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Question 1 top Download PDF

A 65-year-old woman presents with a one-week history of progressive dyspnoea. On admission, there are signs of shock, a systolic murmur and an elevated jugular venous pressure. The ECG shows sinus tachycardia but no other abnormality. An antero-posterior chest X-ray shows cardiomegaly. The serum troponin I level is 0.5 mg/L [<0.1]. A computed tomography (CT) scan is shown below.

 

 

What is the most likely diagnosis?
A. Pulmonary embolism.
B. Right ventricular infarction.
C. Pericardial tamponade.
D. Myocarditis.
E. Acute mitral regurgitation.

Answer: C

The key here is that all the above if presenting as an emergency cannot be differentiated by the any of the presenting signs listed

A. Pulmonary embolism

CLINICAL


SYMPTOMS / SIGNS — Specific symptoms and signs are not helpful diagnostically because their frequency is similar among patients with and without PE. In a large prospective study, the following frequencies of symptoms and signs were noted among patients without preexisting cardiopulmonary disease
Symptoms and signs of acute pulmonary embolism

 

Frequency

Symptom

Dyspnea

73 percent

Pleuritic chest pain

66 percent

Cough

37 percent

Hemoptysis

13 percent

Sign

Tachypnea

70 percent

Rales

51 percent

Tachycardia

30 percent

Fourth heart sound

24 percent

Accentuated pulmonic component of second heart sound

23 percent

Circulatory collapse

8 percent

Data from Stein, PD, et al. Chest 1991; 100:598.
Data from Stein, PD, et al. Am J Cardiol 1991; 68:1723.

 

Troponin — Serum troponin I and troponin T are elevated in 30 to 50 percent of patients with a moderate to large pulmonary embolism]. The presumed mechanism is acute right heart overload]. The troponin elevations usually resolve within 40 hours with pulmonary embolism in contrast to the more prolonged elevation with acute myocardial injury].

RADIOLOGY
Chest radiography — Radiographic abnormalities are common in patients with PE; however, they are not helpful diagnostically because they are similarly common in patients without PE


This site http://www.msit.com/phys_art03.html provides some CT images of PE


B. Right Ventricular Infarction


CLINICAL

  • The classic clinical triad of right ventricular infarction includes distended neck veins, clear lung fields, and hypotension
  • Infrequent clinical manifestations include right ventricular third and fourth heart sounds, which are typically audible at the left lower sternal border and increase with inspiration.
  • On hemodynamic monitoring, disproportionate elevation of right-sided filling pressures compared with left-sided hemodynamics represents the hallmark of right ventricular infarction.

Differences between left and right ventricular myocardial infarction

 

Left Ventricular MI

Right Ventricular MI

Clinical

Pulmonary congestion
Third and fourth heart sounds
New mitral regurgitation

Clear lung fields
Right-sided third heart sound
New tricuspid regurgitation
Hypotension with distended neck veins

ECG

ST elevation in standard leads

ST elevation in V4R
Commonly associated with inferior MI
Frequent atrioventricular block

Heamodynamic findings

Increased pulmonary capillary wedge pressure PCWP

Right atrial pressure (RAP) >10mmHg
RAP: PCWP >0.8

Specific Managmenet

Fluid restriction
Preload and afterload reduction
Reperfusion therapy
Ionotropic agents if necessary

Fluid resuscitation
Avoid Preload reduction
Reperfusion therapy
Ionotropic agents if necessary

 

Imaging  = TTE  is the most appropriate

  • In the appropriate clinical setting, a diagnosis of right ventricular infarction can be made using noninvasive techniques, or the patient may require right ventricular catheterization and hemodynamic monitoring.
  • Echocardiography is useful as a modality to rule out pericardial disease and tamponade, which are the major differential diagnoses in the setting of a right ventricular infarction.
  • Gated equilibrium radionuclide angiography and technetium 99m pyrophosphate scintigraphy are useful in diagnosing right ventricular infarction noninvasively (Sugimoto et al, 1996). In the case of radionuclide angiography, the right ventricle is demonstrated to be enlarged and poorly contractile, with a reduced ejection fraction. When technetium 99m pyrophosphate is employed, the right ventricular free wall is "hot," indicating significant infarction
C. Pericardial tamponade.

Cardiac tamponade is a clinical syndrome caused by the accumulation of fluid in the pericardial space, resulting in reduced ventricular filling and subsequent hemodynamic compromise. Cardiac tamponade is a medical emergency. The overall risk of death depends on the speed of diagnosis, the treatment provided, and the underlying cause of the tamponade.

Symptoms vary with the underlying cause and the acuteness of the tamponade. Patients with acute tamponade may present with dyspnea, tachycardia, and tachypnea. Cold and clammy extremities from hypoperfusion are also observed in some patients.

 

Distended neck veins are a common feature in patients with tamponade. Evidence of chest wall injury may be present in trauma patients. Tachycardia, tachypnea, and hepatomegaly are observed in more than 50% of patients with cardiac tamponade, and diminished heart sounds and a pericardial friction rub are present in approximately one third of patients.
The Beck triad or acute compression triad

  • Described in 1935, this complex of physical findings refers to increased jugular venous pressure, hypotension, and diminished heart sounds.
  • These findings result from a rapid accumulation of pericardial fluid. However, this classic triad is usually observed in patients with acute cardiac tamponade.

Pulsus paradoxus or paradoxical pulse:

  • This is an exaggeration (>12 mm Hg or 9%) of the normal inspiratory decrease in systemic blood pressure.
  • To measure the pulsus paradoxus, patients are often placed in a semirecumbent position; respirations should be normal. The blood pressure cuff is inflated to at least 20 mm Hg above the systolic pressure and slowly deflated until the first Korotkoff sounds are heard only during expiration. At this pressure reading, if the cuff is not further deflated and a pulsus paradoxus is present, the first Korotkoff sound is not audible during inspiration. As the cuff is further deflated, the point at which the first Korotkoff sound is audible during both inspiration and expiration is recorded. If the difference between the first and second measurement is greater than 12 mm Hg, an abnormal pulsus paradoxus is present.
  • The paradox is that while listening to the heart sounds during inspiration, the pulse weakens or may not be palpated with certain heartbeats, while S1 is heard with all heartbeats.
  • A pulsus paradoxus can be observed in patients with other conditions, such as constrictive pericarditis, severe obstructive pulmonary disease, restrictive cardiomyopathy, pulmonary embolism, rapid and labored breathing, and right ventricular infarction with shock.
  • A pulsus paradoxus may be absent in patients with markedly elevated LV diastolic pressures, atrial septal defect, pulmonary hypertension, and aortic regurgitation.

Kussmaul sign

  • This was described by Adolph Kussmaul as a paradoxical increase in venous distention and pressure during inspiration.
  • This sign is usually observed in patients with constrictive pericarditis but occasionally is observed in patients with effusive-constrictive pericarditis and cardiac tamponade.

Ewart sign

  • Also known as the Pins sign, this is observed in patients with large pericardial effusions.
  • It is described as an area of dullness, with bronchial breath sounds and bronchophony below the angle of the left scapula.

The y descent

  • The y descent is abolished in the jugular venous or right atrial waveform.
  • This is due to an increase in intrapericardial pressure, preventing diastolic filling of the ventricles.

ECG

With a 12-lead electrocardiogram the following findings are suggestive but not diagnostic of pericardial tamponade.

    • Sinus tachycardia
    • Low-voltage QRS complexes
    • Electrical alternans (also observed during supraventricular and ventricular tachycardia): Alternation of QRS complexes, usually in a 2:1 ratio, on electrocardiogram findings is called electrical alternans. This is due to movement of the heart in the pericardial space. Electrical alternans is also observed in patients with myocardial ischemia, acute pulmonary embolism, and tachyarrhythmias.
  • PR segment depression

RADOIOLOGY

Chest radiography findings may show cardiomegaly, water bottle–shaped heart, pericardial calcifications, or evidence of chest wall trauma

D. Myocarditis.

Physical: Physical findings can range from nearly normal examination findings to signs of fulminant CHF.

  • Patients with mild cases of myocarditis have a nontoxic appearance and simply may appear to have a viral syndrome.
  • Tachypnea and tachycardia are common. Tachycardia is often out of proportion to fever.
  • More acutely ill patients have signs of circulatory impairment due to left ventricular failure.
  • A widely inflamed heart shows the classic signs of ventricular dysfunction including the following:
    • Jugular venous distention
    • Bibasilar crackles
    • Ascites
    • Peripheral edema
  • S3 or a summation gallop may be noted with significant biventricular involvement.
  • Intensity of S1 may be diminished.
  • Cyanosis may occur.
  • Hypotension caused by left ventricular dysfunction is uncommon in the acute setting and indicates a poor prognosis when present.
  • Murmurs of mitral or tricuspid regurgitation may be present due to ventricular dilation.
  • In cases where a dilated cardiomyopathy has developed, signs of peripheral or pulmonary thromboembolism may be found.
  • Diffuse inflammation may develop leading to pericardial effusion, without tamponade, and pericardial and pleural friction rub as the inflammatory process involves surrounding structures.

 

E. Acute mitral regurgitation.

ETIOLOGY — Although there are many causes of acute mitral regurgitation (MR), many of which can, under other circumstances, also cause chronic MR, there are only three basic mechanisms of acute native valve acute MR

  • Flail leaflet due to myxomatous disease (mitral valve prolapsed), infective endocarditis, or trauma
  • Chordae tendineae rupture due to trauma, spontaneous rupture, infective endocarditis, or acute rhematic fever
  • Papillary mucle dysfunction or rupture due to acute myocardial infarction or severe ischaemia or trauma

Different mechanisms are responsible for acute MR in prosthetic valves:

  1. Tissue valve leaflet rupture due to degeneration, calcification, or endocarditis.
  2. Impaired closure of mechanical valve occluders due to valve thrombosis, infection, or pannus formation. With older generation mechanical valves, there were instances of strut fracture and disk escape, but these have not been reported with currently implanted valves.
  3. Paravalvular regurgitation due to infection or suture rupture (often related to a calcified or scarred annulus).

Acute mitral regurgitation typically presents as a cardiac emergency with the sudden onset and rapid progression of pulmonary edema, hypotension, and signs and symptoms of cardiogenic shock. In some cases, the pulmonary hypertension leads to acute right-sided heart failure.
The presentation may not be as dramatic if acute MR is superimposed upon chronic MR or the patient is younger and physically fit. Such patients may present subacutely in the office or clinic, rather than in the Emergency Department. However, they may note a sudden and marked increase in symptoms of heart failure and a low output state, with increasing shortness of breath, dyspnea on exertion, fatigue, and weakness.

Physical examination — The patient with acute MR is often in pulmonary edema and there is evidence of poor tissue perfusion with peripheral vasoconstriction, pallor, and diaphoresis. The arterial pulse is often rapid and of low amplitude or thready due to the reduction in forward output. When there is an associated increase in right-sided pressure, the neck veins become distended; they may also become pulsatile with a marked "v" wave if the elevated right ventricular pressure leads to tricuspid regurgitation.
The chest radiograph usually shows a normal size cardiac silhouette, with severe left-sided congestive heart failure and pulmonary edema. An enlarged left ventricle and atrium may be present if chronic MR has been present prior to the acute event.

ECG
There are generally no electrocardiographic abnormalities specifically associated with acute MR. There may, however, be changes that reflect the etiology, such as an acute myocardial infarction, left ventricular hypertrophy, or P-mitrale reflecting underlying chronic MR.

Summary of presentation signs and symptoms related to options

 

Pulmonary embolism

Right ventricular infarction

Pericardial tamponade

Myocarditis

Acute mitral regurgitation

Progressive dyspnoea

yes

Yes

Yes

yes

yes

Shock

yes

Yes

Yes

yes

Yes

Systolic murmur

yes

TR

Y

?

sometimes

Elevated jugular enous pressure

yes

Yes

Y

?

Yes

ECG sinus tachycardia only

Yes

Should be ST elevation

Y

Yes

Possible

CXR cardiomegaly

Preexisiting poss

?

Y

Yes

possible

Increased trop I 0.5

Possible

 Yes Inferior MI as mechanism

Y

possible

Ischaemia may be mechanism

CT – bilateral pleural effusion pericardial effusion

CT has a role
No – thrombus identified

 

Usually echo but CT does have a role

? usually echo

? usually echo

Topic

Cardiology: Pericardial Disease

Question 2 top Download PDF

QUESTION 2
A 35-year-old mother with breast cancer reports that her aunt had developed breast cancer at 48 years of age. She is keen to clarify the risk of her young daughter developing breast cancer. A blood sample from the mother is submitted for mutation analysis of the BRCA1 and BRCA2 genes, but no mutation is found.
What impact does the mutation analysis have on the estimate of the daughter’s risk of Developing breast cancer?

A. The maternal studies place the daughter at low risk of developing breast cancer.
B. The maternal studies do not clarify the daughter’s risk.
C. The maternal studies place the daughter at high risk of developing breast cancer.
D. The daughter’s risk cannot be clarified without studies of her father’s BRCA1 and
BRCA2 genes.
E. The daughter’s risk cannot be clarified without studies of her own BRCA1 and
BRCA2 genes.

 

The family history carries its own genetic risk however the question ask about the mutation analysis

The answer is B which is a bit tricky – My interpretation of that answer is that the genetic studies do not clarify the daughter’s risk but the family history does.

A is incorrect as you need other information ie family history
C the family history not the maternal studies place her at higher risk
D and E incorrect the screening must commence with an individual who is affected by breast or ovarian cancer, so the screening would have stopped with the negative result from mum

From the lecture

With regard to genetic testing

  • Mutation screening must commence with an individual who has been affected by breast or ovarian cancer.
  • if a mutation is identified in the family other members can be offered predictive testing.
  • If first degree relative risk of having mutation is 50% based on autosomal inheritance.

BRACA1/2 Cancer Risks
BRCA1

  • Breast cancer risk 40-80%
  • Ovarian cancer risk 10-40%
  • Prostate cancer risk for males 15%
  • Colon cancer small increase

BRCA2

  • Breast cancer risk 40-80%
  • Ovarian cancer risk 10-30%
  • Breast cancer risk in males 6%
  • Increased risk pancreatic and prostate cancer

BRACA1

  • Chromosome 17q, 5592bp, 22 exons (exon 11 = 60%)
  • Mutation prevalence 1 in 1000
  • Mutations account for 1-4% of all breast cancers
  • >80% of mutations are truncating
  • 5’-end higher risk of ovarian ca, 2 last exons more severe phenotype
  • Critical role in cellular response to DNA damage
  • Interacts with proteins of the DNA machinery
  • Alterations not found in sporadic breast cancer (but found in sporadic ovarian cancer)
  • Tumours associated with a BRCA1 mutation appear to have typical histological features.
    • High grade
    • Hormone receptor negative
    • Pushing borders
    • Less DCIS
      • Inc medullary histology

BRACA2

  • 13q
  • 27 exons (exon 11 > 50% coding region)
  • Thought to act as tumour suppressor gene
  • Less association with Ovarian cancer
  • Ovarian Cancer Cluster Region (OCCR) 3.3 kb in exon 11
  • Higher risk of male breast cancer
  • Mutation prevalence about 1 in 1000
  • While distinct histological features are seen with BRCA 1 breast cancers BRCA
  • 2 tumours do not seem to have specific phenotypic features.

 

FAMILY HISTORY AND GENETIC RISK FACTORS — Family history is an important risk factor for breast cancer. However, a positive family history is only reported by 15 to 20 percent of women with breast cancer.
The risk associated with having an affected first or second degree maternal or paternal relative is modulated by the age of both the case patient and the family member at diagnosis, and the number of female first-degree relatives with and without cancer. As an example, in a pooled analysis using data from over 50,000 women with breast cancer and 100,000 controls, the risk of breast cancer for a woman with one affected first-degree relative was increased 1.80 fold. With two affected first-degree relatives, the risk is increased 2.93 fold. The risk ratios were highest for women with young affected relatives. Thus, the risk was increased 2.9 fold for a woman whose relative was diagnosed before age 30, but only 1.5 fold increased if the affected relative was diagnosed after age 60. Similarly, the risk of breast cancer before age 40 was increased 5.7-fold if one relative had breast cancer before age 40.

 

Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease.

Lancet 2001 Oct 27;358(9291):1389-99.

BACKGROUND: Women with a family history of breast cancer are at increased risk of the disease, but no study has been large enough to characterise reliably how, over women's lives, this risk is influenced by particular familial patterns of breast cancer. This report, on the relevance of breast cancer in first-degree relatives, is based on combined data from 52 epidemiological studies. METHODS: Individual data on breast cancer in first-degree relatives (mothers, sisters, and daughters) of 58209 women with breast cancer and of 101986 controls were collected, checked, and analysed centrally. Risk ratios for breast cancer were calculated by conditional logistic regression, stratified by study, age, menopausal status, number of sisters, parity, and age when the first child was born. Breast-cancer incidence and mortality rates for particular family histories were calculated by applying age-specific risk ratios to breast-cancer rates typical for more-developed countries. FINDINGS: Altogether 7496 (12.9%) women with breast cancer and 7438 (7.3%) controls reported that one or more first-degree relatives had a history of breast cancer: 12% of women with breast cancer had one affected relative and 1% had two or more. Risk ratios for breast cancer increased with increasing numbers of affected first-degree relatives: compared with women who had no affected relative, the ratios were 1.80 (99% CI 1.69-1.91), 2.93 (2.36-3.64), and 3.90 (2.03-7.49), respectively, for one, two, and three or more affected first-degree relatives (p<0.0001 each). The risk ratios were greatest at young ages, and for women of a given age, were greater the younger the relative was when diagnosed. The results did not differ substantially between women reporting an affected mother (9104) or sister (6386). Other factors, such as childbearing history, did not significantly alter the risk ratios associated with a family history of breast cancer. For women in more-developed countries with zero, one, or two affected first-degree relatives, the estimated cumulative incidence of breast cancer up to age 50 was 1.7%, 3.7%, and 8.0%, respectively; corresponding estimates for incidence up to age 80 were 7.8%, 13.3%, and 21.1%. Corresponding estimates for death from breast cancer up to age 80 were 2.3%, 4.2%, and 7.6%. The age when the relative was diagnosed had only a moderate effect on these estimates. INTERPRETATION: Eight out of nine women who develop breast cancer do not have an affected mother, sister, or daughter. Although women who have first-degree relatives with a history of breast cancer are at increased risk of the disease, most will never develop breast cancer, and most who do will be aged over 50 when their cancer is diagnosed. In countries where breast cancer is common, the lifetime excess incidence of breast cancer is 5.5% for women with one affected first-degree relative and 13.3% for women with two.

Topic

Oncology: Breast Cancer

Genetics: Cancer Genetics

Repeat Question: 2004 paper two question 88

 

Question 3 top Download PDF

QUESTION 3
In assessment of cancer patients, the Karnofsky performance scale best correlates with:
A. treatment dose.
B. survival.
C. analgesic requirement.
D. rehabilitation needs.

E. cancer volume.

A number of metrics have been developed to quantify performance status; among them, the Karnofsky performance status (KPS) is the most commonly used. The KPS ranges from values of 100, signifying normal functional status with no complaints nor evidence of disease, to 0, signifying death

Karnofsky performance status scale


Value

Level of Functional Capacity

100

Normal, no complaints, no evidence of disease

90

Able to carry on normal activity, minor signs or symptoms of disease

80

Normal activity with effort, some signs or symptoms of disease

70

Cares for self, unable to carry on normal activity or to do active work

60

Requires occasional assistance, but is able to care for most needs

50

Requires considerable assistance and frequent medical care

40

Disabled, requires special care and assistance

30

Severely disabled, hospitalization is indicated although death is not imminent

20

Hospitalization is necessary, very sick, active supportive treatment necessary

10

Moribund, fatal processes progressing rapidly

0

Dead

Numerous studies have described an association between survival in patients with cancer and their KPS The magnitude of the association is described differently depending upon the statistical methods employed in various trials, but a KPS of less than 50 percent consistently suggests a life expectancy of less than 8 weeks for patients enrolled in palliative care programs. A similar relationship has been reported in studies in which the KPS was augmented with information about self-care, oral intake and level of consciousness, a scale referred to as the palliative perfomance scale (PPS)

Answer survival A

Topic

Oncology:Principles of anticancer therapies

Repeat Question: 2004 paper two question 72

 

Question 4 top

Question 5 top

Question 6 top Download PDF

Question 6

Which one of the following events is least likely to occur in a person with diet-controlled type 2 (non-insulin-dependent) diabetes mellitus who is commenced on a thiazolidinedione (eg pioglitazone) as a sole agent?

A. Increased body fat

B. Lowering of glycosylated haemoglobin (HbA1c).

C. Hypoglycaemia

D. Increased high-density lipoprotein (HDL) concentration.

E. Peripheral oedema

 

Thiazolidinedione

  • A selective and potent agonist at the peroxisomal proliferator activated gamma nuclear receptor
  • Improves glycaemic control by improving insulin sensitivity at key sites of insulin resistance, namely adipose tissue, skeletal muscle and liver
  • Requires insulin to be present for their action
  • An effect to lower glucose production by the liver also has been reported
  • Increase glucose transport into muscle and adipose tissue by enhancing the synthesis and translocation of specific forms of the glucose transporter proteins
  • Can activate genes that regulate free fatty-acid metabolism in peripheral tissue
  • Adverse reactions: peripheral, pulmonary, macular oedema; hepatobiliary effects; hypercholesterolaemia; heart failure; cardiac ischaemia; CV events; anaemia; decreased haeatocrit; WBC; weight gain; hypoglycaemia

Topic

Pharmacology: Endocrinology

Question 7 top Download PDF

QUESTION 7
Which one of the following is the most common complication of endoscopic biliary sphincterotomy?
A. Haemorrhage.
B. Pancreatitis.
C. Cholangitis.
D. Perforation.
E. Diarrhoea.

 

Endoscopic retrograde cholangiopancreatography (ERCP
Endoscopic biliary sphincterotomy

  • Removal of bile-duct stones
  • Facilitate placement of stents, through malignant and benign biliary strictures
  • Surgical exploration of common bile duct during cholecystectomy

 

ERCP – 1 in 20 complication of pancreatitis
Sphincterotomy – 1 in 100 bleeding
Perforation rare complication

Topic

Gastroenterology:endoscopy

 

Question 8 top Download PDF

Which  one of the following clinical features best differentiates inclusion body myositis from polymyositis?
A.  Quadriceps wasting
B. Deltoid wasting
C. Weakness of long finger flexors
D. Bilateral ptosis
E. Truncal Weakness

Both inclusion body myositis and polymyositis share the features

  • proximal lower extremity weakness is usually the first sign with subsequent involvement of upper extremity and distal muscle groups.
  • Proximal muscle weakness is typically more pronounced although distal weakness is predominant in some patients.
  • The facial muscles may be involved,
  • oculomotor muscles are spared.

It just seems a random fact that weakness of long finger flexors is more suggestive of IBM – however there are some more diffinitive differentiators between the two that would make a better question

Answer C

Inflammatory myopathy
Polymyositis and dermatomyositis
Dalakas MC, Hohlfeld R
The Lancet - Vol. 362, Issue 9388, 20 September 2003, Pages 971-982
The inflammatory myopathies are a heterogenous group of subacute, chornic or actue acquired disease of skeletal muscle.  They have in common the presence of moderate to severe muscle weakness and inflammation in the muscle

Clinical presentation
Onset is acute or subacute over a period of several weeks and may follow systemic infection.  Systemic symptoms prevail at onset eg lassitude and are the followed by muscle weakness.  Extensive oedema of skin and subcutaneous tissues is common (especially in the periorbital region)

Polymyositis

  • Muscles may be painful and tender in 60% of cases though onset is often painless
  • Proximal muscles are first involved and initially weakness may be asymmetrical eg one quad only
  • Weakness of posterior neck muscles will result in the head ‘lolling’ forwards
  • Occasionally weakness may spread into distal limb muscle groups
  • Pharyngeal and laryngeal involvement results in dysphagia nad dysphonia
  • Cardiac muscles may also be involved
  • Respiratory muscle weakness causes respiratory failure ( this may be disproportionately severe)
  • The eye muscles are not involved unless there is coexistent myasthenia gravies
  • Reflexes are retained (if absent, consider underlying carcinoma and added neuropathy)
  • Immunopathology: in polymyositis and inclusion-body myositis, CD8 positive cells invade MCH-1 antigen expressing muscle fibres

Dermatomyositis

  • Often more severe and acute
  • Characterisd by skin rash.  Violet discoloration of light exposed skin including heliotropic discolouration of eyelids; raised scaly erythematosus rash involving nose and cheeks, shoulders, extensor surfaces of limbs and knuckles
  • Telangiectasia and tightening of skin are common and small ulcerated vasculiti lsions develop over bony prominences
  • Childhood form – multisystem involvement.  Calcification develops in skin and muscle with extrusion through skin.  Muscle contractures develop – tip-toe gait.  Gastrointestinal ulceration occurs
  • Immunopathology: the primary antigenic target in dermatomyositis is the endoethlium of the endomysial capillaries.  The disease begins when putative antibodies adirected agains endothelial cells activate complement C3

Differential diagnosis

  • Inclusion body myositis
  • Acid maltase deficiency (presenting as respiratory failure)
  • Limb girdle dystrophy
  • Drug induced, toxic and metabolic myopathies

Investigation

  • Ck elevated – indicates disease activity and severity
  • Electromyography – shows typical myopathic pattern
  • Muscle biopsy shows necrosis of muscle fibres  with inflammatory cells – lumphocytes. Plasma cells and leucocytes
  • Antibodies RA and ANA present in 40%
  • ESR elevated in most patients

Treatment

  • Steroids

Inclusion body myositis
Sporadic inclusion body myositis (IBM) is classified along with polymyositis and dermatomyositis as one of the idiopathic inflammatory myopathies. However, despite some histologic similarities, the clinicopathologic manifestations of IBM are clearly distinct from the other two disorders

  • Presents after age 50yrs. 
  • Patchy and asymmetric in distribution. 
  • Muscle biopsy shows basophilic inclusion granules. 
  • Often clinically confused with polymositis but response to immunotherapy is poor

 

Physical examination — The physical examination helps to determine the distribution of muscle weakness and atrophy. Findings of quadriceps, and finger flexor weakness and wasting and of foot drop due to tibialis anterior weakness is often noted

Differentiation between inclusion body myositis and polymyositis

 

Inclusion body myositis

Polymyositis

Sex

Male>female

Female > male

Age

Rare before 50

Common before 50

Onset

Insidious

Acute or subacute

Course

Slowly progressive

rapid

Distribution of weakness

Variable may be primarily distal,

proximal symmetric

CK

Normal or <10x normal

Often >10x normal

EMG

Myopathic or mixed myopathic and neurogenci

 myopathic

Muscle biopsy

Inflammation, rimmed vacuoles Inclusions

inflammation, fiber necrosis

Response to therapy

Generally poor

expected

Topic

Neurology:myelopathy

Question 9 top Download PDF

A 50-year-old man is receiving palliative care for advanced squamous cell carcinoma of the pharynx. He experiences persistent pain, has become increasingly distressed by his loss of independence and mentions thoughts of ending his life by suicide.
Which one of the following is likely to be the chief factor contributing to his suicidal ideation?
A. Major depression.
B. Unrelieved pain.
C. Personality disorder.
D. Normal grief reaction.
E. Delirium.

 

In patients with cancer, the mean prevalence of depression is 25%, but depression occurs in 40 to 50% of patients with cancers of the pancreas or oropharynx. Extreme cachexia, common with some cancers, may be misinterpreted as part of the symptom complex of depression; the higher prevalence of depression in patients with pancreatic cancer nevertheless persists when compared to those with advanced gastric cancer. Initiation of antidepressant medication in cancer patients has been shown to improve quality of life as well as mood. Psychotherapeutic approaches, particularly group therapy, may have some effect on short-term depression, anxiety, and pain symptoms and, speculatively, on recurrence rates and long-term survival

Desire for death in the terminally ill.
Chochinov HM; Wilson KG; Enns M; Mowchun N; Lander S; Levitt M; Clinch JJ
Am J Psychiatry. 1995 Aug;152(8):1185-91.

OBJECTIVE: Euthanasia and physician-assisted suicide have become prominent medical and social issues. This study investigated the prevalence of the desire for death in terminally ill patients, the stability of this desire over time, and its association with psychiatric disorders. METHOD: Two hundred terminally ill inpatients were given semistructured interviews that assessed their desire for death and evaluated them for major and minor depressive episodes according to the Research Diagnostic Criteria. Each patient also completed a short form of the Beck Depression Inventory and provided ratings of pain and social support. When possible, patients who expressed a desire for death received a follow-up interview after a 2-week interval. RESULTS: Although occasional wishes that death would come soon were common (reported by 44.5% of the patients), only 17 (8.5%) of these individuals acknowledged a serious and pervasive desire to die. The desire for death was correlated with ratings of pain and low family support but most significantly with measures of depression. The prevalence of diagnosed depressive syndromes was 58.8% among patients with a desire to die and 7.7% among patients without such a desire. Follow-up interviews were conducted with six patients; in four cases, the desire to die had decreased during the 2-week interval. CONCLUSIONS: The desire for death in terminally ill patients is closely associated with clinical depression--a potentially treatable condition--and can also decrease over time. Informed debate about euthanasia should recognize the importance of psychiatric considerations, as well as the inherent transience of many patients' expressed desire to die.

Topic

Oncology: pallative care

General medicine: psychiatry

 

Question 10 top Download PDF

A 25-year-old man presents with recent onset of lethargy, fever, bruising and abdominal pain.
On examination, he is clinically anaemic and is noted to have scattered bruises, bilateral pleural effusions, an abdominal mass and cervical and axillary lymphadenopathy.
Full blood examination shows:

haemoglobin                                         76 g/L [128-175]
mean corpuscular volume (MCV)            100 fL [80-97]
white cell count                                                 3.2 x 109/L [3.9-12.7]
differential:
neutrophils                                1.6 x 109/L [1.9-8.0]
lymphocytes                             1.1 x 109/L [0.9-3.3]
monocytes                                0.2 x 109/L [0.3-1.1]
eosinophils                               0.2 x 109/L [0-0.5]
basophils                                  0.1 x 109/L [0-0.1]
platelet count                                        32 x 109/L [150-396]
More than 90% of the nucleated cells in the bone marrow aspirate have the appearance shown below (examples indicated by arrows).

Coagulation parameters are normal.
The most likely marrow karyotypic abnormality is:
A. monosomy 7.
B. t (9;22).
C. 5q minus.
D. t (8;14).
E. t (15;17).

Presentation:

  • Pancytopenia (anaemia, neutropenia, thrombocytopenia)
  • Buising
  • Pleural efussions
  • Abdominal masses
  • Cervical and axillary lymphadenopathy

This bone marrow shows cells with  vacuoles where the arrow is pointing.   These cells in the bone marrow and peripheral blood are typical in Burkitts lymphoma.

Burkitts lymphoma | t(8:14) |vacuoles
 Burkitt's lymphoma

  • Aggressive NH lymphoma
  • B-cell lymphoma

Burkitt's lymphoma tumor cells are monomorphic, medium-sized cells with round nuclei, multiple nucleoli, and basophilic cytoplasm

  •  Cytologically, Burkitt's lymphoma (BL) cells resemble the small non-cleaved cells within normal germinal centers of the secondary lymphoid follicle.
  • These cells differ from lymphoblastic lymphoma cells in two respects; they have intermediate sized non-convoluted nuclei with coarse chromatin, and the cells have more abundant cytoplasm.
  • Cytoplasmic lipid vacuoles are usually evident on imprints or smears.

 

Defining features of Burkitt's lymphoma —

  • c-myc deregulation, as a consequence of which the tumor cells remain constantly in cycle. It is this phenomenon that results in both its morphologic  homogeneity and its clinical behavior.
  •  Unfortunately, detection of c-myc translocation is not practical in all clinical specimens for technical reasons.
  • In addition, some DLBCLs have t(8;14) and c-myc deregulation, and it is not clear if all such cases should be treated like BL.
  • The best practical surrogate for c-myc deregulation is thought to be the proliferation fraction: in a tumor with c-myc deregulation, 100 percent of viable cells should be in cycle, and should express Ki-67.
  • Thus, the WHO committees concluded the following:
    • Diagnosis of BLL should only be made in a tumor with morphologic features intermediate between BL and DLBCL, in which the Ki-67 fraction of viable cells is at least 99 percent. This tumor will be considered a subtype of BL in the WHO classification .
    • Cases with morphologic features of DLBCL with a high proliferation fraction [or t(8;14)], and cases that are morphologically borderline between BL and DLBCL with a lower proliferation fraction, should be classified as DLBCL.

Gene expression profiling may be helpful in enhancing current pathologic methods for distinguishing DLBCL from BL, as well as establishing prognosis, and, ultimately, appropriate treatment

 

Translocations involving the c-myc oncogene — In 90 percent of the cases studied, BL involves a translocation between the long arm of chromosome 8, the site of the c-myc oncogene (8q24), and one of three locations :

  • The Ig heavy chain region on chromosome 14 : t(8;14)
  • The kappa light chain locus on chromosome 2: t(2;8)
  • The lambda light chain locus on chromosome 22: t(8;22).

 

CLINICAL FEATURES — Three distinct clinical forms of Burkitt's lymphoma can be recognized: endemic, sporadic, and immunodeficiency-associated . Although they are histologically identical and have similar clinical behavior, there are differences in epidemiology, clinical presentation, and genetic features between the three forms:

  • The endemic (African) form presents as a jaw or facial bone tumor  that spreads to extranodal sites including mesentery, ovary, testis, kidney, breast, and especially to the bone marrow and meninges.
  • The nonendemic or American form has an abdominal presentation, most often with massive disease and ascites, involving distal ileum, stomach , cecum and/or mesentery, kidney, testis, ovary, breast, bone marrow, or central nervous system.
  • Immunodeficiency-related cases more often involve lymph nodes; both these and sporadic cases may present as acute leukemia.

Myeolodysplasia, acute myeloid leukaemia | monosomy 7 |

Aplastic anemia versus hypocellular MDS — Although most patients with MDS have normal or increased bone marrow cellularity, 8 to 28 percent have bone marrow cellularity of less than 25 percent and/or cellularity which is lower than expected based upon the patient's age . The distinction between aplastic anemia and hypocellular MDS is important because the clinical course and management of these two entities may differ.

Presence of a clonal chromosomal abnormality (eg, 5q-, monosomy 7) confirms the diagnosis of MDS . Expression of the tumor necrosis factor (TNF) receptor on bone marrow stem cells by flow cytometry may discriminate AA from MDS . Patients with AA have a markedly greater TNF receptor expression than those with MDS. Patients with hypocellular MDS may have a better prognosis than those with normal/hypercellular marrows .

Chronic myeloid leukaemia | Philadelphia chromosome t(9; 22) |

Chronic myelogenous leukemia (CML, also known as chronic myelocytic or chronic myeloid leukemia) is classified as one of the myeloproliferative disorders, along with polycythemia vera (PV), essential thrombocythemia (ET), and agnogenic myeloid metaplasia (AMM)

Philadelphia chromosome t(9; 22) – present in 90% CML

Myelodysplasia | 5q minus | monolobula megakaryocytes

 

PRIMARY MYELODYSPLASTIC SYNDROMES — Clonal chromosomal abnormalities can be detected in bone marrow cells in 40 to 70 percent of patients with primary MDS ]. This fraction is somewhat lower than the 70 to 95 percent detected in patients with AML de novo.

There are two features that distinguish the cytogenetic changes in primary MDS from those in AML de novo:

  • Although +8 (trisomy 8), -5/del(5q) [11-14], -7/del(7q) [15], and del(20q) are common in both disorders, the specific structural rearrangements (balanced translocations) that are closely associated with distinct subsets of AML de novo are almost never seen in MDS. Deletions of chromosomes 5 and 7 are particularly characteristic of therapy-related MDS induced by alkylating agents and/or radiation therapy. How these deletions might promote myeloid leukemogenesis is described elsewhere.
  • With occasional exceptions (such as the 5q- syndrome), chromosomal abnormalities in MDS have not correlated with specific clinical or morphological subsets using the FAB or WHO criteria (show table 2).

Cytogenetics as a predictor of prognosis — The ability of cytogenetic analysis to predict the outcome of any individual patient with MDS is made difficult because many patients die from persistent and profound pancytopenia, regardless of whether or not transformation to acute leukemia occurs. Despite this limitation, there are data demonstrating the prognostic significance of particular cytogenetic abnormalities for predicting survival as well as progression to AML, which occurs in 22 to 35 percent of patients overall .

  • Patients with a normal karyotype have a low likelihood of progression to AML.
  •  Among patients with an abnormal karyotype, the outcome is
    •  more favorable for those with del(5q) or del(20q) as single defects
    • intermediate with most other single abnormalities, and
    • poor with complex karyotypes (most also have abnormalities of chromosome 5 or 7, or both)
    • The outcome is also poor in patients with a single defect involving chromosome 7, particularly band 7q32

Acute promyelocitic leukaemia | t(15;17) | auer rods

Peripheral smear from a patient with acute myeloid leukemia. There are two myeloblasts, which are large cells with high nuclear-to-cytoplasmic ratio and nucleoli. Each myeloblast has a pink/red rod-like structure (Auer rod) in the cytoplasm (arrows)

Auer rods within leukemic blasts are rare but their presence serves to identify the FAB category of RAEB-T. However, with the WHO recommendation that the blast count for the diagnosis of acute myeloid leukemia (AML) should be dropped from 30 to 20 percent, it was the consensus that the RAEB-T category within MDS should be dropped . Thus, the presence of Auer rods in a patient with a prior diagnosis of MDS should lead to the suspicion that the patient has already transformed into AML.

 

15;17 translocation in APL — Acute promyelocytic leukemia (AML-M3) is typically characterized by a structural rearrangement involving the long arms of chromosomes 15 and 17; the rearrangement is defined as t(15;17)(q22;q11-12) . This rearrangement is highly specific for acute promyelocytic leukemia (APL) and has not been found in patients with any other type of leukemia or with a solid tumor.

APL is a unique clinicopathological entity characterized by infiltration of the bone marrow by promyelocytes in association with clinical or laboratory evidence of disseminated intravascular coagulation, which may worsen during the initial cytolytic response to chemotherapy. A characteristic folded, reniform (kidney-shaped), or bilobed nucleus is invariably found in some of the promyelocytes; coarse azurophilic granules and multiple Auer rods are also common .  The microgranular variant of APL differs from the more frequent hypergranular type in that the cytoplasmic granules in the leukemia cells are smaller and sometimes beneath the limit of resolution of the light microscope

The leukemic cells in patients with APL and the t(15;17) are exquisitely sensitive to the differentiating effect of ATRA. The optimal use of ATRA therapy has not yet been determined, but it has become a mandatory component of treatment. The PML/RAR-alpha gene can now be routinely identified within 24 hours by PCR methods, allowing confirmation of the diagnosis of APL and appropriate remission induction therapy (ATRA and anthracycline). Having achieved a remission, many patients remain disease-free after intensive consolidation chemotherapy using an anthracycline (daunorubicin or idarubicin). Cases of APL that lack the t(15;17) do not respond to ATRA; the PLZF/RAR-alpha fusion protein that is produced in the t(11;17) rearrangement in rare cases shows reduced sensitivity to retinoic acid that cannot be overcome by pharmacologic doses of ATRA alone.

Topic

Haematology:Lymphomas-Hodgkin's disease and the non Hodgkin lymphomas