Examination Medicine: A Guide to Physician Training (64 page)

FIGURE 12.2 
Myasthenia (face). The patient has bilateral asymmetrical ptosis and needs to use the frontalis muscle to elevate the eyelids. S R Hamilton.
Albert and Jakobiec’s principles and practice of ophthalmology 
, 3rd edn. Elsevier, 2008, with permission.

1. 
Acetylcholine receptor antibodies (anti-AChR)
– these occur in 80–90% of cases, with false-positive results being rare (but the frequency of positive tests is lower in pure ocular and inactive myasthenia gravis). The titre is not directly related to disease severity. Antistriated muscle antibody is detectable in 90% of patients with a thymoma, but is also common in elderly patients without a thymoma; muscle specific kinase antibodies (MuSK) are present in 40% of ‘seronegative’ (ACh antibody negative) patients.

2. 
Electromyogram (EMG)
– in myasthenia gravis, repetitive stimulation at low frequencies causes an asymptotic reduction (there is progressively less reduction with each shock) in muscle action potential amplitudes if that particular muscle is affected. Needle examination of affected muscles shows motor unit potential variation and, sometimes, fibrillation potentials and myopathic change. Single-fibre EMG shows increased jitter and blocking.

3. 
Thymoma investigations
– chest X-ray, thoracic CT scan or MRI.

4. 
Associated conditions
– hyperthyroidism and autoimmune diseases (check thyroid function tests, rheumatoid factor and antinuclear antibodies).

5. 
Respiratory function tests
– these patients may have severe respiratory impairment.

Treatment

The prognosis of myasthenia gravis is good: 50% of patients have a remission, although 5–10% die from respiratory failure.

SYMPTOMATIC

1. 
Anticholinesterases are the mainstay of treatment in mild cases. Pyridostigmine is the usual one prescribed. Potassium supplements and potassium-sparing diuretics (e.g. spironolactone) may give additional improvement, but are rarely used these days.

2. 
It is important to avoid drugs that interfere with neuromuscular transmission, including streptomycin, gentamicin, quinidine and procainamide.

3. 
Sudden worsening of the patient’s symptoms so as to be life-threatening (because of respiratory failure) is called a myasthenic crisis. It is often precipitated by infection, which must be treated aggressively with antibiotics (not aminoglycosides) and intensive respiratory support. Mechanical ventilation and a course of plasmapheresis may be required.

4. 
Sometimes the problem may be excessive anticholinesterase inhibitor treatment (cholinergic crisis). Temporary suspension of drug treatment and monitoring of muscle strength may be all that is required for these episodes.

DISEASE-SUPPRESSING

1. 
Steroids are indicated for generalised severe disease when anticholinesterases are inadequate. They are then needed in the long term. They may aggravate disease initially (in the first week to 10 days), so all patients should be observed closely when treatment is commenced.

2. 
Failed steroid treatment in patients with severe disease is an indication for immunosuppressive drug therapy (e.g. azathioprine, cyclosporin, mycophenolate). Azathioprine has been shown to be effective as a steroid-sparing agent and to reduce relapses and prolong remissions. It should not be used as initial management or on its own. There is less evidence for other treatment, however.

3. 
Rituximab has been tried in desperate cases. This chimeric antibody attaches to the CD20 membrane site of B lymphocytes and attracts killer T cells and antibodies
that destroy the lymphocytes which make the pathological antibodies. A course of treatment is very expensive.

4. 
Thymectomy is advisable early for many patients with generalised myasthenia gravis if they are ACh-antibody positive. The exceptions are elderly patients or those with an easily inducible remission. Thymomas occur in 10% of cases (and of these, 25% are malignant) and thymic hyperplasia occurs in 65%. Of such patients, after resection, 70% show improvement and 25% of those who improve undergo remission. Causes of failed response to thymectomy include incomplete removal, ectopic tissue and fulminant disease.

5. 
Plasmapheresis is useful in acute situations such as in myasthenic crisis, preparation for surgery or in the peripartum period. Very ill patients may need repeated treatments.

Differential diagnosis

The differential diagnosis of proximal muscle weakness is important. The ocular muscle dystrophies also need to be considered. The Lambert-Eaton syndrome is occasionally confused with myasthenia gravis. This syndrome results from presynaptic failure of release of acetylcholine, caused by small cell carcinoma of the lung (in 50% of cases) or autoimmune disease. In the Lambert-Eaton syndrome:

• 
there is proximal muscle weakness and pain, and power may increase on repeated effort; reflexes are reduced or absent

• 
the ocular and bulbar muscles are usually spared

• 
the EMG is helpful (high-frequency stimulation causes an increment, whereas low-frequency stimulation causes a decrement and muscle action potential amplitudes are low).

Symptoms may be reduced by 3,4-diaminopyridine (DAP: safe and effective) or guanidine; steroids and plasma-exchange therapy can also be effective. Some patients with small cell carcinoma of the lung have a neurological remission if the tumour is completely removed. Treatment with d-penicillamine may cause a mild reversible form of myasthenia.

Guillain-Barré syndrome

This disease is not uncommon in the examination, as patients may be in hospital for an extended period and present management difficulties. It is the most common acute polyneuropathy and can affect both sexes and all ages.

The history

1. 
Ask about the presenting symptoms of ascending motor weakness, their time course and whether they are decreasing or increasing. The patient may report difficulty breathing. Other symptoms include paraesthesiae or sensory loss (sensory neuropathy is usually minimal) and symptoms of cranial nerve palsies, particularly bulbar lesions (all cranial nerves except I, II and VIII can be affected).

2. 
Ask about a preceding respiratory or gastrointestinal infection (which occurs in up to 50% of cases 1–3 weeks beforehand –
Campylobacter
, mycoplasma, EBV and influenza). Also enquire about other precipitating events, such as surgical operation, vaccination, intercurrent malignant disease (e.g. Hodgkin’s disease), SLE and HIV infection.

3. 
Ask about previous episodes of disease (in chronic relapsing polyneuropathy).

4. 
Ask about evidence of autonomic neuropathy, such as postural hypotension, labile blood pressure, difficult to control arrhythmias and, rarely, sphincter dysfunction (see
Table 16.42
).

5. 
Ask about neuropathic pain.

6. 
Enquire about the social history, family support, etc.

The examination

1. 
Predominantly, distal muscle weakness without atrophy is present, although 25% have more proximal than distal weakness. The upper limbs may be more affected than the lower limbs. Tendon reflexes are reduced or absent concomitant with the degree of weakness. Muscle tenderness is common (one-third of cases).

2. 
Signs of autonomic neuropathy (severe postural changes in blood pressure and cardiac arrhythmias) must be looked for.

3. 
Sensory loss is usually minimal, but if present affects the posterior columns (vibration and proprioception) more than the spinothalamic tracts.

4. 
Always measure forced expiratory time.

5. 
Look for pressure sores and signs of deep venous thrombosis in bed-bound patients.

Investigations

Guillain-Barré syndrome is a clinical diagnosis. Helpful tests include the following:

1. 
immune stimulus
– identify the immune stimulus by Monospot test, cold agglutinins, tests for cytomegalovirus, HIV or
Campylobacter

2. 
cerebrospinal fluid examination
– look for a raised protein level and the relative lack of white blood cells in 90% of cases; 10% have 10–50 mononuclear cells/mL

3. 
respiratory function tests (FEV1, FVC)
– assess the progressive involvement of respiratory muscles; the patient can progress rapidly (even over hours) to respiratory failure requiring intubation and should be admitted to hospital, even if only mildly affected

4. 
nerve conduction and EMG studies
– many nerves may have to be studied to find abnormalities because this disease is patchy, but abnormalities include slowed motor conduction, conduction blocks, increased distal motor latencies, reduced sensory action potentials and increased F wave latencies. EMG evidence of denervation takes 10 days to 3 weeks to appear and may indicate axonal involvement with a worse prognosis.

Treatment

Prognosis is good – most patients make a complete recovery over time (up to a year), but 2% die (usually of respiratory complications, pulmonary emboli, cardiac arrhythmias) and 10% have a major residual deficit. If the deficit does not diminish in 3 weeks or the patient has autonomic neuropathy, a poorer prognosis is more likely.

1. 
Physiotherapy is used to prevent contractures. Respiratory support in an intensive care unit is essential if the vital capacity is less than 1 L.

2. 
Plasmapheresis or intravenous gammaglobulin shortens the time to recovery from respiratory paralysis and hastens the return of mobility. They are equally effective and combined treatment offers no additional benefit. Treatment should be begun as soon as possible. Rapid improvement is much more likely if treatment is begun within 2 weeks of the first symptoms. Relapses may occur and are more common after intravenous gammaglobulin than after plasmapheresis.

3. 
Steroids (and ACTH) are not beneficial.

Differential diagnosis

Infections such as glandular fever, acute viral hepatitis,
Mycoplasma
pneumonia,
Campylobacter jejuni
and HIV can cause Guillain-Barré syndrome. Post-influenza vaccine disease is rare. The differential diagnosis of acute ascending motor paralysis includes diphtheria, polio, polyarteritis nodosa, acute intermittent porphyria, tick or snake bites and rhabdomyolysis, arsenic poisoning and botulism. Critical illness
myopathy or polyneuropathy must not be missed. Remember that diphtheria, botulism and myasthenia gravis usually begin with bulbar symptoms.

The differential diagnosis of autonomic neuropathy includes diabetes mellitus, alcoholism, acute intermittent porphyria and amyloidosis.

Transient ischaemic attacks and ‘funny turns’

Patients presenting with a ‘funny turn’ can pose a difficult diagnostic problem as there are many possible explanations. The problem may be neurological, cardiac, endocrinological or psychiatric. A careful history and physical examination should enable the candidate to produce a sensible differential diagnosis and management plan. Treatment is usually fairly straightforward once the diagnosis is made.

The history

1. 
It may be possible from the history to establish whether cerebrovascular disease and, in particular, transient ischaemic attacks (TIAs) explain the funny turns.

a. 
TIAs occur suddenly; there is focal neurological loss that is maximal at onset and does not spread or intensify. By definition, the symptoms must resolve within 24 hours. Specific enquiry should be made about unilateral weakness or clumsiness, difficulty understanding or expressing spoken language, altered sensation unilaterally, and partial or complete loss of vision in one eye or bilateral blindness.

b. 
Faintness, confusion, simultaneous bilateral weakness, slurred speech and spinning sensations are not localising symptoms and are less suggestive of a TIA.

2. 
Neurological deficits that have lasted for longer than 24 hours are consistent with the syndrome of a completed stroke.

a. 
The absence of focal symptoms in a patient with severe headache and vomiting suggests subarachnoid haemorrhage. Vomiting and focal symptoms may occur with intracerebral haemorrhage, but headache is present in less than 50% of these patients.

b. 
In ischaemic stroke, the symptoms typically begin abruptly, often during sleep, and are not usually associated with headache or vomiting.

3. 
Presyncope refers to a sense of impending loss of consciousness, manifest as faintness or light-headedness and is often associated with sweating, nausea, anxiety and visual dimming.

a. 
Causes of this condition can include cardiac arrhythmias, postural hypotension, cough syncope and micturition syncope.

b. 
Vasovagal syncope or presyncope can often be diagnosed clinically if the history is typical: an episode begins with clamminess, sweating and nausea and often occurs in a crowded room or after something upsetting has happened.

4. 
Epilepsy needs to be considered in the differential diagnosis.

a. 
Partial epilepsy is usually accompanied by an aura or a warning (e.g. flashing lights, twitching of the face or a limb, unilateral tingling or numbness, buzzing noises or humming).

b. 
Primary generalised epilepsy begins with loss of consciousness.

c. 
Eyewitness accounts are crucial in making a diagnosis. Tongue-biting and incontinence with tonic–clonic movements suggest primary generalised epilepsy.

d. 
Remember that seizure activity may accompany cerebral hypoxia of any cause (e.g. Stokes-Adams attacks). A long period of drowsiness often follows a major seizure.