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Cardiology
T opic - Coronary Artery disease

• Coronary Artery disease


• Differential diagnosis of chest pain ( Commonly asked clinical Vignette in MD
Entrance) (MCQ)
o Costochondritis/musculoskeletal:
§ Sharp, localized pain and reproducible tenderness
§ oftenexacerbated by exercise
o Myocardial infarction/angina:
§ Chest heaviness, pressure
§ pain, typically radiating to left arm, shoulder, or jaw
o Pericarditis:
§ Chest pain radiating to shoulder, neck, or back,
§ worse with deep breathing or cough (pleuritic)
§ relieved by sitting up/leaning forward(MCQ)
o Aortic dissection:
§ Severe chest pain radiating to the back
§ associated with unequal pulses or unequal blood pressure in
right and left arms(MCQ)
o Abscess/mass:
§ Often sharp, localized pain, pleuritic(MCQ)
o Pulmonary embolism:
§ Often pleuritic.
§ Frequently associated withtachypnea and tachycardia
o Pneumonia:
§ Pleuritic, frequently associated with hypoxia(MCQ)
o GERD/esophageal spasm/tear:
§ Burning pain, dysphagia, may be similarto pain of myocardial
infarction (MI)
o Other causes of chest pain:
§ Peptic ulcer disease, biliary disease, herpes zoster, anxiety,
pneumothorax
• Risk factors for coronary artery disease (MCQ)
o Modifiable:
§ Smoking ,Hypercholesterolemia ,Hypertension
§ Obesity (apple-shaped) ,Diabetes mellitus , Physical inactivity
o Nonmodifiable:
§ Age ,Male , Family history
o Criteria for family history of coronary artery disease:(MCQ)
§ MI before age 40 in men
§ MI before age 55 in women
• Evaluation of CAD
o Exercise Stress Testing

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§ Patients are asked to walk on a treadmill at increasing levels of


difficulty to reach a heart rate that is 85% of predicted
maximum for age.
§ Alternatively, pharmacologic agents such as dobutamine may be
administered IV to stimulate myocardial function in a patient
who cannot exercise.(MCQ)
§ ECG monitoring during the procedure detects changes.
§ A test is considered positive for coronary artery disease if the
patientdevelops:(MCQ)
• ST elevation
• ST depression > 1 mm in multiple leads
• Decreased BP
• Failure to exercise more than 2 minutes due to
symptoms
§ Failure to complete the test due to reasons other than cardiac
symptoms (i.e., arthritis) is not diagnostic.
o Stress Myocardial Perfusion Imaging
§ Patients are injected with a radioisotope (thallium 201 or
technetium 99m sestamibi) and stressed (with exercise or
pharmacologic agent). (MCQ)
§ Nuclear imaging is obtained immediately after exercise and in 4
hours.
§ The test can detect:
• Myocardial perfusion
• Ventricular volume
• Ejection fraction
o Cardiac Catheterization
§ The right heart is accessed by the femoral or internal jugular vein.
§ The left heart is accessed by the femoral or radial artery (from the
rightheart).
• Acute coronary syndromes (ACS)
o Classified as non-ST-elevation and ST-elevation events.
o Non-ST-elevation events include non-ST-elevation MI and unstable
angina (UA). ACS is due to an imbalance of myocardial oxygen
demand and supply.
o The most common cause of decreased oxygen supply is narrowing of
coronary artery by thrombus or plaque that has become unstable.
o Cardiac enzymes :
§ Myoglobin: (MCQ)
• Elevated within 1 hour of MI but is nonspecific
• Creatinine phosphokinase (CPK):
• Elevated within 4 to 8 hours of MIbut is nonspecific
§ CK MB isoenzyme:(MCQ)
• Specific marker for myocardial tissue damage
§ Troponin T or I: (MCQ)

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• Very sensitive and specific markers for cardiac


muscleinjury.
• Elevated within 3 hours and can stay elevated for more
than a week
• Renal insufficiency can lead to erroneously high levels
depending on the type of troponin and the cutoff value
used.
§ “Serial enzymes”:
• Consists of cardiac biomarkers drawn every 6 to 8hours
for a 24-hour period(MCQ)
• Initial Evaluation of ACS
o Typical symptoms:
§ Left-sided/substernal chest pressure with radiation to left
shoulder, arm, or jaw
§ Shortness of breath
§ Diaphoresis
§ Nausea or vomiting
o Unstable angina is associated with
§ increasing frequency and/or severity of symptoms
§ symptoms at rest
§ new onset of symptoms.
o Presentation may be atypical in diabetics and women.
o Initial test: ECG
• Determining the Type of ACS and Management protocol
o ST-elevation MI (STEMI) or new left bundle branch block (LBBB)
on ECG:
§ These patients are admitted and managed according to
guidelines for STEMI.
o Unstable angina/non-ST-elevation MI: (MCQ)
§ These two have similar pathogenesis.
§ Non-ST-elevation MI differs from unstable angina in that the
lack of oxygen is severe enough to cause myocardial
damage and enzyme leakage (unlike unstable angina, where
there is no enzyme leakage).
o Clinical scenario 1: If normal ECG and normal cardiac enzymes and
no recurrence ofsymptoms(MCQ)
§ patient can have echocardiogram to assess left ventricular function.
o Clinical scenario 2: If either test is abnormal(MCQ)
§ patient should be managed as acute ischemia.
o Clinical scenario 3: If ST depression, inverted T-waves, positive
cardiac enzymes, or recurrence of symptoms (but no ST elevation
on ECG)(MCQ)
§ patient should be admitted to the hospital and managed as acute ischemia.
• Risk Stratification
o TIMI Risk Score(MCQ)
§ Age>65
§ Presence of 3 or more CAD risk factors
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§ Prior coronary stenosis 50%


§ Presence of ST segment deviation on admission ECG
§ At least two anginal episodes in last 24 hours
§ Elevated serum cardiac biomarkers
§ Use of ASA in prior 7 days
o Risk of all cause mortality @ 14 days =
§ 0/14.7% ,2 8.3% ,33.2 %
§ 419.9% , 5 26.2% , 6/740.9%
• Initial Treatment for All ACS
o Anti-ischemic treatments:
§ Oxygen
§ Nitroglycerin (NTG)
• for chest pain
• can be given sublingually
• Ifpain persists, can be given intravenously.
§ Morphine
• Given if pain persists despite NTG
§ Beta blockers(MCQ)
• decreasecardiac oxygen demand
• have been shownto decrease mortality
• Aim for a pulse rate of 60 .
o Antiplatelet and anticoagulation:
§ Aspirin (chewable preferred).
§ Clopidogrel is an alternative for those with true aspirin allergy.
§ Both unfractionated heparin and low-molecular-weight
heparin can be used.
§ GP IIb/IIa inhibitors have shown to be beneficial for(MCQ)
• high-risk patients
o elevated troponin
o TIMI risk score > 4
o ongoing ischemia
• patients undergoing percutaneous intervention.
§ Thrombolytics are not used in unstable angina or non-ST-
elevation MI because in 60 to 80% the infarcted artery is not
occluded.(MCQ)
• Treatment for Unstable Angina and Non-ST-Elevation MI
o General ACS anti-ischemic and antiplatelet treatment
o Early invasive treatment (cardiac catheterization) if any of the following
are present:(MCQ)
§ Elevated troponin
§ Recurrent chest pain despite medical therapy
§ CHF
§ Positive stress test
§ Left ventricular EF < 40%
§ Sustained ventricular tachycardia
§ Cardiac stent within 6 months
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o Early conservative therapy with medical management can be


considered in patients who respond to medical managementwithout
any of the features mentioned above.
• Treatment for ST-Elevation MI
o Patients include those with new left bundle branch block.
o Requires early revascularization with thrombolytics and/or
cardiaccatheterization and stent
o Cardiac catheterization/percutaneous transluminal coronary
angioplasty (PTCA):(MCQ)
§ Coronary angiogram can demonstrate the coronary anatomy as
well as the specific diseased vessel causing symptoms.
§ The occlusion of the vessel can be reopened by balloon
angioplasty and/or coronary stent placement.
§ Success rate as high as 90% compared to 60% with
thrombolytics.
§ Preferred over thrombolytics if:(MCQ)
• Skilled lab is available in < 12 hours from onset of
symptoms and
• < 30 minutes from entering the ER
• High risk of ST-elevation MI (i.e., cardiogenic shock)
• Late presentation (> 3 hours after symptoms)
o Thrombolytics
§ Thrombolytics are preferred (MCQ)
• if patient presents within 12 hours of symptoms ,
preferably within 3 hours
• if there will be a delay to PTCA or if cardiac
catheterization is not an option.
§ Thrombolytics work to break up clots.
§ Examples include streptokinase, urokinase, anistreplase,
alteplase, and reteplase.
§ Absolute contraindications to thrombolytics:(MCQ)
• Any prior intracranial hemorrhage
• Stroke within 1 year
• Intracranial neoplasm
• Active internal bleeding
• Suspected aortic dissection
§ Relative contraindications to thrombolytics:(MCQ)
• Available cath lab within 90 minutes of presentation
• Systolic blood pressure (sBP) > 180
• diastolic blood pressure (DBP)> 110
• Prior stroke or intracranial lesion other than above
• Bleeding disorder
• warfarin use with international normalized ratio(INR) > 2
• Major surgery within 3 weeks
• Age>75

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• Cardiopulmonary resuscitation (CPR)


• Peptic ulcer
• Medications at Discharge for Patients with ACS(MCQ)
o Aspirin indefinitely
o Beta blocker indefinitely
o Angiotensin-converting enzyme (ACE) inhibitor indefinitely
§ initially recommended for patients with ejection fraction (EF) <
40% or anterior wall MI
o Statin to maintain LDL < 70
o Clopidogrelfor 1 to 12 months depending on stent placement and type
• Postinfarction Complications
o Ruptures (usually occur within 4 to 5 days of a large MI):
o Free wall rupture
o Acute ventricular septal perforation
o Acute mitral regurgitation from papillary muscle rupture
o Arrhythmias:
o Ventricular tachycardia:(MCQ)
§ If within 48 hours of MI, usually just from reperfusion of
myocardium.
§ If it occurs later than 48 hours, consider implantable
defibrillator.
o Bradycardia (usually from inferior wall MI)
o Atrioventricular (AV) block:(MCQ)
§ If inferior wall MI, this will usually reverse
§ ifanterior wall MI, usually will require pacemaker
o Dressler’s syndrome: (MCQ)
§ Usually occurs 1 or 2 weeks after cardiac injury (MI or cardiac
surgery).
§ It is associated with fever, pericarditis, and sometimes
pericardial or pleural effusions; likely a hypersensitivityprocess.
§ Treat with NSAIDs.
• Secondary Preventionof unstable angina/non-ST-elevation MI and ST-
elevation MI:
o Smoking cessation
o Aggressive diabetes management
o Aggressive control of hypertension (maintain < 140/90)
o Lipid control with statins as above and dietary modification
§ ANGINA
• Unstable angina
o An acute coronary syndrome diagnosed by the following history:
§ New-onset angina
§ Angina that changes or accelerates in pattern, location, or
severity
§ Angina at rest
• Stable angina:
o A chronic, episodic pain syndrome due to temporary myocardial
ischemia.
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o Pattern of pain is similar to that of acute MI , but resolves with rest or


medication.
• Prinzmetal’s angina:
o Angina due to coronary vasospasm, not linked to exertion.
o Distinguished from unstable angina by chronic, intermittent nature.
o Pain usually occurs at a specific hour in the early morning
o Coronary vessels are angiographically normal.
o Etiology :Temporary myocardial ischemia
o Diagnosis
§ ECG
• ST segment depression or elevation
• T wave inversion
• May be normal
o Treatment
§ For Stable Angina(MCQ)
• Beta blockade: Reduces myocardial oxygen demand
• Aspirin: Reduces risk of MI in asymptomatic patients
• Morphine: For analgesia, but does not affect outcome
• Modify risk factors for coronary artery disease.
• Sublingual NTG for episodic pain
• Echocardiogram to assess left ventricular function
• Exercise stress test
• Consider coronary revascularization after
aforementioned tests: PTCAor coronary artery bypass
graft (CABG).
§ For Prinzmetal’s Angina
• Calcium channel blockers and nitrates to reduce
vasospasm
• Clinical Pearls :
• The maximum heart rate is estimated as: [220 −patient’s age].(MCQ)
• ECG Changes(MCQ)
o Inferior wall MI:
§ ST elevation in II, III, aVF
o Corpulmonale:
§ ST depression in II, III, aVF
o Anteroseptal MI:
§ ST elevation in V1, V2,
o Lateral wall MI:
§ ST elevation in V4, V5, V6
o Posterior wall MI:
§ ST depression in V1, V2
• Low-molecular-weight heparin

o given sub-Q every 12 hours.

o PT/PTT does not need to be checked.


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• The thrombolytic streptokinase


o highly immunogenic
o cannot be used in the same patient twice within a 6-month period.
• Clinical Vignette in MD Entrance :(MCQ)
o A 64-year-old man who was discharged from the hospital after MI 2
weeks ago presents with fever, chest pain, and generalized malaise. ECG shows
diffuse ST-T wave changes

§ Diagnosis: Dressler’s syndrome.

§ Treat with nonsteroidal anti-inflammatory drugs (NSAIDs).

• Clinical Vignette in MD Entrance :(MCQ)


o A 72-year-old smoker presents complaining of three episodes of severe
heavy chest pain this morning. Each episode lasted 3 to 5 minutes, but
he has no pain now . He has never had this type of pain before.
o Diagnosis: Unstable angina.

• Clinical Vignette in MD Entrance :(MCQ)


o A 70-year-old man presents with frequent episodes of dull chest pain
on and off for 8 months. He says the pain wakes him from sleep.

o Diagnosis: Prinzmetal’s angina.

Serum Markers for MI

ENZYME ONSET(HRS) PEAK (HRS) DURATION

Myoglobin 1-4 6-8 24hrs

Troponin T/I 3-12 18-24 7-10 days

Cratinine kinase 3-12 18-24 3-4 days

Lactate dehydrogenase 6-12 24-48 6-8 days

T opic - Hypertension

• Hypertension

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• Defined as an SBP 140 or DBP 90 on two separate occasions (MCQ)


• 25 to 35% of adults have hypertension
• Etiology
o Essential hypertension (primary, idiopathic)
o Secondary causes:
§ Renal parenchymal disease (chronic pyelonephritis)(MCQ)
§ Renal artery stenosis
§ Primary hyperaldosteronism (Cushing’s and Conn’s syndromes)
§ Pheochromocytoma(MCQ)
§ Eclampsia and preeclampsia
§ Coarctation of the aorta (congenital)(MCQ)
• Pathophysiology
o Usual mechanism is a normal cardiac output with increased peripheral
vascular resistance.(MCQ)
• Risk factors
o Diabetes
o High-sodium diet (MCQ)
o Obesity
o Tobacco use
o Family history of hypertension
o Black race
o Malegender(MCQ)
• Signs and symptoms
o Most patients with hypertension have no symptoms.
o Patients with severe hypertension may present with:
§ Light-headedness
§ Morning occipital headaches
§ Epistaxis
§ Hematuria
§ Blurred vision
§ Angina
§ Congestive heart failure
• Diagnosis/evaluation
o Blood pressure in both arms, repeated if abnormal
o Funduscopic examination to look for AV nicking, hemorrhage,
papilledema(MCQ)
o Auscultation for renal artery bruits (MCQ)
o ECG may show LVH or left ventricular strain.(MCQ)
o Urinalysis to look for active sediment, hematuria
o Blood urea nitrogen (BUN)/creatinine, serum potassium (evidence of
renal insufficiency)
• Treatment
o For repeated elevated blood pressure measurements:
§ Dietary changes: (MCQ)
• High fruits, vegetables

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• low-fat dairy products, lowtotal and saturated fats, low


salt
§ Weight loss, physical exercise
§ Low-dose thiazide diuretics are first choice for stage 1
hypertension.(MCQ)
§ Low-dose ACE inhibitor, calcium channel blockers, or beta
blockers arealso effective.(MCQ)
o Two- or three-drug therapy for patients not initially controlled
• Complications of hypertension (MCQ)
o Stroke
o MI
o Atrial fibrillation
o Heart failure
o Peripheral vascular disease
o Renal disease
• Hypertensive emergency
o Malignant hypertension is characterized by severely elevated blood
pressure accompanied by end-organ damage.
o Features that should alert the physician to the need for rapid blood
pressure reduction.(MCQ)
§ New-onset neurologic signs, papilledema
§ chest pain
§ heart failure
§ renal failure
o Diagnosis
§ Presence of end-organ damage (ECG changes, new-onset renal
failure, active urinary sediment, intracranial bleed, etc.)
o Treatment
o Reduce the mean arterial pressure by no more than 20%.(MCQ)
o Common intra- venous agents include:(MCQ)
§ Labetalol
§ Nitroprusside
§ Phentolamine for pheochromocytoma
§ Hydralazine or magnesium for preeclampsia-related
hypertension
Clinical Pearls :

• Over 90% of hypertension is essential, or idiopathic.

• Hypertension due to pheochromocytoma is characterized by ectopic


production of epinephrine and norepinephrine , causing wide swings in
blood pressure.(MCQ)

• A 29-year-old woman with preeclampsia treated with IV drip of magnesium


complains of difficulty breathing and has diminished reflexes. What is next step?

o Stop magnesium and give IV calcium.(MCQ)

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• An active urinary sediment contains blood, protein, and red and white cell
casts.

• Use parenteral blood pressure–lowering agents only if end-organ damage is


found, due to the risk of rapid reduction in coronary and cerebral perfusion.

• The mean arterial pressure is :
(2DBP SBP)/3(MCQ)

• Nitroprusside can cause cyanide toxicity.(MCQ)

Definition of Hypertension (JNC-7)

HYPERTENSION SYSTOLIC BLOOD PRESSURE DIASTOLIC BLOOD PRESSURE

Normal < 120 < 80

Prehypertension 120-139 80-89

Stage 1 140-159 or 90-99

Stage 2 > 160 or > 100

• Low potassium intake is associated with higher blood pressure in some patients; an
intake of 90 mmol/d is recommended(MCQ)
• Polycythemia, whether primary or due to diminished plasma volume, increases
blood viscosity and may raise blood pressure. (MCQ)
• Nonsteroidal anti-inflammatory drugs (NSAIDs) produce increases in blood
pressure averaging 5 mm Hg and are best avoided in patients with borderline or
elevated blood pressures.
• The metabolic syndrome (sometimes also called syndrome X or the "deadly
quartet") consists of (MCQ)
o upper body obesity
o hyperinsulinemia and insulin resistance
o hypertriglyceridemia
o hypertension
• Liddle syndrome (MCQ)
o anautosomal dominant condition
o characterized by
§ early-onset hypertension
§ hypokalemic alkalosis
§ low renin and low aldosterone levels.

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o This is caused by a mutation that results in constitutive activation of the


epithelial sodium channel of the distal nephron, with resultant unregulated
sodium reabsorption and volume expansion.
• Renal artery stenosis (MCQ)
o present in 1–2% of hypertensive patients.
o Its cause in most younger individuals is fibromuscular hyperplasia,
particularly in women under 50 years of age.
o The remainder of renal vascular disease is due to atherosclerotic stenoses
of the proximal renal arteries
• Renal vascular hypertension should be suspected in the following circumstances: if
the documented onset is before age 20 or after age 50 years(MCQ)
o hypertension is resistant to three or more drugs
o if there are epigastric or renal artery bruits
o if there is atherosclerotic disease of the aorta or peripheral arteries (15–
25% of patients with symptomatic lower limb atherosclerotic vascular disease
have renal artery stenosis
o if there is abrupt deterioration in kidney function after administration of
ACE inhibitors(MCQ)
o ifepisodes of pulmonary edema are associated with abrupt surges in blood
pressure
• In young patients with fibromuscular disease, angioplasty is very effective, but
there is controversy regarding the best approach to the treatment of atheromatous
renal artery stenosis.
• Although ACE inhibitors have improved the success rate of medical therapy of
hypertension due to renal artery stenosis, they have been associated with marked
hypotension and (usually reversible) kidney dysfunction in individuals with bilateral
disease.(MCQ)

T opic - Bacterial endocarditis

• Bacterial endocarditis
• is a localized infection of the endocardium
• characterized by vegetations involving the valve leaflets or walls.
• It can also be classified as acute (ABE) or subacute (SBE).
o ABE
§ Infection of healthy valves by high-virulence organisms
§ Produces metastatic foci
§ Usually fatal if not treated within 6 weeks
§ Most common organism is S. aureus (MCQ)
o SBE
§ Seeding of previously damaged valves (rheumatic heart disease,
con-
§ genital valve defects: mitral valve prolapse)
§ causedby low-virulence organisms
§ Does not produce metastatic foci
§ Most common organism is Streptococcus viridans(MCQ)
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§ Mitral valve is most often affected(MCQ)


• Etiology
o Acute: S. aureus, gram negative(MCQ)
o Subacute:
§ Streptococcusviridans,otheroralflora,groupAbeta-
hemolyticstrep, enterococci, Staphylococcus epidermidis
o IV drug users: S. aureus, streptococci, enterococci, Candida
o Prosthetic valves (10 to 20% of cases):
§ S. aureus, Streptococcus viridans,gram negative bacilli,
fungi(MCQ)
o Nosocomial infections:
§ Indwelling venous catheters, hemodialysis, CTsurgery
• Signs and symptoms
o ABE
§ Acute onset of fever, chills, rigors
§ New cardiac murmur
§ Metastatic infections—meningitis, pneumonia
o SBE
§ Gradual onset of fever, sweats, weakness, arthralgia,
anorexia, weight loss, and cutaneous lesions
§ New cardiac murmur
§ Splenomegaly
§ Petechiae:
• Multiple nonblanching red macules on upper chest and
mu-cous membranes
§ Osler’s nodes:(MCQ)
• Tender violaceous subcutaneous nodules on fingers
andtoes
§ Splinter hemorrhages:(MCQ)
• Fine linear hemorrhages in middle of nailbed
§ Janeway lesions: (MCQ)
• Multiple hemorrhagic nontender macules or noduleson
palms
§ Roth’s spots:(MCQ)
• Retinal hemorrhages seen on funduscopy
§ Conjunctival hemorrhages
• Diagnosis
o Duke’s criteria(A very High yield MCQ in MD Entrance )
§ Patient must have 2 major, 1 major + 3 minor, or 5 minor
criteria for diagnosis):
§ Major Criteria
• Two positive blood cultures taken at least 12 hours
apart, or 3positive cultures taken at least 1 hour apart
• Echocardiography—vegetations are pathognomonic but
their absence does not rule out endocarditis
• transesophageal echo is more sensitive.
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§ Minor Criteria
• Predisposing lesion on valve or intravenous drug use

• Fever > 38 ̊C

• Arterial emboli (Janeway lesions)


• Osler’s nodes, Roth’s spots
• Positive blood cultures not meeting major criteria
• Echocardiogram suspicious for endocarditis but not
meeting major criteria
• Treatment
o Streptococci: Penicillin G or ceftriaxone 4 weeks(MCQ)
o Staphylococci:Nafcillin or oxacillin4 weeks(MCQ)
o MRSA: Vancomycin4 weeks(MCQ)
• Clinical Pearls :
o Endocarditis prophylaxis is given to patients with ValvularHD and those
with previous history of endocarditis 30 minutes prior to:(MCQ)

§ Dentalprocedures

§ GIprocedures

§ Urologicprocedures

o There is a strong association between Streptococcus bovis


endocarditis and colonic neoplasms.(MCQ)

o IV drug users: (MCQ)

§ Right-sided ABE most often affects the tricuspid valve

§ septic pulmonary emboli are common.

T opic - Heart Sounds

Heart Sounds

§ S, is loud in short PR interval


§ S2 is heard due to closure of A V values

§ The intensity of S 1 depends upon

§ Position of mitral leaflets at the onset of ventricular systole

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o In short PR interval mitral leaflets are at a greater\ distance than


normal due to decreased interval between atrial contraction and
ventricular systole
§ The rate of rise of the left ventricular pressure pulse
o In VSD & MR rate of rise of pressure is low leading to soft S1
§ Pressure or absence of structural disease of mitral valve (defective
closure in MR, leading to soft S p calcified valve in MS leading to soft S,).
§ Causes of soft S1

§ Long PR interval

§ Mitral regurgitation

§ Immoble mitral leaflet because of rigidity and calcification as in MS*

§ Left bundle branch block


§ VSD

§ Tricuspid regurgitation

§ Causes of loud S 1

§ Shortened diastole due to tachycardia*


§ Short PR interval

§ Mitral stenosis if the valve is pliable*

§ Third Heart sound (S3) is a low pitched sound produced 0.14 to 0.16 S after
A2 at the termination of RAPID FILLING.
§ S3 usually (in age > 40 yrs) indicates.

§ Impairment of ventricular function.

§ AV valve regurgitation.
§ Conditions that increase rate or volume of ventricular filling.

§ Causes of S 3

§ Physiological

§ Healthy young adults.

§ Athletes.
§ Pregnancy
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§ fever

§ Pathological

§ Large, poorly contracted early LV , Mitral reflux.

§ An S 3 that is 'pericardial knock' present in


constrictive pericarditis.

§ In pure MS, S3 is never heard as rapid filling is not possible due


to stenosed AV valve.

§ S4 is low pitched, presystolic sound, produced in ventricle during 2nd rapid


filling phase
§ It is associated with effective atrial contraction.

§ S4 is seen in following conditions;

§ Hypertension
§ Aortic stenosis

§ Hypertrophic cardiomyopathy

§ Ischaemic heart disease

§ Acute mitral regurgitation

T opic - Pericardial tamponade


• Pericardial tamponade
• Tamponade is the physiologic result of rapid accumulation of fluid in the in-
elastic pericardial sac.
• It impairs cardiac filling and reduces cardiac output.
• Etiology
o Pericarditis
o Trauma (accidental or iatrogenic)
o Ruptured ventricular wall (post MI)
o Aortic dissection with rupture into pericardium
• Signs and symptoms
o Beck’s Triad (MCQ)
§ Hypotension
§ Muffled heart sounds
§ Jugular vein distention (JVD)
• Other Symptoms/Signs
o Dyspnea
o Tachycardia
o Pulsusparadoxus—decrease by > 10 mm Hg of sBP with
inspiration(MCQ)
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o Narrow pulse pressure


o JVD
• Diagnosis
o Auscultation may demonstrate distant heart sounds. (MCQ)
o ECG may show low voltage or electrical alternans.(MCQ)
o CXR may show enlarged cardiac silhouette.(MCQ)
o Echocardiogram will show large pericardial effusion.
• Treatment
o Immediate pericardiocentesis for unstable patients(MCQ)
o Infuse fluids to expand volume.
o Pericardial window (surgery) for meta-stable and stable patients
• Clinical Pearls :
o Pulsusparadoxus is a transient fall in measured blood pressure > 10
mm Hg associated with inspiration (due to reduced stroke volume
during inspiration).(MCQ)

o Tamponade physiology:

§ During inspiration, venous return to the right atrium increases.

§ In tamponade, the transiently enlarged right atrium bulges


leftward, reducing left ventricular volume and output, causing
BP to fall with inspiration.

o Pericardiocentesisyielding clotting blood probably came from the


right ventricle, not the pericardial sac.

• Swan-Ganz Catheterization

o In tamponade, near equalization (within 5 mm Hg) of the right


atrial, right ventricular diastolic, pulmonary arterial diastolic, and
pulmonary capillary wedge pressure (reflecting left atrial pressure)
occurs. (MCQ)

o The right atrial pressure tracings display a prominent systolic x descent


and abolished systolic y descent.(MCQ)

o Boltwood et al described the diastolic equalization of pulmonary


capillary and right atrial pressures as predominantly inspiratory ;
this is known as the inspiratory traction sign. It results from inspiratory
traction of the taut pericardium by the diaphragm. (MCQ)

• With a 12-lead electrocardiogram (see the image below), the following findings
suggest, but are not diagnostic for, pericardial tamponade:

• Sinus tachycardia

• Low-voltage QRS complexes

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• Electrical alternans - Also observed during supraventricular and ventricular


tachycardia

• PR segment depression

• Electrical alternans(MCQ)
o Alternation of QRS complexes, usually in a 2:1 ratio, on
electrocardiographic findings is called electrical alternans.
o It is caused by movement of the heart in the pericardial space.
o Electrical alternans is also observed in patients with myocardial
ischemia, acute pulmonary embolism, and tachyarrhythmias
• Chest radiography
o Shows cardiomegaly, a water bottle–shaped heart, pericardial
calcifications, or evidence of chest wall trauma (MCQ)
• A bowed catheter sign on chest radiography in children after central venous
catheter insertion may be suggestive of tamponade (MCQ)
• Echocardiography signs
o An echo-free space posterior and anterior to the left ventricle and
behind the left atrium –
o After cardiac surgery, a localized, posterior fluid collection without
significant anterior effusion may occur and may readily compromise
cardiac output
o Early diastolic collapse of the right ventricular free wall (MCQ)
o Late diastolic compression/collapse of the right atrium (MCQ)
o Swinging of the heart in its sac (MCQ)
o LV pseudohypertrophy(MCQ)
o Inferior vena cava plethora with minimal or no collapse with
inspiration(MCQ)
o A greater than 40% relative inspiratory augmentation of right-side flow (MCQ)
o A greater than 25% relative decrease in inspiratory flow across the mitral
valve(MCQ)
Most important table based on which lot of MCQs are tested in MD
Entrance exam

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Charecteristic Tamponade Constrictive Restrictive RVMI


Pericarditis Cardiomyopathy
Clinical
Pulsus paradoxus Common Usually Rare Rare
absent
Jugular veins
Prominent y descent Absent Usually Rare Rare
present
Prominenty x descent Present Usually Present Rare
present
Kussmaul’s sign Absent Present Present Present
Third heard sound Absent Absent Rare May be
present
Pericardial knock Absent Often Absent Absent
present
Electrocardiogram
Low ECG voltage May be May be May be present Absent
present
Electrical alternans May be Absent Absent Absent
present
Echocardiography
Thickened Absent Present Absent Absent
pericardium
Pericardial Absent Often Absent Absent
calcification present
Pericardial effusion Present Absent Absent Absent
RV size Usually Usually Usually normal Enlarged
small normal
Myocardial thickness Normal Normal Usually increased Normal
Right atrial collapse Present Absent Absent Absent
and RVDC
Increased early filling, Absent Present Present May be
↑ mitral flow velocity present
Exaggerated Present Present Absent Absent
respiratory variation
CT/MRI
Thickened/calcific Absent Present Absent Absent
pericardium
Cardiac
catheterization
Equalization of Usually Usually Usually absent Absent or
diastolic pressures present present present
Cardiac biopsy No No Sometimes No
helpful?

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T opic - Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy

§ Hypertrophy of the interventricular septum narrows the LV outflow tract


§ High-velocity systolic flow draws the anterior leaflet of the mitral valve into
the tract (via the Bernoulli effect) .(MCQ)
§ causes a dynamic left ventricular outflow tract obstruction.
§ Etiology
o ∼50% idiopathic
o ∼50% familial (autosomal dominant, with variable penetrance).(MCQ)
§ Conditions that increase the LV end diastolic volume decrease the
obstruction .(A frequently asked MCQ in MD Entrance )
o increased blood volume
o negative inotropic drugs
o rest
o increased peripheral resistance
§ Outflow obstruction can result in left atrial dilatation, atrial fibrillation, CHF ,
right heart failure, etc.
§ Signs and symptoms
o Angina.(MCQ)
§ Occurs at rest and during exercise
§ Frequently unresponsive to nitroglycerin
§ May respond to recumbent position (pathognomonic but rare)
o Syncope
§ Most often occurs following exercise
o Arrhythmias: Atrial fibrillation, ventricular tachycardia
o Signs of CHF
o Sudden death is usually due to an arrhythmia..(MCQ)
§ Diagnosis
o Systolic ejection murmur.(MCQ)
§ heard best along the left sternal border
§ decreases with increased LV blood volume (squatting)
§ increases with
• increased blood velocities (exercise)
• decreased LV end-diastolic volume (Valsalva)
o Paradoxical splitting of S2
§ ECG: .(MCQ)
o LVH, PVCs, atrial fibrillation
o inferiorlateral Q waves
o nonspecific ST segment and T wave abnormalities
§ Echocardiography:
o Septal hypertrophy, LVH, small LV
§ Treatment
o Patient should refrain from vigorous exercise.
o Beta blockers–first line agents.(MCQ)
§ reduce heart rate

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§ increasing LV filling time


§ decreasinginotropy
o calcium channel blockers considered second-line agents.
o The roles of antiarrhythmics, septal myomectomy, pacemaker, and
defibrillator are all controversial.
§ Avoid anything that decreases preload(nitrates, diuretics, volume depletion) as this
will worsen obstruction by allowing left ventricular collapse..(MCQ)
§ Clinical Vignette in MD Entrance :.(MCQ)
o A18-year-old athlete from Bihar becomes severely dyspneic and
collapses while running laps. His father had died suddenly at an early age.
o Diagnosis :Hypertrophic cardiomyopathy.
§ Very few murmurs decrease with squatting (HCM does)..(MCQ)

T opic – ECG

ECG Rate

• The usual paper speed is 25mm/sec


• 1mm (small square) = 0.04 sec
• 5mm (big square) = 0.2 sec
• Calculate atrial and ventricular rates separately if they are different (e.g. complete
heart block).
• For regular rhythms: Rate = 300 / number of large squares in between each
consecutive R wave. (MCQ)
• For very fast rhythms: Rate = 1500 / number of small squares in between each
consecutive R wave. (MCQ)
• For slow or irregular rhythms: Rate = number of complexes on the rhythm
strip x 6 (this gives the average rate over a ten-second period).
• Interpretation (adults)
o 60–100beats/min -Normal
o >100beats/min -Tachycardia
o <60beats/min –Bradycardia
• Normal Heart Rates in Children (MCQ)
o Newborn: 110 – 150 bpm
o 2 years: 85 – 125 bpm
o 4 years: 75 – 115 bpm
o 6 years+: 60 – 100 bpm

ECG Rhythm

Rhythm strip - On a 12 lead ECG this is usually a 10 second recording from Lead II.

A useful 7 step approach to rhythm analysis

1. Rate —

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a. Tachycardia or bradycardia?
b. Normal rate is 60-100/min.
2. Pattern of QRS complexes —
a. Regular or irregular?
b. If irregular is it regularly irregular or irregularly irregular?
3. QRS morphology —
a. Narrow complex — sinus, atrial or junctional origin.
b. Wide complex — ventricular origin, or supraventricular with aberrant
conduction.
4. P waves —
a. Absent — sinus arrest, atrial fibrillation
b. Present — morphology and PR interval may suggest sinus, atrial,
junctional or even retrograde from the ventricles.
5. Relationship between P waves and QRS complexes —
a. A V association (may be difficult to distinguish from isorhythmic
dissociation)
b. A V dissociation
i. complete — atrial and ventricular activity is always independent.
ii. incomplete — intermittent capture.
6. Onset and termination —
a. Abrupt — suggests re-entrant process.
b. Gradual — suggests increased automaticity.
7. Response to vagal manoeuvres —
a. Sinus tachycardia, ectopic atrial tachydysrhythmia — gradual
slowing during the vagal manoeuvre, but resumes on cessation.
b. AVNRT or AVRT — abrupt termination or no response.
c. Atrial fibrillation and atrial flutter — gradual slowing during the
manoeuvre.
d. VT — no response.

Narrow Complex (Supraventricular) Tachycardias

Regular Irregular
Atrial • Sinus tachycardia • Atrial
• Atrial tachycardia fibrillation
• Atrial flutter • Atrial flutter
• Inappropriate sinus with variable
tachycardia block
• Sinus node re-entrant • Multifocal
tachycardia atrial
tachycardia

Atrioventricular • Atrioventricular re-entry


tachycardia (A VRT)
• A V nodal re-entry
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tachycardia (A VNRT)
• Automatic junctional
tachycardia

• Broad Complex Tachycardias


o Regular
§ Ventricular tachycardia
§ Antidromicatrioventricular re-entry tachycardia (AVRT).
§ Any regular supraventricular tachycardia with aberrant conduction
— e.g. due to bundle branch block, rate-related aberrancy.
o Irregular
§ Ventricular fibrillation
§ Polymorphic VT
§ Torsades de Pointes
§ AF with Wolff-Parkinson-White syndrome
§ Any irregular supraventricular tachycardia with aberrant
conduction — e.g. due to bundle branch block, rate-related
aberrancy.
o All regular BCTs should be considered to be VT until proven otherwise.( MCQ)
• Bradycardias

o P waves present

§ Each P wave is followed by a QRS complex (= sinus node


dysfunction)

• Sinus bradycardia

• Sinus node exit block

• Sinus pause / arrest

§ Not every P wave is followed by a QRS complex (= A V node


dysfunction)

• A V block: 2nd degree, Mobitz I (Wenckebach)

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• A V block: 2nd degree, Mobitz II

• A V block: 2nd degree, “fixed ratio blocks” (2:1, 3:1)

• A V block: 2nd degree, “high grade A V block”

• A V block: 3rd degree (complete heart block)

o P waves absent

§ Narrow complexes

• Junctional escape rhythm

§ Broad complexes

• Ventricular escape rhythm

• For escape rhythms to occur there must be a failure of sinus node impulse generation or
transmission by the AV node.

ECG Axis

• the mean direction of electrical forces in the frontal plane ( limb leads) as
measured from the zero reference point (lead 1)
• Normal values
o P wave: 0 to 75 degrees
o QRS complex: -30 to 90 degress
o T wave: QRS-T angle <45 degrees frontal or <60 degrees precordial

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o Quick look tests

o The simplest method of identifying gross deviations in axis is to look at the


QRS complexes in leads I and aVF.

o Lead I is a left-sided lead, and as aVF is perpendicular to lead I, it can


be considered a right-sided lead.
o Both leads I and aVF have mainly positive QRS complexes = normal
axis.
o Lead I is positive and aVF is negative=left axis deviation (LAD).
o Lead I is negative and aVF is positive=right axis deviation (RAD).
• Both leads negative=extreme RAD or “North-West” axis

QRS Deflection Axis


Lead I Lead II Lead III
Positive Positive Positive or Negative Normal
Positive Negative Negative LAD
Negative Positive or Negative Positive RAD

Measuring ECG axis (simple version 1)

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QRS deflection Axis


Lead 1 Avf
Positive Positive Normal
Positive Negative LAD
Negative Positive RAD
Negative Negative Extreme RAD or Extreme
LAD

Measuring ECG axis (simple version 2)

• Interpretation of QRS Axis

• Normal
o 0 to 90 degrees
• Right Axis Deviation (RAD)
o > 90 degrees
§ moderate RAD: 90 to 120 degrees
§ marked RAD: 120 to 180 degrees
o Differential diagnosis
§ Right Ventricular Hypertrophy (RVH) — most common
§ Left Posterior Fascicular Block (LPFB) — diagnosis of
exclusion
§ Lateral and apical MI
§ Acute Right Heart Strain, e.g. acute lung disease such as
pulmonary embolus
§ Chronic lung disease, e.g. COPD
§ Dextrocardia
§ Ventricular pre-excitation (WPW) — LV free wall accessory
pathway
§ Ventricular ectopy
§ Hyperkalemia
§ Sodium-channel blockade, e.g. tricyclic toxicity
§ Secundum ASD — rSR’ pattern
§ Normal in infants and children
§ Normal young or slender adults with a horizontally positioned
heart can also demonstrate a rightward QRS axis on the
ECG.
• Left Axis Deviation (LAD)
o <-30 degrees
§ moderate LAD: -30 to -45 degrees
§ marked LAD: -45 to -90 degrees
o Differential diagnosis
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§Left ventricular hypertrophy (LVH)


§Left Anterior Fascicular Block (LAFB) — diagnosis of
exclusion
§ LBBB
§ inferior MI
§ ventricularectopy
§ paced beats
§ Ventricular pre-excitation (WPW)
§ Primum ASD — rSR’ pattern
• Extreme Axis Deviation
o 180 to -90 degrees - rare
o Differential diagnosis
§ Right Ventricular Hypertrophy (RVH)
§ Apical MI
§ VT
§ Hyperkalemia

• Rotation

o can be thought of as the axis of the heart in the transverse axis (the
precordial leads)
o Normal
§ isoelectric QRS in V3 and V4, indicating the transition point
between the right and left ventricular electric forces
o Clockwise rotation
§ isoelectric QRS in V5, V6
o Anti-clockwise rotation
§ isoelectric QRS in V1, V2
• Rule of thumb: the heart rotates towardshypertropy and away from infarction
• 12 Lead ECG
– Monitors 12 leads (V1–6), (I, II, III) and (aVR, aVF, aVL)

– Allows interpretation of specific areas of the heart

– – Inferior (II, III, aVF)

– – Lateral (I, aVL, V5, V6)

– – Anterior (V1–4)

The P wave

• The P wave is the first positive deflection on the ECG


• It represents atrial depolarization
• Characteristics of the Normal Sinus P Wave
• Morphology
o Smooth contour
o Monophasic in lead II
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o Biphasic in V1
• Axis
o Normal P wave axis is between 0° and +75°
o P waves should be upright in leads I and II, inverted in aVR
• Duration - < 120 ms

• Amplitude

o < 2.5 mm in the limb leads,

o < 1.5 mm in the precordial leads

• Atrial abnormalities are most easily seen in the inferior leads (II, III and aVF)
and lead V1, as the P waves are most prominent in these leads .

• The Atrial Waveform – Relationship to the P wave

o Atrial depolarisation proceeds sequentially from right to left, with the


right atrium activated before the left atrium.
o The right and left atrial waveforms summate to form the P wave.
o The first 1/3 of the P wave corresponds to right atrial activation, the
final 1/3 corresponds to left atrial activation; the middle 1/3 is a
combination of the two.
o In most leads (e.g. lead II), the right and left atrial waveforms move in
the same direction, forming a monophasic P wave.
o However, in lead V1 the right and left atrial waveforms move in opposite
directions. This produces a biphasic P wave with the initial positive
deflection corresponding to right atrial activation and the subsequent
negative deflection denoting left atrial activation.
o This separation of right and left atrial electrical forces in lead
V1 means that abnormalities affecting each individual atrial waveform
can be discerned in this lead. Elsewhere, the overall shape of the P wave
is used to infer the atrial abnormality.
• Normal P-wave Morphology – Lead II

o The right atrial depolarisation wave (brown) precedes that of the left
atrium (blue).
o The combined depolarisation wave, the P wave, is less than 120 ms
wide and less than 2.5 mm high.

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• Right Atrial Enlargement – Lead II

o In right atrial enlargement, right atrial depolarisationlasts longer than


normal and its waveform extends to the end of left atrial depolarisation.
o Although the amplitude of the right atrial depolarisation current remains
unchanged, its peak now falls on top of that of the left atrial
depolarisation wave.
o The combination of these two waveforms produces a P waves that is
taller than normal (> 2.5 mm), although the width remains
unchanged (< 120 ms).

• Left Atrial Enlargement – Lead II

o In left atrial enlargement, left atrial depolarisation lasts longer than


normal but its amplitude remains unchanged.
o Therefore, the height of the resultant P wave remains within normal
limits but its duration is longer than 120 ms.
o A notch (broken line) near its peak may or may not be present (“P
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mitrale”).

• Normal P-wave Morphology – Lead V1

o The P wave is typically biphasic in V1, with similar sizes of the positive and
negative deflections.

Normal P wave in V1

• Right Atrial Enlargement – Lead V1

o Right atrial enlargement causes increased height (> 1.5mm) in V1 of the


initial positive deflection of the P wave.

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This patient also has evidence ofright ventricular hypertrophy.

• Left Atrial Enlargement – Lead V1

o Left atrial enlargement causes widening (> 40ms wide) and deepening (>
1mm deep) in V1 of the terminal negative portion of the P wave.

• Biatrial Enlargement

o Biatrial enlargement is diagnosed when criteria for both right and left
atrial enlargement are present on the same ECG.

• The spectrum of P-wave changes in leads II and V1 with right, left and bi-atrial
enlargement is summarised in the following diagram:

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• Common P Wave Abnormalities

o Common P wave abnormalities include

o P mitrale (bifid P waves), seen with left atrial enlargement.

o P pulmonale (peaked P waves), seen with right atrial enlargement.

o P wave inversion, seen with ectopic atrial and junctional rhythms.

o V ariable P wave morphology, seen in multifocal atrial rhythms.


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o P mitrale

o The presence of broad, notched (bifid) P waves in lead II is a sign of


left atrial enlargement, classically due to mitral stenosis.

Bifid P waves (P mitrale) in left atrial enlargement

o P Pulmonale

The presence of tall, peaked P waves in lead II is a sign of right atrial


enlargement, usually due to pulmonary hypertension (e.g. corpulmonale
from chronic respiratory disease).

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Peaked P waves (P pulmonale) due to right atrial enlargement

o Inverted P Waves

o P-wave inversion in the inferior leads indicates a non-sinus origin of


the P waves.

§ When the PR interval is < 120 ms, the origin is in the A V


junction (e.g. accelerated junctional rhythm)

§ When the PR interval is ≥ 120 ms, the origin is within the atria
(e.g. ectopic atrial rhythm)

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o V ariable P-Wave Morphology

o The presence of multiple P wave morphologies indicates multiple ectopic


pacemakers within the atria and/or A V junction.

§ If ≥ 3 different P wave morphologies are seen, then multifocal atrial


rhythm is diagnosed:

§ If ≥ 3 different P wave morphologies are seen and the rate is ≥ 100,


then multifocal atrial tachycardia (MAT) is diagnosed:

o The Q wave
o A Q wave is any negative deflection that precedes an R wave

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o Origin of the Q Wave

§ The Q wave represents the normal left-to-right depolarisation


of the interventricular septum

§ Small ‘septal’ Q waves are typically seen in the left-sided leads


(I, aVL, V5 and V6)

o Q waves in different leads

§
Small Q waves are normal in most leads
§
Deeper Q waves (>2 mm) may be seen in leads III and aVR as
a normal variant
§ Under normal circumstances, Q waves are not seen in the right-
sided leads (V1-3)
o Pathological Q Waves

§ Q waves are considered pathological if:

• > 40 ms (1 mm) width

• > 2 mm deep

• > 25% of depth of QRS complex

§ Seen in leads V1-3

§ Pathological Q waves usually indicate current or prior myocardial


infarction.

§ Differential Diagnosis


Myocardial infarction

Cardiomyopathies — Hypertrophic (HOCM), infiltrative
myocardial disease
• Rotation of the heart — Extreme clockwise or counter-
clockwise rotation
• Lead placement errors — e.g. upper limb leads placed
on lower limbs
o Loss of normal Q waves

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§ The absence of small septal Q waves in leads V5-6 should be


considered abnormal.
§ Absent Q waves in V5-6 is most commonly due to LBBB.

Abnormalities of the R wave

o Causes of Dominant R wave in V1

o Normal in children and young adults


o Right Ventricular Hypertrophy (RVH)
o Pulmonary Embolus
o Persistence of infantile pattern
o Left to right shunt
o Right Bundle Branch Block (RBBB)
o Posterior Myocardial Infarction (ST elevation in Leads V7, V8, V9)
o Wolff-Parkinson-White (WPW) Type A
o Incorrect lead placement (e.g. V1 and V3 reversed)
o Dextrocardia
o Hypertrophic cardiomyopathy
o Dystrophy
o Myotonic dystrophy
o Duchenne Muscular dystrophy

o Causes of Dominant R wave in aVR

o Poisoning with sodium-channel blocking drugs (e.g. TCAs)


o Dextrocardia
o Incorrect lead placement (left/right arm leads reversed)
o Commonly elevated in ventricular tachycardia (VT)
o Poisoning with sodium-channel blocking drugs

§ Causes a characteristic dominant terminal R wave in aVR

§ Poisoning with sodium-channel blocking agents is suggested


if:

• R wave height > 3mm

• R/S ratio > 0.7

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o Dextrocardia

o ECG shows all the classic features of dextrocardia:

§ Positive QRS complexes (with upright P and T waves) in aVR


§ Negative QRS complexes (with inverted P and T waves) in lead
I
§ Marked right axis deviation
§ Absent R-wave progression in the chest leads (dominant S waves
throughout)

o Left arm/right arm lead reversal

o The most common cause of a dominant R wave in aVR is incorrect


limb lead placement, with reversal of the left and right arm electrodes.

o This produces a similar pattern to dextrocardia in the limb leads but


with normal R-wave progression in the chest leads.

o Note that absent R wave progression is characteristically seen in


dextrocardia

o With LA/RA lead reversal

§ Lead I becomes inverted

§ Leads aVR and aVL switch places

§ Leads II and III switch places

o Poor R wave progression

o Poor R wave progression is described with an R wave ≤ 3 mm inV3 and


is caused by:

§ Prior anteroseptal MI

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§ LVH

§ Inaccurate lead placement

§ May be a normal variant

T Wave

§ The T wave is the positive deflection after each QRS complex.


§ It represents ventricularrepolarisation.
§ Characteristics of the normal T wave

o Upright in all leads except aVR and V1


o Amplitude < 5mm in limb leads, < 15mm in precordial leads
§ T wave abnormalities

o Hyperacute T waves
o Inverted T waves
o Biphasic T waves
o ‘Camel Hump’ T waves
o Flattened T waves
§ Peaked T waves

o Tall, narrow, symmetrically peaked T-waves are characteristically seen in


hyperkalaemia.
§ Hyperacute T waves

o Broad, asymmetrically peaked or ‘hyperacute’ T-waves are seen in


the early stages of ST-elevation MI (STEMI) and often precede the
appearance of ST elevation and Q waves.
o They are also seen with Prinzmetal angina.
§ Loss of precordial T-wave balance

o Loss of precordial T-wave imbalance occurs when the upright T wave


is larger than that in V6.

o This is a type of hyperacute T wave.

o The normal T wave in V1 is inverted.


o An upright T wave in V1 is considered abnormal — especially if it is tall
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(TTV1), and especially if it is new (NTTV1).


o This finding indicates a high likelihood of coronary artery disease , and
when new implies acute ischemia.
§ Inverted T waves

o Inverted T waves are seen in the following conditions:

§ Normal finding in children


§ Persistent juvenile T wave pattern
§ Myocardial ischaemia and infarction
§ Bundle branch block
§ Ventricular hypertrophy (‘strain’ patterns)
§ Pulmonary embolism
§ Hypertrophic cardiomyopathy
§ Raised intracranial pressure
o T wave inversion in lead III is a normal variant.

o New T-wave inversion (compared with prior ECGs) is always abnormal.

o Pathological T wave inversion is usually symmetrical and deep


(>3mm).

§ Paediatric T waves

o Inverted T-waves in the right precordial leads (V1-3) are a normal


finding in children, representing the dominance of right ventricular
forces.
§ Persistent Juvenile T-wave Pattern

o T-wave inversions in the right precordial leads may persist into


adulthood and are most commonly seen in young Afro-Caribbean
women.
o Persistent juvenile T-waves are asymmetric, shallow (<3mm) and
usually limited to leads V1-3.
§ Myocardial Ischaemia and Infarction

o T-wave inversions due to myocardial ischaemia or infarction occur in


contiguousleads based on the anatomical location of the area of
ischaemia/infarction:

§ Inferior = II, III, aVF


§ Lateral = I, aVL, V5-6

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§ Anterior = V2-6
o Dynamic T-wave inversions are seen with acute myocardial ischaemia.
o Fixed T-wave inversions are seen following infarction, usually in
association with pathological Q waves.
§ Bundle Branch Block

o Left Bundle Branch Block

§Left bundle branch block produces T-wave inversion in the


lateral leads I, aVL and V5-6.
o Right Bundle Branch Block

§ Right bundle branch block produces T-wave inversion in the


right precordial leads V1-3.
§ Ventricular Hypertrophy

o Left Ventricular Hypertrophy

§
Left ventricular hypertrophy produces T-wave inversion in the
lateral leads I, aVL, V5-6 (left ventricular ‘strain’ pattern), with a
similar morphology to that seen in LBBB.
o Right Ventricular Hypertrophy

§Right ventricular hypertrophy produces T-wave inversion in the


right precordial leads V1-3 (right ventricular ‘strain’ pattern)
and also the inferior leads (II, III, aVF).
§ Pulmonary Embolism

o Acute right heart strain (e.g. secondary to massive pulmonary


embolism) produces a similar pattern to RVH, with T-wave inversions in
the right precordial (V1-3) and inferior (II, III, aVF) leads.
o Pulmonary embolism may also produce T-wave inversion in lead III as
part of the SI QIII TIII pattern (S wave in lead I, Q wave in lead III, T-
wave inversion in lead III).
§ Hypertrophic Cardiomyopathy (HOCM)

o HOCM is associated with deep T wave inversions in all the precordial


leads.
§ Raised intracranial pressure

o Events causing a sudden rise in ICP (e.g. subarachnoid haemorrhage)


produce widespread deep T-wave inversions with a bizarre

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morphology.
§ Biphasic T waves

o There are two main causes of biphasic T waves:

§ Myocardial ischaemia
§ Hypokalaemia
o The two waves go in opposite directions:

§ Ischaemic T waves go up then down


§ Hypokalaemic T waves go down then up
§ Wellens’ Syndrome

o Wellens’ syndrome is a pattern of inverted or biphasic T waves in V2-3


(in patients presenting with ischaemic chest pain) that is highly specific
for critical stenosis of the left anterior descending artery.

o There are two patterns of T-wave abnormality in Wellens’ syndrome:

§Type 1 Wellens’ T-waves are deeply and symmetrically inverted


§Type 2 Wellens’ T-waves are biphasic, with the initial deflection
positive and the terminal deflection negative
§ ‘Camel hump’ T waves

o Used to describe T-waves that have a double peak or ‘camel hump’


appearance.

o There are two causes for camel hump T waves:

§ Prominent U waves fused to the end of the T wav e, as seen in


severe hypokalaemia
§ Hidden P waves embedded in the T wave, as seen in sinus
tachycardia and various types of heart block
§ Flattened T waves

o Flattened T waves are a non-specific finding, but may represent

§ ischaemia (if dynamic or in contiguous leads) or

§ electrolyte abnormality, e.g. hypokalaemia (if generalised).


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§ Ischaemia

o Dynamic T-wave flattening due to anterior ischaemia


o T waves return to normal once the ischaemia resolves
§ Hypokalaemia

o Note generalised T-wave flattening with prominent U waves in the


anterior leads (V2 and V3).
The U wave

§ The U wave is a small (0.5 mm) deflection immediately following the T wave,
usually in the same direction as the T wave.
§ It is best seen in leads V2 and V3.
§ Source of the U wave

o The source of the U wave is unknown.

o Three common theories regarding its origin are:

§ Delayed repolarisation of Purkinje fibres


§ Prolonged repolarisation of mid-myocardial “M-cells”
§ After-potentials resulting from mechanical forces in the
ventricular wall
§ Features of Normal U waves

o The U wave normally goes in the same direction as the T wave


o U -wave size is inversely proportional to heart rate : the U wave grows
bigger as the heart rate slows down
o U waves generally become visible when the heart rate falls below 65
bpm
o The voltage of the U wave is normally < 25% of the T-wave voltage:
disproportionally large U waves are abnormal
o Maximum normal amplitude of the U wave is 1-2 mm
§ Abnormalities of the U wave

o Prominent U waves
o Inverted U waves
§ Prominent U waves

o U waves are prominent if > 1-2mm or 25% of the height of the T wave.
o The most common cause of prominent U waves is bradycardia.
o Abnormally prominent U waves are characteristically seen in severe
hypokalaemia.

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o Prominent U waves may also be seen with:

§ Hypocalcaemia
§ Hypomagnesaemia
§ Hypothermia
§ Raised intracranial pressure
§ Left ventricular hypertrophy
§ Hypertrophic cardiomyopathy
o The following drugs may cause prominent U waves:

§ Digoxin
§ Phenothiazines (thioridazine)
§ Class Iaantiarrhythmics (quinidine, procainamide)
§ Class III antiarrhythmics (sotalol, amiodarone)
o Note that many of the conditions causing prominent U waves will also cause a long
QT.
§ Inverted U waves

o U-wave inversion is abnormal (in leads with upright T waves)


o A negative U wave is highly specific for the presence of heart disease
o The main causes of inverted U waves are:

§ Coronary artery disease


§ Hypertension
§ Valvular heart disease
§ Congenital heart disease
§ Cardiomyopathy
§ Hyperthyroidism
o In patients presenting withschest pain, inverted U waves:

o Are a very specific sign of myocardial ischaemia


o May be the earliest marker of unstable angina and evolving
myocardial infarction
o Have been shown to predict a ≥ 75% stenosis of the LAD / LMCA
and the presence of left ventricular dysfunction

o Delta Wave
o The characteristic ECG findings in the Wolff-Parkinson-White syndrome
are:

§ Short PR interval (< 120ms)


§ Broad QRS (> 100ms)
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§ A slurred upstroke to the QRS complex (the delta wave)


§ Osborn Wave (J Wave)
o The Osborn wave (J wave) is a positive deflection at the J point
(negative in aVR and V1)
o It is usually most prominent in the precordial leads
o Causes

§Characteristically seen in hypothermia (typically T<30C), but


they are not pathognomonic.
o J waves may be seen in a number of other conditions:
§ Normal variant
§ Hypercalcaemia
§ Medications
§ Neurological insults such as intracranial hypertension, severe
head injury and subarachnoid haemorrhage
§ Le syndrome d’Haïssaguerre (idiopathic VF)
o In Hypothermia ,the height of the J wave is roughly proportional to the
degree of hypothermia

§ Epsilon Wave
o The epsilon wave is a small positive deflection (‘blip’) buried in the
end of the QRS complex.
o It is the characteristic finding in arrhythmogenic right ventricular
dysplasia (ARVD).
o The ECG changes in ARVD include:

§ Epsilon wave (most specific finding, seen in 30% of patients)


§ T wave inversions in V1-3 (85% of patients)
§ Prolonged S-wave upstroke of 55ms in V1-3 (95% of patients)
§ LocalisedQRS widening of 110ms in V1-3
§ Paroxysmal episodes of ventricular tachycardia with a LBBB
morphology

o PR interval
o The PR interval is the time from the onset of the P wave to the start of
the QRS complex.
o It reflects conduction through the A V node.
o PR interval
§ The normal PR interval is between 120 – 200 ms duration (three
to five small squares).
§ If the PR interval is > 200 ms,first degree heart block is said to be
present.
§ PR interval < 120 ms suggests pre-excitation (the presence of
an accessory pathway between the atria and ventricles) or AV
nodal (junctional) rhythm.
o First degree AV block (PR >200ms)

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§ Delayed conduction through the A V node


§ May occur in isolation or co-exist with other blocks (e.g., second-
degree A V block, trifascicular block)
o Short PR interval (<120ms)

§ A short PR interval is seen with:

• Preexcitation syndromes.

• A V nodal (junctional) rhythm.


o Pre-excitation syndromes

§ Wolff-Parkinson-White (WPW) and Lown-Ganong-Levine (LGL)


syndromes.
§ These involve the presence of an accessory pathway connecting
the atria and ventricles.
§ The accessory pathway conducts impulses faster than normal,
producing a short PR interval.
§ The accessory pathway also acts as an anatomical re-entry circuit,
making patients susceptible to re-entry tachyarrhythmias.
§ Patients present with episodes of paroxsymal supraventricular
tachycardia (SVT), specifically atrioventricular re-entry tachycardia
(A VRT), and characteristic features on the resting 12-lead ECG.
o Wolff-Parkinson-White syndrome

§
The characteristic features of Wolff-Parkinson-White syndrome are
a short PR interval, broad QRS and a slurred upstroke to the
QRS complex, the delta wave.
o Lown-Ganong-Levine syndrome

§The features of LGL syndrome are a very short PR interval with


normal P waves and QRS complexes and absent delta waves.
o AV nodal (junctional) rhythm

§ Junctional rhythms are narrow complex, regular rhythms arising


from the A V node.
§ P waves are either absent or abnormal (e.g. inverted) with a
short PR interval (=retrograde P waves).
The PR segment

§ The PR segment is the flat, usually isoelectric segment between the end of the
P wave and the start of the QRS complex.
§ PR segment abnormalities occur in two main conditions:

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o Pericarditis
o Atrial ischaemia
§ Pericarditis

§ The characteristic changes of acute pericarditis are:

o PR segment depression.
o Widespread concave (‘saddle-shaped’) ST elevation.
o Reciprocal ST depression and PR elevation in aVR and V1
o Absence of reciprocal ST depression elsewhere.
§ PR segment changes are relative to the baseline formed by the T-P segment.
J point

• The J point is the the junction between the termination of the QRS complex and
the beginning of the ST segment.
• Abnormalitites

o Elevation or depression of the J point is seen with the various causes of ST


segment abnormality.
o Notching of the J point occurs with benign early repolarisation.
o A positive deflection at the J point is termed a J wave (Osborn wave)
and is characteristically seen with hypothermia.
QRS Complex

• QRS Width

o Normal QRS width is 70-100 ms (a duration of 110 ms is sometimes


observed in healthy subjects).
o The QRS width is useful in determining the origin of each QRS
complex (e.g. sinus, atrial, junctional or ventricular).
§ Narrow complexes (QRS < 100 ms) are supraventricular in
origin.
§ Broad complexes (QRS > 100 ms) may be either ventricular in
origin, or may be due to aberrant conduction of
supraventricular complexes (e.g. due to bundle branch block,
hyperkalaemia or sodium-channel blockade).
o Sinus rhythm with frequent ventricular ectopic beats (VEBs) in a
pattern of ventricular bigeminy.
o The narrow beats are sinus in origin, the broad complexes are
ventricular.
• Narrow Complexes

o Narrow (supraventricular) complexes arise from three main places:

§ Sino-atrial node (= normal P wave)


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§Atria (= abnormal P wave / flutter wave / fibrillatory wave)


§AV node / junction (= either no P wave or an abnormal P wave
with a PR interval < 120 ms)
• Broad Complexes

o A QRS duration > 100 ms is abnormal


o A QRS duration> 120 ms is required for the diagnosis of bundle branch
block or ventricular rhythm
• Broad complexes may be ventricular in origin or due to aberrant conduction
secondary to:

o Bundle branch block


o Hyperkalaemia
o Poisoning with sodium-channel blocking agents (e.g. tricyclic
antidepressants)
o Pre-excitation (i.e. Wolff-Parkinson-White syndrome)
o Ventricular pacing
o Hypothermia
o Intermittent aberrancy (e.g. rate-related aberrancy)
• Ventricular tachycardia: Broad QRS complexes with no visible P waves.
o Fortunately, many causes of broad QRS can be identified by pattern
recognition:

§ Right bundle branch block produces an RSR’ pattern in V1 and


deep slurred S waves in the lateral leads.
§ Left bundle branch block produces a dominant S wave in V1
with broad, notched R waves and absent Q waves in the
lateral leads.
§ Hyperkalaemia is associated with a range of abnormalities
including peaked T waves
§ Tricyclic poisoning is associated with sinus tachycardia and tall
R’ wave in aVR
§ Wolff-Parkinson White syndrome is characterised by a short PR
interval and delta waves
§ Ventricular pacing will usually have visible pacing spikes
§ Hypothermia is associated with bradycardia, long QT, Osborn
waves and shivering artifact
• Low Voltage

o The QRS is said to be low voltage when:

§ The amplitudes of all the QRS complexes in the limb leads are
< 5 mm; or
§ The amplitudes of all the QRS complexes in the precordial leads
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are < 10 mm
• Electrical Alternans

o This is when the QRS complexes alternate in height.


o The most important cause is massive pericardial effusion, in which the
alternating QRS voltage is due to the heart swinging back and forth
within a large fluid-filled pericardium.
• High Voltage


Increased QRS voltage is often taken to infer the presence of left ventricular
hypertrophy.
• However, high left ventricular voltage (HLVV) may be a normal finding in
patients less than 40-45 years of age, particularly slim or athletic
individuals.
• There are multiple “voltage criteria” for left ventricular hypertrophy.
• Probably the most commonly used are the Sokolov-Lyon criteria (S wave
depth in V1 + tallest R wave height in V5-V6 > 35 mm).
• Voltage criteria must be accompanied by non-voltage criteria to be
considered diagnostic of left ventricular hypertrophy.
• QT Interval
• The QT interval is the time from the start of the Q wave to the end ofthe T wave.
• It represents the time taken for ventricular depolarisation and repolarisation
• The QT interval is inversely proportional to heart rate:

o The QT shortens at faster heart rates


o The QT lengthens at slower heart rates
• An abnormally prolonged QT is associated with an increased risk of
ventricular arrhythmias, especially Torsades de Pointes.
• The recently described congenital short QT syndrome has been found to be
associated with an increased risk of paroxysmal atrial and ventricular
fibrillation and sudden cardiac death.
• The QT interval should be measured in either lead II or V5-6
• Corrected QT

o The corrected QT interval (QTc) estimates the QT interval at a heart


rate of 60 bpm.
o This allows comparison of QT values over time at different heart rates
and improves detection of patients at increased risk of arrhythmias .
o Bazett’s formula: QTC = QT / √ RR

o The RR interval is given in seconds (RR interval = 60 / heart rate).

o Bazett’s formula is the most commonly used due to its simplicity. It


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over-corrects at heart rates > 100 bpm and under-corrects at heart


rates < 60 bpm, but provides an adequate correction for heart rates
ranging from 60 – 100 bpm.
• Normal QTc values

o QTc is prolonged if > 440ms in men or > 460ms in women


o QTc> 500 is associated with increased risk of torsades de pointes
o QTc is abnormally short if < 350ms
o A useful rule of thumb is that a normal QT is less than half the
preceding RR interval
• Causes of a prolonged QTc (>440ms)

o Hypokalaemia
o Hypomagnesaemia
o Hypocalcaemia
o Hypothermia
o Myocardial ischemia
o Post-cardiac arrest
o Raised intracranial pressure
o Congenital long QT syndrome
o DRUGS
• Hypokalaemia

o Hypokalaemia causes apparent QT c prolongation in the limb leads


(due to T-U fusion) with prominent U waves in the precordial leads.
• Hypocalcaemia

o Hypocalcaemia typically prolongs the ST segment, leaving the T wave


unchanged.
• Hypothermia

o Severe hypothermia can cause marked QTc prolongation, often in


association with bradyarrhythmias (especially slow AF), Osborne waves
and shivering artifact.
• Myocardial Ischaemia

o Myocardial ischemia tends to produce a modest increase in the QTc, in


the 450-500 ms range. This may be useful in distinguishing hyperacute
MI from benign early repolarization (both may produce similar
hyperacute T waves, but BER will usually have a normal QTc).
• Raised ICP

o A sudden rise in intracranial pressure (e.g. due to subarachnoid


haemorrhage) may produce characteristic T wave changes (‘cerebral T
waves’): widespread, deep T wave inversions with a prolonged QTc.
• Congenital Long QT Syndrome

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o There are several congenital disorders of ion channels that produce a long
QT syndrome and are associated with increased risk of torsades de
pointes and sudden cardiac death.
§ Causes of a short QTc (<350ms)

o Hypercalcaemia
o Congenital short QT syndrome
o Digoxin effect
§ Hypercalcaemia

o Hypercalcaemia leads to shortening of the ST segment and may be


associated with the appearance of Osborne waves.
§ Congenital short QT syndrome

o Congenital short QT syndrome (SQTS) is an autosomal-dominant


inherited disorder of potassium channels associated with an increased
risk of paroxysmal atrial and ventricular fibrillation and sudden
cardiac death.
o The main ECG changes are very short QT c (<300-350ms) with tall,
peaked T waves.
o Short QT syndrome may be suggested by the presence of:

§ Lone atrial fibrillation in young adults


§ Family member with a short QT interval
§ Family history of sudden cardiac death
§ ECG showing QT c< 350 ms with tall, peaked T waves
§ Failure of the QT interval to increase as the heart rate slows
§ Digoxin

o Digoxin produces a relative shortening of the QT interval , along with


downward sloping ST segment depression in the lateral leads
(‘reverse tick’ appearance), widespread T-wave flattening and
inversion, and a multitude of arrhythmias (ventricular ectopy, atrial
tachycardia with block, sinus bradycardia, regularized AF, any type of A V
block).
§ Drug-induced QT-Prolongation and Torsades

o In the context of acute poisoning with QT-prolonging agents, the


risk of TdP is better described by the absolute rather
than corrected QT.
o QTc-prolonging drugs that are associated with a relative tachycardia
(e.g. quetiapine) are much less likely to cause TdP than those that are
associated with a relative bradycardia (e.g. amisulpride).
The ST segment

o The ST segment is the flat, isoelectric section of the ECG between the end of
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the S wave (the J point) and the beginning of the T wave.


o It represents the interval between ventricular depolarization and repolarization.
o The most important cause of ST segment abnormality (elevation or depression)
is myocardial ischaemia or infarction.
o Causes of ST Segment Elevation

o Acute myocardial infarction


o Coronary vasospasm (Printzmetal’s angina)
o Pericarditis
o Benign early repolarization
o Left bundle branch block
o Left ventricular hypertrophy
o Ventricular aneurysm
o Brugada syndrome
o Ventricular paced rhythm
o Raised intracranial pressure
o Morphology of the Elevated ST segment

o Myocardial Infarction

§ Acute STEMI may produce ST elevation with either concave,


convex or obliquely straight morphology.
§ Acute ST elevation myocardial infarction (STEMI)causes ST
segment elevation and Q-wave formation in contiguous leads,
either:

• Septal (V1-2)
• Anterior (V3-4)
• Lateral (I + aVL, V5-6)
• Inferior (II, III, aVF)
• Right ventricular (V1, V4R)
• Posterior (V7-9)
§ There is usually reciprocal ST depression in the electrically
opposite leads. For example, STE in the high lateral leads I
+ aVL typically produces reciprocal ST depression in lead III
o Coronary V asospasm (Prinzmetal’s angina)

§ This causes a pattern of ST elevation that is very similar to acute


STEMI — i.e. localised ST elevation with reciprocal ST
depression occurring during episodes of chest pain.

§ However, unlike acute STEMI the ECG changes are transient,


reversible with vasodilators and not usually associated with
myocardial necrosis. It may be impossible to differentiate
these two conditions based on the ECG alone.
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o Pericarditis

§ Pericarditis causes widespread concave (“saddleback”) ST


segment elevation with PR segment depression in multiple
leads, typically involving I, II, III, aVF , aVL, and V2-6.

§ There is reciprocal ST depression and PR elevation in leads


aVR and V1. Spodick’s sign — a downward sloping TP
segment — may also be seen.

o Benign Early Repolarization

§ BER causes mild ST elevation with tall T-wavesmainly in the


precordial leads and inferior leads

§ Is a normal variant commonly seen in young, healthy patients.

§ There is often notching of the J-point — the “fish-hook”


pattern.

§ The ST changes may be more prominent at slower heart rates


and disappear in the presence of tachycardia .

o Left Bundle Branch Block

§In left bundle branch block, the ST segments and T waves show
“appropriate discordance” — i.e. they are directed opposite
to the main vector of the QRS complex .
§ This produces ST elevation and upright T waves in leads with
a negative QRS complex (dominant S wave), while producing
ST depression and T wave inversion in leads with a positive
QRS complex (dominant R wave).
o Left Ventricular Hypertrophy

§LVH causes a similar pattern of repolarization abnormalities as


LBBB, with ST elevation in the leads with deep S-waves
(usually V1-3) and ST depression/T-wave inversion in the
leads with tall R waves (I, aVL, V5-6).
o Ventricular Aneurysm

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§This is an ECG pattern of residual ST elevation and deep Q


waves seen in patients with previous myocardial infarction.
o Brugada Syndrome
§ This in an inherited channelopathy (a disease of myocardial
sodium channels) that leads to paroxysmal ventricular
arrhythmias and sudden cardiac death in young patients.
§ The tell-tale sign on the resting ECG is the “Brugada sign” —
ST elevation and partial RBBB in V1-2 with a “coved”
morphology.
o Ventricular Paced Rhythm

§
Ventricular pacing (with a pacing wire in the right ventricle)
causes ST segment abnormalities identical to that seen in LBBB.
There is appropriate discordance, with the ST segment and T wave
directed opposite to the main vector of the QRS complex.
o Raised Intracranial Pressure

§ Raised ICP (e.g. due to intracranial haemorrhage, traumatic brain


injury) may cause ST elevation or depression that simulates
myocardial ischaemia or pericarditis.

§ More commonly, raised ICP is associated with widespread, deep


T-wave inversions (“cerebral T waves”).

o Less Common Causes of ST segment Elevation

§
Pulmonary embolism and acute corpulmonale (usually in lead III)
§
Acute aortic dissection (classically causes inferior STEMI due to
RCA dissection)
§ Hyperkalaemia
§ Sodium-channel blocking drugs (secondary to QRS widening)
§ J-waves (hypothermia, hypercalcaemia)
§ Following electrical cardioversion
§ Others: Cardiac tumour, myocarditis, pancreas or gallbladder
disease
o Causes of ST Depression

o Myocardial ischaemia / NSTEMI


o Reciprocal change in STEMI
o Posterior MI
o Digoxin effect
o Hypokalaemia
o Supraventricular tachycardia
o Right bundle branch block
o Right ventricular hypertrophy
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o Left bundle branch block


o Left ventricular hypertrophy
o Ventricular paced rhythm
o Morphology of ST Depression

o Myocardial Ischaemia

§ ST depression can be either upsloping, downsloping, or


horizontal.
§ Horizontal or downsloping ST depression ≥ 0.5 mm at the J-
point in ≥ 2 contiguous leads indicates myocardial ischaemia
(according to the 2007 Task Force Criteria).
§ Upsloping ST depression in the precordial leads with
prominent “De Winter’s” T waves is highly specific for
occlusion of the LAD.
§ Reciprocal change has a morphology that resembles “upside
down” ST elevation and is seen in leads electrically opposite
to the site of infarction .
§ Posterior MI manifests as horizontal ST depression in V1-3 and
is associated with upright T waves and tall R waves.
§ ST depression due to subendocardialischaemia may be present in
a variable number of leads and with variable morphology.

§ It is often most prominent in the left precordial leads V4-6 plus


leads I, II and aVL.

§ Widespread ST depression with ST elevation in aVR is seen in


left main coronary artery occlusion and severe triple vessel
disease.

§ ST depression localised to the inferior or high lateral leads is more likely to


represent reciprocal change than subendocardialischaemia. The corresponding
ST elevation may be subtle and difficult to see, but should be sought.
§ Reciprocal Change

• ST elevation during acute STEMI is associated with


simultaneous ST depression in the electrically opposite
leads:

• Inferior STEMI produces reciprocal ST depression in


aVL (± lead I).
• Lateral or anterolateral STEMI produces reciprocal ST
depression in III and aVF (± lead II).
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Reciprocal ST depression in V1-3 occurs with posterior
infarction
o Posterior Myocardial Infarction

§
Acute posterior STEMI causes ST depression in the anterior
leads V1-3, along with dominant R waves (“Q-wave
equivalent”) and upright T waves.
§ There is ST elevation in the posterior leads V7-9.
o De Winters T Waves

§This pattern of upsloping ST depression with symmetrically


peaked T waves in the precordial leads is considered to be a
STEMI equivalent, and is highly specific for an acute occlusion
of the LAD.
o Digoxin Effect

§
Treatment with digoxin causes downsloping ST depression
with a “sagging” morphology, reminiscent of Salvador Dali’s
moustache.
o Hypokalaemia

§Hypokalaemia causes widespread downsloping ST depression


with T-wave flattening/inversion, prominent U waves and a
prolonged QU interval.
o Right ventricular hypertrophy

§RVH causes ST depression and T-wave inversion in the right


precordial leads V1-3.
o Right Bundle Branch Block

§RBBB may produce a similar pattern of repolarisation


abnormalities to RVH, with ST depression and T wave
inversion in V1-3.
o Supraventricular tachycardia

§ Supraventricular tachycardia (e.g. AVNRT) typically causes


widespread horizontal ST depression, most prominent in the
left precordial leads (V4-6).
§ This rate-related ST depression does not necessarily indicate the
presence of myocardial ischaemia, provided that it resolves with
treatment.
T opic - Pulmonary embolism

Pulmonary embolism
§ Thrombus, usually formed in the systemic veins or rarely in the right heart
(10% of cases), may dislodge and embolize into the pulmonary arterial
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system.
§ Most clots which cause clinically relevant pulmonary emboli actually come from
the pelvic and abdominal veins, but femoral deep venous thrombosis, and even
occasionally axillary thrombosis, can be the origin of the clot. (MCQ)
§ Pathophysiology
o Emboli can also occur from tumour, fat (long bone fractures), amniotic fluid and
foreign material during i.v.drug abuse.
After some hours the non-perfused lung no longer produces surfactant.
o Alveolar collapse occurs and exacerbates hypoxaemia.
o The primary haemodynamic consequence of pulmonary embolism is a
reduction in the cross-sectional area of the pulmonary arte- rialbed which
results in an elevation of pulmonary arterial pressure and a reduction in cardiac
output.
o The zone of lung that is no longer perfused by the pulmonary artery may
infarct, but often does not do so because oxygen continues to be supplied by
the bronchial circulation and the airways.

§ Clinical features
o Sudden onset of unexplained dyspnoeais the most common, and often
the only symptom of pulmonary embolism. (MCQ)
o Pleuritic chest pain and haemoptysis are present only when infarction has
occurred.(MCQ)
o Many pulmonary emboli occur silently, but there are three typical clinical
presentations.
§ Small/medium pulmonary embolism
§ In this situation an embolus has impacted in a terminal
pulmonary vessel.
§ Symptoms are pleuritic chest pain and breathlessness. (MCQ)
§ Haemoptysis occurs in 30%, often 3 or more days after the initial
event.
§ On examination, the patient may be tachypnoeic with a localized
pleural rub and often coarse crackles over the area involved.
§ An exudative pleural effusion (occasionally blood-stained) can
develop. The patient may have a fever, and cardiovascular
examination is normal.
§ Massive pulmonary embolism
§ This is a much rarer condition where sudden collapse occurs
because of an acute obstruction of the right ventricular outflow
tract. (MCQ)
§ The patient has severe central chest pain (cardiac ischaemia due
to lack of coronary blood flow) and becomes shocked, pale and
sweaty..
§ Multiple recurrent pulmonary emboli
§ This leads to increased breathlessness, often over weeks or
months. It is accompanied by weakness, syncope on exer- tion
and occasionally angina.
§ The physical signs are due to the pulmonary hypertension that
has developed from multi-ple occlusions of the pulmonary
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vasculature.
§ On examination, there are signs of right ventricular overload with
a right ventricular heave and loud pulmonary second
sound.(MCQ)
§ Diagnosis
o The symptoms and signs of small and medium-sized pulmo- nary emboli
are often subtle and non-specific, so the diagnosis is often delayed or
even completely missed.
o Pulmonary embolism should be considered if patients present with
symptoms of unexplained cough, chest pain, haemoptysis, new-onset
atrial fibrillation (or other tachycardia), or signs of pulmonary
hypertension if no other cause can be found.(MCQ)
§ Investigations
§ Small/medium pulmonary emboli
o Chest X-ray
§ It is often normal,
§ linear atelectasis or blunting of a costophrenic angle (due to a
small effusion) is not uncommon. (MCQ)
§ A raised hemidiaphragmis present in some patients.(MCQ)
§ More rarely, a wedge-shaped pulmonary infarct, the abrupt cut-
off of a pulmonary artery or a translucency of an underperfused
distal zone is seen (Hampton’s hump ) . (MCQ)
Previous infarcts may be seen as opaque linear scars.
o ECG
§ It is usually normal, except for sinus tachycardia(MCQ)
§ sometimesatrial fibrillation or another tachyarrhythmia occurs.
§ There may be evidence of right ventricular strain.
§ S1Q3T3 is characteristic pattern(MCQ)
o Blood tests.
§ Pulmonary infarction results in a
polymorphonuclearleucocytosis, an elevated ESR and increased
lactate dehydrogenase (LDH) levels in the serum.
§ Immediately prior to commencing anticoagulants a thrombophilia
screen should be checked.
§ Plasma D-dimer – if this is undetectable, it excludes a diagnosis
of pulmonary embolism.(MCQ)
o Radionuclide ventilation/perfusion scanning ( V Q scan) is a good and
widely available diagnostic investigation.
o Pulmonary 99mTc scintigraphydemonstrates underperfusedareas which,
if not accompanied by a ventilation defect on a ventilation scintigram
performed after inhalation of radioactive xenon gas, is highly suggestive of a
pulmonary embolus.
o Ultrasound scanning can be performed for the detection of clots in pelvic
or iliofemoral veins
o CT scans.
§ Contrast-enhanced multidetector CT angiograms (CTA have a
sensitivity of 83% and specificity of 96%, with a positive
predictive value of 92%. These values will increase with the use of
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64-multislice scanners.
o MR imaging gives similar results and is used if CT angiography is
contraindicated.
§ Massive pulmonary emboli
o Chest X-ray may show pulmonary oligaemia,
o sometimes with dilatation of the pulmonary artery in the hila. Often there
are no changes.
o Blood gases show arterial hypoxaemia with a low arterial CO2 level, i.e.
type I respiratory failure pattern. (MCQ)
o Echocardiography shows a vigorously contracting left ventricle, and
occasionally a dilated right ventricle and a clot in the right ventricular
outflow tract.
o Pulmonary angiography has now been replaced by CT and MR
angiography.
§ Multiple recurrent pulmonary emboli
o Chest X-ray may be normal.
o Enlarged pulmonaryarterioles with oligaemic lung fields indicate
advanced disease.(MCQ)
o ECG can be normal or show signs of pulmonaryHypertension
o Leg imaging with ultrasound and venography may show thrombi.
o Further tests looking for exercise-induced hypoxaemia and catheter
studies to estimate pulmonary artery pressures are sometimes required.
§ Treatment
§ Acute management
o All patients should receive high-flow oxygen (60–100%) unless they have
significant chronic lung disease.
o Patients with pulmonary infarcts require bed rest and analgesia.
o In severe cases, intravenous fluids and even inotropic agents to improve
the pumping of the right heart are sometimes required, and very ill
patients will require care on the intensive therapy unit (MCQ)
o Fibrinolytic therapy such as streptokinase (250000 units by i.v . infusion
over 30 minutes, followed by streptokinase 100000 units i.v . hourly for
up to 12–72 hours according to manufacturer’s instructions) (MCQ)
o Surgical embolectomy is rarely necessary, but theremay be no alternative
when the haemodynamic circumstances are very severe.
§ Prevention of further emboli
o A comparison of low-molecular-weight heparin (LMWH) with
unfractionated heparin has shown no difference. As LMWHs simplify
treatment they are used exclusively if available, although they are more
expensive.
o The most common method by which pulmonary embolism is treated in
this situation is by insertion of a filter in the inferior vena cava via the
femoral vein to above the level of the renal veins.

T opic -Arterial pulse

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Arterial pulse

§ The character of the pulse is best appreciated at the carotid level(MCQ)

§ Carotid pulsations are not normally apparent on inspection of the neck


§ A weak and delayed pulse (pulsusparvus et tardus ) defines severe aortic
stenosis (AS). (MCQ)

§ Some patients with AS may also have a slow, notched, or interrupted upstroke
(anacrotic pulse) with a thrill or shudder. (MCQ)

§ With chronic severe AR, by contrast, the carotid upstroke has a sharp rise and
rapid fall-off (Corrigan's or water- hammer pulse).(MCQ)

§ A collapsing pulse is characteristic of aortic valvular regurgitation or a


persistent ductusarteriosus. (MCQ)

• They may be visible (Corrigan’s sign) in conditions associated with a large-


volume pulse, including high output states (such as thyrotoxicosis,
anaemia or fever) and in aortic regurgitation
§ Bifid pulse

o Some patients with advanced AR may have a bifid or bisferiens pulse,


in which two systolic peaks can be appreciated. (MCQ)

o A bifid pulse is also described in patients with hypertrophic obstructive


cardiomyopathy (HOCM), with inscription of percussion and tidal
waves. (MCQ)

o A bifid pulse is easily appreciated in patients on intra-aortic balloon


counterpulsation (IABP), in whom the second pulse is diastolic in
timing.(MCQ)

§ Pulsusparadoxus

o refers to a fall in systolic pressure >10 mmHg with inspiration

o seen in patients with pericardial tamponade(MCQ)

o also is described in those with massive pulmonary embolism,


hemorrhagic shock, severe obstructive lung disease, and tension
pneumothorax.(MCQ)

o Pulsusparadoxus is measured by noting the difference between the


systolic pressure at which the Korotkoff sounds are first heard
(during expiration) and the systolic pressure at which the Korotkoff
sounds areheard with each heartbeat, independent of the respiratory
phase. Between these two pressures, the Korotkoff sounds are heard
only intermittently and during expiration . The cuff pressure must be

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decreased slowly to appreciate the finding

o It can be difficult to measure pulsusparadoxus in patients with


tachycardia, atrial fibrillation, or tachypnea.

o A pulsusparadoxus may be palpable at the brachial artery or femoral


artery level when the pressure difference exceeds 15 mmHg. . (MCQ)

o This inspiratory fall in systolic pressure is an exaggerated consequence


of interventricular dependence.

§ Pulsusalternans

o defined by beat-to-beat variability of pulse amplitude.

o It is present only when every other phase I Korotkoff sound is


audible as the cuff pressure is lowered slowly, typically in a patient with a
regular heart rhythm and independent of the respiratory cycle.

o Pulsusalternans is seen in patients with severe left ventricular systolic


heart failure .(MCQ)

o it is thought to be due to cyclic changes in intracellular calcium and


action potential duration.

o Interestingly, when pulsusalternans is associated with


electrocardiographic T-wave alternans, the risk for an arrhythmic
event appears to be increased.. (MCQ)

§ A small-volume pulseis seen in cardiac failure, shock and obstructive valvular or


vascular disease. (MCQ)

§ It may also be present during tachyarrhythmias, or vascular disease.

§ In patients in whom the diagnosis of either temporal arteritis or polymyalgia


rheumatica is suspected, the temporal arteries also should be examined.

§ Simultaneous palpation of the radial and femoral pulses may reveal a femoral
delay in a patient with hypertension and suspected aortic coarctation.

§ Ascending aortic aneurysms can rarely be appreciated as a pulsatile mass in the


right parasternal.

§ Femoral and/or popliteal artery aneurysms should be sought in patients with


abdominal aortic aneurysm disease.

§ Arterial Bruit

o A cervical bruit is a weak indicator of the degree of carotid artery


stenosis; the absence of a bruit does not exclude the presence of
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significant luminal obstruction.. (MCQ)

o If a bruit extends into diastole or if a thrill is present, the obstruction is


generally severe.

o Other causes of arterial bruits include an arteriovenous fistula with


enhanced flow .

§ Abnormal pulse oximetry (a >2% difference between finger and toe oxygen
saturation) can be used to detect lower extremity peripheral arterial disease
and is comparable in its performance characteristics to the ankle-brachial
index.

§ Bigeminal pulse (pulsusbigeminus)(MCQ)

o This is due to a premature ectopic beat following every sinus beat.

o The rhythm is not regular because every weak pulse is premature

§ Rhythm
§ The rhythm is regular except for a slight quickening in early
inspiration and a slowing in expiration (sinus arrhythmia).(MCQ)
§ Premature beats occur as occasional or repeated irregu- larities
superimposed on a regular pulse rhythm.
§ Similarly, intermittent heart block is revealed by occasional beats
dropped from an otherwise regular rhythm.
§ Atrial fibrillation produces an irregularly irregular pulse. (MCQ)
§ This irregular pattern persists when the pulse quickens in response to exercise , in
contrast to pulse irregularity due to ectopic beats, which usually
disappears on exercise.

T opic -Jugular venous pressure

Jugular venous pressure

• internal jugular vein is preferred because the external jugular vein is valved
and not directly in line with the superior vena cava and right atrium

• external jugular vein has been used to discriminate between high and low
central venous pressure (CVP) when tested among medical students, residents,
and attending physicians.

• Venous pressure traditionally has been measured as the vertical distance


between the top of the jugular venous pulsation and the sternal inflection

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point (angle of Louis).

• A distance >4.5 cm at 30° elevation is considered abnormal. (MCQ)

• In patients in sinus rhythm, the venous waveform is typically biphasic,


whereas the carotid upstroke is monophasic.

• Jugular venous pulse wave tracing

o A wave

§ representsright atrial presystolic contraction(MCQ)

§ occurs just after the electrocardiographic P wave (MCQ)

§ occurs just before the first heart sound (I).(MCQ)

§ A prominent a wave is seen in patients with reduced right


ventricular compliance(MCQ)

§ acannon a wave occurs with atrioventricular (AV)


dissociation and right atrial contraction against a closed tricuspid
valve. (MCQ)

§ In a patient with a wide complex tachycardia, the appreciation


of cannon a waves in the jugular venous waveform identifies the
rhythm as ventricular in origin. (MCQ)

§ The a wave is not present with atrial fibrillation(MCQ)

o x descent

§ defines the fall in right atrial pressure after inscription of the a


wave.

§ follows the “a wave” just as atrial pressure continues to


fall(MCQ)

o c wave interrupts this x descent and is followed by a further descent.

§ It may reflect the carotid pulsation in the neck and/or an early


systolic increase in right atrial pressure as the right ventricle
pushes the closed tricuspid valve into the right atrium

o v wave

§ representsatrial filling (atrial diastole)during ventricular


systole

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§ occurs during ventricular systole(MCQ)

§ peaks at the second heart sound (II). (MCQ)

§ The height of the v wave is determined by (MCQ)

• right atrial compliance

• volume of blood returning to the right atrium either

o antegrade from the cavae or

o retrograde through an incompetent tricuspid


valve.

§ In patients with TR, the v wave is accentuated and the


subsequent fall in pressure (y descent) is rapid. (MCQ)

§ With progressive degrees of TR, the v wave merges with the c


wave, and the right atrial and jugular vein waveforms become
"ventricularized." (MCQ)

o y descent

§ follows the peak of the v wave (MCQ)

§ corresponds to the fall in right atrial pressure after tricuspid valve


opening

§ can become prolonged or blunted with obstruction to right


ventricular inflow, as may occur with tricuspid stenosis (TS)
or pericardial tamponade. (MCQ)

§ prominent and rapid y descent, corresponds in timing to the


pericardial knock (K) in Constrictive pericarditis(MCQ)

o Kussmaul's sign

§ Normally, the venous pressure should fall by at least 3 mmHg


with inspiration. Kussmaul's sign is defined by either a rise or a
lack of fall of the JVP with inspiration classically associated with
constrictive pericarditis(MCQ)

§ it has been reported in patients with restrictive


cardiomyopathy, massive pulmonary embolism, right
ventricular infarction, and advanced left ventricular systolic
heart failure.(MCQ)

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o Abdominojugular reflex

§ Venous hypertension sometimes can be elicited by performance


of the abdominojugular reflex or with passive leg elevation.

§ When these signs are positive, a volume-overloaded state with


limited compliance of an overly distended or constricted venous
system is present.

§ The abdominojugular reflex is elicited with firm and consistent


pressure over the upper portion of the abdomen, preferably over
the right upper quadrant, for at least 10 s.

§ A positive response is defined by a sustained rise of more than


3 cm in JVP for at least 15 s after release of the hand

§ The abdominojugular reflex is useful in predicting a pulmonary


artery wedge pressure in excess of 15 mmHg in patients with
heart failure.(MCQ)

§ anelevated JVP has prognostic significance in patients with


both symptomatic heart failure and asymptomatic left
ventricular systolic dysfunction.

§ The presence of an elevated JVP is associated with a higher risk


of subsequent hospitalization for heart failure, death from heart failure , or
both.

Summary of Frequently asked MCQs in exam


§ Raised JVP, normal waveform(MCQ)
o Bradycardia
o Fluid overload
o Heart Failure
§ Raised JVP, absent pulsation(MCQ)
o Superior vena cava syndrome
§ Large 'a' wave (increased atrial contraction pressure) (MCQ)
o tricuspid stenosis
o Right heart failure
o Pulmonary hypertension
§ Giant cannon waves occur in complete heart block and ventricular
tachycardia.(MCQ)

§ Cannon 'a' wave (atria contracting against closed tricuspid valve)(MCQ)


o Atrial flutter
o Premature atrial rhythm (or tachycardia)
o third degree heart block
o Ventricular ectopics
o Ventricular tachycardia
§ Absent 'a' wave (no unifocal atrial depolarisation)(MCQ)
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o atrial fibrillation
o A steepy descent is seen in constrictive pericarditis and tricuspid
incompetence.
§ Slow 'y' descent(MCQ)
o Tricuspid stenosis
§ Parodoxical JVP (Kussmaul's sign: JVP rises with inspiration, drops with
expiration)(MCQ)
o Pericardial effusion
o Constrictive pericarditis
o Pericardial tamponade

T opic - Heart Failure

§ Congestive Heart Failure


§ failure of the heart to pump blood effectively to the tissues.
§ Left heart failure (LHF) causes pulmonary venous congestion (blood
flow back-up into the lungs) and compromised systemic circulation.
§ Right heart failure (RHF) causes systemic venous congestion.
§ Etiology
o Can be precipitated by: (MCQ)
§ MI/ischemic heart disease (most common)
§ Pulmonary embolus (usually right-sided failure)
§ Dysrhythmias
§ Thyrotoxicosis/wet beriberi (high-output failure)
§ Viral (casuses a dilated cardiomyopathy)
§ EtOH
§ Signs and symptoms
o Left Heart Failure(MCQ)
§ Orthopnea
§ Paroxysmal nocturnal dyspnea(PND)
§ Rales
§ Dyspnea on exertion (DOE)
§ Cough
§ Nocturia
§ S3 gallop
§ Diaphoresis
§ Tachycardia
o Right Heart Failure(MCQ)
§ RUQ pain (due to hepatic congestion)
§ Hepatomegaly
§ Hepatojugular reflex
§ Jugular venous distention (JVD) Ascites
§ Cyanosis
§ Peripheral edema
§ The most common cause of RHF is LHF .(MCQ)
§ Diagnosis

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o Chest film:
§ Enlargement of cardiac silhouette
§ pulmonary vascular congestion with redistribution to upper
lobes(MCQ)
o Echocardiogram:
§ Assess left ventricular function.
o Basic natriuretic peptide (BNP): Elevates in CHF .(MCQ)
§ Treatment
o Nonpharmacologic
§ Sodium and water restriction
§ exercise,
§ avoidance of alcohol
o Pharmacologic
§ First-Line Therapy(MCQ)
• ACE inhibitors:
o Decrease symptoms and mortality in patients
withNYHA class II–IV(MCQ)
o decrease incidence of heart failure symptoms
anddecrease hospitalization
• Diuretics:
o Use in class II–IV for fluid retention.
o Mild:(MCQ)
§ Use thiazide diuretic once daily.
o Significant:
§ Use loop diuretics, twice daily PO (IV
in acute exacerba- tion).(MCQ)
• Beta blockers:
o For NYHA class II–III
o decrease symptoms, improve survival (MCQ)
o Use after ACE inhibitors and diuretics.
• Digoxin:
o Add for NYHA class III–IV
o Used for symptomatic relief only, does not
improve survival.(MCQ)
• Spironolactone:
o Low dose, use in NYHA classIII–IV .
o Decreases mortality by 34%(MCQ)
o Monitor K+ carefully, especially with
concomitant use of ACE inhibitors. (MCQ)
§ Second-Line Therapy
• Angiotensin receptor blockers (ARBs):
o If ACE inhibitors are not well tolerated (e.g.,
cough)
• Nitrate–hydralazine combination:
o Improve symptoms and survival

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o High rate of intolerance and lower effect on


mortality make thistherapy a second line to ACE
inhibitors(MCQ)
§ Acute Pulmonary Edema
§ Acute pulmonary edema (APE) is caused by rapid decompensation of left
ventricular function, due to:(MCQ)
o Dysrhythmias
o MI
o Noncompliance with medications
o Increased dietary or intravenous sodium load
o Drugs that cause decreased inotropy
o Strain
§ Treatment: NTG, oxygen, morphine, aspirin, diuretic (NOMAD)
§ Paroxysmal Nocturnal Dyspnea
§ also called cardiac asthma(MCQ)
§ A brief episode of breathless- ness that awakens patient from sleep
§ Etiology:
o Due to increased volume load on heart when lying in the horizontal
position or sudden decrease in myocardial contractility, which results in
pulmonary edema, impairing the exchange of oxygen
§ Diagnosis:
o Distinguished from true asthmaby(MCQ)
§ improvement with walking a few steps
§ lack of improvement with bronchodilators
§ Treatment: NTG, oxygen, morphine, aspirin, diuretic (NOMAD)(MCQ)

T opic - Torsades de pointes

• T orsades de pointes
o Arrhythmia with rotating axis and prolonged QT
o Etiology (A very frequently tested MCQ in MD Exam)
§ Hypokalemia
§ Hypomagnesemia
§ Phenothiazines
§ Tricyclic antidepressants
§ Intracranial bleed
§ Congenital prolonged QT syndrome
§ Idiopathic
§ Type I antidysrhythmics: Quinidine and procainamide
o Treatment (MCQ)
§ Magnesium IV
§ Overdrive pacing
§ Beta blockers for prolonged QT syndrome
o Clinical Pearls :
§ Cause of short QT: Hypercalcemia (MCQ)

§ Congenital long QT syndrome (MCQ)


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• recurrentsyncope
• along QT interval (usually 0.5–0.7 second)(MCQ)
• documentedventricular arrhythmias
• sudden death
• may occur in the presence ( Jervell-Lange-Nielsen
syndrome) or absence (Romano-Ward syndrome) of
congenital deafness(MCQ)
§ The management of torsades de pointes differs from that of other
forms of ventricular tachycardia.
• Class I, Ic, or III antiarrhythmics, which prolong the QT
interval, should be avoided—or withdrawn immediately if
being used (MCQ)
• Intravenous -blockers may be effective, especially in the
congenital form (MCQ)
• Intravenous magnesium should be given acutely.(MCQ)
• An effective approach is temporary ventricular or atrial
pacing, which can both break and prevent the
rhythm.(MCQ)

T opic - Mitral stenosis

• Mitral stenosis
o Rheumatic heart disease (most common), congenital (rare) (MCQ)
o Most cases occur in women.(MCQ)
o Signs and symptoms
§ Dyspnea on exertion (DOE)(MCQ)
§ Rales
§ Cough
§ Hemoptysis
§ Systemic embolism (due to stagnation of blood in enlarged left
atrium)
§ Accentuated right ventricle precordial thrust
§ Signs of right ventricular failure(MCQ)
§ Hoarse voice(MCQ)
• due to enlarged left atrium impinging on recurrent laryngeal
nerve
o Diagnosis
o Murmur (MCQ)
§ mid-diastolic with opening snap
§ low-pitched rumble.
§ Best heard over left sternal border between 2nd to 4th
o CXR
§ straight left heart border due to enlarged left atrium(MCQ)
§ Kerley B lines from pulmonary effusion.(MCQ)
o ECG (MCQ)

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§ left atrial enlargement


§ right ventricular hypertrophy
§ atrial fibrillation
o Echocardiography demonstrates diseased valve.
o TREATMENT
§ Endocarditis prophylaxis(MCQ)
§ Treat for heart failure (diuretics, digitalis) and dysrhythmias as
needed.
§ Anticoagulation for atrial thrombus/fibrillation if present
§ Surgical repair or balloon valvuloplasty in symptomatic patients
withorifice 1.2 cm2(MCQ)
§ Dilation of the left atrium is a major cause of atrial
fibrillation.(MCQ)
§ Balloon valvuloplasty in mitral stenosis effective intervention
• it has a low incidence of restenosis, in contrast to aortic
stenosis.(MCQ)
• Clinical pearls :
o Exertional dyspnea, orthopnea, and paroxysmal nocturnal dyspnea
when the stenosis becomes severe.(MCQ)
o Symptoms often precipitated by onset of atrial fibrillation or pregnancy .
o Two syndromes occur(MCQ)
§ one with moderate mitral stenosis and pulmonary edema
§ one with severe mitral stenosis, pulmonary hypertension, and
low cardiac output.
o Prominent mitral first sound, opening sna p (usually), and apical diastolic
rumble.(MCQ)
o Surgery indicated for symptoms or evidence of pulmonary hypertension .
o Most symptomatic patients have a valve area less than 1.5 cm2(MCQ)
o The interval between the opening snap and aortic closure sound(MCQ)
§ is long when the LA pressure is low
§ shortens as the LA pressure rises and approaches the aortic
diastolic pressure.
o the heart murmur is best heard at the apex with the patient in the left
lateral position(MCQ)
o As mitral stenosis worsens, there is a localized diastolic murmurlow in
pitch whose duration increases with the severity of the stenosis,
o Brief exercise, such as sit ups, increase the heart rate and cardiac output
resulting in increased flow across the mitral valve and increased audibility
of the mitral rumble .(MCQ)
o mild to moderate mitral stenosis - measured valve area is usually between
1.8 cm2 and 1.3 cm2.(MCQ)
o severe mitral stenosis (valve area < 1.0 cm2)(MCQ)
o severe pulmonary hypertension develops due to a "secondary stenosis"
of the pulmonary vasculature (MCQ)
§ In this condition, pulmonary edema is uncommon
§ but symptoms of low cardiac output and right heart failure
predominate.

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o Conversion to and subsequent maintenance of sinus rhythm are most


commonly successful when the (MCQ)
§ duration of atrial fibrillation is brief (< 6–12 months)
§ LA is not severely dilated (diameter < 4.5 cm).
o Once atrial fibrillation occurs, the patient should receive warfarin
anticoagulation therapy even if sinus rhythm is restored, since atrial
fibrillation often recurs even with antiarrhythmic therapy and 20–30% of these
patients will have systemic embolization if untreated (MCQ)
o Systemic embolization in the presence of only mild to moderate disease
is not an indication for surgery but should be treated with warfarin
anticoagulation.
o Mechanical mitral prosthetic valves are more prone to thrombosis t han aortic
valves.
o Bioprosthetic valves degenerate after about 10–12 years and percutaneous
balloon valvuloplasty procedures cannot be done on bioprosthetic valves
should stenosis occur.
o Younger patients and those with end-stage renal disease do least well
with bioprosthetic heart valves,
o Percutaneous balloon valvuloplasty can safely be done during pregnancy if
symptoms warrant

T opic -Mitral regurgitationON

• Mitral regurgitation
o Etiology (MCQ)
§ Acute
• MI with papillary muscle rupture
• Endocarditis
§ Chronic
• Rheumatic fever
• Mitral prolapse
• Left ventricular dilation
o Signs and symptoms(MCQ)
§ Dyspnea
§ Fatigue
§ Weakness
§ Cough
§ Atrial fibrillation
§ Systemic emboli
o Diagnosis/signs
§ Murmur is loud, holosystolic, apical radiating to the axilla.(MCQ)
§ ECG shows enlarged left atrium..(MCQ)
§ Echocardiography demonstrating diseased/prolapsed valve
o Treatment
§ Medical therapy:

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• Not definitive but used until surgery, or in poor surgi- cal


candidates
• Diuretics to reduce volume load.(MCQ)
• V asodilators to reduce afterload favoring aortic exit (e.g.,
ACE inhibitors).(MCQ)
• Anticoagulation for atrial fibrillation.(MCQ)
§ Surgical therapy:
• V alve replacement or repair if signs of LV dysfunction
• Acute MR usually results in severe CHF and requires
emergent surgery.
• Patient with mitral regurgitation has a good prognosis if
LV function is preserved.
Clinical Pearls

• May be asymptomatic for many years (or for life) or may cause left-sided heart
failure..(MCQ)
• ECG shows LA abnormality or atrial fibrillation and LVH
• radiograph shows LA and LV enlargement.
• Echocardiographic findings can help decide when to operate.
• For primary mitral regurgitation, surgery is indicated for .(MCQ)
o Symptoms
o when the LV ejection fraction is < 60%
o the echocardiographic LV end-systolic diameter is > 4.0 cm.
• In patients with mitral prolapse and severe mitral regurgitation,early surgery
is indicated if mitral repair can be performed.
• Mitral regurgitation places a volume load on the heart (increases preload) but
reduces afterload..(MCQ)
• The result is an enlarged LV with an increased ejection fraction (EF).
• Over time, the stress of the volume overload weakens the LV; when this occurs,
there is a drop in EF and a rise in end-systolic volume..(MCQ)
• Clinical findings in MR
o ahyperdynamicLV impulse and a brisk carotid upstroke.(MCQ)
o a prominent third heart sound ( S3) due to the increased volume
returning to the LV in early diastole .(MCQ)
o Pansystolic murmur at the apex, radiating into the axilla
• Regurgitant orifice areas > 40 mm2 are considered severe..(MCQ)

T opic - Aortic stenosis

• Aortic stenosis
o Etiology
§ Degenerative calcific disease (idiopathic, older population)
§ Bicuspid aortic valve (MCQ)
• most common congenital valve abnormality
• can result in aortic stenosis around age 40.
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o Symptoms
§ Usually asymptomatic early in course
§ Dyspnea
§ Angina and syncope (typically exertional): (MCQ)
• Occurs particularly during exercise—peripheral resistance
falls, LV pressure remains the same due to stenotic valve,
• CO cannot maintain BP causing syncope(MCQ)
• low BP to coronary arteries causes angina
§ Heart failure
o Diagnosis/signs
§ Forceful apex beat with normally located PMI
§ Loud systolic ejection murmur(MCQ)
• crescendo–decrescendo
• medium pitched
• loudestat 2nd R interspace
• radiates to carotids
§ Paradoxical splitting of S2 (MCQ)
§ Narrow pulse pressure(MCQ)
§ ECG may show left ventricular strain pattern.(MCQ)
§ Echocardiography demonstrates diseased valve.
§ Calcification of aortic valve may be seen on CXR.
o Treatment
§ Avoid strenuous activity.
§ Avoid afterload reduction.(MCQ)
§ V alve replacement is definitive therapy.(MCQ)
§ V alvuloplastyproduces only temporary improvement as rate of
restenosis is very high.
o Prognosis:
§ Mean survival for patients withAS and:(MCQ)
• Angina5 years
• Syncope2–3 years
• Heart failure1–2 years
o Clinical pearls :
§ Left ventricular strain pattern is ST segment depression and T wave
inversion in I, aVL, and left precordial leads.(MCQ)
§ Patients with aortic stenosis should be considered for valve
replacement for:(MCQ)
• Persistent symptoms
• Aortic orifice <0.7 cm2 body surface area
• Gradient >70 mm Hg
§ Congenital bicuspid aortic valve, usually asymptomatic until
middle or old age.
§ "Degenerative" or calcific aortic stenosis;same risk factors as
atherosclerosis.(MCQ)
§ Symptoms likely once the peak echo gradient is > 64 mm
Hg.(MCQ)
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§ Delayed and diminished carotid pulses.(MCQ)


§ Soft, absent, or paradoxically split S2.(MCQ)
§ Harsh systolic murmur, sometimes with thrill along left sternal border ,
often radiating to the neck; may be louder at apex in older
patients.(MCQ)
§ ECG usually shows LVH
§ calcified valveis seen on radiography or fluoroscopy.
§ Echocardiography/Doppler is diagnostic.(MCQ)
§ Surgery indicated for symptoms.
§ Surgical risk is typically low even in the very elderly.(MCQ)
§ Surgery considered for asymptomatic patients with severe aortic
stenosis.
§ In mild or moderate cases where the valve is still pliable, an ejection
click may precede the murmur.
§ Gallaverdinphenomenon(MCQ)
• The characteristic systolic ejection murmur is heard at the
aortic area and is usually transmitted to the neck and
apex.
• In some cases, only the high-pitched components of the
murmur are heard at the apex, and the murmur may sound
like mitral regurgitation (so-called Gallaverdin
phenomenon)
§ In severe aortic stenosis(MCQ)
• apalpable LV heave or thrill
• aweak to absent aortic second sound
• reversed splitting of the second sound is present
§ When the valve area is less than 0.8–1 cm2 (normal, 3–4 cm 2),
ventricular systole becomes prolonged and the typical carotid pulse
pattern of delayed upstroke and low amplitude is present (MCQ)
§ LVH increases progressively, with resulting elevation in ventricular
end-diastolic pressure
§ Cardiac output is maintained until the stenosis is severe (with a
valve area < 0.8 cm2).(MCQ)
§ Syncope (MCQ)
• typicallyexertional and a late finding.
• Syncope occurs with exertion as the LV pressures rises,
stimulating the LV baroreceptors to cause peripheral
vasodilation.
• This vasodilation results in the need for an increase in
stroke volume, which increases the LV systolic pressure
again, creating a cycle of vasodilation and stimulation of
the baroreceptors that eventually results in a drop in BP ,
as the stenotic valve prevents further increase in stroke volume
§ A BNP > 550 pg/mL has been associated with a poor outcome in
these patients regardless of the results of dobutamine testing. (MCQ)

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T opic -Aortic regurgitation

Aortic regurgitation

• Etiology
o Aortic root dilatation: (MCQ)
§ Idiopathic (correlates with hypertension [HTN] and age),
§ collagen vascular disease
§ Marfan’s syndrome
o V alvular disease: Rheumatic heart disease, endocarditis
o Proximal aortic root dissection:
§ Cystic medial necrosis (Marfan’ssyn- drome),
§ syphilis, HTN
§ Ehlers–Danlos,
§ Turner’s syndrome
§ 3rd trimester pregnancy(MCQ)
• Signs and symptoms
o Dyspnea, orthopnea, paroxysmal nocturnal dyspnea
o Angina(MCQ)
§ due to reduced diastolic coronary blood flow due to low pressure
in aortic root
o Left ventricular failure
o Wide pulse pressure
o Bounding “Corrigan” pulse(MCQ)
o “pistol shot”femorals(MCQ)
o pulsusbisferiens (dicrotic pulse with two palpable waves in systole)(MCQ)
o Duroziez sign: (MCQ)
§ Presence of diastolic femoral bruit when femoral artery
iscompressed enough to hear a systolic bruit
o Hill’s sign: (MCQ)
§ Systolic pressure in the legs 20 mm Hg higher than in thearms
o Quincke’s sign: (MCQ)
§ Alternating blushing and blanching of the fingernailswhen gentle
pressure is applied
o De Musset’s sign: (MCQ)
o Bobbing of head with heartbeat
• Diagnosis/signs
o High-pitched, blowing, decrescendo diastolic murmur
§ best heard over 2nd right interspace or 3rd left interspace(MCQ)
§ accentuated by leaning forward(MCQ)
o Austin Flint murmur:(MCQ)
§ Observed in severe regurgitation(MCQ)
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§ low-pitched diastolic rumble due to regurgitated blood striking the


anterior mitral leaflet (similar sound to mitral regurgitation) (MCQ)
o Hyperdynamic down and laterally displaced PMI due to L V enlargement
o ECG shows left ventricular hypertrophy(MCQ)
o Echocardiography demonstrates regurgitant valve.
• Treatment
o Treat left ventricular failure.
o Endocarditis prophylaxis
o V alve replacement(MCQ)
§ necessary for severe cases
§ the only definitive treatment.
• Clinical Pearls for MD Entrance :
• Conditions with wide pulse pressure:(MCQ)
o Aorticregurgitation
o Hyperthyroidism
o Anemia
o Wetberiberi
o Hypertrophicsubaorticstenosis
o Hypertension
• Acute valvular disorders (e.g., acute MR or AR)
o result in severe decompensation into CHF due to the absence of
hemodynamic compensation.
• The Murmurs
• Mitral stenosis––(MCQ)
§ diastolic rumble with opening snap
• Mitral regurgitation (chronic)(MCQ)
§ holosystolic blowing murmur radiating to axilla
• Mitral valve prolapse(MCQ)
§ mid-systolic click
• Hypertrophic cardiomyopathy (HCM)(MCQ)
§ systolic, brisk upstroke, parasternal lift
• Patent ductusarteriosus (PDA)(MCQ)
§ continuous, machinery murmur
• Atrial septal defect (ASD)(MCQ)
§ fixed, split S2
• Ventricular septal defect (VSD)(MCQ)
§ systolic, radiates to right
• Aortic regurgitation(MCQ)
§ water- hammer pulse, decrescendo mid-diastolic
• Aortic stenosis(MCQ)
§ harsh, systolic murmur that radiates to carotids, “parvus et tardus”
• A rumbling diastolic murmur can be due to mitral stenosis (MS) or
tricuspid stenosis (TS).
§ TS will increase with inspiration.
§ Emergent surgery is required.
• Aortic regurgitation (CHRONIC REGURGITATION)
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o Usually asymptomatic until middle age


o presents with left-sided failure or chest pain.
o Wide pulse pressure.
o Hyperactive, enlarged LV .
o Diastolic murmur along left sternal border.
o ECG shows LVH; radiograph shows LV dilation.
o Echocardiography/Doppler is diagnostic.
o Afterload reduction may be beneficial if (MCQ)
§ theLV is dilated (LV end-diastolic dimension > 5.0 cm)
§ there is evidence for systolic blood pressure elevation.
o Surgery indicated
§ for symptoms, (MCQ)
§ EF < 55%,
§ LV end-systolic dimension > 5.0 cm

T opic - Mitral valve prolapsed

• Mitral valve prolapse


• Etiology
o Most commonvalvular disorder (MCQ)
o Idiopathic, rheumatic heart disease, ischemic heart disease, ASD, orMarfan’s
syndrome(MCQ)
o More common in women (90% of cases) (MCQ)
o Genetic predisposition (can be inherited as an autosomal dominant
trait)

o Normal variant
• Signs and symptoms
o Mostly asymptomatic
o Atypical chest pain(MCQ)
o Shortness of breath (SOB)
o Fatigue
• Diagnosis/signs
o Mid-systolic click; followed by late-systolic, high-pitched murmur (if
mild regurgitation is present also)(MCQ)
o Best heard at apex
o S3 sometimes present(MCQ)
o Wide splitting of S2(MCQ)
o Echocardiography demonstrates diseased valve.
• TREATMENT
o Prophylaxis for endocarditisis required(MCQ)
§ if a murmur is audible
§ ifmyxomatous leaflets
o Vigilant follow-up
• Clinical Vignette in MD Entrance :
o A young woman presents with atypical chest pain and mid-systolic click.

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o Clinical diagnosis Mitral valve prolapse.(MCQ)


• Clinical pearls :
o Often associated with skeletal changes (straight back, pectus, scoliosis) or
hyperreflexivity of joints. (MCQ)
o The smaller the LV chamber, the greater the degree of prolapse, and thus
auscultatory findings are often accentuated in the standing
position.(MCQ)
o Mitral prolapse is often associated with aortic root disease, and any
evidence for a dilated aorta by chest radiography should prompt either CT
or MRI angiography.
o -Blockers in low doses (MCQ)
§ used to treat the hyperadrenergic state when present
§ are usually satisfactory for treatment of arrhythmias.
o Mitral valve repair is favored over valve replacement
o Stitching of the leaflets together to create a double orifice mitral valve is also
used at times (Alfieri procedure)(MCQ)

T opic -Heart block

• Heart block
• First-Degree Heart Block
o Prolonged PR interval (0.20 s) (MCQ)
o No treatment required
• Second-Degree Heart Block
o Mobitz I (Wenckebach) (MCQ)
§ Progressive PR prolongation with progressive shortening of
the R-R interval until a beat is dropped
§ this phenomenon is almost always due to abnormal conduction
within the AV node(MCQ)
§ For inadequate perfusion, treat with atropine or temporary
pacing.(MCQ)
o Mobitz II (MCQ)
§ Fixed prolonged PR interval followed by a nonconducted beat
at a regular interval
§ It is usually due to block within the His bundle system.
§ Treat with atropine, temporary pacing, and permanent
pacemaker.(MCQ)
§ Dangerous!
§ Always place pacemaker!(MCQ)
§ Important to treat quickly, as this can rapidly degenerate into
complete heart block.
• Third-Degree Heart Block (Complete Heart Block)
o Independent atrial and ventricular activity
o Treat symptomatic patients with atropine and temporary pacing, fol-
o lowed by permanent pacemaker.(MCQ)
o Always needs pacemaker (dangerous rhythm)
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• Causes of Mobitz I:(MCQ)


o Inferior wall MI
o Digitalis toxicity
o Increased vagaltone
• Causes of Mobitz II:(MCQ)
o Inferior wall or septalMI
o Conduction system disease
• Causes of third-degree heart block:
o Inferior wallMI
o Digitalis toxicity
o Conduction system disease
• Bradycardia:
o If the R-R distance is at least one inch, consider: (MCQ)
§ Overmedication
§ Inferior wall MI Increased intracranial pressure
§ Normal variant
§ Carotid sinus hypersensitivity
§ Hypothyroidism
• Clinical pearls:
• The width of the QRS complexes assists in determining whether the block
is nodal or infranodal. (MCQ)
o When they are narrow, the block is usually nodal
o when they are wide, the block is usually infranodal.
• The indications for permanent pacing(MCQ)
o symptomaticbradyarrhythmias
o asymptomaticMobitz II A V block
o complete heart block

T opic - Supraventricular tachycardia’

Supraventricular tachycardia’ (SVT)

• These are usually associated with a narrow QRS complex and are characterised
by a re-entry circuit or automatic focus involving the atria.

• The term SVT is misleading, as in many cases the ventricles also form part of
the re-entry circuit, such as in patients with AV re-entrant tachycardia.

Atrioventricular nodal re-entranttachycardia (AVNRT)

• This is due to re-entry in a circuit involving the A V node and its two right atrial
input pathways: a superior ‘fast’ pathway and an inferior ‘slow’ pathway

• This produces a regular tachycardia with a rate of 120–240/min.

• It tends to occur in hearts that are otherwise normal


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• Episodes may last from a few seconds to many hours.

• The patient is usually aware of a fast heart beat and may feel faint or
breathless.

• Polyuria, mainly due to the release of atrial natriuretic peptide, is sometimes a


feature, and cardiac pain or heart failure may occur if there is coexisting
structural heart disease.

• The ECG usually shows a tachycardia with normal QRS complexes but
occasionally there may be rate-dependent bundle branch block

Management

• Treatment is not always necessary. However, an episode may be terminated by


carotid sinus pressure or other measures that increase vagal tone (e.g.
V alsalvamanœuvre).

• Intravenous adenosine or verapamil will restore sinus rhythm in most cases.

• Suitable alternative drugs include β-blockersor flecainide.

• In rare cases when there is severe haemodynamic compromise, the tachycardia


should be terminated by DC cardioversion

Wolff–Parkinson–White syndromeand Atrioventricular re-entranttachycardia


(AVRT)

In these conditions, an abnormal band of conducting tissue connects the atria and
ventricles. It resembles Purkinje tissue in that it conducts very rapidly, and is known as
an accessory pathway

Manifest accessory pathway VS Concealed accessory pathway

• In around half of cases, this pathway only conducts in the retrograde direction
(from ventricles to atria) and thus does not alter the appearance of the ECG in
sinus rhythm. This is known as a concealed accessory pathway.
• In the remainder, conduction takes place partly through the A V node and partly
through the accessory pathway. Premature acti- vation of ventricular tissue via
the pathway produces a short PR interval and a ‘slurring’ of the QRS com- plex,
called a delta wave This is known as a manifest accessory pathway.
AV node re-entrant tachycardia vs WPW syndrome

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As the A V node and accessory pathway have different conduction speeds and refractory
periods, a re-entry circuit can develop, causing tachycardia; when this is associated with
symptoms, the condition is known as Wolff– Parkinson–White syndrome.

• A V node re-entrant tachycardia.

o The mechanism of A VNRT occurs via two right atrial A V nodal input
pathways: the slow (S) and fast (F) pathways.

o Antegrade conduction occurs via the slow pathway; the wavefront enters the
A V node and passes into the ventricles, at the same time re-entering the atria
via the fast pathway

• WPW syndrome

o In WPW syndrome there is a strip of accessory conducting tissue that allows


electricity to bypass the A V node and spread from the atria to the ventricles
rapidly and without delay.

o When the ventricles are depolarised through the A V node the ECG is
normal, but when the ventricles are depolarised through the
accessory conducting tissue the ECG shows a very short PR interval and a
broad QRS complex

The ECG appearance of this tachycardia may be indistinguishable from that of A VNRT

3 ECG appearences

Sinus rhythm.

• In sinus rhythm the ventricles are depolarised through (1) the A V node
and (2) the accessory pathway, producing an ECG with a short PR
interval and broadened QRS complexes; the characteristic
slurring of the upstroke of the QRS complex is known as a delta wave.

Orthodromic tachycardia.

o This is the most common form of tachycardia in WPW .

o The re-entry circuit passes antegradely through the A V node and


retrogradely through the accessory pathway.

o The ventricles are therefore depolarised in the normal way, producing a


narrow- complex tachycardia that is indistinguishable from other
forms of SVT.

Atrial fibrillation.

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• In this rhythm the ventricles are largely depolarised through the


accessory pathway, producing an irregular broad-complex
tachycardia which is often more rapid.

Clinical presentation and treatment

• Carotid sinus pressure or intra- venous adenosine can terminate the


tachycardia. If atrial fibrillation occurs, it may produce a dangerously
rapid ventricular rate because the accessory pathway lacks the rate-
limiting properties of the AVnode .This is known as pre-excited atrial
fibrillation and may cause collapse, syncope and even death.
• It should be treated as an emergency, usually with DC cardioversion.
• Catheter ablation is first-line treatment in symptomatic patients and is
nearly always curative.

• Prophylactic anti-arrhythmic drugs, such as flecainide, propafenone or


amiodarone, can also be used. These slow the conduction rate and
prolong the refractory period of the accessory pathway.

• Digoxin and verapamil shorten the refractory period of the accessory


pathway and should be avoided.

T opic -Wolff–Parkinson–White syndrome

• Wolff–Parkinson–White syndrome
o WPW is a ventricular preexcitation syndrome (MCQ)
o An abnormal bundle of fast-conducting fibers connects the atria and
ventricles and allow electrical impulse generated by the sinus node to
bypass the normal anatomic conduction pathways.(MCQ)
o Anterograde conduction occurs down the His–Purkinje system and
back up the accessory bypass tract (narrow-complex). (MCQ)
o Retrograde conduction occurs down the accessory bypass tract and up
the His–Purkinje system (wide-complex).(MCQ)
o Diagnosis
§ ECGshows a
• “delta” wave(MCQ)
• aslurred upstroke of the QRS complex
§ Patients with suspected WPW should have electrophysiologic
testing in the cardiac catheterization lab and radiofrequency
ablation of the detected bypass tract.(MCQ)
o Treatment
§ Patients with WPW and rapid atrial fibrillation with rapid
ventricular response require emergent synchronized
cardioversion.
§ StablepatientswithWPWandatrialfibrillationorwide-
complexSVTare treated with amiodarone, flecanide,
procainamide, propafenone, or sotalol.(MCQ)
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§Adenosine, beta blockers, calcium channel blockers, and


digoxin are contraindicated because they preferentially block
conduction at the A V node, allowing unopposed conduction down
the accessory bypass tract.(MCQ)
o Clinical Pearls:
§ Don’t give ABCD (adenosine, beta blockers, calcium channel
blocker, or digoxin) to someone with WPW .
§ Procainamide is the classic choice.
§ The ECG shows a “delta” wave, a slurred upstroke of the QRS
complex(MCQ)
§ Accessory pathways or bypass tracts between the atria and the
ventricle bypass the compact A V node predispose to reentrant
arrhythmias, such as A VRT and atrial fibrillation.
• Lown-Ganong-Levine syndrome
o wholly or partly within the node (Mahaim fibers)
o yield a short PR interval and normal QRS
morphology(MCQ)
• Wolff-Parkinson-White syndrome
o More commonly, they make direct connections
between the atria and ventricle through Kent
bundles(MCQ)
§ Some patients have a delta wave found incidentally on ECG. In
the absence of palpitations, light-headedness, or syncope , these patients do not
require specific therapy.(MCQ)
§ As with A VNRT, radiofrequency ablation has become the
procedure of choice in patients with accessory pathways and
recurrent symptom (MCQ)
§ In which situation is prophylactic radiofrequency ablation of
preexcitation syndrome is indicated ?(MCQ)
• Patients with preexcitation syndromes who have episodes of
atrial fibrillation or flutter should be tested by induction of
atrial fibrillation in the electrophysiologic laboratory, noting duration
of the RR cycle; if it is l ess than 220 ms, a short refractory
period is present.
• These individuals are at highest risk for sudden death, and
prophylactic ablation is indicated

T opic -Atrial fibrillation

Atrial fibrillation

• Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia

• The prevalence rises with age

• Atrial fibrillation is a com-plex arrhythmia characterised by both abnormal


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automatic firing and the presence of multiple interacting re-entry circuits


looping around the atria.

• Episodes of atrial fibrillation are usually i nitiated by rapid bursts of ectopic


beats arising from conducting tissue in the pulmonary veins or from
diseased atrial tissue.

• AF becomes sustained because of initiation of reentrant conduction within


the atria or sometimes because of continu- ous ectopic firing (

• Re-entry is more likely to occur in atria that are enlarged, or in which


conduction is slow (as is the case in many forms of heart disease).

• During episodes of AF, the atria beat rapidly but in an uncoordinated and
ineffective manner. The ventricles are activated irregularly at a rate determined by
conduction through the A V node. This produces the character- istic ‘irregularly
irregular’ pulse.

• The ECG shows normal but irregular QRS complexes; there are no P waves
but the baseline may show irregular fibrillation waves.

• AF can be classified as paroxysmal (intermittent, self- terminating episodes),


persistent (prolonged episodes that can be terminated by electrical or chemical
car- dioversion) or permanent.

• When AF persists for a period of months , structural remodelling occurs with


atrial fibrosis and dilatation that further predispose to AF . Thus early treatment
of AF will prevent this and reinitiation of the arrhythmia.

Etiology

• AF may be the first manifestation of many forms of heart disease particularly


those that are asso- ciated with enlargement or dilatation of the atria .

• Alcohol excess, hyperthyroidism and chronic lung disease are also common
causes of AF

What is ‘lone atrial fibrillation’?

• About 50% of all patients with paroxysmal AF and 20% of patients with
persistent or permanent AF have structurally normal hearts ; this is known as
‘lone atrial fibrillation’.

Clinical Presentation

AF is often completely asymptomatic, in which case it is usually dis- covered as a


result of a routine examination or ECG.

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AF can cause palpitation, breathlessness and fatigue.

In patients with poor ventricular function or valve disease it may precipitate or


aggravate cardiac failure because of loss of atrial function and heart rate control. A fall
in BP may cause lightheadedness, and chest pain may occur with underlying coronary
disease.

Management

• Biochemical evidence of hyperthyroidism is found in a small minority of


patients with otherwise unexplained AF .

• When AF complicates an acute illness (e.g. chest infec- tion, pulmonary


embolism), effective treatment of the primary disord er will often restore sinus
rhythm.

• The main objectives are to restore sinus rhythm as soon as possible, prevent
recurrent episodes of AF, optimise the heart rate during periods of AF,
minimise the risk of thromboembolism and treat any underlying disease.

Paroxysmal atrial fibrillation

• Beta-blockers are normally used as first-line therapy if symptoms are


troublesome, and are particularly useful for treating patients with AF associ- ated
with ischaemic heart disease, hypertension and cardiac failure.

• Beta-blockers reduce the ectopic firing that normally initiates AF .

• Class Ic drugs, such as propafenone or flecainide, are also effective at


preventing episodes but should not be given to patients with coronary disease or
left ventricular dysfunction.

• Flecainideis usually prescribed along with a rate limiting Beta 


because it
occasionally precipitates atrial flutter.

• Other antiarrythmics

o Amiodarone is the most effective agent for pre- venting AF but its side-
effects restrict its use to patients in whom other measures fail.

o Digoxin and verapamil are not effective drugs for preventing


paroxysms of AF, although they serve to limit the heart rate when AF
occurs by blocking the A V node.

• Catheter ablation in AF

o In patients with AF in whom Beta  or class Ic drugs are ineffective or


cause side-effects, catheter ablation can be considered.
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o Ablation is used to isolate electrically the pulmonary veins from the


LA, preventing ectopic triggering of AF . Sometimes ablation is used to
create lines of conduction block within the atria to prevent re-entry.

o Ablation prevents AF in approximately 70% of patients with prior


drug-resistant episodes, although drugs may subsequently be needed to
maintain sinus rhythm.

o Ablation for AF is an evolving treatment which is associated with a small


risk of embolic stroke or cardiac tamponade.

Persistent and permanent atrial fibrillation

• 2 options for treating persistent AF:

• rhythm control: attempting to restore and maintain sinus rhythm

• rate control: accepting that AF will be permanent and using treatments to


control the ventricular rate and to prevent embolic complications.

Rhythm control.

• An attempt to restore sinus rhythm is particularly appropriate if the arrhythmia


has precipitated troublesome symptoms and there is a modifiable or
treatable underlying cause.

• Electrical cardioversionis initially successful in three-quarters of patients but


relapse is frequent (25–50% at 1 month and 70–90% at 1 year).

• Attempts to restore and maintain sinus rhythm are most successful if AF has
been present for < 3 months, the patient is young and there is no important
structural heart disease.

• Immediate DC cardioversion after the administration of intravenous heparin is


appropriate if AF has been present for < 48 hours.

• An attempt to restore sinus rhythm by infusing intravenous flecainide (2


mg/kg over 30 minutes, maximum dose 150 mg) is a safe alternative to
electrical cardioversionif there is no underlying structural heart disease .

• In other situations, DC cardioversion should be deferred until the patient has


been established on warfarin, with an international normalised ratio (INR) > 2.0
for a minimum of 4 weeks , and any underlying problems, such as hypertension or
alcohol excess, have been eliminated.
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• Anticoagulation should be maintained for at least 3 months following


successful cardioversion; if relapse occurs, a second (or third) cardioversion may
be appropriate.

• Concomitant therapy with amiodarone orbeta may reduce the risk of


recurrence.

• Catheter ablation is sometimes used to help restore and maintain sinus rhythm
in resistant cases, but it is a less effective treatment for persistent AF than for
paroxysmal AF .

Ratecontrol.

• Ifsinusrhythmcannotberestored,treatment should be directed at maintaining an


appropriate heart rate.

• Digoxin, Beta or rate-limiting calcium antagonists such as verapamil


or diltiazem will reduce the ventricular rate by increasing the degree of A V
block. This alone may produce a striking improve- ment in overall cardiac
function, particularly in patients with mitral stenosis.

• Beta-blockers and rate -limiting calcium antagonists are often more


effective than digoxin at controlling the heart rate during exercise and may have
additional benefits in patients with hypertension or structural heart disease.
Combination therapy (e.g. digoxin + atenolol) is often advisable.

What is meant by ‘pace and ablate’ strategy ?

In exceptional cases, poorly controlled and symptomatic AF can be treated by


deliberately inducing complete A Vnodalblockwithcatheterablation;apermanentpacemaker
must be implanted beforehand. This is known as the ‘pace and ablate’ strategy.

Prevention of thromboembolism

• Treatment with adjusted-dose warfarin (target INR 2.0–3.0) reduces the risk of
stroke by about two-thirds, at the cost of an annual risk of bleeding of
approximately 1–1.5%, whereas treatment with aspirin reduces the risk of stroke
by only one-fifth Warfarin is thus indicated for patients with AF who have
specific risk factors for stroke.

• For patients with intermittent AF , the risk of stroke is pro- portionate to the
frequency and duration of AF episodes. Those with frequent, prolonged (> 24
hours) episodes of AF should be considered for warfarin anticoagulation.

• An assessment of the risk of embolism helps to define the possible benefits of


antithrombotic therapy which must be balanced against its potential haz- ards.
Echocardiography is valuable in risk stratification.

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• Warfarin is indicated in patients at high or very high risk of stroke, unless


anticoagulation poses unacceptable risks.

• Comorbid conditions that may be complicated by bleeding, such as peptic ulcer,


uncontrolled hypertension, alcohol misuse, frequent falls, poor drug compliance
and potential drug interactions , are all relative contraindications to warfarin.

• Young patients (under 65 years) with no evidence of structural heart


disease have a very low risk of stroke ; they do not require warfarin but may
benefit from aspirin.

How to asses risk of thromboembolism in atrial fibrillation: the CHADS score

• Congestive heart failure (1 point)


• Hypertension (1 point)
• Diabetes mellitus (1 point)
• Stroke or transient ischaemic attack (2 points)

CHADS score Stroke risk/yr (%) 95% CL


0 1.9 1.2-3.0
1 2.8 2.0-3.8
2 4.0 3.1-5.1
3 5.9 4.6-7.3
4 8.5 6.3-11.1
5 12.5 8.2-17.5
6 18.2 10.5-27.4
Score: 0 = aspirin therapy only, 1 = warfarin or aspirin, ≥2 = warfarin

T opic -Atrial flutter

Atrial flutter

• Atrial flutter is characterised by a large (macro) re-entry circuit, usually within the
RA encircling the tricuspid annulus.

• The atrial rate is approximately 300/min, and is usually associated with 2:1, 3:1
or 4:1 A V block (with corresponding heart rates of 150, 100 or 75/min).

• The ECG shows saw-toothed flutter waves

• When there is regular 2:1 A V block, it may be difficult to identify flutter waves
which are buried in the QRS complexes and T waves

• Atrial flutter should always be suspected when there is a narrow complex


tachycardia of 150/min .

• Carotid sinus pressure or intra- venous adenosine may help to establish the
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diagnosis by temporarily increasing the degree of A V block and revealing the


flutter waves

Management

• Digoxin, β-blockersor verapamil can be used to control the ventricular rate


However, in many cases it may be preferable to try to restore sinus rhythm by
direct current (DC) cardioversion or by using intra- venous amiodarone .

• Beta-blockers or amiodarone can also be used to prevent recurrent episodes of


atrial flutter.

• Although flecainide can also be used for acute treatment or prophylaxis, it


should be avoided because there is a risk of slowing the flutter circuit and
facilitating 1:1 AV nodal conduction. This can cause a paradoxical
tachycardia and haemodynamic compromise.

• If used, it should always be prescribed along with an A V node-blocking drug,


such as aBeta

• Catheter ablation offers a 90% chance of complete cure and is the treatment of
choice for patients with persistent, troublesome symptoms.

T opic -Ventricular tachycardia (VT)

Ventricular tachycardia (VT)

• The common causes of VT include acute MI, cardiomyopathy and chronic


ischaemic heart disease, particularly when it is associated with a ventricular
aneurysm or poor left ventricular function.

• In these set- tings it is serious because it may cause haemodynamic


compromise or degenerate into ventricular fibrillation .

• It is caused by abnormal automaticity or triggered activity in ischaemic tissue, or


by re-entry within scarred ventricular tissue .

• Patients may complain of palpitation or symptoms of low cardiac output,


such as dizziness, dyspnoea or syncope.

• The ECG shows tachy- cardia with broad, abnormal QRS complexes with a
rate > 120/min

• VT may be difficult to distinguish from SVT with bundle branch block or pre-
excitation (WPW syndrome).

Features in favour of ventricular tachycardia in the differential diagnosis of broad -

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complex tachycardia

• History of MI

• A V dissociation (pathognomonic)

• Capture/fusion beats (pathognomonic,

• Extreme left axis deviation

• Very broad QRS complexes (> 140 ms)

• No response to carotid sinus massage or i.v . adenosine

ECG distinction between supraventricular tachycardia (SVT) with bundle branch


block and ventricular tachycardia (VT)

VT is more likely than SVT with bundle branch block where there is:

• a very broad QRS (> 0.14 s)


• atrioventricular dissociation
• a bifid, upright QRS with a taller first peak in V1
• adeepSwaveinV6
• a concordant (same polarity) QRS direction in all chest leads (V1–V6)

VT vsidioventricular rhythm (‘slow’ VT)

• Patients recovering from MI sometimes have periods of idioventricular


rhythm (‘slow’ VT) at a rate only slightly above the preceding sinus rate
and below 120/ min. These episodes often reflect reperfusion of the infarct
territory and may be a good sign.

• They are usually self-limiting and asymptomatic, and do not require


treatment.

What is ‘normal heart VT’?

• VT occasionally occurs in patients with otherwise healthy hearts (‘normal heart


VT’), usually because of abnormal automaticity in the right ventricular
outflow tract or one of the fascicles of the left bundle branch .

• The prognosis is good and catheter ablation can be curative.

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Management

• Synchronised DC cardioversion is the treatment of choice if systolic BP is <


90mmHg.

• If the arrhythmia is well tolerated, intravenous amiodarone may be given as a


bolus followed by a continuous infusion

• Intravenous lidocaine can be used but may depress left ventricular function,
causing hypotension or acute heart failure.Hypokalaemia, hypomagnesaemia,
acidosis and hypoxaemia should be corrected.

• Beta-blockers are effective at preventing VT by reducing automaticity and by


blocking conduction in scar re-entry circuits.

• Amiodaronecan be added if additional control is needed.

• Class Ic anti-arrhythmic drugs should not be used for prevention of VT in


patients with isch- aemic heart disease or heart failure because they depress
myocardial function and can be pro-arrhythmic (increase the likelihood of a
dangerous arrhythmia).

• In patients at high risk of arrhythmic death (e.g. those with poor left
ventricular function, or where VT is associated with haemodynamic
compromise), the use of an implantable cardiac defibrillator is recommended

T opic - Ventricular fibrillation

Ventricular fibrillation

• This is very rapid and irregular ventricular activation with no mechanical


effect.

• The patient is pulseless and becomes rapidly unconscious, and respiration


ceases (cardiac arrest).

• The ECG shows shapeless, rapid oscillations and there is no hint of organized
complexes.

• It is usually provoked by a ventricular ectopic beat.

• The only effective treatment is electrical defibrillation. Basic and advanced


cardiac life support is needed .

• If the attack of ventricular fibrillation occurs during the first day or two of an
acute myocardial infarction, it is probable that prophylactic therapy will be
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unnecessary.

• If the ventricular fibrillation was not related to an acute infarction, the long-
term risk of recurrent cardiac arrest and sudden death is high.

What is the indication forImplantable cardioverter–defibrillators

• Survivors of these ventricular tachyarrhythmias are, in the absence of an


identifiable reversible cause (e.g. acute myo- cardial infarction, severe metabolic
disturbance), at high risk of sudden death. Implantable cardioverter–defibrillators
(ICDs) are first-line therapy in the management of these patients

The Brugada syndrome

• This inheritable condition accounts for part of a group of patients with idiopathic
ventricular fibrillation who have no evidence of causative structural cardiac
disease.

• It is more common in young male adults and in South East Asia .

• The diagnosis is made by identifying the classic ECG changes that may be
present spontaneously or be provoked by the administration of a class I
antiarrhythmic (flecainide); right bundle branch block with coved ST
elevation in leads V1–V3

• In 20% of cases it is a monogenic inheritable condition associated with loss of


sodium channel function due to a mutation in the SCN5A gene.

• It can present with sudden death during sleep, resuscitated cardiac arrest
and syncope, or the patient may be asymptomatic and diagnosed incidentally or
during familial assessment. There is a high risk of sudden death , particularly in
the symptomatic patient or those with spontaneous ECG changes.

• The only successful treatmentis an ICD. Beta-blockade is not helpful and may
be harmful in this syndrome

T opic -Pulmonary hypertension

Pulmonary hypertension (PH) is a condition characterized by a sustained elevation of


mean pulmonary artery pressure to > 25 mm Hg at rest or > 30 mm Hg with exercise.

Pulmonary hypertension is classified by the World Health Organization into five major
categories.

• Group Ipulmonary hypertension is referred to as pulmonary arterial


hypertension (PAH).

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• PAH requires three findings:

o PH as defined above,

o a mean pulmonary capillary wedge pressure > 15 mm Hg,


and

o an elevated pulmonary vascular resistance > 3 Wood units.

• Group I encompasses idiopathic (primary), familial, and venous


(or capillary)-related pulmonary hypertension .

o Idiopathic PAH(previously termed primary pulmonary


hyperten- sion or PPH)

§ most common in young females (female:male ratio


is 2:1).

§ Mean age of onset is 36 years.

o Familial PAH refers to inheritable disorders.

§ Other causes of PH in this group include collagen


vascu- lar disease, congenital systemic-to-pulmonary
shunts, portal hypertension, HIV infection, drugs or
toxins (e.g., anorexigens), glycogen storage disease,
hereditary hemorrhagic
telangiectasia,andhemoglobinopathies.

o Venous or capillary-related PH includes veno-occlusive


disease and pulmonary–capillary hemangiomatosis.

• Group II is PH from pulmonary venous hypertension as a result of


left-sided atrial or ventricular heart disease or left-sided valvular
(mitral or aortic) heart disease.

• Group III encompasses PH associated with chronic hypoxemia,as in


COPD, interstitial lung disease, sleep-disordered breathing, alveolar
hypoventilation disorders, or chronic exposure to high altitudes.

• Group IV PH is due to chronic thrombotic disease, embolic disease,


or both.

• Group V is the miscellaneous classification of PH.

o It includes sarcoidosis, pulmonary Langerhans’-cell


histiocytosis, lymphangiomatosis, and external
compression of the pulmonary vessels (from
adenopathy, tumor, etc.)
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Pathology and Pathophysiology

• The pulmonary circulation is normally a low-resistance, high-compliance vascular


system.

• The pulmonary circulation is the only organ to receive 100% of the cardiac
output.

• Pulmonary blood flow can increase four to five times its baseline during exercise
or times of stress, by increasing CO and decreasing pulmonary vascular resistance
(PVR).

• The pathologic changes that occur in PAH are vasoconstriction, smooth


muscle and endothelial cell proliferation, in situ thrombosis, and plexiform
lesions in end-stage PAH.

• Endothelin-1 is the most powerful vasoconstrictor found endogenously.

Clinical Features, Diagnosis, and Clinical Course

• Fatigue appears to be the most common symptom and is present in


approximately 60% of patients at diagnosis.

• Dyspnea occurs in 60% of patients when they initially present but is


encountered by all as the disease progresses.

• Syncopeandangina,particularlywithexertion,arelatemanifestationsofthedisease,
suggest ing the presence of severe pulmonary hypertension causing reduced
cardiac output.

• On physical exam, there is a loud second heart sound (P2), jugular venous
distension (JVD), hepatomegaly, lower-extremity edema, and ascites, and
there may be a murmur of pulmonary and/or tricuspid regurgitation .

• An echocardiogram is the best screening test for PH, but to make the
diagnosis, a right heart catheterization must be performed.

• Chestradiographymayshowperipheralpulmonaryhypovascularity(“pruning”),
prominent proximal pulmonary arteries, and right ventricular enlargement
into the retrosternal space.

• The electrocardiogram showsright axis deviation, right atrial enlargement,


right ventricular hypertrophy, and right ventricular strain.

• With an echocardiogram, the right ventricle and pulmonary artery pressures


can be esti- mated, right ventricular and left atrial enlargement are seen, and

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tricuspid and pulmonary valve regurgitation are seen with color Doppler.
However, the right ventricle and pulmonary pressures are only estimated
and may not be accurate.

• A right heart catheterization ( Swan–Ganz catheter) is required to confirm a


suspected diagnosis of PH .

Prognosis

• Historically, the prognosis for patients with PAH has been poor, with an
estimated mediansurvival of 2.8 years

Therapy

• Conventional medical therapy for pulmonary hypertension has centered on the


use of supple- mental oxygen (with goal oxygen saturation >90%),
diuretics, anticoagulants (warfarin with goal international normalized ratio
[INR] between 1.5 and 2.5), and vasodilators.

• Diuretics must be used with caution in patients with higher right-sided pressures
to avoid significant reductions in cardiac preload that could further reduce
cardiac output.

• Anticoagulation is recommended to achieve an INR of 1.5–2.5 times that of


normal controls.

• Digoxin is always recommended for use in patients who have pulmonary


hypertension with evidence of left ventricular dysfunction.

• Calcium channel blockers used include nifedipine (dose range, 30–240


mg/day) anddiltiazem (120–900 mg/day).

• The prostacyclin derivatives include intravenous (IV) epoprostenol, inhaled


iloprost, and subcutaneous, intravenous, or inhaled treprostinil.

• Epoprostenol is currently the most effective therapy but has a short half-
life and must be administered continuously via an IV infusion. Side effects
may limit its use and include flushing, headache, nausea, vomiting,
diarrhea, jaw pain, hypotension, and delivery-site complications.

• Iloprost is given via inhalation, but its half-life is short , and so it requires
six to nine inhalations per day.

• Treprostinil is a longer- acting prostacyclin analog, is infused


subcutaneously or intravenously, and is complicated by site infusion pain that
can be severe enough to cause discontinuation.

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• The endothelin receptor antagonists include bosentan and ambrisentan, both


of which are administered orally

• Sildenafil and tadalafil comprise the phosphodiesterase type-5 inhibitors that


have been approved for the treatment of PAH.

o They work in the same pathway as exogenous nitric oxide by increasing


cyclic GMP and causing vasodilation.

T opic -Constrictive pericarditis

Constrictive pericarditis

Etiology

• Certain causes of pericarditis such as tuberculosis, haemopericardium,


bacterial infection and rheumatic heart disease result in the pericardium
becoming thick, fibrous and calcified.

• This may also develop late after open heart surgery, and fibrosis also occurs
with the use of dopamine agonists, e.g. cabergoline, perigolide.

• Constrictive pericarditisvsrestrictive cardiomyopathy

o Constrictive pericarditis should be distinguished from restrictive


cardiomyopathy .The two conditions are very similar in their
presentation, but the former is fully treatable, whereas most cases of
the latter are not.

Clinical features

• The symptoms and signs of constrictive pericarditis occur due to:

o reduced ventricular filling (similar to cardiac tamponade, i.e.


Kussmaul’s sign, Friedreich’s sign, pulsusparadoxus)
o systemic venous congestion (ascites, dependent oedema, hepatomegaly
and raised JVP)
o pulmonary venous congestion (dyspnoea, cough, orthopnoea, PND)
less commonly
o reduced cardiac output (fatigue, hypotension, reflex tachycardia)
o rapid ventricular filling (‘pericardial knock’ heard in early diastole at the
lower left sternal border)
o atrial dilatation (30% of cases have atrial fibrillation).

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Investigations

• Chest X-ray shows a relatively small heart in view of the symptoms of heart
failure.

o Pericardialcalcification is present in up to 50%.

o A lateral chest film may be useful in detecting calcification that is


missed on an AP film. However, a calcified pericardium is not necessarily
a constricted one

• ECG reveals low-voltage QRS complexes with generalized T wave


flattening or inversion.
• Echocardiography shows thickened calcified pericardium, and small
ventricular cavities with normal wall thickness.
• CT and CMR are used to assess pericardial anatomy and thickness (3 mm
or greater)
• Endomyocardial biopsy may be helpful in distinguishing constrictive
pericarditis from restrictive cardiomyopathy in difficult cases.
• Cardiac catheterization.
• End-diastolic pressures in the left and right ventricles measured during this
procedure are usually equal, owing to pericardial constriction.
Treatment

• The treatment for chronic constrictive pericarditis is complete resection of the


pericardium. This is a risky procedure with a high complication rate due to the
presence of myo- cardial atrophy in many cases at the time of surgery. Thus
early pericardiectomy is suggested in non-tuberculous cases, before severe
constriction and myocardial atrophy have developed.
• In cases of tuberculous constriction, the presence of pericardial calcification
implies chronic disease.
o Current evidence tends to favourearly pericardiectomy with antituberculous
drug cover in these cases.
o If there is no calcification, a course of antituberculous therapy should be
attempted first.
o If the patient’s haemodynamic state remains static or deteriorates after 4–6
weeks of therapy, pericardi- ectomy is recommended.

T opic - Cardiomyopathy

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§ Dilated cardiomyopathy
o Left or right ventricular enlargement with loss of contractile function
causing congestive heart failure, dysrhythmias, or thrombus
formation.
o Patients typically have symptoms of CHF that is slowly progressive
o leads to death in approximately 3 years. (MCQ)
o Etiology
§ Infectious
• Viral myocarditis (one-third improve, one-third stay the
same, one- third get worse)(MCQ)
§ Toxic(MCQ)
• Reversible—prolonged EtOH abuse
• Irreversible—doxorubicin (Adriamycin), cocaine, heavy
metals (Pb,Hg, Cb)
§ Endocrine(MCQ)
• Reversible—thyroid disease (hypo or hyper)
• Irreversible—acromegaly, pheochromocytoma
§ Metabolic(MCQ)
• Reversible—hypocalcemia, hypophosphatemia, thiamine
deficiency (wet beriberi), selenium deficiency
§ Genetic: 20% of cases have positive family histories
§ Pregnancy: Similar prognosis as viral
§ Other:
• Neuromuscular disease (usually irreversible)
• idiopathic (usuallyirreversible)
§ Mechanical
• Dysrhythmias
• Valvular disease
o Signs and symptoms
§ Symptoms of heart failure
§ Angina due to increased O2 demands of enlarged ventricles
§ Neurologic deficits from thrombus emboli
o Diagnosis
§ Auscultation—(MCQ)
• S3/S4 gallop murmurs (stiffened ventricular walls)
• regurgitant valves, rales
§ ECG—
• ventricular hypertrophy
• bundle branch blocks
• nonspecific ST segment/T wave changes,
• dysrhythmias (atrial fibrillation most common)
§ CXR—
• enlarged cardiac silhouette, pulmonary venous congestion
§ Echocardiography—
• Enlargedventricles/atria,regurgitantvalves

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• lowejection fractions(MCQ)
o Treatment
§ ACE inhibitorsand diuretics reduce mortality)(MCQ)
§ Anticoagulation with Coumadin (even if no evidence of
thrombus)
§ Implanted automatic defibrillator for patients with life-
threatening dysrhythmias(MCQ)
§ Heart transplant(MCQ)

§ Restrictive cardiomyopathy
o Scarring and infiltration of the myocardiumcausing decreased right or
left ventricular filling
o Etiology(MCQ)
§ Amyloidosis ,Endomyocardial fibrosis
§ Hemochromatosis ,Sarcoidosis
§ Carcinoid heart disease
§ Congenital: Gaucher, Hurler, and glycogen storage diseases
o Signs and symptoms
§ Signs of left/right heart failure, right failure usually
predominates
§ Exercise intolerance is a common presenting symptom
o Diagnosis
§ Auscultation—
• S3and/or S4gallopmurmurs (MCQ)
• Occasionalmitralortricuspid regurgitation
§ ECG—
• low voltages, conduction abnormalities
• nonspecific ST seg- ment/T wave changes
• leftbundle branch block(MCQ)
§ CXR—
• normalcardiac silhouette or enlarged atria(MCQ)
• pulmonary venous congestion
§ Echocardiography—
• normal-sized ventricles, large atria
• thickened ventricular walls
• mitral/tricuspid regurgitation
• typically has a speckled appearance if amyloid is cause
§ Endomyocardial biopsy(MCQ)
• may detect eosinophilic infiltration ormyocardial
fibrosis.
o Treatment
§ No specific treatment or cure
§ Mainstay is to treat resulting heart failure.
§ Anticoagulate and rate control atrial fibrillation if present.
§ Treat underlying cause.
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§ Permanent pacemaker for complete heart block (MCQ)


§ Heart transplant for refractory cases
o Restrictive cardiomyopathy is often difficult to distinguish from
constrictive pericarditis—biopsy can usually confirm.(MCQ)

T opic - Myocarditis

Myocarditis

§ Etiology
o Viral—(MCQ)
§ coxsackie A or B, echovirus, HIV
§ cytomegalovirus (CMV),
§ influenza, Epstein–Barr
§ hepatitis B virus (HBV), adenovirus
o Bacterial—
§ group A beta-hemolytic strep (rheumatic fever)
§ Corynebacterium, Meningococcus
§ B. burgdorferi (Lyme),Mycoplasma pneumoniae
o Parasitic
§ Trypanosomacruzi (Chagas’)
§ Toxoplasma, Trichinella,Echinococcus
o Systemic disease
§ Kawasaki’s, systemic lupus erythematosus (SLE)(MCQ)
§ sarcoidosis, inflammatory conditions
o Drug allergies—
§ sulfonamides, penicillins , Cocaine(MCQ)
o Idiopathic—common
§ Signs and symptoms
o Spectrum of disease ranges from asymptomatic to fulminant cardiac
failure and death.
o Retrosternal or precordial chest pain
o Fever, fatigue
o Preceding upper respiratory infection (URI)
o Palpitations, syncope
o Signs of CHF (dyspnea, rales, peripheral edema, JVD)
§ Diagnosis
o Auscultation—
§ S3/S4, mitral or tricuspid regurgitation
§ friction rub (if pericardium involved)
o ECG—
§ ST segment changes
§ low voltage, dysrhythmias(MCQ)
§ conduction disturbances
o CXR—
§ often normal
§ may see cardiomegaly or pulmonary venous congestion
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o Echocardiography—
§ hypokinetic wall movements,
§ dilated ventricles/ atria
§ pericardial effusion
o Labs—
§ leukocytosis, elevated ESR
§ elevated cardiac enzymes
• slower rise and fall than acute MI, troponin I is most
sensitive)(MCQ)
o Myocardial biopsy
§ TREATMENT
o Primarily supportive—admit to ICU , limit activity
o Treat heart failure, dysrhythmias
o ACE inhibitors reduce necrosis andinflammation(MCQ)
o digoxin should be used cautiously as its effects may beexaggerated by
the inflamed myocardium.(MCQ)
o Immunosuppressive agents are contraindicated (steroids,
cyclosporine,NSAIDs).(MCQ)
o IV immunoglobulin G (IgG) may be of benefit. (MCQ)

T opic -Pericarditis

§ Pericarditis
o Etiology
§ Viral—
• pericarditis frequently occurs following a recent viral URI
§ Bacterial—TB, streptococci, staphylococci
§ Metastases—1tumors usually breast or lung (MCQ)
§ Acute myocardial infarction:
• Immediate post-MI pericarditis
o occurswithin 24 hours of a transmural infarction due
to direct pericardial irritation
• Dressler’s syndrome—(MCQ)
o pericarditis occurring one week to months after an
MI (MCQ)
o due to an autoimmune response to infarcted
myocardium, can progress to chronic
condition(MCQ)
§ Uremia—chronic renal failure, mental status changes(MCQ)
§ Radiation—radiotherapy, occupational/environmental exposure
§ Drug reaction—hydralazine, procainamide, isoniazid(MCQ)
§ Collagen vascular tissue—SLE, scleroderma(MCQ)
§ Myxedema
§ Trauma—
• postpericardiotomy syndrome following CT surgery
(usuallybrief clinical course) (MCQ)
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§ Idiopathic
o Signs and symptoms
§ Chest pain, often pleuritic (inspiratory), radiating to left trapezial
ridge
§ Pain often relieved by sitting up and leaning forward(MCQ)
§ Pain does not respond to nitroglycerin.(MCQ)
o Diagnosis
§ Auscultation—
• pericardial friction rub on expiration(MCQ)
• pathognomonic but variably present
§ ECG—
• diffuse ST elevations and PR depressions(MCQ)
• low voltage
§ CXR—
• possiblyenlarged cardiac silhouette 2to pericardial
effusion
• Echocardiography—possible pericardial effusion
o TREATMENT
§ NSAIDs to relieve pain and reduce inflammation (ASA, indometh-
acin, ibuprofen)
§ Steroids for intractable cases (e.g., Dressler’s)(MCQ)

T opic -Atrial myxoma

• This is the most common primary cardiac tumour.

• It occurs at all ages and shows no sex preference.

• mostmyxomas are sporadic

• Histologically they are benign.

• The majority of myxomas are solitary, usually develop in the left atrium

• The tumour may obstruct the mitral valve or may be a site of thrombi that then
embolize.

• It is also associated with constitutional symptoms: the patient may present with
dyspnoea, syncope or a mild fever.

• The physical signs are a loud first heart sound, a tumour ‘plop’ (a loud third
heart sound produced as the peduncu- latedtumour comes to an abrupt halt),
a mid-diastolic murmur and signs due to embolization.

• A raised ESR is usually present.

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• The diagnosis is easily made by echocardiography because the tumour is


demonstrated as a dense space- occupying lesion

• Surgical removal usually results in a complete cure.

T opic -Coarctation of the aorta


• A coarctation of the aorta is a narrowing of the aorta at, or just distal to, the insertion of
the ductus arteriosus, i.e. distal to the left subclavian artery
• It occurs twice as commonly in men as in women. It is also associated with
Turner’s syndrome
• In 80% of cases the aortic valve is bicuspid (and potentially stenotic or
endocarditic).
• Other associations include patent ductus arteriosus, ventricular septal defect,
mitral stenosis or regurgitation and circle of Willis aneurysms.
• Severe narrowing of the aorta encourages the formation of a collateral arterial
circulation involving the periscapular and intercostal arteries.
• Decreased renal perfusion can lead to the development of systemic hypertension
that persists even after surgical correction.
§ Clinical features
o Coarctation of the aorta is often asymptomatic for many years.
o Headaches and nosebleeds (due to hypertension), and claudication
and cold legs (due to poor blood flow in the lower limbs) may be
present.
o Physical examination reveals hypertension in the upper limbs, and
weak, delayed (radiofemoral delay) pulses in the legs.
o If coarcation is present in the aorta , proximal to the left subclavian artery,
there will be asynchronious radial pulses in right and left arms. Poor peripheral
pulses are seen in severe cases
o Heart sounds and murmurs
§ Mid–late systolic murmur may be heard over the upper precordium or the
back.
§ Vascular bruits from the collateral circulation may also be heard
§ Investigations
o Chest X-ray may reveal a dilated aorta indented at the site of the
coarctation.
o This is manifested by an aorta (seen in the upper right mediastinum)
shaped like a ‘figure 3’.
o In adults, tortuous and dilated collateral intercostal arteries may
erode the undersurfaces of the ribs (‘rib notching’).
o ECG demonstrates left ventricular hypertrophy.
o Echocardiography sometimes shows the coarctation and other asso-
ciated anomalies.
o CT and CMR scanning can accurately demonstrate the coarctation and
quantify flow .
o ECG demonstrates left ventricular hypertrophy.
o Echocar- diography sometimes shows the coarctation and other
associated anomalies.

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o CT and CMR scanning can accurately demonstrate the coarctation and


quantify flow .
§ Treatment
§ Treatment is usually indicated if the pressure gradient across the
coarctation is greater than 30 mmHg.
§ This involves surgical excision of the coarctation and end-to-end
anastomosis of the aorta.
§ If the coarctation is extensive, prosthetic vascular grafts may be needed.
§ When surgery is performed in early childhood, hypertension usually resolves
completely. However, when the operation is performed on adolescents or
adults, the hypertension persists in 70% because of previ- ous renal damage
§ There is also an increased risk of accelerated atherosclerosis and strokes
in these individuals.
§ Balloon dilatation is used in some centres for either primary disease or post-
surgical recurrence, although there is a higher incidence of aneurysm formation and
post-dilatation recurrence.
§ Surgical correction in childhood gives a good 25-year survival rate of 83%.
o If this is delayed until adulthood (20–40 years), the 25-year survival rate
drops to 75%.
o If coarctation is left uncorrected, however, only 25% of patients are alive at
50, while cardiac failure ensues in two-thirds of surviving patients over
40.
T opic -Rheumatic fever
§ Rheumatic fever is an inflammatory disease that occurs in children and
young adults (the first attack usually occurs at between 5 and 15 years of age as a
result of infection with group A streptococci .
o Pharyngeal infection with group A streptococcus is followed by the
clinical syndrome of rheumatic fever. This is thought to develop
because of an autoimmune reaction trig- gered by molecular mimicry
between the cell wall M proteins of the infecting Streptococcus
pyogenes and cardiac myosin and laminin.
o The condition is not due to direct infection of the heart or to the
production of a toxin.
§ It affects the heart, skin, joints and central nervous system
§ Pathology
o All three layers of the heart may be affected.
o The characteristic lesion of rheumatic carditis is the Aschoff nodule,
which is a granulomatous lesion with a central necrotic area
occurring in the myocardium.
o Small, warty vegetations may develop on the endocardium,
particularly on the heart valves.
o A serofibrinous effusion characterizes the acute pericarditis that
occurs.
o The synovial membranes are acutely inflamed during rheumatic
fever, and subcutaneous nodules (which are also granulomatous lesions)
are seen in the acute stage of the disease.
§ Clinical features
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§ The disease presents suddenly, with fever, joint pains, malaise and loss
of appetite.
§ Diagnosis relies on the presence of two or more major clinical manifestations or
one major manifestation plus two or more minor features.
§ Revised Jones criteria for the diagnosis of rheumatic fever
o Major criteria
§ Carditis
§ Polyarthritis
§ Chorea
§ Erythema marginatum
§ Subcutaneous nodules
o Minor criteria
§ Fever
§ Arthralgia
§ Previous rheumatic fever Raised ESR/C- reactive protein
Leucocytosis
§ Prolonged PR interval on ECG
§ Plus evidence of antecedent streptococcal infection, e.g.
positive throat cultures for group A streptococci, elevated
antistreptolysin O titre (250 U) or other streptococcal antibodies,
or a history of recent scarlet fever

§ Carditis manifests as:


o new or changed heart murmurs
o development of cardiac enlargement or cardiac failure
o appearance of a pericardial effusion
o ECG changes of pericarditis, myocarditis, AV block or other
cardiac arrhythmias.
§ Most commonly involved valve is - Mitral valve
§ Least commonly involved valve is - Pulmonary valve
§ Carey coomb's murmur
o It is a delayed diastolic murmur heard during the course of acute
rheumatic fever.
o It is a low pitched murmur.
o Although it is believed to indicate myocarditis, it is very unlikely
that carey coomb's
o murmur is due to myocarditis per se.
o No other myocorditis results in a mitral diastolic murmur unless
associated with significant mitral regurgitation.
o It is most likely due to increased diastolic flow secondary to mitral
regurgitation across inflamed cusps.
o The dissappearance can be explained by the decrease in the left
ventricular size following subsidence of myocarditis, and better function
of the mitral valve papillary muscle complex
§ Non-cardiac features include the following:
o Fever.
o The arthritis associated with rheumatic fever is classically a fleeting
migratory polyarthritis affecting large joints such as the knees, elbows,
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ankles and wrists.


§ Once the acute inflammation disappears, the rheumatic
process leaves the joints normal.
o Sydenham’s chorea (or St Vitus’ dance) is involvement of the central
nervous system that develops late after a streptococcal infection.
§ Sufferers are noticeably ‘fidgety’ and display spasmodic,
unintentional choreiform movements.
§ Speech is often affected.
o Skin manifestations include erythema marginatum, a transient pink
rash with slightly raised edges, which occurs in 20% of cases.
§ The erythematous areas found mostly on the trunk and
limbs coalesce into crescent- or ring-shaped patches.
o Subcutaneous nodules, which are painless, pea-sized, hard nodules
beneath the skin, may also occur.

§ Investigations
o Throat swabs are cultured for the group A streptococcus.
o Antistreptolysin O titre and antiDNAse B may be elevated.
o ESR and CRP are usually high.

§ Treatment
o Patients with active arthritis or carditis should be rested in bed.
o When the clinical syndrome has subsided (e.g. no pyrexia, normal
pulse rate, normal ESR, normal white cell count) the patient is
mobilized.
o Residual streptococcal infections should be eradicated with oral
phenoxymethylpenicillin 500 mg four times daily for 1 week.
§ This therapy should be administered even if nasal or
pharyngeal swabs do not culture the streptococci.
o The arthritis of rheumatic fever responds dramatically to NSAIDs.
o There is no good evidence that steroids are of benefit, although
some experts give high-dose prednisolone if there is severe carditis.
o Recurrences are most common when persistent cardiac damage is
present, and are preven- ted by the continued administration of oral
phenoxymethyl- penicillin 250 mg twice daily or intramuscular
benzathine penicillin G 1.2 million units monthly until the age of 20
years or for 5 years after the latest attack
o Erythromycin is used if the patient is allergic to penicillin.

T opic -Tricuspid stenosis

• Etiology
o Rheumatic heart disease
o congenital
o carcinoid (MCQ)
• Signs and symptoms
o Peripheral edema
o JVD
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o Hepatomegaly, ascites, jaundice


• Diagnosis
o Murmur is diastolic, rumbling, low pitched(MCQ)
o Murmur accentuated with inspiration(MCQ)
o Best heard over left sternal border between 4th to 5th interspace (MCQ)
o Echocardiography demonstrates diseased valve.
• Treatment
o Surgical repair
• Clinical Pearls :
o Female predominance.
o History of rheumatic heart disease.
o Carcinoid disease more common etiology in the West (MCQ)
o Elevated JVP with prominent a wave.(MCQ)
o Presents with Right heart failureafter tricuspid surgery or in rheumatic disease or
carcinoid syndrome.
o Echocardiography/Doppler is key to diagnosis.
o Mean valve gradient > 5 mm Hg by echocardiography indicates severe
tricuspid stenosis.(MCQ)
o Tricuspid stenosis should be suspected when "right heart failure"
appears in the course of mitral valve disease or in the postoperative period
after tricuspid valve repair or replacement.( Important Clinical Vignette for
MD Entrance)(MCQ)
o A giant a wave is seen in the JVP , which is elevated
o In sinus rhythm, a presystolic liver pulsation may be found.
o The normal valve area of the tricuspid valve is 10 cm2, so significant
stenosis must be present to produce a gradient. (MCQ)
o Hemodynamically, a mean diastolic pressure gradient of > 5 mm Hg is
considered significant, though even a 2 mm Hg gradient can be considered
abnormal.
o Neither surgical nor percutaneous valvuloplasty is effective for tricuspid
stenosis, as residual tricuspid regurgitation is common.
o Tricuspid valve replacement is clearly the preferred surgical approach. (MCQ)
o Mechanical tricuspid valve replacement is rarely done because the low
flow predisposes to thrombosis and because the mechanical valve cannot
be crossed should the need arise for right heart catheterization or pacemaker
implantation. Therefore, bioprosthetic valves are almost always used.
(MCQ)
o Often tricuspid valve replacement is done in conjunction with mitral valve
replacement for mitral stenosis.

T opic -Tricuspid regurgitation

• Tricuspid regurgitation
o Etiology
§ Increased pulmonary artery pressure (MCQ)
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• from left-sided failure or mitral regurgitation/stenosis


§ Right ventricular dilation stretching the outflow (MCQ)
• fromright heart failure, infarction, or tricuspid regurgitation itself
§ Right papillary muscle rupture from infarction(MCQ)
§ Tricuspid valvular lesions(MCQ)
• fromrheumatic heart disease or bacterial endocarditis
o Signs and symptoms
§ Signs of right heart failure: Prominent JVD, pulsatile liver
o Diagnosis
§ Holosystolic, blowing, medium-pitched murmur(MCQ)
• heard best along the left sternal border in the 5th
interspace,
• accentuated with inspiration
§ ECG shows right ventricular enlargement.(MCQ)
§ Atrial fibrillation is common.
§ Echocardiography demonstrates diseased valve.
o Treatment
§ Treat left heart failure, if applicable.
§ Diuresis to reduce volume load(MCQ)
§ Surgical repair and endocarditis prophylaxis if valve defective
o Clinical pearls:
o Right-sided bacterial endocarditis is most frequently associated with
nonsterile technique in IV drug abuser (MCQ)

o A holosystolic murmur can be due to mitral regurgitation,


tricuspid regurgitation, or ventricular septal defect.(MCQ)

o Systolic c-v wave in jugular venous pulsations.(MCQ)

o Tricuspid valve apparatusversus Mitral valve apparatus.

§ Besides having three leaflets rather than two, the tricuspid valve
has many chordae that attach to the RV endocardium rather
than to discrete papillary muscles, and chordal attachments
to the RV septum

o Tricuspid valvular incompetence often occurs whenever there is


RV dilation from any cause.(MCQ)

o The RV dilation is often secondary to left heart failure (MCQ)

o The JVP waveform

§ Normally ,itshould decline during ventricular systole (the x


descent).

§ The timing of this decline can be observed by palpating the


opposite carotid artery.
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§ As tricuspid regurgitation worsens, more and more of this


valley in the JVP is filled with the regurgitant wave until all
of the x descent is obliterated and a positive systolic waveform will be
noted in the JVP(MCQ)

o Cyanosis may be present if

§ the increased RA pressure stretches the atrial septum and


opens a PFO

§ there is a true ASD (eg, in about 50% of patients with Ebstein


anomaly).(MCQ)

o If the PA or RV systolic pressure is < 40 mm Hg, primary


tricuspid regurgitation should be suspected.(MCQ)

T opic –Dyslipidemia

• About half of all cases of coronary artery disease are associated with disorders
of lipid metabolism.
• Major Lipoproteins
o Chylomicrons:
§ Transport cholesterol from the gut in the bloodstream (MCQ)
o Chylomicron remnants:
§ Left over after lipoprotein lipase liberates freefatty acids from
chylomicrons for use in tissues(MCQ)
o Very low-density lipoprotein (VLDL):
§ Secreted from the liver (MCQ)
§ Carriescholesterol in the bloodstream
o Intermediate-density lipoprotein (IDL):
§ Metabolized from VLDL
o LDL:
§ Metabolized from IDL, it carries cholesterol in the bloodstream
totissues
o HDL:
§ Uptakes free cholesterol secreted by tissues and transports it
tothe liver
• Isolated Hypercholesterolemia(MCQ)
o Familial hypercholesterolemia:
§ Elevated LDL (type IIa)
o Familial defective apo B100:
§ Elevated LDL (type IIa)
o Polygenic hypercholesterolemia:
§ Elevated LDL (type IIa)
• Isolated Hypertriglyceridemia(MCQ)
o Familial hypertriglyceridemia:
§ Elevated VLDL (type IV)
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o Familial lipoprotein lipase deficiency:


§ Elevated chylomicrons (type I, V)
o Familial apo CII deficiency:
§ Elevated chylomicrons (type I, V)
• Combined Hypertriglyceridemia and Hypercholesterolemia(MCQ)
o Combined hyperlipidemia:
§ Elevated VLDL, LDL (type IIb)
o Dysbetalipoproteinemia:
§ Elevated VLDL, IDL (type III)
• Signs and symptoms
o Xanthelasma:
§ Painless, nonpruritic raised yellow plaques that occur oneyelids near
inner canthi
o Xanthoma:
§ Reddish brown papules on scalp, face, trunk, and flexor surfaces of
limbs
• Diagnosis
o Serum lipoprotein analysis is done after a 12-hour fast.
o One-time sample cholesterol levels may not represent true levels in the
following circumstances:(MCQ)
§ Weight loss
§ Pregnancy
§ Major surgery
§ Severe illness
o In patients who have MI, lipoprotein levels obtained within the first 24
hours will more closely approximate true pre-MI levels than later
levels, which may not return to baseline for several weeks.
• Treatment of hypercholesterolemia
o Goals of treatment: (MCQ)
§ For a patient with 0–1 risk factors (low risk),keep LDL<160.
§ For a patient with 1–2 risk factors (moderate risk), keep LDL
<130.
§ For a patient with known atherosclerotic heart disease (high
risk), keepLDL<100.

Cholesterol Levels Associated with Familial Disease

TOTAL CHOLESTEROL

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Type Level LDL LEVEL VLDL CHYLOMICRONS


(mg/DL)
Familial IIa 275-500 High Normal Normal
hypercholesterolemia
Familial defective apo IIa 275-500 High Normal Normal
B100
Polygenic IIa 240-350 High Normal Normal
hypercholesterolemia
Familial IV 250-750 Normal/High High Normal/High
hypertriglyceridemia
Familial lipoprotein I, > 750 Normal/High Normal/High High
lipase deficiency (I,V)
Familial apoprotein CII I, > 750 Normal/High Normal/High High
deficiency (I,V)
Familial combined IIb 250-500 High High Normal/High
hyperlipidemia
Dysbetalipoproteinemia II 250-500 Normal High Normal/High

• Treatment of Hypercholesterolemia
o Diet therapy
§ Therapeutic Lifestyle Changes (TLC) diet(MCQ)
• Total fat -−30% total calories
• Polyunsaturated fat< 10%
• Monounsaturated fat< 20%
• Carbohydrate 50–60%
• Fiber 20–30 g/day
• Protein 15% total calories
• Saturated fat< 10%
• Dietary cholesterol300 mg/day
§ Step 2 diet reduces total cholesterol by 10–12%.
§ Exercise variably raises HDL.
§ If diet therapy and exercise fail by 6 weeks, progress to
medications.
o Statins (MCQ)

§ Statins are HMG-CoA reductase inhibitors

§ act to reduce LDL and increase HDL.

§ Can lower LDL cholesterol by 35% and raise HDL by

o Bile acid sequestrants

§ Cholestyramine and colestipol

§ bind bile acids in the gut.

§ Reduces LDL cholesterol by 15–20%


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o Nicotinic acid

§ Reduces lipolysis in adipose tissue(MCQ)

§ inhibits hepatic synthesis of cholesterol

§ Can reduce LDL cholesterol by over 6 months

§ Side effects include cutaneous flushing, abdominal pain,


nausea.

o Fibrinates(MCQ)

§ Best for reducing triglycerides (in VLDL and chylomicrons)

§ Increases HDL by 5–30%

A very important table for MD Entrance prep

LDL goals and treatment cutpoints: Recommendations of the NCEP Adult Treatment Panel III.

Risk category LDL Goal (mg/dL) LDL Level at which LDL Level at Which
to Initiate Lifestyle to Consider Drug
Changes (mg/dL) Therapy1 (mg/dL)
High risk: CHD2 or <100 (optional goal: ≥1005 ≥1006 ( <100:
CHD risk <70 mg/dL)4 consider drug
equlvalents3 (10- year options)1
risk >20%)
Moderately high risk: <1309 ≥1305 ≥130 (100-129;
2+ risk factors7 (10- consider drug
year risk 10% to options)10
20%)8
Moderate risk: 2+ <130 ≥130 ≥160
risk factors (10-year
risk < 10%)8
Low risk: 0-1 risk <160 ≥160 ≥190 (160-189:LDL-
factors11 lowering drug
optional)

Clinical Pearls :

• Extremely high levels of chylomicrons or VLDL particles (triglyceride level


above 1000 mg/dL) result in the formation of eruptive xanthomas(MCQ)

• High LDL concentrations result in tendinousxanthomas on certain tendons


(MCQ)

• Lipemiaretinalis (cream-colored blood vessels in the fundus) is seen with


extremely high triglyceride levels (above 2000 mg/dL)(MCQ)

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• The goal of therapy should be to reduce the LDL cholesterol to below 100
mg/dL or optimally to below 70 mg/dL. (MCQ)

• Evidence suggests that treatment with a statin is effective even if the starting
LDL cholesterol is below 100 mg/dL(MCQ)

• Risk factors include (MCQ)

o cigarettesmoking

o hypertension(blood pressure 140/90 mm Hg or on antihypertensive


medication)

o lowHDL cholesterol (< 40 mg/dL)

o family history of premature CHD (CHD in male first-degree relative < 55


years of age; CHD in female first-degree relative < 65 years of age)

o age (men 45 years; women 55 years).

• Treatment of high low-density lipoprotein cholesterol(MCQ)

o Quitting smoking

o Exercise (and weight loss)

o Modest alcohol use (1–2 ounces a day) also raises HDL levels and appears
to have a salutary effect on CHD rates.

o Torcetrapib(MCQ)
§ cholesteryl ester transfer protein inhibitors

§ raises HDL cholesterol levels.

• Ezetimibe (MCQ)

o Ezetimibe is a lipid-lowering drug that inhibits the intestinal absorption


of dietary and biliary cholesterol

o blocks passage across the intestinal wall by inhibiting a cholesterol


transporter.

o reduces LDL cholesterol between 15% and 20% when used as


monotherapy

o can further reduce LDL in patients taking statins who are not yet at
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therapeutic goal.

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Neurology
Topic - STROKE AND CEREBROVASCULAR DISEASE

§ Hypertension is the most treatable stroke risk factor (MCQ)


§ Thrombo- embolic infarction (80%), cerebral and cerebellar haemorrhage
(10%) and subarachnoid haemorrhage (SAH) (about 5%) are the main causes;
arterial dissection and arteriovenous malformations also contribute. (MCQ)
§ Definitions
o Stroke. Stroke is defined as a syndrome of rapid onset of cerebral deficit
(usually focal) lasting >24 hours or leading to death, with no cause
apparent other than a vascular one. (MCQ)
o Completed stroke means the deficit has become maximal , usually
within 6 hours. (MCQ)
o Stroke-in-evolution describes progression during the first 24 hours.
(MCQ)
o Minor stroke. Patients recover without significant deficit, usually
within a week.
o Transient ischaemic attack (TIA) means a sudden focal deficit, e.g. a
weak limb, aphasia or loss of vision lasting from seconds to 24 hours
with complete recovery. This definition is unsatisfactory as after 1 hour
ischaemic damage has already occurred
§ Pathophysiology
o Completed stroke is caused by:
§ arterial embolism from a distant site (usually heart, carotid,
vertebral or basilar arteries) and subsequent brain infarction
§ arterial thrombosis in atheromatous carotid, vertebral or cerebral
arteries with subsequent infarction
§ haemorrhage (intracranial or SAH).
o Less commonly, other processes cause stroke:
§ venous infarction
§ carotid or vertebral artery dissection
§ polycythaemia and hyperviscosity syndromes (MCQ)
§ fat and air embolism
§ multiple sclerosis – demyelinating plaque(s)
§ mass lesions (e.g. brain tumour, abscess, subdural haemorrhage).
§ Transient ischaemic attacks
o TIAs are usually the result of microemboli
o TIAs may be caused by a fall in cerebral perfusion (e.g. a cardiac
dysrhythmia, postural hypotension or decreased flow through
atheromatous arteries). Infarction is usually averted by autoregulation
o 25% of TIAs have MRI changes showing small infarcts
o a clinical TIA is not a reliable indicator of thromboembolism. (MCQ)
o Principal sources of emboli to the brain are cardiac thrombi and
atheromatous plaques/thrombi within the great vessels, carotid and
vertebral systems.
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o Cardiac thrombi (mural and valvular) follow atrial fibrillation, often


secondary to valvular disease, or myocardial infarction.
o Polycythaemia is also a cause.
o Thromboembolism from sources outside the brain generates 80% of
TIAs and also 70% of strokes.
o Features of transient ischaemic attacks

§ Anterior circulation

§ Carotid system(MCQ)
• Amaurosis fugax
• Aphasia
• Hemiparesis
• Hemisensory loss
• Hemianopic visual loss
§ Posterior circulation

§ Vertebrobasilar system(MCQ)

• Diplopia,

• Vertigo

• vomiting

• Choking and dysarthria

• Ataxia

• Hemisensory loss

• Hemianopic visual loss

• Bilateral visual loss

• Tetraparesis

• Loss of consciousness (rare)

• Transient global amnesia (possibly)

o Risk factors and prevention.


§ Low-dose aspirin is used in primary prevention in men and
women with a 10-year risk of coronary heart disease greater than
10%; its effect on stroke prevention is unclear.
§ For brain haemorrhage, hypertension, bleeding disorders,
anticoagulants and antiplatelet drugs, pre-existing cerebral
aneurysms and A VMs are risk factors.
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o Rarer risk factors and other causes of stroke


§ Thrombocythaemia and thrombophilia (protein C
deficiency, factor V Leiden) are weakly associated with arterial
stroke but predispose to cerebral venous thrombosis.
§ Anti-cardiolipin and lupus anticoagulant antibodies
(antiphospholipid syndrome,) predispose to arterial thrombotic
strokes in young patients.
§ Endocarditis – thromboembolic stroke may be the presenting
feature.
§ Low-dose oestrogen-containing oral contraceptives do not
increase stroke risk significantly in healthy women but probably
do so with other risk factors, e.g. uncontrolled hypertension or
smoking.

§ Migraine is a rare cause of cerebral infarction


§ V asculitis (systemic lupus erythematosus (SLE), polyarteritis,
giant cell arteritis, granulomatous CNS angiitis) is a rare cause of
stroke.
§ Amyloidosis can present as recurrent cerebral haemorrhage
(MCQ)
§ Hyperhomocysteinaemia predisposes to thrombotic strokes.
Folic acid therapy does not reduce the incidence. (MCQ)
§ Neurosyphilis, SLE, mitochondrial disease.
§ Drugs of abuse e.g. cocaine, and possibly over-the- counter cold
remedies containing vasoconstrictors.
§ Cox-2 inhibitors are associated with a slightly increased
incidence of stroke

• CADASIL (cerebral dominant arteriopathy with subcortical infarcts and


leucoencephalopathy) (MCQ)
o a rare inherited cause of stroke/vascular dementia.
o There is a mutation in the NOTCH3 gene on chromosome 19.
o Characteristic damage to small brain arterioles follows with multiple
infarcts, which can be seen on MRI in the subcortical white matter.
o A skin biopsy shows granular osmophilic material (GOM).
o Familial migraine and depression occur in youth, progressing to TIA and
stroke in the third and fourth decades, and dementia in the sixth.
• Vascular anatomy
o The circle of Willis is supplied by the two internal carotid arteries and by the
basilar.
o Stenoses and plaques proximal to the circle of Willis are seen typically at four
extracranial sites
§ origin of common carotid artery
§ origin of internal carotid artery
§ origin of vertebral artery
§ subclavian artery and carotid artery syphon – within the cavernous
sinus.
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• Autoregulation
o Usually, constant cerebral blood flow (CBF) is maintained at mean arterial
blood pressures between 60 and 120 mmHg, smooth muscle in small
arteries responding directly to changes in pressure. (MCQ)
o CBF is normally independent of perfusion pressure , i.e. there is
autoregulation.
o In disease, CBF autoregulation can fail. Contributory causes are: (MCQ)
§ severe hypotension with systolic BP <75 mmHg
§ severe hypertension with systolic BP >180 mmHg
§ increase in blood viscosity, e.g. polycythaemia
§ raised intracranial pressure
§ increase in arterial Pco2 and/or fall in arterial Po2.

Transient ischaemic attacks (TIAs)

§ Features
§ TIAs cause sudden loss of function , usually within seconds, and last for
minutes or hours (but by classical definition <24 hours). (MCQ)
§ Amaurosis fugax(MCQ)
o This is a sudden transient loss of vision in one eye.
o When due to the passage of emboli through the retinal arteries, arterial
obstruction is sometimes visible through an ophthal-moscope during an
attack.
o A TIA causing an episode of amaurosis fugax is often the first clinical
evidence of internal carotid artery stenosis – and forerunner of a
hemiparesis. Amaurosis fugax also occurs as a benign event in
migraine.
§ Transient global amnesia
§ Episodes of amnesia/confusion lasting several hours, occurring
principally in people over 65 and followed by complete recovery, are
presumed to be due to posterior circulation ischaemia. (MCQ)
§ Episodes rarely recur
§ Clinical findings in TIA
o Consciousness is usually preserved in TIA.
§ Differential diagnosis
o Focal epilepsy is usually recognized by its positive features (e.g. limb
jerking and loss of consciousness) and progression over minutes.
o In a TIA, involuntary limb movements do occur occasionally; deficit is
usually instantaneous.
o A focal prodrome in migraine sometimes causes diagnostic difficulty.
Headache, common but not invariable in migraine, is rare in TIA.
o Typical migrainous visual disturbances are not seen in TIA.

§ Prognosis
o Prospective studies show that 5 years after a single thromboembolic TIA:
§ 30% have had a stroke, a third of these in the first year
§ 15% have suffered a myocardial infarct.
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o TIAs in the anterior cerebral circulation carry a more serious


prognosis than those in the posterior circulation

Cerebral infarction

• What is meant by ischaemic penumbra


o Following vessel occlusion, brain ischaemia occurs, followed by
infarction.
o The infarcted region is surrounded by a swollen area which does not
function but is structurally intact.
o This is the ischaemic penumbra, which is detected on MRI
o Patient can regain function with neurological recovery.
• How does hypoxia leads to neuronal damage within the ischaemic area ?
(MCQ)
o There is a fall in ATP with release of glutamate , which opens calcium
channels with release of free radicals.
o These alterations lead to inflammatory damage, necrosis and
apoptotic cell death.
• Clinical features
o The stroke most typically seen is caused by infarction in the internal
capsule following thromboembolism in a middle cerebral artery
branch
§ A similar picture is caused by internal carotid occlusion
§ There is a contralateral hemiplegia or hemiparesis with facial
weakness.
§ Aphasia is usual when the dominant hemisphere is affected.
(MCQ)
§ Weak limbs are at first flaccid and areflexic.
§ After a variable interval, usually several days, reflexes return,
becoming exaggerated
§ Headache is unusual.
§ Consciousness is usually preserved. (MCQ)
§ An extensor plantar response appears.
§ Weakness is maximal at first; recovery occurs gradually over
days, weeks or many months.
o Brainstem infarction
§ The lateral medullary syndrome ( posterior inferior cerebellar
artery (PICA) thrombosis and Wallenberg’s syndrome) is a
common example of brainstem infarction presenting as acute
vertigo with cerebellar and other signs
§ It follows thromboembolism in the PICA or its branches,
vertebral artery thromboembolism or dissection.
• Clinical signs in the lateral medullary syndrome (PICA
thrombosis)

o Ipsilateral (MCQ)

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§ Facial numbness (Vth)

§ Diplopia (VIth)

§ Nystagmus

§ Ataxia (cerebellar)

§ Horner’s syndrome

§ IXth and Xth nerve lesions

o Contralateral (MCQ)
§ Spinothalamic sensory loss
§ Hemiparesis (mild, unusual)
• Coma follows damage to the brainstem reticular activating
system.
• The locked-in syndrome is caused by upper brainstem
infarction (MCQ)
• Pseudobulbar palsy can follow lower brainstem infarction.
(MCQ)

Features of brainstem infarction

Clinical feature Structure involved


Hemiparesis or tetraparesis Corticospinal tracts
Sensory loss Medial lemniscus and spinothalamic tracts
Diplopia Oculomotor system
Facial numbness Vth nerve nuclei
Facial weakness VIIth nerve nucleus
Nystagmus, vertigo Vestibular connections
Dysphagia, dysarthria IXth and Xth nerve nuclei
Dysarthria, ataxia, hiccups, vomiting Brainstem and cerebellar connections
Horner’s syndrome Sympathetic fibres
Coma, altered consciousness Reticular formation

o Lacunar infarction
o Lacunes are small (< 1.5 cm3) infarcts seen on MRI or at autopsy. (MCQ)
o Hypertension is commonly present. (MCQ)
o Minor strokes (e.g. pure motor stroke, pure sensory stroke, sudden
unilateral ataxia and sudden dysarthria with a clumsy hand ) are
syndromes caused typically by single lacunar infarcts.
o Lacunar infarction is often symptomless. (MCQ)
§ Hypertensive encephalopathy
o This is due to cerebral oedema, causing severe headaches, nausea and
vomiting.

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o Agitation, confusion, fits and coma occur if the hypertension is not


treated.
o Papilloedema develops, either due to ischaemic optic neuropathy or
following the brain swelling due to multiple acute infarcts.
o MRI shows oedematous white matter in the parieto-occipital regions.
(MCQ)
§ Multi-infarct dementia (vascular dementia)
o Multiple lacunes or larger infarcts cause generalized intellectual loss
seen with advanced cerebrovascular disease.
o In the late stages, there is dementia, pseudobulbar palsy and a
shuffling gait – the marche à petits pas (small steps), some- times
called atherosclerotic parkinsonism. (MCQ)
§ Binswanger’s disease is a term for widespread low attenuation in cerebral white
matter, usually with dementia, TIAs and stroke episodes in hypertensive patients
(the changes being seen on imaging/autopsy). (MCQ)
§ Anton’s syndrome

o Visual cortex infarction(MCQ)


o Posterior cerebral artery infarction or infarction of the middle cerebral
artery macular branch causes combinations of hemianopic visual loss and
cortical blindness (Anton’s syndrome). (MCQ)
§ Weber’s syndrome
o Ipsilateral IIIrd nerve palsy with contralateral hemiplegia is due to a
unilateral infarct in the midbrain. (MCQ)
o Paralysis of upward gaze is usually present. (MCQ)
§ Watershed (borderzone) infarction
o Cortical infarcts, often multiple, follow prolonged periods of low
perfusion (e.g. hypotension after massive myocardial infarction or
cardiac bypass surgery). (MCQ)
o Infarcts occur in the borderzones, between areas supplied by the
anterior, middle and posterior cerebral arteries.
o Cortical visual loss, memory loss and intellectual impairment are
typical.
o In some cases a vegetative state or minimal conscious state follows
§ Acute stroke: immediate care, and thrombolysis
o The benefit of thrombolysis decreases with time, even within the time
window of 4.5 hours . (MCQ)
o If thrombolysis is not given, aspirin 300 mg daily should be given as
soon as a diagnosis of ischaemic stroke or thromboembolic TIA is
confirmed, reducing to 75 mg after several days. (MCQ)
o Following thrombolysis aspirin should not be started until 24–48
hours later. (MCQ)
§ Investigations

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o Sources of embolus should be sought (e.g. carotid bruit, atrial


fibrillation, valve lesion, evidence of endocarditis, previous emboli or
TIA) and hypertension/postural hypotension assessed.
o Brachial BP should be measured on each side; 20mmHg difference is
suggestive of subclavian artery stenosis.
o CT and MRI:
§ Non-contrast CT will demonstrate haemorrhage immediately
but cerebral infarction is often not detected or only subtle
changes are seen initially
§ MRI shows changes early in infarction and a later MRI shows
the full extent of the damaged area or penumbra
§ Diffusion-weighted MRI (DWI) can detect cerebral infarction
immediately but is as accurate as CT for the detection of
haemorrhage.
§ Perfusion-weighted images and diffusion-weighted MRI will
differentiate the infarct core and the penumbral area which is
potentially recoverable. (MCQ)
o MR angiography (MRA) or CT angiography is valuable in
anterior circulation TIAs to confirm surgically accessible
arterial stenoses, mainly internal carotid stenosis
o If ultrasound suggests carotid stenosis , normotensive patients
with TIA or stroke in the anterior circulation should have vascular
imaging.
o Carotid Doppler and duplex scanning. demonstrate accurately the
degree of internal carotid stenosis (MCQ)
§ Treatment of acute stroke
o In a massive middle cerebral artery infarct, hemispheric swelling
occurs with oedema .
o Decompressive hemicraniectomy reduces the intracranial pressure and
the mortality but extensive neurological deficits remain.
o Thrombolysis in acute ischaemic stroke

§ Eligibility (MCQ)
• Age >18 years
• Clinical diagnosis of acute ischaemic stroke
• Assessed by experienced team
• Measurable neurological deficit
• Blood tests: results available
• CT or MRI consistent with acute ischaemic stroke
• Timing of onset well established
• Thrombolysis should commence as soon as possible and
up to 4.5 hours after acute stroke
§ Exclusion criteria (MCQ)
• Historical
o Stroke or head trauma within the prior 3
months
o Any prior history of intracranial haemorrhage
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o Major surgery within 14 days


o Gastrointestinal or genitourinary bleeding within
the previous 21 days
o Myocardial infarction in the prior 3 months
o Arterial puncture at a non-compressible site
within 7 days
o Lumbar puncture within 7 days
• Clinical
o Rapidly improving stroke syndrome
o Minor and isolated neurological signs
o Seizure at the onset of stroke if the residual
impairments are due to postictal phenomena
o Symptoms suggestive of subarachnoid
haemorrhage, even if the CT is normal
o Acute MI or post-MI pericarditis
o Persistent systolic BP >185, diastolic BP > 110
mmHg, or requiring aggressive therapy to control
BP
o Pregnancy or lactation
o Active bleeding or acute trauma (fracture)
• Laboratory
o Platelets < 100000/mm3
o Serum glucose < 50 mg/dL or > 400 mg/dL
o INR > 1.7 if on warfarin
o Elevated partial thromboplastin time if on
heparin
§ Dose of i.v. alteplase (tissue plasminogen activator)
o Total dose 0.9 mg/kg (maximum 90 mg)
o 10% of total dose by initial i.v . bolus over 1 minute
o Remainder infused i.v . over 60 minutes
o
§ Long-term management
o Antihypertensive therapy(MCQ)
§ Recognition and good control of high blood pressure is the
major factor in primary and secondary stroke prevention.
§ Transient hypertension, often seen following stroke, usually
does not require treatment provided diastolic pressure does
not rise > 100 mmHg. Sustained severe hypertension
needs treatment
§ BP should be lowered slowly to avoid any sudden fall in
perfusion.
o Antiplatelet therapy
§ Long-term soluble aspirin (75 mg daily) reduces
substantially the incidence of further infarction following
thromboembolic TIA or stroke. (MCQ)
§ Aspirin inhibits cyclo-oxygenase, which converts arachidonic
acid to prostaglandins and thromboxanes; predominant
therapeutic effects are reduction of platelet aggregation.
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§ Clopidogrel and dipyridamole are also used (MCQ)


§ Combined aspirin 75 mg daily and dipyridamole 200 mg
twice daily possibly provide optimal prophylaxis against
further thromboembolic stroke or TIA. (MCQ)
o Anticoagulants
§ Heparin and warfarin should be given when there is atrial
fibrillation, other paroxysmal dysrhythmias or when there are
cardiac valve lesions (uninfected) or cardiomyopathies.
§ Brain haemorrhage must be excluded by CT/MRI.
§ Anticoagulants are potentially dangerous in the two weeks
following infarction because of the risk of provoking cerebral
haemorrhage
o Statin therapy should be given for all.
§ Surgical approaches
o Internal carotid endarterectomy
§ Surgery is usually recommended in TIA or stroke patients with
internal carotid artery stenosis > 70%. (MCQ)
§ Successful surgery reduces the risk of further TIA/stroke by
around 75%. (MCQ)
§ Endarterectomy has a mortality around 3%, and a similar risk of
stroke.
o Percutaneous transluminal angioplasty (stenting) is an alternative
§ Intracranial haemorrhage
o This comprises:
§ intracerebral and cerebellar haemorrhage
§ subarachnoid haemorrhage
§ subdural and extradural haemorrhage/haematoma.
o Intracerebral haemorrhage
§ Aetiology
• Intracerebral haemorrhage causes approximately 10% of
strokes. (MCQ)
• Rupture of microaneurysms ( Charcot–Bouchard
aneurysms, 0.8–1.0 mm diameter) and degeneration of
small deep penetrating arteries are the principal
pathology. (MCQ)
• Such haemorrhage is usually massive, often fatal, and
occurs in chronic hypertension and at well-defined sites –
basal ganglia, pons, cerebellum and subcortical
white matter.
• In normotensive patients, particularly over 60 years,
lobar intracerebral haemorrhage occurs in the frontal,
temporal, parietal or occipital cortex. Cerebral
amyloid angiopathy (rare) is the cause in some of these
haemorrhages
• Tendency to rebleed is associated with particular
apolipoprotein E genotypes. (MCQ)
§ Recognition
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§ Intracerebral haemorrhage tends to be dramatic with


severe headache.
§ It is more likely to lead to coma than
thromboembolism.
§ Brain haemorrhage is seen on CT imaging immediately as
intraparenchymal, intraventricular or subarachnoid blood.
§ Routine MRI may not identify an acute small
haemorrhage correctly in the first few hours but MRI
diffusion weighted (MRI DW) is as good as CT. (MCQ)
§ Cerebellar haemorrhage
§ There is headache, often followed by stupor/coma and
signs of cerebellar/brainstem origin (e.g. nystagmus,
ocular palsies).
§ Gaze deviates towards the haemorrhage.
§ Skew deviation may develop. (MCQ)
§ Management: haemorrhagic stroke
§ The immediate prognosis is less good.
§ Antiplatelet drugs and, of course, anticoagulants are
contraindicated.. (MCQ)
§ Urgent neurosurgical clot evacuation is occasionally
necessary when there is deepening coma and coning (par-
ticularly in cerebellar haemorrhage).
§ Cerebellar haemorrhage sometimes causes acute
hydrocephalus, a potential surgical emergency.
o Subdural haematoma (SDH)
§ SDH means accumulation of blood in the subdural space
following rupture of a vein. (MCQ)
§ This usually follows a head injury, sometimes trivial.
§ The interval between injury and symptoms can be days, or
extend to weeks or months.
§ Chronic, apparently spontaneous SDH is common in the
elderly, and also occurs with anticoagulants.
§ Headache, drowsiness and confusion are common; symptoms
are indolent and can fluctuate.
§ Focal deficits, e.g. hemiparesis or sensory loss, develop.
§ Epilepsy occasionally occurs.
§ Stupor, coma and coning may follow .
§ Subdural bleeding usually needs less immediate attention but
close neurosurgical liaison is necessary. Even large collections
can resolve spontaneously without drainage. (MCQ)
o Extradural haemorrhage (EDH)
§ EDH typically follows a linear skull vault fracture tearing a branch
of the middle meningeal artery. (MCQ)
§ Extradural blood accumulates rapidly over minutes or hours.
§ A characteristic picture is of a head injury with a brief duration of
uncon- sciousness, followed by improvement (the lucid interval).

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§ The patient then becomes stuporose, with an ipsilateral dilated


pupil and contralateral hemiparesis, with rapid transtentorial
coning. (MCQ)
§ Bilateral fixed dilated pupils, tetraplegia and respiratory arrest
follow(MCQ)
§ Management
o CT is the most widely used investiga- tion because of its
immediate availability.
o MRI is more sensitive for the detection of small haematomas.
o T1 weighted MRI shows bright images due to the presence
of methaemoglobin.
o EDHs require urgent neurosurgery: if it is performed early,
the outlook is excellent. (MCQ)
o When far from a neurosurgeon, e.g. in wartime or at sea,
drainage through skull burr-holes has been lifesaving when
an EDH has been diagnosed clinically. (MCQ)
o Cortical venous thrombosis and dural venous sinus thrombosis
§ Intracranial venous thromboses are usually (>50%) associated with
a pro-thrombotic risk factor, e.g. oral contraceptives, pregnancy,
genetic or acquired pro-thrombotic states and dehydration.
(MCQ)
§ Head injury is also a cause.
§ Infection, e.g. from a paranasal sinus, may be present.
§ Venous thromboses can also arise spontaneously.
§ Cortical venous thrombosis
o The venous infarct leads to headache, focal signs (e.g.
hemi- paresis) and/or epilepsy, often with fever. (MCQ)
§ Dural venous sinus thromboses
o Cavernous sinus thrombosis causes ocular pain, fever,
proptosis and chemosis. (MCQ)
§ External and internal ophthalmoplegia with
papilloedema develops.
o Sagittal and lateral sinus thrombosis cause raised intra-
cranial pressure with headache, fever, papilloedema and often
epilepsy.
§ Management
o MRI, MRA and MR venography (MRV) show occluded
sinuses and/or veins. Treatment is with heparin initially,
though its value is questioned, followed by warfarin for 6
months.
o Clinical Pearls :
§ Middle cerebral artery Stroke (MCQ)
o Contralateral hemiparesis (face and hand more affected)
o Contralateral hemisensory deficit
o Homonymous hemianopsia opposite to occluded artery
o blindness affecting the right or the left half of the visual fields of both
eyes MCQ)
o If dominant MCA affected (left side in 92–94% of people),
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o patient will be aphasic MCQ)


o If nondominant MCA affected, MCQ)
§ confusion, constructional apraxia
§ contralateral body neglect
§ Anterior cerebral
o Contralateral weakness of leg or foot
o Broca’s aphasia MCQ)
o Incontinence
o Abulia (lack ofmotivation) MCQ)
§ Internal carotid
o Presentation similar to MCA occlusion
§ Posterior cerebral artery
o Homonymous hemianopsia of contralateral visual field
o Pupillary reflexes spared (occipital cortex) MCQ)
o Other visual field defects including vertical gaze and oculomotor
nerve palsy MCQ)
o If dominant hemisphere affected, anomia (difficulty naming
objects) or alexia (inability to read) may occur MCQ)
§ Posterior inferior cerebellar artery stroke
o Lateral medullary (Wallenberg’s) syndrome
o Sudden onset of: Nausea/vomiting
o Vertigo
o Hoarseness
o Ataxia
o Ipsilateral palate and tongue weakness MCQ)
o Contralateral disturbance of pain and temperature sensation MCQ)
o Dysphagia, dysarthria, and hiccup
o Ipsilateral Horner’s syndrome (ptosis, miosis, hemianhidrosis, and
apparent enophthalmos) MCQ)
o Motor system typically spared MCQ)
§ Anterior inferior cerebellar artery stroke
o Infarction of lateral portion of pons
o Ipsilateral facial weakness
o Gaze palsy MCQ)
o Deafness Tinnitus
o No Horner’s syndrome, dysphagia, or dysarthria MCQ)

§ Lacunar

o Lenticulostriate branches of the middle cerebral artery (midbrain)


become occluded as a result of chronic hypertension.

o Symptoms may present gradually over several days

o CT or MRI may not detect stroke

o 4 Lacunar Presentations: MCQ)

o Pure motor hemiparesis: Affecting face, arm, leg without


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other disturbances

o Pure sensory stroke: Hemisensory loss

o Ataxic hemiparesis:

§ Pure motor hemiparesis combined with ataxia

o Clumsy hand dysarthria:

§ Dysarthria, dysphagia, facial weakness, and


weakness/clumsiness 
of contralateral hand

§ Thrombotic strokes often show relatively slow progressive onset, often during
sleep. MCQ)
§ Embolic strokes present suddenly, often in discrete steps (“stuttering on- set”), most
often during waking hours. MCQ)
§ Hemorrhagic strokes evolve over minutes, invariably during waking hours.
MCQ)
§ Twenty percent of stroke patients have a history of at least one TIA.

§ TIAs preceding thrombotic strokes tend to present with similar symptoms


because the transient ischemia is locked to the distribution of the stenotic artery.

o Conversely, TIAs preceding embolic strokes tend to have more variable


presentation. MCQ)

§ Ischemic Stroke Management


o Treat sBP > 220, dBP > 110, or mean arterial pressure (MAP) >
130. MCQ)
o Start with labetalol 10 mg IV .
o Do not decrease the MAP more than 20%.
o For patients who present within 3 hours of symptom onset, IV t-PA
is an FDA-approved option, currently considered standard of care.

o Patients must have a moderate-sized stroke and have no


contraindications to thrombolytic therapy.

o Anticoagulation is not indicated acutely; there is little evidence to


sup- port its use in any given case, although you will still see it being
used. MCQ)
o Often reserved for refractory cases and posterior circulation
stroke.
o Aspirin or other antiplatelet agent both acutely and once daily
following hospital discharge MCQ)

§ Hemorrhagic Stroke Management


o Elevate head of the bed 30 degrees.
o Provide a quiet environment, analgesia, and sedation as needed.

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o Treat elevated intracranial pressure with hyperventilation, hyperosmolar


agents (mannitol, glycerol), and steroids as needed.
o Prevent straining (Valsalva) with antitussives and stool softeners as
needed.
o Nimodipine 60 mg for subarachnoid hemorrhage (to reduce
vasospasm) MCQ)
o BP control (more important in hemorrhagic than ischemic stroke)
MCQ)

Topic - Epilepsy

§ Seizure’ means a convulsion or other transient event caused by a paroxysmal


discharge of cerebral neurones.
§ Epilepsy is the continuing tendency to have seizures, even if a long interval
separates attacks.
§ A generalized convulsion (grand mal fit) is the most common recognized
event.
§ Mechanisms and definitions
o Spread of electrical activity between neurones is normally restricted and
synchronous discharge of neurones takes place in confined groups,
producing normal EEG rhythms.
o During a seizure, large groups of neurones are activated repetitively,
unrestrictedly and hypersynchronously; synaptic inhibition between
them fails.
o High-voltage spike-and-wave activity is the result, epilepsy’s EEG
hallmark.
o A partial seizure is epileptic activity confined to one area of cortex with
a recognizable clinical pattern.
§ This activity either remains focal or spreads to generate
epileptic activity in both hemispheres and thus a generalized
seizure. This spread is called secondary generalization.
§ An apparent generalized tonic–clonic seizure may either have
started as a focal seizure or be a primary generalized
convulsion
o Aura means a stereotyped perception caused by initial focal electrical
events before a partial seizure, such as a smell, tingling in one limb, or
strange recognizable inner feelings.

Classification

----------------------------------

International League against Epilepsy

1. Generalized seizure types

A Absence seizures

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(a) Typical absences with 3 Hz spike-and-wave discharge (petit mal)

(b) Atypical absences with other EEG changes

B Generalized tonic–clonic seizures (grand mal)

C Myoclonic seizures

D Tonic seizures

E Akinetic seizures

2. Partial seizure types

These start by neurone activation in one part of one hemisphere (focal seizures)

A Simple partial seizures (without impaired awareness,

e.g. Jacksonian seizures)

B Complex partial seizures (with impaired awareness)

C Partial seizures evolving to tonic–clonic seizures

D Apparent generalized tonic–clonic seizures, with EEG

but not clinical evidence of focal onset

3. Unclassifiable seizures

Seizures that do not fit a category above

Generalized means bilateral abnormal electrical activity, with bilateral motor manifestations and
impaired consciousness.

§ A partial (focal) seizure means the electrical abnormality is localized to one part
of the brain:
o simple – without loss of awareness, e.g. one limb jerking ( Jacksonian
seizure)
o complex – with loss of awareness , e.g. a temporal
§ Generalized seizure types
o Typical absence seizures (petit mal)
§ This generalized epilepsy almost invariably begins in
childhood.
§ Each attack is accompanied by 3 Hz spike-and-wave EEG
activity
§ Activity ceases, the patient stares and pales slightly for a few
seconds.
§ The eyelids twitch; a few muscle jerks may occur.
§ After an attack, normal activity is resumed.

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§ Typical absence attacks are never due to acquired lesions such as


tumours. They are a developmental abnormality of neuronal
control.
§ Children with petit mal attacks tend to develop generalized
tonic–clonic sei- zures in adult life (known as primary
generalized epilepsy).
o Petit mal describes these 3 Hz absence seizures only; clinically similar
episodes can also be produced by temporal lobe foci (partial
seizures), a source of confusion.
o Generalized tonic–clonic seizures (GTCS, grand mal seizures)
§ Following a vague warning, the tonic phase commences.
§ The body becomes rigid, for up to a minute.
§ The patient utters a cry and falls, sometimes suffering serious
injury.
§ The tongue is usually bitten.
§ There may be incontinence of urine or faeces.
§ The clonic phase then begins, with generalized convulsing,
frothing at the mouth and bilateral, rhythmic jerking of
muscles. This lasts from a few seconds to several minutes.
§ Seizures are usually self-limiting, followed by drowsiness,
confusion or coma for several hours.
o Myoclonic, tonic and akinetic seizures
§ Myoclonic seizures describe isolated muscle jerking.
§ Juvenile myoclonic epilepsy is one variety, seen in adolescence.
§ Tonic means intense stiffening of the body, not followed by
jerking. Akinetic means cessation of movement, falling and loss
of consciousness.
o Partial seizure types
§ Simple partial seizures
§ One example is a focal motor seizure (Jacksonian).
§ These simple partial seizures originate within the motor cortex.
§ Jerking typically begins on one side of the mouth or in one
hand, sometimes spreading to involve the entire side. This
visible spread of activity is called the march of a seizure.
§ With a frontal lesion, conjugate gaze deviates away from the
epileptic focus and the head turns; this is known as an adversive
seizure.
§ Local temporary paralysis of the limbs affected sometimes
follows – Todd’s paralysis.
o Temporal lobe seizures
§ These partial seizures, either simple or complex, can produce
feelings of unreality (jamais vu) or undue familiarity (de ́jà
vu) with the surroundings. Blank episodes of staring, vertigo,
visual hallucinations (i.e. visions or faces) are other examples of
temporal lobe seizures.

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§ Many other types of partial seizure occur: panic attacks with


overbreathing (temporal), strange smells (frontal), sensory
disturbances (parietal) and crude visual shapes (occipital) .
Aetiology and precipitants

§ Epilepsy: aetiological factors


o Genetic predisposition
o Developmental, e.g. hamartomas, neuronal migration abnormalities
o Hippocampal sclerosis
o Brain trauma and surgery
o Pyrexia
o Intracranial mass lesions, e.g. tumour, neurocysticercosis Vascular, e.g.
cerebral infarction, A VM
o Encephalitis and inflammatory conditions, e.g. herpes simplex, MS
o Metabolic abnormalities, e.g. porphyria, hypocalcaemia
o Neural degenerative disorders, e.g. Alzheimer’s
o Provoked seizures, e.g. photosensitivity, sleep deprivation
o Drugs, e.g. ciclosporin, lidocaine, quinolones, SSRIs, interferons,
cocaine, lithium, withdrawal of amfetamines, barbiturates
o Alcohol withdrawal
§ Hippocampal sclerosis is a cause of symptomatic epilepsy (resection may be
possible)
§ About 30% of epilepsy patients have first-degree relatives with seizures.
§ Hydrocephalus also lowers seizure threshold.
§ Epilepsy is three times commoner in MS patients than in the general
population.
§ Phenothiazines, monoamine oxidase inhibitors, tricyclic antidepressants,
SSRIs, amfetamines, lidocaine, propofol and nalidixic acid sometimes
provoke fits
§ Withdrawal of antiepileptic drugs (especially phenobarbital) and
benzodiazepines may provoke seizures.
§ Seizures can follow:
o hypocalcaemia, hypoglycaemia, hyponatraemia
o acute hypoxia
o uraemia, hepatocellular failure
o mitochondrial disease, porphyria.
§ Provoked seizures: photosensitivity, pyrexia
§ Seizures are occasionally precipitated by flashing lights or a flickering television
screen.
§ High pyrexia can provoke convulsions in children under 5 years (febrile
convulsions). In most, there is no recurrence; febrile convulsions are not
labelled as epilepsy.
§ A convulsion sometimes follows missing a night’s sleep in a susceptible
person.
Diagnosis

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o EEG evidence of seizure activity is shown typically by focal cortical


spikes (e.g. over a temporal lobe) or by generalized spike-and-wave
activity.
o 3 Hz spike-and-wave occurs specifically in petit mal always during an attack
and frequently in between them.
o A normal EEG between attacks (interictal) does not exclude epilepsy;
many people with epilepsy have normal interictal EEGs.
o An abnormal interictal EEG does not prove that a particular attack was
epileptic.
Treatment

§ Emergency measures
§ A prolonged seizure (longer than 3 minutes) or repeated seizures are
treated with rectal (10 mg) or i.v . diazepam or midazolam.
§ If there is any suspicion of hypoglycaemia , take blood for glucose and give
i.v . glucose.
§ Status epilepticus
o This medical emergency means continuous seizures without recovery
of consciousne ss.
o Status epilepticus has a mortality of 10–15 %.
o 25% of apparent status turns out to be pseudostatus
o Not all status is convulsive. In absence status, for example, status is
non-convulsive – the patient is in a continuous, distant, stuporose state.
o Focal status also occurs.
o Epilepsia partialis continua is continuous seizure activity in one part
of the body , such as a finger or a limb, without loss of consciousness .
This is often due to a cortical neoplasm or, in the elderly, a cortical
infarct.
§ Status epilepticus – management

o At home, give immediate diazepam 10–20 mg i.v . at 5 mg/ min and


repeat once. If i.v . access is impossible, give rectal diazepam or
paraldehyde
o Give thiamin i.v. (250 mg) if nutrition is poor or alcohol abuse
suspected.
o Antiepileptic drugs (AEDs):
§ Give lorazepam i.v . 4 mg at 2 mg/min
§ Reinstate previous AEDs. Measure levels urgently. Has the
patient had phenytoin recently?
§ If status continues, i.v . phenytoin or fosphenytoin is used
• Phenytoin: give 15 mg/kg i.v . diluted to 10 mg/mL in
0.9% saline into a large vein at < 50 mg/min (Phenytoin
250 mg 5 mL ampoule)
• Fosphenytoin: this is a pro-drug of phenytoin and can be
given faster than phenytoin.
o Doses are expressed in phenytoin equivalents
(PE): fosphenytoin 1.5 mg =1 mg phenytoin

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o Give 15 mg/kg (PE) fosphenytoin (15 mg .1.5


=22.5 mg) diluted to 10 mg/mL in 0.9% saline
at 50– 100 mg (PE)/min (Fosphenytoin sodium
750 mg 10 mL ampoule)
§ If status continues, give phenobarbital 10 mg/kg diluted 1 in
10 in water for injection at <100 mg/min. (Phenobarbital 200
mg/mL 1 mL vial in propylene glycol 90% with water for
injection 10%.)
§ Intravenous clonazepam, paraldehyde and clomethiazole are
also used
§ If status persists >90 minutes, use thiopental or propofol
anaesthesia with assisted ventilation
§ Antiepileptic drugs (AEDs)
o For both partial and generalized seizures, monotherapy with an
established first-line AED is the initial choice

Principal antiepileptic drugs and common sezure types


Generalized tonic- Petit mal Myoclonic Atypical
clonic seizures absence, tonic
(grand mal) and and akinetic
partial
First-line Carbamazepine Ethosuximide Valproate Valproate
Lamotrigine Valproate Clonazepam Lamotrigine
Phenytoin Lamotrigine Clonazepam
Valproate
Second-line Phenobarbital Clobazam Clobazam Topiramate
and/or add-ons Primidone Clonazepam Levetiracetam Clobazam
Levetiracetam Topiramate Topiramate Levetiracetam
Topiramate Newer Lamotrigine Phenobarbital
drugs (Table 21.35) Acetazolamide
May worsen Carbamazepine Carbamazepine
attacks Phenytoin Phenytoin
o Doses should start low and be increased until control is achieved or
tolerance exceeded. If control is not achieved, a second drug is added.
o Intoxication with all AEDs causes ataxia, nystagmus and dysarthria .
Chronic phenytoin causes gum hypertrophy, hypertrichosis,
osteomalacia, folate defi- ciency, polyneuropathy and
encephalopathy.
o Majority of severe skin reactions (e.g. toxic epi- dermal necrolysis)
following phenytoin, carbamazepine, valproate (and phenobarbital) occur
within the first 8 weeks of treatment .
o Vigabatrin can cause irreversible visual field defects and is no longer
advocated.
o Contraception.
o AEDs that induce enzymes (e.g. carbamazepine, phenytoin and
phenobarbital) reduce efficacy of oral contraceptives; valproate
does not.

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o A combined contraceptive pill containing either ethinylestradiol 50


g or mestranol 50 g g provides greater contraceptive security at
the risk of side-effects.
o An IUCD or barrier methods of contraception are an alternative.
o Women, epilepsy, pregnancy and AEDs
o There is some reduction of fertility in women with epilepsy.
o irregular menstrual cycles, anovulatory cycles and polycystic
ovaries. are possibly more frequent in patients taking valproate.
o The overall risk of birth defect s in babies of mothers who take
one AED is around 7%, higher than the 3% in the population.
o If drugs are continued, monotherapy with a first-line drug is
preferable with folic acid (5 mg/day) supple- ment. Careful
antenatal screening is required.
o Vitamin K 20 mg orally should also be taken daily during the
week before delivery to prevent neonatal haemorrhage (caused by
inhibition of vitamin K transplacental transport).
o Drug withdrawal
o Withdrawal should not usually be considered until all fits have
been absent for at least 2–3 years.
o Neurosurgical treatment
o Amputation of the non-dominant anterior temporal lobe can
be performed in a patient with uncontrolled seizures and
hippocampal sclerosis defined by imaging and confirmed by
EEG.

Antiepileptic drugs: some idiosyncratic unwanted effects

Drug Non-dose-related effects


Phenytoin Rashes
Blood dyscrasias
Lymphadenopathy
Systemic lupus erythematosus
Toxic epidermal necrolysis
Carbamazepine Rashes
Blood dyscrasias, e.g. servere leucopenia
Toxic epidermal necrolysis
Valproate Anorexia
Hair loss
Liver damage
Lamotrigine Toxic epidermal necrolysis

Topic – Subarachnoid haemorrhage

Subarachnoid haemorrhage (SAH)

§ SAH means spontaneous arterial bleeding into the subarachnoid space ,


§ Causes
§ Underlying causes of subarachnoid haemorrhage
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o Saccular (berry) aneurysms 70%


o Arteriovenous malformation (A VM) 10%
o No arterial lesion found 15%
§ Rare associations (<5%)
o Bleeding disorders
o Mycotic aneurysms – endocarditis
o Acute bacterial meningitis
o Tumours, e.g. metastatic melanoma,
o oligodendroglioma
o Arteritis (e.g. SLE)
o Spinal A VM →spinal SAH
o Coarctation of the aorta
o Marfan’s, Ehlers–Danlos syndrome
o Polycystic kidneys
§ Saccular (berry) aneurysms
o Saccular aneurysms develop within the circle of Willis and adjacent
arteries.
o Common sites are at arterial junctions:
o between posterior communicating and internal carotid artery –
posterior communicating artery aneurysm
o between anterior communicating and anterior cerebral artery –
anterior communicating and anterior cerebral artery aneurysm
o at the trifurcation or a bifurcation of the middle cerebral artery –
middle cerebral artery aneurysm.
o an enlarging unruptured posterior communicating artery aneurysm is
the commonest cause of a painful IIIrd nerve palsy

§ Arteriovenous malformation (AVM)


o A VMs are collections of arteries and veins of developmental origin .
o An A VM may also cause epilepsy, often focal.
o Once an A VM has ruptured, the tendency is to rebleed – 10% will then
do so annually.

§ Clinical features of subarachnoid haemorrhage


§ There is a sudden devastating headache, often occipital.
§ Headache is usually followed by vomiting and often by coma and death.
Survivors may remain comatose or drowsy for hours, days, or longer. SAH is
a possible diagnosis in any sudden headache .
§ Following major SAH there is neck stiffness and a positive Kernig’s sign.
Papilloedema is sometimes present, with retinal and/or subhyaloid
haemorrhage (tracking beneath the retinal hyaloid membrane).
§ Investigations
§ CT imaging is the immediate investigation needed
§ Lumbar puncture is not necessary if SAH is confirmed by CT, but should
be performed if doubt remains.
§ CSF becomes yellow (xanthochromic) several hours after SAH.

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§ Spectrophotometry to estimate bilirubin in the CSF released from


lysed cells is used to define SAH with certainty.
§ MR angiography is usually performed in all potentially fit for surgery, i.e.
generally below 65 years and awake.
§ In some, no aneurysm or source of bleeding is found, despite a definite
SAH.
§ Differential diagnosis
§ SAH must be differentiated from migraine.
§ Thunderclap headache is used to describe either SAH or a sudden (benign)
headache for which no cause is ever found.
§ Acute bacterial meningitis occasionally causes a very abrupt headache,
when a meningeal microabscess ruptures; SAH also occasionally occurs at the
onset of acute bacterial meningitis.
§ Cervical arterial dissection can present with a sudden headache.
§ Complications
§ Blood in the subarachnoid space can lead to obstructive hydrocephalus,
seen on CT.
§ Hydrocephalus can be asymptomatic but may cause deteriorating
consciousness following after SAH.
§ Shunting may be necessary.
§ Arterial spasm (visible on angiography and a cause of coma or
hemiparesis) is a serious complication of SAH and a poor prognostic
feature.
§ Management
§ Immediate treatment of SAH is bed rest and supportive measures.
Hypertension should be controlled.
§ Dexamethasone is often prescribed to reduce cerebral oedema; it also is
believed to stabilize the blood–brain barrier.
§ Nimodipine, a calcium-channel blocker, reduces mortality.
§ All SAH cases should be discussed urgently with a neu- rosurgical centre.
Nearly half of SAH cases are either dead or moribund before reaching
hospital.
§ Failure to diagnose SAH, e.g. mistaking SAH for migraine, contrib- utes to
this mortality.
§ Patients who remain comatose or who have persistent severe deficits
have a poor outlook.
§ In others, who are less impaired, and where angiography demonstrates
aneurysm, either a direct approach to clip the aneurysm neck or intravas-
cular coiling is carried out.
§ For A VMs, surgery, microembolism and focal radiotherapy (gamma
knife) are used, when appropriate.

Topic - Myasthenia Gravis

Myasthenia gravis (MG)

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• It is characterized by weakness and fatiguability of proximal limb, bulbar


and ocular muscles, the latter sometimes in isolation.
• The heart is not affected.
• MG is twice as common in women as in men, with a peak age incidence around
30.
• The underlying cause is unknown.
• Antibodies to acetylcholine receptor protein (anti-AChR antibodies) are
commonly found.
• A second group of antibodies against muscle-specific receptor tyrosine kinase
(anti-MuSK antibodies) has more recently been identified in anti-AChR
antibody negative cases.
• Ocular muscle MG is another subgroup.
• Thymic hyperplasia is found in 70% of MG patients below the age of 40.
o In some 10% a thymic tumour is found, the incidence increasing
with age antibodies to striated muscle can be demonstrated in some
of these patients.
o Young patients without a thymoma have an increased association with
HLA-B8 and DR3.
• There is an association between MG and thyroid disease, rheumatoid disease,
pernicious anaemia and SLE.
• Transient MG is sometimes caused by d-penicillamine treatment.
• Clinical features
o Fatiguability is typical.
o Limb muscles (proximal), extraocular, speech, facial expression
and mastication muscles are commonly affected.
o Respiratory difficulties can be prominent.
o The clinical picture of fluctuating, fatiguable weakness is usually
diagnostic. Muscle pain is typically absent.
o Complex extraocular palsies, ptosis and fluctuating proximal
weakness are found.
o The reflexes are initially preserved but may be fatiguable, i.e. disappear
following repetitive activity.
o Wasting is sometimes seen after many years.
• Investigations
o Serum anti-AChR and anti-MuSK antibodies.
§ Anti-AChR antibodies are present in some 80–90% of cases of
generalized MG.
§ In pure ocular MG, anti-AChR antibodies are detectable in less
than 30% of cases.
§ Anti-MuSK antibodies define a subgroup of MG patients
characterized by weakness predominantly in bulbar, facial
and neck muscles.
o Repetitive nerve stimulation.
§ A characteristic decrement occurs in the evoked muscle
action potential during repetitive stimulation.
o Tensilon (edrophonium) test.

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§Edrophonium 10 mg is given intravenously following a 1–2 mg


test dose from the 10 mg vial.
§ When the test is positive, there is substantial improvement in
weakness within seconds and this lasts for up to 5 minutes.
§ The sensitivity of the test is 80% but there are false negative and
positive tests.
§ Occasionally edrophonium (an anticholinesterase) causes
bronchospasm and syncope.
§ Course and management
o Exacerbations may be brought on by infections and by
aminoglycosides.
o Magnesium sulphate enemas can provoke severe weakness.
§ Treatment
o Oral anticholinesterases
§ Pyridostigmine (60 mg tablet) is widely used.
• The duration of action is 3–4 hours
• Pyridostigmine prolongs acetylcholine action by
inhibiting cholinesterase.
§ Overdose of anticholinesterases causes severe weakness
(cholinergic crisis).
§ Muscarinic side-effects, e.g. colic and diarrhoea, are
common; oral atropine (antimuscarinic) 0.5 mg helps reduce
this.
§ Anticholinesterases help weakness but do not alter the
natural history of myasthenia.
o Immunosuppressant drugs
§ These drugs are used in patients who do not respond to
pyridostigmine or who relapse on treatment.
§ Steroids are often used.
§ Azathioprine, mycophenolate are also used.
o Thymectomy
§ Thymectomy improves prognosis, more so in women than
men below 50 years with positive AchR antibodies, even in
patients without a thymoma.
§ Cases positive for anti-MuSK antibodies tend not to
improve following thymectomy.
§ When a thymoma is present, the potential for malignancy
also makes surgery necessary.
o Plasmapheresis and intravenous immunoglobulin
§ During exacerbations these interventions are of value.

Lambert–Eaton myasthenic– myopathic syndrome (LEMS)

§ This paraneoplastic manifestation of small-cell bronchial carcinoma


§ It is due to defective acetylcholine release at the neuromuscular junction.
Proximal limb muscle weakness, sometimes with ocular/bulbar muscles
develops, with some absent tendon reflexes, a cardinal sign.
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§ Weakness tends to improve after a few minutes of muscular contraction ,


and absent reflexes return (cf. myasthenia).
§ Diagnosis is con-firmed by EMG and repetitive stimulation (increment).
Antibodies to P/Q-type voltage-gated calcium channels are found in
most cases (90%).
§ 3,4-Diaminopyridine (DAP) is a reasonably safe and sometimes effective
treatment.

Topic - Parkinson’s disease

Idiopathic Parkinson’s disease

§ MPTP . Minute doses of a pyridine compound, methylphen-


yltetrahydropyridine (MPTP), a byproduct of illicit stimulant drug production,
cause severe parkinsonism.
§ Genetic factors.
§ Mutations in the parkin gene on chromosome 6 have been found in
families with autosomal recessive cases of PD and some young apparently
sporadic cases.
§ Parkin mutations probably account for most PD cases with onset below
the age of 40.

§ Pathology
o In idiopathic PD, the pars compacta of the substantia nigra undergoes
progressive neuronal degeneration
o eosinophilic inclusion bodies (Lewy bodies) develop.
o These contain protein filaments of ubiquitin and synuclein.
o There is loss of dopamine (and melanin) in the striatum .
§ Symptoms and signs
o The combination of tremor, rigidity and akinesia develops slowly, over
months or several years, together with changes in posture.
o Common initial symptoms are tremor and slowness.
o Limbs and joints feel stiff; they ache.
o Fine movements become difficult.
o Slowness causes difficulty rising from a chair or getting into or out of
bed. Writing becomes small (micrographia) and spidery, tending to
tail off. impassive face.
o Idiopathic PD is almost always initially more prominent on one side.
o Tremor
o The characteristic 4–7 Hz pill-rolling tremor at rest
(movements between thumb and forefinger) typically decreases
with action.
o Rigidity
o Stiffness develops throughout movements and is equal in
opposing muscle groups, in contrast to the selective increase in limb
tone found in spasticity.

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o This lead pipe-like increase in tone (plastic rigidity) is usually


more marked on one side and present in the neck and axial
muscles.
o Plastic rigidity is more easily felt when a joint is moved slowly and
gently; tone increases when the opposite arm moves actively.
o When stiffness occurs with tremor, smooth lead pipe rigidity is
broken up into a jerky resistance to passive movement –
cogwheeling (cogging).
o Akinesia
o Poverty/slowing of movement ( bradykinesia) is an additional
handicap, distinct from rigidity.
o There is difficulty initiating movement.
o Rapid fine finger movements, such as piano- playing, become
indistinct, slow and tremulous.
o Facial immobility gives a mask-like semblance of depression.
o Frequency of spontaneous blinking diminishes, producing a
serpentine stare.
o Postural and gait changes
o Stooping is characteristic.
o Gait becomes hurrying (festinant) and shuffling with poor
arm swinging. The posture is some- times called simian to
describe the ape-like forward flexion, immobility and lack of
animation.
o Balance deteriorates, but despite this the gait retains a narrow
base.
o Falls, toppling like a falling tree, are common in later stages.
o Speech
o Pronunciation is initially a monotone and progresses to
tremulous slurring dysarthria, the result of akinesia, tremor
and rigidity.
o Eventually, speech may be lost (anarthria).
o Cognitive changes
o Cognitive decline may occur early in the condition and is
rarely absent in advanced disease.
o Depression is common.
o Gastrointestinal and other symptoms
o These include constipation, sometimes an early symptom,
heartburn, dribbling, dysphagia and weight loss .
o Urinary difficulties are common, especially in men.
o Skin is greasy and sweating excessive.
§ Natural history and other features
o PD worsens over the years
o Remissions are unknown except for rare, remarkable short-lived periods
of release .
o These can occur at times of emotion, fear or excitement, when the sufferer
is released for seconds or minutes and able to move quickly.
o While bradykinesia and tremor worsen, power remains normal until
immobility makes its assessment difficult.
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Patients often complain bitterly of limb and joint discomfort.


o
There is no sensory loss.
o
The reflexes are brisk; their asymmetry follows the increase in tone.
o
The plantar responses remain flexor.
o
o Usually the course is over 10–15 years, with death resulting from
bronchopneumonia with immobility and cognitive impairment.
o Diagnosis
o Other diffuse and multifocal brain diseases can cause features of
parkinsonism, i.e. slowing, rigidity and tremor seen in idiopathic PD.
Examples are Alzheimer’s disease, multi-infarct dementia, sequelae of repeated head
injury , and late effects of severe hypoxia or CO poisoning .
o Slowing also occurs in hypothyroidism, and in depression.
§ Treatment
o While drugs alter little, if at all, the natural history of PD,
o levodopa and/or dopaminergic agonists produce striking initial
improvement.
o antimuscarinics, e.g. trihexyphenidyl (benzhexol) remain of some value in
severe tremor.
o Levodopa
o Levodopa is combined with an aromatic amino acid decarboxylase
inhibitor – benserazide or carbidopa (
o The decarboxylase inhibitor reduces peripheral side-effects, principally
nausea, of levodopa and its metabolites.
o Levodopa treatment is commenced and gradually increased.
o Unwanted effects of levodopa therapy
§ Nausea and vomiting are the most common immediate
symptoms of excess levodopa.
§ Confusion, formed visual pseudo-hallucinations and chorea
also occur. There are difficult issues with long-term therapy (e.g.
levodopa-induced involuntary movements).
§ After several years levodopa gradually becomes ineffective,
even with increasing doses. As treatment continues, episodes of
immobility develop (freezing). Falls are common.
§ Fluctuation in response to levodopa also emerges, its effect
turning on and off , to cause freezing alternating with dopa-
induced dyskinesias, chorea and dys- tonic movements.
§ Levodopa’s duration of action shrinks, with dyskinesias
becoming prominent several hours after a dose (end-of-dose
dyskinesia).
§ The patient begins to suffer from a chronic levodopa-induced
movement disorder.
§ Levodopa does not alter the natural progression of PD.
o Approaches to treatment of these complications include:
§ Shortening the interval between levodopa doses and increasing
each dose.
§ Monoamine oxidase B inhibitors inhibit catabolism of
dopamine in the brain. They are used to smooth out the end-of-
dose fluctuations with levodopa.
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§ Dopaminergic agonists are added, or replace levodopa.


§ Catechol-O-methyl transferase (COMT) inhibitors
(entacapone and tolcapone) prevent the peripheral breakdown of
levodopa, allowing lower doses to be used.
§ Apomorphine by subcutaneous pump.
§ Dopamine receptor agonists
§ Bromocriptine, pergolide, cabergoline (all ergot derivatives),
pramipexole, ropinirole and rotigotine are oral, directly acting
dopamine receptor agonists, acting principally on D1 and D2 receptors,
and also on receptors D3–5.
§ Of these, ropinirole is the usual drug of choice , as an alternative or an
addition to levodopa therapy.
§ The ergot derivatives are associated with pulmonary, retroperitoneal
and pericardial fibrotic reactions and are little used.
§ Dopamine receptor agonists are in general less effective than levodopa
in treating symptoms, but cause fewer late unwanted dyskinesias.
§ What is the drug of choice
o The trend is towards the use of receptor agonists as primary treatment
(before levodopa) in cases below 65, and levodopa initially for older
cases.
§ Apomorphine, a potent D1 and D2 agonist, given by sub- cutaneous
metered infusion, is one method of attempting to smooth out fluctuations
in response to levodopa.
o Vomiting is common.
o Haemolytic anaemia is an unusual side-effect.
§ Antioxidant compounds such as vitamins C and E as possi- ble
neuroprotective agents are sometimes suggested; their role is uncertain and
evidence of benefit is poor.
§ Amantadine, originally marketed as an antiviral drug, occasionally has a
modest effect in PD.
§ Rasagiline and rivastigmine may help cognitive changes and possibly the
movement disorder.
§ Stereotactic neurosurgery
o Stereotactic lesions, usually unilateral in the ventrolateral nucleus of
the thalamus or in the globus pallidus (pallidotomy), were used
widely before levodopa.
o Surgery still provides effective, if temporary improvement in tremor and
dyskinesia with minor relief of bradykinesia .
o Thalamic stimulation is used increasingly, sometimes with dramatic
improvement.
§ Neuropsychiatric aspects
o Cognitive impairment and depression are common as PD progresses.
SSRIs are the drugs of choice for depression.
o Tricyclic antidepressants (e.g. amitriptyline) have extrapyra- midal
side-effects.
o Type A MAO inhibitors (e.g. phenelzine) are contraindicated with
levodopa.

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o All antiparkinsonian drugs can provoke visual hallucinations ,


especially at night, and exacerbate cognitive impairment.
§ Parkinsonism-plus
o This term describes disorders in which there is parkinsonism with
additional features and specific pathology.
o Progressive supranuclear palsy (Steele–Richardson–Olzewski
syndrome) is the commonest.
o It consists of parkinsonism, axial rigidity, falls, dementia and
inability to move the eyes vertically or laterally.
o multiple system atrophies (MSA), such as olivo-ponto-cerebellar
degeneration
o Pathologically MSA shows -synuclein positive glial cytoplasmic
inclusions
o striatonigral degeneration and primary autonomic failure ( Shy– Drager
syndrome).
o Drug-induced parkinsonism
o Phenothiazines and butyrophenones (also reserpine and methyldopa,
once used to treat hypertension) induce parkinsonism, usually with little
tremor.
o Tricyclic antidepressants also cause some slowing.

Topic- Multiple Sclerosis

MULTIPLE SCLEROSIS (MS)

§ MS is a chronic inflammatory disorder of the CNS.


§ There are multiple plaques of demyelination within the brain and spinal cord.
§ Plaques are disseminated both in time and place, hence the earlier name
‘disseminated sclerosis’.
§ Prevalence
o prevalence is directly proportional to distance of residence from the
equator.
o At the equator MS is a rarity.
§ Aetiology and pathogenesis
o there is an inflammatory process in the white matter of the brain and
cord mediated by CD4 T cells.
o In active lesions (plaques) there is an increase in inflammatory cells,
active myelin deg- radation and phagocytosis.
o Lymphocytes and monocytes gain access to the brain parenchyma from
the circulation by adhering to vascular endothelial cells via the
glycoprotein integrin expressed on their surface.
o This integrin (very late antigen VLA4) is also a regulator of immune cell
activation.

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o Antibodies against myelin oligodendrocyte glycoprotein (MOG), a


protein specific to the CNS, have also been found in vitro.
o Familial incidence, HLA linkage and migration
§ First-degree relatives of a patient have an increased chance of
developing MS,
o Infection
§ measles. scrapie , Chlamydia -implicated
§ Pathology
o Plaques of demyelination , initially 2–10 mm in size, are the
o cardinal features.
o Plaques are perivenular with a predilection for distinct CNS sites: optic
nerves, the periventricular region, the brainstem and its cerebellar connections and the
cervical cord (corticospinal tracts and posterior columns).
o Acute relapses are caused by focal inflammatory demyelination, which causes
conduction block. Remission follows as inflammation subsides and
remyelination occurs, helping recovery.
o When damage is severe, secondary permanent axonal destruction
occurs.
o In the cord, plaques rarely destroy large groups of anterior horn cells,
thus focal muscle wasting (e.g. small hand muscles) is unusual.
o Plaques are not seen in myelin sheaths of peripheral nerves .
§ Clinical features
o The commonest age of onset is between 20 and 45 years
o diagnosis before puberty or after 60 is rare.
o MS is more common in women.
o The Macdonald criteria (revised in 2005) provide a fairly sensitive
method which can be used for the diagnosis and use the clinical
presentation along with radiological findings.
o MS is often recognizable clinically by different patterns:
§ relapsing and remitting MS (80–90%)
§ primary progressive MS (10–20% )
§ secondary progressive MS – this follows on from
relapsing/remitting disease
§ occasionally (<10%) MS runs a fulminating course over some
months (fulminant MS).
§ Three characteristic common presentations of relapsing and remitting MS are
optic neuropathy, brainstem demyelination and spinal cord lesions,
§ Optic neuropathy (ON)
o Symptoms
§ Blurring of vision in one eye develops over hours or days
§ varying from a frosted glass effect to severe unilateral visual
loss
§ Mild ocular pain is usual.
§ Recovery occurs, typically within 2 months.
§ Bilateral ON can occur.
o Signs

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§ The optic disc appearance depends upon the site of the plaque
within the optic nerve. When the lesion is in the nerve head there
is disc swelling (optic neuritis)
§ If the lesion is several millimetres behind the disc there are no
ophthalmoscopic abnormalities – retrobulbar neuritis
§ Worsening of vision in ON during a fever, hot weather or after
exercise is known as Uthoff’s phenomenon – central
conduction is slowed by an increase in body temperature.
§ Disc swelling from optic neuritis causes early visual acuity loss, thus
distinguishing it from disc swelling from raised intracranial pressure.
§ A relative afferent pupillary defect is often found, and persists
after recovery.
§ Late sequelae of optic neuropathy
• There is often no residual loss of vision , but small
scotomata and defects in colour vision can be found.
• Following optic neuropathy, disc pallor can develop
(optic atrophy), first on the temporal side.
§ Visual evoked responses (VER) remain abnormal
§ Brainstem demyelination
o Acute MS in the brainstem causes combinations of diplopia, vertigo,
facial numbness/weakness, dysarthria or dysphagia.
o Pyramidal signs in the limbs occur when the corticospinal tracts are
involved.
o A typical picture is sudden diplopia, and vertigo with nystagmu s, but
without tinnitus or deafness. This lasts for some weeks before recovery.
Diplopia is produced by many lesions –
§ a VIth nerve lesion
§ internuclear oph- thalmoplegia (INO)
§ Spinal cord lesions
o Spastic paraparesis developing over days or weeks is a typical result of
a plaque in the cervical or thoracic cord , causing difficulty in walking and lower
limb numbness.
o Lhermitte’s sign may be present
o Urinary symptoms are common.
§ Unusual presentations
o Epilepsy and trigeminal neuralgia occur more com- monly in MS
patients than in the general population.
o Tonic spasms (brief spasms of one limb)
o Organic psychosis is occasionally seen in early MS.
§ End-stage multiple sclerosis
o Late MS causes severe disability with spastic tetraparesis, ataxia, optic atrophy,
nystagmus, brainstem signs (e.g. bilat- eral INO), pseudobulbar palsy and urinary
incontinence.
o Dementia is common.
o Death follows from uraemia and/or bronchopneumonia.
§ Investigations
§ MRI of brain and cord is the definitive structural investigation.

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o Multiple plaques are seen), principally in the periventricular region, corpus


callosum, cerebellar peduncles, juxtacortical posterior fossa, brainstem and cervical cord.
o Head MRI scans show lesions (elliptical in shape with discrete borders and
lack ofa mass effect ) in 85% of patients with clinical MS.
o Typical lesions are multifocal (2 mm to 2 cm), with 10 or more lesions.
o Gadolinium can enhance active lesions.
§ CSF analysis
o shows oligoclonal IgG bands in 80% of cases but these are not
specific.
o The CSF cell count may be raised (5–60 mononuclear cells/mm3).
§ Evoked responses.
o Delay in visual evoked responses (VER) is seen in optic neuropathy.
o Some ON attacks are subclinical: a delayed VER provides evidence of a
previous, silent optic nerve lesion. This is helpful for diagnosis if there
had been, for example, a previous apparently solitary cord lesion.
o Brainstem and somatosensory evoked potentials become delayed
when these pathways have been damaged.

§ Management and prognosis


o a florid MR lesion load at initial presentation is a strong predictor towards
serious disability.
o MS therapies
§ Acute relapses.
• Short courses of steroids, such as i.v .
methylprednisolone
§ Preventing relapse and disability.
• Beta-interferon (both INF-1b and 1a) by self-
administered injection is used in relapsing and remitting
disease.
o This is defined as at least two attacks of neurological
dysfunction over the previous 2 or 3 years followed by a
reasonable recovery.
• IFN-1b is also now licensed for secondary
progressive MS.
§ Interferon
• certainly reduces relapse rate in some patients and
prevents an increase in lesions seen on MRI.
• Unwanted effects are flu-like symptoms and irritation
at injection sites.
§ Immunosuppressants and antineoplastic drugs ( azathioprine,
cyclophosphamide, mitoxantrone and others) are also used
§ Glatiramer acetate,
• an immunomodulator
• reduce relapse frequency in ambulatory patients with relapsing
remitting MS – similar to beta-interferon.
§ Natalizumab
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• is a monoclonal antibody which inhibits migration of


leucocytes into the central nervous system
• has inhibitory  integrins found on the surface of
lymphocytes and monocytes.
• It is useful in severe, relapsing remitting MS that is
unresponsive to other treatments.
• It is associated with a risk of progressive multifocal
leucoencephalopathy (PML) and all patients need close
surveillance for this and hypersensitivity reactions.

Topic - Huntington’s Disease

Huntington’s disease

• autosomal dominant transmission, affecting both males and females


• usually starts in adult life.
• It is due to expansion of a tri- nucleotide CAG repeat in the Huntingtin gene on
chromosome 4
• The disease frequently demonstrates the phenomenon of anticipation , in
which there is a younger age at onset as the disease is inherited through generations , due to
progressive expansion of the repeat.
• Slightly different features of the disease occur, depending on whether the
abnormal gene is inherited from father or mother.
• Pathophysiology
o The disease is thought to be caused by accumulation of the abnormal
Huntingtin protein in neurons, leading to cellular dysfunction and
neuronal death.
• Clinical features
o Symptoms usually begin in middle adult life with the development of
chorea, which gradually worsens.
o This is accompanied by cognitive impairment which often manifests
initially as psychiatric symptoms, but later becomes frank dementia.
o In juvenile-onset disease, there may be parkinsonian features with
rigidity (the ‘Westphal variant’).
o Seizures may occur late in the disease.
• Investigations
o The diagnosis is made clinically
o Atrophy of the caudate nucleus on CT or MRI.
o Genetic testing can be used to confirm the diagnosis and provide pre-
symptomatic testing for other family members after appropriate
counselling
• Management
o The chorea may respond to tetrabenazine or dopamine antagonists
such as sulpiride.
o Depressive symptoms are common, and may be helped by
antidepressant medication.
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Topic- Guillain–Barré Syndrome

• Guillain–Barré Syndrome
• Syndrome of transient immune-mediated ascending paralysis usually
following a viral upper respiratory tract infection
• Etiology
o Most cases are preceded by a respiratory or GI infection.
o Campylobacter jejuni, HSV , CMV , EBV , and Mycoplasmahave all
been identified as potential causes. (MCQ)
o V accines have been implicated as a potential cause in the past (i.e .,
influenza, rabies vaccines). (MCQ)
• Pathophysiology
o An immune-mediated demyelination of axons/axonopathy can also
occur
• Signs and symptoms
o Initial symptoms include paresthesias in the feet (or arms) and leg
weakness, which progresses as an ascending motor paralysis, usually
over several days. (MCQ)
o Distal muscle weakness is common soon afterward—may last a few
weeks. (MCQ)
o Deep aching pain in back and legs
o Areflexia
o Tachypnea
o Quadriparesis
o Respiratory muscle paralysis occur in 30% of patients(MCQ)
§ one-third of patients will need mechanical ventilation.
§ can be fatal.
o Cranial nerves can be involved.
• Diagnosis
o CSF shows increased protein, but no WBCs. (MCQ)
o EMG shows signs of demyelination with marked decrease in action
potential conduction velocities. (MCQ)
o The diagnosis is usually made clinically since CSF and EMG testing are
often normal in the early course of this syndrome.
• Treatment
o Most patients will have to be hospitalized.
o Mechanical ventilation for respiratory muscle paralysis (MCQ)
o Plasma exchange and IV immunoglobulin in selected patients (MCQ)
o Reassurance. Most patients make a full recovery, although < 5% of
patients die from respiratory failure.
o Most cases resolve spontaneously over the course of several weeks to
o months. (MCQ)
• Clinical Pearls :
o Weakness is more severe than sensory disturbances. (MCQ)
o Acute dysautonomia (MCQ)

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§ common and may be life-threatening.


o Autonomic disturbances (MCQ)
§ Severe tachycardia, cardiac irregularities, hypotension or hypertension,
facial flushing, abnormalities of sweating
§ pulmonary dysfunction
§ impaired sphincter control
o The axonal subtypes of the syndrome
§ Include
• acute motor axonal neuropathy [AMAN]
• acute motor and sensory axonal neuropathy [AMSAN])
§ are caused by antibodies to gangliosides on the axon
membrane and especially by antibodies to GM1, GM1b, and
GD1a (and GalNac-GD1a to AMAN). (MCQ)
o Cerebrospinal fluid
§ characteristically contains a high protein concentration with a
normal cell content(MCQ)
§ these changes may take 2 or 3 weeks to develop
• Differential diagnosis
o porphyric, diphtheritic, or toxic (heavy metal, hexacarbon,
organophosphate) neuropathies.
o Poliomyelitis, botulism, and tick paralysis
o The presence of pyramidal signs , a markedly asymmetric motor
deficit, a sharp sensory level, or early sphincter involvement should
suggest a focal cord lesion(MCQ)
• Treatment with prednisone is ineffective and may prolong recovery
time(MCQ)
Topic- Motor Neuron Disease

• This is a progressive disorder of unknown cause,


• there is degeneration of motor neurons i n the spinal cord and cranial nerve nuclei,
and of pyramidal neurons in the motor cortex .
• Between 5 and 10% of cases are familial
• caused by a mutation in the superoxide dismutase (SOD1) gene.
• Clinical features
o Patients present with a combination of lower and upper motor neuron
signs without sensory involvement .
o The presence of brisk reflexes in wasted fasciculating limb muscles
is typical.
o Onset
§ Usually after the age of 50 years
§ Very uncommon before the age of 30 years
o Affects males more commonly than females
o Symptoms
§ Limb muscle weakness, cramps, occasionally fasciculation
§ Disturbance of speech/swallowing (dysarthria/dysphagia)
o Signs
§ Wasting and fasciculation of muscles
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§ Weakness of muscles of limbs, tongue, face and palate


§ Pyramidal tract involvement causing spasticity, exaggerated
§ tendon reflexes, extensor plantar responses
§ External ocular muscles and sphincters usually remain intact
§ No objective sensory deficit
§ No intellectual impairment in most cases
o Course
§ Symptoms often begin focally in one part and spread gradually
but relentlessly to become widespread
• Motor neuron disease is relentlessly progressive; the mean time
from diagnosis to death is 1 year, with most patients dying
within 3–5 years of the onset of symptoms.
• Younger patients and those with early bulbar symptoms tend
to show a more rapid course.
• Death is usually from respiratory infection and failure, and the
complications of immobility.
o Patterns of involvement in motor neuron disease
o Progressive muscular atrophy
o Predominantly spinal motor neurons affected
o Weakness and wasting of distal limb muscles at first
o Fasciculation in muscles
o Tendon reflexes may be absent

o Progressive bulbar palsy


o Early involvement of tongue, palate and pharyngeal muscles
o Dysarthria/dysphagia
o Wasting and fasciculation of tongue
o Pyramidal signs may also be present
o Amyotrophic lateral sclerosis
o Combination of distal and proximal muscle-wasting
and weakness, fasciculation
o Spasticity, exaggerated reflexes, extensor plantars
o Bulbar and pseudobulbar palsy follow eventually
o Pyramidal tract features may predominate
Investigations

o Potentially treatable disorders such as diabetic amyotrophy, spinal


disorders and multifocal motor neuronopathy should be excluded.
o Electromyography helps to confirm the presence of
fasciculation and denervation, and is particularly helpful when
pyramidal features predominate.
o Sensory nerve conduction and motor conduction studies are
normal
o Spinal imaging and brain scanning may be necessary to exclude
focal spinal or cerebral disease.
o CSF examination is usually normal
§ Management

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§ The glutamate antagonist, riluzole, has been shown to have a small


effect in prolonging life expectancy by about 2 months (
§ Other agents such as nerve growth factor show promise.
§ Feeding by percutaneous gastrostomy may be necessary because of
bulbar failure.
§ Non-invasive ventilatory support has been shown to improve the qual-
ity of life by alleviating symptoms from weak respiratory muscles and has
a small effect on prolonging life

Topic- Peripheral Nerve Disease

• All are myelinated except C fibres that carry impulses from pain receptors.
• Mechanisms of damage to peripheral nerves
o myelin sheath is produced by Schwann cells
o Blood supply is via vasa nervorum.
o Demyelination
§ Is seen in Guillain–Barré syndrome, post-diphtheritic
neuropathy and many hereditary sensorimotor neuropathies.
o Axonal degeneration
§ Axon damage leads to the nerve fibre dying back from the
periphery. Conduction velocity initially remains normal (cf.
demyelination) because axonal continuity is maintained in surviving
fibres.
§ Axonal degeneration occurs typically in toxic neuropathies.
o Wallerian degeneration
§ This describes changes following nerve section.
§ Both axon and distal myelin sheath degenerate, over several
weeks.
o Compression
o Focal demyelination at the point of compression causes
disruption of the myelin sheath .
o This occurs typically in entrapment neuropathies, e.g. carpal
tunnel syndrome
o Infarction
o Microinfarction of vasa nervorum occurs in diabetes and
arteritis, e.g. polyarteritis nodosa, Churg–Strauss syndrome ,
o Wallerian degeneration occurs distal to the ischaemic zone.
o Infiltration
o Infiltration of peripheral nerves by inflammatory cells occurs
in leprosy and granulomas, e.g. sarcoid, and by neoplastic cells,
causing neural metastases.
• Axonal growth takes place at up to 1 mm/day.
• Definitions
o Polyneuropathy describes diffuse, symmetrical disease, usually commencing
peripherally.
§ The course may be acute, chronic, static, progressive, relapsing or
towards recovery.
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§Polyneuropathies are motor, sensory, sensorimotor and autonomic.


§They are classified broadly into demyelinating and axonal types,
§Widespread loss of tendon reflexes is typical, with distal weakness
and distal sensory loss.
o Radiculopathy means disease affecting nerve roots
o Plexopathy, the brachial or lumbosacral plexus.
o Myelopathy means disease of the cord.
MONONEUROPATHIES

Neurology Notes

A, B and C fibres in peripheral nerves

Diameter (μm) Conduction velocity m/s Function


Aα (1-20) c. 70 Motor; proprioception
Aβ (5-10) 30-60 Touch
Aγ (3-6) 20-30 Fusimotor, to spindles
Aδ (2-5) 20-30 Sharp pain
B (<3) 5-15 Autonomic,
Preganglionic
C (<1.3) 0.5-2 Slow pain

Nerve compression and entrapment

Nerve Entrapment/compression site


Median Carpal tunnel (wrist)
Ulnar Cubital tunnel (elbow)
Radial Spiral groove (of humerous)
Posterior interosseous Supinator muscle (forearm)
Lateral cutaneous of thigh Inguinal ligament
Common peroneal Neck of fibula
Posterior tibial Tarsal tunnel (flexor retinaculum-foot)

§ Carpal tunnel syndrome (CTS


o median nerve entrapment at the wrist
o CTS is typically not associated with any underlying disease.
o CTS is, however, seen in:
§ hypothyroidism
§ diabetes mellitus
§ pregnancy (third trimester)
§ obesity
§ rheumatoid disease
§ acromegaly
§ amyloid
§ renal dialysis patients.
§ CTS also occurs following wrist trauma.
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o There is nocturnal tingling and pain in the hand and/or forearm,


followed by weakness of thenar muscles .
o Sensory loss in the palm and radial three-and-a-half fingers develops,
followed by wasting of abductor pollicis brevis .
o Tinel’s sign is often present
§ Tinel’s is elicited by tapping the flexor aspect of the wrist : this causes
tingling and pain.
o Phalen’s test positive
§ In Phalen’s, symptoms are reproduced on passive maximal wrist
flexion.
o A wrist splint at night or a local steroid injection in the wrist gives
relief in mild cases.
o In pregnancy CTS is often self-limiting as fluid retention subsides
postpartum.
o Reduction in obesity usually alleviates CTS.
o Surgical decompression of the carpal tunnel is the definitive treatment.
§ Ulnar nerve compression
o The nerve is compressed in the cubital tunnel at the elbow .
o This follows prolonged or recurrent pressure and elbow fracture.
o Weakness and wasting of ulnar innervated muscles leads to clawing of
the hand – hypothenar muscles, interossei and medial two lumbricals
o with sensory loss in the ulnar one- and-a-half fingers .
o The deep, solely motor branch of the ulnar nerve can be damaged in
the palm by repeated trauma, e.g. from a crutch, screwdriver handle, or
cycle handlebars.
§ Radial nerve compression
o The radial nerve is compressed acutely against the humerus , e.g. when
the arm is draped over a hard chair for several hours, known as Saturday
night palsy.
o Wrist drop and weakness of brachioradialis and finger extension
follow . Recovery is usual, though not invariable, within 1–3 months.
o Posterior interosseous nerve compression in the forearm also leads
to wrist drop, without weakness of brachioradialis .
§ Lateral cutaneous nerve of the thigh compression
o This is also known as meralgia paraesthetica
§ Common peroneal nerve palsy
o The common peroneal nerve (lateral popliteal nerve) is compressed
against the head of the fibula following prolonged squatting, yoga, pressure
from a cast, prolonged bed rest or coma , or for no apparent reason.
o There is foot drop and weakness of ankle eversion.
o The ankle jerk (S1) is preserved.
o A patch of numbness develops on the anterolateral border of the
dorsum of the foot and/or lower shin – the nerve has a small sensory
twig.
§ Multifocal neuropathy (mononeuritis multiplex, multiple mononeuropathy)
o This occurs in:
§ diabetes mellitus
§ leprosy
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§ vasculitis
§ sarcoidosis
§ amyloidosis
§ malignancy
§ neurofibromatosis
§ HIV infection
o Diagnosis is largely clinical, supported by electrical studies.
§ Several nerves become affected sequentially or
simultaneously, e.g. ulnar, median, radial and lateral popliteal nerves.
§ When multifocal neuropathy is symmetrical, there is difficulty
distinguishing it from polyneuropathy.
§ Where leprosy is prevalent, e.g. in India, a single nerve lesion can
be the presenting feature.
§ Polyneuropathies
o Chronic sensorimotor neuropathy: no cause found
§ progressive symmetrical numbness and tingling occurs in hands
and feet, spreading proximally in a glove and stocking
distribution.
o Diphtheritic neuropathy
§ Palatal weakness followed by pupillary paralysis and a
sensorimotor neuropathy occur several weeks after the throat
infection
o Cranial polyneuropathy
§ These can develop in diabetes, malignant infiltration, particularly with
nasopharyngeal and breast carcinoma, lymphomas, sarcoidosis , as part of a
paraneoplastic syndrome and occasionally with giant cell arteritis.
Metabolic, toxic and vitamin deficiency neuropathies

Metabolic
Diabetes mellitus
Uraemia
Hepatic disease
Thyroid disease
Porphyria
Amyloid disease
Malignancy
Refsum’s disease
Critical illness

Toxic
Drugs (Table 21.55)
Alcohol
Industrial toxins, e.g. lead, organophosphates

Vitamin deficiency
B1 (thiamin)
B6 (pyridoxine)
Nicotinic acid
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B12

Drug-related neuropathies

Drug Neuropathy Mode/site of action


Phenytoin M A
Chloramphenicol S, M A
Metronidazole S, S/M A
Isoniazid S, S/M A
Dapsone M A
Antiretroviral drugs S>M A
Nitrofurantoin S/M A
Vincristine S>M A
Paclitaxel S>M A
Disulfiram S, M A
Cisplatin S A
Amiodarone S, M D, A
Chloroquine S, M A, D
Suramin M>S D, A
A, axonal; D, demyelinating; M, motor; S, sensory.

§ Metabolic neuropathies
o Diabetes mellitus.
§ Several varieties of neuropathy occur
• symmetrical sensory polyneuropathy
• acute painful neuropathy
• mononeuropathy and multiple mononeuropathy:
• cranial nerve lesions
• isolated peripheral nerve lesions (e.g. carpal tunnel
syndrome)
• diabetic amyotrophy
• autonomic neuropathy.
o Uraemia.
§ Progressive sensorimotor neuropathy develops in chronic
uraemia.
§ the neuropathy usually improves after transplantation.
o Thyroid disease.
§ A mild chronic sensorimotor neuropathy is sometimes seen in
both hyperthyroidism and hypothyroidism
§ Myopathy also occurs in hyperthyroidism
o Porphyria.
§ In acute intermittent porphyria there are episodes of a severe,
mainly proximal neuropathy in the limbs, sometimes with abdominal pain,
confusion and coma.
§ Alcohol, barbiturates and intercurrent infection can
precipitate attacks.
o Amyloidosis - Polyneuropathy develops

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o Refsum’s disease or multifocal neuropathy


§ This is an autosomal recessive rarity.
§ It is a treatable sensorimotor polyneuropathy with ataxia,
retinal damage and deafness
§ due to defective phytanic acid metabolism.
§ Toxic neuropathies
o Alcohol
§ Polyneuropathy, mainly in the lower limbs, occurs with chronic
alcohol abuse.
§ Calf pain is common.
§ Recurrence and progression occur with even small amounts of
alcohol.
o Drugs and industrial toxins
§ lead – motor neuropathy
§ acrylamide (plastics industry ), trichlorethylene, hexane, fat-
soluble hydrocarbons, e.g. glue-sniffing,
§ arsenic and thallium – polyneuropathy, initially sensory.
§ Vitamin deficiencies
o Thiamin (vitamin B1)
§ Dietary deficiency causes beriberi
§ polyneuropathy and cardiac failure.
§ Alcohol is the commonest
§ Anorexia nervosa can cause
§ Wernicke–Korsakoff syndrome
• thiamin-responsive encephalopathy
• due to ischaemic damage in the brainstem and its
connections.
• It consists of:
• eye signs – nystagmus, bilateral lateral rectus palsies,
conjugate gaze palsies, fixed pupils and, rarely,
papilloedema
• ataxia – broad-based gait, cerebellar signs and
vestibular paralysis with absent calorics
• cognitive change – amnestic syndrome with
confabulation, restlessness, stupor and coma
• delirium tremens
• hypothermia and hypotension – due to hypothalamic
involvement
§ Erythrocyte transketolase activity is reduced but the test is
rarely available.
§ Pyridoxine (vitamin B6)
o Deficiency causes a mainly sensory neuropathy. In practical terms this is
seen as limb numbness developing during anti- TB therapy in slow
isoniazid acetylators
o Prophylactic pyridoxine 10 mg daily is given with isoniazid.
§ Vitamin B12 (cobalamin)
o Deficiency causes damage to the spinal cord, peripheral nerves and brain.
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o Subacute combined degeneration of the cord (SACD).


§ Combined cord and peripheral nerve damage is a sequel of
Addisonian pernicious anaemia
§ Initially there is numbness and tingling of fingers and toes, distal sensory
loss, particularly posterior column, absent ankle jerks and, with cord
involvement, exaggerated knee jerks and extensor plantar s.
§ Optic atrophy and retinal haemorrhage may occur.
§ In later stages sphincter disturbance, severe generalized
weakness and dementia develop.
§ Exceptionally, dementia develops in the early stages.
§ Macrocytosis with megaloblastic marrow is usual though not
invariable in SACD.
§ Parenteral B12 reverses nerve damage but has little effect on the
cord and brain.
§ Without treatment, SACD is fatal within 5 years.
§ Copper deficiency is a very rare cause of a similar picture.
§ Charcot–Marie–Tooth disease
o Charcot–Marie–Tooth (CMT) disease is also called peroneal muscular
atrophy.
§ distal limb wasting and weakness that slowly progresses over
many years, mostly in the legs, with variable loss of sensation and
reflexes.
§ In advanced disease, distal wasting is so marked that the legs are
said to resemble inverted champagne bottles.
§ Mild cases have pes cavus and toe clawing that can pass
unnoticed.
§ HSMN Ia (CMT 1A) – the commonest
§ autosomal dominant demyelinating neuropathy
§ caused by duplication (or point mutation) of a 1.5 megabase
portion p11.2 of chromosome 17 encompassing the peripheral
myelin protein 22 gene (PMP-22, 17p11.2).
o HSMN III
§ HSMN III is a rare childhood demyelinating sensory
neuropathy (Déjérine–Sottas disease) leading to severe
incapacity during adolescence. Nerve roots become
hypertrophied.
§ CSF protein is greatly elevated to 10 g/L or more
§ Neuropathy in cancer
o Polyneuropathy is seen as a paraneoplastic syndrome (non- metastatic
manifestation of malignancy), sometimes with anti-neuronal antibodies
o Polyneuropathy occurs in myeloma and other dysproteinaemic state
§ Neuropathies in systemic diseases
o Vasculitic neuropathy occurs in SLE ,polyarteritis nodosa , Churg–Strauss
syndrome ,rheumatoid disease ,sarcoidosis and giant cell arteritis
§ POEMS syndrome.
o chronic inflammatory demyelinating Polyneuropathy
o Organomegaly (hepatomegaly 50%),

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o Endocrinopathy (gynaecomastia and atrophic testes),


o an M protein band
o Skin hyperpigmentation.
§ Autonomic neuropathy
o Autonomic neuropathy causes postural hypotension, urinary retention, erectile
dysfunction, diarrhoea or occasionally constipation, diminished sweating, impaired
pupillary responses and cardiac arrhythmias.
o This can develop in diabetes and amyloidosis and may complicate
Guillain–Barré syndrome.
§ HIV-associated polyneuropathies
o Inflammatory demyelinating neuropathies similar to Guillain–Barré
syndrome and CIDP are seen early in HIV infection, particularly during
seroconversion.
o The most common neuropathy seen later in HIV is a chronic distal
neuropathy that is symmetrical and painful.
o Severe lumbosacral polyradiculoneuropathy develops develops, with
profound lower limb flaccid paralysis, areflexia and sphincter dysfunction.
o All HIV -associated neuropathies respond poorly to retroviral therapy
§ Critical illness polyneuropathy
o Some 50% of critically ill ITU patients with multiple organ failure and/or
sepsis develop an axonal polyneuropathy.
Topic-Lobar Dysfunction

Site of lesion Disorder


Frontal, either Intellectual impairment
Personality change
Urinary incontinence
Monoparesis or hemiparesis
Frontal, left Broca’s aphasia
Temporo-parietal, left Acalculia
Alexia
Agraphia
Wernicke’s aphasia
Right-left disorientation
Homonymous field defect
Temporal, right Confusional states
Failure to recognize faces
Homonymous field defect

Temporal, right Confusional states


Failure to recognize faces
Homonymous field defect
Parietal, either Contralateral sensory loss or neglect
Agraphaesthesia
Homonymous field defect
Parietal, right Dressing apraxia
Failure to recognize faces
Parietal, left Limb araxia
Occipital/occipitoparietal Visual field defects
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Visuospatial defects
Disturbances of visual recognition

Site of lesion Effects


Frontal Partial seizures-focal motor seizures of
contralateral limbs
Conjugate deviation of head and eyes away
from the lesion
Temporal Formed visual hallucinations
Complex partial seizures
Memory disturbances (e.g. déjà vu)
Parietal Partial seizures-focal sensory seizures of
contralateral limbs
Parieto-occipital Crude visual hallucinations (e.g. shapes in one
part of the field)
Occipital Visual disturbances (e.g. flashes)

Topic- Headache

§ Tension-type headache
o This is the most common type of headache
o Emotional strain or anxiety is a common precipitant to tension-type
headache
o The pain of tension headache is usually constant and generalised but
often radiates forward from the occipital region.
o It is described as ‘dull’, ‘tight’ or like a ‘pressure’, and there may be a
sensation of a band round the head or pressure at the vertex.
o In contrast to migraine, the pain may continue for weeks or months
without interruptio n
o there is no associated vomiting or photophobia.
o The patient can usually continue normal activities, and the pain may be
less noticeable when the patient is occupied.
o The pain is characteristically less severe in the early part of the day and
becomes more troublesome as the day goes on.
o Local tenderness may be present over the skull vault or in the
occiput but this should be distinguished from the acute pain precipitated by
skin contact in trigeminal neuralgia and the exquisite tenderness of
temporal arteritis. Typically, the headache does not respond well to
treatment with analgesics.
o Management
§ Physiotherapy (with muscle relaxation and stress management)
is usually bene- ficial
§ low-dose amitriptyline sometimes helps.
§ Migraine
o affects about 20% of females and 6% of males at some point in life.
o Migraine usually presents before the age of 40
o Pathophysiology

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§Aura is due to dysfunction of ion channels which leads to a spreading


front of cortical depolarisation (excitation) followed by
hyperpolarisation (depression of activity).
§ Family history is common in migraine
§ contraceptive pill does appear to exacerbate migraine in many
patients, and to increase the small risk of stroke in patients who
suffer from migraine with aura.
§ In some patients there are identifiable dietary precipitants such as
cheese, chocolate or red wine.
§ When psychological stress is involved, the migraine attack often
occurs after the period of stres s, so that some patients tend to
have attacks at weekends or at the beginning of a holiday .
§ The headache is associated with vasodilatation of extracranial
vessels
o Clinical features
§ Migraine presents with a symptom triad of
• paroxysmal headache
• nausea and/or vomiting
• ‘aura’ of focal neurological events (usually visual).
§ ‘classical’ migraine versus ‘common’ migraine
o Patients with all three of these features are said to
have migraine with aura (‘classical’ migraine).
o Those with paroxysmal headache (with or without
vomiting) but no ‘aura’ are said to have migraine
without aura (‘common’ migraine).
§ A classical migraine attack starts with a non-specific pro-
drome of malaise and irritability followed by the aura of a
focal neurological event, and then a severe, throbbing,
hemicranial headache with photophobia and vomiting.
§ During the headache phase, patients prefer to be in a quiet,
darkened room and to sleep.
§ The headache may persist for several days.
§ The aura most often takes the form of fortification spectra,
which are shimmering, silvery zigzag lines which march
across the visual fields over a period of about 20 minutes,
sometimes leaving a trail of temporary visual field loss.
§ In some patients there is a sensory aura which is a spreading
front of tingling followed by numbness which moves, over 20–30
minutes, from one part of the body to another.
§ If the dominant hemisphere is involved, the patient may
also experience transient aphasia.
§ Limb weakness can occur in migraine and is termed
hemiplegic migraine.
§ In some patients the focal events may occur by themselves
(‘migraine equivalent’

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§ In a smaller number of patients, the symptoms of the aura do


not resolve, leaving more permanent neurological disturbance
(‘complicated migraine’).
o Management
§ Treatment of an acute attack consists of simple analgesia
with aspirin or paracetamol, often combined with an
antiemetic such as metoclopramide or domperidone.
§ Long-term use of codeine-containing analgesic
preparations should be avoided.
§ Severe attacks can be treated with one of the ‘ triptans’ (e.g.
sumatriptan),
§ 5-HT agonists that are potent vasoconstrictors of the extracranial
arteries.
§ These can be administered orally, sublingually, by
subcutaneous injection or by nasal spray.
§ Ergotamine preparations should be avoided since they easily
lead to dependence.
§ dependence is less likely to happen with the triptans, but it
can occur.
§ If attacks are frequent, they can often be prevented with
propranolol , tricyclic such as amitriptyline , sodium valproate or
topiramate

Cluster headache

§ Cluster headaches (also known as migrainous neuralgia)


§ 10–50 times less common than migraine.
§ There is a 5:1 predominance of males and onset is usually in the third decade.
§ Pathophysiology
o there are no provoking dietary factors and there is a male
predominance.
o Patients are usually heavy smokers with a higher than average alcohol
consumption.
§ Clinical features
o The characteristic presentation is with periodic, severe, unilateral
periorbital pain accompanied by unilateral lacrimation, nasal
congestion and conjunctival injection, often with the other features of
Horner’s syndrome.
o The pain, whilst being very severe, is characteristically brief (30–90
minutes). Typically, the patient develops these symptoms at a
particular time of day (often in the early hours of the morning ).
o The syndrome may occur repeatedly for a number of weeks , followed
by a respite for a number of months before another cluster occurs.
§ Management
o Acute attacks can usually be halted by subcutaneous injections of
sumatriptan or by inhalation of 100% oxygen
o other migraine therapies are ineffective
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o Preventative therapy with the agents used for migraine is often


ineffective
o Attacks can be prevented in some patients by verapamil (80–120mg 8-
hourly), methysergide or short courses of oral corticosteroids.
o Patients with severe and debilitating clusters can be helped with lithium
therapy,

Trigeminal neuralgia

§ This is characterised by lancinating pain in the second and third divisions of the
trigeminal nerve territory
§ usually in patients over the age of 50 years .
§ Pathophysiology
o Trigeminal neuralgia is thought to be caused by an aberrant loop of the
cerebellar arteries compressing the trigeminal nerve as it enters the
brain stem.
o When trigeminal neuralgia occurs in multiple sclerosis, there is a plaque
of demyelination in the trigeminal root entry zone.
§ Clinical features
o The pain is severe and very brief but repetitive , causing the patient to
flinch as if with a motor tic (hence the French term for the condition, ‘tic
douloureux’).
o It may be precipitated by touching trigger zones within the trigeminal
territory, by cold wind blowing on the face, or by eating.
o Physical signs are usually absent.
o There is a tendency for the condition to remit and relapse over many
years.
§ Management
o The pain usually responds to carbamazepine
o In patients who cannot tolerate carbamazepine, gabapentin or
pregabalin may be effective.
o Various surgical treatments
o injection of alcohol or phenol into a peripheral branch of the nerve.
o Probably more effective is making a radiofrequency lesion in the
nerve near the Gasserian ganglion.
o Alternatively, the vascular compression of the trigeminal nerve can be
relieved through a posterior craniotomy, often with substantial
success. This approach is usually favoured in younger patients .

Topic- Meningitis

• Etiology

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o Streptococcus pneumonia (60%), group B streptococci (14%), Haemophilus


injluenzae (7%), Neisseria meningitidis (15%), and Listeria (2%) account for over
95% of cases. (MCQ)
o Staphylococcus occurs in those with recent neurosurgery. (MCQ)

Clues to Answering the “Most Likely Diagnosis” Question


Symptom Diagnosis
Stiff neck, photophobia, meningismus Meningitis
Confusion Encephalitis
Focal neurological findings Abscess

• Presentation
o Acute bacterial meningitis presents over several hours
o Cryptococcal meningitis may be present for several weeks.
Organism Specific Presentations/”What is the Most Likely Diagnosis?”
Presentation The most likely diagnosis is….
AIDS with<100 CD4 cells/μl Cryptococcus
Camper/hiker, rash shaped like a target, joint Lyme disease
pain, facial palsy, tick remembered in 20%
Camper/hiker, rash moves from arms/legs to Rocky Mountain spotted fever (Rickettsia)
trunk, tick remembered in 60%
Pulmonary TB in 85% Tuberculosis
None Viral
Adolescent, petechial rash Neisseria

• Diagnostic Tests : The best initial test and most accurate test is an LP . (MCQ)

Cerebrospinal Fluid Evaluation


Bacterial Cryptococcus, Tuberculosis Viral
meningitis Lyme, Rickettsia
Cell count 1000s, 10s-100s 10s-100s 10s-100s
neutrophils lymphocytes lymphocytes lymphocytes
Protein level Elevated Possibly elevated Markedly Usually normal
elevated
Glucose level Decreased Possibly May be low Usually normal
decreased
Stain and culture Stain: 50-70%; Negative Negative Negative
culture; 90%

• When Is a Head CT the Best Initial Test?

o Head CT is necessary prior to an LP only if there is the possibility that a


space- occupying lesion may cause herniation.

o For a MCQ in PG Medical Entrance ,answer head CT first when any of


the following is present: (MCQ)

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§ Papilledema

§ Seizures

§ Focal neurological abnormalities

§ Confusion interfering with the neurological examination

o If there is a contraindication to immediate LP, giving antibiotics is the


best initial step in management.

• Bacterial Antigen Detection (Latex Agglutination Tests)

o These tests are similar to a Gram stain.


o If antigen detection methods are positive, they are extremely specific.
o If they are negative, the person could still have the infection.
o These tests by themselves are not sufficiently sensitive to exclude bacterial
meningitis.
o When is a bacterial antigen test indicated?
§ When the patient has received anti- biotics prior to the LP and the
culture may be falsely negative.
• Organism Specific Diagnostic Tests/"What Is the Most Accurate Diagnostic Test?"
o Tuberculosis:
§ Acid fast stain and culture on 3 high-volume lumbar punctures.
§ Centrifuge the specimen to concentrate the organisms.
§ TB has the highest cerebrospinal fluid (CSF) protein level.
(MCQ)
§ An acid fast stain of a single, uncentri- fuged sample of CSF has
only 10% sensitivity.
o Lyme and Rickettsia: Specific serologic testing, ELISA, western blot, PCR.
o Cryptococcus:
§ India ink is 60% to 70% sensitive. (MCQ)
§ Cryptococcal antigen is more than 95% sensitive and specific.
(MCQ)
o Viral: Generally a diagnosis of exclusion.
• Treatment
o The best initial treatment for bacterial meningitis is ceftriaxone,
vancomycin, and steroids.
o You will base your treatment answer on the cell count.
o Culture takes 2 to 3 days and is never available at the time that a treatment
decision is made.
o Gram stain is good if it is positive; however, the false negative rate is 30% to
50%.
o Protein and glucose levels are too nonspecific to allow for a treatment
decision. (MCQ)
o Although steroids (dexamethasone) have been proven to lower mortality
only in S. pneumoniae infection, you must give them when you see thousands

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of neutrophil s because you will not know the culture results for several days.
(MCQ)
• Listeria Monocytogenes
o Listeria is resistant to all cephalosporins but sensitive to penicillins.
o You must add ampicillin to ceftriaxone and vancomycin if the case
describes risk factors for Listeria. (MCQ)
o These risk factors for Listeria. are: (MCQ)
§ Elderly
§ Neonates
§ Steroid use
§ AIDS or HIV
§ Immunocompromised,including alcoholism
§ Pregnant
• Neisseria meningitidis: Additional Management
o Respiratory isolation(MCQ)
o Rifampin, ciprofloxacin, or ceftriaxone to the close contacts to decrease
nasopharyngeal carriage (MCQ)
o Definition of "Close contacts” of Nisseria (Important issue in PG
Medical entrance)
§ "Close contacts" means those who have major respiratory fluid
contact, such as household contacts, kissing, or sharing cigarettes or eating
utensils.
§ Routine school and work contacts are not close contacts.
§ Sitting in class with someone with Neisseria infection does not make
them a close contact.
§ Health care workers qualify only if they intubate the patient,
perform suctioning, or have contact with respiratory secretions.
o Encephalitis
§ Look for the acute onset of fever and confusion.
§ Although there are many causes of encephalitis, herpes simplex is
by far the most common cause. (MCQ)
§ You must do a head CT first because of the presence of confusion.
§ Treatment
• Acyclovir is the best initial therapy for herpes encephalitis.
(MCQ)
• Famciclovir and valacyclovir are not available as
intravenous formulations.
• Foscarnet is used for acyclovir-resistant herpes. (MCQ)

3 Classical MCQs for PG Medical Entrance

1. A 46 year old man from Patna man comes to the emergency department with fever, severe
headache, neck stiffness, and photophobia. On physical examination he is found to have
weakness of his left arm and leg. What is the most appropriate next step in the management of
this patient?

a. Ceftriaxone, vancomycin, and steroids b. Head CT


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c. Ceftriaxone

d. Steroids

2. What is the most accurate test of herpes encephalitis?

a. Brain biopsy

b. PCR of CSF

c. Serology for herpes (lgG, lgM)

d. Viral culture of CSF e. Tzanck prep

3. .A 64 year old woman from New Delhi is admitted for herpes encephalitis confirmed by PCR.
After 4 days of acyclovir her creatinine level begins to rise.

What is the most appropriate next step in management?

a. Stop acyclovir.

b. Reduce the dose of acyclovir and hydrate.

c. Switch to oral famciclovir or valacyclovir.

d. Switch to foscarnet.

Topic- Alzheimer’s disease

• This is the commonest dementia, a degenerative disease of the cortex,


• The cardinal clinical features are:
o progressive loss of ability to learn, retain and process new
information (i.e. memory loss)
o decline in language – difficulty in naming and in understanding what is
being said (various aphasias)
o apraxia – impaired ability to carry out skilled motor activities
o Agnosia – failure to recognize objects, e.g. clothing, places or people
o progressive loss of executive function – organizing, planning and
sequencing
o behavioural change – agitation, aggression, wandering and persecutory
delusions
o loss of insight, relative or complete
o Depression – though severe depression is unusual,perhaps because of
loss of insight.
• The onset is gradual.

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• Alzheimer’s disease (AD) is rare below the age of 50


• Disturbance of gait, motor and occasionally sensory abnormalities and seizures occur
late.
• Neuropathology and neurochemical changes
o Loss of neurones, neurofibrillary tangles, senile plaques and
amyloid angiopathy are seen
o Seen especially within the frontal, temporal and parietal cortex,
hippocampi, substantia innominata and locus caeruleus.
o Neurofibrillary tangles in neuronal cell bodies are made up of the
microtubular-associated tau protein in paired helical filaments.
o Ubiquitin is also seen in association with tangles.
o Aggregation of beta-amyloid appears to play a central role, developing
progressively in extracellular senile plaques.
o Apoptosis follows, leading to cell death
o There is marked reduction in choline acetyltransferase,
acetylcholine itself, noradrenaline and serotonin.
• Aetiology
o Incidence is increased in Down’s syndrome.
o The gene encoding apolipoprotein E e4 allele is a possible candidate.
• Dementia with Lewy bodies (DLB)
o This accounts for some 25% of dementias
o characterized by fluctuating cognition with pronounced variation in
attention and alertnes s.
o Impairment in attention, frontal, subcortical and visuospatial ability
is often prominent.
o Depression and sleep disorders occur.
o Recurrent formed visual hallucinations , e.g. strange faces, frightening
creatures, are a common feature. Parkinsonism, i.e. slowing and rigidity, is
common, with repeated falls.
o Delusions and transient loss of consciousness occur.
o Cortical Lewy bodies at autopsy are a hallmark of DLB.
• V ascular dementia (multi-infarct dementia)
o Widespread vessel disease seen on MRI is the typical finding
o It may produce a variety of cognitive deficits reflecting the site of
ischaemic damage.
• Frontotemporal dementia
o Progressive deterioration of social behaviour, disinhibition and
personality develops in middle life, followed by decline in memory,
intellect and language.
o Imaging shows selective atrophy of frontal and temporal lobes .
o There is no excess of either senile plaques or neurofibrillary tangles.
Cytoplasmic inclusion bodies – silver-staining, Pick’s bodies – are
seen.
• Subcortical encephalopathies comprise disorders that affect subcortical
structures such as the basal ganglia.

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o They include dementia occurring in idiopathic Parkinson’s, Huntington’s,


progressive supranuclear palsy and dementia occurring in rarities such as cerebral
vasculitis.
o Rarer conditions such as Creutzfeldt–Jakob disease , Wilson’s disease and
Whipple’s cause progressive dementia.
• Dementia also occurs commonly in the late stages of MS .
• Investigations
o On MRI, bilateral atrophy in the hippocampi is seen in AD
o increased tau protein in the CSF in AD
o a reduction of glucose metabolism in bilateral temporo-parietal regions on
PET scanning in AD
• Management and social consequences
o A treatable cause for dementia is found in hypothyroidism.
o Participation in cognitively demanding activities in later life may
protect against or delay the onset of dementia.
o Treatment with antioxidants, mainly vitamin E, has shown some
possible, slight benefit.
o Anticholinesterase inhibitors (donepezil, rivastigmine and galantamine)
o Memantine, an N-methyl d-aspartate (NMDA) receptor antagonist that affects
glutamate transmission slow the rate of cognitive decline in AD.

Topic- Cysticercosis

Cysticercosis

§ Human cysticercosis is acquired by ingesting T. solium tapeworm ova, from


either contaminated fingers or food
§ The larvae are liberated from eggs in the stomach, penetrate the intestinal
mucosa and are carried to many parts of the body where they develop and form
cysticerci, 0.5–1cm cysts that contain the head of a young worm .
§ They do not grow further or migrate.
§ Common locations are the subcutaneous tissue, skeletal muscles and brain.
§ Clinical features
o When superficially placed, cysts can be palpated under the skin or
mucosa as pea-like ovoid bodies.
o Here they cause few or no symptoms, and will eventually die and
become calcified.
o Heavy brain infections, especially in children, may cause features of
encephalitis.
o More commonly, however, cerebral signs do not occur until the
larvae die, 5–20 years later.
o Epilepsy, personality changes, staggering gait or signs of internal
hydrocephalus are the most common features.
§ Investigations
o Calcified cysts in muscles can be recognised radiologically
o Antibody detection is available for serodiagnosis.
§ Management and prevention
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o Albendazole, 15 mg/kg daily for a minimum of 8 days , has now become


the drug of choice for parenchymal neurocysticercosis .
o Praziquantel is another option, 50mg/kg in three divided doses daily for
10 days.
o Prednisolone, 10mg 8-hourly, is also given for 14 days, starting 1 day
before the albendazole or praziquantel.
o In addition, anti-epileptic drugs should be given until the reaction in
the brain has sub- sided.
o Operative intervention is indicated for hydrocephalus.

Topic- Spinal cord Compression

SPINAL CORD COMPRESSION

• Principal features of chronic and subacute cord compression


o spastic paraparesis or tetraparesis,
o radicular pain at the level of compression
o sensory loss below the compres-sion
• For example, in compression at T4, a band of pain radiates around the thorax ,
characteristically worse on coughing or straining.
• What is meant by sensory level.
o Numbness commencing in the feet rises to the level of compression. This is
called the sensory level.
• Retention of urine and constipation develop.
• Cord compression is a medical emergency.
• Causes
o Spinal cord neoplasms.
§ Extramedullary tumours, both extradural and intradural, cause
cord compression gradually over weeks to months , often with root pain
and a sensory level
§ The rarer intramedullary tumours (e.g. glioma) typically
progress slowly, sometimes over many years.
§ Sensory disturbances similar to syringomyelia may develop
o Tuberculosis.
§ Spinal TB is the commonest cause of cord compression
§ There is destruction of vertebral bodies and disc spaces , with
local spread of infection.
§ Cord compression and paraparesis follow, culminating in paralysis
– Pott’s paraplegia.
o Disc and vertebral lesions.

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§ Central cervical disc and thoracic disc protrusion cause cord


compression
o Spinal epidural abscess.
o Epidural haemorrhage and haematoma.
§ These are rare sequelae of anticoagulant therapy, bleeding
disorders or trauma and can follow lumbar puncture when
clotting is abnormal.
• Management
o MRI shows spinal cord pathology extremely well and is the imaging tech-
nique of choice .
o Radiotherapy is used to treat cord malignancies, with largely poor outcome.
• Syringomyelia and syringobulbia
o The syrinx, a fluid-filled cavity within the cervical or thoracic spinal
cord, is the essential feature.
o Syringobulbia means a cavity in the brainstem.
o Aetiology and mechanism
§ Syringomyelia is frequently associated with the Arnold–Chiari
malformation
§ The syrinx is in continuity with the central canal of the cord.
o Pathological anatomy
§ The expanding cavity in the cord, usually between C2 and T9,
gradually destroys spinothalamic neurones, anterior horn cells and lateral
corticospinal tracts.
§ In the medulla (syringobulbia), trigeminal nuclei, sympathetic trunk,
IXth, Xth, XIth and XIIth nerve nuclei and the vestibular connections are
destroyed by the expanding syrinx.
o Clinical features
§ Syringomyelia cases with the Arnold–Chiari malformation usually
develop symptoms around the age of 20–30.
§ Upper limb pain exacerbated by exertion or coughing is typical.
Spinothalamic sensory loss – pain and temperature – leads to
painless upper limb burns and trophic changes.
§ Paraparesis develops.
§ The following are typical signs of a substantial cervical syrinx
• Areas of dissociated sensory loss, i.e. spinothalamic loss
without loss of light touch ..
• Loss of upper limb reflexes.
• Muscle wasting in the hand and forearm.
• Spastic paraparesis – initially mild.
• Neuropathic joints, trophic skin changes (scars, nail
dystrophy) and ulcers.
§ Brainstem signs – as the syrinx extends into the brainstem
(syringobulbia) there is tongue atrophy and fasciculation, bulbar palsy,
nystagmus, Horner’s syndrome, hearing loss and impairment of facial
sensation.
o Course, investigation and management

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§MRI demonstrates the cavity and herniation of cerebellar


tonsils. Syringomyelia is gradually progressive over several
decades.
o Other causes of syrinx formation
§ bony anomalies at the foramen magnum, spina bifida
,arachnoiditis, hydrocephalus, intrinsic cord tumours (e.g. glioma
and ependymoma) and trauma.
Cauda Equina and Conus Medullaris Syndromes

o The spinal cord tapers and ends at the level between the first and second
lumbar vertebrae in an average adult.
o The most distal bulbous part of the spinal cord is called the conus
medullaris, and its tapering end continues as the filum terminale.
o Distal to this end of the spinal cord is a collection of nerve roots, which are
horsetail-like in appearance and hence called the cauda equina

o Cauda equina syndrome refers to a characteristic pattern of neuromuscular and


urogenital symptoms resulting from the simultaneous compression of multiple
lumbosacral nerve roots below the level of the conus medullaris.

o These symptoms include low back pain, sciatica (unilateral or, usually, bilateral),
saddle sensory disturbances, bladder and bowel dysfunction, and variable lower
extremity motor and sensory loss

o The lesion is technically involves nerve roots and represents a


"peripheral" nerve injury
o damage may be irreversible and cauda equina syndrome may be a surgical emergency
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o Anatomy of CE
o The CE provides sensory innervation to the saddle area, motor
innervation to the sphincters, and parasympathetic innervation to
the bladder and lower bowel (ie, from the left splenic flexure to the
rectum).

o The nerves in the CE region include lower lumbar and all of the sacral
nerve roots.

o The pelvic splanchnic nerves carry preganglionic parasympathetic fibers from


S2-S4 to innervate the detrusor muscle of the urinary bladder .

o Conversely, somatic lower motor neurons from S2-S4 innervate the


voluntary muscles of the external anal sphincter and the urethral sphincter via the
inferior rectal and the perineal branches of the pudendal nerve , respectively.

o Hence, the nerve roots in the CE region carry sensations from the lower
extremities, perineal dermatomes, and outgoing motor fibers to the lower extremity
myotomes.\
o Conus Medullaris syndrome (Mixed UMN and LMN) vs Cauda Equina
syndrome ( Pure LMN )
o Conus medullaris
o constitutes part ofthe spinal cord (the distal part of the cord) and is in
proximity to the nerve roots .
o Thus, injuries to this area often yield a combination of upper motor
neuron (UMN) and lower motor neuron (LMN) symptoms and signs
in the dermatomes and myotomes of the affected segments.
o Cauda equina lesion
o is an LMN lesion because the nerve roots are part of the PNS
o The most common causes of cauda equina and conus medullaris
syndromes are the following:
o Lumbar stenosis (multilevel)
o Spinal trauma including fractures
o Herniated nucleus pulposus (cause of 2-6% of cases of cauda equina
syndrome)
o Neoplasm, including metastases, astrocytoma, neurofibroma, and
meningioma; 20% of all spinal tumors affect this area
o Spinal infection/abscess (eg, tuberculosis, herpes simplex virus, meningitis,
meningovascular syphilis, cytomegalovirus, schistosomiasis)
o Idiopathic (eg, spinal anesthesia): these syndromes may occur as
complications of the procedure or of the anesthetic agent (eg, hyperbaric
lidocaine, tetracaine)
o Spina bifida and subsequent tethered cord syndrome

Cauda Equina Versus Conus Medullaris Syndrome


Features Cauda Equina Syndrome Conus Medullaris
Vertebral level L2-sacrum L1-L2
Spinal level Injury to the lumbosacral Injury of the sacral cord
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nerve roots segment (conus and epiconus)


and roots
Severity of symptoms and Usually severe Usually not severe
signs
Symmetry of symptoms and Usually asymmetric Usually symmetric
signs
Pain Prominent, asymmetric, and Usually bilateral and in the
radicular perineal area
Motor Weakness to flaccid paralysis Normal motor function to
mild or moderate weakness
Sensory Saddle anesthesia, may be Symmetric saddle distribution,
asymmetric sensory loss of pin prick, and
temperature sensation (Tactile
sensation is spared.)
Reflexes Areflexic lower extremities; Areflexic lower extremities
bulbocavemosus refles is
absent in low EC (sacral)
lesions (if the epiconus is involved,
patellar reflex may be absent,
whereas bulbocavemosus
reflex may be spared.)
Symptoms and Signs of Conus Medullaris and Cauda Equina Syndromes
Conus Medullaris Syndrome Cauda Equina Syndrome
Presentation Sudden and bilateral Gradual and unilateral
Reflexes Less severe More severe
Radicular pain Less severe More severe
Low back pain More Less
Sensory symptoms and signs Numbness tends to be more Numbness tends to be more
localized to perianal area; localized to saddle area;
symmetrical and bilateral; asymmetrical, may be
sensory dissociation occurs unilateral; no sensory
dissociation; loss of sensation
in specific dermatomes in
lower extremities with
numbness and paresthesia;
possible numbness in pubic
area, including glans penis or
clitoris
Motor strength Typically symmetric, Asymmetric areflexic
hyperreflexic distal paresis of paraplegia that is more
lower limbs that is less marked; fasciculations rare;
marked; fasciculations may be atrophy more common
present
Impotence Frequent Less frequent; erectile
dysfunction that includes
inability to have erection,
inability to maintain erection,
lack of sensation in pubic area
(including glans penis or
clitoris), and inability to
ejaculate
Sphincter dysfunction Urinary retention and atonic Urinary retention; tends to
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anal sphincter cause overflow present late in course of


urinary incontinence and fecal disease
incontinence; tend to present
early in course of disease

Features of radicular pain

Nerve root pain


• Unilateral leg pain worse than low back pain
• Pain radiates beyond knee
• Paraesthesia in same distribution
• Nerve irritation signs (reduced straight leg raising which reproduces leg pain)
Cauda equine syndrome
• Difficulty with micturition
• Loss of anal sphincter tone or faecal incontinence
• Saddle anaesthesia
• Gait disturbance
• Pain, numbness or weakness affecting one or both legs

Pain and Deficits Associated with Specific Nerve Roots


Nerve Root Pain Sensory Deficit Motor Deficit Reflex Deficit
L2 Anterior medial Upper thigh Slight quadriceps Slightly
thigh weakness; hip diminished
flexion; thigh suprapatellar
adduction
L3 Anterior lateral Lower thigh Quadriceps Patellar or
thigh weakness; knee suprapatellar
extension; thigh
adduction
L4 Posterolateral Medial leg Knee and foot Patellar
thigh, anterior extension
tibia
L5 Dorsum of foot Dorsum of foot Dorsiflexion of Hamstrings
foot and toes
S1-2 Lateral foot Lateral foot Plantar flexion Achilles
of foot and toes
S3-5 Perineum Saddle Sphincters Bulbocavemosus;
anal

Topic- Motor Control Systems

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MOTOR CONTROL SYSTEMS

§ There are three systems, each of which interacts by feedback


§ loops with the other two, with sensory input and the reticular formation:
o The corticospinal (or pyramidal) system
§ enables purposive, skilled, intricate, strong and organized
movements.
§ Defective function is recognized by a distinct pattern of signs –
loss of skilled voluntary movement, spasticity and reflex
change – seen, for example in a hemiparesis, hemiplegia or paraparesis.
o The extrapyramidal system
§ facilitates fast, fluid movements that the corticospinal system has
generated.
§ Defective function produces slowness (bradykinesia), neurone
§ stiffness (rigidity) and/or disorders of movement (rest
tremor, chorea and other dyskinesias).
§ One feature (e.g. stiffness, tremor or chorea) will often
predominate.
o The cerebellum and its connections
§ have a role coordinating smooth and learned movement, initiated by
the pyramidal system, and in posture and balance control.
§ Cerebellar disease leads to unsteady and jerky movements (ataxia),
with characteristic limb signs of past pointing, action tremor
and incoordination, gait ataxia and/or truncal ataxia .
§ Corticospinal (pyramidal) system
o The corticospinal tracts originate in neurones of the cortex and terminate
at motor nuclei of cranial nerves and spinal cord anterior horn cells .
o congregate in the internal capsule and cross in the medulla
(decussation of the pyramids), passing to the contralateral cord as
the lateral corticospinal tracts.
o This is the pyramidal system, disease of which causes upper motor neurone
(UMN) lesions.
o Characteristics of pyramidal lesions
§ Signs of an early pyramidal lesion may be minimal.
§ Weakness, spasticity or changes in superficial reflexes can
pre- dominate, or be present in isolation.

§ Features of upper motor neurone lesions

Drift of upper limb


Weakness with characteristic distribution
Changes in tone: flaccid→spastic
Exaggerated tendon reflexes
Extensor plantar response
Loss of skilled finger/toe movements
Loss of abdominal reflexes
No muscle wasting
Normal electrical excitability of muscle

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§ What is Pyramidal drift of an upper limb


o Normally, the outstretched upper limbs are held symmetrically, when
the eyes are closed.
o With a pyramidal lesion, when both upper limbs are held
outstretched, palms uppermost, the affected limb drifts downwards and
medially.
o The forearm tends to pronate and the fingers flex slightly . This sign
is often first to emerge, sometimes before weakness and/or reflex changes
become apparent.
§ Weakness and loss of skilled movement
o A unilateral pyramidal lesion above the decussation in the medulla causes
weakness of the opposite limbs .
o When acute and complete, this weakness will be immediate and total,
e.g. a hemiplegia following an internal capsule infarct.
o With slowly progressive lesions (e.g. a hemisphere glioma) a characteristic
pattern of weakness emerges – a hemiparesis .
o Pattern of weakness
§ In the upper limb, flexors remain stronger than extensors,
whereas in the lower limb, extensors remain stronger than
flexors.
§ In the upper arm, weaker movements are thus shoulder
abduction and elbow extension
§ in the forearm and hand, wrist and finger extensors and abductors
are weaker than their antagonists.
§ In the lower limb, weaker movements are hip flexion and
abduction, knee flexion, ankle dorsiflexion and eversion.
o There is also loss of skilled movement – fine finger and toe control
diminishes.
o Wasting (except from disuse) is not a feature.
o Muscles remain normally excitable electrically.
o When a UMN lesion is below the decussation of the pyramids, e.g. in
the cervical cord, hemiparesis is on the same side as the lesion , an unusual
situation.
§ Changes in tone and tendon reflexes
o An acute lesion of one pyramidal tract (e.g. internal capsule stroke) causes
initially flaccid paralysis with loss of tendon reflexes .
o Increase in tone follows, usually within several days due to loss of
inhibitory effects of the corticospinal pathways and an increase in spinal reflex
activity. This increase in tone (spasticity) is detectable most easily in
stronger muscles.
o Spasticity is characterized by sudden changing resistance to passive
movement – the clasp-knife effect.
o Relevant tendon reflexes become exaggerated; clonus may emerge.
§ Changes in superficial reflexes
o The normal flexor plantar response becomes extensor (a positive
Babinski).

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o In a severe acute lesion, this extensor response can be elicited from a


wide area of the foot. As recovery progresses, the receptive area
diminishes until the lateral posterior third of the sole remains
receptive to an orange-stick stimulus (an appropriate instrument).
o An extensor plantar is certain when great toe dorsiflexion is accom-
panied by abduction of adjacent toes .
o Abdominal (and cremasteric) reflexes are abolished on the side
affected.
§ Patterns of UMN disorders
o There are three main patterns:
§ Hemiparesis means weakness of the limbs on one side; it is
usually caused by a lesion in the brain and occasionally in the
cord.
§ Paraparesis means weakness of both lower limbs and is usually
diagnostic of a cord lesion; bilateral brain lesions occasionally
cause paraparesis.
§ Tetraparesis (syn. quadriparesis) means weakness of four limbs.

§ Hemiparesis
§ Motor cortex.
o Weakness and/or loss of skilled movement confined to one
contralateral limb (an arm or a leg – mono- paresis) or part of a
limb (e.g. a clumsy hand) is typical of an isolated motor cortex lesion
(e.g. a secondary neoplasm).
o A defect in cognitive function (e.g. aphasia) and focal epilepsy
may occur.
§ Internal capsule.
o Corticospinal fibres are tightly packed in the internal capsule (about
1 cm2), thus a small lesion causes a large deficit.
o A middle cerebral artery branch infarction produces a sudden,
dense, contralateral hemiplegia.
§ Pons.
o A pontine lesion (e.g. an MS plaque) is rarely confined to the
corticospinal tract.
o Adjacent structures, e.g. VIth and VIIth nuclei, MLF and PPRF
are involved – diplopia, facial weakness, internuclear ophthalmoplegia (INO)
and/or a lateral gaze palsy occur with contralateral hemiparesis.
§ Spinal cord.
o An isolated lesion of one lateral corticospinal tract (e.g. a cervical
cord injury) causes an ipsilateral UMN lesion, the level indicated by
changes in reflexes (e.g. absent biceps, C5/6 ), features of a Brown–
Séquard syndrome and muscle wasting at the level of the lesion
§ Paraparesis
o Paraparesis indicates bilateral damage to corticospinal path- ways .
o Cord compression or cord diseases are the usual causes; cerebral
lesions occasionally produce parapa- resis.

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Causes of spastic paraparesis

Spinal lesions
Spinal cord compression (Table 21.47)
Multiple sclerosis
Myelitis, e.g. varicella zoster
Motor neurone disease
Subacute combined degeneration of the cord
Syringomyelia
Syphilis
Familial or sporadic paraparesis
Vascular, e.g. cord infarction, arteriovenous malformation
Paraneoplastic syndromes
Tropical spastic paraparesis
HIV-associated myelopathy
Rarities, e.g. lathyrism, copper deficiency

Cerebral lesions (rare)


Parasagittal cortical lesions:
Meningioma
Sagittal sinus thrombosis
Hydrocephalus
Multiple cerebral infarction
§ EXTRAPYRAMIDAL SYSTEM
o The extrapyramidal system is a general term for basal ganglia motor
systems, i.e. corpus striatum (caudate nucleus+globus pallidus +putamen),
subthalamic nucleus, substantia nigra and parts of the thalamu s.
o The most common extrapyramidal disorder is Parkinson’s disease.
o In basal ganglia/extrapyramidal disorders, two features (either or
both) become appar- ent, in limbs and axial muscles:
§ reduction in speed (bradykinesia, meaning slow movement)
or akinesia (no movement), with muscle rigidity
§ involuntary movements (e.g. tremor, chorea,
hemiballismus, athetosis, dystonia).
Extrapyramidal disorders are classified broadly into akinetic– rigid syndromes where poverty
of movement predominates, and dyskinesias where there are involuntary movements

o LOWER MOTOR NEURONE (LMN) LESIONS


o The LMN is the pathway from anterior horn cell (or cranial nerve nucleus)
via a peripheral nerve to muscle motor end- plates.
o The motor unit consists of one anterior horn cell, its single fast-
conducting axon that leaves the cord via the ante- rior root, and the
group of muscle fibres (100–2000) supplied via the nerve .
o Anterior horn cell activity is modulated by impulses from:
§ corticospinal tracts
§ extrapyramidal system
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§ cerebellum
§ afferents via posterior roots.
Features of lower motor neurone lesions

Weakness
Wasting
Hypotonia
Reflex loss
Fasciculation
Fibrillation potentials (EMG)
Muscle contractures
Trophic changes in skin and nails

Spinal levels, recording/Interpretation of tendon reflexes


Level Reflex Symbol for reflex Meaning
C5-6 Supinator 0 Absent
C5-6 Biceps +/- Present with
reinforcement
C7 Triceps + Normal
L3-4 Knee ++ Brisk, normal
S1 Ankle +++ Exaggerated
(abnormal)
CL Clonus

o Causes
o Examples of LMN lesions at various levels are:
§ cranial nerve nuclei (Bell’s palsy)
§ anterior horn cell (motor neurone disease)
§ spinal root – cervical and lumbar disc protrusion, neuralgic
amyotrophy
§ peripheral (or cranial) nerve – trauma, entrapment
polyneuropathy

Topic- Brainstem Stroke

Brain-stem lesions

§ Lesions of the brain stem typically present cranial nerve, cerebellar and upper
motor neuron dysfunction
§ most commonly caused by vascular disease.
§ Weber’s syndrome
o Example : a patient presenting with sudden onset of upper motor
neuron features affect-ing the right face, arm and leg in association
with a left 3rd nerve palsy.
o The lesion would have to be in the left cerebral peduncle in the brain
stem

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o the pathology is likely to have been a small stroke as the onset was
sudden.
§ The lower cranial nerves, 9, 10, 11 and 12, are frequently affected bilaterally,
producing dysphagia and dysarthria
§ What is ‘bulbar palsy’
o lower motor neuron lesions , at either
o nuclear or fascicular level within the medulla
o from bilateral lesions of the lower cranial nerves outside the brain
stem. The tongue is wasted and fasciculating
o palate moves very little.
§ What is ‘pseudobulbar palsy’
o arises from an upper motor neuron lesion of the bulbar muscles
o from lesions of the corticobulbar pathways in the pyramidal tracts.
o Here the tongue is small and contracted, and moves lowly
o the jaw jerk is brisk

Major focal brain-stem syndromes

Name of syndrome Site of lesions Clinical features


Weber Anterior Ipsilateral 3 rd palsy
Cerebral Contralateral upper motor
Peduncle neuron
(mid-brain) 7th palsy
Contralateral hemiplegia
Claude Cerebral Ipsilateral 3 rd palsy
Peduncle Contralateral cerebellar signs
Involving red nucleus
Parinaud Dorsal mid-brain (tectum) Vertical gaze palsy
Convergence disorders
Convergence retraction
nystamus
Pupillary and lid disorders
Millard Gubler Ponto medullary junction Ipsilateral 6 th palsy
Ipsilateral lower motor
neuron
7th palsy
Contralateral hemiplegia
Wallenberg Lateral medulla Ipsilateral 5 th, 9th, 10, 11 th
palsy
Ipsilateral Horner’s syndrome
Ipsilateral cerebellar signs
Contralateral spinothalamic
sensory loss
Vestibular disturbance

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Causes of pseudobulbar and bulbar palsy

Pseudobulbar Bulbar
Genetic Kennedy’s disease
(X-linked bulbo-spinal
neuronopathy)
Vascular Bilateral hemisphere Medullary infarction
(lacunar) infarction
Degenerative Motor neuron disease Motor neuron disease
Syringobulbia
Inflammatory/infective Multiple sclerosis Myasthenia
Guillain-Barre
Cerebral vasculitis Poliomyelitis
Lyme disease
Neoplastic High brain-stem tumours Brain-stem glioma
Malignant meningitis

Topic- Brain Tumors

§ Brain Tumors
§ Etiology
o Exposure to ionizing radiation
o Hereditary syndromes (i.e., neureofibromatosis, tuberous sclerosis)
o HIV (lymphoma is typically of the B-cell subtype) (MCQ)
§ Most common solid tumor of childhood is brain tumor (MCQ)
§ Originates from brain, spinal cord, or meninges (MCQ)
§ Most common: Glial origin (50 to 60%) , Meningiomas (25%) (MCQ)
§ Signs and symptoms
o Headache (40%); (MCQ)
§ usually the result of increased intracranial pressure:
§ Present upon awakening and disappears within 1 hour (but
can take any form)
§ Can wake patient from sleep
§ Worse while lying supine
§ New headache in middle-aged or older person
§ Change in headache character in person with chronic
headaches
o Nausea or vomiting especially on awakening
o Irritability, apathy
o Sometimes vision loss, weakness of extremities
o Seizures, focal neurologic deficits
o Lethargy, weight loss more common with metastatic disease
§ Diagnosis/workup
o MRI/CT for detection of mass and preliminary diagnosis
o Biopsy for histology and definitive diagnosis
o PET scans and EEG occasionally have some diagnostic role.
§ Treatment
o Corticosteroids to decrease edema and intracranial pressure (MCQ)
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o Surgical resection, if possible


o Radiation and perhaps chemotherapy for high-grade tumors
§ Different Histologic types of brain tumors
o Astrocytoma
§ Most common neuroectodermal tumor
§ Those occurring in adults are usually high grade—poor
prognosis. (MCQ)
o Glioblastoma multiforme (GBM)
§ an aggressive anaplastic type.
o Central nervous system lymphomas
§ Originate from B cells that have entered the CNS (MCQ)
§ Commonly affects eyes, spinal cord, or leptomeninges
§ Presents with headache, vision problems, and behavioral/personality
changes Diagnose by identifying malignant lymphocytes.
§ Treatment with chemotherapy, radiation, and steroids
o Oligodendrogliomas
§ Tend to calcify (MCQ)
§ More benign and better prognosis than astrocytoma
§ Epileptogenic
o Ependymoma
§ In adults, characteristically found in spinal canal
§ In children, most common location in 4th ventricle (MCQ)
§ With excision, 5-year survival rate is 80%.
o Meningiomas
§ Most common mesodermal tumor (MCQ)
§ Usually benign and slow growing, but usually discovered at
large size
§ Clinically, may present as a cranial nerve palsy
o Schwannomas
§ Most common cranial nerve tumor
§ Vestibular (acoustic) neuromas are 8th cranial nerve tumors
§ Anyone with unilateral deafness should have this ruled out.
(MCQ)
§ Associated with neurofibromatosis type 1 > type 2(MCQ)
o Metastatic tumors to CNS
o More common than primary tumors
o Metastases common from lung, breast, and malignant melanoma
§ Clinical Pearls :
o Astrocytomas are the most common primary intracranial neoplasms.
(MCQ)

o In migraines, prolonged headache may be followed several hours later


by vomiting. In brain tumors, acute headache is followed immediately
by vomiting. (MCQ)

Topic- Dementia

• Loss of cognitive function with normal sensorium


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• Etiology
o Stroke
o Infection (particularly syphilis, AIDS, Creutzfeldt–Jakob)
o Epilepsy
o Vitamin deficiency (folate, B12, thiamine, niacin) (MCQ)
o Normal pressure hydrocephalus (NPH)
o Neurodegenerative disorders
o Alzheimer’s disease
o Parkinson’s disease, Huntington’s disease
o amyotrophic lateral sclerosis
o Trauma ,Toxins,Tumors
• Diagnosis/workup
o Dementia workup should include CBC, electrolyte panel, B12, folate,
rapid plasma reagin (RPR), and head CT.
Clinical pearls :

• Dementia
o Progressive decline of intellectual function.
o Loss of short-term memory and at least one other cognitive deficit.
o Deficit severe enough to cause impairment of function.
o Not delirious. (MCQ)
• Dementia is an acquired persistent and progressive impairment in intellectual
function, with compromise of memory and at least one other cognitive
domain,
o most commonly language impairment
o apraxia (MCQ)
§ inability to perform motor tasks, such as cutting a loaf of bread,
despite intact motor function
o agnosia (MCQ)
§ inability to recognize objects
o impaired executive function
§ poor abstraction, mental flexibility, planning, and judgment
• Alzheimer disease (AD) accounts for roughly two-thirds of dementia cases
(MCQ)
• vascular dementia (either alone or combined with AD) and dementia with
Lewy bodies accounting for much of the rest of cases
• Depression is a common concomitant of early dementia
• Dementia can be classified as cortical or subcortical.

o Cortical dementias (MCQ)

§ arise from a disorder affecting the cerebral cortex, the outer


layers of the brain that play a critical role in thinking abilities like
memory and language.

§ Alzheimer's and Creutzfeldt-Jakob disease are two forms of


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cortical dementia.

§ People with cortical dementia typically show severe memory


loss and aphasia -- the inability to recall words and understand
language.

o Subcortical dementias (MCQ)

§ result from dysfunction in the parts of the brain that are beneath the
cortex.

§ Usually, the forgetfulness and language difficulties that are


characteristic of cortical dementias are not present.

§ Rather, people with subcortical dementias, such as Parkinson's


disease, Huntington's disease, and AIDS dementia
complex, tend to show changes in their speed of thinking
and ability to initiate activities.

• "Subcortical" dementias (eg, the dementia of Parkinson disease, and some


cases of vascular dementia) are characterized by (MCQ)

o psychomotor slowing

o reduced attention

o early loss of executive function

o personality changes.

• Dementia with Lewy bodies (MCQ)

o confused with delirium, as fluctuating cognitive impairment is


frequently observed.

o Rigidity and bradykinesia are the primary signs, and tremor is rare.

o Response to dopaminergic agonist therapy is poor. (MCQ)

o Complex visual hallucinations—typically of people or animals—may


be an early feature that can help distinguish dementia with Lewy bodies
from AD. (MCQ)

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o These patients demonstrate a hypersensitivity to neuroleptic therapy,


and attempts to treat the hallucinations may lead to marked worsening
of extrapyramidal symptoms. (MCQ)

• Frontotemporal dementias (MCQ)

o a group of diseases that include Pick disease, dementia associated


with amyotrophic lateral sclerosis, and other

o Patients manifest

§ personality change (euphoria, disinhibition, apathy)

§ compulsive behaviors (often peculiar eating habits or


hyperorality).

o In contrast to AD, visuospatial function is relatively preserved. (MCQ)

• Dementia in association with motor findings, such as extrapyramidal features or


ataxia, may represent a less common disorder (MCQ)

o progressive supranuclear palsy

o corticobasal ganglionic degeneration

o olivopontocerebellar atrophy

• AD typically presents with early problems in memory and visuospatial


abilities

o becoming lost in familiar surroundings,

o inability to copy a geometric design on paper (MCQ)

o yet social graces may be retained despite advanced cognitive decline.

o Personality changes and behavioral difficulties may develop as the


disease progresses. (MCQ)

§ Wandering

§ inappropriate sexual behavior

§ agitation

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• Hallucinations may occur in moderate to severe dementia.

• End-stage disease is characterized by (MCQ)

§ near-mutism

§ inability to sit up

§ hold up the head

§ track objects with the eyes

§ difficulty with eating and swallowing; weight loss

§ bowel or bladder incontinence;

§ recurrent respiratory or urinary infections.

Topic- Bladder Dysfunction

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§ Detrusor instability
o An overactive bladder without neurologic impairment. (MCQ)
o External sphincter functions normally (MCQ)
o It may complicate multiple sclerosis or a stroke but in most cases, the
cause is unknown.
o The symptoms are those of urge incontinence. (MCQ)
o Diagnosis can be made only on cystometry, spikes of increased intravesical
pressure appearing without the specific instruction to void, and which cannot be
inhibited. (MCQ)
o Treatment
§ based on inhibiting the symptoms of urgency and increasing
the interval between voids. (MCQ)
§ Options include bladder training, biofeedback and hypnosis,
and drugs. (MCQ)
§ Surgery may also be considered either to interrupt the nervous
pathways or to increase bladder capacity.
§ A common approach is resection of the vesical plexus
approached vaginally. (MCQ)
§ Drugs with antimuscarinic activity e.g. oxybutinin, are used in
the pharmacologic management of detrusor stability because they
inhibit the cholinergically innervated unstable detrusor
muscle contractions. (MCQ)
§ oxybutynin - this drug also has a direct smooth-muscle
relaxant action on the bladder in addition to its antimuscuranic
action, is widely used in the management of detrusor instability.
§ Oxybutin is however associated with a high incidence of side
effects which limits its use.
§ Modified release oxybutinin, propiverine and tolderodine may
be considered as an alternative for patients unable to tolerate
conventional-release oxybutinin (MCQ)
§ propiverine, solifenacin and trospium are newer
antimuscarinic drugs licensed for urinary frequency, urgency, and
incontinence(MCQ)
§ Neurogenic bladder
o Bladder can be Over or Underactive d/t in the presence of any
neuological disorder
o Example - DM - Underactive Bladder d/t Peripheral Neuropathy
o Atonic neurogenic bladder (a sensory neurogenic bladder)
§ neurogenic bladder due to destruction of sensory nerve fibers
from the bladder to the spinal cord(MCQ)
§ absence of control of bladder functions and of desire to urinat e, bladder
overdistention
§ an abnormal amount of residual urine
§ As the bladder fills, incontinence and dribbling occur, but no
micturition reflex is initiated by the increase in pressure.
§ usually associated with tabes dorsalis or pernicious anemia.
(MCQ)
o Automatic bladder (A UMN bladder)
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§ neurogenic bladder due to complete transection of the spinal


cord above the sacral segments(MCQ)
§ loss of micturition reflexes and bladder sensation(MCQ)
§ involuntary urination
§ automatic is a hypertonic or spastic bladder....lesion at or
above D12
§ an abnormal amount of residual urine. (MCQ)
o Autonomic bladder (A LMN Bladder)
§ neurogenic bladder due to a lesion in the sacral spinal cord
§ interrupting the reflex arc controlling the bladder (MCQ)
§ with loss of normal bladder sensation and reflexes
§ inability to initiate urination normally (MCQ)
§ incontinence. (MCQ)
§ autonomic bladder....lower motor neuron at or below the
level of S2...flaccid bladder
§ Treatment
o Stress incontinence may be treated with surgical and nonsurgical
means. (MCQ)
o Urge incontinence may be treated with behavioral modification or
with bladder-relaxing agents. (MCQ)
o Mixed incontinence may require medications as well as surgery.
o Overflow incontinence may be treated with some type of catheter
regimen. (MCQ)
o Functional incontinence may be resolved by treating the underlying cause
(eg, urinary tract infection, constipation ) or by simply changing a few
medications.

Topic- Brain herniation

§ Brain herniation
o The movement of brain tissue into a space that it does not normally
occupy, which can lead to coma and death.
o It is usually caused by a mass/lesion; can be caused by a bleed.
o Classification
§ Transtentorial herniation: (MCQ)
• The upper thalamic region herniates down- ward
through the tentorium.
§ Uncal herniation
• a common type of transtentorial herniation in which the
gyrus moves through the anterior section of the
tentorial opening.
• The third nerve is often affected by the brain tissue that
is displaced. (MCQ)
• Patients often present with an
o enlarged pupil on the ipsilateral side of the
herniation (MCQ)
o contralateral hemiparesis. (MCQ)
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• This is often followed by coma. (MCQ)


§ Subfalcine herniation:
• The cingulate gyrus herniates across the midline. (MCQ)
• Clinically, this may compromise blood flow through the
anterior cerebral artery and can present as a headache.
(MCQ)
• Anterior cerebral artery infarction is a complication of
this type of herniation.
§ Central herniation:
• The entire cerebral hemisphere herniates across the
tentorium as a result of increased intracranial pressure.
§ Tonsillar herniation:
• This is a result of increased pressure in the posterior
fossa, causing parts of the cerebellum to herniate through
the foramen magnum.
• This type of herniation results in compression of the
lower brain stem. (MCQ)
Topic- NPH

• NORMAL PRESSURE HYDROCEPHALUS (NPH)


• A distinct clinical syndrome in the setting of hydrocephalus without in-
creased intracranial pressure
• Etiology
o Most patients have no clear cause for the NPH
o can be seen after a CNS event ( SAH, meningitis, trauma, tumor)
(MCQ)
• Signs and symptoms
o Classic Triad (MCQ)
§ Gait disorder (most responsive to treatment)
§ Urinary incontinence
§ Dementia (most refractory to treatment)
• Diagnosis
o Normal pressure on lumbar puncture (LP) (MCQ)
o Enlarged ventricles on CT or MRI(MCQ)
o Clinical improvement after LP and removal of a volume of CSF
• Treatment
o CSF ventricular shunt(MCQ)
o Choroid plexectomy in some cases
• Clinical Pearls :
o NPH is one of the few reversible causes of dementia. (MCQ)

Topic- Spinal Cord Tumors

Spinal tumors

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o Adults
o extradural – 55%
o intradural extramedullary – 40%
o intramedullary – 5-10%
o In children, 50% intradural lesions are extramedullary, 50% - intramedullary.
o intramedullary tumors are more common in children
o extramedullary tumors are more common in adults.
o Intramedullary spinal tumors
o Pathology
o 90% are benign - subject to potential resection.
o extend over many spinal cord segments* - signs and symptoms are more
variable (than those of extramedullary tumors).
o 70% are associated with cysts
o syringomyelia (most frequent with HEMANGIOBLASTOMA) -
indistinguishable from other forms of syringomyelia.
o 50% in thoracic cord
o Common Intramedullary tumors
o Ependymoma (56-70%; only 30% in children)
o Astrocytoma (29%; in children 55-70%):
o Hemangioblastoma (3-5%)
o Oligodendroglioma (3%)
o ASTROCYTOMAS and EPENDYMOMAS are more common in
patients with neurofibromatosis type 2.
o CLINICAL FEATURES
o Progressive myelopathy (mimics syringomyelia) - Central Cord
Syndrome
o slow-growing nature - symptoms precede diagnosis by ≈ 2 years
(vs. extramedullary tumors – shorter period ).
o neurologic manifestations commonly begin unilaterally (full-
blown Brown-Sequard syndrome is rare), becoming bilateral
when tumor is quite large.
o dull, aching back pain (from level of lesion; local or radiating)
often is earliest symptom!
• characteristically at night when patient is supine (related
to venous outflow
• disturbance); may be increased by coughing or sneezing.
• pain is usually less prominent than of extramedullary
tumor.
o progressive paraparesis predominates early (LMN* → UMN);
scoliosis or torticollis (generally in children).
o at tumor level - aid in localization
• dissociated sensory loss with sacral sparing
• sphincter dysfunction
• trophic changes.
o hydrocephalus (15%, esp. in malignant tumors) – due to increased
CSF viscosity from elevated protein content.
o Intradural Extramedullary Spinal Tumors

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o PATHOLOGY
o most are slow-growing and benign (vs. epidural tumors).
o usually involve only few spinal segments.
o if tumor occludes spinal arteries → myelomalacia.
o Common Extramedullary Spinal Tumors
o Neurofibromas
o Meningiomas
o Schwannomas (Schwann cells form covering of spinal nerve
roots)
o CLINICAL FEATURES
o MYELOPATHY & RADICULOPATHY - Extramedullary Cord
/ Root Compression
o initial symptoms of nerve sheath tumors – prominent focal pain
and paresthesias (involvement of dorsal roots). i.e. tend to cause
RADICULOPATHY before becoming large enough to cause
MYELOPATHY
o initial symptoms of meningiomas – MYELOPATHY
(RADICULOPATHY develops later).
o compression first interrupts functions of pathways that lie at
periphery of spinal cord.
o Somatotopic organization of Fibres
• The fibers that enter the spinal cord below the sixth
thoracic segment form the fasciculus gracilis (gracile tract),
whereas fibers that enter the cord above the sixth
thoracic segment are located laterally and form the
fasciculus cuneatus (cuneate tract).
• the nerve fibers in the posterior funiculus are
somatotopically arranged with the greatest number of
medial fibers arising from the sacral levels and the
greatest number of lateral fibers coming from the
cervical levels



o eccentrically placed tumors may cause typical Brown-Sequard
syndrome.
o if untreated → complete loss of function below level of lesion
(complete spinal cord transection).
o large cervical tumors (esp. with extradural component) may be
palpated.
o Extradural Spinal Tumors, Vertebral Tumors

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o PATHOLOGY
o usually involve only few spinal segments.
o occasionally, tumor extends through intervertebral foramina,
lying partially within and partially outside of spinal canal
(“dumbbell” or “hourglass” tumor).
o epidural mass lesion can produce damage to spinal cord:
• mechanical distortion → demyelination, axonal destruction.
• vascular compromise → venous congestion and vasogenic
edema → ischemia,
• myelin loss.
o Metastatic Vertebral Tumors
• typically lymphoma or renal cell cancers
• spine is 3rd most common site for metastasis (after lung
and liver):
• 94-98% - epidural and/or vertebrae
• isolated epidural involvement is particularly common in
lymphoma and renal cell carcinoma.
• 40-80% cancer patients develop bony metastases, most
commonly in vertebrae
• Why metastases favor vertebrae:
– large volume of blood that slowly courses through
bidirectional venous channels (Batson plexus) in
epidural space.
– rich concentration of growth factors in bone
marrow .
o Most common tumors with predilection to metastasize to
vertebrae:
• prostate
• breast
• lung
• renal cell
• gastric
o Primary sources for spinal metastases:
• lung - 31%
• breast - 24%
o Spread from primary tumors:
• arterial route
• retrograde spread through Batson plexus (during
Valsalva maneuver)
• direct invasion through intervertebral foramina
o Vertebral body is often involved first in metastasis;
o 70% symptomatic lesions are found in thoracic region (small
diameter of canal);
o exceptions - prostate and ovarian cancers - metastases favor sacral
and lumbar vertebrae (spread through Batson's plexus)

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o 50% cases have several levels of involvement (in 10-38% sites


are noncontiguous)
o 85 % cases of epidural spinal cord compression arise f rom
vertebral metastases
o 10-15% - from tumors* spreading through intervertebral
foramina.
CLINICAL FEATURES

o Most frequent initial symptom - gradually worsening constant


focal back pain, unresponsive to rest (and may actually be most severe
when recumbent at night forcing some patients to sleep in sitting
position)
o exacerbated by Valsalva maneuver
o percussion tenderness; movement such as turning over in bed
or rising from lying position may be painful
o later – radicular pain may develop;
o *vs. degenerative joint disease – pain may improve with
recumbent position
o Neoplastic disease often presents with back pain indistinguishable
from benign causes!
§ bone pain - bony destruction (stretching of periosteum),
pathologic fractures (vertebral collapse → mechanical
instability).
§ neuropathic pain (root / meningeal irritation).
o Neurologic complications - MYELOPATHY &
RADICULOPATHY - Extramedullary Cord / Root
Compression.
o pain typically precedes signs of cord compression by
weeks ÷ months
o Once cord compression occurs, it is always rapidly
progressive (paraplegia may develop in hours).
o RADICULOPATHY may appear before
MYELOPATHY.
o Constitutional symptoms (in malignant disease)
§ hypercalcemia (polyuria, pre-renal failure).

Clinical Guidelines to Differentiate Intramedullary and


Extramedullary Tumors
Symptoms/Signs Intramedullary Tumors Extramedullary Tumors
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Radicular pain Unusual Common, may occur early


Vertebral pain Unusual Common
Funicular pain Common Less common
Upper motor neuron signs Yes, late Yes, early
Lower motor neuron signs Prominent and diffuse Unusual, if present, segmental
Paresthesiae progression Descending progression distribution
Sphincter abnormalities Early with caudal lesions Ascending
(conus/cauda equine) Late
Trophic changes Common Unusual

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Hematology
Topic - Iron Deficiency Anemia

• Iron deficiency anemia


• Etiology
o Blood loss (chronic GI bleed or menorrhagia most common)
o Malnutrition
o Pregnancy
• Signs and symptoms
o Fatigue, exertional dyspnea
o Glossitis ,Angular cheilosis
o Pallor ,Koilonychia (spoon nails) ,Pica
• Diagnosis
o Low hemoglobin/hematocrit
o Low MCV (microcytic) (MCQ)
o High TIBC (MCQ)
o Low ferritin(MCQ)
o Low Percent transferrin saturation (MCQ)

• Clinical Pearls
• Serum ferritin < 12 mcg/L. (MCQ)
• Iron deficiency is the most common cause of anemia worldwide.
• Absorption occurs in the stomach, duodenum, and upper jejunum ..
• In general, iron metabolism is balanced between absorption of 1 mg/d and
loss of 1 mg/d. (MCQ)
• Pregnancy may also upset the iron balance, since requirements increase to
2–5 mg of iron per day during pregnancy and lactation
• The average monthly menstrual blood loss is approximately 50 mL, or
about 0.7 mg/d. (MCQ)
• Many iron-deficient patients develop pica, craving for specific foods (ice chips,
etc) often not rich in iron.
• After iron stores have been depleted, red blood cell formation will continue
with deficient supplies of iron.
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• Iron deficiency anemia


o Serum iron values decline to less than 30 mcg/dL(MCQ)
o Transferrin levels rise, leading to transferring saturation of less than
15%(MCQ)
o In the early stages, the MCV remains normal(MCQ)
o Subsequently, the MCV falls and the blood smear shows hypochromic
microcytic cells (see blood smear).
o With further progression, anisocytosis (variations in red blood cell size)
and poikilocytosis (variation in shape of red cells) develop.
o Severe iron deficiency will produce a bizarre peripheral blood smear,
with (MCQ)
§ severely hypochromic cells, target cells
§ hypochromic pencil-shaped cells
§ small numbers of nucleated red blood cells
o The platelet count is commonly increased(MCQ)
• Causes of microcytic anemia (MCQ)
o anemia of chronic disease
o thalassemia
o sideroblastic anemia.
o Iron deficiency anemia
• Anemia of chronic disease is characterized by (MCQ)
o normal or increased iron stores in the bone marrow
o normal or elevated ferritin level(MCQ)
o serum iron is low
o total iron-binding capacity (TIBC) is either normal or low(MCQ)
• Oral Ferrous sulfate is the preferred therapy.
o 325 mg three times daily(MCQ)
o provides 180 mg of iron daily of which up to 10 mg is absorbed (MCQ)
o An appropriate response is a return of the hematocrit level halfway
toward normal within 3 weeks with full return to baseline after 2 months.
o Iron therapy should continue for 3–6 months after restoration of normal
hematologic values to replenish iron stores (MCQ)
• Parenteral Iron therapy
o Sodium ferric gluconate is available and has been shown to result in a
lower incidence of severe anaphylaxis , allowing wider use of
parenteral therapy. (MCQ)
o Parenteral Iron dose :
o The dose (total 1.5–2 g) may be calculated by estimating the
decrease in volume of red blood cell mass and then supplying 1
mg of iron for each milliliter of volume of red blood cells below
normal. (MCQ)
o Approximately 1 g should then be added for storage iron(MCQ)
o Total body iron ranges between 2 g and 4 g(MCQ)
§ approximately 50 mg/kg in men
§ 35 mg/kg in women.
o Most (70–95%) of the iron is present in hemoglobin in circulating red
blood cells.

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o One milliliter of packed red blood cells (not whole blood) contains
approximately 1 mg of iron . (MCQ)
o In men
§ red blood cell volume is approximately 30 mL/kg.
§ A 70-kg man will therefore have approximately 2100 mL of
packed red blood cells and consequently 2100 mg of iron in his
circulating blood. (MCQ)
o In women,
§ the red cell volume is about 27 mL/kg(MCQ)
§ a 50-kg woman will thus have 1350 mg of iron circulating in her
red blood cells.
o Hemoglobin iron deficit (mg) = weight (kg) x (14 - Hgb) x
(2.145)
o Volume of product required (mL) = [weight (kg) x (14 - Hgb) x
(2.145)] / C
o Where C= concentration of elemental iron (mg/ml) in the
product being used: (MCQ)
• Iron dextran: 50 mg/mL
• Iron sucrose: 20 mg/mL.
• Ferric gluconate: 12.5 mg/mL

Topic- Macrocytosis Anemia

• Causes of macrocytosis (MCV > 100) (MCQ)


o Folate deficiency
o Vitamin B12 deficiency
o Alcohol abuse
o Liver disease
o Hypothyroidism
o Myelodysplasia
• Folate deficiency anemia
o Anemia is due to impaired DNA synthesis.
o Treatment is oral folate.
o Risk factors (MCQ)
§ Alcoholism
§ Diet low in folic acid
§ Pregnancy
§ Malabsorption
o Signs and Symptoms

§ Diarrhea ,Cheilosis ,Glossitis

o Diagnosis -Blood smear:

§ Macrocytosis (high mean corpuscular volume [MCV]) (MCQ)

§ basophilic stippling(MCQ)
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§ hypersegmented neutrophils(MCQ)

§ low reticulocyte count(MCQ)

• VITAMIN B12 (COBALAMIN) DEFICIENCY

o Etiology

§ Pernicious anemia (no intrinsic factor)

§ Vegan diet (excludes meat, eggs, milk products)

§ Fish tapeworm (Diphyllobothrium latum)

§ Malabsorption (ileal resection, bacterial overgrowth, sprue)

o Signs and symptoms

§ Symptoms of anemia
§ Neurologic symptoms from subacute combined degeneration
of the dorsal columns causing (MCQ)
• paresthesias,
• positive Romberg
• slowed reflexes
• impaired touch and temperature sensitivity
• ataxia
§ Dementia
§ Atrophy of lingual papillae and glossitis(MCQ)
o Diagnosis
§ Blood smear shows macrocytosis, basophilic stippling, hypersegmented
neutrophils, low reticulocyte count
§ Decreased plasma cobalamin levels
• Pernicious anemia
o Absence of intrinsic factor (IF) causing vitamin B12 deficiency.
o Normally, IF and hydrogen ions are both produced by parietal cells of
stomach.
o IF binds to vitamin B12 and is absorbed in the terminal ileum.
o antibodies against parietal cells, destroys them. (MCQ)
o Signs and symptoms
§ Same as vitamin B12 deficiency; insidious onset
§ Associated with vitiligo(MCQ)
§ Associated with chronic gastritis
o Diagnosis
§ Schilling test, anti-IF antibody levels(MCQ)
• Clinical Pearls :
o A 45-year-old male with HIV on HAART, with macrocytosis. Cause?
Zidovudine(MCQ)

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o Folate deficiency can be differentiated from vitamin B12 deficiency by


the lack of neurologic abnormalities. (MCQ)

o Glossitis is a chronic appearance of the tongue characterized by redness


(beefy red), swelling, and loss of papillae.

o Causes of vitamin B12 deficiency “VITAMIN B” (MCQ)

§ Vegan

§ Ileal resection

§ Tapeworm

§ Autoimmune (pernicious anemia)

§ Megaloblastic anemia

§ Inflammation of terminal ileum

§ Nitrous oxide

§ Bacterial overgrowth

o Anemia precedes neurologic symptoms in vitamin B12 deficiency.


(MCQ)
o B12 replacement can cause hypokalemia. (MCQ)
o You should see reticulocytes in peripheral smear by 4th day after
treating Megalobalstic anemia(MCQ)
o Pernicious anemia is associated with an increased risk of gastric
cancer. (MCQ)

o Causes of normochromic, normocytic anemia: (MCQ)

§ Bone marrow problems

• aplastic anemia, myelodysplastic syndrome

§ Anemia of chronic disease

§ Early deficiency in iron, B12, folate

o Serum vitamin B 12 level less than 100 pg/mL (MCQ)


o Vitamin B12 absorption (MCQ)
§ Other cobalamin-binding proteins ( called R factors) compete
with intrinsic factor for vitamin B 12.
§ Vitamin B12 bound to R factors cannot be absorbed.

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§ The vitamin B12–intrinsic factor complex travels through the


intestine and is absorbed in the terminal ileum by cells with
specific receptors for the complex.
§ It is then transported through plasma and stored in the liver.
o Three plasma transport proteins have been identified.
§ Transcobalamins I and III (differing only in carbohydrate
structure) are secreted by white blood cells. (MCQ)
§ Although approximately 90% of plasma vitamin B 12 circulates
bind to these proteins, only transcobalamin II is capable of
transporting vitamin B 12 into cells. (MCQ)
§ The liver contains 2000–5000 mcg of stored vitamin B 12. (MCQ)
o Since daily losses are 3–5 mcg/d, the body usually has sufficient stores of
vitamin B12 so that vitamin B 12 deficiency develops more than 3 years
after vitamin B12 absorption ceases. (MCQ)
o Abdominal surgery may lead to vitamin B 12 deficiency in several ways.
o Gastrectomy will eliminate that site of intrinsic factor production
§ Blind loop syndrome will cause competition for vitamin B 12 by
bacterial overgrowth in the lumen of the intestine
§ surgical resection of the ileum will eliminate the site of
vitamin B12 absorption.,
o Pancreatic insufficiency causes failure to inactivate competing
cobalamin-binding proteins(MCQ)
o Severe Crohn disease, causing sufficient destruction of the ileum to
impair vitamin B12 absorption(MCQ)
o Vitamin B12 deficiency manifestations
§ Peripheral nerves are usually affected first, and patients
complain initially of paresthesias. (MCQ)
§ The posterior columns next become impaired, and patients
complain of difficulty with balance.
§ In more advanced cases, cerebral function may be altered as
well, and on occasion dementia and other neuropsychiatric
changes may precede hematologic changes.
o A characteristic finding of Vit B12 deficiency is the macro-ovalocyte,
but numerous other abnormal shapes are usually seen
o Bone marrow morphology in Vitamin B12 deficiency
§ Marked erythroid hyperplasia is present as a response to
defective red blood cell production (ineffective erythropoiesis).
(MCQ)
§ Megaloblastic changes in the erythroid series include
abnormally large cell size and asynchronous maturation of the
nucleus and cytoplasm—ie, cytoplasmic maturation continues
while impaired DNA synthesis causes retarded nuclear
development.
§ In the myeloid series, giant metamyelocytes are
characteristically seen
o Two findings of Vit B12 deficiency which are a reflection of
intramedullary destruction of developing abnormal erythroid cells and
are similar to those observed in peripheral hemolytic anemias.
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§ elevated serum lactate dehydrogenase (LDH) (MCQ)


§ modest increase in indirect bilirubin. (MCQ)
o The diagnosis of vitamin B12 deficiency (MCQ)
§ Normal vitamin B 12 level is > 240 pg/mL
§ most patients with overt vitamin B 12 deficiency will have serum
levels < 170 pg/mL
§ with symptomatic patients usually having levels < 100 pg/mL.
§ A level of 170–240 pg/mL is borderline.
o When the serum level of vitamin B 12 is borderline, the diagnosis is best
confirmed by finding an elevated level of serum methylmalonic acid
(> 1000 nmol/L) (MCQ)
o Patients with pernicious anemia have historically been treated with
parenteral therapy.
§ Intramuscular injections of 100 mcg of vitamin B12 are adequate
for each dose.
§ Replacement is usually given daily for the first week, weekly for
the first month, and then monthly for life (MCQ)
§ A brisk reticulocytosis occurs in 5–7 days
§ hematologic picture normalizes in 2 months.
§ Central nervous system symptoms and signs are reversible if they
are of relatively short duration (less than 6 months) but become
permanent if treatment is not initiated promptly
o Total body stores of folate are approximately 5000 mcg, enough to
supply requirements for 2–3 months.
o Folic acid deficiency is treated with folic acid, 1 mg/d orally. (MCQ)

Topic- Aplastic Anemia

• Marrow failure resulting in severe pancytopenia


• Two mechanisms for are postulated:
o Stem cell defect
o Immune-mediated destruction
• Etiology
o Viral hepatitis
o Chloramphenicol (idiosyncratic)
o Parvovirus B19 with sickle cell anemia (MCQ)
o Benzene (dose related), lindane, DDT
• Signs and symptoms
o Weakness, fatigue
o Mucosal bleeding
o Pallor
• Diagnosis
o Normochromic, normocytic pancytopenia
o Low reticulocyte count(MCQ)
• Treatment
o Bone marrow transplant is treatment of choice

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o prior blood transfusions can impair success due to sensitization to minor


HLA antigens. (MCQ)
o Immunosuppression (steroids, cyclophosphamide) (MCQ)
• Clinical Pearls :
o Patients with erythema infectiosum (causative agent: parvovirus B19)
should avoid contact with patients with sickle cell anemia due to the risk
of aplastic anemia. (MCQ)
o No abnormal cells seen on peripheral smear
o Causes of aplastic anemia. (MCQ)
§ Congenital (rare)
§ "Idiopathic" (probably autoimmune)
§ Systemic lupus erythematosus
§ Chemotherapy, radiotherapy
§ Toxins: benzene, toluene, insecticides
§ Drugs: chloramphenicol, phenylbutazone, gold salts, sulfonamides, phenytoin,
carbamazepine, quinacrine, tolbutamide
§ Posthepatitis
§ Pregnancy
§ Paroxysmal nocturnal hemoglobinuria
o Causes of pancytopenia. (MCQ)
§ Bone marrow disorders
• Aplastic anemia
• Myelodysplasia
• Acute leukemia
• Myelofibrosis
• Infiltrative disease: lymphoma, myeloma, carcinoma, hairy cell
leukemia
• Megaloblastic anemia
§ Nonmarrow disorders
• Hypersplenism
• Systemic lupus erythematosus
• Infection: tuberculosis, AIDS, leishmaniasis, brucellosis
o Severe aplastic anemia is defined by a (MCQ)
§ neutrophil count of less than 500/mcL
§ platelets less than 20,000/mcL
§ reticulocytes less than 1%,
§ bone marrow cellularity less than 20%
o Treatment of choice for young adults (under age 50) who have HLA-matched
siblings is allogeneic bone marrow transplantation. (MCQ)
o Children or young adults may also benefit from allogeneic transplantation
using an unrelated donor. (MCQ)
o For adults over age 50 years or those without HLA-matched donors, the
treatment of choice for severe aplastic anemia is immunosuppression with
antithymocyte globulin (ATG) plus cyclosporine (or tacrolimus) (MCQ)
o High-dose immunosuppression with cyclophosphamide, has produced
remissions in refractory cases and should be considered for patients without
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suitable bone marrow donors. (MCQ)


o Androgens (oxymetholone) have been widely used in the past, with a low
response rate.

Topic- Hemolytic Asnemia

• Immune-mediated hemolytic anemia


o Presence of autoantibodies to one’s RBCs, resulting in hemolysis and
splenomegaly
o Warm hemolytic anemia
§ Most common form of immune-mediated hemolytic anemia
§ IgG antibodies to Rh factor (MCQ)
§ Do not usually fix complement (MCQ)
§ Active at body temperature
§ Treated with steroids(MCQ)
§ Seen with lymphomas, leukemias, SLE, and other autoimmune diseases, and
drugs. (MCQ)
§ Sixty percent of cases are idiopathic.
o Cold hemolytic anemia
§ IgM antibodies(MCQ)
§ Active at cool temperatures (dissociate at 3°C) such as in distal
body parts
§ Fixes complement(MCQ)
§ Seen acutely with mycoplasma and infectious mononucleosis
(resolve spontaneously) (MCQ)
§ Seen chronically with myeloproliferative disorders(MCQ)
§ Degree of hemolysis is variable.
§ Treatment includes keeping warm and corticosteroids.
o Paroxysmal cold hemoglobinuria
§ Also called cold hemolysis
§ IgG antibodies against P group antigen (Donath–Landsteiner Ab)
(MCQ)
§ Active at cool temperatures, dissociate at 3°C to cause hemolysis
§ Fix complement(MCQ)
§ Clinically characterized by acute intermittent massive hemolysis
and hemoglobinuria following exposure to cold(MCQ)
• Clinical Pearls :
o The antibody is most commonly directed against a basic component of
the Rh system present on most human red blood cells.
§ When IgG antibodies coat the red blood cell, the Fc portion of the
antibody is recognized by macrophages present in the spleen and
other portions of the reticuloendothelial system. (MCQ)
§ The interaction between splenic macrophage and the antibody-
coated red blood cell results in removal of red blood cell membrane
and the formation of a spherocyte because of the decrease in
surface-to-volume ratio of the red blood cell.
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§ These spherocytic cells have decreased deformability and become


trapped in the red pulp of the spleen because of their inability to
squeeze through the 2-mcm fenestrations.
o When large amounts of IgG are present on red blood cells, complement may
be fixed. (MCQ)
o Direct lysis of cells is rare, but the presence of C3b on the surface of red
blood cells allows Kupffer cells in the liver to participate in the hemolytic
process because of the presence of C3b receptors on Kupffer cells.
(MCQ)
o Approximately 10% of patients with autoimmune hemolytic anemia have
coincident immune thrombocytopenia (Evans syndrome). (MCQ)
o Reticulocytosis is usually present(MCQ)
o Spherocytes are seen on the peripheral blood smear
o In cases of severe hemolysis, the stressed bone marrow may also release
nucleated red blood cells
o The Coombs antiglobulin test forms the basis for diagnosis. (MCQ)

§ The Coombs reagent is a rabbit IgM antibody raised against human


IgG or human complement.
§ Because the patient's serum usually contains the autoantibody , it
may be difficult to obtain a compatible cross-match with donor's
cells.
o Treatment with rituximab, a monoclonal antibody against the B cell antigen
CD20, is effective in some cases. (MCQ)
o High-dose intravenous immune globulin may be highly effective in
controlling hemolysis. (MCQ)
o Splenectomy is often successful in controlling the disorder. (MCQ)
o Cold agglutinin disease
o Cold agglutinin disease is an acquired hemolytic anemia due to an IgM
autoantibody usually directed against the I antigen on red blood
cells. (MCQ)
o Increased reticulocytes and spherocytes on peripheral blood smear.
o Coombs test positive only for complement. (MCQ)
o Positive cold agglutinin test. (MCQ)
o Hemolysis results indirectly from attachment of IgM , which in the
cooler parts of the circulation (fingers, nose, ears) binds and fixes
complement
o When the red blood cell returns to a warmer temperature, the IgM
antibody dissociates, leaving complement on the cell. (MCQ)

Topic- Hereditary Spherocytosis

Hereditary spherocytosis

• a disorder of the red blood cell membrane


• leads to chronic hemolytic anemia
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• The membrane defect in hereditary spherocytosis is an abnormality in spectrin


or actin, the proteins providing most of the scaffolding for the red blood cell
membranes.
• The result is a decrease in surface-to-volume ratio that results in a spherical
shape of the cell.
• These spherical cells are less deformable and unable to pass through 2-mcm
fenestrations in the splenic red pulp.
• Hemolysis takes place because of trapping of red blood cells within the spleen.
• Symptoms and Signs
o autosomal dominant disease of variable severity. (MCQ)
o It is often diagnosed during childhood
o Anemia may or may not be present, since the bone marrow may be able
to compensate for shortened red cell survival.
o Severe anemia (aplastic crisis) may occur in folic acid deficiency or
when bone marrow compensation is temporarily impaired by infection.
o Chronic hemolysis causes jaundice and pigment (calcium bilirubinate)
o gallstones, leading to attacks of cholecystitis .
o Examination may reveal icterus and a palpable spleen. -
• Laboratory Findings
o The anemia is of variable severity, and the hematocrit may be normal.
Reticulocytosis is always present.
o The peripheral blood smear shows the presence of spherocytes, small
cells that have lost their central pallor.
o Hereditary spherocytosis is the only important disorder associated with
microcytosis and an increased mean corpuscular hemoglobin
concentration (MCHC), often greater than 36 g/dL. (A very High yield
MCQ)
o As with other hemolytic disorders, there may be an increase in indirect
bilirubin.
o The Coombs test is negative. (A very High yield MCQ)
o Because spherocytes are red cells that have lost some membrane
surface, they are abnormally vulnerable to swelling induced by
hypotonic media.
o Increased osmotic fragility merely reflects the presence of spherocytes
and does not distinguish hereditary spherocytosis from other
spherocytic hemolytic disorders such as autoimmune hemolytic anemia.
o Cytometry has the advantages of better reliability and the ability to
distinguish spherocytes from other red blood cell abnormalities such as
elliptocytosis.
• Treatment
o Patients should receive uninterrupted supplementation with folic acid
(MCQ)
o The treatment of choice is splenectomy (MCQ)

Topic - Sickle cell anemia

• autosomal recessive disorder (MCQ)


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• abnormal hemoglobin leads to chronic hemolytic anemia


• A single DNA base change leads to an amino acid substitution of valine for
glutamine in the sixth position on the Beta-globin chain. (MCQ)
• The abnormal Beta chain has a tetramer of alpha2Beta(s)2 is designated
hemoglobin S. (MCQ)
• The rate of sickling is influenced by a number of factors (MCQ)
o most importantly by the concentration of hemoglobin S in the
individual red blood cell. Red cell dehydration makes the cell quite
vulnerable to sickling.
o Hemoglobin F cannot participate in polymer formation, and its
presence markedly retards sickling.
o Other factors that increase sickling are those that lead to formation of
deoxyhemoglobin S, eg, acidosis and hypoxemia, either systemic or
locally in tissues.
• Clinical Findings
o The disorder has its onset during the first year of life, when hemoglobin
F levels fall as a signal is sent to switch from production of Gamma-
globin to Beta-globin. (MCQ)
o Chronic hemolytic anemia produces jaundice, pigment (calcium
bilirubinate) gallstones, splenomegaly, and poorly healing ulcers
over the lower tibia.
o Severe anemia is produced by hemolytic or aplastic crises.
o Aplastic crises occur when the ability of the bone marrow to
compensate is reduced by viral or other infection or by folate
deficiency. (MCQ)
o Hemolytic crises may be related to splenic sequestration of sickled
cells (primarily in childhood, before the spleen has been infarcted as a
result of repeated sickling) or with coexistent disorders such as G6PD
deficiency.
o Acute painful episodes due to acute vaso-occlusion may occur
spontaneously or be provoked by infection, dehydration, or hypoxia.
§ Common sites of acute painful episodes include the bones
(especially the back and long bones) and the chest .
§ Acute vaso-occlusion may also cause strokes due to sinus
thrombosis and priapism. (MCQ)
§ Vaso-occlusive episodes are not associated with increased
hemolysis.
§ Repeated episodes of vascular occlusion affect a large number of
organs, especially the heart, lungs, and liver.
§ Ischemic necrosis of bone occurs, rendering the bone
susceptible to osteomyelitis due to staphylococci or (less
commonly) salmonellae. (MCQ)
§ Infarction of the papillae of the renal medulla causes renal
tubular concentrating defects and gross hematuria , more
often encountered in sickle cell trait than in sickle cell anemia.
(MCQ)

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§ Retinopathy similar to that noted in diabetes is often present and


may lead to blindness. (MCQ)
§ Pulmonary hypertension may develop and is associated with a
poor prognosis.
o These patients are prone to delayed puberty. (MCQ)
o An increased incidence of infection is related to hyposplenism as well as
to defects in the alternative pathway of complement.
o On examination, patients are often chronically ill and jaundiced.
o There is hepatomegaly, but the spleen is not palpable in adult life.
o The heart is enlarged, with a hyper-dynamic precordium and systolic
murmurs. (MCQ)
o Nonhealing ulcers of the lower leg and retinopathy may be present.
• Laboratory Findings
o Chronic hemolytic anemia is present.
o The hematocrit is usually 20-30%.(MCQ)
o The peripheral blood smear is characteristically abnormal, with
irreversibly sickled cells comprising 5-50% of red cells.
o Other findings include reticulocytosis (10-25%), nucleated red blood
cells, and hallmarks of hyposplenism such as Howell-Jolly bodies and
target cells. The white blood cell count is characteristically elevated
to 12,000-15,000/mcL(MCQ)
o thrombocytosis may occur.
o Indirect bilirubin levels are high.
o Most clinical laboratories offer a screening test for sickle cell hemoglobin,
and the diagnosis of sickle cell anemia is then confirmed by hemoglobin
electrophoresis
o Hemoglobin F levels are variably increased, and high hemoglobin F
levels are associated with a more benign clinical course.
• Treatment
o Patients are maintained on folic acid supplementation
o given transfusions for aplastic or hemolytic crises .
o Pneumococcal vaccination reduces the incidence of infections with
this pathogen. (MCQ)
o The patient should be kept well hydrated, and oxygen should be given
if the patient is hypoxic.
o Acute vaso-occlusive crises can be treated with exchange transfusion.
(MCQ)
o These are primarily indicated for the treatment of intractable pain
crises, priapism, and stroke.
o Long-term transfusion therapy has been shown to be effective in
reducing the risk of recurrent stroke in children.
o Cytotoxic agents increase hemoglobin F levels by stimulating
erythropoiesis in more primitive erythroid precursors.
§ Hydroxyurea reduces the frequency of painful crises in patients
whose quality of life is dis¬rupted by frequent pain crises. (MCQ)
o Allogeneic bone marrow transplantation is being studied as a possible
curative option for severely affected young patients.
• Sickle cell trait
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o Patients with the heterozygous genotype (AS) have sickle cell trait.
o These persons are clinically normal and have acute painful episodes
only under extreme conditions such as vigorous exertion at high
altitudes (or in unpressurized aircraft).
o They may, however, have a defect in renal tubular function, causing an
inability to concentrate the urine, and experience episodes of gross
hematuria. (MCQ)
o A screening test for sickle hemoglobin will be positive
o hemoglobin electrophoresis will reveal that approximately 40% of
hemoglobin is hemoglobin S
• Hemoglobin C disorders
o Hemoglobin C is formed by a single amino acid substitu¬tion at the
same site of substitution as in sickle hemoglobin but with lysine instead
of valine substituted for glutamine at the Beta 6 position. (MCQ)
o Hemoglobin C is nonsickling but may participate in polymer
formation in association with hemoglobin S.
o The peripheral blood smear shows generalized red cell targeting and
occasional cells with rectangular crystals of hemoglobin C. (MCQ)

Topic- Thalasemia

• Types of hemoglobin (MCQ)


o Hemoglobin A: 2/2 globin chains (normal hemoglobin)
o Hemoglobin F: 2/2 globin chains (fetal hemoglobin)
o Hemoglobin A2: 2/2
• Normal distribution of Hb in adults is: 96%- HbA 3%- HbF 1%- HbA2
• There are two and one gene on each chromosome, making a total of four
genes and two genes in each chromosome pair.
• Thalassemia
o Genetic defects causing gene deletions of chains
o Epidemiology
§ /—thalassemia trait is most common in Asians. (MCQ)
§ –/–thalassemia trait is most common in Africans.
o Pathophysiology
§ Ineffective production of globin chains causes globin
chains to accumulate. (MCQ)
o Signs and symptoms
§ Depends on how many of the four foci are deleted or mutated:
(MCQ)
• 1/4 foci involved silent thalassemia ,Asymptomatic
• 2/4 foci involved thalassemia trait ,Mild anemia
• 3/4 foci involved
o Hemoglobin H disease
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o Microcytic, hypochromic, hemolytic anemia with


marked splenomegaly.
o Patient may need occasional transfusions.
• 4/4 foci involved 
o Hemoglobin Barts
o hydrops fetalis
o Incompatible with life
o Diagnosis
§ Blood smear: Microcytic anemia, hypochromia, target cells, Heinz
bodies(MCQ)
§ HbH precipitates on staining with brilliant cresyl blue(MCQ)
• Beta-thalassemia
o Gene defects including deletions, abnormalities of transcription and
translation, and instability of mRNA in globin hemoglobin
o Pathophysiology
§ Ineffective production of globin chains causes globin chains
to accumulate in the cell.
§ The accumulation of chains form insoluble aggregates that
damage cell membranes.
§ A partial compensatory increase of the and chains yields
elevated levels of HbA2 (22) or HbF (22). (MCQ)
o Signs and symptoms
§ -Thalassemia major (Cooley’s anemia): Associated with jaundice,
hep- atosplenomegaly, and jaundice
§ -Thalassemia minor: Mild or no anemia
o Diagnosis
§ Elevated HbF and HbA2 measurements on hemoglobin
electrophoresis
o Treatment
§ -Thalassemia major: (MCQ)
• Aggressive transfusions
• Splenectomy to enhance survival of RBCs , bone marrow
transplant
§ -Thalassemia minor: No treatment indicated.
• Clinical Pearls :
o Abnormal red blood cell morphology with microcytes, acanthocytes, and
target cells. (MCQ)
o In -thalassemia, elevated levels of hemoglobin A 2 or F . (MCQ)
o The thalassemias are hereditary disorders characterized by reduction in the
synthesis of globin chains ( or ).
o Two copies of the -globin gene are located on chromosome 16, (MCQ)
o The -globin gene resides on chromosome 11 adjacent to genes encoding
the -like globin chains, and .(MCQ)
o In cases of severe thalassemia, the marked expansion of the erythroid
element in the bone marrow may cause severe bony deformities,
osteopenia, and pathologic fractures.

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o Hemoglobin electrophoresis will show the presence of a fast migrating


hemoglobin (hemoglobin H), which comprises 10–40% of the
hemoglobin. (MCQ)
o A peripheral blood smear can be stained with supravital dyes to
demonstrate the presence of hemoglobin H. (MCQ)
o Compared to iron deficiency anemia, patients with thalassemia have a (MCQ)
§ lower MCV
§ a more normal red blood count
§ a more abnormal peripheral blood smear at modest levels of anemia.
§ Iron studies are normal.
o Patients with hemoglobin H disease (MCQ)
§ should take folate supplementation
§ avoid medicinal iron and oxidative drugs such as sulfonamides.
o Patients with severe thalassemia are maintained on a regular transfusion
schedule and receive folate supplementation.
o Splenectomy is performed if hypersplenism causes a marked increase in the
transfusion requirement.
o Patients with regular transfusion requirements should be treated with iron
chelation
o Subcutaneous infusion of deferoxamine has largely been replaced by the oral
agent deferasirox. (MCQ)
o Allogeneic bone marrow transplantation is the treatment of choice for -
thalassemia major(MCQ)

Topic- Polycythemia vera (pv)

• A myeloproliferative disease that results in increased red blood cells, in addition to


mild increases in leukocytes and platelets
• Etiology
• Primary PV: A primary bone marrow cause (low erythropoietin)
• Secondary PV (other causes that result in increased erythropoietin) (MCQ)
o Hypoxia (high altitudes, lung disease)
o Smoking (due to carboxyhemoglobin)
o Renal cell carcinoma
• Males more commonly affected (MCQ)
• More common in people 60
• Associated with high risk of cerebrovascular accidents (hypercoagulation), MIs,
and bleeding(MCQ)
• Risk of progression to leukemia or myelofibrosis (MCQ)
• Signs and symptoms
• Pruritus, Plethora
• Splenomegaly ,Epistaxis (MCQ)
• Neuro symptoms such as vision changes
• Diagnosis
• Low erythropoietin in primary(MCQ)

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• High erythropoietin in secondary


• Treatment
• Serial phlebotomy to decrease blood volume
• Consider hydroxyurea for myelosuppression (in primary) (MCQ)
• Aspirin to prevent thrombosis(MCQ)
• Clinical Pearls :
• 2° polycythemia is associated with hypernephroma, cerebellar hemangioma, hepatoma,
and giant uterine myomas. (MCQ)

• Bone marrow fibrosis is a late complication of polycythemia vera.

• Increased red blood cell mass.

• Splenomegaly is seen in PV(MCQ)

• Normal arterial oxygen saturation. is seen in PV(MCQ)

• A mutation in JAK2, a signaling molecule, has been demonstrated in 95% of


cases(MCQ)
• Common complaints related to expanded blood volume and increased blood
viscosity are headache, dizziness, tinnitus, blurred vision, and fatigue

• Generalized pruritus (Aquagenic pruritis) (MCQ)

o especially following a warm shower or bath

o related to histamine release from the basophilia.

• Epistaxis

o related to engorgement of mucosal blood vessels in combination with abnormal


hemostasis due to qualitative abnormalities in platelet function.

• median age at presentation is 60 years.

• Thrombosis

o most common complication of polycythemia vera (MCQ)

o major cause of morbidity and death in this disorder.

o It is related both to increased blood viscosity and abnormal platelet function..

o Paradoxically, in addition to thrombosis, increased bleeding also


occurs.

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• There is a high incidence of peptic ulcer disease (MCQ)

• The hallmark of polycythemia vera is a hematocrit above normal, at times greater


than 60%.(MCQ)

• Red blood cell morphology is normal

• The bone marrow is hypercellular, with panhyperplasia of all hematopoietic


elements

o bone marrow examination is usually not necessary to establish the


diagnosis.

• Iron stores are usually absent from the bone marrow, having been transferred
to the increased circulating red blood cell mass.

• Spurious polycythemia(MCQ)

o an elevated hematocrit is due to contracted plasma volume rather than


increased red cell mass,

o related to diuretic use or may occur without obvious cause.

• One unit of blood (approximately 500 mL) is removed weekly until the
hematocrit is less than 45%;

• Anagrelide may be substituted or added when hydroxyurea is not well tolerated but is
not the preferred initial agent. (MCQ)

• Over time, polycythemia vera may convert to myelofibrosis or to chronic


myeloid leukemia. (MCQ)

Topic- Multiple Myeloma

• Malignant disease of plasma cells that is characterized by:


o Presence of monoclonal immunoglobulin or light chains in the serum
and urine
o Bone destruction (lytic lesions) because myeloma cells produce
osteoclastic activating factor (MCQ)
• Median age at diagnosis 68
• Signs and symptoms MCQ)
o Hypercalcemia
o Pathologic fractures/lytic bone lesions
o Renal failure
o Anemia
• Diagnosis
o Radiography: Lytic lesions on x-ray MCQ)
o Electrophoresis: Monoclonal elevation of one immunoglobulin
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o Urinalysis: Free kappa and lambda light chains (Bence Jones proteins)
o Bone marrow biopsy: 10 to 20% plasma cells (normal is 5%)
o Peripheral smear: Rouleaux formation MCQ)
• TREATMENT
o There is no cure.
o Chemotherapy: MCQ)
§ Alkylating agent (melphalan or cyclophosphamide)
§ Thalidomide (antiangiogenesis agent)
§ Prednisone
o Calcitonin, bisphosphonates for high calcium
o Bone marrow transplant is effective MCQ)
• Clinical pearls :
• Multiple myeloma:
o Common triad of back pain, anemia, and renal insufficiency.
• Clinical Vignette in MD Entrance

o A 60-year-old man with punched out lytic lesioin the skull and mild
anemia. MCQ)

§ Diagnosis : Multiple myeloma.

• Clinical Vignette in MD Entrance ( MCQ)

• A 68-year-old man presents with low back pain, hypercalcemia,


anemia, and azotemia.

o Diagnosis : Multiple myeloma.

o Malignant plasma cells can form tumors (plasmacytomas) that may cause
spinal cord compression

o Very high paraprotein levels (either IgG or IgA) may cause hyperviscosity,
though this is more often caused by IgM in Waldenström macroglobulinemia.
(MCQ)

o The light chain component of the immunoglobulin often leads to kidney failure
(often aggravated by hypercalcemia). (MCQ)

o Light chain components may be deposited in tissues as amyloid, worsening


kidney failure with albuminuria (MCQ)

o Myeloma patients are especially prone to infections with encapsulated


organisms such as Streptococcus pneumoniae and Haemophilus influenzae.

o Splenomegaly is absent unless amyloidosis is present

o The hallmark of myeloma is the finding of a paraprotein on serum protein


electrophoresis (SPEP). (MCQ)

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o The majority of patients will have a monoclonal spike visible in the -


or -globulin region

o Overall, approximately 60% of patients with myeloma will have an IgG


paraprotein, 25% an IgA, and 15% light chains only. (MCQ)

o In sporadic cases, no paraprotein is present (" nonsecretory myeloma");


these patients have particularly aggressive disease

o The bone marrow will be infiltrated by variable numbers of plasma cells ranging
from 20% to 100%

o Lytic lesions are most commonly seen in the axial skeleton: skull, spine,
proximal long bones, and ribs.

o The radionuclide bone scan is not useful in detecting bone lesions in myeloma,
as there is usually no osteoblastic component.

o The International Staging System for myeloma relies on two factors, 2 -


microglobulin and albumin. (MCQ)

o Stage 1 patients have both 2 -microglobulin < 3.5 mg/L and albumin
3.5

o Stage 3 is diagnosed when 2 -microglobulin > 5.5 mg/L,

o Stage 2 is diagnosed with values in between.

o The other laboratory finding of important prognostic significance is genetic


abnormalities diagnosed by FISH involving the immunoglobulin heavy chain
locus at chromosome 14q32. (MCQ)

o The translocations involved are usually t(4;14) and less commonly t(14;16).
(MCQ)

o Abnormalities of chromosome 17p also appear to confer a poor prognosis.


(MCQ)

o Hypercalcemia is an important laboratory finding in myeloma and is associated


with kidney failure. (MCQ)

o Monoclonal gammopathy of unknown significance (MGUS) ( MCQ)

o MGUS is far more common than myeloma.

o Most commonly, patients with MGUS will have a monoclonal IgG


spike less than 2.5 g/dL, and the height of the spike remains stable.

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o In approximately 25% of cases, MGUS progresses to overt malignant


disease, but this may take many years.
o Myeloma is distinguished from MGUS by findings of replacement of the
bone marrow, bone destruction, and progression.

o If there is doubt about whether paraproteinemia is benign or


malignant, the patient should be observed without therapy, since there
is no advantage to early treatment of asymptomatic multiple myeloma.

o Treatment :

o lenalidomide

§ second-generation agent

§ both more active and less toxic than thalidomide (MCQ)

§ major side effect of lenalidomide is cumulative


myelosuppression

§ some type of prophylaxis is needed to prevent deep venous


thrombosis(MCQ)

o Bortezomib

§ a proteosome inhibitor(MCQ)

§ highly active

§ has the advantages of producing rapid responses and of being


effective in poor-prognosis myeloma.

§ The major side effect of bortezomib is neuropathy (both


peripheral and autonomic), ( MCQ)

§ it has the disadvantage of requiring frequent intravenous


administration.

o 2 Induction regimes(MCQ)

§ At the present time, induction therapy should include


dexamethasone and either lenalidomide or bortezomib or
both.

§ The combination of bortezomib, dexamethasone, and the


chemotherapeutic agent doxorubicin liposomal is also highly
successful.

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o After induction therapy, the optimal consolidation therapy for patients


under age 70 years with myeloma is autologous stem cell
transplantation.
o Allogeneic transplantation
§ potentially curative in myeloma
§ its role has been limited because of the unusually high
mortality rate (40–50%) in myeloma patients
§ Patients who derive significant benefit from autologous stem
cell transplantation as part of initial therapy. ( MCQ)
• Patients with low-stage disease (low 2-microglobulin
and normal albumin)
• who lack the high-risk genomic changes involving
chromosome 14q32 respond very well to treatment

Topic- Leukemogenic factors

Leukemogenic factors (MCQ)


o radiation and some toxins (benzene)
o cyclophosphamide, melphalan, other alkylating agents
o etoposide
• The leukemias seen after toxin or chemotherapy exposure often develop from a
myelodysplastic prodrome and are often associated with abnor¬malities in
chromosomes 5 and 7 (MCQ)
• Acute lymphoblastic leukemia (ALL)
• comprises 80% of the acute leukemias of childhood
• peak incidence is between 3 and 7 years of age.
• It is also seen in adults, causing approximately 20% of adult acute
leukemias.
• The hallmark of acute leukemia is the combination of pancytopenia with
circulating blasts.
• However, blasts may be absent from the peripheral smear in as many as 10%
of cases ("aleukemic leukemia").
• The bone marrow is usually hypercellular and dominated by blasts.
• More than 20% blasts are required to make a diagnosis of acute leukemia.
(MCQ)
• Hyperuricemia maybe seen.
• Patients with ALL (especially T cell) may have a mediastinal mass visible
on chest radiograph. (MCQ)
• AML cells usually express myeloid antigens such as CD 13 or CD
33(MCQ)
• ALL cells of B lineage (MCQ)
o express CD 19, common to all B cells
o most cases will express CD 10, formerly known as the " common ALL
antigen."
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• ALL cells of T lineage (MCQ)


o usually not express mature T-cell markers, such as CD 3,4, or 8
o express some combination of CD 2, 5, and 7
o do not express surface immunoglobulin.
• Almost all ALL cells express terminal deoxynucleotidyl transferase (TdT).
(MCQ)
• The uncommon Burkitt type of ALL has a "lymphoma" phenotype,
expressing CD19, CD20 and surface immunoglobulin but not TdT.
(MCQ)
• ALL is most usefully classified by immunologic phenotype as follows:
common, early B lineage, and T cell. (MCQ)
• In ALL, the hyperdiploidy (with more than 50 chromosomes) is
associated with a better prognosis, but is seldom seen in adults.
• Unfavorable cytogenetics in ALL are the Philadelphia chromosome
t(9;22) and t(4;ll), which has fusion genes involving the MLL gene at
Ilq23. (MCQ)
• Differential Diagnosis
o ALL must be separated from other lymphoproliferative disease such as
chronic lymphocytic leukemia, lymphomas, and hairy cell
leukemia.
o It may also be con-fused with the atypical lymphocytosis of
mononucleosis and pertussis.
• Treatment
• What is complete remission? (MCQ)
§ complete remission is defined as normal peripheral blood
with resolution of cytopenias, normal bone marrow with no
excess blasts, and normal clinical status.
• Adults with ALL are treated with combination chemotherapy, including
daunorubicin, vincristine, pred-nisone, and asparaginase . (MCQ)
• This treatment produces complete remissions in 90% of patients .
• Those patients with Philadelphia chromosome-positive ALL (or bcr-abl
plus ALL) should have imatinib (or dasatinib) added to their initial
chemotherapy. (MCQ)
• Remission induction therapy for ALL is less myelosuppressive than
treatment for AML and does not necessarily produce marrow aplasia.
• After achieving complete remission, patients receive central nervous
system prophylaxis so that meningeal sequestration of leukemic cells
does not develop.
• Chemotherapy versus high-dose chemotherapy plus bone marrow
transplantation. (MCQ)
§ As with AML, patients may be treated with either chemotherapy
or high-dose chemotherapy plus bone marrow
transplantation.
§ Low-risk patients with ALL may be treated with chemotherapy with
a 70% chance of cure.

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§ Intermediate-risk patients have a 30-50% chance of cure with


chemotherapy, High-risk patients with adverse cytogenetics
or poor responses to chemotherapy are best treated with
allogeneic transplantation.
• Autologous transplantation is a possibility in high-risk patients who
lack a suitable donor. (MCQ)

Topic- Acute Myelocytic Leukemia (AML)

• Acute Myelocytic Leukemia (AML)


• More common in adults
• association with benzene (MCQ)
• 8 subtypes M0–M7:
o M1–M3 have granulocytic differentiation. (MCQ)
o M4 and M5 are monocytic precursors. (MCQ)
o M6 have predominance of erythroblasts. (MCQ)
o M7 is mainly megakaryocytic. (MCQ)
• Signs and symptoms
o Fatigue, hemorrhage, or bruising (30%) (MCQ)
o Infection of lung, skin (25%)
o Splenomegaly is rare (25%) compared to other types of leukemia.
• Diagnosis
o M3:
§ Associated with DIC, Auer rods(MCQ)
§ t(15;17) (MCQ)
§ add all-trans retinoic acid to chemo
o M5:
§ Associated with gingival hyperplasia(MCQ)
o M4, M5: CNS manifestations(MCQ)
• t(8;21) and t(15;17) have better prognosis. (MCQ)
• Treatment
o Three steps of chemotherapy:
§ Induction:
• High doses of chemotherapy are used to induce remission.
§ Consolidation:
• Chemotherapy is then administered to eradicate
residual,undetectable malignant cells.
§ Maintenance:
• Ongoing chemotherapy to keep the number of malignant
cells low
§ Complete remission is the goal in cancer patients.
• Definition of CR
o normal marrow elements are being produced
o less than 5% residual blasts are present in the bone
marrow .
§ Induction:
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• Cytarabine an anthracycline (daunorubicin) (MCQ)


§ 50 to 80% receive remission
§ Stem cell transplantation is also potentially curative.
§ M3 treated with all-trans retinoic acid in addition to cytarabine and
daunorubicin. (MCQ)
• Clinical Pearls :
o M3 = DIC

o M5 = gingival hyperplasia

o Adverse effects of chemotherapy agents: (MCQ)


§ Cisplatin= nephrotoxicity
§ Bleomycin= pulmonary fibrosis
§ Vincristine= neurotoxic, palsies
§ Doxorubicin = cardiotoxic
§ Tamoxifen vaginal bleeding
§ Acute lukemia
o More than 20% blasts in the bone marrow. (MCQ)

o Blasts in peripheral blood in 90% of patients.

§ a number of chemotherapeutic agents may cause leukemia especially(MCQ)

o cyclophosphamide

o melphalan

o other alkylating agents, and etoposide

§ Acute promyelocytic leukemia (APL)

o characterized by chromosomal translocation t(15;17) (MCQ)

o produces the fusion gene PML-RAR which interacts with the retinoic
acid receptor(MCQ)

o produce a block in differentiation that can be overcome with


pharmacologic doses of retinoic acid

§ The most dramatic presentation is hyperleukocytosis

o a markedly elevated circulating blast count (usually > 200,000/mcL)

o leads to impaired circulation, presenting as headache, confusion, and


dyspnea.

o Such patients require emergent leukapheresis and chemotherapy.

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§ Patients with ALL (especially T cell) may have a mediastinal mass visible on
chest radiograph

§ The Auer rod, an eosinophilic needle-like inclusion in the cytoplasm, is


pathognomonic of AML (see micrograph) and, if seen, secures the diagnosis
(MCQ)

§ Histochemistry of AML will demonstrate (MCQ)

o peroxidase in myeloid cells

o butyrate esterase in monocytic cells

o ALL cells will not contain either of these enzymes.

§ Cytogenetics :

o AML cells

§ usually express myeloid antigens such as CD 13 or CD 33(MCQ)

§ ALL cells of B lineage will express CD19, common to all B cells

§ most cases of ALL will express CD10, formerly known as the


"common ALL antigen." (MCQ)

o ALL cells of T lineage

§ usually not express mature T-cell markers, such as CD 3, 4, or 8,


(MCQ)

§ express some combination of CD 2, 5, and 7 (MCQ)

§ do not express surface immunoglobulin.

o Almost all ALL cells express terminal deoxynucleotidyl transferase


(TdT). (MCQ)

o The uncommon Burkitt type of ALL

§ has a "lymphoma" phenotype

§ express CD19. CD20 and surface immunoglobulin but not TdT.


(MCQ)

o APL –

§ has unique biologic features


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• unique response to non-chemotherapy treatments.

• characterized by the cytogenetic finding of t(15;17) and the


fusion gene PML-RAR alpha. (MCQ)

o AML

§ Favorable cytogenetics

• t(8;21) and inv(16)(p13;q22) (MCQ)

• termed the "core-binding factor" leukemias because of


common genetic lesions affecting DNA-binding
elements.

• These patients have a higher chance of achieving both


short- and long-term disease control.

o AML of intermediate risk - largest subgroup

§ Favorable cytogenetics

• mutations of nucleophosmin 1 (NPM1) (MCQ)

• lacking the internal tandem duplication of the FLT3 gene.


(MCQ)

§ cytogenetics causing poor prognosis

• monosomy 5 or 7(MCQ)

§ For patients with high-risk APL based on an initial white blood cell count >
10,000/mcL, the addition of arsenic trioxide may be beneficial (MCQ)

§ Allogeneic transplantation is the treatment of choice, but cure rates are only
20–30%.
Topic- CML

• CML
• myeloproliferative condition
• has 25% risk/year of transforming to acute leukemia (blastic
transformation).(MCQ)
• Signs and symptoms
o Chronic phase:
§ WBC counts increase, spleen and liver enlarge
o Accelerated phase:
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§ RBC, platelets decrease


§ symptoms include bone pain,fever, night sweats, and weight loss
o Blastic phase:
§ Peripheral blood and marrow are filled with rapidly proliferating
leukemic blast cells.
• Diagnosis
o Examining the peripheral blood film shows increased myeloblasts and
basophils, white blood cells
o Leukocyte alkaline phosphatase is low in CML cells. (MCQ)
o 90% have Philadelphia chromosome t(9;22). (MCQ)
• Treatment
o Allogenic bone marrow transplant treatment of choice for younger
patients(MCQ)
o Imatinib inhibits Philadelphia chromosome and induces indefinite
remission (MCQ)
o Chemotherapy
§ busulfan and hydroxyurea (MCQ)
• for those that cannot have BMT (chronic phase)
§ vincristine and prednisone (MCQ)
• for those in the accelerated/blastic phase.
• Clinical Pearls :
o Better prognosis of CML is associated with: (MCQ)
§ Young age(<40)
§ No thrombocytopenia
§ Early stage
§ Low percentage of blasts
o 90% of patients with CML have the Philadelphia chromosome t(9;22).
(MCQ)

o Philadelphia chromosome
§ a reciprocal translocation between the long arms of chromosomes 9
and 22(MCQ)
§ A large portion of 22q is translocated to 9q, and a smaller piece of
9q is moved to 22q.
§ The portion of 9q that is translocated contains abl, a protooncogene
that is the cellular homolog of the Ableson murine leukemia virus.
§ The abl gene is received at a specific site on 22q, the break point
cluster (bcr). (MCQ)
§ The fusion gene bcr/abl produces a novel protein that differs from
the normal transcript of the abl gene in that it possesses tyrosine
kinase activity (a characteristic activity of transforming genes).
(MCQ)
o Rarely, the patient will present with a clinical syndrome related to
leukostasis(MCQ)
§ Presents with blurred vision, respiratory distress, or priapism .
§ white blood count in these cases is usually greater than
500,000/mcL.
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o the spleen is enlarged in CML (often markedly so),


o sternal tenderness may be present as a sign of marrow overexpansion.
o The peripheral blood is characteristic
§ The myeloid series is left-shifted, with mature forms dominating and
with cells usually present in proportion to their degree of maturation.
§ Blasts are usually less than 5%.
§ Basophilia and eosinophilia of granulocytes may be present.
(MCQ)
§ At presentation, the patient is usually not anemic.
§ Red blood cell morphology is normal, and nucleated red blood cells
are rarely seen.
§ The platelet count may be normal or elevated (sometimes to
strikingly high levels).
o The hallmark of the disease is that the bcr/abl gene is detected by the
polymerase chain reaction (PCR) test in the peripheral blood.
o A bone marrow examination
§ not necessary for diagnosis
§ it is useful for prognosis and for detecting additional
chromosomal abnormalities in addition to the Philadelphia
chromosome.
o Blast phase CML is diagnosed when blasts comprise more than 30% of
bone marrow cells.
§ Treatment is usually not emergent even with white blood counts
over 200,000/mcL, since the majority of circulating cells are mature
myeloid cells that are smaller and more deformable than primitive
leukemic blasts(MCQ)
o A "major cytogenetic response" is identified when < 35% of metaphases
contain the Philadelphia chromosome
o A "complete cytogenetic response" indicates the absence of the
abnormal chromosome by standard cytogenetic testing.
o The current goal of therapy is to achieve a "good molecular response," with
at least a 3-log reduction in bcr/abl level. (MCQ)
o Patients with an accelerated phase of CML should initially be treated with
imatinib, , or dasatinib, but should be considered for allogeneic
transplantation
o The only proven curative therapy for CML is allogeneic bone marrow
transplantation. (MCQ)
o The best results (80% cure rate) of BMT are obtained in patients (MCQ)
§ who are under 40 years of age
§ transplanted within 1 year after diagnosis from HLA-matched
siblings

Topic- CLL

• Chronic lymphocytic lukemia


• Most common type of leukemia (MCQ)

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• Malignant clonal disorder of mature lymphocytes which can disrupt normal


marrow elements of production (MCQ)
• Since it predominantly affects the B cells, there is an impairment of the humoral
immunity
• Generally a chronic disorder that can last for years
• Signs and symptoms
o Lymphadenopathy and splenomegaly often present at discovery of
disease
o Infections because of neutropenia, hypogammaglobulinemia(MCQ)
o At later stages of disease, patient may have symptoms of fever, night
sweats, weight loss(MCQ)
• Diagnosis
o Often suspected or found incidentally on routine CBC (increased
lymphocytes)
o Lymph node biopsy
o Usually B cell origin
• Treatment

o There is no cure, but several treatments are effective

o often, just watchful waiting initially

o Drugs for CLL(MCQ)


§ Fludarabine (purine analog)
§ Rituximab (antibody to CD20) (MCQ)
§ Alkylating agent like chlorambucil or cyclophosphamide
§ COP: Cyclophosphamide, vincristine, prednisone (MCQ)
§ IV IgG for hypogammaglobulinemia(MCQ)

Clinical Pearls :

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• CLL shows Coexpression of CD19, CD5 on lymphocytes. (MCQ)


• The hallmark ofCLL is isolated lymphocytosis. (MCQ)
o The white blood count is usually greater than 20,000/
• The immunophenotype of CLL demonstrates coexpression of (MCQ)
o B lymphocyte lineage marker CD19
o T lymphocyte marker CD5
o this finding is commonly observed only in CLL and mantle cell lymphoma
• CLL is distinguished from mantle cell lymphoma by (A frequently asked MCQ)
o the expression of CD23
o low expression of surface immunoglobulin and CD20
o absence of overexpression of cyclin D1.
• Patients whose CLL cells have mutated forms of the immunoglobulin gene have a
more indolent form of disease (MCQ)
o these cells typically express low levels of the surface antigen CD38
o do not express the zeta-associated protein (ZAP-70).
• Cytogenetics and Prognosis : (MCQ)
o The finding of deletions of chromosome 17p or 11q confers a poor
prognosis
o those whose only genomic change is deletion of 13q have a very
favorable outcome.
• Indications for treatment (MCQ)
o progressive fatigue,
o symptomatic lymphadenopathy, or anemia or thrombocytopenia.
o These patients have either symptomatic and progressive Rai stage II
disease or stage III/IV disease
• The initial treatment of choice is the combination of the chemotherapeutic agent
fludarabine plus the antibody rituximab , with or without the addition of the
chemotherapeutic drug cyclophosphamide(MCQ)
• The addition of cyclophosphamide
o appears to have greater anti-leukemic effectiveness
o also increases the risk of treatment-related infection
• Chlorambucil was the standard treatment prior to the development of
fludarabine. (MCQ)
• Monoclonal antibody alemtuzumab (MCQ)

o approved for treatment of refractory CLL

o can be especially useful in clearing the blood and bone marrow of


disease.

o it produces significant immunosuppression

o its role in primary therapy has been limited due to the risk of severe and
fatal infections.

• Lenalidomide - effective in refractory cases of CLL (MCQ)


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• Investigational agent flavopiridol (MCQ)

o produced encouraging results in types of CLL (such as those with deletions


of 17p) that have not responded to other treatments.
• Associated autoimmune hemolytic anemia or immune thrombocytopenia may
require treatment with rituximab, prednisone, or splenectomy.
• Allogeneic transplantation (MCQ)
o offers potentially curative treatment for patients with CLL
o it should be used only in patients whose disease cannot be controlled by
standard therapies.
• Nonmyeloablative allogeneic transplant has produced encouraging results and may
expand the role of transplant in CLL. (MCQ)
• Some subtypes of CLL with genomic abnormalities such as 17p deletions have a
sufficiently poor prognosis with standard therapies that early intervention with
allogeneic transplant is needed(MCQ)

Topic- Lymphoma

• Hodgkin’s lymphoma
o Follicular B cells undergo a transformation to malignant cells. (MCQ)
o Four subtypes based on histology of lymph node and cell type: (MCQ)
§ Lymphocyte predominant
§ Nodular sclerosing:
• Most common type(MCQ)
• typically presents as cervical lymph node enlargement or
mediastinal mass
§ Mixed cellularity
§ Lymphocyte depleted:
• Rare, worst prognosis (MCQ)
• Disease with bimodal distribution having peaks in 30s
and 70s
• May have an association with Epstein–Barr virus (EBV)
(MCQ)
o Clinical
§ Presents with asymptomatic lymph node enlargement or CXR
showing mediastinal mass(MCQ)
§ “B” symptoms (MCQ)
• occur in patients with more widespread disease.
• These include fever, night sweats, weight loss, and
shortness of breath .
o Diagnosis
§ Lymph node biopsy
§ Presence of Reed–Sternberg cells is required for diagnosis.
(MCQ)

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o Treatment
§ Curable depending on stage.
§ Based on staging and pathology, both chemotherapy and
radiotherapy are utilized(MCQ)
§ prognosis is dependent on extension of disease .
§ Generally, if the lesion is small and only on one side of the
diaphragm, radiation is used alone. (MCQ)
§ Otherwise, add chemotherapy. (MCQ)
• Non-hodgkin’s lymphoma
o Most originate from B cells.
o B cell lymphomas are further classified based on the tissue type
origination from lymph node: germinal center, mantle zone, or
marginal zone
o The working classification is most widely used
§ It categorizes lymphoma by low, intermediate, and high grade
based on median survival.
o Signs and symptoms/treatment
§ Lymphadenopathy
§ Fatigue, weight loss, fever, and night sweats are common
symptoms.
§ Involvement of mesenteric nodes and extranodal disease is
more common. (MCQ)
§ Hepatosplenomegaly
o Follicular NHL
§ A common presentation of the low-grade follicular
lymphomas is asymptomatic, painless, diffuse, long-
standing lymphadenopathy in a middle-aged individual. (MCQ)
§ Bone marrow involvement is present in the majority of patients.
(MCQ)
§ Treatment includes alkylating agent (cyclophosphamide) and
prednisone. (MCQ)
§ Least aggressive (MCQ)
§ median survival is 6 years.
o Diffuse Large Cell Lymphoma type NHL
§ Most common intermediate-grade lymphoma
§ Diffuse large cell lymphoma may present in a variety of
extranodal sites,
§ particularly the gastrointestinal tract and the head and neck.
(MCQ)
§ Patients treated with chemotherapy—CHOP (MCQ)
• Cyclophosphamide
• doxorubicin
• vincristine [Oncovin]
• prednisone
o Lymphoblastic Lymphoma type NHL
§ High grade lymphomas derived from thymic T-cells(MCQ)
§ Often seen in children
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§ Associated with a large mediastinal mass (MCQ)


§ Shows testicular, CNS, and marrow involvement(MCQ)
o Burkitt’s Lymphoma type NHL
§ High-grade lymphoma
§ more common in children than adults(MCQ)
§ High incidence of bone marrow involvement
§ African type has higher association with EBV and jaw
involvement than American type.
§ Marrow with “starry-sky” appearance(MCQ)
§ Treatment includes high-dose cyclophosphamide,
methotrexate, and cytarabine and intensive CNS
prophylaxis. (MCQ)
§ Unlike Hodgkin’s disease, histology of the nodes is a major
predictor of prognosis in NHL. (MCQ)
o Prognosis
§ Depends on histology of malignancy, not spread of disease.
§ Generally, prognosis is better if histology is nodular or
follicular and cell size is small. (MCQ)
§ Prognosis is worse if histology is diffuse and cell size is large.
(MCQ)
• Clinical Pearls
o Non Hodgkins Lymphoma :
§ Often presents with painless lymphadenopathy(MCQ)
§ Burkitt lymphoma
• characteristic cytogenetic abnormality of translocation
between the long arms of chromosomes 8 and 14 has
been identified. (MCQ)
• The protooncogene c-myc is translocated from its
normal position on chromosome 8 to the heavy chain locus on
chromosome 14(MCQ)
• Cells committed to B cell differentiation are likely to have
enhanced expression of this heavy chain locus
• overexpression of c-myc (in its new anomalous
position) is related to malignant transformation.
§ Follicular lymphomas
• the t(14,18) translocation is characteristic (MCQ)
• results in overexpression of bcl-2, resulting in
protection against apoptosis (MCQ)
§ Bone marrow involvement is manifested as paratrabecular
lymphoid aggregates
§ In some high-grade lymphomas, the meninges are involved and
malignant cells are found with cerebrospinal fluid cytology.
§ The chest radiograph may show a mediastinal mass in
lymphoblastic lymphoma. (MCQ)
§ The serum LDH has been shown to be a useful prognostic
marker and is now incorporated in risk stratification of treatment

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§ Treatment with the anti-CD20 antibody rituximab is a


commonly used treatment because of its very low toxicity and
avoidance of chemotherapy. (MCQ)
§ Common chemotherapy regimens include
• fludarabine
• the combination of cyclophosphamide, vincristine, and
prednisone (R-CVP) (MCQ)
• cyclophosphamide, doxorubicin, vincristine, prednisone
(R-CHOP). (MCQ)
§ Radioimmunoconjugates - yttrium-90 ibritumomab
tiuxetan(MCQ)
• fuse anti-B cell antibodies with radiation
• produce improved results
§ Some patients with clinically aggressive low-grade
lymphomas may be appropriate candidates for allogeneic
transplantation.
§ Those with lymphoblastic lymphoma receive regimens similar
to those used for T cell ALL.
§ Mantle cell lymphoma
• not effectively treated with standard chemotherapy regimens.
• Intensive initial therapy including autologous stem cell
transplantation has been shown to improve outcomes
and is now the standard of care.
• Reduced-intensity allogeneic stem cell
transplantation offers curative potential.
§ Patients with mucosal associated lymphoid tumors (MALT
lymphomas) of the stomach
• treated with combination antibiotics directed against
Helicobacter pylori (MCQ)
• require frequent endoscopic monitoring.
§ Factors that confer adverse prognosis are
• age over 60 years
• elevated serum LDH(MCQ)
• stage III or stage IV disease
• poor performance status
o Hodgkin disease
§ The malignant cell is derived from B lymphocytes of germinal
center origin.
§ An important feature of Hodgkin disease is its tendency to arise
within single lymph node areas and spread in an orderly
fashion to contiguous areas of lymph nodes. (MCQ)
§ Only late in the course of the disease will vascular invasion lead
to widespread hematogenous dissemination
§ The staging nomenclature (Ann Arbor) is as follows: (MCQ)
• Stage I, one lymph node region involved

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• Stage II, involvement of two lymph node areas on one side


of the diaphragm
• Stage III, lymph node regions involved on both sides of
the diaphragm
• Stage IV, disseminated disease with bone marrow or
liver involvement
• stage A if they lack constitutional symptoms
• stage B if 10% weight loss over 6 months, fever, or night sweats
are present.
§ Treatment of Hodgkin disease (MCQ)

• Radiation therapy used as initial treatment only for patients


with low-risk stage IA and IIA disease.

o addition of limited chemotherapy for some


patients treated with radiation appears promising.
• Most patients with Hodgkin disease (including all with
stage IIIB and IV disease) are best treated with
combination chemotherapy using doxorubicin
(Adriamycin), bleomycin, vincristine, and
dacarbazine (ABVD)

Topic-PNH

• Paroxysmal nocturnal hemoglobinuria (PNH)


• an acquired clonal stem cell disorder (MCQ)
• results in abnormal sensitivity of the red blood cell membrane to lysis by
complement.
• underlying cause is a defect in the gene for phosphatidylinositol class A (PIC-
A) which results in a deficiency of the glycosylphosphatidylinositol (GPI)
anchor for cellular membrane proteins. (MCQ)
• the complement-regulating proteins CD55 and CD59 are deficient. (MCQ)
• Clinical Findings
o Classically, patients report episodic hemoglobinuria resulting in reddish
brown urine. (MCQ)
o Hemoglobinuria is most often noticed in the first morning urine, (MCQ)
o prone to anemia
o prone to thrombosis(MCQ)
§ especially mesenteric and hepatic vein thrombosis
§ central nervous system (saggital vein) thrombosis
§ skin thrombosis, with formation of painful nodules.

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§ hypercoagulopathy may be related to platelet activation by


complement.
o As this is a stem cell disorder, PNH may progress either to aplastic anemia,
to myelodysplasia, or to acute myeloid leukemia. (MCQ)
o Suspect PNH in confusing cases of hemolytic anemia or pancytopenia.
• Laboratory findings
o Anemia (MCQ)
§ reticulocytosis
§ macro-ovalocytes.
o Since the episodic hemolysis in PNH is intravascular, the finding of urine
hemosiderin is a useful test. (MCQ)
o Serum LDH is characteristically elevated. (MCQ)
o Iron deficiency is commonly present and is related to chronic iron loss from
hemoglobinuria, since hemolysis is primarily intravascular.
o The white blood cell count and platelet count may be decreased
o The best screening test is flow cytometry to demonstrate deficiency of
CD59 and CD55 on red blood cells. (MCQ)
o Bone marrow morphology is variable and may show either generalized
hypoplasia or erythroid hyperplasia.
o Flow cytometric assays may confirm the diagnosis by demonstrating the
absence of CD59. (MCQ)
o Flow cytometry is best screening test. (MCQ)
• Treatment
• Prednisone is effective in decreasing hemolysis, and some patients can be
managed effectively with alternate-day steroids. (MCQ)
• In severe cases and cases of transformation to myelodysplasia, allogeneic
bone marrow transplantation has been used to treat the disorder.
• The anti-complement C5 antibody eculizumab has been shown to be
effective in reducing hemolysis and transfusion requirements. (MCQ)

Topic- Hairy cell leukemia

o Hairy cell leukemiais an indolent cancer of B lymphocytes.


o Clinical Findings
§ characteristically presents in middle-aged men.
§ median age at presentation is 55 years
§ here is a striking 5:1 male predominance.
§ Most patients present with gradual onset of fatigue,
§ symptoms related to markedly enlarged spleen (MCQ)
§ symptoms related to infection.
§ Splenomegaly is almost invariably present and may be massive.
(MCQ)
§ liver is enlarged in 50% of cases (MCQ)
§ lymphadenopathy is uncommon.

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§course is dominated by pancytopenia and recurrent infections,


including mycobacterial infections. (MCQ)
o Laboratory findings
§ The hallmark of hairy cell leukemia is pancytopenia. (MCQ)
§ Anemia is nearly universal
§ Nearly all patients have striking monocytopenia, which is
encountered in almost no other condition. (MCQ)
§ "hairy cells" (MCQ)
• usually present in small numbers on the peripheral blood smear
• have a characteristic appearance with numerous
cytoplasmic projections
§ Bone marrow
• usually inaspirable (dry tap),
• diagnosis is made by characteristic morphology on bone
marrow (MCQ)
• hairy cells have a characteristic histochemical staining pattern,
with tartrate-resistant acid phosphatase (TRAP) (MCQ)
§ On immunophenotyping, the cells co-express the antigens CD11c
and CD22. Pathologic examination of the spleen (MCQ)
§ HCL shows marked infiltration of the red pulp with hairy cells .
• his is in contrast to the usual predilection of lymphomas to
involve the white pulp of the spleen. (MCQ)
o Treatment
§ The treatment of choice is intravenous cladribine (2-
chlorodeoxyadenosine; CdA), (MCQ)
§ Treatment with pentostatin produces similar results, but that drug is
more cumbersome to administer. (MCQ)
§ More than 95% of patients with hairy cell leukemia will live longer
than 10 years.

Topic- Myelodysplastic

• Myelodysplastic syndromes are a group of acquired clonal disorders of the


hematopoietic stem cell
• They are characterized by the constellation of cytopenias, a usually hypercellular
marrow, and a number of morphologic and cytogenetic abnormalities.
• usually idiopathic
• may be seen after cytotoxic chemotherapy.
• Ultimately, the disorder may evolve into acute myeloid leukemia, and the term
"preleukemia" has been used in the past to describe these disorders.
• there are frequently abnormalities involving the long arm of chromosome 5 (which
contains a number of genes encoing both growth factors and receptors involved in
myelopoiesis) as well as deletions of chromosomes 5 and 7. (MCQ)
• Myelodysplasia without excess bone marrow blasts are termed "refractory anemia," with
or without ringed sideroblasts.

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• One important subgroup of the refractory anemia patients are those with the 5q-
syndrome, characterized by the cytogenetic finding of loss of part of the long arm
of chromosome 5. (MCQ)
• Those with excess blasts are diagnosed as "refractory anemia with excess blasts"
(RAEB 5-19% blasts). (MCQ)
• Those with a proliferative syndrome including peripheral blood monocytosis
greater than 1000/mcL are termed " chronic myelomonocytic leukemia"
(CMML). (MCQ)
• An International Prognostic Scoring System (IPSS) has been developed that
classifies patients by risk status based on the percentage of bone marrow blasts,
cytogenetics, and the severity of cytopenias(MCQ)
• Clinical Findings
o Patients are usually over age 60 years.
o Many are diagnosed while asymptomatic because of the finding of
abnormal blood counts
o Patients usually present with fatigue, infection, or bleeding related to
bone marrow failure.
o The course may be indolent, and the disease may present as a wasting
illness with fever, weight loss, and general debility.
o On examination, splenomegaly may be present in combination with
pallor, bleeding, and various signs of infection.
• Laboratory Findings
o Anemia may be marked and may require transfusion support.
o The MCV is normal or i ncreased(MCQ)
o macro-ovalocytes may be seen on the peripheral blood smear.
o neutropenia is common.
§ neutrophils may exhibit a deficient segmentation of the nucleus
with bilobed nucleus (Pelger-Huet) (MCQ)
o The myeloid series may be left shifted
o Small numbers of promyelocytes or blasts may be seen.
o hypogranular platelets may be present.
o The bone marrow is characteristically hypercellular, but may be
hypocellular. (MCQ)
§ Erythroid hyperplasia is common, and signs of abnormal
erythropoiesis include megaloblas-tic features, nuclear
budding, or multinucleated erythroid precursors
§ Prussian blue stain may demonstrate ringed sideroblasts.
§ myeloid series is often left shifted, with variable increases in
blasts.
§ A characteristic abnormality is the presence of dwarf
megakaryocytes with a unilobed nucleus.
o Cytogenetic abnormalities in the bone marrow are characteristic of
myelodysplasia
§ patients with an indolent form of the disease have an isolated
partial deletion of chromosome .5 (5q- syndrome) . (MCQ)
§ monosomy 7 or complex abnormalities is associated with
more aggressive disease. (MCQ)
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• Differential Diagnosis
o Myelodysplasia is arbitrarily separated from acute myeloid leukemia by
the presence of less than 20% blasts. (MCQ)
• Treatment
o Lenalidomide
§ approved for the treatment of transfusion-dependent anemia
due to myelodysplasia.
§ treatment of choice in patients with the 5q- cytogenetic
abnormality(MCQ)
§ most common side effects are neutropenia and
thrombocytopenia
§ venous thrombosis is also seen and warrants prophylaxis with
aspirin. (MCQ)
o Deferasirox(MCQ)
§ Iron chelation in order to prevent serious iron overload
§ Oral agent has largely replaced the cumbersome use of
subcutaneous infusion of deferox-amine.
§ Patients affected primarily with severe neutropenia may benefit
from the use of myeloid growth factors such as G-CSF ..
o Azacitidine (5-azacytidine) (MCQ)
§ approved as an effective treatment based on its ability to improve
both symptoms and blood counts and to prolong both overall
survival and the time to conversion to acute leukemia
§ treatment of choice for many patients, especially those with
higher risk disease based on increased blasts in the bone
marrow
§ Decitabine, can produce similar responses.
o Antithymocyte globulin (ATG).
o Allogeneic stem cell transplantation (MCQ)
§ only curative therapy for myelodysplasia(MCQ)
§ its role is limited by the advanced age of many patients and the
indolent course of disease in some subsets of patients.
• Prognosis
o Myelodysplasia is an ultimately fatal disease
o Patients with refractory anemia may survive many years, and the risk
of leukemia is low (< 10%). (MCQ)
o Those with excess blasts or CMML have short survivals (usually < 2
years) and have a higher (20-50%) risk of developing acute leukemia.

Topic- Myelofibrosis

• Myelofibrosis (myelofibrosis with myeloid metaplasia, agnogenic myeloid


metaplasia)
• a myeloproliferative disorder characterized by fibrosis of the bone marrow ,
splenomegaly, and a leukoerythroblastic peripheral blood picture with teardrop
poikilocytosis (MCQ)

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• In response to bone marrow fibrosis, extramedullary hematopoiesis takes place in


the liver, spleen, and lymph nodes.
• abnormalities of JAK2 signaling pathways may be involved in the pathogenesis.
(MCQ)
• Clinical Findings
o Myelofibrosis develops in adults over age 50 years and is usually insidious
in onset.
o Patients most commonly present with f atigue due to anemia or abdominal
fullness related to splenomegaly. (MCQ)
o On examination, splenomegaly is almost invariably present and is
commonly massive.
o The liver is enlarged in more than 50% of cases.
o Anemia becomes severe, requiring transfusion.
o Progressive thrombocytopenia leads to bleeding.
o The spleen continues to enlarge, which leads to early satiety.
o Painful episodes of splenic infarction may occur.
o Late in the course, the patient becomes cachectic and may experience severe
bone pain, especially in the upper legs.
o Hematopoiesis in the liver leads to portal hypertension with ascites,
esophageal varices
o transverse myelitis is caused by myelopoiesis in the epidural space.
• Laboratory Findings . , { ,.
o Patients are almost invariably anemic at presentation
o The peripheral blood smear is dramatic, with significant poikilocytosis and
numerous teardrop forms in the red cell line.
o Nucleated red blood cells are present and the myeloid series is shifted, with
imma¬ture forms including a small percentage of promyelocytes or
myeloblasts.
o Platelet morphology may be bizarre, and giant degranulated platelet
forms (megakaryocyte frag¬ments) may be seen.
o The triad of teardrop poikilocytosis, leukoerythroblastic blood, and
giant abnormal platelets is highly suggestive of myelofibrosis. (MCQ)
o The bone marrow usually cannot be aspirated (dry tap), though early in
the course of the disease it is hypercellular, with a marked increase in
megakaryocytes. (MCQ)
o Fibrosis at this stage is detected by a silver stain demonstrating increased
reticulin fibers(MCQ)
o Later, biopsy reveals more severe fibrosis, with eventual replacement of
hematopoietic precursors by collagen
• Differential Diagnosis
o A leukoerythroblastic blood picture from other causes may be seen in
response to severe infection, inflammation, or infiltrative bone marrow
processes. However, teardrop poikilocytosis and giant abnormal platelet
forms will not be present. (MCQ)
o Bone marrow fibrosis may be seen in metastatic carcinoma, Hodgkin
disease, and hairy cell leukemia. (MCQ)

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o Concerning other myeloproliferative disorders, chronic myeloid leukemia


is diagnosed when there is marked leukocytosis, normal red blood cell
morphology, and the presence of the bcr/abl fusion gene
o Polycythemia vera is characterized by an elevated hematocrit.
o Essential throm-bocytosis shows predominant platelet count elevations.
• Treatment Course & Prognosis
o Thalidomide(MCQ)
§ has produced definite responses with acceptable toxicity
§ lenalidomide has at least the same efficacy with less toxicity.
o Clinical trials testing the effect of JAK2 inhibitors are currently being
performed
o Allogeneic bone marrow transplantation has been performed successfully
with 50% long-term survival and should be considered in younger patients.
(MCQ)
o Splenectomy is not routinely performed but is indicated for splenic enlargement
causing recurrent painful episodes, severe thrombocytopenia, or an
unacceptable transfusion requirement.
o Median survival from time of diagnosis is approximately 5 years(MCQ)

Topic- Hemophilia

• Hemophilia A
• Sex-linked recessive disease (MCQ)
• a deficiency of factor VIII
• Signs and symptoms
o Dependent on amount of active factor:
§ 5 to 25% normal factor VIII activity (mild): (MCQ)
• Abnormal bleeding when subjected to surgery or dental
procedures
§ 2 to 5% (moderate) (MCQ)
§ 2% (severe) normal VIII activity: (MCQ)
• Deep tissue bleeding
• intra-articular hemorrhages (usually knees)
• nerve impingement
• intracranial bleeding (following trauma)
• Diagnosis
o Prolonged aPPT, normal bleeding time(MCQ)
o Assess Factor VIII coagulant activity level
• Treatment
o Cryoprecipitate
o Recombinant factor VIII(MCQ)
o DDAVP (desmopressin) for patients with mild hemophilia A
Hemophilia B (christmas disease)

o Pathophysiology
§ X-linked recessive disease (MCQ)
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§ causes a deficiency of factor IX


§ Factor IX assay
o Treatment
§ Fresh frozen plasma (FFP) (MCQ)
§ Recombinant factor IX
• Clinical Pearls :
o FFP - Can be used for both vWD, hemophilias

o Unlike in vWD, bleeding time in hemophilia A is unaffected because no


abnormality with platelets is present. (MCQ)

• DDAVP dose
o 0.3 mcg/kg IV in 50 mL saline over 20 minutes
o nasal spray 300 mcg for weight > 50 kg
o 150 mcg for < 50 kg
o given every 12–24 hours(MCQ)
o maximum of three doses in a 48-hour period.
o If more than two doses are used in a 12–24 hour period, free water
restriction and/or monitoring for hyponatremia is essential. (MCQ)
• EACA useful for mucosal bleeding/dental procedures.
• Factor VIII concentrate
o dose is 50 units/kg IV initially followed by 25 units/kg every 8 hours
followed by lesser doses at longer intervals. (MCQ)
• Factor IX concentrate
o dose is 100 units/kg IV initially followed by 50 units/kg every 8 hours
(MCQ)
o vWF-containing factor VIII concentrate dose is 60–80 RCoF units/kg
IV every 12 hours initially followed by lesser doses at longer intervals
once hemostasis has been established.
• FFP

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o typically administered in 4-unit boluses and may not need to be re-


bolused after the initial administration due to the long half-life of factor
XI.
• The cyclooxygenase (COX)-2 selective nonsteroidal anti-inflammatory drug
celecoxib may be used to treat arthritis symptoms(MCQ)
• generally, other NSAIDs and aspirin should be avoided due to the increased
risk of bleeding from inhibition of platelet function. (MCQ)

Topic- Von willebrand disease

Von willebrand disease

• vWF
o unusually large multimeric glycoprotein
o binds to its receptor, platelet glycoprotein Ib (MCQ)
o bridges platelets together and tethering them to the subendothelial
matrix at the site of vascular injury. (MCQ)
o vWF also has a binding site for factor VIII, prolonging its half-life in
the circulation. (MCQ)
• Type 1 vWD
o Between 75% and 80% of patients with vWD have type 1. (Most
Common type ) (MCQ)
o It is a quantitative abnormality of the vWF molecule that usually does
not feature an identifiable causal mutation in the vWF gene.
• Type 2 vWD
o In type 2A or 2B vWD, a qualitative defect in the vWF molecule is
causative.
o Type 2N and 2M vWD
§ Occur due to defects in vWF that decrease binding to factor
VIII or to platelets, respectively.
§ Type 2N vWD
• clinically resembles hemophilia A, with the exception of
a family history that shows affected females. (MCQ)
• Factor VIII activity levels are markedly decreased, and
vWF activity and antigen (Ag) are normal.
§ Type 2M vWD features a normal multimer pattern.
• Type 3 vWD
o Rare
o mutational homozygosity or double heterozygosity leads to undetectable
levels of vWF and severe bleeding in infancy or childhood.

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• Laboratory Findings
o In type 1 vWD ,the vWF activity (by ristocetin co-factor assay) and
Ag are mildly depressed, whereas the vWF multimer pattern is normal
(MCQ)
o Laboratory testing of type 2A or 2B vWD typically shows a ratio of vWF
Ag:vWF activity of approximately 2:1 and a multimer pattern that lacks
the highest molecular weight multimers.
o Thrombocytopenia is common in type 2B vWD due to a gain-of-
function mutation of the vWF molecule, which leads to increased
binding to its receptor on platelets, resulting in clearance
o a ristocetin-induced platelet aggregation (RIPA) study shows an
increase in platelet aggregation in response to l ow concentrations of
ristocetin. (MCQ)
o Except in the more severe forms of vWD that feature a signifi¬cantly
decreased factor VIII activity, the aPTT and PT in vWD are usually
normal. (MCQ)
• Treatment
o DDAVP
§ useful in the treatment of mild bleeding in most cases of type
1 and some cases of type 2 vWD. (MCQ)
§ DDA VP causes release of vWF and factor VIII from storage
sites, leading to increases in vWF and factor VIII twofold to
sevenfold that of baseline levels
§ Due to tachyphylaxis and the risk of significant hyponatremia
secondary to fluid retention, more than two doses should not be
given in a 48-hour period.
o Cryoprecipitate should not be given due to lack of viral inactivation.
o Antifibrinolytic agents (eg, aminocaproic acid) may be used
adjunctively for mucosal bleeding or procedures.
o Pregnant patients with vWD usually do not require treatment
because of the natural physiologic increase in vWF levels (up to threefold
that of baseline) that are observed by the time of delivery (MCQ)
Bernard-Soulier syndrome (BSS) and Glanzmann thrombasthenia

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o Bernard-Soulier syndrome (BSS)


§ rare, autosomal recessive bleeding disorder (MCQ)
§ it is due to reduced or abnormal platelet membrane expression
of glycoprotein Ib/IX (vWF receptor). (MCQ)
o Glanzmann thrombasthenia
§ results from a qualitative or quantitative abnormality in
glycoprotein Ilb/IIIa receptors on the platelet membrane,
which are required to bind fibrinogen and vWF , both of which
bridge platelets during aggregation. (MCQ)
§ Inheritance is autosomal recessive. (MCQ)
o Laboratory Findings
§ Bernard-Soulier syndrome
• there are abnormally large platelets (approaching the
size of red cells), moderate thrombocytopenia, and a
prolonged bleeding time. (MCQ)
• Platelet aggregation studies show a marked defect in
response to ristocetin, whereas aggregation in
response to other agonists is normal; the addition of
normal platelets corrects the abnormal aggregation.
(MCQ)
• The diagnosis can be confirmed by platelet flow
cytometry. (MCQ)
§ Glanzmann thrombasthenia
• platelet aggregation studies show marked impairment of
aggregation in response to stimulation with typical
agonists. (MCQ)
o Treatment
§ The mainstay of treatment (including periprocedural prophylaxis)
is transfusion of normal platelets , although desmopressin
acetate (DDA VP), antifibrinolytic agents, and recombinant
human activated factor VII also have been used successfully.

Topic- ITP

• ITP
o an autoimmune condition
o pathogenic antibodies bind platelets, resulting in accelerated platelet
clearence.(MCQ)
o The disorder is primary and idiopathic in most adult patients
o it can be associated with
§ connective tissue disease (such as lupus)
§ lymphoproliferative disease (such as lymphoma)
§ medications, and infections (such as hepatitis C virus and HIV
infections).

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o Targets of antiplatelet antibodies include glycoproteins Ilb/IIIa and


Ib/IX on the platelet membrane ( MCQ)
o antibodies are demonstrable in only two-thirds of patients .
o direct suppression of platelet production occur in HIV and cirrhosis-
related splenomegaly [hepatitis C virus]
o Clinical Findings
§ Mucocutaneous bleeding manifestations may be present,
depending on the platelet count.
§ The typical presentation of drug-induced thrombocytopenia
involves detection of severe thrombocytopenia and
mucocutaneous bleeding 7-14 days after exposure to a new
drug. (MCQ)
o Laboratory Findings
§ Bone marrow should be examined in patients with additional
unexplained cytopenias, in patients older than 60 years, or in
those who did not respond to primary ITP-specific therapy.
§ Megakaryocyte abnormalities and hypo-cellularity or
hypercellularity are not characteristic of ITP (MCQ)
§ If there are clinical findings suggestive of a lymphoproliferative
malignancy, a CT scan should be performed.
§ In the absence of such findings, otherwise asymptomatic
patients with unexplained isolated thrombocytopenia of
recent onset may be considered to have ITP .
o Treatment
§ Discontinuation of the offending agent leads to resolution of
drug-induced thrombocytopenia within 7-10 days in most cases
§ For other etiologies of ITP , only individuals with platelet
counts < 20,000-30,000/mcL or those with significant
bleeding should be treated; the remainder may be monitored
serially for progression. (MCQ)
§ The mainstay of initial treatment is a short course of
corticosteroids with or without IVIG or anti-D (WinRho)
(MCQ)
§ Responses are generally seen within 3-5 days of initiating
treatment.
§ Platelet transfusions may be given concomitantly if active
bleeding is present.
§ Although over two-thirds of patient s with ITP respond to initial
treatment, most relapse following reduction of the corticosteroid
dose.
§ Patients with a persistent platelet count < 30,000/mcL or
clinically significant bleeding are appropriate candidates for
treatment. (MCQ)
§ To bring the platelet count into a safe range quickly, an
increased dose of corticosteroids can be administered initially,
with the goal of rapid taper once the response has been regained.
§ Then, IVIG or anti-D may be administered once every 2-3
weeks as directed by platelet counts < 30,000/mcL; serial anti-
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D treatment may allow adult patients to delay or avoid


splenectomy.
§ The monoclonal anti-B cell antibody rituximab leads to initial
responses in about 50% of adults with corticosteroid-refractory
chronic ITP . (MCQ)
§ thrombopoietin receptor agonists (MCQ)
• romiplostim (administered subcutaneously weekly)
• eltrombopag (taken orally daily)
• led to improvement in platelet counts in most patients with
prednisone-refractory ITP
§ Splenectomy
• has a durable response rate of over 60
• usually is reserved for cases of severe thrombocytopenia
that is refractory to second-line agents
• patients should receive pneumococcal, Haemophilus
influenzae type b, and meningococcal vaccination at
least 2 weeks before the procedure. ( MCQ)
• If available, laparoscopic splenectomy is preferred
§ Management of pregnancy-associated ITP
• The goal of management of pregnancy-associated ITP is a
platelet count > 10,000/mcL in any trimester, >
30,000/ mcL during the second or third trimester, or >
50,000/mcL prior to cesarean section or vaginal delivery.
(MCQ)
• Moderate-dose oral prednisone or intermittent
infusions of IVIG are standard. (MCQ)
• Splenectomy is reserved for failure to respond to these
therapies and may be performed in the first or second
trimester. (MCQ)

Topic- Thrombotic Thrombocytopenic Purpura

• Thrombotic thrombocytopenic purpura (TTP))


o A hemolytic anemia that results from deposition of abnormal vWF
multimers into microvasculature.(MCQ)
o This is a life-threatening emergency!
o Etiology
§ Infection (especially HIV and E. coli 0157:H7) .(MCQ)
§ Malignancy
§ Drugs (antiplatelet agents, chemotherapy agents, contraceptives ) .(MCQ)
§ Autoimmune disorders
§ Pregnancy .(MCQ)

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o Signs and symptoms


§ Fever
§ Altered mental status (waxing and waning, depending on location
and movement of clot) .(MCQ)
§ Renal dysfunction (hematuria, oliguria)
§ Thrombocytopenia—can be mild to severe
§ Microangiopathic hemolytic anemia.(MCQ)
o Diagnosis
§ Evidence of hemolysis:
• Schistocytes on peripheral smear
• decreased haptoglobin.(MCQ)
• elevated LDH.(MCQ)
• elevated total bilirubin
§ Renal failure: Elevated BUN, creatinine
§ Fever, confusion.(MCQ)
§ Normal PT and PTT (Most important MCQ)
o Treatment
§ Do not transfuse platelets. .(MCQ)
§ Plasmapheresis is mainstay of treatment (given daily, until platelet
count rises to normal). .(MCQ)
§ May give FFP if plasmapheresis not available.(MCQ)
o Clinical Pearls :
§ E. coli 0157:H7 is an invasive gastroenteritis resulting in hemolytic
uremic syndrome (HUS). .(MCQ)
§ HUS differs from TTP in severity and lack of neurologic
symptoms. .(MCQ)
§ Diagnostic pentad for TTP: .(MCQ)
• Fever
• Anemia
• Thrombocytopenia
• Renal dysfunction
• Neurologic dysfunction
§ Transfusing platelets in TTP is thought to “fuel the fire” and
exacerbate consumption of platelets and clotting factors, resulting
in more thrombi in the microvasculature. (MCQ)

Topic- Transfusion Complications

• Acute Hemolytic Transfusion Reactions


o Life threatening!
o Due to ABO incompatibility
o Host antibodies against one of the ABO major blood groups on donor
(MCQ)
o blood activates complement system and results in immediate
intravascular hemolysis.
o Direct Coombs’ test is positive (antibodies on RBCs) (MCQ)
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o Usually due to human error (improper identification or mislabeling of


blood) (MCQ)
o Signs and symptoms
§ Begins soon after starting the transfusion
§ Usually sudden clinical deterioration:
• Fever+/chills
• Dyspnea ,Tachycardia
• Back pain, chest pain, abdominal pain
• Hypotension
o Sequelae:
§ Death (40%) ,Acute renal failure ,Shock ,DIC
o Treatment
§ Discontinue transfusion immediately!
§ Hemodynamic support/supportive care
§ Recheck compatibility of blood with blood bank.
• Delayed Hemolytic Transfusion Reactions
o Milder than immediate type
o Predominantly extravascular hemolysis (MCQ)
o Occur 2 to 10 days after transfusion (MCQ)
o Due to anamnestic antibody response
o Pretransfusion antibody level low →screening and crossmatch tests usually
negative
o Often has high LDH, high total bilirubin, low haptoglobin (MCQ)
o Signs and symptoms
§ Most Common - Fever ,Recurrent anemia ,Asymptomatic
§ Less Common –
• Jaundice
• Hemoglobinemia/hemoglobinuria
• Renal failure →death
o Treatment
§ Usually no treatment required
§ More severe reactions may require hydration, transfusion of
properly crossmatched RBCs. (MCQ)
• Febrile Nonhemolytic Transfusion Reactions
o 0.5 to 3.0% of patients receiving transfusions
o Chill followed by fever within a few hours of transfusion; mild
o Lasts only a few hours
o Due to host Ab against antigens on transfused leukocytes and platelets
or cytokines from donor leukocytes(MCQ)
o Treatment
§ Discontinue transfusion (can occur after).
§ Rule out acute hemolysis
§ Can give Tylenol and Benadryl as prophylaxis
• Allergic Reactions to Plasma
o Incidence of 1 to 3%
o Can get hives, bronchospasm, anaphylaxis(MCQ)

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o People with congenital IgA deficiency can have anaphylactic reactions


to the IgA in donor blood. (MCQ)
• Transfusion-Related Acute Lung Injury (TRALI)
o Sudden severe respiratory distress similar to ARDS(MCQ)
o Occurs within several hours of transfusion
o Pathophysiology :
§ Caused by donor Ab against recipient granulocytes
→agglutination of granulocytes and complement activation in
the pulmonary vascular bed →capillary endothelial damage
→fluid leak into the alveoli(MCQ)
§ Resolves within 48 to 96 hours without residual effects (interim
respiratory support often required)
o Signs and symptoms
§ Chills/fever ,Chest pain
§ Hypotension ,Cyanosis, dyspnea, crackles/rales
§ Chest x-ray (CXR) shows diffuse pulmonary edema
o Treatment is supportive.
• Clinical Pearls :
o General anesthesia is a frequent setting for blood transfusion.
o In this setting, immediate hemolytic transfusion reaction should be
suspected with: (MCQ)
§ Severe hypotension
§ Coagulopathic oozing
§ Hemoglobinuria
o Precipitation of free hemoglobin in the renal tubules is not a major
contributor to renal failure.
o The use of leukocyte- reduced blood products may reduce the
incidence of febrile nonhemolytic transfusion reactions. (MCQ)

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Endocrinology
Topic 01-Congenital adrenal hyperplasia

§ Etiology and pathophysiology.


o Caused by a defect in one of the enzymes ( 21-hydroxylase or 11-beta-
hydroxylase) necessary for the synthesis of cortisol.
o Cortisol deficiency stimulates ACTH, which results in overproduction
of steroid precursors in the early parts of the blocked pathway.
o One of these, 17-hydroxyprogesterone, is converted to adrenal
androgens, resulting in virilization.
o Patients with 21-hydroxylase deficiency may develop salt wasting due
to decreased production of mineralocorticoids
o Patients with 11-beta-hydroxylase deficiency may develop hypertension
may due to accumulation of steroid precursors with mineralocorticoid
effects

§ Clinicalfeatures
o Androgen excess is caused by increased adrenal production of
dehydroepiandrosterone,androstenedione, and testosterone.
o If present during fetal development, this disorder may cause ambiguous
genitalia infemale infants.
o If androgen excess is manifested in the postnatal period, it may
causevirilization in prepubertal girls or in young women.
o In male infants, the consequence of androgen excess during fetal
development is macro genitosomia. In the postnatal period, the
consequence is precocious puberty.

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o The cortisol deficit usually does not cause major clinical


manifestations, because the ACTH stimulation and adrenal hyperplasia
maintain cortisol levels in the low-normal range, despitethe enzyme
deficiency.
o 21-Hydroxylase deficiency
§ accounts for 95% of cases of adrenal hyperplasia.
§ In the mild (simple virilizing) form, only the androgen-excess
symptoms are of
§ importance.
§ In the severe (salt-losing) form, the production of aldosterone is
impaired, as well as
§ that of cortisol; mineralocorticoid deficiency leads to
hyponatremia, hyperkalemia, dehydration, and hypotension.
o 11-hydroxylase deficiency
§ deoxycorticosterone, a mineralocorticoid, as well as adrenal
androgens are overproduced.
§ This causes hypertension through mechanisms that are similar to
those causing hypertension in primary aldosteronism.
o 17-hydroxylase deficiency
§ deoxycorticosterone is overproduced, resulting in hypertension.
§ However, because 17-hydroxylase is necessary for sex steroid
synthesis, there is androgen deficiency as well as estrogen
deficiency.
§ This causes the development of ambiguous genitalia in male
infants and primary amenorrhea in women.

§ Diagnosis.
o Concentrations of adrenal androgens and precursors of cortisol are
increased in blood and urine.
o The most useful measurements are of blood testosterone,
androstenedione, dehydroepiandrosterone, and 17-hydroxyprogesterone
(a cortisol precursor), as well as urinary 17-ketosteroids and pregnanetriol
(a metabolite of 17-hydroxyprogesterone).
§ Medicaltherapy
o CortisoladministrationsuppressestheoverproductionofACTHandadrenala
ndrogens.
o In the salt-losing syndrome, mineralocorticoid replacement with
fludrocortisone may be necessary.
§ Surgery.
o Reconstructive surgery of the external genitalia in female infants is
done in the firstfew years of life.

Topic 02- Cushing’s syndrome

Cushing’s syndrome

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• Cushing’s syndrome is the term used to describe the clinical state of increased
free circulating glucocorticoid.
• It occurs most often following the therapeutic administration of synthetic
steroids or ACTH
• Pathophysiology and causes
o Causes of Cushing’s syndrome are usually subdivided into two groups
§ increased circulating ACTH from the pituitary (65% of cases ),
known as Cushing’s disease,
§ Ectopic, non-pituitary, ACTH-producing tumour elsewhere in the
body (10%) with consequent glucocorticoid excess (ACTH dependent
Cushing’s)
o Primary excess of endogenous cortisol secretion (25% of
spontaneous cases) by an adrenal tumour or nodular hyperplasia, with
subsequent (physiological) suppression of ACTH.
o Aberrant expression of receptors for other hormones (e.g.glucose-
dependent insulinotrophic peptide (GIP), LH or catecholamines) in
adrenal cortical cells (‘ACTH independent’ Cushing’s).

Clinical features

The clinical features of Cushing’s syndrome are those of glucocorticoid excess.

Pigmentation occurs only with ACTH-dependent causes.

A Cushingoid appearance can be caused by excess

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alcohol consumption (pseudo-Cushing’s syndrome)

Impaired glucose tolerance or frank diabetes is

common, especially in the ectopic ACTH syndrome.

Hypokalaemiadue to the mineralocorticoid activity of

cortisol is common with ectopic ACTH secretion.

Symptoms

• Weight gain (central)


• Change of appearance
• Depression
• Insomnia
• Amenorrhoea/ oligomenorrhoea
• Poor libido
• Thin skin/easy bruising
• Hair growth/acne
• Muscular weakness
• Growth arrest in children
• Back pain
• Polyuria/polydipsia
• Psychosis
Signs

• Moon face
• Plethora
• Depression/psychosis Acne
• Hirsutism
• Frontal balding (female) Thin skin
• Bruising
• Kyphosis
• ‘Buffalo hump’
• (dorsal fat pad)
• Central obesity
• Striae (purple or red) Rib fractures
• Oedema
• Proximal myopathy Proximal muscle wasting Glycosuria
• Poor wound healing
• Pigmentation
• Skin infections
• Hypertension
• Osteoporosis
• Pathological fractures (especially vertebrae and ribs)
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Diagnosis

§ Random cortisol measurements are of no value


§ 48-hour low-dose dexamethasone test
o Normal individuals suppress plasma cortisol to 50 nmol/L.
o Patients with Cushing’s syndrome fail to show complete suppression
of plasma cortisol levels
o This test is highly sensitive (97%).
o The overnight dexamethasone test has a higher false-positive rate.
§ 24-hour urinary free cortisol measurements.
o This is simple, but less reliable
§ Circadian rhythm.
o After 48 hours in hospital, cortisol samples are taken at 0900 h and
2400 h (without warning the patient).
o Normal subjects show a pronounced circadian variation
o Those with Cushing’s syndrome have high midnight cortisol levels
(100 nmol/L), though the 0900 h value may be normal.
o Midnight salivary cortisol collected at home gives the same
information more simply where the assay is available.
§ The classical ectopic ACTH syndrome is distinguished by a short history,
pigmentation and weight loss, unprovoked hypokalaemia, clinical or
chemical diabetes and plasma ACTH levels above 200 ng/L
o Many ectopic tumours are benign and mimic pituitary disease closely,
both clinically and biochemically.
§ Severe hirsutism/virilizationsuggests an adrenal tumour.
§ Adrenal CT or MRI scan.
o Adrenal adenomas and carcinomas causing Cushing’s syndrome are
relatively large and always detectable by CT scan.
o Carcinomas are distinguished by large size, irregular outline and signs
of infiltration or metastases.
o Bilateral adrenal hyperplasia may be seen in ACTH-dependent causes
or in ACTH-independent nodular hyperplasia.
§ Plasma potassium levels.
o Hypokalaemiais common with ectopic ACTH secretion. (All diuretics
must be stopped.)
§ High-dose dexamethasone test
o Failure of significant plasma cortisol suppression suggests an ectopic
source of ACTH or an adrenal tumour .
§ Plasma ACTH levels.
o Low or undetectable ACTH levels (10 ng/L) on two or more
occasions are a reliable indicator of non-ACTH-dependent disease.
§ CRH test.
o An exaggerated ACTH and cortisol response to exogenous CRH
suggests pituitary-dependent Cushing’s disease, as ectopic sources rarely
respond.
§ Selective catheterization of the inferior petrosal sinus to measure ACTH for
pituitary lesions, or blood samples taken throughout the body in a search for
ectopic sources.
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§ Radiolabelled octreotide (111In octreotide) is occasionally helpful in locating


ectopic ACTH sites.
Treatment

§ Untreated Cushing’s syndrome has a very bad prognosis, with death from
hypertension, myocardial infarction, infection and heart failure..
§ The usual drug is metyrapone, an 11-hydroxylase blocker
§ Keto-conazole (200 mg three times daily) is also used and is synergistic with
metyrapone.
§ Aminoglutethimide and trilostane (which reversibly inhibits 3-hydroxysteroid
dehydrogenase)
§ Plasma cortisol should be monitored, aiming to reduce the mean level during
the day to 150–300 nmol/L, equivalent to normal production rates.
§ Cushing’s disease (pituitary-dependent hyperadrenalism)
§ Transsphenoidal removal of the tumour is the treatment
§ of choice.
§ External pituitary irradiation alone is slow acting, only effective in 50–
60% even after prolonged follow-up and mainly used after failed
pituitary surgery.
§ Children, however, respond much better to radiotherapy, 80% being
cured.
§ Bilateral adrenalectomyperformed laparoscopically.is an effective last
resort if other measures fail to control the disease
§ Adrenal adenomas should be resected after achievement of clinical remission
with metyrapone or ketoconazole.
§ Adrenal carcinomas are highly aggressive and the prognosis is poor.
§ If the source of ACTH is not clear , cortisol hypersecretion should be
controlled with medical therapy until a diagnosis can be made.
§ Nelson’s syndrome
§ Nelson’s syndrome is increased pigmentation (because of high levels of
ACTH) associated with an enlarging pituitary tumour
§ occurs in about 20% of cases after bilateral adrenalectomy for Cushing’s
disease.
§ itsincidence may be reduced by pituitary radiotherapy soon after
adrenalectomy.
§ The Nelson’s adenoma may be treated by pituitary surgery and/or
radiotherapy (unless given previously).

Topic 03- Addisons disease

Adrenal insufficiency can be either

Primary - Diseases of the adrenal cortex ( Addison’s disease)

Secondary - Pituitary pathology (ACTH)

Tertiary - Hypothalamic pathology (CRH)

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Adrenal insufficiency should be considered in patients with

- Fatigue, weight loss,


- Increased skin/ mucosal pigmentation, darkening of skin creases & scars
- Anorexia, nausea, vomiting, vague non localizing abdominal pain
- Unexplained hypoglycaemia, hypotension and fever
- Hyponatraemia & hyperkalaemia,
- Eosinophilia & Anaemia
- Vitiligo and other organ-specific autoimmune conditions including Type 1 diabetes,
autoimmune thyroid disorders, primary hypoparathyroidism, primary gonadal failure,
pernicious anaemia and coeliac disease.

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Suspected Adrenal Insufficiency

9am cortisol

>450nmol/l 80 – 450 nmol/l <80nmol/l

Possible Highly suggestive

Unlikely pass SST

fail

↑ACTH ↓ACTH

1° Adrenal insufficiency 2° or 3° Adrenal


insufficiency
(Addison’s disease)

Consider screening for


other organ-specific
autoimmune disorders

* SST- short synacthen test

Management of Adrenal Insufficiency


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1. Adrenal crisis & initial management

§ The aim of initial management is to treat hypotension by correcting the blood


volume deficit, reverse the electrolyte abnormalities and cortisol deficiency.
§ Large volumes of normal saline solution should be given intravenously. The
glucocorticoid deficiency should be treated by immediate i.v . hydrocortisone..
2. Long term management

§ Glucocorticoid replacement -Patients with primary adrenal insufficiency


require lifelong glucocorticoid and mineralocorticoid replacement.
3. Mineralocorticoid replacement

§ It is given in the form of fludrocortisone.


§ The dose of fludrocortisone is titrated individually on the basis of the clinical
examination (postural BP variation) ± the levels of plasma renin activity.
4. Androgen replacement

§ In women, the adrenal cortex is the primary source of androgen in the form
of dehydroepiandrosterone .
5. 2° & 3° Adrenal deficiency

§ In chronic secondary or tertiary adrenal insufficiency, glucocorticoid


replacement is similar to that in primary adrenal insufficiency.
§ Mineralocorticoid replacement is rarely required , while replacement of
other anterior pituitary deficits might be necessary.

Topic 04 – Pheochromocytoma

• Pheochromocytoma
• Tumor of the adrenal medulla resulting in catecholamine excess
• Equal incidence in men and women. (MCQ)
• Tumors in women are three times as likely to be malignant.(MCQ)
• Etiology
o Multiple endocrine neoplasiatypes II and III
§ MEN II:(MCQ)
• Pheochromocytoma, parathyroid tumor, and medullary
thyroid tumor
§ MEN III: (MCQ)
• Pheochromocytoma, parathyroid tumor, and mucosal
neuromas
o Neurofibromatosis
o Von Hippel–Lindau disease:(MCQ)
§ Pheochromocytoma, retinal angiomas
§ CNS hemangioblastomas, renal cell carcinoma
§ pancreaticpseudocysts, ependymal cystadenoma

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• Signs and symptoms


o Patients experience “paroxysmal attacks” of high blood pressure.
o Physical exam usually normal outside of an attack .
o Symptoms of catecholamine (sympathetic) excess will predominate
during an attack.
o 5H’s(MCQ)
§ Headache
§ Hypertension
§ Hot (diaphoretic)
§ Heart (palpitations)
§ Hyperhidrosis
o Other Symptoms
§ Tremor
§ Anxiety
§ Weight loss
• Diagnosis
o Elevated urine vanillylmandelic acid (urine catecholamines)
o Hypercalcemia
o Hyperglycemia
o CT to look for adrenal mass
• Treatment
o Surgical resection
o Alpha-adrenergic blockade (may also add beta blocker)
• Clinical Pearls
o Pheochromocytoma: Rule of 10s:(MCQ)
§ 10% are extra-adrenal
§ 10% are bilateral
§ 10% are malignant
§ 10% are familial
§ 10% are pediatric
§ 10% calcify
§ 10% recur after resection

• Clinical Vignette in MD Entrance (MCQ)

o A 38-year-old woman on labetalol presents with poorly


controlled hypertension, frequent headaches, and
palpitations.

o Clinical diagnosis :Pheochomocytoma .

• Patients with pheochromocytoma may carry an incorrect diagnosis of


anxiety disorder.
• Hypertension, frequently sustained but often paroxysmal, especially
during surgery or delivery(MCQ)

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• Both pheochromocytomas and non–head-neck paragangliomas are


tumors of the sympathetic nervous system.
• Pheochromocytomas(MCQ)
o arise from the adrenal medulla
o usually secrete both epinephrine and norepinephrine.
• Paragangliomas ("extra-adrenal pheochromocytomas") (MCQ)
o arise from sympathetic paraganglia,
o oftenmetastasize
o secretenorepinephrine or are nonsecretory.
• Excessive levels of norepinephrine or neuropeptide Y cause
hypertension,(MCQ)
• Excessive levels of epinephrine causestachyarrhythmias.
• Aberrant locations for Pheo- mediastinum, heart, or bladder
• Patients with VHL develop pheochromocytomasthat are (MCQ)
o less likely to be malignant or extra-adrenal
o more likely to be bilateral
o more likely to present at an early age.
• Pheochromocytomas that arise in patients with VHL secrete exclusively
norepinephrine and its metabolite normetanephrine. Therefore,
individuals who carry type 2 VHL mutations should be screened for
pheochromocytoma with plasma normetanephrine levels.(MCQ)
• Certain drugs can precipitate attacks: (MCQ)
o monoamine oxidase (MAO) inhibitors, caffeine, nicotine
o decongestants, amphetamines
o cocaine, ionic intravenous contrast, and epinephrine
• Bladder paragangliomas may present with paroxysms during
micturition (micturationsyncope )(MCQ)
• Paroxysms typically produce hypertension and symptoms such as
o severe headache (80%) (most common)(MCQ)
o perspiration (70
o palpitations (60%)
o other symptoms may include anxiety (50%), a sense of impending doom,
or tremor (40%).
• Plasma fractionated free metanephrines is the single most sensitive test
for secretory pheochromocytomas and paragangliomas. (MCQ)
o Normal levels rule outpheochromocytoma and paraganglioma with some
certainty and the work-up can usually end there.
• However, misleading elevations in metanephrines or normetanephrinescan be
caused by factors such as physical or emotional stress, sleep apnea, and
MAO inhibitors. Therefore, patients with elevated plasma metanephrines or
normetanephrines levels require further evaluation.
• Urinary assay for total metanephrines is about 97% sensitive for
detecting functioning pheochromocytomas. (MCQ)
• Urinary assay for vanillylmandelic acid (VMA) is about 89% sensitive and
is not usually required.
• Serum chromogranin A(MCQ)
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o elevated in 90% of patients with pheochromocytoma


o levels correlate with tumor size, being higher in patients with metastatic
disease
o misleadingly elevated in patients with azotemia or hypergastrinemia,
and in those treated with corticosteroids or proton pump inhibitors .
• neuron-specific enolase(MCQ)
o high levels implicate a malignant pheochromocytoma, while normal
levels are nonspecific.
• Both CT and MRI scanning have a
o sensitivity of about 90% for adrenal pheochromocytoma
o sensitivity of 95% for adrenal tumors over 0.5 cm in diameter.
o However, both CT and MRI are less sensitive for detecting recurrent
tumors, metastases, and extra-adrenal paragangliomas.
• Whole-body [ 123I]m-Iodobenzylguanidine ( 123I-MIBG) scan(MCQ)
o can localize tumors with a sensitivity of 85% and a specificity of 99%.
o It is less sensitive for MEN 2A- or MEN 2B-related
pheochromocytomas.
• Somatostatin receptor imaging using 111In-labeled octreotide(MCQ)

o quite sensitive for detecting extra-adrenal pheochromocytomas


(paragangliomas) and metastatic pheochromocytomas, sometimes
locating tumors that were missed by 123I-MIBG scanning.
• PET scanning(MCQ)
o usually detects tumors using 18F-labeled deoxyglucose (18FDG-PET) or
18F-labeled dopamine ( 18FDA-PET

o may demonstrate tumors that are not visible on 123I-MIBG scanning.


o Combining PET scan with noncontrast CT produces a PET/CT
fusion scan with exceptional sensitivity.
• Medical Treatment
• Alpha-Blockers (prazocin or phenoxybenzamine) (MCQ)
§ typically administered preparatory to surgery.
§ Many surgeons insist upon alpha -blockade preoperatively
§ Optimal -blockade is achieved when
• supine arterial pressure is below 140/90 mm Hg or
• as low as possible for the patient to have a standing
arterial pressure above 80/45 mm Hg.
• Calcium channel blockers (nifedipine ER or nicardipine ER) (MCQ)
§ very effective and may be used with or without -blockers.
§ They are superior to phenoxybenzamine for long-term use,
since they cause less fatigue, nasal congestion, and orthostatic
hypotension
• Beta Blockers (eg, metoprolol XL) (MCQ)
§ required by most patients after institution of Alpha-blockade or
calcium channel blockade.

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§ The use of alpha -blocker as initial antihypertensive therapy has


resulted in "unopposed alpha" that causes paradoxical
worsening of hypertension. (MCQ)
• Surgical removal of pheochromocytomas or abdominal paragangliomas is
the treatment of choice.
• Intraoperative severe hypertension is managed with
§ continuous intravenous nicardipine
§ nitroprusside,
• Tachyarrhythmia is treated with intravenous atenolol, esmolol, or lidocaine.
• For inoperable or metastatic tumors, metyrosine reduces
catecholamine synthesis(MCQ)

Topic 05 - Primary hyperaldosteronism

Primary hyperaldosteronism

§ Pathophysiology
o This condition is caused by excess aldosterone production leading to
sodium retention, potassium loss and the combination of
hypokalaemia and hypertension.
§ Causes
o Adrenal adenomas (Conn’s syndrome) originally accountedfor 60% of
cases of primary hyperaldosteronism
§ Clinical features
o The usual presentation is simply hypertension.
o Hypokalaemia (3.5 mmol/L) was a hallmark of the condition as
originally described but is now frequently absent.
o Adenomas, often very small, are more common in young females, while
bilateral hyperplasiararely occurs before age 40 years and is more
common in males.
§ Investigations
o Beta-blockersmay interfere with renin activity, and spironolactone,
ACE inhibitors and AII-R antagonists will all affect results and all
should be discontinued if possi- ble.
o Plasma aldosterone:renin ratio (ARR) is now most frequently used as
a screening test for the condition
§ raised ARR alonedoes not confirm the diagnosis (if the renin is
low enough ARR will always be high).
§ Elevated plasma aldosterone levels that are notsuppressed
with 0.9% saline infusion (2 L over 4 hours) or fludrocortisone
administration.
§ Between 30% and 50% of patients with raised ARR on
screening will suppressnormally, excluding the diagnosis.
o Suppressed plasma renin activity or immunoreactivity.
o Hypokalaemiais often present but a normal serum potassium does not
exclude the diagnosis.
o Urinary potassium loss.
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§ Levels 30 mmol daily during hypokalaemia are inappropriate.


o Once a diagnosis of hyperaldosteronism is established, differentiation of
adenoma from hyperplasia involves adrenal CT or MRI, but small
adenomas may be missed and non- functioning incidentalomas also
occur.
o Further information may be obtained from
§ diurnal/postural changes in plasma aldosterone levels (which tend
to rise with adenomas between 0900 h supine and 1300 h
erect samples; in contrast, they fall with hyperplasia),
§ measurement of 18-OH cortisol levels (raised in adenoma)
§ venous catheterization for aldosterone levels.
§ Treatment
o An adenoma can be removed surgically – usually laparoscopically;
§ BP falls in 70% of patients.
o Those with hyperplasia should be treated with the aldosterone
antagonist spironolactone ,frequent side-effects include nausea, rashes
and gynaecomastia,
o pure aldosterone receptor antagonist eplerenone is a useful alternative
Secondary hyperaldosteronism

o This situation arises when there is excess renin (and hence angiotensin
II) stimulation of the zonaglomerulosa.
o Common causes are accelerated hypertension and renal artery
stenosis, when the patient will be hypertensive.
o Causes associated with normotension include congestive cardiac
failure and cirrhosis, where excess aldosterone production contributes to
sodium retention.
o Angiotensin-converting enzyme inhibitors (e.g. captopril, enalapril
or lisinopril) and angiotensin II antagonists (e.g. losartan,
candesartan) are effective in heart failure, both symptomatically and in
increasing life
o Spironolactone is of value in both situations, and 25 mg/day has been
shown to improve survival in heart failure

Topic 06 – SIADH

• SIADH
• Excess production of ADH
• Etiology
o Idiopathic overproduction via the hypothalamic-posterior pituitary axis
o often associated with (MCQ)
§ disorders of the CNS (encephalitis, stroke, head trauma)
§ pulmonary disease (TB, pneumonia)
§ Ectopic production by malignant tumors, particularly small cell
lung cancer and pancreatic carcinoma(MCQ)
o Pharmacologic stimulation of the hypothalamic–pituitary axis: (MCQ)
§ Carbamazepine
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§ Chlorpropamide
§ clofibrate, vincristine
• Signs and symptoms
o Attributable to hyponatremia
• Diagnosis(MCQ)
o Hyponatremia
o Low serum osmolality
o High urinary sodium(MCQ)
o Osmolality of urine serum
• Treatment
o Fluid restriction
o Hypertonic saline in severe hyponatremia(MCQ)
o Demeclocycline:
§ Has side effect of decreasing collecting duct response to ADHH
• Clinical Pearls :
o Other causes of excess ADH secretion: (MCQ)

§ Adrenal failure

§ Renal failure

§ Edema

§ Fluid loss

• Pathophysiology of SIADH

o In SIAD, the excessive retention of water expands extracellular and


intracellular volume, increases glomerular filtration and atrial natriuretic
hormone, suppresses plasma renin activity, and increases urinary sodium
excretion. (MCQ)

o This natriuresisreduces total body sodium, and this serves to counteract


the extracellular hypervolemia but aggravates the hyponatremia.(MCQ)

o The osmotically driven increase in intracellular volume results in swelling


of brain cells and increases intracranial pressure; this is probably responsible
for the symptoms of acute water intoxication .

o Within a few days, this swelling may be counteracted by inactivation or


elimination of intracellular solutes , resulting in the remission of
symptoms even though the hyponatremiapersists(MCQ)

o SIAD is a diagnosis of exclusion that usually can be made from the history,
physical examination, and basic laboratory data(MCQ)

• Treatment of SIADH

o If the symptoms or signs of water intoxication are mild and less severe
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§ the objective is to reduce body water gradually by restricting total


fluid intake to less than the sum of urinary and insensible
losses.(MCQ)

§ Because the water derived from food (300–700 mL/d) usually


approximates basal insensible losses in adults, total discretionary
intake (all liquids) should be at least 500 mL less than urinary
output.(MCQ)

§ If achievable, this usually reduces body water and increases serum


sodium by about 1–2% per day.(MCQ)

o If the symptoms or signs of water intoxication are more severe,

§ thehyponatremia can be corrected more rapidly by supplementing


the fluid restriction with IV infusion of hypertonic (3%)
saline(MCQ)

§ if plasma sodium is raised too rapidly or too much and the


hyponatremia has been present for >24–48 hours, it also has the
potential to produce central pontinemyelinolysis, an acute,
potentially fatal neurologic syndrome characterized by
quadriparesis, ataxia, and abnormal extraocular
movements(MCQ)

§ CPM can be minimized by observing several precautions(MCQ)

• 3% saline should be infused at a rate  0.05 mL/kg body


weight per min

• the effect should be monitored continuously by STAT


measurements of serum sodium at least once every 2 hours;

• infusion should be stopped as soon as serum sodium


increases by 12 mmol/L or to 130 mmol/L, whichever
comes first.

• Management of chronic SIAD

o hyponatremia can be corrected by treatment with demeclocycline or


fludrocortisone(MCQ)

o Conivaptan(MCQ)

§ Nonpeptide AVP antagonists that block the antidiuretic effect of


A VP

§ a combined V2/V1a antagonist

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Topic 07 - Diabetes insipidus

• Diabetes insipidus :
• Central DI: Inadequate pituitary secretion of ADH
• Nephrogenic DI: Lack of renal response to ADH
• Etiology
o Central DI
§ Idiopathic: Accounts for 50% of cases
§ Posterior pituitary or hypothalamic damage
• tumor, trauma, neurosurgery .(MCQ)
§ Systemic:
• Sarcoidosis, neurosyphilis, encephalitis.(MCQ)
o Nephrogenic DI
§ Familial
§ Chronic renal disease
§ Sickle cell anemia (renal papillary necrosis) .(MCQ)
§ Hypokalemia.(MCQ)
§ Hypercalcemia .(MCQ)
§ Drugs:
• Lithium, demeclocycline, methoxyflurane.(MCQ)
• Signs and symptoms
o Polyuria (3 to 15 L/day)
o Thirst
o Dilute urine (specific gravity 1.005)
• Diagnosis
o High plasma osmolality (280 to 310) due to incomplete compensation for
the inability to resorb free water .(MCQ)
o Water deprivation followed by exogenous ADH:.(MCQ)
§ Central DI: .(MCQ)
• Low urine osm→high urine osm
§ Nephrogenic DI: .(MCQ)
• Low urine osm→low urine osm
§ Normal:
• High urine osm→high urine osm
o Infusion of hypertonic saline normally results in a sharp decrease in urine
output; patients with DI do respond.
• Treatment
o Desmopressin (DDAVP):.(MCQ)
§ Analog of ADH, useful in central DI
o Thiazide diuretics: .(A frequently asked MCQ in MD Entrance exam)
§ Paradoxically decrease urine output in patients with DI by
increasing sodium and water resorption in the proximal tubule.
§ They are the only therapy useful in nephrogenic DI.
o Chlorpropamide:
§ Oral hypoglycemic with side effect of potentiating secretion and
action of endogenous ADH.
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§ Partial function must exist for this therapy to be of use. .(MCQ)


• Clinical pearls :
o Psychogenic polydipsia:

§ Psychiatric disorder of compulsive water drinking

§ most common in young to middle-aged women. .(MCQ)

§ Presents with polyuria and dilute urine

§ distinguished from DI by low plasma osmolality.(MCQ)

§ Antidiuretic hormone (ADH) deficiency causes central diabetes insipidus with


polyuria (2–20 L/d) and polydipsia.
§ Hypernatremia occurs if fluid intake is inadequate
§ Diabetes insipidus also occurs in Wolfram syndrome.(MCQ)
§ a rare autosomal recessive disorder
§ known by the acronym DIDMOAD.(MCQ)
• diabetesinsipidus
• type 1 diabetes mellitus
• optic atrophy
• deafness
§ Vasopressinase-induced diabetes insipidus
§ seen in the last trimester of pregnancy and in the puerperium
§ often associated with oligohydramnios, preeclampsia, or hepatic dysfunction
§ A urine volume of < 2 L/24 h (in the absence of hypernatremia) essentially rules
out diabetes insipidus..(MCQ)
§ Hyperuricemia occurs in many patients with diabetes insipidus
§ Cause :
• reduced vasopressin stimulation of the renal V1 receptor causes a
reduction in the renal tubular clearance of urate..(MCQ)
§ Central diabetes insipidus must be distinguished from polyuria caused by(MCQ)
§ diabetes mellitus
§ Cushing syndrome or corticosteroid treatment
§ Lithium
§ hypercalcemia, hypokalemia
§ nocturnal polyuria of Parkinson disease
§ Adverse effects ofdesmopressin preparations (MCQ)
§ Hyponatremia
§ emotional changes, such as depression or agitation
§ erythromelalgia
§ All desmopression preparations, including tablets, are subject to heat degradation
and should be refrigerated.
§ Both central and nephrogenic diabetes insipidus respond partially to
hydrochlorothiazide, 50–100 mg/d orally (with potassium supplement or
amiloride). (MCQ)
§ Mechanism of action of Thiazide diureticsin DI (MCQ)
• Thiazide diuretics (25 mg once or twice daily) cause a mild
volume depletion, which will cause the body to retain more
fluid.

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•An initial reduction of sodium reabsorption in the distal


tubule increases sodium excretion and causes extracellular
fluid volume contraction.
• Even a small drop in body weight due to fluid loss (1-1.5
kg) can cause a drop in urine output of over 50%.
• As a result, the glomerular filtration ratedecreases and the
proximal tubular sodium and water reabsorption
increases.
• Consequently, less water and sodium are delivered to the
collecting tubules and, as a result, less water is excreted
• The mild hypovolemia caused by HCTZ treatment leads to
increased sodium and water reabsorption in the
proximal tubule, therefore even though you are giving a
diuretic, the net effect is water retention.
§ Then Why we don't use loop diuretics instead of Thiazides (MCQ)
• Although loop diuretics also cause hypovolemia, the action
of loop diuretics on the ascending loop of henle diminishes
the medullary concentration gradient and thus less water
is reabsorbed.
• This is also why loop diuretics tend to be more effective
diuretics than thiazides
§ Nephrogenic diabetes insipidus may respond to combined treatments of
indomethacin-hydrochlorothiazide, indomethacin-desmopressin, or
indomethacin-amiloride. Indomethacin, 50 mg orally every 8 hours, is effective in
acute cases.(MCQ)
§ Why Indomethacin in used for the treatment (MCQ)
• itinhibits PGE2 that causes Afferent arteriolar dilation therefore
causing vasoconstriction.
• this causes decreased GC hydrostatic pressure and
decreased GFR and also decreased RPF , therefore causing
decreased FF of Na . Thereby reducing Na loss

Topic 08 - Diabetes mellitus

Diabetes mellitus

Diabetes mellitus (DM) is a syndrome of chronic hyperglycaemia due to relative insulin


deficiency, resistance, or both.

Glucose metabolism – basic biochemistry

§ Hormonal regulation
o In the fasting state ,insulin’s main action is to regulate glucose release
by the liver, and in the postprandial state it additionally facilitates glucose
uptake by fat and muscle.
o The effect of counteregulatory hormones ( glucagon, epinephrine
(adrenaline), cortisol and growth hormone ) is to cause greater
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production of glucose from the liver and less utilization of glucose in fat
and muscle for a given level of insulin.
§ Glucose transport
o GLUT-1 – enables basal non-insulin-stimulated glucose uptake into
many cells
o GLUT-2 – transports glucose into the beta cell : a prerequisite for
glucose sensing.
o GLUT-3 – enables non-insulin-mediated glucose uptake into brain
neurones and placenta.
o GLUT-4 – enables much of the peripheral action of insulin . It is the
channel through which glucose is taken up into muscle and adipose tissue
cells following stimulation of the insulin receptor

§ Factors that regulate insulin secretion from beta-cells.

o Glucose enters the beta-cell via the GLUT-2 transporter protein, which
is closely associated with the glycolytic enzyme glucokinase.

o Metabolism of glucose within the beta-cell generates ATP .

o ATP closes potassium channels in the cell membrane (A). If a


sulphonylurea binds to its receptor, this also closes potassium channels.

o Closure of potassium channels predisposes to cell membrane


depolarization, allowing calcium ions to enter the cell via calcium
channels in the cell membrane

o The rise in intracellular calcium triggers activation of calcium-


dependent phospholipid protein kinase which, via intermediary
phosphorylation steps, leads to fusion of the insulin-containing granules
with the cell membrane and exocytosis of the insulin-rich granule
contents.

§ Fasting and postprandial effects of insulin.

o In the fasting state,insulin concentrations are low and it acts mainly as a


hepatic hormone, modulating glucose production (via glycogenolysis and
gluconeogenesis) from the liver. Hepatic glucose production rises as insulin
levels fall.

o In the postprandial state insulin concentrations are high and it then suppresses
glucose production from the liver and promotes the entry of glucose into
peripheral tissues (increased glucose utilization).

§ insulinsignalling in peripheral cells.

o The insulin receptor consists of alpha- and beta-subunits linked by disulphide


bridges

o The beta- subunits straddle the cell membrane.

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o The transporter protein GLUT-4 is stored in intracellular vesicles. The binding


of insulin to its receptor initiates many intracellular actions including
translocation of these vesicles to the cell membrane, carrying GLUT-4 with
them.

CLASSIFICATION OF DIABETES

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Type 1 diabetes mellitus

§ Epidemiology
o Type 1 diabetes is a disease of insulin deficiency.

o Most common form - immune-mediated form of the disease (type 1A).

o Type 1 diabetes is prominent as a disease of childhood, reaching a peak


incidence around the time of puberty

o A ‘slow-burning’ variant with slower progression to insulin deficiency


occurs in later life and is sometimes called latent autoimmune diabetes
in adults (LADA).

§ Causes
o Type 1 diabetes belongs to a family of HLA-associated immune-mediated
organ-specific diseases.

o Autoantibodies directed against pancreatic islet constituents appear in the


circulation within the first few years of life, and often predate clinical onset by
many years.

o Genetic susceptibility and inheritance

§ Increased susceptibility to type 1 diabetes is inherited, but the disease is


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not genetically predetermined.

§ The identical twin of a patient with type 1 diabetes has a 30–50%


chance of developing the disease, which implies that non-genetic
factors must also be involved.

o HLA system

§ The HLA genes on chromosome 6 are highly polymorphic and


modulate the immune defence system of the body.

§ More than 90% of patients with type 1 diabetes carry HLA-DR3-


DQ2, HLA-DR4-DQ8, or both, as compared with some 35% of the
background population.

§ All DQB1 alleles with an aspartic acid at residue 57 confer neutral to


protective effects with the strongest effect from DQB1*0602 (DQ6),
while DQB1 alleles with an alanine at the same position (i.e. DQ2 and
DQ8) confer strong susceptibility. Genotypic combinations have a
major influence upon risk of disease. For example, HLA DR3-
DQ2/HLA DR4-DQ8 heterozygotes have a considerably increased
risk of disease, and some HLA class I alleles also modify the risk
conferred by class II susceptibility genes.

o Autoimmunity and type 1 diabetes


§ Type 1 diabetes overlaps with other organ-specific autoimmune
diseases including autoimmune thyroid disease, coeliac
disease, Addison’s disease and pernicious anaemia .

§ Several islet antigens have been characterized, and these include


insulin itself, the enzyme glutamic acid decarboxylase (GAD),
protein tyrosine phosphatase (IA-2) and the cation transporter
ZnT8.

o Environmental factors

§ Exposures to dietary constituents, enteroviruses such as Coxsackie B4


or vaccinations have often been suspected

Type 2 diabetes mellitus


• Epidemiology
o The four major determinants are increasing age, obesity, ethnicity and
family history.

o Obesity increases the risk of type 2 diabetes 80–100 fold,

o Type 2 diabetes is associated with central obesity, hypertension,


hypertriglyceridaemia, a decreased HDL- cholesterol, disturbed
haemostatic variables and modest increases in a number of pro-
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inflammatory markers.

o The International Diabetes Federation has proposed criteria based on


increased waist circumference (or BMI 30) plus two of the following:
diabetes (or fasting glucose 108 mg/dl), hypertension, raised triglycerides
or low HDL cholesterol.

• Causes of type 2 diabetes


o Inheritance
§ Population-based studies show that identical twins of patients
with type 2 diabetes have 50% chance of developing diabetes;
the risk to non-identical twins or siblings is of the order of
25%. These observations confirm a strong genetic component to
the disease.

§ Type 2 diabetes is a polygenic disorder, and, as with type 1


diabetes, with numerous susceptibility loci related to genes
subserving beta-cell development or function

§ Another difference is that there is no major gene susceptibility,


equivalent to the HLA region, in type 2 diabetes.

o Environmental factors: early and late


§ An association has been noted between low weight at birth and
at 12 months of age and glucose intolerance later in life,
particularly in those who gain excess weight as adults.
o CLINICAL PRESENTATION OF DIABETES

§ Glycosuria is not diagnostic of diabetes but indicates the need


for further investigations.
§ About 1% of the population have renal glycosuria.
• This is an inherited low renal threshold for glucose,
transmitted either as a Mendelian dominant or recessive
trait.
§ The presence of the characteristic retinopathy is diagnostic of
diabetes

§ Patients with severe insulin resistance may have


acanthosisnigricans, which is characterized by blackish
pigmentation at the nape of the neck and in the axillae.

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Tablet treatment for type 2 diabetes

§ Biguanide (Metformin)
o It activates the enzyme AMP-kinase, which is involved in GLUT4
metabolism and fatty acid oxidation
o It reduces the rate of gluconeogenesis , and hence hepatic glucose
output, and increases insulin sensitivity.

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o It does not affect insulin secretion, does not induce hypoglycaemia and
does not predispose to weight gain.
o It is thus particularly helpful in the overweight, although normal weight
individuals also benefit, and may be given in combination with
sulfonylureas or thiazolidinediones.
o Metformin was as effective as sulfonylurea or insulin in glucose control
and reduction of microvascular risk in the United Kingdom Prospective
Diabetic Study (UKPDS), but proved unexpectedly beneficial in
reducing cardiovascular risk, an effect that could not be fully explained
by its glucose-lowering actions.
o Metformin is currently the only oral agent to have demonstrated
unequivocal cardiovascular protection within a randomized controlled
trial. Adverse effects include anorexia, epigastric discomfort and
diarrhoea, and these prohibit its use in 5–10% of patients.
o Diarrhoea should never be investigated in a diabetic patient without
testing the effect of stopping metformin!
o Lactic acidosis has occurred in patients with severe hepatic or renal
disease, and metformin is contraindicated when these are present
§ Sulfonylureas
o These act upon the beta-cell to promote insulin secretion in
o response to glucose and other secretagogues.
o They are ineffective in patients without a functional beta-cell mass, and
they are usually avoided in pregnancy.
o Their action is to bind to the sulfonylurea receptor on the cell membrane,
which closes ATP-sensitive potassium channels and blocks
potassium efflux. The resulting depolarization promotes influx of
calcium, a signal for insulin release
o Sulfonylureas are cheap and more effective than the other main agents in
achieving short-term (1–3 years) glucose control, but their effect wears
off as the beta-cell mass declines. There are theoretical concerns that they
might hasten beta-cell apoptosis and promote weight gain, and are
therefore best avoided in the overweight.
o They can also cause hypoglycaemia and although the episodes are
generally mild, fatal hypoglycaemia may occur.
o Sulfonylureas should be used with care in patients with liver disease.
Patients with renal impairment should only be given those primarily
excreted by the liver.
o Tolbutamide is the safest drug in the very elderly because of its
short duration of action.
§ Thiazolidinediones
o The thiazolidinediones (‘glitazones’) reduce insulin resistance by
interaction with peroxisome proliferator-activated receptor-gamma
(PPAR-gamma), a nuclear receptor which regulates large numbers of
genes including those involved in lipid metabolism and insulin action.
o Fatty tissue is redistributed in patients taking a glitazone, with a
reduction of central adiposity but an increase in peripheral fat. One
suggestion as to their action is that they act indirectly via the glucose–

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fatty acid cycle, lowering free fatty acid levels and thus promoting
glucose consumption by muscle.
o The glitazones lower circulating insulin relative to plasma glucose, but do
not return glucose levels to normal . They can be used alone or in
combination with other agents.
o The glitazonesreduce hepatic glucose production, an effect that is
synergistic with that of metformin, and also enhance peripheral glucose
uptake.
o Like metformin, the glitazonespotentiate the effect of endogenous or
injected insulin.
o Unwanted effects include weight gain of 5–6 kg, together with fluid
retention and increased risk of heart failure, anaemia and osteoporosis.
o Rosiglitazone and pioglitazone should not be used in patients with
heart failure
o rosiglitazone should not be used in patients with ischaemic heart
disease.
§ Meglitinides
o Meglitinides, e.g. repaglinide and nateglinide, are insulin
secretagogues.Meglitinides are the non-sulfonylurea moiety of
glibenclamide.

o As with the sulfonylureas, they act via closure of the K -ATP channel
in the beta-cells

o They are short-acting agents that promote insulin secretion in response


to meals.

Injection therapies

§ Incretins
o What is incretin effect
§ Insulin response to oral glucose is greater than the response to
intravenous glucose. This is known as the incretin effect, and is
due to release of two peptide hormones, glucose-dependent
insulinotropic peptide (GIP) and glucagon-like peptide-1
(GLP-1) from the L cells in the intestine.
o The incretin effect is diminished in type 2 diabetes.
o GLP-1 has a very short half-life, and exenatide and liraglutide, longer-
acting analogues, are now available.
o Exenatide, which must be given by twice-daily subcutaneous
injection, promotes insulin release, inhibits glucagon release, reduces
appetite and delays gastric emptying, thus blunting the postprandial
rise in plasma glucose.
o Its main clinical disadvantage is the need for injection, and its
advantage is that it improves glucose control whilst inducing useful
weight reduction. Side-effects include nausea, and acute pancreatitis
has been reported.
o At present it is used as an alternative to insulin , particularly in the
overweight.
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§ Dipeptidyl peptidase 4 (DPP4) inhibitors


o The enzyme dipeptidyl peptidase 4 (DPP4) rapidly inactivates GLP-1 as
this is released into the circulation, and inhibition of this enzyme thus
potentiates the effect of endogenous GLP-1 secretion.
o DDP4 inhibition is an alternative approach to incretin-based therapy.
o The two agents currently available, sitagliptin and vildagliptin ,
o Moderately effective in lowering blood glucose but do not induce
weight loss.
o They are likely to be most effective in the early stages of type 2
diabetes when insulin secretion is relatively preserved.
o The main sideeffect is nausea.

• Acarbose
o Acarbose is Intestinal enzyme inhibitor
o Competitively inhibits alpha-glucosidase enzymes situated in the
brush border of the intestine, reducing absorption of dietary
carbohydrate.
o Undigested starch may then enter the large intestine where it will be
broken down by fermentation.
o Abdominal discomfort, flatulence and diarrhoea can result, and
dosage needs careful adjustment to avoid these side-effects.
• Orlistat
o Orlistat is a lipase inhibitor whichreduces the absorption of fat from the
diet.
o It benefits diabetes indirectly by promoting weight loss in patients
under careful dietary supervision on a low fat diet .
o This is necessary to avoid unpleasant steatorrhoea.
• Rimonobant
o Rimonobant is a cannabinoid that promotes weight loss in people with
type 2 diabetes.
o At least half of all patients using it experience a mood change whilst on
the medication
o it should not be routinely used in those with a past history of
depression.
o It can help those type 2 patients who gain a lot of weight when they
go onto insulin.
Insulin treatment

§ Short-acting insulins
o Short-acting insulins are used for pre-meal injection in multiple dose
regimens, for continuous intravenous infusion in labour or during
medical emergecies, and in patients using insulin pumps.
o Human insulin
i. Human insulin isabsorbed slowly

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ii. reaches a peak 60–90 minutes after subcutaneous injection, and


its action tends to persist too long after meals, predisposing to
hypoglycaemia.
iii. Absorption is delayed because soluble insulin is in the form of
stable hexamers (six insulin molecules around a zinc core) and
needs to dissociate to monomers or dimers before it can enter the
circulation.
o Short-acting insulin analogues
i. Short-acting insulin analogues have been engineered to
dissociate more rapidly following injection without altering the
biological effect.
ii. Insulin analogues such as insulin lispro, insulin aspart and
insulin glulisine enter the circulation more rapidly than human
soluble insulin, and also disappear more rapidly.
iii. Although widely used, the short-acting analogues have little
effect upon overall glucose control in most patients, mainly
because improved postpran- dial glucose is balanced by higher
levels before the next meal

§ Longer-acting insulins
o The action of human insulin can be prolonged by the addition of zinc
or protamine derived from fish sperm.

o NPH (isophane insulin)

§ It has the advantage that it can be premixed with soluble


insulin to form stable mixtures, of which the combination of
30% soluble with 70% NPH is most widely used.

§ Long-acting analogues have their structure modified to delay


absorption or to prolong their duration of action .

o Insulin glargine is soluble in the vial as a slightly acidic (pH 4)


solution, but precipitates at subcutaneous pH, thus prolonging its
duration of action.

o Insulin detemir has a fatty acid ‘tail’ which allows it to bind to serum
albumin, and its slow dissociation from the bound state prolongs its
duration of action.

§ theseinsulinshave little advantage over NPH in most clinical


situations, although useful in those on intensified therapy or
with troublesome hypoglycaemia.

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Type 2 diabetes Management

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Hyperosmolar hyperglycaemic state


§ This condition, in which severe hyperglycaemia develops without significant
ketosis, is the metabolic emergency characteristic of uncontrolled type 2
diabetes.
§ Patients present in middle or later life, often with previously undiagnosed
diabetes.
§ Common precipitating factors include consumption of glucose-rich fluids ,
concurrent medication such as thiazide diuretics or steroids, and intercurrent
illness.
§ Hyperosmolar hyperglycaemic state versus ketoacidosis
o Age. The extreme dehydration characteristic of hyperosmolar
hyperglycaemic state may be related to age.
§ Old people experience thirst less acutely, and more readily
become dehydrated.
§ In addition, the mild renal impairment associated with age results
in increased urinary losses of fluid and electrolytes.
o The degree of insulin deficiency. This is less severe in the
hyperosmolar hyperglycaemic state.
o Endogenous insulin levels are sufficient to inhibit hepatic
ketogenesis, whereas glucose production is unrestrained.
§ Clinical features
o The characteristic clinical features on presentation are dehydration and
stupor or coma.
o Impairment of consciousness is directly related to the degree of
hyperosmolality.
o Evidence of underlying illness such as pneumonia or pyelonephritis
may be present,
o hyperosmolar state may predispose to stroke, myocardial infarction or
arterial insufficiency in the lower limbs.
§ Investigations and treatment
o The plasma osmolality is usually extremely high. It can be measured
directly or calculated as (2(NaK) glucose urea), all in
mmol/L. Many patients are extremely sensitive to insulin, and the
glucose concentration may plummet. The resultant change in osmolality
may cause cerebral damage. It is sometimes useful to infuse insulin at a
rate of 3 U per hour for the first 2–3 hours, increasing to 6 U/h if
glucose is falling too slowly.
o The standard fluid for replacement is 0.9% physiological saline.
o Avoid 0.45% saline, since rapid dilution of the blood may cause more
cerebral damage than a few hours of exposure to hypernatraemia.
§ Prognosis
o The reported mortality ranges as high as 20–30%, mainly because of
the advanced age of the patients and the frequency of intercurrent
illness. Unlike ketoacidosis, the hyperosmolar hyperglycaemia state is not
an absolute indication for subsequent insulin thera py, and survivors
may do well on diet and oral agents.

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Topic 09 - Diabetic ketoacidosis

Diabetic ketoacidosis

§ Diabetic ketoacidosis is the hallmark of type 1 diabetes .


§ Pathogenesis
o Insulin deficiency is a necessary precondition since only a modest
elevation in insulin levels is sufficient to inhibit hepatic ketogenesis, and
stable patients do not readily develop ketoacidosis when insulin is with-
drawn.
o Other factors include counter-regulatory hormone excess and fluid
depletion.
o In the absence of insulin , hepatic glucose production accelerates, and
peripheral uptake by tissues such as muscle is reduced.
o Rising glucose levels lead to an osmotic diuresis, loss of fluid and
electrolytes, and dehydration.
o Plasma osmolality rises and renal perfusion falls.
o In parallel, rapid lipolysis occurs, leading to elevated circulating free
fatty-acid levels.
o The free fatty acids are broken down to fatty acyl-CoA within the liver
cells, and this in turn is converted to ketone bodies within the
mitochondria
o Accumulation of ketone bodies produces a metabolic acidosis.
o Vomiting leads to further loss of fluid and electrolytes.
o The excess ketones are excreted in the urine but also appear in the breath,
producing a distinctive smell similar to that of acetone .
o Respiratory compensation for the acidosis leads to hyperventilation,
graphically described as ‘air hunger’.
o Progressive dehydration impairs renal excretion of hydrogen ions
and ketones, aggravating the acidosis.
o As the pH falls below 7.0 ,pH-dependent enzyme systems in many
cells function less effectively.
§ Clinical features
o The features of ketoacidosis are those of uncontrolled diabetes with
acidosis, and include prostration, hyperventilation (Kussmaul
respiration), nausea, vomiting and, occasionally, abdominal pain.
The latter is sometimes so severe that it can be confused with a surgical
acute abdomen.
o Up to 5% present in coma.
o Evidence of marked dehydration is present and the eyeball is lax to
pressure in severe cases.
o Hyperventilation is present but becomes less marked in very severe
acidosis owing to respiratory depression.
o The skin is dry and the body temperature is often subnormal, even in
the presence of infection; in such cases, pyrexia may develop later.
§ Diagnosis
o This is confirmed by demonstrating hyperglycaemia with ketonaemia
or heavy ketonuria, and acidosis

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§ Management
o Replace the fluid losses with 0.9% saline.
§ Average loss of water is 5–7 litres with a sodium loss of 500
mmol.
o Replace the electrolyte losses.
§ Potassium levels need to be monitored.
§ Patients have a total body potassium deficit of 350 mmol ,
although initial plasma levels may not be low . Insulin therapy
leads to uptake of potassium by the cells with a consequent fall in
plasma Klevels. Potassium is therefore given as soon as insulin
is started.
o Restore the acid–base balance.
§ A patient with healthy kidneys will rapidly compensate for the
metabolic acidosis once the circulating volume is restored.
§ Bicarbonate is seldom necessary and is only considered if the
pH is below 7.0 and is best given as an isotonic (1.26%) solution.
o Replace the deficient insulin.
§ Modern treatment is with relatively modest doses of insulin,
which lower blood glucose by suppressing hepatic glucose output
rather than by stimulating peripheral uptake, and are therefore
much less likely to produce hypoglycaemia.
§ Soluble insulin is given as an intravenous infusion where
facilities for adequate supervision exist, or as hourly intramuscular
injections.
§ The subcutaneous route is avoided because subcutaneous
blood flow is reduced in shocked patients.
o Monitor blood glucose closely
§ Hourly measurement is needed in the initial phases of
treatment.
o Replace the energy losses.
§ When plasma glucose falls to near-normal values (12 mmol/L),
saline infusion should be replaced with 5% dextrose
containing 20 mmol/L of potassium chloride . The insulin
infusion rate is reduced and adjusted according to blood glucose.
o Two common markers of infection are misleading: fever is unusual
even when infection is present, and polymorpholeucocytosis is present
even in the absence of infection.
DKA -Case management

§ .Phase 1 management
o Insulin: soluble insulin i.v . 6 units/h by infusion, or 20 unitsi.m. stat.
followed by 6 units i.m. hourly.
o Fluid replacement:
§ 0.9% sodium chloride with 20 mmolKCl per litre.
§ An average regimen would be 1 L in 30 minutes, then 1 L in 1
hour, then 1 L in 2 hours, then 1 L in 4 hours, then 1 L in 6
hours.

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o Adjust KCl concentration depending on results of 2 hourly blood


K+measurement.
o ifBlood pressure below 80 mmHg, give plasma expander.
o ifpH below 7.0 give 500 mL of sodium bicarbonate 1.26% plus 10 mmolKCl.
o Repeat if necessary to bring pH up to 7.0.
§ Phase 2 management

o When blood glucose falls to 180–216 mg/dL change infusion fluid to 1 L 5%


dextrose plus 20 mmolKCl 6-hourly.

o Continue insulin with dose adjusted according to hourly blood glucose test
results (e.g. i.v . 3 units/h glucose when270 mg/dL; 2 units/h when glucose 180
mg/dL).

§ Phase 3 management

o Once stable and able to eat and drink normally, transfer patient to four times
daily subcutaneous insulin regimen (based on previous 24 hours’ insulin
consumption, and trend in consumption).

§ Problems of management
o Hypotension.
§ This may lead to renal shutdown.
§ Plasma expanders (or whole blood) are therefore given if the
systolic blood pressure is below 80 mmHg.
§ A central venous pressure line is useful in this situation.
§ A bladder catheter is inserted if no urine is produced within 2
hours, but routine catheterization is not necessary.
o Coma.
§ It is essential to pass a nasogastric tube to prevent aspiration,
since gastric stasis is common and carries the risk of aspiration
pneumonia if a drowsy patient vomits.
o Cerebral oedema.
§ This is a rare, but serious complication and has mostly been
reported in children or young adults.
§ Excessive rehydration and use of hypertonic fluids such as
8.4% bicarbonate may sometimes be responsible.
§ The mortality is high.
o Hypothermia.
§ Severe hypothermia with a core temperature below 33°C may
occur and can be overlooked unless a rectal temperature is taken
with a low-reading thermometer.
o Late complications.
§ These include pneumonia and deep-vein thrombosis (DVT
prophylaxis) and occur especially in the comatose or elderly
patient.
o Complications of therapy.
§ These include hypoglycaemia and hypokalaemia, due to loss
of K in the urine from osmotic diuresis.
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§ Overenthusiastic fluid replacement may precipitate pulmonary


oedema in the very young or the very old.
§ Hyperchloraemic acidosis may develop in the course of
treatment since patients have lost a large variety of negatively
charged electrolytes, which are replaced with chloride. The
kidneys usually correct this spontaneously within a few days.

Topic 10 – Hyperparathyroidism

Parathyroid hormone

• PTH, an 84-amino-acid hormone derived from a 115-residue


preprohormone
• PTH is secreted from the chief cells of the parathyroid glands. PTH
levels rise as serum ionized calcium falls.
• Hypocalcemiais detected by specific G protein- coupled calcium-
sensing receptors on the plasma membrane of the parathyroid
cells.
• PTH has several major actions,all serving to increase plasma calcium
by:
o increasing osteoclasticresorption of bone (occurring
rapidly)
o increasingintestinal absorption of calcium (a slow response)
o increasing synthesis of 1,25-(OH)2D3
o increasingrenal tubular reabsorption of calcium
o increasingexcretion of phosphate.
• PTH effects are mediated at specific membrane receptors on the
target cells, resulting in an increase of adenylcyclase messenger
activity.

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Hypercalcaemia


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• Pathophysiology and causes


o primary hyperparathyroidism and malignancies are by far
the most common (90% of cases).
o Hyperparathyroidism itself may be primary, secondary or
tertiary.
o Primary hyperparathyroidism is caused by single (80%)
parathyroid adenomas or by diffuse hyperplasia of all the
glands (15–20%
o Involvement of multiple parathyroid glands may be part of
a familial syndrome (e.g. multiple endocrine neoplasia
(MEN) syndrome type 1 or 2a).
o Hyperparathyroidism–jaw tumour syndrome is a rare
familial cause of hyperparathyroidism which may be associated
with parathyroid carcinoma and maxillary or mandibular
tumours.
o Primary hyperparathyroidism
§ Itis of unknown cause
§ Chromosomal rearrangements in the 5′regulatory
region of the parathyroid hormone gene have been
identified
o Secondary hyperparathyroidism
§ It is physiological compensatory hypertrophy of all
parathyroids because of hypocalcaemia, such as occurs
in renal failure or vitamin D deficiency.
§ PTH levels are raised but calcium levels are low or
normal, and PTH falls to normal after correction of the
cause of hypocalcaemia where this is possible.
o Tertiary hyperparathyroidism
§ It is the development of apparently autonomous
parathyroid hyperplasia after long- standing
secondary hyperparathyroidism, most often in renal
failure.
§ Plasma calcium and phosphate are both raised, the
latter often grossly so.
§ Parathyroidectomy is necessary at this stage.
Symptoms and signs

§ Mild hypercalcaemia (e.g. adjusted calcium 3mmol/L) is


frequently asymptomatic
§ More severe hypercalcaemia can produce a number of symptoms:
§ tiredness, malaise, dehydration and depression.
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§ Renal
§ Renal colic from stones, polyuria or nocturia,
haematuria and hypertension occurs.
§ The polyuria results from the effect of
hypercalcaemia on renal tubules, reducing their
concentrating ability – a form of mild
nephrogenic diabetes insipidus.
§ Primary hyperparathyroidism is present in about
5% of patients who present with renal calculi.
§ Bones.
§ There may be bone pain.
§ Hyperparathyroidism mainly affects cortical bone,
and bone cysts andlocally destructive ‘brown
tumours’ occur but only in advanced disease.
§ Abdominal. There may be abdominal pain.
§ Chondrocalcinosis and ectopic calcification.
§ Corneal calcification. This is a marker of long-
standinghypercalcaemia but causes no symptoms
§ Malignant disease is usually advanced by the time
hypercalcaemia occurs, typically with bony metastases.
§ The common primary tumours are bronchus, breast,
myeloma, oesopha- gus, thyroid, prostate, lymphoma
and renal cell carcinoma.
§ True ‘ectopic PTH secretion’ by the tumour is very rare,
and most cases are associated with raised levels of PTH-
related protein..
§ Severe hypercalcaemia (3 mmol/L) is usually associated with
malignant disease, hyperparathyroidism, renal failure or
vitamin D therapy.
Investigations and differential diagnosis

§ Serum PTH.
§ The hallmark of primary hyperparathyroidism is
hypercalcaemia and hypophosphataemia with detectable or
elevated intact PTH levels during hypercalcaemia. When
this combination is present in an asymptomatic patient
then further investigation is usually unnecessary.
§ There is often a mild hyperchloraemic acidosis.
§ 24-hour urinary calcium or single calcium creatinine ratio should
be measured in a young patient with modest elevation in calcium
and PTH to exclude familial hypocalciurichypercalcaemia
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§ Elevated serum alkaline phosphatase is found in severe


parathyroid bone disease, but otherwise it suggests an alternative
cause for hypercalcaemia.
§ Where PTH is undetectable or equivocal, a number of other
tests may lead to the diagnosis:
§ protein electrophoresis: to exclude myeloma
§ serum TSH: to exclude hyperthyroidism
§ 0900 h cortisol and/or ACTH test: to exclude Addiso n’s
disease
§ Serum ACE: helpful in the diagnosis of sarcoidosis
§ Hydrocortisone suppression test: hydrocortisone 40 mg
§ three times daily for 10 days leads to suppression of plasma
calcium in sarcoidosis, vitamin D-mediated hypercalcaemia and
some malignancies.
Imaging

§ Abdominal X-rays may show renal calculi or nephrocalcinosis.


High-definition hand X-rays can show subperiosteal erosions in the
middle or terminal phalanges.
§ DXA bone density scan is useful to detect bone effects in
asymptomatic patients with hyperparathyroidism (HPT) in whom
conservative management is planned.
§ Imaging is frequently far less accurate than parathyroid
exploration by an expert surgeon where the success rate is at least
90%. However, with the advent of minimally invasive surgery,
preoperative imaging is increasingly used.
§ Methods include:
o ultrasound which, though insensitive for small tumours, is
simple and safe
o high-resolution CT scan or MRI (more sensitive)
o radioisotope scanning using 99mTc-sestamibi, which is
o approximately 90% sensitive in detecting adenomas.

Treatment of primary hyperparathyroidism

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§ New therapeutic agents that target the calcium-sensing receptors


(e.g. cinacalcet) are of proven value in parathyroid carcinoma and in
dialysis patients
§ Indications for surgery in primary hyperparathyroidism
§ patients with renal stones or impaired renal function
§ bone involvement or marked reduction in cortical bone
§ densityunequivocal marked hypercalcaemia
§ the uncommon younger patient, below age 50 years with a
previous episode of severe acute hypercalcaemia.
Treatment of acute severe hypercalcaemia

§ Acute hypercalcaemia often presents with dehydration, nausea and


vomiting, nocturia and polyuria, drowsiness and altered
consciousness.
§ The serum Ca2is over 3 mmol/L and sometimes as high as 5
mmol/L.
§ Immediate treatment is mandatory if the patient is seriously ill or if
the Ca2is above 3.5 mmol/L.
§ Rehydrate at least 4–6 L of 0.9% saline on day 1, and 3– 4 L for
several days thereafter. Central venous pressure (CVP) may need to
be monitored to control the hydration rate.
§ Intravenous bisphosphonates are the treatment of choice for
hypercalcaemia of malignancy or of undiagnosed cause.
o Pamidronate is preferred
o Levels fall after 24–72 hours, lasting for approximately two
weeks
§ Prednisolone (30–60 mg daily) is effective in some instances (e.g.
in myeloma, sarcoidosis and vitamin D excess) but in most cases is
ineffective.
§ Calcitonin (200 units i.v . 6-hourly) has a short-lived action and is
little used.
§ Oral phosphate (sodium cellulose phosphate 5 g three times
daily) produces diarrhoea.
Familial hypocalciurichypercalcaemia

§ This uncommon autosomal dominant, and usually


asymptomatic, condition demonstrates increased renal reabsorp-
tion of calcium despite hypercalcaemia.
§ PTH levels are normal or slightly raised and urinary calcium is low.

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§ It is caused by loss of function mutations in the gene on the long


arm of chromosome 3 encoding for the calcium-ion-sensing G
protein-coupled receptor in the kidney and parathyroid gland.
§ Family members are often affected, detected by genetic analysis.
Parathyroid surgery is not indicated as the course appears benign.
§ This diagnosis can be differentiated from hyperparathyroidism in
an isolated case by the calcium creatinine ratio in blood and urine.

Topic 11 – Hypoparathyroidism

Hypoparathyroidism

• Etiology
o Idiopathic
o DiGeorge syndrome (MCQ)
o Postsurgical
o Infiltrative carcinoma (MCQ)
o Irradiation
o Hypomagnesemia(MCQ)
o magnesium is necessary for parathyroid gland to secrete PTH
• Signs and symptoms
o Equal incidence in men and women
o Signs and symptoms of hypocalcemia(MCQ)
§ Seizures
§ Perioral paresthesia
§ Fasciculations, tetany, and muscle weakness
§ CNS depression, irritability, confusion
§ Chvostek’s and Trousseau’s signs
§ Faint heart sounds
§ Bronchospasm
§ Anxiety, psychosis
• Diagnosis
o QT prolongation on ECG (MCQ)
o Low serum calcium(MCQ)
o High serum phosphorus (MCQ)
o Normal or low PTH
o Normal 25-OH vit D
o Low 1,25-(OH)2vit D
• Treatment
o Treat severe, life-threatening hypocalcemia with intravenous calcium
(MCQ)
o Maintenance therapy with calcitriol and oral calcium supplementation
• Clinical Pearls :
o Clinical Vignette for MD Entrance :

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§A 34-year-old woman presents with perioral paresthesias and a


long QT interval on ECG. She recently had surgery for a thyroid
goiter(MCQ)
§ Diagnosis :Hypoparathyroidism (due to neck surgery with probable
accidental resection of the parathyroids).
o Vitamin D acts on the intestines to increase absorption of calcium and
phosphate
§ It enters the skin via sunlight as a previtamin and is converted to
an inactive intermediate (25-OH vit D) in the liver before being
converted to its active form 1,25-(OH)2vit D (calcitriol) in the
kidney.
• Positive Chvostek sign and Trousseau phenomenon.(MCQ)

• Serum calcium low; serum phosphate high; alkaline phosphatase normal; urine
calcium excretion reduced.(MCQ)

• Serum magnesium may be low .(MCQ)

• Functional hypoparathyroidism(MCQ)
o may also occur as a result of magnesium deficiency (malabsorption,
chronic alcoholism), which prevents the secretion of PTH.
o Correction of h ypomagnesemia results in rapid disappearance of the
condition
• PGA type I (PGA-1)
o also known as autoimmune polyendocrinopathy-candidiasis-
ectodermal dystrophy (APECED). (MCQ)
o PGA-1 presents in childhood with at least two of the following
manifestations: candidiasis, hypoparathyroidism, or Addison disease.
Cataracts, uveitis, alopecia, vitiligo, or autoimmune thyroid disease
may also develop.(MCQ)
o Fat malabsorption occurs in 20% of patients with PGA-1 and may
present as weight loss, diarrhea, or malabsorption of vitamin D, a fat-
soluble vitamin used to treat the hypoparathyroidism. (MCQ)
o The fat malabsorption may be due to a deficiency in the
jejunalenteroendocrine cells that produce cholecystokinin, causing a
reduction in bile acid secretion(MCQ)
• Parathyroid deficiency may also be the result of damage from (MCQ)
o heavy metals such as copper (Wilson disease)
o iron (hemochromatosis, transfusion hemosiderosis)
o granulomas, sporadic autoimmunity
o Riedel thyroiditis, tumors, or infection.
• Serum calcium is largely bound to albumin.
o In hypoalbuminemia, the serum ionized calcium may be determined, but
it has had surprisingly poor clinical utility.
o Alternatively, the serum calcium level can be corrected for serum
albumin level as follows:(MCQ)

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o
• Radiographs or CT scans of the skull may show basal ganglia calcifications
• bones may be denser than normal (MCQ)
• Cutaneous calcification may occur.
• Slit-lamp examination may show early posterior lenticular cataract
formation.(MCQ)
• Patients with chronic hypoparathyroidism tend to have increased bone mineral
density, particularly in the lumbar spine.(MCQ)
• Congenital pseudohypoparathyroidism(MCQ)
o a group of disorders characterized by resistance to PTH.(MCQ)
o There are several subtypes caused by different mutations involving the
PTH receptor or its G protein or adenylyl cyclase.(MCQ)
o Renal tubular resistance to PTH causes hypercalciuria with resultant
hypocalcemia.(MCQ)
o PTH levels are high(MCQ)
o PTH receptors in bone are typically not involved, such that bony
changes of hyperparathyroidism may be evident .
o Various phenotypic abnormalities—classically, short stature, round face,
obesity, short fourth metacarpals ,ectopic bone formation, and
mental retardation—may be associated with congenital
pseudohypoparathyroidism. (MCQ)
o Patients without hypocalcemia but sharing the phenotypic
abnormalities are said to have
"pseudopseudohypoparathyroidism."(MCQ)

Topic 12 – Osteoporosis

Osteoporosis

§ It is characterized by decreased bone mass, with thinning of the cortices and


loss of trabeculae, leading to increased bone fragility and risk of fracture. Bone
density (and bone loss) can be quantified with dual energy x-ray
absorptiometry.
§ Osteopenia is defined as abone mass 1.0 to 2.5 standard deviations below the
mean peak bone mass of a sex- and height-matched control pop- ulation.
§ Osteoporosis is defined as abone mass value more than 2.5 standard
deviations below the peak bone mass of a sex- and height-matched control
population.
§ Etiology
o The most common types of osteoporosis are postmenopausal osteo-
porosis, characterized by high turnover of bone, and senile osteoporosis,
which occurs in older men and women.
o Osteoporosis may be secondary to hypogonadism,
hyperparathyroidism, hyperthyroidism, or hypercortisolism.

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o It is associated with malnutrition (eg, calcium deficiency, protein


malnutrition, vitamin C deficiency, and alcoholism), malabsorption,
neoplastic disorders (eg, multiple myeloma, leukemia, lymphoma, and
systemic mastocytosis), and abnormalities of bone collagen (eg,
osteogenesisimperfecta).
o Drugs such as corticosteroids, heparin, methotrexate, and GnRH
analogues all increase bone loss. Immobilization also promotes bone
loss.
§ Clinical Features
o Osteoporosis is characterized by the occurrence of fracture with minimal trauma and
normal serum levels ofcalcium, phosphate, and alkaline phosphatase.
o Fractures can occur with minor trauma and be axial or appendicular.
Osteoporotic fractures heal normally.
o Vertebral fractures lead to loss of height and spinal deformity
(kyphoscoliosis and dowager hump).
o Other osteoporotic fractures include those of the hip and distal radius
(Colles fracture).
o The serum levels of calcium, phosphate, and alkaline phosphatase
are normal in osteoporosis.
o The serum level of alkaline phosphatase may be increased slightly
during fracture healing.
o Lateral spine radiographs show a loss of horizontal trabeculae and an
apparent prominence of the vertical trabeculae, biconcave vertebrae, and
a decrease in vertebral height.
o Bone mineral density can be assessed by dual energy x-ray
absorptiometry of the lumbar vertebrae (although vessel wall
calcification and vertebral deformity with advancing age can make this
measurement unreliable) or the hip.
o A decrease of 1 standard deviation from peak bone density of a
control population leads to a doubling of the fracture risk.
§ Diagnosis
o The diagnosis of osteoporosis is based on the finding of low bone mass
with or without fractures and the exclusion of other causes of
osteopenia, such as osteomalacia, multiple myeloma, and metastatic
disease.
o Bone densitometry should be used as a screening study for patients at
risk of osteoporosis (eg, postmenopausal women not taking preventive
measures).
o Bone densitometry is indicated for patients who have radiologic
evidence of previous vertebral fracture.
o It also is helpful in determining the need for surgery in
hyperparathyroidism.
o During the evaluation of a patient who has a fracture, it is impor- tant to
remember that osteomalacia may coexist with osteoporosis.
§ Prevention and Treatment of Osteoporosis
o To a certain extent, bone loss can be prevented by timely estrogen
replacement in women at and beyond menopause and by the
provision of adequate calcium and vitamin D intake in all adults
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§ In premenopausal women and men younger than 65 years,


1,000 mg daily of elemental calcium; in postmenopausal women
and men older than 65 years, 1,500 mg daily
o Other measures to ensure attainment (and maintenance) of adequate
bone mass include regular weight-bearing exercise and avoidance of
alcohol and tobacco abuse.
o Estrogen replacement
§ effective for the prevention and treat- ment of osteoporosis in
women who do not have contraindications to it
§ Estrogen can be given orally or transdermally. Women
receiving estrogen replacement therapy require a breast
examination and mammography annually.
§ To decrease the risk of endometrial hyperplasia, progesterone is
also administered in a cyclical or continuous fashion if the
patient has an intact uterus.
o Alendronate and risedronate are oral bisphosphonates with potent
antiresorptive effects; they prevent bone loss and increase bone density.
§ They have been shown to reduce fracture risk and to be effective
in preventing steroid-induced bone loss.
§ Bisphosphonates are now regarded as first-line therapy in the
treatment of osteoporosis.
§ Side effects include dyspeptic symp- toms and esophagitis ,
particularly if the medication is taken incorrectly.
§ Oral bisphosphonates should be taken in the morning with a
glass of waterand on an empty stomach (any food or other
drink may interfere with intestinal absorption), and the patient
should not lie down for 30 to 60 minutes after the dose.
o Calcitonin is a weak antiresorptive agent and is administered by nasal
spray.
§ Very useful for management of painful vertebral fractures.
o .Recombinant PTH is also now available for treatment of osteo-
porosis after clinical trials demonstrated the ability of this agent to
increase bone formation and bone mass when given by daily sub-
cutaneous injection.
§ This treatment is indicated for patients who have not shown
improvement with bisphosphonate therapy or who are unable
to tolerate those drugs orally or intravenously.
§ Prior radiotherapy is a contraindication to PTH therapy
because of the risk of sarcoma.

Topic 13 - Myxedema Coma

• MYXEDEMA COMA
o Life-threatening complication of hypothyroidism with profound lethargy
or coma usually accompanied by hypothermia.
o Mortality is 20 to 50% even if treated early.

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• Etiology
o Sepsis
o Prolonged exposure to cold weather
o CNS depressants (sedatives, narcotics) (MCQ)
o Trauma or surgery
• Signs and symptoms
o Profound lethargy or coma is obvious.
o Hypothermia: Rectal T 35C (95F)(MCQ)
o Bradycardia or circulatory collapse
o Delayed relaxation phase of DTRs, areflexia if severe (this can be a
veryimportant clue).(MCQ)
• Treatment
o Airway management with mechanical ventilation if necessary.
o Prevent further heat loss.
o Monitor patient in intensive care unit.
o Pharmacologic therapy:
§ Intravenous levothyroxine
§ Glucocorticoids (until coexisting adrenal insufficiency is
excluded)(MCQ)
o IV hydration (D 1⁄2 NS) 5
o Rule out and treat any precipitating causes (antibiotics for suspected
infection).
o Hypothermia is often missed by tympanic thermometers.
o Use a rectal probe if hypothermia is suspected.
• Differential diagnosis of myxedema coma:(MCQ)
o Severedepressionorprimary psychosis
o Drug over dose or toxic exposure
o CVA
o Liverfailure
o Hypoglycemia
o CO2 narcosis
o CNSinfection

Topic 14 – Hyperthyroidism

• Hyperthyroidism
• Increased synthesis and secretion of free thyroid hormones resulting in hyper-
metabolism
• Ten times more common in women than in men (MCQ)
• Etiology
o Graves’ disease (most common cause, 80% of cases)
o Toxic multinodular goiter
o Toxic adenoma (Plummer’s disease)(MCQ)
o Iatrogenic (lithium therapy)(MCQ)
o inadvertent toxic ingestion
o factitious(thyrotoxicosis factitia)

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o Transient hyperthyroidism (subacute thyroiditis)(MCQ)


• Pathophysiology
o High levels of free thyroid hormones increase levels of cellular metabolism
and cause multiple effects, resulting in a general state of
hypermetabolism.(MCQ)
• Signs and symptoms
o Heat intolerance, sweating
o Palpitations(MCQ)
o hyperthyroidism is a common cause of atrial fibrillation (MCQ)
o Weight loss
o Tremor
o Nervousness and anxiety
o Weakness and fatigue
o Hyperdefecation(MCQ)
• Diagnosis
o Measure TSH, free T4, and free T3 (if the T4 level is normal)
• Treatment
o Depends on underlying disorder

• Clinical pearls :
• Causes of large tongue (macroglossia):

o Acromegaly

o Myxedema

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• T oxic multinodular goiter and Thyroid adenomas


• Autonomous toxic adenomas of the thyroid may be single (Plummer disease)
or multiple (toxic multinodular goiter).(MCQ)
• Jodbasedow disease, or iodine-induced hyperthyroidism(MCQ)
o occur in patients with multinodular goiters after intake of large
amounts of iodine in the diet or in the form of radiographic contrast
materials or drugs, especially amiodarone.
o This condition is not associated with infiltrative ophthalmopathy or
dermopathy.
o Antithyroid antibodies are usually not present in the plasma, and tests
for TRAb are negative(MCQ)
• Subacute (de quervain) thyroiditis
o typically presents with a moderately enlarged, tender thyroid, and
hyperthyroidism. (MCQ)
o It is thought to be due to a viral infection.
o If the gland is nontender, the disorder is called "silent
thyroiditis."(MCQ)
o Hyperthyroidism is followed by hypothyroidism.
o During thyrotoxicosis, thyroid radioactive iodine (RAI) uptake is
low.(MCQ)
• A similar problem of low RAI is seen with interleukin-2 therapy and after
neck surgery for hyperparathyroidism. (MCQ)
• Patients taking lithium may rarely experience thyrotoxicosis due to silent
thyroiditis.(MCQ)
• Struma ovarii
o Thyroid tissue is contained in about 3% of ovarian dermoid tumors
and teratomas. (MCQ)
• Amiodarone-induced thyrotoxicosis
• Pregnancy and trophoblastic tumors
• The prevalence of hyperthyroidism in pregnancy—most commonly due to
Graves disease
• Newborns have an increased risk of intrauterine growth retardation, prematurity, and
transient thyrotoxicosis from transplacental transfer of TRAb. (MCQ)
o Although hCG generally has a low affinity for the thyroid's TSH
receptors, very high serum levels of hCG may cause sufficient receptor
activation to cause thyrotoxicosis.
o Mild gestational hyperthyroidism may occur during the first 4 months
of pregnancy, when hCG levels are very high.
o Pregnant women are more likely to have thyrotoxicosis and
hyperemesis gravidarum if they have high serum levels of asialo-hCG ,
a subfraction of hCG with greater affinity for TSH receptors.(MCQ)
• Thyrotoxicosis may also be caused by the high serum levels of hCG seen in molar
pregnancy, choriocarcinoma, and testicular malignancies.(MCQ)
• Eye findings in hyperthyroidism of any etiology(MCQ)
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o upper eyelid retraction (Dalrymple sign),


o lid lag with downward gaze (von Graefe sign),
o astaring appearance (Kocher sign)—
o There may be weakness of upward gaze (Stellwag sign).
• Hypokalemic periodic paralysis (A very high yield MCQ in MD Entrance )
o occurs in about 15% of Asian men with thyrotoxicosis. (MCQ)
o It usually presents abruptly with symmetric flaccid paralysis (and few
thyrotoxic symptoms), often after intravenous dextrose, oral carbohydrate, or
vigorous exercise.
o Attacks last 7–72 hours.
• Thyroid acropachy
• extreme and unusual manifestation of Graves disease.
• It presents with
o digital clubbing,
o swelling of fingers and toes
o aperiosteal reaction of extremity bones. (MCQ)
• It is ordinarily associated with ophthalmopathy and thyroid
dermopathy.(MCQ)
• Most patients are smokers.
• The presence of thyroid acropachy is an indication of the severity of the
autoimmunity; most patients have high serum titers of thyroid-stimulating
immunoglobulin(MCQ)

Topic 15 – Thyroiditis

• Thyroiditis
• Can be divided into three common types
o Hashimoto’s thyroiditis
o Subacutethyroiditis
o Silent thyroiditis
o Suppurativethyroiditis
o Riedel’s thyroiditis
• Etiology
o Hashimoto’s thyroiditis:
§ Autoimmune disorder that involves CD4 lymphocyte-mediated
destruction of the thyroid. (MCQ)
§ The lymphocytes are specific for thyroid antigens.
§ Cause for activation of these cells is un- known.
o Subacute thyroiditis:
§ Possibly a postviral condition because it usually follows a viral
URI. (MCQ)
§ Not considered an autoimmune reaction.(MCQ)
o Silent thyroiditis:
§ Usually occurs postpartum and is thought to be autoimmune
mediated(MCQ)
o Suppurative thyroiditis:
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§ Usually, a bacterial infection, but fungi and parasites have also


been implicated in some cases.
§ Commonly seen in HIVpatients with PCP .
o Riedel’s thyroiditis:
§ Also called fibrous thyroiditis, fibrous infiltration of the thyroid
of unknown etiology.(MCQ)
• Signs and symptoms
o Hashimoto’s:
§ There may be signs of hyper- or hypothyroidism depending on
the stage.
§ Usually, there is diffuse, firm enlargement of the gland, but it
may be of normal size if the disease has progressed. (MCQ)
o Subacutethyroiditis:
§ Tender, enlarged gland. (MCQ)
§ Fever, and signs of hyperthyroidism are initially present.
§ Hypothyroidism may develop.(MCQ)
o Silent thyroiditis:
§ Similar to subacute except there is no tenderness of the gland
(painless thyroiditis).(MCQ)
o Suppurative thyroiditis::
§ Fever with severe neck pain. (MCQ)
§ Focal tenderness of involved portion of the gland.
o Riedel’sthyroiditis::
§ Slowly enlarging rock-hard mass in the anterior neck.
§ Tight, stiff neck . (MCQ)
§ Must differentiate from thyroid CA.
§ Hypothyroidism may occur if advanced.
§ Fibrosis may involve mediastinum.
• Diagnosis
o History
§ Presentation following viral URI is suggestive of subacute
thyroiditis.
§ Presentation after penetrating injury to the neck is suggestive
of suppurative processes.(MCQ)
§ Postpartum presentation is suggestive of silent thyroiditis.
o Laboratory Examination
§ TSH and free T4 may be normal or indicative of hypo or hyperthy-
roidism.
§ WBC with differential should be obtained to look for
leukocytosis and left shift (subacute and
suppurative).(MCQ)
§ Antimicrosomal antibodies are present in(MCQ)
• 90% with Hashimoto’s
• 50 to 80% with silent thyroiditis.
§ Serum thyroglobulin levels(MCQ)
• elevated in subacute and silent thyroiditis (test is very
nonspecific).
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• Imaging Studies
o Radioactive iodine uptake (RAIU) can be useful to distinguish
§ Graves’ disease (increased RAIU) (MCQ)
§ Hashimoto’s thyroiditis (decreased RAIU).(MCQ)
• Treatment
o Treat hypothyroidism, if present, with levothyroxine for 6 to 8 weeks
o Reevaluate the TSH level.
o Control symptoms of hyperthyroidism , if present, with propranolol.
o Pain management in patients with subacute thyroiditis should be
accomplished with NSAIDs.
o If ineffective , begin steroids.
o IV antibiotics and abscess drainage, if present, should be performed
insuppurative thyroiditis.
o Do not give PTU or methimazole in thyroiditis.(MCQ)
• Prognosis
o Hashimoto’sthyroiditis:
§ Most patients do not completely recover their total thyroid
function.(MCQ)
o Subacute thyroiditis:Hypothyroidism persists in 10%.
o Silentthyroiditis: Hypothyroidism persists in 6%.
o Suppurativethyroiditis: Full recovery is common.
o Riedel’s thyroiditis:
§ Hypothyroidism occurs when the entire gland un-dergoes
fibrosis.(MCQ)
• The thyroid in Hashimoto’s is nontender, which distinguishes it from other
forms of thyroiditis.
• Clinical Vignette in MD Entrance exam :(MCQ)
o A 39year-old female with a history of hyperthyroidism and a recent
viral influenza presents with neck pain and an elevated ESR.
o Diagnosis :Subacute thyroiditis.
• Differential diagnosis of thyroiditis:
o The hyperthyroid stage of Hashimoto’s, subacute, or
silentthyroiditis , may mimic Graves’ disease.
o Riedel’s must be differentiated from thyroid CA.
o Subacutecanbe mistaken for oropharyngeal or tracheal
infections or for suppurative thyroiditis.

Topic 16 - Multiple endocrine neoplasia

Multiple endocrine neoplasia

o The condition is inherited in an autosomal dominant manner


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o arise from the expression of recessive oncogenic mutations, most of which


have been isolated.
o Affected persons may pass on the mutation to their offspring in the germ
cell, but for the disease to become evident a somatic mutation must also
occur, such as deletion or loss of a normal homologous chromosome.
o The defect in MEN 1 is in a novel gene (menin) on the long arm of chromo-
some 11
o Menin represses a transcription factor (JunD) and lack of JunD sup-
pression leads to decreased apoptosis and oncogenesis.
o What is the ‘two hit’ hypothesis in MEN Syndrome
o Patients with the MEN1 gene carry one mutant gene and a wild type
gene (i.e. are heterozygous).
o When the wild type gene undergoes a random somatic mutation during
life, this leads to loss of heterozygosity and explains the late onset of
tumours at any stage (the ‘two hit’ hypothesis ).
o MEN 2a and 2b are caused by mutations of the RET proto-oncogene on
chromosome 10
o This gene encodes for a transmembrane glycoprotein receptor.
o For MEN 2a the mutation is in the extracellular domain; for 2b it is in the
intracellular domain.
Management

o Treatment of established tumours in MEN is largely the same as treatment for


similar tumours occurring sporadically.
o In MEN 1 four-gland parathyroidectomy is usually recommended when
surgery is needed since all glands are typically involved.
o However, the essence of management in MEN is annual screening to detect
tumours at an early, treatable stage.
o Screening
o Screening for type 1
§ Hyperparathyroidism is usually the first manifestation, and
serum calcium is the simplest screening test in families with
no identified mutation..
o Screening for type 2
§ Serum calcium levels will easily detect hyperparathyroidism.
§ Medullary carcinoma of thyroid (MCT) – with the known
presence of the gene defect, total thyroidectomy is
recommended in early childhood or as soon as the gene defect
is identified.
§ Calcitonin is a useful tumour marker.
§ Phaeochromocytoma–metanephrine or catecholamine
estimations.

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Topic 17 - Hereditary haemochromatosis

Hereditary haemochromatosis

§ Hereditary haemochromatosis (HH) is an inherited disease characterized by


excess iron deposition in various organs leading to eventual fibrosis and
functional organ failure.
§ Prevalence and aetiology
o HH is transmitted by an autosomal recessive gene
o It is the most common single gene disorder in Caucasians.
o The most common form of HH is due to a mutation in a gene, HFE,
on the short arm of chromosome 6.
o Between 85% and 90% of patients with overt HH are homozygous for
the Cys 282 Tyr (C282Y mutation).
o Dietary intakes of iron and chelating agents (ascorbic acid) may be
relevant.
o Iron overload may be present in alcoholics, but alcohol excess per se
does not cause HH although there is a history of excess alcohol intake in
25% of patients.
§ Mechanism of damage.
o The HFE gene protein interacts with the transferrin receptor 1, which
is a mediator in intestinal iron absorption
o Iron is taken up by the mucosal cellsinappropriately, exceeding the
binding capacity of transferrin.
o Hepatic expression of the hepcidin gene is decreased in
HFEhaemochromatosis, facilitating liver iron overload.
o Excess iron is then taken up by the liver and other tissues gradually over
a long period.
o It seems likely that it is the iron itself that precipitates fibrosis.
§ Pathology
o In symptomatic patients the total body iron content is 20– 40 g,
compared with 3–4 g in a normal person.
o The ironcontent is particularly increased in the liver and pancreas (50–
100 times normal) but is also increased in other organs (e.g. the
endocrine glands, heart and skin).
o In established cases the liver shows extensive iron deposition and
fibrosis.
§ Early in the disease, iron is deposited in the periportal
hepatocytes (in pericanalicular lysosomes).
§ Later it is distributed widely throughout all acinar zones, biliary
duct epithelium, Kupffer cells and connective tissue.
o Cirrhosis is a late feature.
§ Clinical features
o Overt clinical manifestations occur more frequently in men; the
reduced incidence in women is probably explained by physiological blood
loss and a smaller dietary intake of iron.
o Most affected individuals present in the fifth decade.

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o The classic triad of bronze skin pigmentation (due to melanin


deposition), hepa- tomegaly and diabetes mellitus is only present in cases
of gross iron overload.
o Hypogonadism secondary to pituitary dysfunction is the most common
endocrine feature.
o Cardiac manifestations, particularly heart failure and arrhythmias, are
common, especially in younger patients.
o Calcium pyrophosphate is deposited asymmetrically in both large and
small joints (chondrocalcinosis) leading to an arthropathy.
§ Complications
o Thirty per cent of patients with cirrhosis will develop primary
hepatocellular carcinoma (HCC).
§ Investigations
o Homozygotes
§ Serum iron is elevated (30 mol/L) in 90% with a
reduction in the TIBC and a transferrin saturation of
45%.
§ Serum ferritin is elevated (usually 500 g/L or 240 nmol/L).
§ Liver biochemistry is often normal, even with established
cirrhosis.
o Heterozygotes
§ Heterozygotes may have normal biochemical tests or modest
increases in serum iron transferrin saturation ( 45%) or serum
ferritin (usually 400 g/L).
o Genetic testing
§ If iron studies are abnormal, genetic testing is performed.
o Liver biopsy
§ This is not required for diagnosis, but is useful to assess the
extent of tissue damage, assess tissue iron, and measure the
hepatic iron concentration (180 mol/g dry weight of
liver indicates haemochromatosis).
§ Mild degrees of parenchymal iron deposition in patients with
other forms of cirrhosis, particularly due to alcohol, can often
cause confusion with true homozygous HH.
o Magnetic resonance imaging
§ MRI shows dramatic reduction in the signal intensity of the
liver and pancreas owing to the paramagnetic affect of ferritin
and haemosiderin.
§ A highly T2 weighted gradient recalled echo (GRE)
technique detects all clinically relevant liver iron overload (60
mol/g of liver).
o In secondary iron overload (haemosiderosis), which involves the
reticuloendothelial cells, the pancreas is spared, enabling distinction
between these two conditions.
§ Treatment and management
o Venesection
§ This prolongs life and may reverse tissue damage; the risk of
malignancy still remains if cirrhosis is present.
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§ All patients should have excess iron removed as rapidly as


possible.
§ This is achieved using venesection of 500 mL performed twice-
weekly for up to 2 years, i.e. 160 units with 250 mg of iron per
unit, equals 40 g removed.
§ During venesection, serum iron and ferritin and the mean
corpuscular volume (MCV) should be monitored. These fall
only when available iron is depleted.
§ Serum ferritin should remain within the normal range.
§ Three or four venesections per year are required to prevent
reaccumulation of iron.
§ Manifestations of the disease usually improve or disappear, except
for diabetes, testicular atrophy and chondrocalcinosis.
o In the rare patient who cannot tolerate venesection (because of severe
cardiac disease or anaemia), chelation therapy with desferrioxamine,
either intermittently or continu- ously by infusion, has been successful in
removing iron.
§ Screening
o In all cases of HH, all first-degree family members must be screened
to detect early and asymptomatic disease.
o HFE mutation analysis is performed with measurement of trans- ferrin
saturation and serum ferritin.
o In the general population, the serum iron and transferrin saturation
are the best and cheapest tests available.

Topic 18 - Wilson’s disease

Wilson’s disease (progressive hepatolenticular degeneration)

§ Dietary copper is normally absorbed from the stomach and upper small
intestine.
§ It is transported to the liver loosely bound to albumin. Here it is incorporated
into apocaeruloplasmin forming caeruloplasmin, a glycoprotein synthesized in
the liver, and secreted into the blood.
§ The remaining copper is normally excreted in the bile and excreted in faeces.
§ Wilson’s disease is a very rare inborn error of copper metabolism that results in
copper deposition in various organs, including the liver, the basal ganglia of
the brain and the cornea .
§ It is potentially treatable
§ All young patients with liver disease must be screened for this condition.
§ Aetiology
o It is an autosomal recessive disorder with a molecular defect within a
copper-transporting ATPase encoded by a gene (designated ATP7B)
located on chromosome 13,
o Wilson’s disease occurs particularly where consanguinity is common.

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o There is a failure of both incorporation of copper into


procaeruloplasmin, which leads to low serum caeruloplasmin, and
biliary excretion of coppe r.
o There is a low serum caeruloplasmin in over 80% of patients but this
is not the cause of the copper deposition.
§ Pathology
o The liver histology is not diagnostic and varies from that of chronic
hepatitis to macronodular cirrhosis.
o Stains for copper show a periportal distribution but this can be
unreliable The basal ganglia are damaged and show cavitation
o The kidneys show tubular degeneration, and erosions are seen in
bones.
§ Clinical features
o Children usually present with hepatic problems
o Young adults have more neurological problems, such as tremor,
dysarthria, involuntary movements and eventually dementia.
o The liver disease varies from episodes of acute hepatitis, especially in
children, which can go on to fulminant hepatic failure, to chronic
hepatitis or cirrhosis.
o