothrombin time, partial thromboplastin time, fibrinogen) are normal unless ischemic tissue damage causes secondary DIC. Elevated fibrin degradation products may be seen, as in other acutely ill patients. Renal insufficiency may be present, with an abnormal urinalysis.

Management • • • •

Steroids or Vincristine (in steroid non responders) FFP & Plasma IVI may be needed for severe mucosal or CNS bleeding Plasma exchange Splenectomy, if needing repeat plasma exchange

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Diabetes mellitus Definition

Diabetes mellitus is a clinical syndrome characterised by hyperglycaemia due to absolute (type 1) or relative deficiency (type 2) of insulin, resulting in decreased anabolic & catabolic effects. The actions of insulin are also impaired by insensitivity of target tissues.

Classification

MODY (Maturity onset diabetes of the young) - These are subtypes of diabetes which arise from genetic defects of β cell function & constitute <5% of all cases of diabetes. LADA (Latent autoimmune diabetes in adults) - This is a slow evolving variant of type 1 diabetes in some people with type 2 who have evidence of autoimmune activity against pancreatic β cells. Medicine Page 60

Clinical examination of the Diabetic Patient Observation -

-

Weight loss (insulin deficiency) or Obesity is generally associated with abdominal distribution of fat due to accumulation of fat in the omental and mesenteric regions, producing an abnormally high waist-to-hip ratio (with high-risk upper body obesity defined as a ratio of > 1.0 for men and > 0.8 for women). This "visceral" obesity correlates with insulin resistance; subcutaneous abdominal fat has little if any association with insulin insensitivity. White spots on shoes (glycosuria) Dry mouth & tongue (dehydration) Deep sighing respiration (Kussmaul breathing) Skin & mucosal sepsis - boils, candidiasis Skin pigmentation - vitiligo, dermopathy

Hands - Dupuytren's contracture - may include nodules or thickening of the skin & knuckle pads - Carpal tunnel syndrome - presents with wrist pain radiating into the hand - Trigger finger/thumb - flexor tenosynovitis - Limited joint mobility (prayer sign) - cheiroarthropathy - inability to extend (to 180°) the MCP or IP of at least one finger bilaterally. Painless, may affect the wrists & shoulders - Wasting of small muscles/Sensory abnormality - Peripheral sensorimotor neuropathy though more common in the lower limbs Head - Xanthelasma Eyes -

↓Visual acuity Cataracts/lens opacity Cranial nerve palsy - Ophthalmoplegia, ptosis

Neck - Carotid pulses, Bruits - Thyroid enlargement Axilla - Acanthosis nigricans (dark patches) Abdomen - Hepatomegaly Insulin injection sites - Main areas used; * Anterior abdominal wall * Upper thighs/buttocks * Upper outer arms - Inspection; * Bruising * Lumps (lipodystrophy) * Subcutaneous fat deposition (lipohypertrophy) * Subcutaneous fat loss (lipoatrophy; associated with injection of unpurified animal insulins-rare) * Erythema, infection (rare) Legs Feet -

Muscle wasting Sensory abnormality Granuloma annulare Hair loss ↓ Tendon reflexes Necrobios lipoidica - one or more yellow, atrophic, shiny lesions develop on the legs (typically pretibial); characterized histologically by indistinct areas of necrosis in the dermis. Discolouration of the skin (ischemia) Loss of the plantar arch Clawing of the toes (a feature of neuropathy) Charcot neuroarthropathy Callus formation on weight-bearing areas Presence of ulcers Medicine Page 61

-

Localised infection Fungal infection may affect skin between toes & nails

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Glucose metabolism

Normal blood glucose - 3.5-6.5mmol/L When intestinal glucose absorption declines between meals, hepatic glucose output is increased in response to the counter-regulatory hormones glucagon & adrenaline, & it falls during starvation as other metabolic fuels derived from fat become more important. Insulin is secreted from the pancreatic β cells in response to a rise in blood glucose detected by a receptor in the portal vein & it lowers the glucose by suppressing hepatic glucose production & stimulating peripheral glucose uptake in skeletal muscle & fat, mediated by the glucose transporter GLUT 4

Pro-insulin in the pancreatic β cells is cleaved to release insulin & equimolar amounts of inert C-peptide whose measurement can be used to assess endogenous insulin secretory capacity.

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Investigations

DDx for Glycosuria; • Low renal threshold for glucose seen in; * Pregnancy (The renal threshold falls 2° to an increase in the GFR & in late pregnancy, lactose appears in the urine) * Fanconi syndrome * Young people • 'Lag storage' blood glucose curve/alimentary glycosuria - A rapid but transitory rise of blood glucose following a meal & the concentration exceeds the normal renal threshold; It may occur in; * Normal people * After gastric surgery, when it is caused by rapid gastric emptying & more rapid absorption of glucose into the circulation * Hyperthyroidism * Peptic ulceration * Hepatic disease DDx for solitary ketonuria (with NO Glycosuria) • Alcohol consumption • Repeated vomiting • Fasting • Strenuous exercise • ↑ fat, ↓ carbohydrate diet ** Testing should be performed on urine passed 1-2 hrs after a meal

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Impaired glucose regulation not amounting to diabetes a)

Impaired fasting glucose (fasting) - Fasting plasma glucose between 6.1-6.9mmol/L - Do 2h OGTT to exclude DM ACE-i can prevent progression to DM in those with heart failure There is ↑ risk of developing vascular disease b) IGT (post-prandial) - Fasting plasma glucose <7mmol/L - 2h OGTT - 7.8-11.0mmol/L There may be lower risk of progression to DM in IFG than IGT Managed by lifestyle advice & regular review

False +ve OGTT Found in conditions that impose a burden on pancreatic β cells (stress hyperglycaemia); * Pregnancy * Infection * MI * Severe stress * Diabetogenic drugs e.g. corticosteroids, thiazide diuretics, phenytoin

Glycosylated haemoglobin (HbA1c)

Several minor components of adult haemoglobin (HbA1) are separated from unmodified haemoglobin (HbA0) & increased in diabetes by the slow non-enzymic covalent attachment of glucose & other sugars (glycation) The rate of formation of HbA1c is directly proportional to the ambient blood glucose concentration; a rise of 1% in HbA1c corresponds to an approximate average ↑ of 2mmol/L in blood glucose. Although HbA1c concentration reflects the integrated blood glucose control over the lifespan of the erythrocyte (120 days), the estimate is weighted by changes in glycaemic control occurring in the previous 6-8 weeks before measurement (representing 50% of the HbA1c concentration); a large shift in blood glucose control is rapidly accompanied by a change in HbA1c , detectable within 2-3wks. It is usually normal in patients with impaired OGTT. False -ves; • Anaemia • Pregnancy - Glycated serum proteins ('fructosamine') can be measured to give an indication of glycaemic control over the preceding 2 weeks. Medicine Page 67

control over the preceding 2 weeks. Other proteins throughout the body also undergo glycation as a result of hyperglycaemia & thus HbA1c is used as a predictor of risk for the development of diabetic microvascular complications (e.g., neuropathy, retinopathy, nephropathy). Plasma HbA1C >7% ↑ risk of microvascular complications

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Major manifestations of disease Major manifestations of disease (Hyperglycaemia (& its complications) & Acute metabolic complications) usually begin when up to ≥50% β-cells have been destroyed.

i) Hyperglycaemia Found in conditions that impose a burden on pancreatic β cells (stress hyperglycaemia); * Pregnancy * Infection * MI * Severe stress * Diabetogenic drugs e.g. corticosteroids, thiazide diuretics, phenytoin

Type I Pathogenesis

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DM Type II Pathogenesis a) ↓ Insulin secretion & insulin resistance associated with; - Obesity - ↑ rate of release of non-esterified fatty acids causing post receptor defects in insulin's action - Calorie excess - Exercise lack - Syndrome X

Px

b)

9 Exercise more 9 Weight loss 9 Statins 9 Hypotensives 9 Hypoglycaemics Secondary causes; - Drugs (steroids, thiazides & phenytoin) - Pancreatic disease; * Pancreatitis * Surgery in which >90% pancreas is removed * Haemochromatosis * Cystic fibrosis * Pancreatic cancer - Endocrine disease; * Cushing's disease * Acromegaly * Phaeochromocytoma * Thyrotoxicosis - Others; * Acanthosis nigricans * Congenital lipodystrophy with insulin receptor antibodies * Glycogen storage diseases ≥ 80% concordance in identical twins Most are over 40yrs, but teenagers are increasingly getting it (MODY)

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Management

* Thiazolidinediones e.g. Rosiglitazone are added in the management of Type 2 diabetes as they ↑ insulin sensitivity mainly in adipose tissue * Sulphonylurea of choice - Glibenclamide - Long acting sulphonylurea associated with greater risk of hypoglycaemia; Avoid in the elderly. ▪

▪

Global assessment of risk of macrovascular disease & mortality from MI & stroke; i) Smoking ii) Hypertension * DM Type I - Hypertension usually indicates the presence of diabetic nephropathy & ACEi/ARBs are used as 1st therapy to maintain BP at <130/80mmHg in the presence of nephropathy or <140/90mmHg if no nephropathy. * DM Type II - Treatment of Hypertension in Type 2 patients prevents both macrovascular & microvascular complications & ABC (dihydropyridine CCBs ) D are used to maintain the BP at <140/90mmHg iii) Raised cholesterol - give a statin (↓ cholesterol synthesis in the liver; SE: Rhabdomyolysis thus given nocte) if LDL >3mmol/l or plasma total [cholesterol] is >5mmol/l or SBP>140mmHg + Aspirin prophylaxis. iv) Diabetes (Target HbA1c ≤7%) Diet;

-

Saturated fats ↓ Sugar ↓ Starch - carbohydrate ↑ Moderate protein Do not prohibit coffee (may ↑ insulin sensitivity)

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▪

If creatinine ↑ or microalbuminuria; - ACE-i or ARBs - Restrict protein Oral Hypoglycaemics

Drug Sulphonylureas ⋅ Tolbutamide ⋅ Gliclazide ⋅ Glipizide ⋅ Glimepiride Biguanides ⋅ Metformin (Glucophage®)

MOA ⋅ Insulin secretagogue ⋅ Reduce hepatic release of glucose

α Glucosidase inhibitors

Delay carbohydrate absorption n the GUT by selectively inhibiting disaccharidases Bind peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor that regulates the expression of several genes involved in metabolism, & work by enhancing the actions of endogenous insulin ↑ insulin sensitivity (mainly in adipose tissue) only in patients with insulin resistance Insulin secretagogues

Thiazolidones ⋅ Rosiglitazone ⋅ Pioglitazone

Meglitinides & amiono acid derivatives ⋅ Repaglinide ⋅ Nateglinide

⋅ ↑ insulin sensitivity ⋅ ↑ peripheral glucose uptake ⋅ Impairs glucose absorption by the GIT ⋅ Inhibits hepatic gluconeogenesis

Indication

⋅ Obese patients ⋅ Combination therapy

Combination therapy

Combination therapy

Prescribed with metformin

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SE ⋅ Increase in weight which increases insulin resistance ⋅ Hypoglycaemia ⋅ GI symptoms C/I ⋅ Impaired renal function ⋅ Impaired hepatic function ⋅ Alcoholics in whom the risk of lactic acidosis is increased – treat with bicarbonate, insulin & glucose ⋅ Flatulence ⋅ Abdominal bloating ⋅ Diarrhoea ⋅ Weight gain ⋅ Fluid retention

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* 1° treatment failures - People with type 2 diabetes who fail to respond to initial treatment with sulphonylureas * 2° failures (i.e. after a period of satisfactory glycaemic control); - Late-onset Type I diabetics who develop an absolute deficiency of insulin - Insulin-deficient diabetics (Type 1) who present as Type2 - Diabetics with significant circulating plasma insulin levels who are usually obese & have failed to lose weight while supposedly taking a low-energy diet In diabetic patients who are requiring increasing doses of sulphonylurea or biguanide, either alone or in combination with each other or with a thiazolidinedone, the introduction of a single dose of an intermediateacting insulin (usually isophane) may improve glycaemic control & delay the development of overt pancreatic β cell failure. Insulins The duration of action of short-acting, unmodified insulin ('soluble' or 'regular' insulin), can be extended by; • Addition of protamine & zinc at neutral pH (isophane or NPH insulin) • Addition of excess zinc ions (lente insulin)

It is injected SC into; • Anterior abdominal wall • Upper arms • Outer thighs • Buttocks Local trophic action of insulin at injection sites (lipohypertrophy) delays absorption, so repeated injection at the same site should be avoided. A single dose of insulin consists of short & intermediate-acting insulins in a ratio of 1:2, & the total daily dose is administered ⅔ in the morning & the remaining ⅓ in the evening Insulin therapy is used in Type 2 patients; * After 2° failure * for it's anabolic effects in patients with additional co-morbid factors e.g. TB, severe wasting & other infections, SE; • Hypoglycaemia • Weight gain • Lipodystrophy at injection sites • Morning Hyperglycaemia a) Somogyi effect-Patients with Type 1 may develop nocturnal hypoglycaemia, stimulating an adrenergic and glucagon response and, to a lesser extent, cortisol and growth hormone hypersecretion to produce hyperglycaemia by 7:00 AM. Rx - Reducing inappropriately high doses of administered insulin b) Dawn phenomenon is morning hyperglycaemia and insulin resistance due to predawn surges in growth hormone and, to a lesser extent, other counter regulatory hormones. This phenomenon occurs primarily in younger, generally Type I patients, in most Type 2 and Normal subjects as well. Ix - 3am glucose monitoring for verification Rx - Moving evening intermediate insulin shots to bedtime (10pm), thereby producing peak morning hyperinsulinism at 6am, the peak time of insulin resistance. Serial blood sugars (6am, 11am & 3pm) are used to confirm above phenomena • Peripheral oedema (insulin treatment causes salt & water retention in the short term) • Rare - Insulin antibodies (animal insulins) & Local allergy

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Complications of Hyperglycaemia Mechanisms of Complications Three major theories, which are not mutually exclusive, have been proposed to explain how hyperglycaemia might lead to the chronic complications of DM; i) Increased intracellular glucose leads to nonenzymatic glycosylaton of cellular proteins from the interaction of glucose with amino groups on proteins forming advanced glycosylation end products (AGEs) which have been shown to; • Cross-link proteins (e.g., collagen, extracellular matrix proteins) • Alter extracellular matrix composition and structure • Promote glomerular dysfunction • Induce endothelial dysfunction • Reduce nitric oxide synthesis • Accelerate atherosclerosis ii) Hyperglycaemia increases glucose metabolism via the sorbitol pathway (glucose is converted to sorbitol by the enzyme aldose reductase). Increased sorbitol concentrations affect several aspects of cellular physiology (decreased myoinositol, altered redox potential) and may lead to cellular dysfunction. iii) Hyperglycaemia increases the formation of diacylglycerol leading to activation of certain isoforms of protein kinase C (PKC), which, in turn, affect a variety of cellular events that lead to DM-related complications. Growth factors appear to play an important role in DM-related complications. • Vascular endothelial growth factor (VEGF) is increased locally in diabetic proliferative retinopathy and decreases after laser photocoagulation. • Transforming growth factor β (TGF-β) is increased in diabetic nephropathy and appears to stimulate basement membrane production of collagen and fibronectin by mesangial cells. • Other growth factors, such as platelet-derived growth factor, epidermal growth factor, insulinlike growth factor I, growth hormone, basic fibroblast growth factor, and even insulin, have been suggested to play a role in DM-related complications. Other Possible mechanisms; • Haemodynamic disturbances • Haemorrheological & coagulative abnormalities • Microvascular hypertension • Endothelial dysfunction • Increased capillary permeability

Classification of Complications i)

Macrovascular disease - Increased permeability of arterial endothelium + hyperinsulinaemia + hypertension increases the deposition of artherogenic lipoproteins causing atherosclerosis & arteriosclerosis leading to; • CNS disease - Strokes, TIAs • Cardiac disease - Cardiac failure, Angina & MI • Peripheral vascular disease - Intermittent claudication, Gangrene Macrovascular disease develops prematurely in diabetics and is usually severe, with a striking predominance in diabetic women. BP is normally taken from both arms & ankles.

ii) Microvascular disease, with thickening of the capillary basement membrane & associated increased vascular permeability. It contributes to mortality by; • Nephropathy leading to renal failure • Neuropathy; - Somatic neuropathy - Visceral (Autonomic) neuropathy causes; * Difficulty in walking * Chronic ulceration of the feet * Bowel & bladder dysfunction • Retinopathy leading to blindness With probably small artery occlusion in the heart as well.

Factors Associated with increased mortality & morbidity in diabetic patients • • • •

Duration of diabetes Early age at onset of disease High Glycated Hb (HbA1C) Hypertension

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• • •

Proteinuria; microalbuminuria Obesity Hyperlipidaemia

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a) Diabetes Nephropathy Diabetic nephropathy develops in about ⅓ of type I DM patients and in fewer of type II DM patients.

Risk factors • • • • • •

Poor control of glucose Long duration of diabetes Presence of other microvascular disease Ethnicity (e.g. Asians) Pre-existing hypertension Family history of diabetic nephropathy &/or hypertension

Pathogenesis Hyperglycaemia causes glycosylation of glomerular proteins, leading to thickening of the glomerular capillary basement membrane and mesangial expansion. The most nearly pathognomonic lesion is nodular diabetic glomerular sclerosis, frequently termed the Kimmelstiel-Wilson lesion though the more prevalent, and perhaps of greater pathophysiologic significance, is the diffuse diabetic glomerular sclerosis.

Stages; I- Hyperfiltration (GFR>120mL/min) - 0yrs II- Normal GFR (80-120mL/min) - 10yrs III- ↓GFR (<80mL/min) - Microalbuminuria → Sustained proteinuria ± Hypertension - 10-14yrs ** Microalbuminuria (albumin excretion 25-250mg/d) is reversible sometimes - & more likely if; - Recent onset - HbA1C <8% - SBP <115mmHg - Cholesterol <5mmol/L IV- Nephrotic range proteinuria (>3g/d) - 14yrs V- ESRF (GFR<5mL/min) - 16yrs Type 1 DM nephropathy is characterized by macroalbuminuria (albumin excretion >200µg/min or >300mg/d), ↓ GFR & ↑ BP. It occurs 10-15yrs post diagnosis & ESRF 15-20yrs later (rare after 30yrs) Type 2 DM ('maturity onset') nephropathy - >10-30% have nephropathy at diagnosis Patients with diabetes are prone to other renal disease; • Papillary necrosis • ARF from contrast material • Chronic interstitial nephritis • Type IV renal tubular acidosis (Hyperkalaema; Hyperchloraemic metabolic acidosis)

Prevention/Management; • • •

•

Improved control of blood glucose - In CRF 2° to Diabetic nephropathy, insulin requirements decrease due to ↑ insulin half life due to ↓ tubular metabolism & Post-receptor defect in insulin action leading to resistance BP control; * + proteinuria - 125/75mmHg * - proteinuria - 130/80mmHg Drug prophylaxis - ACE-i/ARBs prophylaxis SE - ARBs: ↑K+, flushing, myalgia, headaches, dyspepsia, renal artery stenosis, cough (rare) Or Non-dihydropyridine CCBs - diltiazem, verapamil - Aspirin 6 monthly tests for microalbuminuria; - Albumin excretion rate of 25-250mg/d - EMU albumin:creatinine ratio >3 * Have a very poor prognosis once dialysis is begun.

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b) Diabetic Neuropathy

Polyneuropathy i)

ii)

Symmetrical sensory polyneuropathy ▫ Symptoms * Pain in the lower limbs (dull, aching &/or lancinating, worse at night, & mainly felt on the anterior aspect of the legs) * Paraesthesia in the feet & rarely, in the hands * Burning sensations in the soles of the feet * Cutaneous hyperaesthesia * An abnormal gait (wide based) - associated with a sense of numbness in the feet * Motor weakness & wasting develop only in advanced cases, but subclinical motor nerve dysfunction is common ▫ Signs * Diminished perception of vibration sensation distally but 'Glove-&-stocking' impairment of all other modalities of sensation * Loss of tendon reflexes in the lower limbs * Toes may be clawed with wasting of the interosseous muscle, which results in increased pressure on the plantar aspects of the metatarsal heads with the development of callus skin at these & other pressure points * Foot ulcers * Charcot neuroarthropathy with disorganisation of joints may cause serious deformity Asymmetrical motor diabetic neuropathy / Diabetic Amyotrophy - Severe & progressive weakness & wasting of the proximal muscles of the lower (& occasionally upper) limbs due to ? Infarction of the lower motor neurons of the lumbosacral plexus S/S * Pain in the lower limbs (dull, aching &/or lancinating, worse at night, & mainly felt on the anterior aspect of the legs); Paraesthesia; Hyperaesthesia * Marked loss of weight ('neuropathic cachexia') * Absent tendon reflexes on affected side(s) * Sometimes there is extensor plantar responses (Babinski +ve) * CSF protein is often raised

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Mononeuropathy - Either motor or sensory function can be affected within a single peripheral nerve. Nerves commonly affected are; * CN III & VI - diplopia * CN VII * Femoral nerve * Sciatic nerve * Truncal radiculopathies - 2° to involvement of other single nerves resulting in paresis & paraesthesia in the thorax & trunk * Nerve compression palsies commonly affect the median nerve - carpal tunnel compression syndrome; & less commonly the ulna nerve; * Common peroneal nerve compression occasionally causes foot drop.

Autonomic neuropathy This is not necessarily associated with peripheral somatic neuropathy & either parasympathetic or sympathetic nerves may be involved predominantly in any one system or more. Involvement tends to be patchy & development is later than somatic neuropathy, & improved control rarely results in amelioration of symptoms • Causes * DM * GBS * HIV * Amyloidosis • S/S

**Postural hypotension ( faints after standing, eating, exercise, or hot baths) - postural drop of ≥ 30/15mmHg; variation of <10bpm with respiration ** Erectile dysfunction causes; • Neuropathy • Vascular disease • Psychological factors - Depression, Anxiety, Reduced libido • Alcohol • Antihypertensive drugs - thiazide diuretics, β blockers • Testosterone deficiency • Prolactinaemia Medicine Page 79

Management

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The Diabetic Foot

Aetiology i) Neuropathy ii) Neuro-ischemia iii) Ischemia The above lead to a usually painless, punched-out ulcer in an area of thick plaque callus skin beneath which tissue necrosis has occurred & this eventually breaks through to the surface as a result of trauma (± superadded infection, pus, oedema, erythema, crepitus, odour)

Texas Classification of Foot Ulceration Grade 0

1

Classification Foot is “at risk” for developing ulcer. Skin remains intact, but there is underlying bony deformity that places foot at risk for skin breakdown Lesion affects skin only

2

Deep lesions that involve underlying tendons, bones, or ligaments

3

Abscess or osteomyelitis present as complication of ulcer

4 5

Gangrene is present in the toes or forefoot Entire foot is gangrenous

Treatment Proper footwear plus other preventive measures such as patient education, & surgical correction Outpatient dressing changes or total contact cast. Antibiotics usually not necessary. Surgical debridement & hospitalization for aggressive wound care & IV antibiotics. Goal is conversion to Grade 1 ulcer Emergency surgery for drainage of acute infection. Wound often left open, with dressing changes performed until definitive closure or amputation is done at a later date Appropriate amputation Appropriate amputation

Management - Normoglycaemia; normal BP - Relieve high pressure areas with bedrest ± therapeutic shoes - Regular chiropody (remove dead tissue)

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-

If there is cellulites -IV Benzyl penicillin 600mg QID + Flucloxacillin 500mg QID ± metronidazole 500mg TDS Surgery; * Abscess or deep infection; Spreading anaerobic infection * Suppurative arthritis * Severe ischemia - gangrene/rest pain

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c) Diabetic Retinopathy Most common cause of blindness in adults 30-65yrs

Risk factors • • • • • • • • •

Early onset, long duration of diabetes Poor glycaemic control Smoking Hypertension Hyperlipidaemia Pregnancy Use of the 'pill' Excessive alcohol consumption Evidence of microangiopathy elsewhere - neuropathy, nephropathy

Pathogenesis Hyperglycaemia has direct effects on retinal endothelial cells & pericytes, loss of which impairs vascular autoregulation →; i) Increased retinal blood flow & metabolism → increased production of vasoactive substances & growth factors including vascular endothelial growth factor which stimulates endothelial cell growth → capillary closure → chronic retinal hypoxia & new vessel formation ii) Increased vascular permeability → exudative changes

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Clinical feature

Description

Microaneurysms

Earliest clinical abnormality detected as tiny, discrete, circular, dark red spots near to, but apparently separate from, the retinal vessels arising mainly from the venous end of capillaries near areas of capillary closure. Occur in the deeper layers of the retina & hence are round & regular in shape – blot haemorrhages. Superficial flame-shaped haemorrhages occur in hypertensive diabetics Occur in the perimacular area as a result of leakage of plasma lipids from abnormal retinal capillaries & overlie areas of neuronal degeneration Occur within 5 disc diameters of the optic disc & represent arteriolar occlusions causing retinal ischemia & hence are a feature of pre-proliferative diabetic retinopathy; also in uncontrolled hypertension Dilated tortuous capillaries representing the remaining patent capillaries in an area where most have been occluded Venodilatation (? 2° to increased blood flow), ‘beading’ (sausage like changes in calibre) & increased tortuosity including ‘oxbow lakes’ & loops indicating widespread capillary non-perfusion, a feature of pre-proliferative retinopathy Arise from the venous circulation on the optic disc - NVD or elsewhere e.g. the retina - NVE in response to areas of ischemic retina. They are liable to rupture, causing haemorrhage which may be intraretinal, pre-retinal (‘sub-hyaloid’) or into the vitreous. Serous products leaking from these new vessel systems stimulate a connective tissue reaction, retinitis proliferans & retinal detachment (in NVD) can occur due to contraction of adhesions between the vitreous & the retina. NVE + Vitreous Haemorrhage - High risk of Blindness

Retinal Haemorrhages

Hard Exudates Cotton wool spots

Intraretinal microvascular abnormalities (IRMA) Venous changes

Neovascularisation

Ix • •

Fundoscopy Fluorescine Angiography - Injected into vessels & leaks are seen

Mx •

•

Retinal Laser Photocoagulation is an effective treatment, provided it is given at a relatively early stage when the patient is usually symptomless. It; * Destroys areas of retinal ischemia * Reduces growth factor production (e.g. VEGF) * Seals leaking microaneurysms * Obliterates new vessels directly on the retinal surface (but not on the optic disc) which may extend to the anterior surface of the iris (rubeosis iridis) obstructing the drainage angle of the eye & the outflow of aqueous fluid, causing 2° glaucoma SE - Can cause extensive scarring causing significant visual field loss & reduce night vision Vitrectomy may be used where visual loss is due to recurrent vitreous haemorrhage which has failed to clear, or retinal detachment resulting from retinitis proliferans

Screening • •

<30yrs - Annual Ophthalmic Examination starting 5yrs after diagnosis >30yrs - Annual Ophthalmic Examination starting at time of diagnosis

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Other causes of visual loss in diabetes Relate to cardiovascular risk factors (smoking, hypertension, hyperlipidaemia) • CN III & VI - diplopia • Age-related macular degeneration • Retinal vessel occlusion • Non-arteritic ischemic optic neuropathy • Glaucoma • Cataract - permanent lens thickness & opacity 2° to; - Age - Increased metabolic insult to the lens in people with diabetes (snow-flake cataract) - does not affect vision Indication for cataract removal; - Degree of visual impairment - When adequate assessment of the fundus, or laser treatment to the retina, is prevented

d) Others Diabetic Cardiomyopathy •

Macrovascular disease causes Angina & Painless myocardial infarction in diabetics are often manifested by atypical symptoms; recurrence is frequent, and the long-term prognosis is poor, with a higher incidence of congestive heart failure and ventricular rupture. • Autonomic neuropathy frequently occurs and results in sympathetic denervation manifested by a fixed tachycardia with subsequent parasympathetic damage that results in lowering of the heart rate. Complete autonomic cardiac denervation finally occurs, resulting in a heart rate that is no longer responsive to such physiologic stimuli as standing (postural hypotension) Echocardiographic studies show abnormal systolic and diastolic function, with impaired diastolic filling as one of the earliest manifestations of diabetic cardiomyopathy. Various studies have shown diabetics to have a delay in the opening of the mitral valve, a longer pre-ejection period, and a shorter left ventricular ejection time, resulting in decreased filling and contractility. The cause of the left ventricular dysfunction is probably multifactorial, reflecting the effects of both hypertension and coronary atherosclerosis.

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ii) Acute metabolic complications a) Hypoglycaemia (Blood glucose <3.5mmol/L)

-

Severe hypoglycaemia - Hypoglycaemia requiring the assistance of another person for recovery. Occasionally, sudden death occurs during sleep in otherwise healthy young patients with type 1 diabetes ('dead-in-bed syndrome'); hypoglycaemia-induced cardiac arrhythmia or acute respiratory arrest with impaired baroreflex sensitivity has been implicated. In a normal person, symptoms are usually experienced when the venous or capillary blood glucose is around 2.5-3mmol/l. In diabetics who are chronically hyperglycaemic, the same symptoms may develop at a higher blood glucose level; conversely, patients with strict glycaemic control or who experience frequent hypoglycaemia may not experience any symptoms even when the blood glucose is well <2.5mmol/l. Nocturnal hypoglycaemia; • Poor quality of sleep • Sweating (may be profuse) • Morning headaches • Restlessness • 'hangover' • Twitching • Chronic fatigue • Convulsions • Vivid dreams/nightmares PX Administration of the evening dose of depot intermediate-acting insulin at bedtime (after 2300hrs) Use of a fast acting insulin analogue before the evening meal Measure blood glucose before going to bed & take additional carbohydrate if reading is <6mmol/l

Treatment • •

Oral carbohydrate if recognised early - A commercial viscous gel solution can be applied into the buccal cavity in children, although jam or honey may be just as effective, but should not be used if the patient is unconscious. If the patient is unable to swallow; - IV glucose (Adults - 30-50ml of 50% dextrose / Children - 0.2g/kg) Or - Glucagon (1mg IM) - given for acute insulin induced hypoglycaemia. Medicine Page 86

* Diazoxide (+ a thiazide diuretic to counteract its water retention properties) is useful in the managements of patients with chronic hypoglycaemia from excess endogenous insulin secretion, either from an islet cell tumour or islet cell hyperplasia. It has no place in the management of acute hypoglycaemia.

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b) Diabetic ketoacidosis

Hyperglycaemic ketoacidotic coma only occurs in Type 1 diabetes & is caused by insulin deficiency & an increase in catabolic hormones, leading to hepatic overproduction of glucose & ketone bodies Precipitants; - Infection - Non-compliance - Wrong insulin dose - MI - Surgery

Signs & Symptoms • • • • • • •

• •

Hyperventilation (Kussmaul breathing) Ketotic breath Vomiting Lethargy Anorexia Abdominal pain Hyperglycaemia - Polyuria • Dehydration - Initially there is intracellular fluid loss but in later stages, there is marked contraction of the size of the extracellular space with haemoconcentration, a decreased blood volume & a fall in BP associated with renal ischemia & oliguria • Electrolyte loss * HypoK+ - Metabolic acidosis forces H+ into cells, displacing K+ which may be lost in urine or through vomiting. Plasma K+ may be raised initially due to disproportionate loss of water & catabolism of protein & glycogen. - Polydipsia Coma Hyperketonaemia

Investigations • • • • • •

• •

Ketonuria - Does not equate with ketoacidosis; consider alcohol if glucose is normal ↑ RBS ↑ WCC (in the absence of infection) HypoNa+ - due to osmolar compensation for the hyperglycaemia. ↑ or ↔ Na+ indicates severe water loss. As treatment commences, Na+ rises as water enters cells. Na+ is also low due to an artefact; corrected plasma [Na+] = Na+ + 2.4[(glucose-5.5)/5.5] To estimate Plasma osmolality = 2[Na+] + 2([K+]) + [Urea] + [glucose] mosmol/Kg Recurrent metabolic ketoacidosis - blood glucose may return to normal long before ketones are removed from the blood, & a rapid reduction in the amount of insulin administered may lead to lack of clearance & return to DKA. This may be avoided by maintaining a constant rate of insulin, e.g. 4-5U/h IVI, & co-infusing dextrose 10-20% to keep plasma glucose at 6-10mmol/L - the extended insulin regimen Acidosis (Bicarbonate <12mmol/l) - but without gross elevation of glucose may occur, but consider; * Overdose (e.g. aspirin) * Lactic acidosis (in elderly diabetics) Serum amylase is often raised (up to *10) & a non-specific abdominal pain is common, even in the absence of pancreatitis

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Management *

* * * * * *

Dehydration is more life-threatening than hyperglycaemia - so it's correction takes precedence

Monitor K+, glucose, creatinine & HCO3-, hourly initially. Aim for a fall in glucose of 5mmol/h, & correction of the acidosis. The use of venous HCO3-, as a guide to progress, may prevent the need for repeated arterial blood gas sampling. K+ disturbance may cause dysrrhythmias. Insert catheter if no urine is passed for >4h Treat infection or give prophylactic antibiotics Give heparin 5000U SC BD (or low molecular weight version) until mobile Change to SC soluble insulin when ketones are ≤1+ & eating If acidosis is severe (pH <7), some give IV bicarbonate - 1mL/Kg of 8.4%,over 1h & recheck pH; SE: Has effects on the Hb-dissociation curve & cerebral circulation leading to cerebral oedema

Complications • • • • • • • • •

Cerebral oedema - may be caused by; * Rapid reduction of blood glucose * Use of hypotonic fluids &/or bicarbonate Aspiration pneumonia ARDS Thromboembolism DIC Acute circulatory failure HypoK+ HypoMg2+ HypoPO42-

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c) Hyperosmolar Non-Ketotic Diabetic Coma (HONK)

Chr; • Severe hyperglycaemia (>50mmol/L) without significant hyperketonaemia or acidosis) • Severe dehydration • Pre-renal uraemia (Plasma osmolality = 2[Na+] + 2([K+]) + [Urea] + [glucose] mmol/L = 280-300mosmol/kg) Conscious level is depressed when it is high (>340mosmol/kg) Mx • 0.45% NS until the osmolality approaches normal, then 0.9% NS • Thromboembolic complications are common & prophylactic SC heparin is recommended

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CNS Lesions Anatomy

** Broca's area - Pars triangularis & Pars opercularis

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Upper motor neuron (UMN) lesions Pre-motor cortex → Motor Cortex →Pyramidal tracts →Internal capsule →Ventral Brain stem →Decussate in the medulla →Cortico-spinal tract in the Lateral columns of cord (synapse with the anterior horn cells (LMN)) Affects muscle groups not individual muscles which are under the uninhibited influence of the spinal reflex mechanisms. General; * Pyramidal lesions • Paresis (Partial or incomplete paralysis) of arm extensors & leg flexors • Spasticity (A state of increased muscular tone (clasp-knife feel) with exaggeration of the tendon reflexes (hyperreflexia)) of arm flexors & leg extensors * Loss of skilled fine finger movements * Babinski +ve - Extension of the Big toe - Fanning of the other toes - Withdrawal of the foot * ± Clonus +ve (elicited by flexing the knee & rapidly dorsiflexing the foot; >3 rhythmic, downward beats of the foot suggest UMNL * ± Hoffman's reflex - passive flicking of a finger DIP causes neighbouring digits to flex * Circumduction i) Cortical lesion; * Motor (Precentral gyrus); - Weakness involving all movements of a hand/foot - Reduced arm swinging during walking & circumduction - Normal/↓ tone - ↑ Reflexes more proximally in the arm/leg * Sensory; - 2-point discrimination & stereognosis sensory loss (The appreciation of the form of an object by means of touch) ii) Internal capsule → * Motor; - Contralateral hemiplegia - Pyramidal distribution of weakness * Sensory; - Contralateral generalised sensory loss iii) Mid-Brain * +ve Jaw Jerk reflex Extrapyramidal signs - CNS motor phenomena relating to the Basal ganglia Abnormality in initiation & maintenance of movement • Negative symptoms; - Bradykinesia/akinesia (slow/absent movement) - Lack of coordination - Loss of postural reflexes • Positive symptoms - Tremor - Rigidity/ Tremor + rigidity = Cogwheel rigidity - Involuntary movements (e.g. chorea, Tics, myoclonus, athetosis, ballismus, & dystonia) Cerebellar lesions (DASHING) • Dysdiadichokinesis - Inability to perform rapid alternating movements. Ipsilateral lack of coordination • Ataxic gait - disorders of the central vermis of the cerebellum • Slurred speech • Hypotonia • Intention tremor - The initial part of the movement is normal but as the target is approached the accuracy of the movement deteriorates; Dysmetria - The distances of targets is misjudged resulting in past-pointing • Nystagmus • Gait abnormality - wide based irregular strides; negative tandem gait • Titubation - A tremor or shaking of the head, of cerebellar origin. iv) Brainstem * Motor; - Ipsilateral CN palsy Medicine Page 94

*

Ipsilateral CN palsy - Contralateral hemiplegia Sensory; - Dissociated sensory loss - contralateral spinothalamic loss with sparing of the dorsal columns thus there is impairment of appreciation of pain and temperature but preservation of sensations of vibration and position. - Crossed sensory loss - Ipsilateral spinothalamic loss on the side of the face with contralateral spinothalamic loss of the rest of the body

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v) Spinal Cord • •

•

The cord ends at the inter vertebral disc between L1 & L2 (L3 at birth) The cord is enlarged in 2 areas; - Cervical enlargement - 50% occupation of the vertebral canal - Lumbar enlargement - 70% " " " " " - Thoracic - 75-90% Blood supply; - C1 - T2/3 - Anterior spinal artery from the vertebral artery - T3 - T8 - Single Radicular artery from T7 - T8 - L1/L2 - Single Radicular artery from T12/L1 junction

*

Dorsal column Transport ipsilateral joint position, vibration sense & accurate touch Damage may cause hypersensitivity or vibratory feelings

*

Lateral spinothalamic tract Transport contralateral pain, temperature & poorly localised touch sensation Symptoms are of severe pain 2-3 dermatome levels lower than the affected sensory level

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a) Congenital anomalies of the Spinal cord (Spinal Dysraphism)

Embryology; Most congenital anomalies of the spinal cord are the result of defective closure of the neural tube during the 4th week (24th-26th day) of development which occurs craniocaudally. The resulting neural tube defects (NTDs) also involve the tissues overlying the spinal cord; • Meninges • Vertebral arch - Spina Bifida • Muscles & skin

Aetiology; Most are sporadic but strong familial tendencies occur • Multifactorial • Chromosomal abnormalities • Racial, geographic & seasonal factors • Maternal - Infections (TORCHES); Diabetes; Alcohol abuse • Teratogens e.g. Na+ valproate • ? Folate deficiency • Basement membrane biochemical abnormalities

1. Spina Bifida - is the result of the failure of the embryonic halves of the vertebral arches to grow normally &

fuse in the median plane a) Spina Bifida Cystica - Involves protrusion of the meninges &/or spinal cord through the defect with a cyst like sac - Incidence - 1:1000 births i) Spina Bifida with Meningocele - Meninges + CSF ii) Spina Bifida with Meningomyelocele - Meningocele + Spinal cord & Spinal roots * Often associated with marked neurological deficit inferior to the level of the protruding sac due to incorporation of nervous tissue in the wall of the sac, which impairs development of the nerve fibres. Skin or a thin easily ruptured membrane may cover it. * Associated anomalies; • CNS - Hydrocephalus (80%), agenesis of the corpus callosum, lobar agenesis, polymicrogyria, rim-cortex (holoprosencephaly), intracranial cysts and lipomas, and encephaloceles. • Skeletal - Kyphoscoliosis, ribcage malformations, Hip dislocation, Talipes equinovarus, Pes cavus, • Genitourinary - Hydronephrosis, Hydroureter, Horseshoe kidney, undescended testes, hydrocele, Sphincter disturbances • Gastrointestinal - Malrotation, omphalocele, Meckel's diverticulum, inguinal hernia iii) Spina Bifida with myelocele/rachischisis - Most severe; The spinal cord is open because the neural folds failed to fuse. The spinal cord in the concerned area is represented by a flattened mass of nervous tissue. It may be caused by a NTD that is caused by a local overgrowth of the neural plate. As a result, the caudal neuropore fails to close at the end of the 4th week. Highly suspected when ↑α-fetoproteins b) Spina Bifida Occulta - Occurs in L5 & S1 in about 5-20% of normal individuals. If the skin is closed, it is indicated by stigmata of dysraphism which indicate the regions of closure of the posterior neuropore; • Hyperpigmentation • Simple dimple with a tuft of hair • Dermal sinus • Lipoma The dimple may be connected to the dura matter by a fibrous cord.

Ix Antenatal detection; • Maternal serum α-fetoproteins • Amniocentesis - α-fetoproteins & acetylcholinesterase • Foetal U/S & X-rays - Sensitivity >80% defects

2. Diastematomyelia - This refers to duplication of the spinal cord. A bony bar divides the two-hemicords, which may have separate or common dura. The conus may fail to migrate cranially.

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b) Spinal Cord Lesions; (A) Compressive; i)

Intradural; ` Intramedullary; • Congenital - Syringomyelia • Tumours Extramedullary; ` • TBM • Tumours - Metastatic deposits; Meningioma • Neurofibromatosis • Arachnoid cyst • Arachnoiditis ii) Extradural - Affect bone • Congenital; - Craniocervical abnormalities - Achondroplasia • Atlanto-axial sublaxation 2° to trauma • Cervical spondylosis • Cervical disc prolapse • Osteoporosis • TB - Epidural Abscess • Metastatic tumours • Multiple Myeloma • RA

(B) Non-Compressive; •

•

•

• •

• •

Cord infarction e.g. due to; - Vasculitis (PAN, Syphilis) - Spinal artery thrombosis - Trauma - Dissecting aortic aneurysm - Arteriovenous malformations - Fibrocartilagenous embolism - In the elderly especially during activity Infections; - Transverse myelitis - Post infectious encephalomyelitis - Zoster myelitis - CMV myelitis especially in HIV - Schistosomiasis - Syphilis Metabolic; - Sub-acute combined degeneration of the cord - B12 deficiency - Folate deficiency - Adenoleucodystrophy Toxic - Cassava poisoning Others; - MS - MND - Tropical myelopathies - HTLV - 1 - Paraneoplastic syndromes - GBS - More progressive Connective tissue disorders e.g. SLE Familial; - Friedriech's Ataxia - Hereditary spastic paraplegia Medicine Page 98

S/S; *

•

•

Motor; - Tetraplegia/paraplegia - Motor & reflex level; * Muscles unaffected above the lesion * LMN signs at level of lesion * UMN signs below the lesion NB - Tone & reflexes are reduced in acute cord compression - 'spinal shock' after trauma - Neurogenic bladder - starts as hesitancy, frequency & later as painless retention * Sensory; - Spinal or root pain - Sensory level i.e. an area of decreased or absent sensation below the lesion with normal sensation above this level (Vertebrae - Cord segment) * C2-C7 - +1 * T1-T6 - +2 * T7-T9 - +3 * T10 - Has L1 & L2 levels behind it * T11 has L3 & L4 * T12 has L5 * L1 has sacral & coccygeal segments * Localizing symptoms in compressive causes; • Intradural - Intramedullary; * No local pain * Early involvement of sphincters - Extramedullary; * Local pain but NO Local tenderness * Sphincter involved late • Extradural; - Local pain & tenderness - Radiculopathy - Sphincter involved late Cervical cord lesions; e.g. syringomyelia or cord tumours * Motor; - High cervical cord lesions - Respiratory muscles are paralysed - C5 lesion; * Tetraplegia * Reverse/inverse reflex - Tapping of the biceps muscle causes finger flexion instead of biceps contraction; Biceps - LMN; Fingers - UMN - Below C5 - Upper limbs are partially spared * Sensory; - Dissociated sensory loss - contralateral spinothalamic loss with sparing of the dorsal columns thus there is impairment of appreciation of pain and temperature but preservation of sensations of vibration and position. Thoracic cord lesions * T10 - Isolates entire lumbar & sacral cord, with paralysis of the lower limbs & viscera * The abdominal reflex is assessed by lightly stroking the four quadrants of the abdomen with a pin just a few centimetres away from the umbilicus. The response is considered normal if the umbilicus moves slightly toward the direction scratched. Its is only useful when asymmetrical - Absence may indicate contralateral spinal cord injury in the T9-11 region. - Beevor's sign - Presence of T9 & T10 roots & absence of T11 & T12 leads to upward movement of the umbilicus with contraction of the abdominal muscles. - An asymmetric abdominal reflex is the most common neurologic abnormality noted with an intrabedullary lesion, such as a syrinx, diastematomyelia, or spinal cord tumour. This reflex is depressed in; - Most central lesions - Obesity - Lax skeletal muscles (e.g. after pregnancy) - Ladies

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•

•

•

•

Lateralized cord lesions (Brown-Séquard syndrome - Syndrome due to damage of lateral half of the spinal cord) * Motor - Ipsilateral paralysis * Sensory; - Ipsilateral Dorsal column loss - Contralateral Spinothalamic loss * At the neurologic level of injury, there is also ipsilateral flaccid weakness and anaesthesia caused by damage to the nerve roots and motor and sensory neurons in that area. Conus medularis (T10-L1/L2 vertebrae) Transection causes cord & nerve root lesions * Motor; - ± Leg weakness - Early urinary retention - Erectile dysfunction * Sensory; - Back pain - Sacral sensory disturbance Cauda equina (L2-S4 nerve roots) Transection causes only nerve root lesions * Motor; - Asymmetrical, atrophic, areflexic, paralysis of the ankle & foot - ↓ sphincter power in the bladder and bowel→ incontinence of urine and faeces - The Bulbocavernosus, Cremasteric reflexes, plantar responses & knee & ankle jerks are lost * Cremasteric Reflex - contraction of scrotal musculature in response to pinching of the medial thigh * Bulbocavernosus reflex - anal sphincter contraction to penile or clitoral compression or downward pressure on the bladder trigone by a Foley catheter balloon when the catheter is gently pulled. It indicates intact sacral motor and sensory pathways when present; absence is consistent with spinal shock or with sacral spinal cord or nerve root injury. * Sensory; - Radicular pain down the legs - Back pain - Sensory loss in a root distribution Spinal shock Immediately following severe injury to the spinal cord or conus medullaris, regardless of level; a) It is characterized by systolic hypotension and bradycardia. The cause is loss of distal sympathetic tone. b) The striated muscle undergoes flaccid paralysis, with numbness below the level of the injury. Reflex response is usually present from the time of injury but is suppressed. With time, the reflex excitability of striated muscle progresses until a spastic state is achieved. c) The smooth muscle of the detrusor and rectum is affected; ƒ Early Retention with overflow incontinence ƒ Rectal impaction Spinal shock may last from a few weeks to 6 months (usually 2-3 months).

Ix • • • • • •

LP - Do not do an LP for compressive causes Plain radiography - CXR, SXR MRI Spinal angiography CT scan Myelography

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Transverse myelitis

Acute or subacute, generally monophasic, inflammatory disorder of the spinal cord. Pathogenesis; - Transverse myelitis results from an autoimmune response triggered by infection and not from direct infection of the spinal cord & often begins as the patient appears to be recovering from the infection - 40% associated with antecedent viral infection or recent vaccination e.g. influenza, measles, varicella, rubeola, mumps, and EBV and CMV, as well as Mycoplasma. C/P; -

Focal neck or back pain, followed by various combinations of; * Paraesthesias & Sensory loss * Motor weakness, and * Sphincter disturbance evolving within hours to several days.

Variations; - Mild sensory symptoms only - Devastating functional transection of the cord - Partial forms may selectively involve posterior columns, anterior spinothalamic tracts, or one hemicord. - Dysesthesias may begin in the feet and ascend either symmetrically or asymmetrically, earlier in one leg than in the other; these symptoms may initially raise a question of GBS, but involvement of the trunk with a sharply demarcated spinal cord level indicates the myelopathic nature of the process. - In severe cases, areflexia indicating spinal shock may be present, but hyperreflexia soon supervenes; persistent areflexic paralysis indicates necrosis over multiple segments of the spinal cord. DDx -

GBS MS Devic's disease - is a demyelinating disorder that presents as transverse myelitis associated with optic neuritis that is typically bilateral. SLE and other collagen-vascular diseases Sjogren's syndrome Behcet's disease Sarcoidosis may produce a subacute transverse myelopathy with severe cord swelling.

Ix; -

Mx; -

CSF may be normal, but more often there is * Pleocytosis, in severe or rapidly evolving cases, polymorphonuclear cells may be present. * CSF protein levels are normal or at most mildly elevated; * Oligoclonal banding is a variable finding but, when present, is associated with future evolution to MS. MRI findings consist of variable swelling of the cord IV methylprednisolone (500 mg qd for 3 days) followed by oral prednisone (1 mg/kg per day for several weeks, then gradual taper) is used for treatment of moderate to severe symptoms.

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Use a 100% silicon catheter changed every 3 months or a silicon coated catheter changes every 2 weeks & put the patient on urinary antibiotics e.g. Fluoroquinolones, nalidixic acid

Lower motor neurone lesions Anterior horn cells in the cord →nerve roots →plexi or peripheral nerves Affect individual muscles (motor unit) General; - Paralysis - Hypotonia / flaccidity - Wasting ± spontaneous involuntary twitching (fibrillations on EMG only) - Reduced reflexes or absent - Babinski -ve - Chronic partial denervation is seen by fasciculations (twitches visible to the naked eye) 2° to reinnervation from neighbouring intact motor neurons

Peripheral neuropathy • •

Motor - Distal pattern of weakness (e.g. foot-drop or weak hand) Sensory - Distal sensory loss

FACIAL NERVE PALSY (OHCM 389) Peripheral paralysis is flaccid and, when complete, involves the entire side of the face, including the forehead. There is movement only on the non-paralyzed side of the face, and the mouth is drawn to that side. On the affected side; * The forehead is smooth * The eye cannot be closed * The nasolabial fold is absent * The corner of the mouth droops. The forehead will wrinkle on the affected side with central paralysis, since only the lower ⅔ of the face is involved as the upper ⅓ has bilateral representation in the brain.

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Aphasia Aphasia is a disorder of the language content of speech detected by the patients inability to produce the correct word (anomia) or production of the wrong word or a nonsense word (paraphasia) Classification (see also above); • Fluent aphasia - Normal or increased number (of the wrong ) words is produced; No hemiparesis • Non-fluent aphasia - Verbal output is reduced + hemiparesis

* * *

Motor cortex - Fluency area Post sensory cortex - Comprehension area Para-Sylvian fisure - Repetition area

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Meningitis Definition - Inflammation of the meninges Types •

•

•

•

Community-acquired meningitis - Adults & older children - Neonates: * Meningococcus * E-coli * Pneumococcus * β-haemolytic streptococci - Elderly & immunocompromised * L. monocytogenes * Pneumococcus - Children <14years * Cryptococcus * H.influenzae if <4yrs & unvaccinated * TB * Meningococcus * L.monocytogenes * Streptococcus pneumoniae * Gram -ve organisms * TB Aseptic meningitis; CSF has cells but is Gram stain -ve & no bacteria are cultured on standard media. - Infective; * Virus (HSV, VZV, HIV, measles, echovirus, mumps, coxsackie, flu) * Partly treated bacterial meningitis * Fungi * Atypical TB * Syphilis * Parasites - do CSF eosinophil count * Lyme disease * Leptospirosis * Listeria * Brucella - Non-Infective; * Meningeal infiltration by malignant cells (leukaemia, lymphoma) * Chemical meningitis (intrathecal drugs, contaminants) * Drugs (NSAIDS, trimethoprim) * Sarcoidosis * SLE * Behçet's disease Nosocomial & post-traumatic meningitis - Klebsiella pneumoniae - E.coli - Pseudomonas aeruginosa - Staph. aureus Special situations - CSF shunts - staphylococcus - Spinal procedures - Pseudomonas

Risk factors • • • • • • •

Place - overcrowded closed communities, schools, day centres Head injury - Basal skull fractures or cranial or spinal injury Septic site - Distant (pneumonia) or near (sinusitis, mastoiditis, otitis media) Host factors - Complement or antibody deficiency; Extremes of age Immunosuppression - Carcinoma, AIDS, no effective spleen, SCD, hypogammaglobulinaemia, DM Foreign body - CSF shunts Associated disease - Causes recurrent meningitis; * Sarcoidosis * SLE * Behçet's disease

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Signs •

•

•

Septic signs; - ↑ T°, ↑ Pulse, ↓ BP, Tachypnoea - Slow capillary refill - Malaise, Arthritis - Odd behaviour/disorientation - present in TBM but NOT in Pneumococcus or Meningococcus - Waterhouse-Friederichsen's syndrome & meningococcemia - Haemorrhage into the adrenal cortex with a fulminant necrotizing meningococcemia, causing; * Fever * Purpura, Rash * DIC * There is shock as normal vascular tone requires cortisol to set activity of the α & β adrenergic receptors - & aldosterone is needed to maintain extracellular fluid volume - Addison's disease * Meningitis, Coma Meningeal signs; - Headache - Photophobia - Stiff neck - Kerning's sign +ve (lower back pain & resistance on passive knee extension with hips & knee fully flexed with spasms of the thigh muscles due to sciatic nerve extension) - Brudzinski sign +ve (hips flex on bending head forward) - Opisthotonus - A tetanic spasm in which the spine and extremities are bent with convexity forward, the body resting on the head and the heels. Signs of ↑ ICP; - Headache * Dull ache often mild * Worse in the morning, improves through the day * Associated with morning vomiting * Worse bending forward, coughing & straining * Relieved by analgesia - Vomiting - Irregular respiration - ↓ Pulse, ↑ BP (late sign) - Papilloedema - CN VI paresis - Gives a false lateralising sign due to its long course - Drowsiness, Irritability, Fits, ↓ consciousness/coma

DDx • • • •

Encephalitis Subarachnoid haemorrhage (blood in CSF) Acute infection (e.g. malaria) Local infection causing neck stiffness e.g. cervical nodes; tetanus (CSF normal in all these)

Investigations a) Do a concurrent RBS to compare sugar levels b) LP - provided there are NO signs of ↑ ICP or focal neurology Examine for; i) Opening pressures * Queckenstedt test - Manual pressure is applied to the jugular vein to elevate venous pressure, & if CSF pressures; ↑ - NO spinal blockage of the subarachnoid space =/≈ - Spinal blockage of the subarachnoid space e.g. a cold abscess (TB), ii) Appearance iii) Pellicle formation on standing - TB due to ↑ protein levels iv) Gram stain - meningococci v) Ziehl-Nielsen stain - TB - cultured for 6wks vi) Because culture and India ink preparations are positive in only ~50% of cases of cryptococcal meningitis, detection of cryptococcal polysaccharide antigen (CRAG) in CSF, serum, or urine is very helpful in the diagnosis of this infection

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* *

Fungal Meningitis - cf TBM Malignant Meningitis - cf TBM with normal/↑ proteins

Interpreting CSF findings: ↑ PMN count - not normally present: ⋅ Bacterial meningitis ⋅ Early phase of an aseptic meningitis Lymphocytosis (Normal - 0-4cells/mm3): ⋅ Infections - TBM, Cryptococcal, Fungal, Listeria meningitis ⋅ Aseptic meningitis ⋅ Demyelinating diseases ⋅ Brain or spinal cord tumour ⋅ Immunologic disorders including collagen vascular diseases ⋅ Chemical irritation (e.g., postmyelogram, intrathecal methotrexate). Hypoglycorrhachia (Normal - 2.8-4.2mmol/L) ⋅ Bacterial meningitis ⋅ Tuberculous meningitis ⋅ Fungal meningitis ⋅ Parasitic meningitis - request for CSF eosinophil count ⋅ Aseptic meningitis ⋅ Neoplastic involvement of the meninges ⋅ Subarachnoid haemorrhage ↑ Protein levels (Normal - 0.15-0.45g/L): ⋅ TBM ⋅ GBS ⋅ Subarachnoid haemorrhage ⋅ Polio RBC – not normally present ⋅ Traumatic tap ⋅ Subarachnoid haemorrhage Bloody CSF should be centrifuged immediately. The supernatant of a bloody tap will be clear, but it will be xanthochromic in the presence of a subarachnoid haemorrhage. Progressive clearing of bloody CSF is noted during the collection of the fluid in the case of a traumatic tap. Xanthochromia may result from: ⋅ Subarachnoid Haemorrhage ⋅ Hyperbilirubinemia

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⋅ Carotenemia ⋅ Markedly elevated CSF protein. Elevation of CSF IgG: ⋅ Multiple sclerosis. ⋅ Subacute sclerosing panencephalitis ⋅ Post infectious encephalomyelitis

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Contraindications for an immediate LP: • Evidence of increased intracranial pressure (other than a bulging fontanel); * Papilloedema - Inspection of the eye grounds is mandatory before proceeding with an LP * CN III or VI palsy with a depressed level of consciousness * Hypertension * Bradycardia with respiratory abnormalities • The patient may develop transtentorial herniation or herniation of the cerebellar tonsils following the procedure - S/S of impending cerebral herniation; * Decerebrate or decorticate posture * A generalized tonic seizure * Abnormalities of pupil size and reaction, with absence of the occulocephalic response and fixed occulomotor deviation of the eyes - CN III palsy * Respiratory abnormalities, including hyperventilation, Cheyne-Stokes, ataxic breathing, apnoea, and respiratory arrest. • Patients in whom positioning for the LP would further compromise cardiopulmonary function; • Infection of the skin overlying the site of the LP. • Thrombocytopenia with a platelet count < 20*109/L is a relative contraindication for immediate LP as it may cause uncontrolled bleeding in the subarachnoid or subdural space. c)

Myelography - X-rays of the spinal cord are taken after a contrast dye is injected into the subarachnoid space via lumbar puncture. Myelography allows visualization of abnormalities in the spinal canal; - Herniated discs - Meningeal metastasis - Extrinsic or intrinsic cord tumours - Arteriovenous malformations - Arachnoiditis - Spondylytic bars

Treatment • • • • • • •

Pneumococcus - Cefotaxime (ceftriaxone) ± vancomycin for 10-14d Meningococcus - Benzyl penicillin. Give rifampicin for 2d before discharge to eliminate nasal carrier states (cefotaxime, ceftriaxone) H.influenzae - Cefotaxime (ceftriaxone, chloramphenicol). Give rifampicin if >3mo old for 4d predischarge in Type b infection E.coli - Cefotaxime (ceftriaxone) Mycobacterium tuberculosis - 2ERHZ + 6EH + (Dexamethasone 8mg TDS for 4-6wks to reduce inflammation in the subarachnoid space which may lead to blockage of the CSF flow & also prevent fibrin formation in the base of the brain that may lead to blindness) Cryptococcus neoformans - Amphotericin B + flucytosine for 2wks then Fluconazole for 4 months L.monocytogenes - Gentamicin + ampicillin for 10-14d

Prognosis & sequelae •

Complications; - Sensorineural deafness - especially meningococcal meningitis - TBM; * Permanent neurological deficit in TBM * The brain is covered by a greenish, gelatinous exudate, especially around the base which lead to fibrosis with occlusion of the optic nerve leading to blindness. - Cerebral oedema - Cranial nerve lesions - Cerebral venous sinus thrombosis - Mental retardation *Viral meningitis has a good prognosis & no long term sequelae

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Encephalitis Inflammation of the brain parenchyma

Causes •

•

•

Viruses - HSV - HIV - Coxsackie virus - Echo virus - Rabies In Immunosuppression; - CMV - Toxoplasmosis - Listeria Abscess formation; - Staph. Aureus

Signs • • • •

Fever Meningism ↓ consciousness Convulsions ± focal CNS or psychiatric features, e.g. temporal lobe fits, amnesia, or odd behaviours

Diagnosis • • •

Unreliable clinical signs (e.g. temporal lobe signs ± temporal lobe swelling especially on the left lobe seen on CT or MRI ± periodic complexes on EEG in HSV-1 encephalitis) Associated infection CSF microscopy

Management • •

Most important cause of acute encephalitis could be due to HSV & should therefore be treated immediately with acyclovir Ceftriaxone, Benzyl penicillin + thiamine (in case of Wernicke's encephalopathy) are reasonable empirical treatments

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Vitamin B12 & Folate Vitamin B12 Deficiency Vitamin B12 is found in Liver & all other animal foods. Body stores are sufficient for 3yrs

Risk factors • • • • • • • • •

Alcoholism Fish-tapeworm infestation Malabsorption syndromes - Crohn's disease Pernicious anaemia Chronic pancreatitis Drugs: oral calcium-chelating drugs, aminosalicylic acid, biguanides Gastrectomy Vegetarian diet, without B12 supplementation Blind loop syndrome

S/S •

CNS

Subacute combined degeneration of the spinal cord. They include posterior and lateral column demyelinization in the spinal cord. Peripheral neuropathy, difficulty with balance, loss of deep tendon reflexes, joint-position & vibration sense are often affected first (dorsal columns) followed by distal paraesthesia (& sensory deficits). If untreated, weakness & stiffness ensue. Pain & T° sensation may be intact even when joint position sense is severely affected The classical triad is; i) Brisk Knee jerks ii) Absent ankle jerks iii) Babinski +ve - Extensor plantars Others; - Ataxia - Tinnitus, Vertigo - Poor finger coordination - Romberg's sign, positive - Lhermitte's sign (an electric shock-like sensation radiating down the back and into the legs on flexion of the neck). In more advanced cases, cerebral function may be altered as well, and on occasion dementia and other neuropsychiatric changes - slowing of mental processes, confusion, depression and memory defects may precede haematological changes. The biochemical basis for the neuropathy is uncertain. Inappropriate administration of moderate or large doses of folate (well in excess of 0.1 mg/d in an adult) to vitamin B12-deficient individuals may precipitate or worsen, subacute combined degeneration of the spinal cord. •

•

P/A CVS -

• Anorexia; weight loss Atrophic glossitis, Sore tongue Hepatosplenomegaly Pallor/Weakness Congestive heart failure Tachycardia/Palpitations Exertional dyspnoea Purpura

Others -

Fever Prematurely grey-haired Skin pigmentation increased Vitiligo Retinal haemorrhages Retrobulbar neuritis

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DDx · Folic acid deficiency · Liver dysfunction · Alcoholism · Myelodysplasia · Hypothyroidism · Haemolysis or bleeding · Drug effects · Neurological disorders without B12 deficiency

Ix •

•

• • •

• •

PBF - Macrocytic anaemia - ↑- MCV (110-140 fl) - Anisocytosis - Ovalocytes, Poikilocytes, Howell-Jolly bodies - Hypersegmented neutrophils - Pancytopaenia Bone marrow; - Hypercellular, megaloblasts - cytoplasmic & nuclear maturation are out of phase - as nuclear maturation is slow due to impaired synthesis of thymidine, & hence DNA - ↑ Iron stores ↓ Serum levels of B12 <150 pg/ml ↑ Homocysteine level and ↑serum methylmalonic acid level The intramedullary haemolysis of megaloblastic erythroid cells is reflected by; - ↓ Reticulocyte count - ↑ Bilirubin (<2 mg/dl) level - ↓ Haptoglobin level - ↑ LDH (often > 1000 units/ml level) - ↓ RBC lifespan. ↑ Serum ferritin Schilling test

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•

CNS -

Spinal cord - myelin degeneration of the dorsal and lateral tracts Peripheral nerve degeneration Degenerative changes of the posterior root ganglia

Rx Parenteral Vitamin B12 (cyanocobalamin) - 100 µg SC for each dose - Administer daily for the first week - Administer weekly for one month - Monthly injections for remainder of life (patients may be taught to give self-injection) Initial improvement is heralded by a marked reticulocytosis (5% after 4-5days, but serum iron falls first)

Possible complications -

HypoK+ may complicate first week of treatment if severely anaemic CNS symptoms may be permanent if patient is not treated in <6mo after symptoms begin Gastric polyps Stomach cancer

Folate Deficiency Folate is found in green vegetables, fruits, liver & is synthesised by GIT bacteria. Body stores are sufficient for 3 months.

Causes • •

• • •

Poor diet (e.g. in alcoholics) ↑ needs; - Pregnancy - deficiency associated with neural tube defects in the foetus - Haemolysis - Dyserythropoiesis - Malignancy - Long-term haemodialysis Malabsorption especially coeliac disease Tropical sprue Drugs - Phenytoin, pyrimethamine, trimethoprim, methotrexate, barbiturates, alcohol

S/S • •

Blunted affect with evidence of depression, irritability, forgetfulness, and sleep deprivation. Folate deficiency is indistinguishable from B12 deficiency in regard to peripheral blood and bone marrow findings, but neurologic lesions (as seen in B12 deficiency) do not occur.

Ix Tissue folate deficiency develops after hepatic folate stores are depleted (>4 months) and is marked by a decrease in RBC folate. Thus in folate deficiency both serum and RBC folate levels are low whereas Vitamin B12 levels are normal. Because RBC folate levels are 30-fold higher than those of serum folate, a haemolysed specimen can falsely raise serum folate levels. Differentiating Vitamin B12 deficiency & Folate deficiency; * Folate; - Urinary excretion of formiminoglutamic acid (Figlu) in folate deficiency - ↑Homocysteine level but = methylmalonic acid level * Vitamin B12 - ↑Homocysteine level and ↑serum methylmalonic acid level

Treatment Homocysteine concentrations in folate-deficient patients can be normalized by folic acid supplementation - 1mg/day PO - which increases availability of the co-substrate, methyltetrahydrofolate, & drives the pathway for homocysteine remethylation Caution: In megaloblastic anaemia, it is important to rule out vitamin B12 deficiency before treating with folic acid, which would alleviate the anaemia but permit neurologic damage to progress.

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Guillian-Barré Syndrome Synonyms - Demyelinating Polyradiculoneuropathy -

Acute Inflammatory DP Post-infective DP

GBS causes demyelination in mainly motor but sometimes also sensory nerves 1-4wks after respiratory infection or diarrhoea in ~70% patients. Idiopathic in 40%.

Incidence - All ages & Not hereditary. Signs

1-4 weeks after Surgery, Flu vaccine, or Infection (URTI, GIT - mycoplasma, VZV, HIV, CMV, EBV, Campylobacter jejuni) an ascending neuropathy occurs (? From cell-mediated hypersensitivity to myelin ± antibody mediated demyelination). Weakness begins usually in the lower extremities and progressively involves the trunk, the upper limbs, and finally the bulbar muscles, a pattern formerly known as Landry's ascending paralysis. It may advance fast affecting all limbs at once. Unlike other neuropathies, proximal muscles are more affected, flaccid tetraplegia. Sensory symptoms are common (e.g. backache, paraesthesia) but signs are usually hard to detect. Bulbar involvement occurs in about 50% of cases. Respiratory insufficiency may result. Dysphagia and facial weakness are often impending signs of respiratory failure. They interfere with eating and increase the risk of aspiration. Extraocular muscle involvement is rare.

Diagnostic Criteria

Features required for the diagnosis; a) Progressive weakness of all 4 limbs b) Areflexia Features strongly supporting diagnosis; - Progression over up to 4wks - Absence of fever at onset - Near symmetry of Symptoms - Sensory symptoms/signs only mild - Bilateral facial weakness - Autonomic dysfunction - Labiality of blood pressure and cardiac rate, postural hypotension, episodes of profound bradycardia and occasional asystole occur. - Cyto-albuminic dissociation - CSF protein ↑ with CSF WCC <10*106/L - Typical electrophysiological tests - Recovery starts 2-3wks after the period of progression has finished. Improvement usually follows a gradient inverse to the direction of involvement, with recovery of bulbar function first and lower extremity weakness resolving last & most patients regain full muscular strength, although some are left with residual weakness. The tendon reflexes are usually the last function to recover. Rarer features; - Papilloedema (? From ↓ CSF resorption) - visual impairment is not clinically evident. - Dysautonomia Features excluding the diagnosis - Purely sensory symptoms - Diagnosis of (DDx); * Myasthenia * Botulism * Poliomyelitis * Diphtheria * Porphyria * Toxic neuropathy

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Variants of GBS

a) Miller Fisher syndrome: Ataxia, Ophthalmoplegia, Areflexia b) AMAN (acute motor axonal neuropathy): pure motor involvement, previous Campylobacter jejuni infection, axonal injury, poorer prognosis for recovery c) AMSAN (acute motor-sensory axonal neuropathy): both motor and sensory involvement, otherwise similar to AMAN d) Bulbar variant: Dysphagia, Dysarthria, Drooling with descending weakness e) Other variants; * Cranial nerves frequently involved. * Pharyngeal-cervical-brachial muscle weakness * Upper extremity weakness may occur before lower extremity weakness; proximal reflexes may be lost before distal. * Only lower extremity weakness * Pure sensory forms f) Chronic inflammatory demyelinating polyradiculopathy (CIDP); Chronic relapsing & Chronic unremitting polyradiculoneuropathy are chronic forms of GBS that recur intermittently or do not improve for a period of months and years. About 7% of children with GBS experience relapses. Patients are usually severely weak and may have a flaccid tetraplegia with or without bulbar and respiratory muscle involvement.

Ix

•

• • • •

DDx • • •

• • • •

Rx

• • • • •

CSF; - ↑ protein (>*2) - present 10 days into disease not before - Glucose is normal - No pleocytosis - <10 white cells/mm3 are found The cyto-albuminic dissociation between high CSF protein and a lack of cellular response in a patient with an acute or subacute polyneuropathy is diagnostic of the GBS. This is due to leakage of proteins through the lesions at the nerve roots. DDx - Froin's syndrome - High protein & low cell count due to CSF block Nerve conduction studies - slow in acute phase Electromyography - neuropathic Vital capacity - Do on admission & 4hrly to asses respiratory function - Normal - 4L Serum CK may be normal or mildly elevated. Psychiatric: hysteria Brain disease: strokes, encephalitis Spinal cord syndromes: transverse myelitis, cord compression, cauda equina syndrome; HIV, Lyme disease, sarcoid meningoradiculitis Peripheral nerve: tick paralysis, diphtheria, porphyria, neurotoxins (heavy meals, shellfish poisoning e.g. ciguatoxin and saxitoxin, glue sniffing), metabolic (hypophosphatemia), drugs (cholesterol lowering agents, chemotherapeutics, nitrofurantoin, others), SLE and polymyositis and PAN Motor neuron: Polio Neuromuscular junction: myasthenia gravis, Eaton-Lambert, toxins (botulism, organophosphates), hypermagnesaemia Muscle disease: toxic myopathy, myositis, metabolic myopathies including HypoK+ periodic paralysis, polymyositis, critical illness polyneuropathy Patients with slow progression may simply be observed for stabilization and spontaneous remission without treatment. Supportive care, such as respiratory support, prevention of decubiti in children with flaccid tetraplegia, and treatment of secondary bacterial infections, is important. Plasmapheresis may be the most effective treatment. IV immunoglobulin (IVIG) is an alternative and has been widely used in the treatment of many autoimmune disorders. Steroids have no role in therapy of Acute GBS & prolong hospital stay. CIDP is treated with plasma exchange, sometimes requiring as many as 10 exchanges daily. Remission in these cases may be sustained, but relapses may occur within days, weeks, or even after many months; relapses usually respond to another course of plasmapheresis. IVIG may be tried in the treatment of CIDP as well as in the acute or subacute stages. Steroid and immunosuppressive drugs are an alternative, but their effectiveness is less predictable. High-dose "pulsed" methylprednisolone given IV is successful in some cases.

Prognosis Medicine Page 115

The prognosis in CIDP is more guarded than in the acute form; • 80% are left with major residual handicaps • 16% do not recover • 4% die

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DVT Risk factors •

•

Clinical risk factors: - Trauma, especially long bone fractures or crush injuries - Surgery, particularly hip and knee surgery - Prolonged immobility - Pregnancy, especially the puerperium following caesarean section (9 fold ↑ risk cf SVD) - Indwelling central venous catheters - Oestrogen use (risk is confined to current usage and is proportional to oestrogen content) - ↑ FVII, VIII, IX & X & ↓ antithrombin III - Extreme high altitude (> 14,000 feet) Pathological risk factors: - Carcinoma - Abdominal, testicular - Neoplastic cells may activate platelets, coagulation proteases, or both by secreting ADP-like activating substances and expressing TF on exposed membrane surfaces. Recurrent or migratory superficial thrombophlebitis may be an early manifestation of abdominal cancer (carcinoma of the pancreas - Trousseau's sign) or other systemic illness, including immune arteritides and hypercoagulable states. The long saphenous vein is most often involved & is associated with occult DVT in about 20% of cases. - HIV causes Vasculitis & Protein S deficiency - Syphilis - Presence of anti-phospholipid antibodies (also known as lupus anticoagulant or anti-cardiolipin antibodies) - Obesity - Nephrotic syndrome - membranous nephropathy - Thrombophilia - Deficiencies of Protein C, Protein S, Antithrombin III, all endogenous anticoagulants - Polycythemia vera - Resistance of Factor V to Activated Protein C due to the The Factor V Leiden Mutation - Mutation on Factor V abolishes a protein C cleavage site conferring resistance and thus prolongs the thrombogenic effect of factor V activation. The mutation is absent in certain populations, e.g., Asians, African Americans, and Native Americans. It may account for 25% of patients with recurrent idiopathic DVT or PE. - Homocystinuria (rare) - Campylobacter jejuni bacteraemia (very rare)

Signs -

Commoner on the left as the left common iliac vein is crossed by the right common iliac & left internal iliac arteries thus increasing resistance to flow. Acute phase - Pallor, Dolour, Colour, Tumour Mild fever Pitting oedema Homan's sign (↑ resistance/pain on forced foot dorsiflexion) should NOT be done as it may dislodge thrombus

Pre-test clinical probability scoring for DVT In patients with symptoms in both legs, the more symptomatic leg is used. i) ii) iii) iv) v) vi) vii) viii) ix)

Score (points)

Clinical feature Active cancer (treatment within last 6mo or palliative) Paralysis, paresis, or recent plaster immobilization of leg Major surgery or recent bedridden for >3d in last 4wks Entire leg swollen Collateral superficial veins (non-varicose) Pitting oedema (> in the symptomatic leg) Local tenderness along distribution of deep venous system Calf swelling >3cm compared to asymptomatic leg (measured 10cm below tibial tuberosity) Alternative diagnosis as likely or more likely than that of DVT • • •

≥3 - High probability 1-2 - Intermediate probability 0 - Lowest probability of DVT

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1 1 1 1 1 1 1 1 -2

DDx -

Cellulitis (may coexist) Ruptured Baker's cyst (both may coexist) - especially in individuals with pre-existing rheumatoid disease of the knee Spontaneous/post-traumatic calf haematoma Osteomyelitis Pyomyositis

Investigations -

Doppler U/S - Gold standard - Not sensitive if there is obstruction e.g. in pregnancy, abdominal tumours Coagulation screen - does not have much of a role Venogram Impedance plethysmography 1ds - labelled fibrinogen (C/I - Pregnancy, sensitive patients) VDRL - surrogate marker for α-cardiolipins (associated with thrombotic events); if negative, do a specific test for T. pallidum α-phospholipids test ↑ D-Dimer, Fibrinopeptides, β-Thromboglobulin - Non-specific

Treatment -

-

Conservative - Elevate limb, serial measurements, TED Stockings, Analgesia Heparin (UFH or LMWH) SC OD/BD 5/7 + Warfarin from Day 4 (Discontinue Heparin when the INR is >2 for ≥2days) * 3 mo if cause will go away (e.g. post-op immobility, illness, caffeine thrombosis) * 6-12mo if no cause is found or in thrombophilic states; Consider indefinite treatment (Reassess regularly to determine risk) * 12mo if Anti-phospholipid antibody +ve + ≥ 2 combined factor V of leiden or prothrombin gene mutation * Cancer - Anti-coagulate with LMWH (not warfarin) for 3-6mo or ? indefinitely or until the cancer is resolved * Lifelong in recurrent DVT, proximal DVT Although anticoagulation is management of choice for most patients, fibrinolytics such as urokinase, streptokinase, & recombinant tissue plasminogen activator (rtPA - Alteplase) have been evaluated clinically. Venous thrombectomy still has a role in the management of patients with extensive iliofemoral disease in which limb loss is imminent, such as in phlegmasia alba dolens. IVC filters may be used in; * Active bleeding * When anti-coagulants fail * To minimize risk of PE during venous thrombectomy

Prevention -

Stop the 'Pill' 4wks pre-op Mobilize early Unfractionated Heparin 5000U SC BD or LMWT Heparin (enoxaparin, dalteparin) - Adv. Less bleeding, no monitoring needed. Support hosiery (C/I: ischemia)

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Anticoagulants Indication -

DVT PE Stroke prevention - Post TIA, MS, MR AF Prosthetic heart valves Prevention of thromboembolism in high risk patients

Standard unfractionated heparin

Chemistry - Glycosaminoglycan (sulfated mucopolysaccharide) Pharmacodynamics Anti-thrombin (an endogenous inhibitor of coagulation) inhibits clotting factor proteases by forming equimolar stable complexes with them. Heparin catalyzes the anti-thrombin-protease reaction without being consumed. Once the anti-thrombin-protease complex is formed, heparin is released intact for renewed binding to more anti-thrombin. Anti-thrombin inhibits the intrinsic pathway; - Factor IIa (Thrombin) - Factor IXa (Christmas factor) - Factor Xa (Stuart-Prower factor) Pharmacokinetics - Onset of action - 30mins - T1/2 - 1.5hrs - Duration of action - 8hrs Indication; - Peri-op - Thromboembolic disease in the acute phase while warfarin is being initiated - Unstable angina Dosage; - 100U/Kg loading dose SC - 10,000U SC TDS * not given IM as it can cause a haematoma Monitoring; - APPT/KCCT - 1.5 - 2.5*ctrl (up to 3 in PE); ≥4 → spontaneous bleeding SE; - Thrombocytopenia - immune mediated & develops after 6-10 days presenting with arterial thrombosis White Clot Syndrome: It results from irreversible aggregation of platelets induced by heparin. The process may lead to severe thromboembolic complications like skin necrosis, gangrene of the extremities that may lead to amputation, MI, PE, stroke, and possibly death. Therefore, switch to anti-thrombin agents - Hirudin - whose action is independent of antithrombin III & is administered parenterally & monitored by APPT/KCCT; LMWT heparin may be used but there is >50% cross-reactivity in patients sensitive to Heparin. - Haemorrhage - Osteoporosis after prolonged use - HyperK+ - due to inhibition of aldosterone secretion - Hypersensitivity - Alopecia (rare) Antidote; - Protamine sulphate 1mg/100U heparin IVI given within 15mins; Max dose; 50mg (if exceeded may itself have anticoagulant effect).

LMWT heparin (enoxaparin (clexane®), dalteparin) -

Inhibit FXa but have less effect on anti-thrombin & on coagulation in general Convenient to use - SC OD/BD Longer duration of action Does not require monitoring Reduce dose in renal insufficiency

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Warfarin

Chemistry - Coumarin derivative Pharmacodynamics Coumarin anticoagulants block the γ-carboxylation of several glutamate residues in factors II, VII, IX, & X as well as the endogenous anticoagulant protein C & S. The blockade results in incomplete molecules that are biologically inactive in coagulation. This protein carboxylation is physiologically coupled with the reductive metabolism of the inactive vitamin K epoxide back to its active hydroquinone form by the reductase enzyme (vitamin K epoxide reductase) thus inhibition of this process produces a state analogous to Vitamin K deficiency with a reduction in Vitamin K dependent factors in the extrinsic pathway; - Factor II (Prothrombin) - Factor VII (Proconvertin) - Factor IXa (Christmas factor) - Factor Xa (Stuart-Prower factor) - Protein C - Protein S Pharmacokinetics - Onset of action - 48-72hrs - T1/2 - 36hrs (3-14days in children) Indication (INR target); - Prosthetic heart valves (an anti-platelet drug e.g. clopidogrel, may also be useful in these patients) (3-4.9) - AF with risk of embolization (2-3) - PE & Above the knee DVT (2-3;3.5 if recurrent) Dosage; - Induction dose - 10mg PO daily for 2 days - Maintenance dose - determined by INR - 3-9mg/d PO (taken at the same time each day) Monitoring; - PTI/INR - 2-3 SE; - Warfarin causes hypercogulability within the first few days of administration due to the rapid degradation of Protein C & S which have a short half life in plasma (2.5-3hrs) compared to the other clotting factors (FII has longest half life) thus heparin is administered initially for the first 5 days followed by warfarin from the 4th day- there is no justification for starting with both. - Hepatic dysfunction * Haemorrhage with purpura fulminans * Jaundice - Teratogenic - Cutaneous necrosis with reduced activity of protein C - Hypersensitivity - Rash - Alopecia - Diarrhoea - Unexplained drop in hematocrit - 'purple toes' - Pancreatitis Antidote; - Stop the drug and administer large doses of vitamin K1 (phytonadione) 10mg - takes 6-8hrs to take effect (disadvantage) & FFP or factor IX concentrates or cryoprecipitates - In emergencies, replace blood for blood as it has clotting factors

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Malaria Pathogenesis

* * * * * *

* *

Development in the mosquito takes from 7-20d while the latent period prior to clinical signs is 7-14d Sporozoites inoculated by an infected mosquito disappear from human blood within 30mins & enter the liver Rupture of the schizont releases more merozoites into the blood & causes fever, the periodicity of which depends on the species of parasite (see below) Gametocytes appear after about 2wks & persist even after treatment & are harmless, but are the source for infecting mosquitoes P. falciparum does not grow well in red cells that contain Hb F, C or especially S; Hb S heterozygotes (AS) are protected against lethal complications of malaria in early childhood. P. vivax cannot enter red cells that lack the Duffy blood group (West Africans & American Blacks)

Recrudescences of fever may result from multiplication in the red blood cells of parasites which have not been eliminated by the treatment & immune processes. In blood transfusion transmitted malaria, the patient gets the chills & fever almost immediately - Prevented by giving antimalarials before transfusion

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Pathology Due to; a) Haemolysis of infected RBCs * Most severe with P. falciparum, which invades red cells of all ages but especially young cells. When severe, this is termed Blackwater fever due to the associated haemoglobinuria after onset of treatment. * P. vivax & P. ovale invade reticulocytes - infections remain lighter * P. malariae invades normoblasts - infections remain lighter b) Adherence of infected RBCs to capillaries In P. falciparum malaria, red cells containing schizonts adhere to capillary endothelium in Brain, Lungs, Liver Kidney & GIT causing congestion & anoxia + rupture of schizonts with release of toxic & antigenic substances → organ damage

C/P -

Non-specific flu-like prodrome - headache, malaise, myalgia & anorexia Cough Fever & chills ± faints Vomiting Mild diarrhoea • P. vivax/ovale * Latent Period - 7-14d * Cold Stage - 0-2hrs after rupture of the RBC - Chills & rigors - Rapid ↑ in T°C * Hot Stage - 3-4hrs - Dehydration, Headache, Hot skin & vomiting - 40°C * Sweating stage - 2-4hrs - Profuse sweating - Gradual ↓ in T°C • P. malariae * Mild disease * Nephritic syndrome in children - Membranous GN • P. falciparum * Jaundice (due to haemolysis & hepatic dysfunction) * Causes of anaemia in Malaria; Medicine Page 122

-

Haemolysis Bone marrow suppression with dyserythropoiesis Splenomegaly Malnutrition - depletion of folate stores Drugs

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• Hyper-reactive malarial splenomegaly Exaggerated immune response to malaria seen in adults (especially females) who have high antibody titres to malaria & low parasitaemia. There is enormous over-production of IgM which aggregates with other immunoglobulins or complement & the aggregates are phagocytosed by reticulo-endothelial cells in the spleen & liver. There is sinusoidal lymphocytosis in the liver (+ anaemia - DDx - leukaemia) & portal hypertension may develop. Ix * Immunofluorescence in a liver biopsy section - Gray silver staining of liver * Serology - ↑IgM Mx Splenomegaly & anaemia usually resolve over a period of months of continuous treatment with Proguanil 100mg/d, which should be continued for life to prevent relapse. Complicating folate deficiency is treated with folinic acid 5mg/d.

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*

*

Severe malaria - parasite count >2% in a non-immune patient Risk of complications is increased in; - Children <3yrs - Impaired immunity in pregnancy & abortion from parasitization of the maternal side of the placenta - Splenectomy Cerebral malaria - Considered if asexual parasites are present in the blood film & the patient has impaired consciousness with confusion or coma usually without localising signs & other encephalopathies have been excluded, particularly bacterial meningitis & locally occurring viral encephalitides. Causes meningism so there is a stiff neck but kerning's is negative Hypoglycaemia - Hyperinsulinaemia induced by the disease & quinine - Impaired liver functioning - Lactic acidosis

Ix •

• • •

Blood films; * Thick - Diagnosis of low level parasitaemia * Thin; - Confirm the diagnosis - Identify the species of parasite - In P. falciparum, to quantify the parasite load (% of infected erythrocytes) Total & differential WBCs Blood cultures Serology tests for P falciparum (ParaSight F®)

Rx •

Severe malaria Quinine 20mg/kg in 10ml/kg 10% Dextrose over 4hrs then (after 8hrs) maintenance dose of 10mg/kg infused over 4hrs TDS + Doxycycline, Tetracycline or Clindamycin (until the patient can swallow tablets to complete the 7d course - Protect Quinine from development of resistance & cover for any superinfections). Doxycycline & Tetracycline are C/I in children <8yrs old. Alternative drug - Malarone (Atovaquone + Proguanil) * Consider exchange transfusion if; - the parasite density is >10% - the patient has altered mental status - non-volume overload pulmonary oedema - renal complications

•

Uncomplicated malaria Artemisinin based drugs - Artemether (IM), Artesunate (IV) for 6 days * Artenam has a rapid parasite clearance rate but is not used for prophylaxis due to it's short half life Possible combinations; - Artemether + Lumefantrine - Coartem® - Artesunate + Amodiaquine - Artesunate + Fansidar - Fansidar + Amodiaquine

•

Radical cure for malaria due to P vivax & P ovale * Primaquine 15mg/d 14d - destroys the hypnozoite phase in the liver; SE - Haemolysis may develop in those who are G6PD deficient, Cyanosis due to the formation of methaemoglobin in the RBCs is more common but not dangerous.

•

Prophylaxis; * WHO 'Roll back malaria' programme - Provision of permethrin-impregnated bed nets

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Malaria resistance • • •

R1 - Treatment reduces parasitaemia to undetectable levels R2 - Treatment initially reduces parasite load to undetectable levels then the parasitaemia increases R3 - Treatment has no effect on parasite load and parasitaemia increases

* *

Proguanil attacks the pre-erythrocytic forms Erythrocytic suppression (Schizonticidal action); - Malarone (atovaquone + proguanil) - Doxycycline - Mefloquine (useful in areas of multiple drug resistance) - Chloroquine; SE - Pruritus, haemolysis in G6PD deficient persons, impaired hearing, confusion, psychosis, seizures, agranulocytosis, exfoliative dermatitis, alopecia, bleaching of hair, hypotension & (QRS widening, T wave abnormalities). The long-term administration of high doses for rheumatologic diseases can result in irreversible ototoxicity, retinopathy, myopathy & peripheral neuropathy. Safe in pregnancy Gametocidal actions; - Chloroquine - effective against all except P. falciparum - Quinine - effective against P. vivax & P. ovale but not P. falciparum - Primaquine - effective against all 4 Fansidar should not be used for chemoprophylaxis; SE - Agranulocytosis, SJS

*

*

C/I Drugs -

Corticosteroids (dexamethasone) Other anti-inflammatory agents Adrenaline Heparin

Poor prognostic indicators/Complications; -

Coma Convulsions Hypoglycaemia Severe anaemia ARF 2° to ATN Metabolic acidosis Hyperparasitaemia

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Tuberculosis Definition Chronic infectious disease caused by - Mycobacterium tuberculosis - an acid-alcohol fast rod shaped bacillus

Classification • • •

Pulmonary tuberculosis (PTB) - Smear +ve PTB - Smear -ve PTB Extra-pulmonary TB Re-treatment cases

Epidemiology The commonest affected age group is from 15-45 years with males>females. Contributing factors to increasing burden; - HIV epidemic - Poor socio-economic status leading to overcrowded slums - Poor nutrition - Limited access to health services

Primary TB Initial infection is usually; a) Pulmonary (by droplet spread). A peripheral lesion forms (Ghon focus), & its draining nodes are infected (Ghon complex). There is early distant spread of the bacilli, then an immune response suspends further multiplication at all sites S/S - Asymptomatic Or - Phlyctenular conjunctivitis - small, multiple, yellow-grey - Cough nodules near the limbus - Sputum ± AAFBs - Lassitude - Fever - Anorexia - Night Sweats - Weight loss - Erythema nodosum - An inflammatory disease of the deep dermis and subcutaneous fat (panniculitis) characterized by tender red nodules, predominantly in the pretibial region but occasionally involving the arms or other areas.

Or

b) GI - Typically affects the ileocaecal junction & associated lymph nodes following consumption of raw milk/meat containing M. bovis

Post-primary TB In normal circumstances, the lifetime risk of development of tuberculosis from latent disease is 10%. This risk increases to 10 times in immunocompromised states e.g.; - Malignancy - Diabetes - Steroids - Debilitation (especially HIV or old age) Mechanisms relevant for the development of TB include; - Reactivation of existent dormant bacilli - Progression from recent infection to disease - Re-infection The lung lesions, Tuberculomas, contain few AAFBs & are usually located in the upper lobe & may progress & fibrose & erode into a bronchus, where favourable environment ensures rapid multiplication, rendering the patient highly contagious (Open TB). Any other site may become the clinical problem.

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PULMONARY TB -

C/P Cough ≥ 3wks ± Haemoptysis (may be massive) Intermittent fever, anorexia & Night sweats Weight loss Close contact with a case of TB Chest pain Shortness of breath

-

Fatigue & malaise Pleurisy Pleural effusion Superimposed pulmonary infection An aspergilloma/mycetoma may form in the cavities

EXTRAPULMONARY TB

a) Tuberculous lymphadenitis

Slow & painless fluctuant enlargement of lymph nodes especially the cervical, followed by matting & eventually discharge of pus. Generalised lymph node enlargement is common in HIV. Tuberculosis resulting from extension into the skin from underlying atypical mycobacterial infection, most commonly of cervical lymph nodes leads to the formation of scrofuloderma.

b) Pleural effusion (Exudative) C/P -

Difficulty in breathing Pain on the affected side of the chest Slight cough Stony dullness to percussion

c) Miliary TB Occurs following haematogenous dissemination of multiple tiny foci throughout the body (including back to the lungs). CXR shows characteristic reticulonodular shadowing with miliary infiltrates <3mm. ± Retinal TB DDx - Miliary Bronchopneumonia - Lymphoma - MTX lung - Fungal infections - Thyroid malignancy - PCP - Tropical eosinophilia - Aspiration Pneumonia - Idiopathic pulmonary haemosiderosis - Pulmonary oedema - Uraemic lung - Sarcoidosis - Leukaemia

d) Meningeal TB Pathology • Occurs shortly after a primary infection in childhood or as part of miliary TB. The usual local source of infection is a caseous infection in the meninges or brain substance adjacent to the CSF pathway. The brain is covered by a greenish, gelatinous exudate, especially around the base which leads to fibrosis with occlusion of the optic nerve leading to blindness. There are also numerous scattered tubercles on the meninges & in the brain parenchyma with massive oedema seen on CT scan as a ring enhancing lesion with a big ring. It rarely recurs after initial therapy Stages I - Clear sensorium with abnormal CSF II - Drowsiness or stupor with focal neurological signs III - Coma. *See meningitis * Severe headache is NOT a sign of TBM

e) Pericarditis i) Acute TB pericarditis - Primary exudative allergic lesion ii) Chronic pericardial effusion & constrictive pericarditis These are chronic granulomata. Fibrosis & calcification may be prominent with spread to myocardium. (Giving steroids (Prednisolone NOT Dexamethasone) to these patients for 6wks with their anti-TB drugs reduces need for pericardiectomy)

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f) Peritoneal TB Causes abdominal pain & GI upset + ascites, weight loss, lack of appetite

g) Genitourinary TB Renal tuberculosis originates in the cortex of the kidney. It progresses slowly; it may take 15-20 years to destroy a kidney in a patient who has good resistance to the infection. As a rule, therefore, there is no renal pain and little or no clinical disturbance of any type until the lesion has involved the calyces or the pelvis, at which time pus and organisms may be discharged into the urine. It is only at this stage that symptoms (of cystitis) are manifested. The infection then proceeds to the pelvic mucosa and the ureter, particularly its upper and vesical ends. This may lead to stricture and back pressure (hydronephrosis). Parenchymal destruction may occur, causing spread into the medulla and associated papillary necrosis or cavitation. S/S (start when the lesion has involved the calyces or the pelvis) - Frequency - Dysuria - Loin/back pain - Painless Haematuria - Sterile pyuria (classic) Dx - Take 3 EMU samples for AAFBs - Renal U/S Mx - Anti-TBs - If unilateral, after 3 months, cultures are still positive and gross involvement of the affected kidney is radiologically evident, nephrectomy should be considered. - If bacteriologic and radiographic studies demonstrate bilateral disease, only medical treatment can be considered. The only exceptions are; * Severe sepsis, pain, or bleeding from one kidney (may require nephrectomy as a palliative or lifesaving measure) * Marked advance of the disease on one side and minimal damage on the other (one may consider removal of the badly damaged organ).

h) TB of the Adrenals The adrenals may become infected with tuberculosis organisms via the bloodstream, causing adrenal masses, or calcification and adrenal insufficiency (Addison's disease).

i) Skin TB (lupus vulgaris) Cutaneous tuberculosis with characteristic jelly-like nodular lesions on the face, particularly about the nose and ears.

j) Bone TB When primary TB occurs in children while the epiphyses are open and the blood supply to bone ends is rich, bacilli often disseminate to the vertebrae and ends of the long bones. Infection may spread into the articular capsule, causing a monarticular arthritis. Weight-bearing joints are commonly involved, but bones of the wrist, hand, and elbow also may be involved, especially after injury. C/P - Localised pain - Swelling - Discharge of pus - Muscle weakness/paralysis - Joint stiffness

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k) TB Spine Incidence 50-60% Extrapulmonary TB Regions; - Children - T6-T11 - Adults - T8-L2 - Elderly - L3-L4 C/P - Pain - 85% - Paraplegia - approx. 50% - Deformity is a late sign - Gibbus; Kyphosis/Scoliosis - A paravertebral swelling at the involved site may represent a cold abscess, which, if neglected, may dissect down the psoas muscle and point on the anterior aspect of the thigh. DDx for a psoas abscess; * Femoral hernia * LN * Aneurysm * Saphenous Varix - Rigidity of the spine is due to muscular spasm, which results from an effort to minimize pain by immobilization. The early symptoms of night cries and restlessness are explained by pain felt when the protective spasm is relaxed during sleep. Pathophysiology Infection in the visceral organs or lungs is spread retrograde through the valveless veins of the thoracic spinal cord (Veins of Burton). Basic lesions include; - Vertebral osteomyelitis - Facet joint arthritis Sites of Infection - Para-discal regions - Anterior vertebral body - Central body - Articular posterior intervertebral joints Ix SXR i) Narrow disc space - 2° to articular cartilage destruction ii) Local osteoporosis iii) Vertebral body collapse (konstantina effect) - 2° to anterior infection of the paradiscal vertebrae leading to collapse of disc → Kyphosis iv) Paraspinal mass Rx Manage pain - Rest & ambulate when pain is controlled. Children <10yrs - Drainage & chemotherapy >10yrs - Surgery + Chemotherapy ± Posterior stabilization Surgical treatment - Radical Anterior debridement & grafting Indications; - Open biopsy, debridement & grafting - Involvement of >1 vertebrae - Resistance to chemotherapy - Signs & symptoms of cord compression - Progressive impairment of pulmonary function/Kyphosis deformity (≥50% loss of intervertebral space) Poor results - Vascular causes - Dural infection - Cord transection - Paralysis for >6mo

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Pott's syndrome Pott's disease begins in the vertebral body commonly in the lower thoracic or upper lumbar vertebrae in adults, and in the thoracic vertebrae in children next to the disc space. Characteristically, two vertebrae are involved and the disk space between them is narrowed by caseation. (This differs from metastatic carcinoma, which involves the vertebrae without narrowing the disc space). If the disease is not diagnosed and treated promptly, the anterior portions of adjacent vertebrae collapse, producing a gibbous deformity, resulting in cord compression leading to paraplegia & bowel & bladder dysfunction. A paravertebral swelling at the involved site may represent a cold abscess, which, if neglected, may dissect down the psoas muscle and point on the anterior aspect of the thigh.

l) HIV & TB Infection by HIV destroys the immune defence mechanism of the body by targeting the T lymphocytes. In normal circumstances, the lifetime risk of development of tuberculosis from latent disease is 10% while this risk increases to 10 times in HIV infected people. * Early HIV infection (CD4 >200cells/mm3) - Smear +ve reactivated upper-lobe open cavitatory PTB. Seen in 20% HIV patients * Late HIV stages - Smear -ve PTB - Miliary & atypical pulmonary TB - Extrapulmonary TB - Pericardial, abdominal, meningeal Interactions of HIV & TB; - Increased reactivation of latent TB - Presentation may be atypical - Extrapulmonary & disseminated disease - Mantoux tests become negative - Previous BCG vaccination does not prevent development of TB - Smears may be -ve for AAFBs; +ve smears tend to contain few AAFBs - follow-up sputum examinations @ 2, 5 & 8 months - Atypical CXR - lobar or bibasal pneumonia, hilar lymphadenopathy - HAART & anti-TB therapy drug interaction toxicities - ARVs should be deferred until after intensive (rifampicin containing) phase of treatment - if a decision is made to start ARVs in the intensive phase of treatment, e.g. in cases where immune suppression is thought to be extreme, & the patient's survival without ARVs is unlikely, then EFV rather than NVP should be used as Rifampicin ↓ blood levels of NVP OR Rifampicin should be substituted for Rifabutin or Rifapentin that have less liver stimulation effects. - Immune reconstitution inflammatory response (IRIS) - ARV reconstitutes CD4 count & immune function, which may lead to a paradoxical worsening of TB symptoms which are immune mediated. Rx • Avoid ARVs during intensive phase • D4T + 3TC + EFV Drug prophylaxis; • Septrin prophylaxis - 960mg/d OD PO • Isoniazid prophylaxis - 5mg/Kg (max 300mg) for 6months + Pyridoxine Indications; - Infants HIV +ve with a sputum +ve TB contact - Infants born to mother with TB - PPD +ve HIV children - 2° prophylaxis - PPD +ve adults ONLY

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Ix •

Microbiology - Relevant clinical samples (sputum, pleural fluid, pleura, urine, pus, ascites, peritoneum, or CSF) for culture - If sputum -ve, bronchoscopy with biopsy & bronchoalveolar lavage (nebulise with warm NS then do chest physiotherapy) - Gastric lavage - Biopsy any suspicious lesions in liver, lymph nodes or bone marrow AAFBs are bacilli that resist acid-alcohol decolourization under Auramine or Ziehl-Neelsen (ZN) staining Procedure for ZN Staining i) Prepare slide as usual ii) Flood with strong carbol fuchsin iii) Heat for 7-10mins, DO NOT boil or allow slide to dry up iv) Wash off the carbol fuchsin v) Decolourize with acid alcohol (3% H2SO4/HCL + 95% Ethanol) until no more pink colour comes off vi) Wash off excess acid alcohol vii) Counterstain with Methylene Blue or Malachite Green (apply for 3-4mins) viii) Wash off counterstain & examine under oil emulsion Results 9 Bright red/pink organisms on a Blue/Green background depending on the counterstain

• •

•

Cultures undergo prolonged incubation (up to 12wks) on Lowenstein-Jensen medium Further investigations are justified only if the results of 3 consecutive sputum smear examinations are negative Histology Caseating granuloma Radiology CXR is helpful in the diagnosis of TB in smear -ve PTB, Extra-pulmonary TB & TB in children; - Inactive disease; - Post 1° TB * Normal radiograph * Consolidation in restricted sites e.g. Apical * Scarring & sequelae * Cavitation - Apical * Calcification in lungs, LN & Pleura * Endobronchial TB - Normal - 1°/Active TB; * Pleuro-Pericardial effusion * Consolidation * Adenopathy - Hilar LN is best demonstrated with a Lateral CXR * Pleuro-Pericardial effusion * Milliary infiltrates <3mm Immunological * TB PCR Allows rapid identification of rifampicin (& likely MDR) resistance; also smear -ve pulmonary cases & in culture specification *

The Mantoux tuberculin skin test is the intradermal injection on the volar (palmar) surface of the forearm of 0.1 mL (5 tuberculin units (TU)) of purified protein derivative (PPD) stabilized with Tween 80. The amount of induration is a cell mediated response to the test is measured 48-72 hr after administration. A positive test indicates immunity, previous exposure or BCG. A strong positive test (skin reaction ≥10mm) in a BCG-vaccinated HIV -ve child or adult or >5mm in a HIV +ve child probably means Active infection. Occasional patients will have the onset of induration more than 72 hr after placement of the test; this is a positive result. Factors that depress the skin test reaction: Host-related factors - Overwhelming tuberculosis - Immunosuppression by disease (Sarcoidosis, AIDS, Lymphoma) or drugs - Corticosteroid therapy may decrease the reaction to tuberculin, but the effect is variable. Tuberculin skin testing done at the time of initiating corticosteroid therapy is usually reliable.

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False-positive reactions to tuberculin ⋅ Cross-sensitization to antigens of non-tuberculous mycobacteria (NTM); produce <10–12 mm of induration. ⋅ Previous vaccination with Bacille Calmette-Guérin (BCG) 3-6mo before False-negative reactions to tuberculin ⋅ poor technique ⋅ misreading the results ⋅ Reactivity usually wanes in 2–3 yr in infants and 5–10 yr after vaccination in older children and adults, which necessitates further diagnostic evaluation and treatment. *

Heaf & Tine test: Used for screening - consist of a circle of primed needles which inject the tuberculin

Diagnosis of TB in children - The Edward Keith score chart Paediatric tuberculosis score chart

i) ii) iii) iv) v) vi) vii) viii) ix)

Positive sputum smear Angle deformity of spine Tuberculin test result ≥15mm (in unvaccinated child) Change in temperament, fits or coma Enlarged painless lymph nodes, sinus present Firm, non fluid, non traumatic swelling of joint Unexplained abdominal swelling or ascites Malnutrition not improving after 4wks of treatment Contact with a person with suspected or confirmed TB x) Night sweats, unexplained fever, no response to malaria treatment xi) Abnormal CXR

Score 7 4 3 3 3 3 3 3 2 2 2

* When score is ≥7, treat as TB

Treatment * In 2 phases, Intensive with DOT & Continuation phase

Diagnosis Adult smear +ve + Extra-pulmonary TB Adult smear –ve + Extra-pulmonary TB Re-treatment for; • Relapse – Smear +ve TB treated & cured • Treatment failure – Smear +ve despite 5(8) months on anti-TB treatment • Resumed – Treatment interrupted now resuming < 15yrs smear –ve + Extra-pulmonary TB

Therapy 2ERHZ / 6EH 2RHZ / 6EH 2SERHZ /1ERHZ / 5ERH 2RHZ / 4RH

* Rifafor® - ERHZ * Ethizide® - EH * Rifater® - RHZ * Rifinah® - RH * Steroid therapy (Dexamethasone 8-10mg/d BD) is indicated for 2-4wks in; - TB meningitis - Miliary TB - Moderate pleural effusion - Endobronchial TB - Pericardial effusion - 6wks - Prednisolone NOT Dexamethasone * A sputum +ve patient once started on treatment is considered infective for at least 2wks * A trial of therapy in patients with pneumonia not responding to antibiotic therapy is indicated for 2wks

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Multi-drug resistance TB (MDR-TB) TB resistant to at least Isoniazid & Rifampicin indicated by lack of a favourable clinical response after 2-3 weeks of therapy and 3 AAFB smears are negative.

Side effects of the anti-TB drugs

Isoniazid - Has a 20-60% CNS penetration - Peripheral neuropathy - treat with Pyridoxine 40mg/d or Vit B complex * Isoniazid promotes the excretion of pyridoxine - Pellagra - Isoniazid therapy has also been associated with niacin deficiency, presumably because of induced pyridoxine deficiency, which decreases the conversion of tryptophan to niacin. - Hepatitis - jaundice - Agranulocytosis - GIT disturbance - take drug with light meal or before going to bed Rifampicin - Hepatitis - jaundice (Withdraw if LFTs >*3) - Red urine & tears - Flu-like syndrome (fever, chills, malaise & headache) - Pruritus ± flushing ± rash involving the face & scalp often with redness & watering of the eyes - Inactivation of 'the Pill' - SOB ± shock & collapse - Abdominal pain & nausea Pyrazinamide - Hepatitis - Jaundice - Arthralgia - Gout is a contraindication; treat as gout till end of therapy Ethambutol - Blurred vision & red-green colour blindness; optic neuritis Streptomycin - Numbness around the mouth & tingling - Tinnitus - risk ↑ with dosage & age; may lead to CN-VIII damage → Deafness ± ataxia - reduce dose by 1/4gm

Complications of TB • • • •

• • • • •

Breakthrough TB - Recurrence of clinical symptoms of TB after completion of the intensive phase of treatment Haemoptysis - Bed rest + sedation (Largactil 25mg BD) Spontaneous pneumothorax (collapse of the lung) - expansion of the lung with underwater seal drainage tube Pleural effusion; - Mild - improves after therapy - Moderate - in the 1st 2-4wks of therapy - Prednisolone 20mg BD to reduce adhesions, pleural thickening & speed clearance of the fluid - Severe - aspiration Bronchiectasis Fibrosis of the lungs Lung abscess Cardio-pulmonary insufficiency (heart lung disease resulting in cor pulmonale) Pericardial effusion - Prednisolone 20mg BD for 6 wks - Prevents pericardial fibrosis & constrictive pericarditis

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HIV Epidemiology & Biology AIDS was first recognised in 1981 & is caused by the Human Immunodeficiency Virus (HIV-1). HIV-2 causes a similar illness to HIV-1 but; - is less aggressive - restricted mainly to Western Africa - produces lower viral loads - 12-fold lower progression to AIDS

Modes of Transmission HIV is present in body fluids - Blood, semen, breast milk & (saliva <0.1% transmission risk after exposure) Risk of contracting infection following exposure to infected fluid (as free virus or within cells) is dependent on; - Integrity of the exposed site - Type & volume of body fluid - Viral load Major modes of transmission; - Sexual (0.2-0.5%) - Parenteral (Blood or blood product recipients (Risk >90%), injection drug users (Risk 0.5-1.0%) & occupational injury) - 1 unit of blood = 1 in 106 risk of HIV transmission - Vertical - MTCT(15-40%) - 80% close to time of delivery; 20% in utero

Virology & Immunology HIV is a double-stranded RNA retrovirus from the Lentivirus family On the basis of DNA, HIV-1 can be subdivided into groups; - M - Major, worldwide distribution Clades (A-K) - A - Africa - C - SA - O - Outlier, West Africa - N-

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Following mucosal exposure, HIV is transported to the lymph nodes via dendritic, CD4 or Langerhans cells, where infection becomes established. Free or cell-associated virus is then disseminated through blood with seedings of 'sanctuaries' (CNS, spleen, testes, intestinal mucosa lymphoid tissue (MALT)) & latent CD4 cell reservoirs. With time, there is gradual attrition of the CD4 cell population, resulting in increasing impairment of CMI with consequent susceptibility to opportunistic infections.

** Coreceptors - CXCR4 & CCR5 Cells expressing the CD4 cell receptor & permissive to infection are; • Helper T-Lymphocytes • Monocyte-macrophages • Follicular dendritic cells • Langerhan cells • Microglial cells in CNS HIV can also affect Astrocytes via CXCR4

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HIV has NO 3' exonuclease for proof reading & thus makes many random errors which is the basis for establishing resistance to various drugs A small percentage of T cells (<0.01%) enter a post-integration latent phase & represent the main reservoir of HIV.

Clinical Diagnosis

*

Persistent generalised lymphadenopathy - Enlarged lymph nodes >1cm at ≥2 extra-inguinal sites for ≥3mo

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Opportunistic Infections The predominant opportunistic infections seen in HIV disease are intracellular parasites or pathogens susceptible to cell-mediated rather than anti-body mediated immune responses. Virus-specific CD8 cytotoxic T-cell lymphocytes develop rapidly after infection & are the most important mechanism in recognising, binding & lysing infected CD4 cells

Laboratory Diagnosis •

• • • • •

ELISA antibody testing for anti- p24, p17, gp120, gp160 * False -ves; - HIV-2 - Seroconversion - (HIV antibody-negative) - The appearance of specific anti-HIV antibodies in serum at 3-12wks (median 8wks) * False +ves - Vertical transmission - HIV maternal antibody-positive Western blot - Shows antibodies developing to early proteins PCR for HIV-RNA CD4 counts (normal - 537-1571 cells/mL) CD8 counts (normal - 235-753 cells/mL) CD4:CD8 ratio (normal - 1.2-3.8)

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Management of HIV * Manage opportunistic infections before even considering ARVs

Clinical criteria for commencing ARV therapy •

•

Adults & adolescents - HIV +ve - WHO clinical stages 2 or 3 with CD4 count <200/mm3 - WHO clinical stage 4 regardless of CD4 count - Viral load >5000 copies/mL Children • <18mo - PCR +ve - WHO stage 1 or 2 CD4% <20% - WHO stage 3 regardless of CD4% • <18mo - PCR not there - Mother HIV +ve & stage 3 with CD4% <20% • >18mo - ELISA +ve - WHO stage 1 or 2 CD4% <15% - WHO stage 3 regardless of CD4% CD4+ Lymphocyte Count (537-1571 cells/mL) - Normal (≥25%) (Good immunity >350 cells/mL) - Moderate reduction (15–24%) - Severe reduction (<15%)

Possible reasons for deferral of ARV Treatment a) b)

c) d)

Suspected poor future adherence Possible or diagnosed TB - ARVs should be deferred until after intensive (rifampicin containing) phase of treatment - if a decision is made to start ARVs in the intensive phase of treatment, e.g. in cases where immune suppression is thought to be extreme, & the patient's survival without ARVs is unlikely, then EFV rather than NVP should be used as Rifampicin ↓ blood levels of NVP OR Rifampicin should be substituted for Rifabutin or Rifapentin that have less liver stimulation effects. 1st trimester of pregnancy - EFV is teratogenic Laboratory evidence of renal, bone marrow or hepatic dysfunction - Creatinine >300µmols/L - Hb <6.5g/dl or neutrophils <500 (do not start AZT) - ALT > 5*upper limit of normal (>175IU/L) - CD4 >200/mm3

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HAART Highly Active Anti-Retroviral Therapy is a combination of ≥ 3 ARVs in the treatment of HIV infection. a) NNRTI based HAART regimen * 2 NRTI + NNRTI b) PI based HAART regimen * 2NRTI + PI c) Triple NRTI regimen (including Abacavir)

*

Fusion inhibitors - T-20 - Enfuvirtide (Fuzeon®)

Adults 1st Line - D4T + 3TC + NVP / EFV * OD NVP is recommended for the first 2wks of treatment to reduce the incidence of hepatotoxicity & severe rash then BD * NVP is recommended in pregnant women or women likely to become pregnant Also - ddI + D4T / AZT 2nd Line - ddI + TDF + (Ritonavir boosted Pis* or NLF) * Ritonavir boosted Pis - LPV/r, SQV/r, IDV/r * Ritonavir cannot be used singly due to its serious GI effects. Also; - ddI + 3TC - AZT + DDC - AZT can replace Tenofovir (It is monophosphorylated not triphosphorylated) Children 1st Line - AZT + 3TC + ABV 2nd Line - D4T + ddI + LPV/r

or

(if patient was on D4T as 1st line)

AZT + ddI + LPV/r (if patient was on AZT as 1st line)

* Zerit® - D4T * Combivir® - ZDV + 3TC * Stocrin® - Effavirenz (given nocte & every other preparation with EFV due to CNS toxicity) C/I -

D4T + AZT - Both compete for Thymidine DDC + NRTI Saquinavir (invirase) except with Ritonavir

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Reasons for changing ARV therapy (When changing drugs, change all of the drugs) •

•

•

Side effects & toxicity - Severe rash, fever, exfoliation (NVP→EFV) - Hepatotoxicity (LFTs >*5) (NVP→EFV), (D4T→AZT) - Peripheral neuropathy (D4T→AZT) - Bone marrow suppression (AZT→D4T) - Pancreatitis - ddI - Lactic acidosis - D4T, ddI - Vivid dreams, Dizziness (EFV→NVP) Drug interactions - TB drugs - Rifampicin ↓ blood levels of NVP thus replace with EFV for the intensive phase then revert back to NVP or replace Rifampicin with Rifabutin or Rifapentin that has less liver stimulation effects. - Oral contraceptives - made ineffective if taken with NNRTIs or Pis - Ketoconazole - blood levels are lowered significantly in patients taking NVP - Benzodiazepines, antihistamines & garlic supplements - should be avoided with EFV - Ritonavir inhibits cytochrome P450 thus can produce large increases in plasma concentrations of certain highly metabolized drugs. Treatment failure - Occurrence of opportunistic infections or failure of existing illness to improve after at least 3mo of ART - Development of WHO stage 4 after a period of good clinical immunity - Documented decline in CD4 count of > 30% in 6mo while on therapy - Not achieving a HIV RNA count <400 copies/mL by 24weeks or <50 copies/mL by 48 weeks in a treatment native patient

Special considerations •

•

Immune recovery syndrome/Immune reconstitution inflammatory response (IRIS) - ARV reconstitutes CD4 count & immune function in 6-8wks & patients with advanced disease could present with; - Skin rash - Mucocutaneous ulceration - Massive Cervical Lymphadenopathy - Immunological response to sub-clinical opportunistic infections e.g. KS & TB - Hodgkin's lymphoma Steroids could be used in some of these cases & careful use of antihistamines. Acute retroviral syndrome/Seroconversion - 2-6wks - Fever - Pharyngitis - Erythematous maculopapular rash with lesions on the face & trunk - Lymphadenopathy - Meningoencephalitis

Follow up * Subsequently after commencement of therapy, follow up monthly & 6 monthly FHG + ESR, CD4, LFTs, RFTs unless more frequent monitoring is indicated clinically

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*

Effavirenz - Teratogenicity, hepatotoxicity & C/I in children <3yrs (or <10kg) as CNS toxicity cannot be monitored

Nevirapine; associated skin rash Grade 1 Erythema, pruritus <50% body Grade 2 Diffuse maculopapular rash or dry desquamation >50% body Grade 3 Vesiculation or moist desquamation or ulceration Grade 4 Mucous membrane involvement, Steven Johnson, Erythema multiforme associated hepatotoxicity (ALT - <35UI/L) Grade 1 40 - 85 Grade 2 85 – 175 Grade 3 175 – 350 Grade 4 >350 Peripheral Neuropathy associated with Stavudine (Zerit®) Grade 1 - Mild Grade 2 - Moderate Grade 3 - Severe Grade 4 - Incapacitating

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Prophylaxis in HIV a) Measures to reduce Vertical transmission -

HAART during pregnancy Perinatal ARV prophylaxis C/S AZT to neonate Avoidance of breastfeeding

b) Co-trimoxazole = 1 part trimethoprim + 5 parts sulfamethoxazole It covers for; • Toxoplasmosis • Streptococcal pneumonia • Pneumocystis carinii pneumonia • Atypical chest infections • Non-typhi salmonella bacteraemia • Isospora belli • Dermatosis Prophylaxis - 960mg OD Treatment - Patients weight / 4= Number of tablets per day in 3-4 divides doses SE - Rash occasionally SJS, leucopoenia, thrombocytopenia, hepatitis

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Clinical syndromes & specific conditions Haematology •

•

•

Anaemia; - Marrow infiltration; * Opportunistic infections (e.g. MAI, TB, CMV) * Neoplasms (non-Hodgkin's lymphoma, KS) - Bone marrow suppression; * Drugs (AZT monophosphate & less frequently other NRTIs) * Direct effect of HIV - GIT; * Chronic blood loss (especially KS) * Malabsorption (chronic protozoal infections) * Hookworm infections Š Ancylostoma duodenale - 0.15mL/worm/d Š Necatar americanus - 0.03mL/worm/d - Haemolytic anaemia in lymphoma Leucopoenia; - Marrow replacement as above - Drug toxicity (e.g. AZT monophosphate & other NRTIs, Co-trimoxazole, Ganciclovir, Chemotherapy agents) - Lymphopaenia (<1000cells/dl) is a good marker for HIV Thrombocytopenia - similar to ITP, with detectable platelet antibodies & short-lived response to IVIG. Treat with repeated doses of IVIG, anti-Rh0(D) IgG, vincristine, danazol, and interferon. Splenectomy is safe and relatively effective, but should be reserved for carefully selected patients with repeat episodes of symptomatic thrombocytopenia.

Rx *

Anaemia & leucopoenia due to AZT mononosphate bone marrow suppression can be treated with GM-CSF & Erythropoietin

Renal • •

HIV Associated Nephropathy (HIVAN) - Light microscopy shows focal segmental glomerulosclerosis, but these patients have more collapsing glomerular lesions. Presents with Nephrotic syndrome &/or Chronic renal disease Drugs; - Co-trimoxazole - Indinavir - renal stones - Pentamidine - Cidofovir

Respiratory - Differential diagnosis of HIV-related pulmonary disease CXR Appearance Diffuse infiltrate Nodules/focal consolidation Hilar lymphadenopathy Pleural effusion

Major causes PCP, Tuberculosis, KS, NHL, atypical bacterial pneumonia Tuberculosis, KS, NHL, Cryptococcus, pyogenic bacterial pneumonia Tuberculosis, KS, NHL, Cryptococcus, Histoplasma Tuberculosis, KS, cavity-based lymphoma, pyogenic bacterial pneumonia

Cardiac • •

Cardiomyopathy - AZT toxicity through drug-induced mitochondrial dysfunction ↑ Cardiac risk factors; - HIV - causes dyslipidaemia predisposing to ischemic heart disease - Protease inhibitor (PI)-related hyperlipidaemia; also EFZ, D4T

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NEOPLASMS

a) Kaposi's sarcoma (KS) This is an indolent sarcoma derived either from capillary endothelial cells or from fibrous tissue associated with HHV8 (γ-herpes virus) Transmission - Sexual, Parenteral, Vertical Histology - Spindle cells, endothelial cells, fibroblasts & inflammatory cells C/P i)

Mucocutaneous KS lesions - discrete, pink to purple, raised papules & nodules that are often symmetrically arranged & develop on crease lines ± hyperkeratotic, coalescing plaques, (painful especially if on the soles of the feet) & bleed or ulcerate. Sites - Nose, Oral, Genitalia, Lower limbs DDx of cutaneous lesions - Bacillary angiomatosis - Granuloma faciale - Vascular proliferation - Purpuric lesions Oral KS - most common oral cancer * Involves the palate, gum margins & fauces * Strong predictor of gastrointestinal & pulmonary disease ii) Visceral KS - Frequently asymptomatic - Hepatosplenomegaly usually indicates disease of these organs iii) Pulmonary KS; Breathlessness, Cough, Haemoptysis, Chest pain, Fever, * Disease affects middle & lower zones with patchy coarse reticulonodular shadowing & malignant pleural effusion * ± Ocular lesions that resemble subconjuctival haemorrhages iv) Glandular KS - It metastasizes to LN presenting with massive cervical LNopathy - Poor prognosis * DDx - TB, Hodgkin's Lymphoma

Types i. Classic - affecting western men >40yrs (M:F - 10:1) with associated lymphoedema (initially unilateral) which may predispose to cellulitis- Good prognosis ii. Endemic (Central Africa) - Peripheral slow growing lesions with rare visceral involvement iii. KS in Immunosuppression - Aggressive with visceral involvement iv. KS in HIV Ix - Biopsy Therapy - For limited & localised disease - Surgical excision, intralesional chemotherapy, liquid nitrogen or laser therapy, radiation or retinoic acid gel - For widespread mucocutaneous or visceral KS; * Cyclical liposomal doxorubicin or * Vincristine + Bleomycin - Refractory or relapse disease - Paclitaxel

b) HIV-associated lymphoma i) Hodgkin's - 100% EBV +ve ii) Non-Hodgkin's - B-cell lineage; 50% EBV +ve - Diffuse large cell - Small-cleaved cell - Burkitt's & non-burkitt's - Large-cell immunoblastic iii) HHV-8 - Found in body cavity (pleura, pericardium or peritoneum) lymphoma & is a high-grade Bcell lymphoma Poor prognostic factors; - Age >35yrs - Previous AIDS diagnosis - CD4<100cells/mm3 - Not being on HAART - Disseminated disease - Poor general health - ↑ LDH Medicine Page 148

Mx; -

↑ LDH IV drug user risk group Chemotherapy (CHOP or VAPEC-B) Support of bone marrow reserve Prevention of infections HIV control - HAART

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CNS a) b) c)

Depression Anxiety Congnitive function disorder (confusion)

d)

HIV-associated dementia HIV is a neurotopic virus that presents as; Aseptic meningoencephalitis at seroconversion ↓ Abulia - minor cognitive defects such as slowed mental processing, loss of initiative, poor shortterm memory, apathy, and withdrawal from usual activities as the disease progresses ↓ Subcortical dementia in later-stage disease - This is characterized by global deterioration of cognitive function, severe psycho-motor retardation, paraparesis, ataxia & urinary & faecal incontinence. Changes in affect are common & depression or psychosis may occur. Predictors of HIV-associated dementia; • Higher plasma & CSF viral load • Lower CD4 count • Age Ix • CT scan - diffuse cerebral atrophy Features of cerebral atrophy; - Widened sulci - Enlarged ventricles - Prominent cerebellar folia • CSF - ↑ protein • EEG - Features of encephalopathy Mx • HAART

e)

Patients with AIDS may develop a subacute or chronic vacuolar myelopathy leading to paraparesis or quadriparesis, sphincter dysfunction, and sensory disturbances.

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Salmonellosis Disease caused by any serotype of the genus Salmonella. Clinical syndromes include; i) Enterocolitis (75%) A condition similar to Reiter's syndrome may follow Salmonella enterocolitis ii) Enteric fever (10%) (see Typhoid fever) iii) Bacteraemia (10%) iv) Localized infection outside GIT v) An asymptomatic carrier state (< 1%) - Infection by Schistosoma mansoni predispose to the carriage of salmonella as the bacteria lodges in the groove between the male & female leading to recurrent salmonellosis

S/S •

•

Acute uncomplicated illness - Fever to 39°C - Nausea, vomiting, diarrhoea - Abdominal cramps - Headache, myalgia Protracted disease - Persistent fever - Hypovolaemia - Arteritis - Bone infection; * Osteomyelitis * Arthritis, reactive or septic * Sacroilitis

-

Generalised infection; * Meningitis * Pneumonia, lung abscess, empyema * Endocarditis, pericarditis * Hepatic (abscess) * Splenic (abscess) * UTIs * Wound infection, soft tissue abscesses

Pathological findings • • •

Mucosal ulceration, haemorrhage and necrosis Reticuloendothelial hyperplasia and hypertrophy Focal organ and soft tissues abscesses

•

Bacteraemia (first 10 days) - Blood cultures positive - Stool cultures negative Enterocolitis - Blood cultures negative - Stool culture positive for Salmonella species - Faecal leucocytes positive - WBC normal or decreased - lymphopaenia Local infections - Polymorphonuclear leucocytosis with ↑neutrophils - Tissue site culture positive Asymptomatic carrier state - Stool culture positive for >1 year - Urine culture may be positive with certain serotypes

Ix

•

• •

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Typhoid fever Typhoid fever is an acute systemic illness unique to humans caused by Salmonella typhi. It is a classic example of enteric fever caused by the Salmonella family of bacteria. Mode of transmission is faecal-oral through ingestion of contaminated food (commonly poultry), water and milk. Incubation period varies from 7 to 21 days.

Pathology Bacteraemia → Localise in the Peyer's patches & Follicles where they swell, ulcerate & heal

S/S •

•

•

1st Week; - Fever - stepladder fashion for 4-5d - Headache - Myalgia - Relative bradycardia - Abdominal discomfort/bloating/constipation - Diarrhoea (& vomiting in children (less common in adults)) End of 1st Week; - Dry cough - Rose spot (transient erythematous maculopapular rash in anterior thorax or upper abdomen) - Splenomegaly - Abdominal distension - Diarrhoea End of 2nd Week; - Delirium, complications, then coma & death (if untreated)

Ix • • • •

•

First 10d - Blood culture 2nd - 3rd Week - Stool m/c/s - Stool culture is not reliable because it may be positive in gastroenteritis without typhoid fever. Cultures of bone marrow occasionally are positive when blood cultures are not. Widal test The interpretation of this test for specific O & H antibodies depends on; - The level of 'enteric' antibodies in the healthy population - Previous vaccination - Previous infection - only H antibodies tend to persist to detectable levels Peak agglutinin titres occur during the third week of the disease & a fourfold rise in O and H antibody titres in paired specimens acquired 2 wks apart suggests S. typhi infection. This test (Widal's agglutination reaction) is only moderately sensitive (30% of culture-proven cases have negative tests) and lacks specificity; * Many non-typhoidal Salmonella strains have cross-reacting O and H antigens * Cirrhosis is associated with non-specific antibody production, causing a falsely positive Widal's reaction Chronic S. typhi carriers can now be identified by a simple passive hemagglutination test using highly purified Vi antigen.

Rx •

•

Antibiotics; - Ceftriaxone and cefoperazone - Septrin - Amoxicillin - Quinolones Corticosteroid therapy is recommended for all patients with suspected typhoid fever who are delirious, obtunded, stuporous, comatose, or in shock.

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Schistosomiasis Life cycle

*

*

Most diseases are due to; - The passage of eggs through the mucosa - The granulomatous reaction to eggs deposited in tissues - granulomas are composed of macrophages, eosinophils, epithelioid & giant cells around an ovum; later there is fibrosis & calcification, often in sufficient numbers to become radiologically visible. S. haematobium pass mainly through the wall of the bladder, but may also involve rectum, seminal vesicles, vagina, cervix & uterine tubes

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C/P •

Recent travellers may present with eosinophilia; residents of endemic areas are more likely to present with chronic urinary pathology or intrahepatic pre-sinusoidal portal hypertension

•

S. haematobium - Painless terminal haematuria - Frequency due to bladder neck obstruction - Haemospermia due to disease of the seminal vesicles - Complications; 9 Frequent UTIs 9 Bladder or ureteric stone formation 9 Hydronephrosis 9 Renal failure with a contracted calcified bladder * Ectopic deposition of eggs may cause transverse myelitis, paraplegia & skin lesions * In several endemic areas, there is a strong epidemiological association of S. haematobium infection with SCC of the bladder S. mansoni - Symptoms begin ≥ 2mo after infection - Abdominal pain - Diarrhoea with blood stained mucous - Rectal polypi - Early hepatomegaly is reversible but portal hypertension may cause massive splenomegaly, fatal haematemesis from oesophageal varices, or progressive ascites; Liver function is initially preserved because the pathology is fibrotic rather than cirrhotic. * Infection predispose to the carriage of salmonella as the bacteria lodges in the groove between the male & female leading to recurrent salmonellosis

•

O/E • • •

Hepatosplenomegaly Lymphadenopathy ± Pneumonia

• •

Eosinophilia S. haematobium; - Terminal stream urine - Terminal spined eggs - Dipstick- blood & albumin - AXR - bladder calcification in chronic S. haematobium infection - Renal U/S - Bladder wall thickening, hydronephrosis & bladder calcification - Cystoscopy - 'sandy' patches, bleeding mucosa & later distortion S. mansoni; - Stool m/c/s - Lateral spined eggs - Rectal biopsy for ova - Sigmoidoscopy - inflammation or bleeding - +ve Schistosomiasis serology - useful as a screening test but remain positive after chemotherapeutic use

Ix

•

Mx • • •

Praziquantel - in early infection will reverse pathologies such as hepatomegaly & bladder wall thickening Oxamniquine - S. mansoni Metrifonate - S. haematobium

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Sickle-cell anaemia (5TH Disease) Sickling disorders are due to the production of abnormal β peptide chains. An amino acid substitution in the gene coding for the β chain (Glu→ Val at position 6), results in the production of HbS rather than HbA. HbA2 & HbF are still produced. The Homozygote (SS) has Sickle-cell anaemia & Heterozygotes (HbAS) have Sickle-cell trait, which causes no disability except in hypoxia, when veno-occlusive events may occur. HbAS; - Provides significant protection against all-cause mortality severe falciparum malaria with high density parasitaemia (>10%) - genetic resistance appears to be limited to the erythrocytic stage & the possible mechanisms include; i) Inhibition of merozoite entry into RBC due to increased membrane rigidity ii) Intracellular loss of K+ during sickling creates hostile environment, impairing intracellular growth of parasite iii) Infected cells are more easily sickled & removed from circulation iv) Prevents erythrocyte lysis that occurs at the end of parasite maturation thus merozoites are not released into blood stream. Symptomatic sickling occurs in Heterozygotes with genes coding other analogous amino acid substitutions (e.g. HbSC & SD diseases). Homozygotes (CC;DD) have asymptomatic mild anaemia.

Pathogenesis HbS polymerizes when deoxygenated, causing RBCs to sickle; Sickle cells are fragile & haemolyse; they also block small vessels.

S/S

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Affected newborns seldom exhibit clinical features of sickle cell disease; haemolytic anaemia due to an RBC lifespan of 10 days gradually develops over the 1st 3-6mo, paralleling the replacement of much of the foetal haemoglobin (Hb F) by Hb S. Other clinical manifestations are uncommon prior to 5–6 mo of age.

` Early •

•

•

Anaemia 2° to; - Haemolysis → Jaundice - Splenic sequestration - Aplastic crisis HbS gives up oxygen to tissues relatively easily compared to HbA hence symptoms of anaemia are relatively mild in relation to severity of anaemia. Acute sickle dactylitis, presenting as the hand-foot syndrome. Its associated findings include painful, usually symmetric, swelling of the hands and feet. The underlying abnormality is ischemic necrosis of the small bones, believed to be caused by a choking off of the blood supply as a result of the rapidly expanding bone marrow. Young children with HbSS may have splenomegaly associated with their haemolytic disease, though splenic phagocytic and reticuloendothelial functions have been shown to be markedly reduced (functional asplenia) from 2-4 yrs, a factor leading to their increased susceptibility to meningitis, sepsis, and other serious infections especially malaria, mainly caused by Pneumococci (leucocytosis, left shift, aplastic crises, ± DIC) and Haemophilus influenza in the absence of specific antibody to the polysaccharide capsular antigens of these organisms. Splenic dysfunction is also caused by sickling of RBC within the spleen & inability of the spleen to filter micro organisms from the blood stream. With progression to the syndrome of hypersplenism, there may be worsening anaemia and sometimes thrombocytopenia. Splenomegaly is rare if >10yrs as the spleen infarcts in children between 6 and 60 mo, causing pain and contributing to the process of "autosplenectomy." Other factors contributing to increased risk of infection; - Dysfunctional IgG & IgM antibody responses - Defects in alternative pathway fixation of complement - Opsonophagocytic dysfunction

` Late •

•

• • • • •

Acute painful vaso-occlusive episodes. In young children pain often involves the extremities; in older patients head, chest, abdominal, and back pain occur more commonly. The joints are red, painful, tender and swollen. There is associated bossing of the skull due to increased marrow activity (Hair-on-end appearance on X-ray) and metacarpal shortening due to frequent infections of the bone reducing bone growth. Pulmonary infarction, often occurring in association with pneumonitis or microscopic fat emboli (from bone marrow infarction) may produce the severe clinical picture of acute chest syndrome. It occurs mostly in infants & entails pulmonary infiltrates (fat embolism from bone marrow, infection with Chlamydia, Mycoplasma, or virus, & sickled RBCs) involving complete lung segments, causing pain, fever, tachypnoea, wheeze & cough. Prodromal painful crisis occur 2.5d before any abnormalities on CXR in 50% of patients. Mx - Bronchodilators with those with wheezing or obstructive pulmonary function at presentation - Antibiotics - Red cell transfusion/Exchange transfusion Long term lung complications - hypoventilation, atelectasis, & lung infiltrates - partly preventable by incentive spirometry - 10 maximal inspirations/2h Osteomyelitis is caused by Salmonella (70%), Staph. Aureus (<25% though more common cause), Pneumococci (15%) Lower Leg ulcers 2° to vascular stasis & local ulceration especially around the medial malleolus in patients >16yrs Renal failure 2° to infarction of the medulla with papillary necrosis; failure to concentrate urine leads to dehydration and nocturnal enuresis is common (drug therapy is inappropriate if <7yrs old) Iron overload from many transfusions The eye; - Proliferative retinopathy - Blunt trauma may cause bleeding into the anterior chamber (hyphaemia) → Sickling of RBCs → Obstructive glaucoma & blindness

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Sickle-cell crises

These may be from thrombosis, haemolysis (rare), marrow aplasia, or sequestration Management of Sickle-cell crises - Rest - Rehydrate with IVI & keep warm - Give prompt generous analgesia, e.g. with opiates - Give O2 by mask if PaO2 ↓ - 'Blind' antibiotics if feverish, after infection screen - GXM - Give blood transfusion if PCV or reticulocytes fall sharply, or if there are CNS or lung complications - when the proportion of sickled cells should be reduced to <30%. i)

Haemolytic crises - Haemolysis; ↑ Bilirubin → Jaundice - ↓Hb (N= 6-8g/dL) - ↑Reticulocytes (N=10-20%) - ± Pain crisis

ii) Thrombotic crises Common, often causing severe pain. Precipitated by; - Dehydration - Acidosis - Deoxygenation / Ischemia e.g. muscle exertion - Infection - Cold May mimic an acute abdomen or pneumonia CNS signs - Fits, focal signs - An impending stroke is preventable by transfusion Priapism - prolonged tumescence of the penis, often accompanied by pain & swelling not associated with sexual desire Bimodal peak frequencies - 5-13yrs & 21-29yrs C/P * Acute - hrs/days or Stuttering - mins/3hrs * Low-flow priapism - ↓ outflow from penile veins leading to haemostasis especially at night - Intracavernosal blood sampling reveals acidosis & ↓ O2 tension - Left untreated, irreversible cellular damage & fibrosis may occur, resulting in impotence hence it is a MEDICAL EMERGENCY * High-flow priapism; - Associated with penile trauma or may be 2° to unregulated arterial inflow, leading to prolonged but painless erection - Bright coloured penis - aspiration of bright red oxygenated carvernosal blood - Fibrosis & cellular damage do not occur hence treatment by arterial embolization or ligation to produce detumescence can occur on an ELECTIVE basis Rx * Extra fluids * Oral analgesics * Exercise - attempt to urinate as soon as priapism begins * If not successful within; - 2hrs - IV hydration + Analgesia + Anxiolytics + O2 - 4hrs - Intracavernosal aspiration + Instillation of an α agonist e.g. epinephrine - 6hrs - Oral terbutaline - 24hrs - cavernous-spongiosum shunting * 2° prevention; - Oral pseudoephedrine at bedtime - Monthly IM leuprolide - Gonadotropin releasing hormone analogue - Diethylstilbestrol, hydroxyurea have been used

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iii) Aplastic crises In common with patients having other forms of chronic inherited hemolytic anemia e.g. thalassemia, hereditary spherocytosis, and pyruvate kinase deficiency. Children with HbSS are at risk of developing a rapid, potentially life-threatening decrease in their hemoglobin level (normally 6-8g/l) in association with parvovirus B19 infection & folate deficiency. Bone marrow activity is usually elevated, *20 to keep up with the hemolytic process. Urgent transfusion is needed. iv)

Sequestration/hepatic crises Spleen & liver enlarge rapidly from trapped RBCs Signs; - RUQ pain - Fever - Leukocytosis - INR/LFT ↑ - ALP may be only moderately elevated. - ↑ Bilirubin → Jaundice - Hb ↓↓ May need exchange transfusion. Also; - Cholelithiasis 2° to; * Haemolysis * Salmonella bacteraemia - Can eventually cause hepatic necrosis, portal fibrosis, regenerative nodules & cirrhosis

DDx The various clinical manifestations of sickle cell disease, including limb pain, heart murmurs, hepatosplenomegaly, and anemia, may suggest a number of other diagnoses, including; • Rheumatic fever or rheumatoid arthritis • Osteomyelitis • Leukemia

Ix • • • • •

Hb (N= 6-8g/dL) Reticulocytes (N=10-20%) Haemolysis is variable; ↑ Bilirubin Electrophoresis distinguishes SS, AS states & other Hb variants; also sickling test PBF - Signs of splenic atrophy; * Target cells * Howell jolly bodies

Management of chronic disease •

• • •

•

Reduce incidence of infection and dehydration which may be due to: - Fever due to the increased BMR in infection - Tachypnoea - Poor feeding/drinking - Micro infarctions in the kidney that reduce it’s concentrating ability Rehydrate the patient with normal saline to dislodge micro infarcts. Prophylactic malaria treatment with proguanil (palludrin®) or mefloquine though the later has more S/E. Splenic infarction leads to hyposplenism & appropriate prophylaxis, in terms of; - Antibiotic - Penicillin V - ? lifelong - Immunization (pneumococcal vaccine (for ≥2yr olds due to poor response if given earlier)) should be adopted & Hep B. vaccine due to frequent blood transfusions Folic acid

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•

•

• •

Hydroxyurea (=hydroxycarbamide) is indicated only when the patient has life threatening complications e.g. cerebral infarction (hemi/quadriplegia, facial palsy and other cranial nerve palsies) and in the presence of frequent painful sickling crises Long term Hydroxyurea causes; - ↓ fibre production via Hb polymerization, with 50% ↓ in both painful crises & episodes of the acute chest syndrome. - ↑ production of HbF & the % of HbF containing RBCs - Improves RBC hydration & lifespan - ↓ number of irreversibly sickled cells - ↓ adhesions of erythrocytes to endothelium These effects may result from fewer episodes of bone marrow ischaemia & embolization. Chronic blood transfusion programmes every 6wks to 2 mo can keep HbS levels <30%, but there is a high incidence of development of antibodies to red cell antigens - Can be prevented by transfusing leukocyte depleted packed cells. Indications for blood transfusion; - Severe anaemia - ↓ Hb >2g/dL below steady state or <6g/dL - Lung consolidation - CVA - Priapism - Before surgery Marrow transplant can be curative, but remains controversial. Mortality 5-10% Febrile children risk septicaemia; repeated admission is avoided by out-patient ceftriaxone. Admission may still be needed if; - Hb <5g/dL - WCC <5 or >30,000 * 109/L - T° >40°C - Severe pain - Dehydration - Lung infiltration

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IDA

Pathophysiology Stage 1: Fe loss exceeds intake, causing progressive depletion of storage Fe (represented by ↓ bone marrow Fe content). Although Hb and serum Fe remain normal, serum ferritin concentration falls (< 20 ng/mL). As storage Fe decreases, there is a compensatory increase in absorption of dietary Fe and in the concentration of transferrin (represented by a ↑ TIBC). Stage 2: Exhausted Fe stores cannot meet the needs of the erythroid marrow. While the plasma-transferrin level increases, the serum Fe concentration declines, leading to a progressive decrease in Fe available for erythropoiesis. When serum Fe falls to < 9 mmol/L and transferrin saturation to < 16%, erythropoiesis is impaired. The serum ferritin receptor concentration rises (> 8.5 mg/L). Stage 3: Anaemia with normal-appearing RBCs and indices occurs. Stage 4: Microcytosis and then hypochromia are present. Stage 5: Fe deficiency affects tissues, resulting in symptoms and signs.

Mx •

•

Oral therapy. - Ferrous sulphate 200mg (65mg elemental iron) PO TDS for 6mo post recovery to replenish iron stores - If S/E - GI symptoms; * Reduce dose to BD or switch to Ferrous Gluconate 300mg BD (70mg elemental iron/d) Parenteral therapy; ** Iron dextran (Ferric OH + dextrans) ** Iron sucrose (Ferric OH + sucrose) - Patient cannot tolerate oral therapy - Continuing blood loss - Malabsorption

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•

- Chronic GIT disease - CRF on dialysis Blood transfusion; - Hb <4g/dL - Angina - Heart failure - Evidence of cerebral hypoxia Therapeutic response; The Hb should rise by O.1-0.2g/dL/d & a reticulocyte count of up to 5% by 7-10 days after Fe replacement begins.

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Oncology BURKITT’S LYMPHOMA i) Non-endemic (Sporadic or American) Burkitt lymphoma ii) Endemic (African) Burkitt lymphoma, often found in the jaw, is the most common childhood cancer in equatorial East Africa and New Guinea. The median age of onset is 5yrs. These regions are holoendemic for Plasmodium falciparum malaria and have a high rate of EBV infection early in life. The constant malarial exposure; * acts as a B-lymphocyte mitogen that contributes to the polyclonal B-lymphocyte proliferation with EBV infection. * impairs the T-lymphocyte control of EBV-infected B lymphocytes. Individuals with Burkitt lymphoma have unusually and characteristically high levels of antibody to Viral Capsid Antigen and Early Antigen that correlate with the risk of developing tumor. All cases of Burkitt lymphoma, including those that are EBV negative, are monoclonal and demonstrate chromosomal translocation of the c-myc proto-oncogene on chromosome 8 to one of the three immunoglobulin genes: ⋅ the constant heavy-chain locus, t(8;14), ⋅ to the kappa constant light-chain locus, t(2;8), ⋅ or to the lambda constant light-chain locus, t(8;22). This results in the deregulation and constitutive transcription of the c-myc gene with overproduction of a normal cmyc product that auto suppresses c-myc production on the untranslocated chromosome. S/S · African: . Mouth pain . Loose teeth - deciduous molars . Jaw mass . Anemia · North American: . Abdominal mass . Abdominal pain

Staging (Ann Arbor) IIIIIIIV-

Confined to single lymph node region Involvement of ≥ 2 regions on the same side of the diaphragm Involvement of nodes on both sides of the diaphragm Spread beyond lymph nodes

Rx ⋅ ⋅ ⋅ ⋅

The most effective protocols for large cell NHL usually contain cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), given for 1-2yrs. Allopurinol is added to any cytotoxic drug regimen to increase the excretion of uric acid that is produced by the resolving malignancy and from the cytotoxic destruction of normal body cells. Surgery plays little/no role in management unless there is a completely resected abdominal mass. Radiotherapy is NOT effective as this is a rapidly growing tumor with a doubling time of 6-14hrs

Prognosis; • •

90% of patients with stage A and over 70% of patients with stages B and C experience long-term remission and possible cure Without treatment, prognosis is grave

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Cytochemistry in Leukaemia Myeloperoxidase

ALL AML

Sudan black B

+ (including Auer + (including rods) Auer rods)

Acid Periodic Nonspecific Terminal Phosphatase Esterase deoxynucleotidyl acid (NSE) Schiff Transferase (PAS) (TdT) + in T-ALL -

+ + M6

+ in M4,M5

+ in T-ALL + M6

Complications of cancer chemotherapy Drug

Delayed toxicity

Doxorubicin (Adriamycin) Vincristine (Oncovin) Methotrexate

Red urine (not haematuria), Cardiotoxicity Areflexia, muscle weakness, peripheral neuritis, paralytic ileus Can be reversed by leucovorin; Folinic acid following methotrexate administration helps to prevent MTX induced mucositis or myelosuppression Diabetes, osteoporosis, mental disturbances, muscle wasting, cushing’s syndrome with moon face, striae and acne, peptic ulceration, growth suppression. A urinary metabolite, acrolein, may cause haemorrhagic cystitis. Mesna will prevent this. Pancytopenia.

Prednisone Cyclophosphamide * *

Common to all - Nausea, vomiting, alopecia, bone marrow depression, stomatitis, mucositis 5-HT3 antagonists e.g. Ondansetron, Granisetron, are approved for use in the prevention of nausea and vomiting associated with surgery and with cancer chemotherapy.

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Multiple Myeloma Definition Malignant proliferation of plasma cells. Normal plasma cells are derived from B cells & produce polyclonal immunoglobulins which contain heavy & light chains but in multiple myeloma, the plasma cells produce a monoclonal protein referred to as a paraprotein. 60% of IgG & IgA myelomas produce only free light chains which are filtered by the kidney & may be detectable in urine as Bence jones proteinuria which precipitate on heating (40°-60°) & dissolve on boiling.

Incidence Median age - 60-70yrs (54yrs in Kenya) M:F - 2:1

Classification • • • •

IgG - 55% IgA - 21% Light chain only - 22% Others (D, E, non-secretory) - 2%

C/P

* Multiple myeloma is; • The most frequent acquired cause of Fanconi syndrome • One of the commonest causes of osteoporosis & vertebral compression fracture in MEN >45yrs Effects on bone are due to Marrow cell proliferation & Increased osteoclastic activity resulting in osteoporosis & the appearance of discrete lytic lesions throughout the skeleton.

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Diagnosis •

Major criteria i) Plasmacytoma on biopsy ii) >30% plasma cells on bone marrow biopsy iii) Monoclonal band on electrophoresis; * >35g/L IgG * 20g/L IgA * >1g/d of light chains excreted in the urine • Minor criteria i) 10-30% plasma cells on bone marrow biopsy ii) Abnormal monoclonal band but levels less than listed above iii) Lytic bone lesions iv) Immunosuppression (other Igs show reduced levels to <50% normal) Diagnosis requires; • 1 major & 1 minor criteria or • 3 minor criteria (including the first 2)

Ix * * * * * *

Boiling test - Precipitation in urine of Bence jones proteinuria on heating (40°-60°) & dissolving on boiling. Plasma viscosity is ↑ & RBCs form rouleaux easily on a slide Only 5% of patients with an ESR persistently above 100mm/hr have myeloma In the absence of fractures or bone repair, the plasma ALP & the bone scan are normal Serum β2-microglobulin estimation may provide a useful assessment of prognosis The absence of immune paresis (reduction of normal Ig levels to <50% normal) should cast doubt on the diagnosis X-Rays; • Generalised osteoporosis • The 'classic' lesions are; - multiple punched-out defects with 'soft' margins (lack of new bone) in the skull, pelvis & proximal femur - a crushed vertebrae - a solitary lytic tumour in a large-bone metaphysis.

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Durie & Salmon staging of Multiple Myeloma Stage I

Criteria Low cell mass (<0.6*1012/m²) All of the following; - Hb >10g/dL - Ca2+ <12mg/dL - Normal bones or single plasmacytoma - Low M component * IgG <5g/dL * IgA <3g/dL * Urinary M component <4g/24h Neither stage I nor III II High cell mass (>1.2*1012/m²) III At least one of the following: - Hb <8.5g/dL - Ca2+ >12g/dL - Advanced bone disease - High M component: * IgG >7g/dL * IgA >5g/dL * Urinary M component: >12g/24h Subclassification A = Serum creatinine < 2.0mg/dL B = Serum creatinine ≥ 2.0mg/dL

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Survival(months)

46

32

23

32 11

Management •

•

• •

Supportive; - High fluid intake to treat renal impairment & HyperCa2+ - Analgesia for bone pain - Bisphosphonates for HyperCa2+- reduces bone pain & skeletal events; may cause apoptosis of malignant plasma cells - Allopurinol to prevent urate nephropathy - Plasmapheresis, which may be necessary for hyperviscosity Chemotherapy - Melphalan ± prednisolone until the paraprotein level is stable for 3 months - plateau phase; Cyclophosphamide is suitable for those patients not eligible for melphalan - Refractory myeloma - Thalidomide + Dexamethasone; Thalidomide has anti-angiogenic effects against the blood vessels supplying tumours & also has immunomodulatory effects; SE: Somnolence, constipation & a peripheral neuropathy - Vincristine + Adriamycin + Dexamethasone (VAD) 4wkly is effective in impaired renal function. Radiotherapy - Effective for localised bone pain not responding to simple analgesia & for pathological fractures - Emergency treatment of spinal cord compression 2° to extradural plasmacytomas Transplantation - <65yrs - Chemotherapy + Stem cell Auto transplants - <55yrs - Allogenic Bone marrow transplantation Auto transplantation improves survival & quality of life by slowing the rate of progression of bone disease.

Complications Death is commonly due to; • Infection • Haemorrhage • Renal failure

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General

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Abulia - Apathy, indifference, and diminished arousal with lack of spontaneity and motivation Causes; - Frontal lobe injury/tumours or ischaemia/infarction due to occlusion of the anterior cerebral artery distal to its junction with the anterior communicating artery - Lesions of the basal ganglia - this may reflect interruption of the circuits that link the striatum to the frontal cortex - Hydrocephalus - Recurrent severe hypoglycaemia - SSRIs (citalopram, fluoxetine, paroxetine, sertraline) Rx; - Amantadine, bromocriptine, methylphenidate, levodopa

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Papilloedema Findings on fundoscopy; The first sign is cessation of normal venous pulsations seen at the disc, & the disc margins then become red (hyperaemic) & indistinct & the whole disc is raised up, often with haemorrhages in the retina.

Causes; •

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Raised intracranial pressure - Cerebral mass lesion (tumour, abscess) - Hydrocephalus, haemorrhage, haematoma - Idiopathic intracranial hypertension Obstruction of ocular venous drainage - Central retinal vein occlusion - Cavernous sinus thrombosis Systemic disorders affecting retinal vessels - Hypertension - Vasculitis - Hypercapnoea Optic nerve damage - Demyelination (optic neuritis/papillitis) - Leber's hereditary optic neuropathy - Ischemia - Toxins (e.g. methanol) - Infiltration of optic disc - Sarcoidosis - Glioma - Lymphoma

Foster Kennedy syndrome Optic atrophy of 1 eye, with papilloedema of the other, from a mass on a frontal lobe's underside, on the side of the optic atrophy

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Reactive thrombocytosis Platelet morphology is normal, but excessive numbers of platelets are seen on the peripheral blood smear though the platelet count seldom exceeds 1,000,000/uL.The bleeding time is normal. Common causes; • Infection • Iron deficiency • Haemorrhage • Malignant tumours • Inflammatory conditions - rheumatoid arthritis and ulcerative colitis • Connective-tissue disorders • Trauma It requires no treatment other than that for the underlying disorder. Patients are not at risk for development of complications associated with thrombocytosis.

FINGER CLUBBING Caused by hypervascularity and the opening of anastomotic channels in the nail bed. Not demonstratable before 6 mo age though may still be seen earlier. GRADES Soft nail bed I. II. Angle at the nail plate is lost and may exceed 180o. III. Parrot beak appearance. Schamroth’s window test negative. IV. Drum stick appearance V. Pulmonary osteoarthropathy - Findings in hypertrophic pulmonary osteoarthropathy include clubbing of the fingertips and bony tenderness of the distal radius and ulna caused by underlying periostitis

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CAUSES Cardiac Cyanotic congenital heart disease Endocarditis Atrial myxoma

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Pulmonary Chronic lung suppuration; ○ Tuberculosis ○ pneumonia ○ Abscess ○ Empyema ○ Bronchiectasis ○ Cystic fibrosis Ca Lung Malignant neoplasms Fibrosing alveolitis

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Pleural Mesothelioma

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Other Hodgkin disease Thyrotoxicosis HIV Ca Prostate

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Gastrointestinal Celiac disease Chronic dysentery Chronic ulcerative colitis Multiple polyposis Regional enteritis Malignancy

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Hepatic Cirrhosis Liver failure

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Genetic Abnormalities a) Single gene abnormalities i) Mendelian; *

Autosomal; Dominant; • Familial hypercholesterolaemia • Familial polyposis coli (APC) • Osteogenesis imperfecta • Von willebrands disease (VWD) • Marfan' s syndrome • Neurofibromatosis • Hereditary spherocytosis • Hereditary haemorrhagic telangiectasia • Autoimmune Porphyria (AIP) • Adult polycystic Kidney disease (APCKD) Recessive; • Inborn errors of metabolism e.g. Lysosomal storage disease, Glycogenosis, Alkaptonuria, Phenylketonuria • Albinism • Haemoglobinopathies e.g. SCD, Thalassaemia • Fanconi anaemia • Cystic fibrosis • Haemochromatosis • Wilson's disease • Xeroderma pigmentosa • Scwann Diamond syndrome * Sex chromosomes; X-Linked; Dominant; • Familial haematuria • Vitamin D resistant rickets (Hypophosphataemic rickets) • Incontentia pigmenti Recessive - Express in males (XY); • Haemophilia A • G6PD • Duschenne muscular dystrophy • Orofacial digital syndrome • Colour blindness • Diabetes insipidus • Dyskeratosis congenita • Chronic granulomatous diseases • Bruton's agammaglobulinaemia Y-Linked; • Hair in ears • Aggressiveness ii) Non-Mendelian Inheritance- In mitochondrial chromosomes (39 genes from mother) - Usually oxidative phosphorylation genes; • Kearns- Sayre syndrome • Leber- optic atrophy iii) Complex Inheritance - Require other factors to express themselves; • Diabetes mellitus • Hypertension • Congenital dislocation of the hip joint

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b) Numerical abnormalities;

Autosomal; • Trisomy 13 - Patau syndrome • Trisomy 18 - Edwards syndrome • Trisomy 21 - Down's syndrome Sex chromosomes; • Turners syndrome - 45XO • Klinefelters syndrome - 44XXY

c) Structural abnormalities;

• 5p- - Cri du chat • 4p- - Wolf Hirschhom syndrome Chromosomal fragility syndromes; Autosomal; • Ataxia telangiectasia • Xeroderma pigmentosa • Fanconi anaemia Sex chromosomes; • Bell's Syndrome - Xq27

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Laboratory Ranges RFTs Na+ K+ ClUrea Creatinine Ca2+ Phosphate Plasma Osmolality Urine Osmolality Microalbumin

135 - 145 mmol/l 3.5 - 4.5 mmol/l 95 - 105 mmol/l 1.7 - 8.3 (Up to 12) mmol/l 60 - 120 μmol/l 2.02 - 2.60 mmol/l O.8 - 1.6 mmol/l 285 - 290 mOsm/Kg < 150 mOsm/Kg <0.1g/L

LFTs Total Protein Albumin Total Bilirubin Direct Bilirubin AST ALT ALP GGT Cholesterol Triglycerides HDL-C LDL-C

66 - 87 g/l 35 - 52 g/l 3 - 23 umol/l 0 - 6.8 umol/l 0 - 37 u/l 0 - 37 u/l 64 - 306 u/l 9 - 40 u/l 0 - 6.7 mmol/l 1.71 - 2.28 mmol/l 0.9 - 1.54 mmol/l 0 - 4.9 mmol/l

BGAs Pa O2 PaCO2 HCO3Anion gap O2 Saturation

10 - 13.33 kPa / 75 - 100mmHg 4.4 - 6.1 kPa / 35 - 45 mmHg 21 - 28 mmol/l 8 - 14 mmol/l >96%

FHG MCV MCH MCHC

76 - 96 fl 0 - 32 0 - 38

Cardiac Enzymes CK LDH

24 - 170 U/L 190 - 360 U/L

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