1. health and fitness
2. disease

Page 1 of 59
DR. RAJENDRAN’S INSTITUTE OF MEDICAL EDUCATION
AIIMS NOVEMBER 2011 - QUESTIONS & ANSWERS
MEDICINE
1) Limb girdle muscle dystrophy includes all of the following groups of disorder except
a. Sarcoglycanopathy
b. Dystroglycanopathy
c. Dysferlinopathy
d. Calpainopathy
Ans: (B)
Muscular dystrophies - Myopathy simply refers to an abnormality of the muscle. Muscular
dystrophies are genetic myopathies usually caused by a disturbance of a structural protein or
enzyme, resulting in necrosis of muscle fibers and replacement by adipose and connective
tissue.
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Sarcoglycanopathies - Mutations in sarcoglycans (α, β, γ, and δ) result in limb-girdle muscular
dystrophy types 2C to 2F. Sarcoglycanopathies often start in childhood. These diseases present
initially as pelvic muscle weakness, including a waddling gait and difficulty performing common
tasks, such as getting up from the floor, climbing the stairs, and running. The trunk muscles are
prominently affected. Distal muscles are generally spared until later in the disease process. These
progressive disorders result in very high levels of serum CK early in the disease; the levels
decrease when patients become wheelchair bound by 12 to 16 years of age. Dilated
cardiomyopathy is often seen. Muscle biopsies show marked regeneration and necrosis.
Dysferlinopathy - Genetic defects in the dysferlin gene result in limb-girdle muscular dystrophy
type 2B and distal muscular dystrophy of the Miyoshi type. These diseases can appear in the late
teens or early 20s. The weakness in the limb-girdle type 2B phenotype affects the quadriceps
muscle first, followed by weakness in the arms in the later stages of the disease. The weakness in
the Miyoshi phenotype occurs predominantly in the gastrocnemius and soleus muscles, thereby
affecting the ability to walk on the toes. The weakness is slowly progressive, with loss of
ambulation generally occurring in the fourth decade, but earlier in some cases. Serum CK levels
are very high during the active phase of the disease.
Dystrophinopathies are caused by mutations in the dystrophin gene. Dystrophin is associated
with Duchenn’s and Becker type of muscular dystrophies and is not associated with limb girdle
dystrophies. These are X-linked recessive disorders. An elevation in serum CK levels is seen in
asymptomatic patients.
LIMB-GIRDLE DYSTROPHIES
LGMD1A
AD
5q22.3-31.3
Myotilin
LGMD1B
AD
1q11-21
Lamin A and C
LGMD1C
AD
3p25
Caveolin-3
LGMD1D
AD
6q23
?
LGMD1E
AD
7q
?
LGMD2A
AR
15q15.1-21.1
Calpain 3
LGMD2B*
AR
2p13
Dysferlin
LGMD2C
AR
13q12
γ-sarcoglycan
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LGMD2D
AR
17q12-21.3
α-sarcoglycan
LGMD2E
AR
4q12
β-sarcoglycan
LGMD2F
AR
5q33-34
δ-sarcoglycan
LGMD2G
AR
17q11-12
Telethonin
LGMD2H
AR
9q31-33
E3-ubiquitin-ligase (TRIM 32)
LGMD2I
AR
19q13
Fukutin-related protein (FKRP)
LGMD2J
AR
2q31
Titin
LGMD2K
AR
9q31
POMT1
LGMD2L
AR
11p14.3
Anoctamin 5
LGMD2M
AR
9q31-33
Fukutin
LGMD2N
AR
1p32
POMGnT1
LGMD2O
AR
14q24
POMT1
th
Firestein: Kelley's Textbook of Rheumatology, 8 edition.
th
Bradley: Neurology in Clinical Practice, 5 edition.
2) Which of the following is the most specific test for rheumatoid arthritis?
a. Anti-ccp antibody
b. Anti-Igm antibody
c. Anti-IgA antibody
d. Anti-IgG antibody
Ans: (A)
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Rheumatoid arthritis – The primary target of this disease is the synovium. Synovial tissues
proliferate in an uncontrolled fashion, resulting in excess fluid production, erosion of surrounding
bone, and damage to tendons and ligaments. See figure below.
The distribution of involved joints is important for diagnosis. Most patients have involvement of
small joints first, classically the proximal interphalangeal, metacarpophalangeal, and
metatarsophalangeal joints, with involvement of large joints occurring later. See figure below. Of
particular importance, rheumatoid arthritis almost always spares the distal interphalangeal (DIP)
joints. In contrast, these joints are often involved in osteoarthritis and psoriatic arthritis.
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CRITERIA FOR RHEUMATOID ARTHRITIS

Must be present for more than 6 weeks

Morning stiffness

Arthritis of three joint areas

Arthritis of the hands

Symmetric arthritis

Rheumatoid nodules

Serum rheumatoid factor

Radiographic changes
Rheumatoid factor is antibody directed against the Fc region of IgG. IgM, IgG, and IgA isotypes of
rheumatoid factor occur in sera from patients with rheumatoid arthritis, although the IgM isotype
is the one most frequently measured by commercial laboratories. Serum IgM RF is been found in
75–80% of patients with rheumatoid arthritis. Rheumatoid factor is positive in about 50% of cases
at presentation and an additional 20–35% of cases become positive in the first 6 months after
diagnosis.
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Rheumatoid factor is not specific for rheumatoid arthritis. It can be seen in wide range of
autoimmune disorders, inflammatory disease and chronic infections. It is found in primary
Sjögren's syndrome, systemic lupus erythematosus, type 2 mixed essential cryoglobulinemia,
subacute bacterial endocarditis and hepatitis B and C. Serum rheumatoid factor may also be
detected in 1–5% of the healthy population.
DIFFERENTIAL OF A POSITIVE RHEUMATOID FACTOR

Rheumatic diseases
o


Infections
o
Viral: Hepatitis B and C, EBV, parvovirus, influenza
o
Bacterial: Endocarditis, osteomyelitis
Chronic inflammatory conditions
o

RA, Sjögren syndrome, SLE
Liver disease, inflammatory bowel disease, others
Aging
Anti-cyclic citrullinate peptide antibody (anti-ccp) test is more specific than rheumatoid factor for
diagnosis of rheumatoid arthritis. It may be positive every early in the course of the disease. AntiCCP antibodies are present in 60–70% of patients with RA at diagnosis, are 90–98% specific for
RA. It correlates strongly with erosive disease. Ordering anti-CCP along with the rheumatoid
factor increases the sensitivity of detecting early rheumatoid arthritis.
Anti-cyclic citrullinate peptide (anti-ccp) antibody testing has ability to identify patients who are
likely to have severe disease and irreversible damage. Anti ccp antibodies have not been found at
a significant frequency in other diseases to date.
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Serum anti-CCP antibodies have the same sensitivity as serum rheumatoid factor for the
diagnosis of rheumatoid arthritis. However, its diagnostic specificity approaches 95%. Therefore,
a positive test for anti-CCP antibodies in an early inflammatory arthritis is useful for
distinguishing rheumatoid arthritis from other forms of arthritis.
Rheumatoid arthritis is associated with multiple other autoantibodies, including antinuclear
antibodies (seen in 30% of patients) and antineutrophilic cytoplasmic antibodies, particularly of
the perinuclear type (seen in 30% of patients).
th
Firestein: Kelley's Textbook of Rheumatology, 8 edition.
th
CURRENT Rheumatology Diagnosis & Treatment, 2 edition; John B. Imboden, David B.
Hellmann, John H. Stone.
th
Harrison's principles of internal medicine, 18 edition.
Preclinical rheumatoid arthritis: identification, evaluation, and future directions for
investigation. Deane KD - Rheum Dis Clin North Am - 01-MAY-2010; 36(2): 213-41.
Rational use of laboratory testing in the initial evaluation of soft tissue and joint
complaints.Waits JB - Prim Care - 01-DEC-2010; 37(4): 673-89, v
3) A young male patient presents with LDL 600 mg/dl and triglycerides 140 mg/dl. What
would be the most likely finding on physical examination?
a. Tendon xanthoma
b. Lipemia retinalis
c. Palmar xanthoma
d. Eruptive xanthomas
Ans: (a)
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Cholesterol and triglycerides are the two main circulating lipids. Elevated levels of LDL
cholesterol are associated with increased risk of atherosclerotic heart disease. Very high LDL
levels are associated with tendinous xanthomas. Extremely high levels of chylomicrons or VLDL
particles are associated with eruptive xanthomas. Very high triglycerides (> 2000 mg/dL) are
associated with lipemia retinalis (cream-colored vessels in the fundus).
Normal L.D.L

Desirable
→ <130 mg/ dl

Borderline high
→ 140 – 160 mf/dl

High risk
→
200 – 500 mg/dl
Norma triglycerides

Desirable
→ <150 mg/ dl

Borderline high
→ 150 – 200 mf/dl

High
→
200 – 500 mg/dl
Increased LDL cholesterol and normal triglycerides suggests hypercholesterolemia. Most patients
presents with cutaneous xanthomas on the hands, wrists, elbow, knees, heels or buttocks. Arcus
cornea is present and some patients have xanthelasmas.
ETIOLOGY OF HYPERCHOLESTEROLEMIA

Idiopathic

Hypothyroidism

Nephrotic syndrome

Chronic renal insufficiency

Obstructive liver disease

Diabetes mellitus

Anorexia nervosa

Cushing’s syndrome

Familial hypercholesterolemia

Drugs: oral contraceptives, thiazides (short-term effect), beta blockers (short-term effect),
corticosteroids, cyclosporine
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Xanthomas - Eruptive xanthomas are the most common form and are associated with
hypertriglyceridemia (types I, III, IV, and V). They occur primarily on the extensor surfaces of the
extremities and the buttocks. See figure below. The most common setting for eruptive xanthomas
is uncontrolled diabetes mellitus.
Eruptive xanthomas
Increased beta-lipoproteins (primarily types II and III) result in xanthelasma, tendon xanthomas,
and plane xanthomas.
Xanthelasma are found on the eyelids. See figure below.
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Xanthelasma
Tendon xanthomas are frequently associated with the Achilles (see figure below) and extensor
finger tendons. Plane xanthomas usually occur over the palmar creases, face, upper trunk, and
scars.
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Tuberous xanthomas are frequently associated with hypertriglyceridemia, but they are also seen
in patients with hypercholesterolemia (type II). They are found most frequently over the large
joints or hand.
The least specific sign for hyperlipidemia is xanthelasmas. At least 50% of the patients with this
finding have normal lipid profiles.
4) C V junction abnormalities are seen in all of the following except
a. Rheumatoid arthritis
b. Ankylosing spondylitis
c. Odontoid dysgenesis
d. Basilar invagination
Ans: (b)
Disorders of the craniovertebral junction are relatively uncommon. The problem common to these
disorders is compression of the CNS at the level of the upper spinal cord and medulla. They
present with brainstem or lower cranial nerve signs and symptoms such as tinnitus, vertigo,
hearing loss, pharyngeal dysfunction, hoarseness, or airway obstruction.
Atlantoaxial dislocation - The most common acquired cause of craniovertebral abnormality is
rheumatoid arthritis. A high incidence of atlantoaxial instability, resulting from destruction of the
normal stabilizing mechanisms by inflammatory tissue, has been reported in patients with
rheumatoid arthritis.
Atlantoaxial instability is common in children with Down syndrome because of hypotonia and
ligamentous laxity, including especially the annular ligament of C1. Cervical neck films in flexion,
extension and neutral position evaluate the atlanto-dens interval (ADI). ADI is normally less than
2.5 mm, but up to 4.5 mm is acceptable in this population. Children with an ADI greater than 4.5
mm should be restricted from contact and collision activities.
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Basilar invagination is a craniocervical junction abnormality where the tip of the odontoid process
projects above the foramen magnum. As the odontoid projects intracranially, it compresses the
medulla. There is stenosis of the foramen magnum and compression of the medulla oblongata
resulting in neurological symptoms, obstructive hydrocephalus, syringomyelia or even death.
1.
Sup. Articulating Process; 2. Transverse Foramina; 3. Transverse Process;
4. Odontoid Process; 5. Spinous Process
Causes - Basilar invagination may be congenital or acquired.
Congenital

Osteogenesis imperfecta

Klippel-Feil syndrome

Achondroplasia

Chiari malformation

Cleidocranial dysostosis

Schwartz-Jampel syndrome
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Acquired

Rheumatoid arthritis

Paget's disease

Hyperparathyroidism

Osteomalacia / rickets
Basilar invagination occurs in around 5 - 10% of patients with cervical rheumatoid arthritis due to
loss of axial supporting structures in the upper cervical spine.
Chiari malformations are characterized by herniation of the contents of the posterior cranial fossa
through the foramen magnum into the upper cervical spine.
The diagnosis is confirmed by lateral radiographic views of the skull. It shows the tip of the
odontoid either extends above Chamberlain's line (a line extending from the posterior edge of the
hard palate to the posterior lip of the foramen magnum) or projects posterior to Wackenheim's
clivus-canal line.
Rheumatoid arthritis - Atlantoaxial and subaxial subluxations as well as basilar invagination can
develop in patients with rheumatoid arthritis. Although basilar invagination is less common than
atlantoaxial and subaxial subluxations, it is more dangerous. Since the compression caused by
basilar invagination affects the brain stem at the level of the foramen magnum, the autonomic
centers may be compromised, resulting in labile blood pressures, arrhythmias, or sudden death.
Ankylosing spondylitis is unlikely to be associated with CV junction anomaly.
Neuroimaging in craniovertebral anomalies as seen in the tropics. Sankhe SS Neuroimaging Clin N Am - 01-NOV-2011; 21(4): 879-95, ix.
th
CURRENT Diagnosis & Treatment: Pediatrics, 20 edition William W. Hay, Jr., Myron J.
Levin, Judith M. Sondheimer, Robin R. Deterding.
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5) All of the following are true about SIADH except
a. Vaptans are approved for its treatment
b. Water-loading test can be used for diagnosis of the condition
c. Urine sodium is usually low or normal
d. Serum sodium may be as low as 125 mEq/L
Ans: (c)
The only physiologic action of AVP is to increase the concentration of urine. ADH increases the
permeability of cells that line the distal tubule and medullary collecting ducts of the nephron.
These cells are permeable to water only in the presence of AVP. They cannot reabsorb water
without AVP. Low AVP concentration results in water diuresis (i.e., the production of large
amounts of urine that is maximally dilute).
Excessive or inappropriate production of AVP results in the production of decreased volumes of
concentrated urine. If water intake is not reduced, water retention and a decrease in plasma
sodium results.
+
Hyponatremia (i.e., serum Na < 135 mEq/L) is a defining feature of SIADH. Hyponatremia is a
+
result of an excess of water and not a deficiency of Na . Enhanced water reabsorption leads to
dilutional hyponatremia. Ingestion of water is an essential prerequisite to the development of the
syndrome; hyponatremia does not occur if water intake is severely restricted. ADH does not have
+
a significant effect on the rate of Na reabsorption.
SIADH (Syndrome of inappropriate antidiuretic hormone secretion) is the most common cause of
euvolemic hyponatremia in hospitalized patients. SIADH consists of hyponatremia,
inappropriately elevated urine osmolality (>100 mOsm/kg), and decreased serum osmolality in a
euvolemic patient.
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+
Urine Na concentration in persons with SIADH is usually more than 40 mEq/L. In SIADH,
+
+
+
Na handling is not abnormal. The urine Na concentration reflects Na intake, which is generally
+
+
more than 40 mEq/d. On a low-Na diet, patients with SIADH may have a urine Na level of less
than 40 mEq/L.
Vasopressin receptor antagonists (aquaretics) - The antidiuretic effect of AVP is mediated via a G
protein-coupled V2 receptor. Inhibition of the AVP V2 receptor reduces the number of aquaporin-2
water channels in the renal collecting duct and decreases the water permeability of the collecting
duct.
There are 2 aquaretics that are currently approved by the US Food and Drug Administration.
Conivaptan is a parenteral nonpeptide dual AVP V1a- and V2-receptor antagonist. It is approved
for use in hospitalized patients with euvolemic (dilutional) and hypervolemic hyponatremia.
Tolvaptan is a selective oral V2 receptor antagonist also approved for use in hospitalized patients
for hypervolemia and euvolemic hyponatremia.
th
Harrison's principles of internal medicine, 18 edition.
th
Goodman and Gilman’s Pharmacological Basis of Therapeutics, 12 edition.
th
Williams Textbook of Endocrinology, 11 edition.
6) A 17-year-old female presents with fever, headache and altered sensorium. CT scan shows
basal exudates with meningeal enhancement. The CSF is most likely to show-
a. Lymphocytic pleocytosis, low sugar, low protein
b. Polymorphonuclear pleocytosis, normal sugar, high protein
c. Lymphocytic pleocytosis, low sugar, high protein
d. Lymphocytic pleocytosis, normal sugar, high protein
Ans: (C)
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TB meningitis - Meningitis with basal exudates is most likely tuberculous. TB meningitis is
usually characterized by less than 2 weeks of fever, headache, and meningismus. There may be
depressed levels of consciousness, diplopia, and rarely, hemiparesis. Physical examination
shows a stiff neck and, occasionally, cranial neuropathy (VI, III, IV, VII in order of frequency) and
long-tract signs. CT of the head may show contrast enhancement over the basilar meninges,
hypodense areas consistent with infarcts, hydrocephalus, and sometimes focal inflammatory
lesions (tuberculomas).
Diagnosis is made by CSF analysis. The typical CSF abnormalities in tuberculous meningitis are
elevated opening pressure, lymphocytic pleocytosis, elevated protein concentration and
decreased glucose concentration.
Lymphocytic and mononuclear cell pleocytosis of 50–500 cells/mL is most often seen, but
polymorphonuclear pleocytosis can occur early and may give an erroneous impression of
bacterial meningitis. CSF protein is usually more than 100 mg/dL and may exceed 500 mg/dL,
particularly in patients with spinal subarachnoid block. The glucose level is usually decreased
and may be less than 20 mg/dL.
Other causes of chronic lymphocytic meningitis include fungal infection, HIV infection, syphilis,
brucellosis, leptospirosis and neurocysticercosis.
PCR nucleic acid amplification for detecting Mycobacterium tuberculosis DNA-specific sequences
shows great promise in the rapid and accurate diagnosis of tuberculous meningitis. However, a
negative PCR result does not exclude the diagnosis of tuberculous meningitis. If high clinical
suspicion remains, empirical therapy should be initiated.
th
Clinical Neurology, 7 edition Roger P. Simon, David A. Greenberg, Michael J. Aminoff.
McPherson & Pincus: Henry's Clinical Diagnosis and Management by Laboratory
st
Methods, 21 edition.
th
Goldman: Goldman's Cecil Medicine, 24 edition.
Infectious Diseases and Impaired Consciousness, Neurologic Clinics - Volume 29, Issue
4 (November 2011).
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7) All are true regarding universal definition of MI except
a. Sudden death is MI
b. New region wall motion with increased biochemical marker is MI
c. 3 times troponin elevation is required for CABG related MI
d. Reinfarction can be diagnosed if elevation in troponin level by 5 to 7% on serial
sampling
Ans: (C) CABG causes the troponin to rise and may remain elevated for 10 days. CPK
usually returns to normal by 48 to 72 h. It peaks at 24 h.
Troponin is the contractile regulatory protein of striated muscle. It contains three subunits: T, C,
and I. Troponin I is released into the circulation after cellular necrosis. Cardiac troponin I is
expressed only in cardiac muscle. Therefore, its presence in serum can distinguish between
myocardial injury and skeletal muscle injury. Cardiac troponin I is measured by immunoassay
using monoclonal antibodies.
CAUSES OF INCREASED CARDIAC TROPONIN

Myocardial infarction (sensitivity 50% at 4 hours, 97% at 6 hours; specificity 95%)

Cardiac trauma

Cardiac surgery

Myocardial damage following PTCA, CABG and other cardiac interventions

Non-ischemic dilated cardiomyopathy

Prolonged supraventricular tachycardia

Acute dissection of the ascending aorta
Slight elevation is noted in patients with recent aggravated unstable angina, muscular disorders,
CNS disorders, HIV infection, chronic renal failure, cirrhosis, sepsis, lung diseases, and endocrine
disorders.
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Cardiac troponin is not increased in skeletal muscle disease (myopathy, myositis, dystrophy),
external electrical cardioversion, non-cardiac trauma or surgery, rhabdomyolysis, severe
muscular exertion, or in chronic renal failure.
Cardiac troponin I is a more specific marker for myocardial infarction than CK-MB with roughly
equivalent sensitivity early in the course of infarction (4–36 hours). Sensitivity and specificity for
peak concentrations of cTnI (100%; 96%) are equivalent to or better than those for CK-MB (88%;
93%) and total CK (73%; 85%). cTnI appears in serum approximately 4 hours after onset of chest
pain, peaks at 8–12 hours, and persists for 5–7 days. This prolonged persistence gives it much
greater sensitivity than CK-MB for diagnosis of myocardial infarction beyond the first 36–48
hours.
MARKER
TIMES TO
INITIAL
ELEVATION
(h)
MEAN TIME TO PEAK
ELEVATIONS
(NONTHROMBOLYSIS)
TIME TO RETURN
TO NORMAL
RANGE
cTnI
3 – 12
24 hr
5 – 10 d
cTnT
3 – 12
12 hr – 48 hr
5 – 14 d
MB - CK
3 – 12
24 hr
48 – 72 hr
MOST COMMON
SAMPLING SCHEDULE
Once at least 12 hr
after chest pain
Once at least 12 hr
after chest pain
Every 12 hr × 3
REVISED UNIVERSAL DEFINITION OF MYOCARDIAL INFARCTION
Criteria for Acute, Evolving, or Recent MI
Either of the following criteria satisfies the diagnosis for acute, evolving, or recent MI:
1
Typical rise and/or fall of biochemical markers of myocardial necrosis with at least one of
the following:
a
Ischemic symptoms
b
Development of pathologic Q waves in the ECG
c
Electrocardiographic changes indicative of ischemia (ST-segment elevation or
depression)
d
Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality
2
Pathologic findings of an acute myocardial infarction
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Criteria for Healing or Healed Myocardial Infarction
Any one of the following criteria satisfies the diagnosis for healing or healed MI:
1
Development of new pathologic Q waves in serial ECGs. The patient may or may not
remember previous symptoms. Biochemical markers of myocardial necrosis may have
normalized, depending on the length of time that has passed since the infarction
developed.
2
Pathologic findings of a healed or healing infarction
Universal definition of myocardial infarction - Myocardial infarction is classified by the clinical
scenario into 5 subtypes.
1
Spontaneous myocardial infarction related to ischemia caused by a primary coronary event such as
plaque erosion and/or rupture, fissuring, or dissection
2
Myocardial infarction secondary to ischemia caused by increased oxygen demand or decreased supply
(e.g., coronary artery spasm, coronary embolism, anemia, arrhythmias, hypertension, hypotension)
3
Sudden unexpected cardiac death, including cardiac arrest, often with symptoms suggestive of
myocardial ischemia, accompanied by presumably new ST-segment elevation, or new LBBB, or
presumably new major obstruction in a coronary artery by angiography and/or pathology, but death
occurring before blood samples could be obtained, or before the appearance of cardiac biomarkers in
the blood
4a
Myocardial infarction associated with PCI
4b
Myocardial infarction associated with stent thrombosis, as documented by angiography or autopsy
5
Myocardial infarction associated with CABG
CABG related MI
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PERIOPERATIVE MYOCARDIAL INFARCTION - DIAGNOSTIC CRITERIA
<24 hours postoperatively

CK-MB (or CK) at least five times the upper limits of normal
> 24 hours postoperatively

CK-MB (or CK) at least five times the upper limits of normal + one of the following:

Evolutionary ST-segment elevation

New Q waves in two or more contiguous leads

New left bundle branch block

CK-MB (or CK) at least three times the upper limits of normal
th
Braunwald's Heart Disease - A Textbook of Cardiovascular Medicine, 9 edition.
McPherson & Pincus: Henry's Clinical Diagnosis and Management by Laboratory
st
Methods, 21 edition.
CURRENT Diagnosis & Treatment: Cardiology, third edition, Michael H. Crawford.
8) All of the following are approved for the treatment of RRMS type of multiple sclerosis
except
a. Interferon β 1a
b. Interferon β 1b
c. Glatiramer acetate
d. Mycophenolate
Ans: (d)
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Multiple sclerosis - Acute demyelinating attacks (relapses) of multiple sclerosis are treated with
high-dose corticosteroid and, in severe cases, plasma exchange. If marked acute disability and
acute corticosteroid therapy has failed, plasma exchange (5 to 7 exchanges on alternate days)
have shown benefit. Corticosteroids shorten the duration and severity of symptoms from an acute
exacerbation but have no proven effect on long-term disability.
Chronic therapy for relapsing forms of MS ((RRMS, SPMS with exacerbations) - First line drugs
used are IFN-β-1a, IFN- β -1b, glatiramer acetate, and fingolimod. Second-line therapy includes
natalizumab or mitoxantrone. Cladribine is currently awaiting approval.
Chronic therapy for secondary progressive MS is with mitoxantrone. No evidence-based
recommendation can be made with regard to its use in this setting.
st
Ferri’s clinical advisor, 2012, 1 edition.
Bope and Kellerman: Conn's Current Therapy 2012, 1st edition.
th
Harrison's principles of internal medicine, 18 edition.
th
Goldman: Goldman's Cecil Medicine, 24 edition.
9) Systemic eosinophiluria with renal failure is least likely to be due to
a. Drug induced interstitial nephritis
b. Contrast nephropathy
c. Atheroembolic renal failure
d. Polyangitis nodosa
Ans: (D)
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Interstitial nephritis - Allergic interstitial nephritis can develop in the setting of infection,
malignancy, or systemic disease or as an idiopathic condition. Antibiotics and nonsteroidal antiinflammatory drugs are the most common causative agents of interstitial nephritis, although it can
occur with almost any medication. The classic triad of fever, rash, and eosinophilia is seen in only
20% of patients. The urine findings include sterile pyuria, white blood cell casts, non–nephroticrange proteinuria, hematuria, and eosinophiluria.
Eosinophiluria is more than 1% of urine leukocytes. It is present in more than 90% of cases of
antibiotic-induced allergic interstitial nephritis when studied using Hansel's stain (demonstrates
the eosinophilic granules more clearly). Lymphocytes may predominate in allergic interstitial
nephritis induced by NSAIDs.
Eosinophiluria is not specific for allergic interstitial nephritis.
CAUSES OF EOSINOPHILURIA

Acute interstitial nephritis (drug induces, contrast agents)

Acute cystitis or prostatitis

Pyelonephritis

Postinfectious or rapidly progressive glomerulonephritis

Renal atheroembolic disease

Acute rejection of renal allograft
th
Brenner: Brenner and Rector's The Kidney, 8 edition.
Current Diagnosis & Treatment: Nephrology & Hypertension Edgar V. Lerma, Jeffrey S. Berns,
Allen R. Nissenson.
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10) Which of the following statements is not true?
a. Parathyroid hormone-related protein is responsible for causing hypercalcemia in
cancer patients
b. The unionized fraction of calcium in the plasma is an important determinant of PTH
secretion
2+
c. Magnesium influences PTH secretion in the same direction as Ca , but is a less
potent secretagogue
d. Ca2+ influences PTH secretion by acting on a calcium sensor G-protein coupled
receptor located in the parathyroid gland
Ans: (B)
PTH secretion is regulated by the extracellular ionized calcium concentration. Circulating ionized
calcium acts directly on the parathyroid glands in a negative feedback fashion to regulate the
secretion of PTH. Parathyroid cells sense changes in extracellular calcium concentration through
a G protein–coupled receptor (GPCR) known as the calcium-sensing receptor (CaR). In the
parathyroid, its activation inhibits PTH secretion. In this way, when the plasma Ca
PTH secretion is inhibited and the Ca
2+
2+
level is high,
is deposited in the bones. When it is low, secretion is
2+
increased and Ca is mobilized from the bones.
Hypercalcemia - Primary hyperparathyroidism and malignancy account for 90% of cases.
Hypercalcemia is common in patients with cancer. The hypercalcemia in 80% of these patients is
due to the elevated circulating levels of parathyroid hormone-related protein or PTHrP (humoral
hypercalcemia of malignancy. Tumor production of PTH-related proteins (PTHrP) is the most
common paraneoplastic endocrine syndrome. The tumours responsible for the hypersecretion
include cancers of the breast, kidney, ovary and skin. Measurements of PTH and PTHrP levels
help distinguish between hyperparathyroidism (elevated PTH) and malignancy-associated
hypercalcemia (suppressed PTH and elevated PTHrP).
About 20% of hypercalcemic patients have bone metastases that produce hypercalcemia by
eroding bone (local osteolytic hypercalcemia). This erosion is produced by prostaglandins such
as prostaglandin E2 from the tumor.
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Magnesium is required to maintain normal parathyroid secretory responses. Plasma
Mg
2+
concentrations also regulate PTH secretion in a similar manner to that of calcium. The
balance of magnesium is closely linked to that of calcium; magnesium depletion or deficiency is
frequently associated with hypocalcemia. This combined decrease in Mg
2+
and Ca
2+
leads to
impairment in the individual's ability to secrete PTH.
th
Ganong’s Review of Medical Physiology, 23 edition; Kim E. Barrett, Susan M. Barman,
Scott Boitano, Heddwen Brooks.
th
Greenspan's Basic & Clinical Endocrinology, 8 edition David G. Gardner and Dolores
Shoback.
th
Williams Textbook of Endocrinology, 11 edition.
rd
Endocrine Physiology, Patricia E. Molina, 3 edition.
11) A 60-year-old male patient with rheumatoid arthritis presents with the following: Hb =
4.5g/dL. Platelet count = 2 lac/mm3. TLC = 6000/mm3. Serum Ferritin = 200 µg/dl. Serum
iron = 30 mg/dL. TIBC = 280 ng/L. Which of the following is the most likely diagnosis?
a. Anaemia of chronic disease
b. Thalassemia minor
c. Iron deficiency anaemia
d. Autoimmune haemolytic anemia
Ans: (A)
Ferritin is the major storage protein for iron. Normal serum ferritin level is 15-300 µg/L. The
serum ferritin level is the best indicator of total body iron stores. Serum ferritin is the test of
choice for diagnosis of iron deficiency anemia. Serum ferritin is decreased in iron deficiency
anemia. It is the earliest and most sensitive test before RBC morphologic change. Serum ferritin is
a more sensitive test for iron deficiency than serum iron and iron-binding capacity (transferrin
saturation).
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Serum ferritin is clinically useful in distinguishing between iron deficiency anemia
(serum ferritin levels diminished) and anemia of chronic disease or thalassemia (levels usually
normal or elevated).
Normal serum iron = 50-150 microgram/dl.
Normal TIBC = 300 - 400 microgram/dl.
In anaemia of chronic disease there will be decreased serum iron, increased storage iron (i.e.,
serum ferritin), decreased serum transferrin and decreased total iron binding capacity.
12) A 29-year-old, 4 month pregnant primigravida has been regularly taking sodium valproate
for juvenile myoclonic epilepsy. She is now seeking an opinion for her antiepileptic
regimen. What would you suggest her?
a. Immediately taper valproate and start lamotrigine
b. Continue valproate with monitoring of drug level
c. Switch to carbamazepine
d. Add lamotrigine to valproate
Ans: (B)
The majority of women with seizure disorders who become pregnant have an uneventful
pregnancy with an excellent outcome. Levels of anticonvulsant medications can change
dramatically during pregnancy. They usually decrease in total concentration as pregnancy
progresses. With close surveillance, seizure frequency should remain the same or even improve
in most epileptic patients during pregnancy. Monitor anticonvulsant levels when necessary.
All anticonvulsants interfere with folic acid metabolism. Anticonvulsant levels should be checked
frequently after implementing or increasing folic acid administration, because folate leads to
lower anticonvulsant levels. Folic acid deficiency has been associated with neural tube defects
and other congenital malformations.
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Anticonvulsant medications are associated with a small increase in congenital malformations
(e.g., cleft lip and palate, congenital heart disease, limb anomalies). Valproate and phenytoin are
the two most teratogenic medications. Valproic acid and carbamezapine increase the risk of
neural tube defects. Monotherapy is associated with a lower birth defect rate compared with
multiagent therapy.
Women with seizure disorders are at increased risk of IUGR and stillbirth.
Early hemorrhagic disease of the newborn can occur in infants exposed to anticonvulsants in
utero, and this appears to be due to a deficiency of the vitamin K–dependent clotting factors II, VII,
IX, and X.
The obstetrician must stress that controlling seizures is of primary importance. The potential
harm of uncontrolled seizures on the mother and fetus is greater than the teratogenic effects of
antiepileptic drugs. The patient will need to take whatever medication or medications are
necessary to achieve this goal throughout her pregnancy. When possible, it seems prudent to
have the patient on monotherapy at the lowest effective dose, especially during the first trimester.
Juvenile myoclonic epilepsy is a generalized seizure disorder of unknown cause that appears in
early adolescence. It is usually characterized by bilateral myoclonic jerks that can be provoked by
sleep deprivation. Consciousness is preserved unless the myoclonus is especially severe. Many
patients also experience generalized tonic-clonic seizures, and up to one-third have absence
seizures. Complete remission is relatively uncommon. The seizures respond well to appropriate
anticonvulsant medication.
th
Gabbe: Obstetrics: Normal and Problem Pregnancies, 5 edition.
Williams Obstetrics, 23edition; F. Gary Cunningham, Kenneth J. Leveno, Steven L. Bloom,
John C. Hauth, Dwight J. Rouse, Catherine Y. Spong.
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13) A lady presents with complaints of abdominal pain. Contrast enhanced CT shows bilateral
papillary necrosis. Which of the following test should not be done to investigate the cause
of her papillary necrosis?
a. Culture for bacteria
b. Sickling test
c. Urine acidification
d. Urine PCR for TB
Ans: (d)
Renal papillary necrosis is ischemic necrosis of the renal papillae or of the entire pyramid. This is
most commonly a complication of diabetes, analgesic abuse, sickle cell hemoglobinopathy, or
obstruction. The role of infection in the development and progression of renal papillary necrosis
is controversial.
CONDITIONS ASSOCIATED WITH RENAL PAPILLARY NECROSIS

Diabetes mellitus

Pyelonephritis

Urinary tract obstruction

Analgesic abuse

Sickle cell hemoglobinopathies

Renal transplant rejection

Cirrhosis of the liver

Dehydration, hypoxia, and jaundice of infants

Miscellaneous: renal vein thrombosis, cryoglobulinemia, renal candidiasis, contrast media injection,
amyloidosis, necrotizing angiitis, rapidly progressive glomerulonephritis, hypotensive shock, acute
pancreatitis.
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The symptoms are usually those of chronic cystitis with recurring exacerbations of
pyelonephritis. The patient usually has hematuria, renal colic, and often a high fever. Laboratory
findings consist of pyuria, hematuria, occasionally glycosuria, and acidosis.
It is treated by intravenous administration of appropriate antibiotics. In the majority of cases relief
of the obstruction caused by necrotic papilla leads to improved renal function. The disease has a
rapid course toward uremia and, if untreated, death. In severe cases, the prognosis is poor. Renal
transplantation may be required.
Analgesic abuse nephropathy is the most common cause of chronic interstitial nephritis. all
analgesics, including acetaminophen, and aspirin can cause the same disease process.
Renal dysfunction is manifested by isosthenuria (impaired urinary concentration) and impaired
sodium conservation that may predispose to intravascular volume depletion. Hematuria can be a
common presenting complaint but it is usually microscopic. Occasionally, patients can present
with flank pain or gross hematuria associated with papillary necrosis. Renal colic occurs when
necrotic renal papillae slough away. Polyuria may be prominent. Signs of acidosis (hyperpnea),
dehydration, and pallor are common. Infection is a frequent complication.
Urinalysis may show evidence of sterile pyuria, urinary tract infection, microscopic or
macroscopic hematuria, and mild proteinuria. Elevated blood urea nitrogen and creatinine and the
electrolyte changes characteristic of metabolic acidosis and renal failure are typically present.
Urinary concentrating impairments are usually present. Renal tubular acidification defects are
also seen.
Patients with analgesic nephropathy are also at increased risk for transitional cell carcinoma of
the uroepithelium.
Bacterial culture is done for UTI. Sick cell disease can be diagnosed by sickling test. Analgesic
nephropathy can be diagnosed by urine acidification. TB is least likely cause of papillary necrosis.
Therefore, urine PCR for TB is not indicated.
Current Diagnosis & Treatment: Nephrology & Hypertension Edgar V. Lerma, Jeffrey S.
Berns, Allen R. Nissenson.
th
Brenner: Brenner and Rector's The Kidney, 8 edition.
th
CURRENT Diagnosis & Treatment: Surgery, 13 edition Edited by Gerard M. Doherty.
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14) In Alzheimer’s disease, all are seen except
a. Aphasia
b. Acalculia
c. Apraxia
d. Agnosia
Ans: (?)
The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for dementia
require a decline in memory, as well as an impairment of at least one other domain of higher
cognitive function (e.g., aphasia, apraxia, agnosia, or executive dysfunction [such as difficulty in
planning, organizing, sequencing, or abstracting]).
Agnosia is a loss of ability to recognize objects, persons, sounds, shapes, or smells while the
specific sense is not defective nor is there any significant memory loss. Visual agnosia is inability
to recognize visual objects. Prosopagnosia is the inability to recognize faces.
Apraxia is the inability to carry out a motor task in the absence of sensory loss, weakness,
incoordination or difficulty in comprehension. Ideational apraxia is loss of ability to carry out
learned complex tasks in the proper order, such as putting on socks before putting on shoes.
Ideational apraxia is commonly associated with confusion states and dementia.
Acalculia is difficulty performing simple calculations such as adding, subtracting, or
multiplying. Acalculia is associated with lesions of the parietal lobe (especially the angular gyrus)
and the frontal lobe. It can be an early sign of dementia.
Alzheimer's disease is the most common cause of dementia in the elderly. The features of classic
dementia of the Alzheimer type include memory impairment, executive dysfunction, aphasia,
visuospatial deficits, and impaired ability in calculation (acalculia) and abstraction. Disturbances
of other cortical functions such as agnosia (impaired recognition) and apraxia may be observed.
th
Bradley: Neurology in Clinical Practice, 5 edition.
th
Duthie: Practice of Geriatrics, 4 edition.
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15) Diabetes is diagnosed when
a. The level of fasting glucose is ≥100 mg/dL and that of postprandial glucose is ≥
140 mg/dL
b. The level of fasting glucose is ≥ 125mg/dL and that of postprandial glucose is ≥199
mg/dL
c. The level of plasma insulin is ≥ 6 IU/dL
d. The HbA1c level is ≥ 5.5%
Ans: (B)
The American Diabetes Association defines DM as follows:
A fasting plasma glucose (FPG) ≥126 mg/dl, which should be confirmed with testing on a different
day; fasting is defined as no caloric intake for at least 8h. The ADA also defines a value <100 mg/dl
on fasting blood sugar as the upper limit of normal for glucose; a fasting glucose level between 100
and 126 mg/dl is classified as “impaired fasting glucose” (IFG).
Symptoms of hyperglycemia and a casual (random) plasma glucose ≥200 mg/dl; random plasma
glucose is defined as any time of the day without regard to time since last meal; classic symptoms of
hyperglycemia include polyuria, polydipsia, and unexplained weight loss
An oral glucose tolerance test (OGTT) ≥200 mg/dl in the 2-hour sample; OGTT using glucose load
containing the equivalent of 75 g (100 g for pregnant women) anhydrous glucose dissolved in water;
furthermore, when results of the OGTT are between 140 and 199 mg/dl, the patient is classified as
“impaired glucose tolerance” (IGT)
A 2010 update to the ADA Guidelines for Standards of Medical Care in Diabetes included a
hemoglobin A1C value ≥6.5% within the diagnostic criteria for diabetes mellitus. An A1C level of
greater than 6.5 percent on two separate occasions is considered diagnostic of diabetes.
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Gestational diabetes
OGTT (100-g load):
o
Fasting, 95 mg per dL (5.3 mmol per L)
o
One hour, 180 mg per dL (10.0 mmol per L)
o
Two hour, 155 mg per dL (8.6 mmol per L)
o
Three hour, 140 mg per dL
Need at least two abnormal results
st
Ferri’s clinical advisor, 2012, 1 edition.
16) All of the following features are seen in myelopathies except
a. Facial sensory impairment
b. Brisk jaw jerks
c. Brisk pectoral jerks
d. Urgency and incontinence of micturition
Ans: (B)
Trigeminal nerve - The three divisions of the trigeminal nerve—ophthalmic, maxillary, and
mandibular—convey information about facial pain, temperature, vibration, and proprioception.
The V nerve also provides sensation to the mouth and part of the dura, and motor supply to the
muscles of the jaw involved in chewing.
The trigeminal sensory nucleus receives the primary afferents of the trigeminal nerve. It is a large
nucleus extending from the midbrain into the cervical spinal cord. The principal and largest
division of the nucleus is located in the pontine tegmentum.
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The main sensory nuclei of nerve V is in the upper half of the pons. There are three sensory
nuclei:
The principal sensory nucleus (touch, joint position sense)
The mesencephalic nucleus (unconscious proprioception)
The spinal trigeminal tract and nucleus (pain and temperature).
The spinal trigeminal tract and nucleus descends from the pons to the C3/C4 segment of the
spinal cord. See figure below. These carry sensations of the face. Hence, a high cervical cord
lesion can cause facial sensory impairment. Facial sensation is involved because the spinal
trigeminal nucleus and tract are located in the upper cervical cord.
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Jaw jerk is elicited by the examiner placing their index finger over the middle of the patient’s chin
with the mouth slightly open and the jaw relaxed. The index finger is then tapped with a reflex
hammer, delivering a downward stroke. The afferent impulse for this reflex is the sensory portion
of the trigeminal nerve. The efferent limb is through the motor (V3) branch of the trigeminal nerve.
Normally, this reflex is absent or very slight. However in individuals with bilateral upper motor
neuron lesions (pseudobulbar palsy), the jaw jerk reflex may be pronounced. Exaggerated
contraction of the masseter suggests bilateral pathology (UMN lesion) above the mid pons.
Bladder is innervated from autonomic nervous system with relay via spinal cord. Diseases of
spinal cord may affect the bladder.
Pectoralis reflex – Keep the patient’s arm in mid-position between abduction and adduction. Place
your finger on the tendon of pectoralis major muscle near its insertion on the greater tuberosity of
the humerus. Tapping the finger causes adduction and slight internal rotation of the arm of the
shoulder. A normal response is little, if any, contraction of the pectoralis muscle. This reflex is
mediated by the medial and lateral anterior thoracic nerves (C5-T1). If there is hyperreflexia when
compared to the opposite side, it is indicative of a corticospinal tract lesion above the level of the
fifth cervical segment.
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th
Gray's Anatomy, 40 Edition - The Anatomical Basis of Clinical Practice.
th
Clinical Neuroanatomy, 26 edition Stephen G. Waxman.
th
Bradley: Neurology in Clinical Practice, 5 edition.
th
Clinical Neurology, 7 edition Roger P. Simon, David A. Greenberg, Michael J. Aminoff.
17) A 17-year-old girl with short height has an enlarged pituitary gland. Her T4 was low and
TSH was increased. Which of the following is the most likely diagnosis?
a. Pituitary adenoma
b. TSH-secreting pituitary tumour
c. Thyroid target receptor insensitivity
d. Primary hypothyroidism
Ans: (d)
In pituitary adenoma (TSH secreting pituitary tumor) increased TSH with increased T3/4 will be
seen. In thyroid hormone resistance, increased T4/3 with low TSH will be seen.
In primary hypothyroidism due to defect in the gland itself, high TSH with low T4 will be seen. The
pituitary is often quite enlarged in primary hypothyroidism due to reversible hyperplasia of TSHsecreting cells. The concomitant hyperprolactinemia seen in hypothyroidism can lead to the
mistaken diagnosis of a TSH-secreting or PRL-secreting pituitary adenoma.
th
Harrison's principles of internal medicine, 18 edition.
th
Williams Textbook of Endocrinology, 11 edition.
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18) What is the most common cause of Addison’s disease in India?
a. Post-partum pituitary insufficiency
b. Tuberculous adrenalitis
c. HIV
d. Autoimmune adrenal insufficiency
Ans: (B)
CAUSES OF PRIMARY ADRENOCORTICAL INSUFFICIENCY

Autoimmune

Metastatic malignancy or lymphoma

Adrenal hemorrhage

Infectious
o
Tuberculosis, CMV, fungi (histoplasmosis, coccidioidomycosis), HIV, syphilis

Adrenoleukodystrophy

Infiltrative disorders
o
Amyloidosis, hemochromatosis

Congenital adrenal hyperplasia

Familial glucocorticoid deficiency and hypoplasia

Drugs
o
Ketoconazole, metyrapone, aminoglutethimide, trilostane, mitotane, etomidat
Tuberculosis is the most common cause of Addison’s disease in India. TB of the adrenal glands
usually is a tertiary disease due to the hematogenous spread of infection to the adrenal glands,
but clinical evidence of the primary infection is not always present.
Autoimmune destruction of the adrenals is the most common cause of Addison disease in the
United States (accounting for about 80% of spontaneous cases). The enzyme 21-hydroxylase is
the main autoantigen.
Idiopathic autoimmune adrenocortical atrophy and tuberculosis (TB) account for nearly 90% of
cases of Addison disease.
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HIV - The adrenocortical insufficiency in patients with AIDS tends to occur late and usually in the
setting of a low CD4 cell count. It is caused by opportunistic infections such as
cytomegalovirus, Mycobacterium avium intracellulare, cryptococci, or Kaposi sarcoma.
Adrenocortical hypofunction in patients with HIV may be due to glucocorticoid resistance
syndrome.
Sheehan syndrome is pituitary insufficiency due to postpartum necrosis of the anterior pituitary
gland in women with severe blood loss and hypotension during delivery. Failure to lactate, breast
involution, and, if untreated, breast atrophy may occur. Fatigue, weight loss, and postural
hypotension are common complaints. Hyponatremia and anemia (usually normocytic and
normochromic) are frequent laboratory abnormalities. There is low thyroxin, TSH, estrogen,
gonadotropin, cortisol, and ACTH levels.
Bilateral adrenal hemorrhage may occur during sepsis, heparin-associated thrombocytopenia or
anticoagulation, or with antiphospholipid antibody syndrome. It may occur in association with
major surgery or trauma, presenting about 1 week later with pain, fever, and shock. It may also
occur spontaneously.
th
Williams Textbook of Endocrinology, 11 edition.
th
Greenspan's Basic & Clinical Endocrinology, 8 edition David G. Gardner and Dolores
Shoback.
th
Harrison's principles of internal medicine, 18 edition.
th
Current Diagnosis & Treatment: Emergency Medicine, 6 edition, C. Keith Stone, Roger L.
Humphries.
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19) All of the following are true about Alzheimer’s disease except
a. Number of senile plaques correlate with age
b. Underlying tau proteins suggest neurodegeneration
c. Number of neurofibrillary tangles is associated with the severity of dementia
d. Extracellular inclusions can be found in the absence of intracellular inclusions
Ans: (B) Tau proteins are present normally.
Alzheimer’s disease is the most common cause of dementia. The characteristic microscopic
findings of Alzheimer’s disease are neurofibrillary tangles and senile plaques (beta-amyloid
plaques).
Neurofibrillary tangles are intracellular deposits containing hyperphosphorylated tau protein (a
microtubule-associated protein) and ubiquitin. In Alzheimer’s disease, hyperphosphorylated tau
accumulates in the perikarya of large and medium pyramidal neurons.
Tau protein is the main constituent of neurofibrillary tangles. Neurons have microtubules that act
like tracks, guiding nutrients and molecules from the cell body down to the ends of the axon and
back. A special kind of protein, called tau, binds to the microtubules and stabilizes them. In
Alzheimer’s disease, tau is changed chemically and the microtubules disintegrate, collapsing the
neuron’s transport system. Tau hyperphosphorylation result in neuronal death. Neurofibrillary
tangles represent a nonspecific response to a cellular injury that is triggered by beta-amyloid.
The hippocampus and entorhinal cortex (medial temporal lobe) are the initial sites of tangle
deposition and neuronal atrophy. This can be seen on brain MRI early in Alzheimer’s disease and
helps in the diagnosis.
Neuritic plaques are extracellular deposits. Plaques are made of beta-amyloid. They also contain
presenilin 1, presenilin 2, alpha1-antichymotrypsin, apolipo-protein E, alpha2-macroglobulin, and
ubiquitin. The neuritic plaque is most pathogenically relevant.
Beta-amyloid is a protein fragment snipped from a larger protein called amyloid precursor protein
(APP). See figure below.
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APP is associated with the cell membrane. APP sticks through the neuron's membrane,
partly inside and partly outside the cell.
Enzymes act on the APP and cut it into fragments of protein, one of which is called betaamyloid.
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The beta-amyloid fragments clump together outside the cell and then join other molecules
and non-nerve cells to form insoluble plaques.
Beta-amyloid begins to accumulate in the brain as long as 20 years before dementia occurs. By
the time that clinical dementia due to Alzheimer's disease is present, large numbers of betaamyloid peptide–containing deposits invariably are found in neuritic plaques. Neuritic plaques
represent the end-stage of the Alzheimer process. The amount of beta-amyloidosis does not
closely mirror the severity of dementia in Alzheimer's disease. The neurofibrillary tangles and
neuronal alterations and loss, not the plaques, correlate best with the severity of the dementia.
Many older people develop some plaques and tangles and their numbers correlate with age. The
brains of people with Alzheimer’s disease have them to a greater extent, especially in certain
regions of the brain that are important in memory.
The most consistent neurotransmitter deficit in Alzheimer's disease is in cholinergic
neurotransmission.
th
Clinical Neurology, 7 edition Roger P. Simon, David A. Greenberg, Michael J. Aminoff.
th
Bradley: Neurology in Clinical Practice, 5 edition.
Kumar: Robbins and Cotran Pathologic Basis of Disease, Professional Edition, 8th edition.
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st
Stern: Massachusetts General Hospital Comprehensive Clinical Psychiatry, 1 edition.
20) A 20-year-old female presents with following lab values: Hb = 9gm%, MCV = 55%, RBC =
4.5 million. There is no history of blood transfusion. What could be the probable
diagnosis?
a. Thalassemia major
b. Thalassemia minor
c. Iron deficiency anemia
d. Anemia of chronic disease
Ans: (B) As there is no history of blood transfusion, thalassemia major is unlikely.
Anemia is a decrease in RBC mass. Methods for measuring RBC mass are time consuming and
expensive. In practice, anemia is diagnosed by measurement of the Hb concentration, hematocrit
or RBC count. Anemia is present if the hemoglobin concentration or the hematocrit is below the
lower limit of the 95% reference interval for the individual's age, sex, and geographic location
(altitude). See table below. Iron deficiency is the most common cause of anemia. All cases of iron
deficiency anemia in adult males are due to chronic blood loss.
NORMAL VALUES FOR PERIPHERAL BLOOD
Males
Females
Hb (g/dL)
13.5 - 17.5
11.5 - 16
PCV (haematocrit; L/L)
0.4 - 0.54
0.37 - 0.47
RBC count (1012/L)
4.5 - 6.0
3.9 - 5.0
MCV (fL)
80 - 96
MCH (pg)
27 - 32
MCHC (g/dL)
32 - 36
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RDW (%)
11 - 15
WBC (109/L)
4.0 - 11.0
Platelets (109/L)
150 - 400
Reticulocytes
0.5 - 2.5% (50-100 × 109/L)
Hemoglobin is a measure of oxygen-carrying capacity of blood. Hematocrit is a measure of solid
elements of blood (mostly RBCs), as percentage of whole blood (remainder is plasma). Both
hematocrit and hemoglobin are low in anemia.
The mean corpuscular volume (MCV) of red cells is the most useful of the RBC indices to classify
and to determine the cause of anemia. Normal MCV is 80 to 100fL (femto litre). Microcytosis is
MCV less than 80fL. Macrocytosis is MCV more than 100fL.
There are only 3 causes of anemia - blood loss, increased RBC destruction (hemolysis), and
decreased production of RBCs. See table below.
CAUSES OF MICROCYTIC HYPOCHROMIC ANEMIA
Serum
Total Iron-
Bone
Iron
Binding Capacity
Marrow
(TIBC)
Iron
Condition
Comment
Iron deficiency
↓
↑
0
Responsive to iron therapy
Chronic
↓
↓
++
Unresponsive to iron therapy
↑
N
++++
Reticulocytosis and indirect
inflammation
Thalassemia
major
Thalassemia
bilirubinemia
N
N-↓
++
minor
Elevation of fetal hemoglobin and
Hb A2, target cells, and
poikilocytosis
Lead poisoning
N
N
++
Basophilic stippling of RBCs
Sideroblastic
↑
N
++++
Ring sideroblasts in marrow
Hemoglobin
N
N
++
Hemoglobin electrophoresis
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The first step to find the cause of anemia is to classify the anemia, based on MCV, as microcytic
(<80 fL), normocytic (80-100 fL), or macrocytic (>100 fL).
Microcytic hypochromic anemia - The anemia is microcytic if the MCV is < 80. The 3 commonest
causes of microcytic anemia are iron deficiency, thalassemia and anemia of chronic diseases.
Ferritin – With a microcytic anemia, an important test is the serum ferritin level. Measurement of
serum ferritin is the most useful indirect estimate of body iron stores. The first test to become
abnormal in iron deficiency anemia is a fall in serum ferritin level. The normal plasma ferritin
levels are between 30–200 ng/mL (=μg/L) for males, and 15–200 ng/mL (=μg/L) for females. Serum
ferritin level less than 15 ng/mL is diagnostic of iron deficiency anemia. In iron deficiency anemia,
the MCV is low, and Hb and hematocrit are relatively lower than the erythrocyte count.
Thalassemia - Hemoglobin consists of heme and globin. Heme is made up of porphyrin and
ferrous iron. Globin is a protein with four polypeptide chains – 2 alpha and 2 beta chains. The
hemoglobin is highly soluble but individual alpha and beta chains are insoluble.
Thalassemia is one of the most common genetic disorders worldwide. Thalassemia is caused by a
partial or complete deficiency of alpha or beta globin chain synthesis. Alpha -thalassemia refer to
reduced synthesis of alpha chains. Relative excess of beta chains due to impaired production of
alpha globin results in less stable chains. This leads to the clinical disease known as alpha
thalassemia. Beta-thalassemia refers to decreased production of beta-chains. Impaired production
of beta globin chains manifests with a more severe disease known as beta thalassemia.
The synthesis of the unaffected alpha or beta globin occurs at normal rate. Therefore, there is
accumulation of either alpha or beta subunits. Accumulation of the unaffected globin chain (i.e.,
alpha chain in beta thalassemia and beta chain in alpha thalassemia) causes hemolysis.
Hemoglobin production is decreased. This cause hypochromic and microcytic anemia.
Clinical classification - Thalassemia major is severe and transfusion-dependent form; thalassemia
intermedia has less severe symptoms; and thalassemia minor (carrier state or trait) is without
clinical symptoms, but with hematologic abnormalities.
Thalassemia major (Cooley's Anemia) can be diagnosed easily during childhood. There is severe
anemia, hepatosplenomegaly and microcytosis. Many patients require chronic blood transfusion.
Thalassemia minor (i.e., thalassemia trait) usually presents as microcytosis and hypochromia, but
only minimal or mild anemia. The MCV is reduced (less than 75 fL). These patients can be
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misdiagnosed as iron deficiency anemia. RBC counts are usually higher than normal. Increased
RBCs in the presence of decreased MCV is the hallmark of thalassemia trait. An MCV/RBC ratio
<13 suggests thalassemia trait; a ratio >13 is more consistent with iron deficiency, but this and
other formulas are not conclusive enough for diagnosis.
Anemia of chronic diseases - MCV is normal or low. Serum iron is low. TIBC is normal or low.
Percent transferrin saturation is low. Serum ferritin is normal or high.
21) A person with aortic stenosis could perform an exercise for 11 minutes in Bruce protocol.
Exercise had to be stopped due to fatigue. He had a peak systolic gradient of 60 mm Hg
across the aortic valve at rest. What is the best management for him?
a. Medical management
b. Aortic valve balloon dilation to prevent worsening
c. Aortic valve replacement
d. Coronary angiography
Ans: (A)
Aortic stenosis (AS) - Left ventricular and aortic pressure is normally nearly equal during systole
(i.e., there is no gradient across the aortic valve during systole). In aortic stenosis, intracavitary
LV pressure must increase above aortic pressure to produce forward flow across the stenotic
aortic valve. Thus, there is a systolic pressure gradient between the LV and aorta in aortic
stenosis.
Critical aortic stenosis - The effective cross-sectional area of the normal aortic valve is 2.5 - 4
cm2. Clinically significant aortic stenosis develops only when the aortic valve orifice is narrowed
to less than 1 cm2. Critical aortic stenosis is present when the systolic pressure gradient across
the aortic valve is more than 50 mm Hg with normal cardiac output or the valve is narrowed to less
2
than 0.7 cm2 in an adult. A gradient > 50 mm Hg or an aortic valve area < 0.7 cm indicates that
the aortic stenosis is severe enough to cause the patient's symptoms.
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Doppler echocardiography is an accurate means of determining the severity of aortic stenosis in
most patients. The Doppler study can be used to determine the gradient across the aortic valve
and to calculate aortic valve area.
Management - The absolute valve area (or transvalvular pressure gradient) is not the primary
determinant of the need for aortic valve replacement. Therapeutic decisions related to corrective
surgery are based largely on the presence or absence of symptoms. Treat asymptomatic patients
conservatively. Recommend surgery in patients with symptoms due to AS. Asymptomatic patients
with calcific AS and severe obstruction should be followed clinically for the development of
symptoms. They need serial echocardiograms for evidence of deteriorating LV function.
Asymptomatic adult patients – Obtain a Doppler echocardiographic study. If the mean gradient is
more than 30 mm Hg, the patient should undergo a history and physical examination every 6
months. When symptoms have developed, repeat the Doppler echocardiographic study to confirm
that the aortic stenosis has worsened.
Prognosis is excellent until the classic symptoms of aortic stenosis (i.e., exertional angina,
syncope or fatigue) develop. Even severe AS may exist for many years without producing any
symptoms because of the ability of the hypertrophied LV to generate the elevated intraventricular
pressures required to maintain a normal stroke volume. In asymptomatic patients with peak
Doppler gradients > 50 mm Hg, the incidence of sudden death is less than 1% per year. Therefore,
surgery is generally not indicated for asymptomatic patients with aortic stenosis.
Symptomatic adult patients - After the onset of symptoms, average survival is 2 to 3 years, with a
high risk of sudden death. Adults with aortic stenosis should be operated on shortly after the
development of symptoms. Treatment modalities include aortic balloon valvotomy, valve
débridement, and valve replacement. There is no effective pharmacologic treatment for severe
aortic stenosis. Although ACE inhibitors prolong life in most cases of congestive heart failure,
they are contraindicated in severe aortic stenosis.
Children in whom the disease has been present from birth respond differently, and sudden death
in the absence of symptoms is common. Asymptomatic children with aortic stenosis should
probably undergo surgery once a peak gradient of 75 mm Hg develops, and sooner if symptoms
are present.
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Aortic balloon valvuloplasty is preferable to operation in many children and young adults with
congenital, noncalcific AS. It is not commonly used in adults with severe calcific AS because of a
very high restenosis rate (80% within 1 year) and the risk of procedural complications. It produces
only transient mild hemodynamic benefits. It should be considered only a palliative measure for
patients whose other severe systemic illnesses preclude surgery. It has been used successfully
as a "bridge to operation" in patients with severe LV dysfunction and shock who are too ill to
tolerate surgery.
Cardiac catheterization – The main purpose is coronary angiography. If the patient is in the
coronary-disease-prone age range, cardiac catheterization to confirm the hemodynamics and to
define coronary anatomy should be performed. It is indicated when symptoms such as angina
pectoris could be caused by coronary disease or aortic stenosis or when valve replacement
surgery is planned.
th
Braunwald's Heart Disease - A Textbook of Cardiovascular Medicine, 9 edition.
Hurst's The Heart, 13e
Current Diagnosis & Treatment: Cardiology, third edition, Michael H. Crawford.
22) Which of the following clinical features of demyelinating myelopathy least likely suggests
a progression to multiple sclerosis?
a. Complete cord transaction
b. Bilateral visual loss
c. Absence of oligoclonal bands
d. Poor prognosis
Ans: (C)
Patients with acute complete transverse myelitis have a cited risk of MS of only 5-10%.
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CSF studies suggest that patients with monosymptomatic disease with positive oligoclonal bands
(OCB) have higher risk of evolution to MS than without OCBs.
23) A 72-year-old man with normal renal function presents with new onset focal seizures.
Which is the best drug to manage this patient?
a. Sodium valproate
b. Oxcarbazepine
c. Levetriacetam
d. Pregabalin
Ans: (B)
Focal Seizures - With the new classification system, the subcategories of "simple focal seizures"
and "complex focal seizures" have been eliminated. Instead, they are classified as focal seizures
with dyscognitive features and focal seizures without dyscognitive features.
Focal seizures without dyscognitive features - Focal seizures can cause motor, sensory,
autonomic, or psychic symptoms without impairment of cognition.
"Jacksonian march" - The motor movements begin in a very restricted region such as the fingers
and gradually progress (over seconds to minutes) to include a larger portion of the extremity. This
is due to the spread of seizure activity over a progressively larger region of motor cortex.
Focal seizures with dyscognitive features - Focal seizures may be accompanied by a transient
impairment of the patient's ability to maintain normal contact with the environment. The patient is
unable to respond to visual or verbal commands during the seizure and has impaired recollection
or awareness of the ictal phase. The start of the ictal phase is often a sudden behavioral arrest or
motionless stare. The behavioral arrest is usually accompanied by automatisms (involuntary,
automatic behaviors).
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Cerebrovascular disease is the most common cause (about 50%) of new cases of epilepsy in
patients older than age 65.
CAUSES OF SEIZURES
Neonates (<1 month)

Perinatal hypoxia and ischemia

Intracranial hemorrhage and trauma

Acute CNS infection

Metabolic disturbances (hypoglycemia, hypocalcemia, hypomagnesemia, pyridoxine deficiency)

Drug withdrawal

Developmental disorders

Genetic disorders
Infants and children (>1 month and <12 years)

Febrile seizures

Genetic disorders (metabolic, degenerative, primary epilepsy syndromes)

CNS infection

Developmental disorders

Trauma

Idiopathic
Adolescents (12–18 years)

Trauma

Genetic disorders

Infection

Brain tumor

Illicit drug use

Idiopathic
Young adults (18–35 years)

Trauma

Alcohol withdrawal

Illicit drug use

Brain tumor

Idiopathic
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Older adults (>35 years)

Cerebrovascular disease

Brain tumor

Alcohol withdrawal

Metabolic disorders (uremia, hepatic failure, electrolyte abnormalities, hypoglycemia,
hyperglycemia)

Alzheimer's disease and other degenerative CNS diseases

Idiopathic
Almost all patients with new-onset seizures should have a brain MRI (CT scan is not adequate) to
exclude the presence of a structural brain lesion. If no cause is found, begin chronic
anticonvulsant therapy based on the probability of recurrence.
Most epileptologists do not recommend chronic anticonvulsant drug treatment following a single
seizure unless an underlying cause is found that is not correctable and is likely to produce
recurrent seizures (e.g., brain tumor). However, recurrent seizures do require anticonvulsant
treatment.
Carbamazepine (or oxcarbazepine), lamotrigine and phenytoin are the drugs of choice for the
initial treatment of focal seizures. Valporate and levetiracetam may also be used
th
Harrison's principles of internal medicine, 18 edition.
th
Clinical Neurology, 7 edition Roger P. Simon, David A. Greenberg, Michael J. Aminoff.
th
Bradley: Neurology in Clinical Practice, 6 edition.
Adams and Victor's Neurology
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24) Primary hyperaldosteronism can be diagnosed by all of the following criteria except
a. Diastolic hypertension without edema
b. Metabolic acidosis present
c. Low plasma rennin activity that is not stimulated by volume depletion
d. Hyperaldosteronism, i.e., increased aldosterone secretion which is not suppressed
by volume expansion
Ans: (b)
Primary hyperaldosteronism – There is autonomous overproduction of aldosterone, with resultant
suppression of the renin-angiotensin system and decreased plasma renin activity.
CAUSES

Solitary aldosterone-secreting adenomas (Conn's syndrome) are small (<2 cm in
diameter), well-circumscribed lesions, more often found on the left than on the right. They
tend to occur in the 30s and 40s, and in women more often than in men. These lesions are
often buried within the gland and may not be visible on CT scanning.

Idiopathic bilateral adrenal hyperplasia rarely occurs before age 40 years and is more
common in males.

Glucocorticoid-remediable hyperaldosteronism is an uncommon cause of primary familial
hyperaldosteronism. In some families, it is caused by a chimeric gene resulting from
fusion betweenCYP11B1 (the 11β-hydroxylase gene) and CYP11B2 (the aldosterone
synthase gene).

Adrenocortical carcinoma is rare.
Pathophysiology – Aldosterone secretion is regulated by renin, serum potassium and sodium
levels, intravascular volume status, and adrenocorticotropic hormone (ACTH). In primary
hyperaldosteronism, there is autonomous aldosterone production (nonsuppressible aldosterone
production). Plasma renin level is suppressed. There is mildly expanded intravascular and
extravascular fluid volume.
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Clinical features - There is excess aldosterone production leading to sodium retention,
hypertension, and hypokalaemia (due to urinary potassium loss). The usual presentation is
hypertension. Hypokalaemia (< 3.5 mmol/L) is frequently absent (up to 40%). Normal serum
potassium does not exclude the diagnosis. Rarely muscle weakness, nocturia and tetany are
seen. Primary hyperaldosteronism may present with hypokalemic metabolic alkalosis (due to
increased renal hydrogen ion loss mediated by hypokalemia and aldosterone).
Primary aldosteronism is typically not associated with edema, despite the volume-expanded state
associated with it. This is due to spontaneous natriuresis and diuresis (aldosterone escape)
mediated by atrial natriuretic peptide.
Screening test - Plasma aldosterone:renin ratio (ARR) is the most frequently used screening test,
but raised ARR alone does not confirm the diagnosis.
Diagnosis is by elevated plasma aldosterone levels that are not suppressed with 0.9% saline
infusion (2 L over 4 hours) or fludrocortisone administration. About 40% of patients with raised
ARR on screening will suppress normally, excluding the diagnosis.
The 24-hour urinary aldosterone (U-Aldo) excretion test is one of the most useful confirmatory
diagnostic tools because it is an index for total daily aldosterone secretion.
Adenoma is differentiated from hyperplasia by adrenal CT or MRI. The distinction between these
2 major causes is vital because the treatment of choice for each is different.
Treatment - The treatment of choice for aldosteronomas is surgical extirpation. The treatment of
choice for idiopathic bilateral adrenal hyperplasia is medical therapy with aldosterone antagonist
spironolactone.
th
Kumar and Clark's Clinical Medicine 7 edition.
Kumar: Robbins and Cotran Pathologic Basis of Disease, Professional Edition, 8th edition.
th
Goldman: Goldman's Cecil Medicine, 24 edition.
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25) A 30-year-old man has complaints of falling asleep at work frequently. He attributes this to
disturbed sleep at night. He also gives history of frequent falls while partying with friends.
Which of the following additional problems might he be facing?
a. Paralysis during sleep-wake transition with hallucinations
b. Snoring and apneas
c. Leg problems while going off to sleep
d. Generalized seizures in the wake state
Ans: (A)
Narcolepsy is characterized by the tetrad of excessive daytime sleepiness, cataplexy, hypnagogic
hallucinations, and sleep paralysis.
Narcolepsy is associated with uncontrollable sleep attacks in inappropriate, embarrassing, and
even dangerous situations (e.g., while driving). Most narcoleptics also have cataplexy (a sudden
loss of muscle tone), hypnagogic hallucinations (dreamlike experiences while falling asleep), and
sleep paralysis (brief paralysis associated with the onset of sleep or wakefulness). However, only
10–15% of narcoleptic patients have all four major symptoms.
Sleep apnea - Respiratory dysfunction during sleep is a common cause of excessive daytime
somnolence and disturbed nocturnal sleep. These episodes may be due to an occlusion of the
airway (obstructive sleep apnea), absence of respiratory effort (central sleep apnea), or a
combination of these factors (mixed sleep apnea). Sleep apnea is particularly prevalent in
overweight men and in the elderly.
Restless leg syndrome – The four core symptoms required for diagnosis are: (1) an urge to move
the legs, (2) symptoms begin or worsen with rest, (3) partial or complete relief by movement, (4)
worsening during the evening or night.
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In about 80% of patients, restless leg syndrome is associated with periodic leg movements during
sleep and occasionally while awake. These involuntary movements are usually brief, lasting no
more than a few seconds, and recur every 5–90 seconds. The restlessness and periodic leg
movements cause of sleep disturbance and daytime sleepiness.
Primary restless leg syndrome is genetic with an autosomal dominant pattern of inheritance.
Secondary restless leg syndrome may be associated with pregnancy, anemia, ferritin deficiency,
renal failure, and peripheral neuropathy.
The pathogenesis probably involves disordered dopamine function, in association with an
abnormality of iron metabolism.
Periodic leg movements also occurs with narcolepsy, sleep apnea, following the use of tricyclic
and serotonin reuptake inhibiting antidepressants, L-dopa, and withdrawal from anticonvulsants
and sedative-hypnotic drugs.
History of fall is highly suggestive of atonia or paralysis that may be due to narcolepsy. In
obstructive sleep apnea, patient usually falls asleep during day with no loss of postural tone.
th
Harrison's principles of internal medicine, 18 edition.
Adams and Victor's Neurology
st
Stern: Massachusetts General Hospital Comprehensive Clinical Psychiatry, 1 edition.
26) Which of these is not a deleterious effect of hypothermia?
a. Cardiac arrhythmias
b. Decreased peripheral resistance
c. Reversible coagulation
d. Renal failure
Ans: (b)
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Systemic hypothermia is a reduction of core (rectal) body temperature below 35°C. To accurately
measure hypothermia, an intravascular, esophageal, rectal or bladder probe that measures
temperatures as low as 25 degrees C is required; oral, axillary, and otic temperatures are
inaccurate and unreliable.
Ventricular fibrillation and asystole may occur spontaneously at core temperatures below 28°C
(82.4°F).
Mild [ 35°C (95°F) – 32.2°C (90°F)]
CVS changes

Tachycardia, then progressive bradycardia

Vasoconstriction

Increase in cardiac output and blood pressure
CNS changes

Depression of cerebral metabolism

Amnesia

Impaired judgment
Moderate [32.2°C (90°F) – 28°C (82.4°F)]
CVS changes

Progressive decrease in pulse and cardiac output

Increased atrial and ventricular arrhythmias

ECG changes (J- wave)
CNS changes

EEG abnormalities

Progressive depression of level of consciousness

Pupillary dilation

Hallucinations
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Severe [<28°C (82.4°F)]
CVS changes

Progressive decrease in pulse and cardiac output

Increased atrial and ventricular arrhythmias

ECG changes (J- wave)
CNS changes

Loss of cerebrovascular autoregulation

Decline in cerebral blood flow

Coma

Loss of ocular reflexes

Progressive decrease in EEG
th
Harrison's principles of internal medicine, 18 edition.
th
Marx: Rosen's Emergency Medicine, 7 edition.
th
CURRENT Diagnosis & Treatment: Emergency Medicine, 6 edition, C. Keith Stone, Roger L.
Humphries.
27) Lid retraction is seen in
a. Brimonidine
b. Apraclonidine
c. Trovaprost
d. Bimatoprost
Ans: (b)
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Apraclodine decreases intraocular pressure by 25% when applied topically. This is achieved by
decreasing aqueous production by primary α2 and subsidiary α1 action in the ciliary body. Its use
restricted to control spikes of intraocular pressure after laser trabecuoplasty or iridoplasty.
Brimonidine is more α1 selective and lipophilic than apraclonidine. It reduces aqueous production
and increases uveoscleral outflow. Both apraclonidine and brimonidine can cause lid retraction.
However, frequency is greater with apraclonidine.
28) A 25-year-old asymptomatic female underwent a pre-op coagulation test. BT = 3minutes.
PT = 15/14. aPTT = 45/35. Platelet count = 2.5 lac/mm3. Factor VIII levels = 100%. What is
the most likely diagnosis?
Normal BT = < 7 minutes
Normal PT = 12.7–15.4 seconds
Normal APPT= 26.3–39.4 seconds
Normal factor VIII = 0.50–1.50 (50–150%)
a. Factor IX deficiency
b. Lupus anticoagulant
c. Factor VIII inhibitors
d. VWD – Type III
Ans: (b)
Normal hemostasis - Disturbance of any one of the mechanisms may produce abnormal
bleeding or abnormal thrombosis.
1) Vessel wall - Following minor injuries, the blood vessels undergo vasoconstriction,
thereby preventing bleeding from the injured site and permitting
repair. Vasoconstriction is an effective method of hemostasis in small vessel injuries but
is not adequate when large vessels are damaged.
2) Platelets form the initial hemostatic plug that seals a site of vascular injury. Platelets also
play a major role in forming the permanent thrombus that seals the injury
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3) Blood coagulation is the formation of fibrin from plasma precursors. Fibrin and platelets
constitute the permanent hemostatic plug.
4) Fibrinolysis is the production of plasmin that lyse and remove fibrin thrombi which have
formed in the circulation.
Bleeding time - A bleeding time and a platelet count are the most important screening tests of
vessel wall and platelet abnormalities. Prolonged bleeding time is commonly due to
thrombocytopenia. It is advisable to check the platelet count before carrying out the bleeding time
test. Patients with a platelet count below 50,000/ml may have a very long bleeding time and the
bleeding may be difficult to arrest. A prolonged bleeding time with a normal platelet count indicate
abnormal platelet function.
Normal BT is < 7 minutes. Any patient with a bleeding time >10 min has an increased risk of
bleeding, but the risk does not become great until the bleeding time is >15 or 20 min.
CAUSES OF PROLONGED BLEEDING TIME

Thrombocytopenia

Disorders of platelet function (e.g., aspirin, uraemia, paraproteinemia, or myelodysplastic
syndromes thrombasthenia, storage pool defect)

VWD

Vascular abnormalities (e.g., Ehler-Danlos's syndrome, pseudoxanthoma elasticum)

Severe deficiency of factor V or XI

Afibrinogenaemia
This 25-year old asymptomatic female has normal BT and platelet count. Therefore,
thrombocytopenia and vessel wall disorders can be ruled out. You have to consider disorders of
coagulation.
Coagulation disorders - There are three principal groups of coagulation disorders.
Deficiency of Coagulation Factors - Of these, factor VIII deficiency (hemophilia A and von
Willebrand's disease) and factor IX deficiency (Christmas disease) are the most common.
Acquired deficiencies of coagulation factors occur in severe liver disease (affects all factors
produced by the liver) and in vitamin K deficiency (prothrombin and factors VII, IX, and X).
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Presence of Circulating Anticoagulants – This group includes anticoagulant therapy, factor VIII
inhibitor and lupus anticoagulant.
Fibrinolytic Activity - Increased fibrinolytic activity in the blood results from increased activation
of the plasmin system.
Prothrombin time screens the extrinsic or tissue factor-dependent pathway. It tests factor VII.
Factor VII has the shortest half-life of about 7 hours. Therefore, PT may become abnormal earlier
than APPT.
Normal PT = 12.7–15.4 seconds.
The activated partial prothrombin time (APTT) measures XII, XI, IX, VIII, X, V, prothrombin and
fibrinogen (i.e., intrinsic pathway). It does not measure factor VII and factor XIII. The normal APPT
is 30 to 50 seconds.
CAUSES OF A PROLONGED APTT

Disseminated intravascular coagulation

Liver disease

Heparin or other anticoagulants

A circulating anticoagulant (inhibitor)

Deficiency of a coagulation factor other than factor VII
DIFFERENTIAL DIAGNOSIS OF ABNORMAL COAGULATION SCREENING TESTS
Abnormal Activated Partial Thromboplastin Time (APTT) Alone

Associated with bleeding: VIII, IX, and XI defects

Not associated with bleeding: XII, prekallikrein (PK), high molecular weight kininogen,
lupus anticoagulants
Abnormal Prothrombin Time (PT) Alone

Factor VII defects
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Combined Abnormal APTT and PT

Medical conditions: Anticoagulants, disseminated intravascular coagulation, liver disease,
vitamin K deficiency, massive transfusion

Rarely dysfibrinogenemia; factor X, V, and II defects
Heparin, which accelerates the inactivation of thrombin and other coagulation factors (such as factor Xa),
preferentially blocks the intrinsic system, leading to prolonged APTTs but not to significant elevations in PT.
On the other hand, the vitamin K antagonist coumadin preferentially blocks factor VII in the extrinsic
system, leading to prolonged PTs but not APTTs.
Normal factor VIII in the above case rules out Hemophilia A and Von Willebrand disease.
Factor IX deficiency (Hemophilia B or Christmas disease) is an X-linked inherited bleeding
disorder. It usually manifested in males. It is transmitted by females when they carry the
abnormality on the X chromosome. A prolonged aPTT with a normal PT and Factor VIII is typical
of hemophilia B. Prolongation of PT alone, or both the PT and aPTT, is not consistent with
hemophilia B alone. Among those with residual FVIII or FIX activity >25% of normal, the disease is
discovered only by bleeding after major trauma or during routine presurgery laboratory tests. The
sex of the case in question is against this diagnosis.
Lupus anticoagulant – It is a misnomer because the lupus anticoagulant is more frequently
encountered in patients without lupus and is associated with thrombosis rather than with
bleeding. The lupus anticoagulant can also present with a prolonged aPTT and can also be
associated with the presence of a specific factor VIII inhibitor.
Factor VIII inhibitors - If the PT or the APTT becomes elevated in the absence of treatment with
heparin or coumadin, and the platelet count is normal, it is important to perform mixing studies of
the patient's plasma with normal plasma to determine if the coagulation time normalizes (i.e.,
whether there is a factor deficiency). If mixing studies do not completely correct the prolonged
coagulation times, the presence of coagulation inhibitors, such as circulating lupus
anticoagulant or antifactor antibodies, should be suspected.
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The presence of a factor VIII inhibitor should be suspected whenever a patient with no prior
bleeding history presents with spontaneous massive bruising or with large, unexplained
hematomas. The aPTT is prolonged, whereas the prothrombin time is normal. The aPTT of a
mixture of the patient's plasma and normal plasma is also prolonged. Confirmation that an
inhibitor acts specifically with factor VIII requires incubating the patient's plasma diluted with an
equal volume of normal plasma and performing assays of factors VIII, IX, XI, and XII at 0, 60, and
120 minutes. If the inhibitor is specific for factor VIII, only factor VIII decreases over time.
th
Hoffman: Hematology: Basic Principles and Practice, 5 edition.
th
Harrison's principles of internal medicine, 18 edition.
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