Weakness is the predominant feature of a myopathy. Its distribution and pattern is of diagnostic importance. A classification of muscle disease is given in Table 18.56. Only the more common conditions are mentioned below.
Muscle fibres are affected by:
1 Acute inflammation and fibre necrosis (e.g. polymyositis)
2 Chronic degeneration of muscle fibres (e.g. Duchenne muscular dystrophy)
3 Regeneration and fibre hypertrophy Complex immune and metabolic disorders. For example:
(a) In myasthenia gravis, there is a reduction in the number of available acetylcholine receptors at the neuromuscular junction due to antibodies to the receptor protein.
(b) In myotonias, defective chloride ion membrane conductance is associated with delayed muscle relaxation.
(c) Enzyme defects in the glycolytic pathway (e.g. myophosphorylase deficiency) result in impaired force generation
With skin lesions (dermatomyositis)
With collagen disease
Viral, bacterial and parasitic infection
Metabolic and endocrine myopathy, due to:
Calcium metabolism disorders
Myasthenic-myopathic (Eaton-Lambert) syndrome
Genetically determined myopathies
Duchenne muscular dystrophy
Limb girdle dystrophy
Specific metabolic myopathies, e.g.
Other defects of glycogen and fatty acid metabolism Mitochondrial disease (ragged red muscle fibres) Malignant hyperpyrexia
Diagnosis is possible on clinical grounds alone in some myopathies. The distribution of weakness and the consistency of the muscles should be noted. Serum muscle enzymes
Serum creatine phosphokinase (and aldolase) is greatly elevated in many dystrophies (e.g. Duchenne muscular dystrophy) and in inflammatory disorders of muscle (e.g. polymyositis). These enzymes are normal in myasthenia, and are usually normal in myotonias and chronic partialdenervation.
When a muscle is weak the normal interference pattern is reduced. An electromyogram is useful to distinguish between primary muscle disease and denervation (e.g. MND). The principal abnormalities are:
MYOPATHY. Short duration ‘spiky’ polyphasic muscle action potentials are seen. Spontaneous fibrillation is occasionally recorded.
DENERVATION. Fibrillation potentials of about 1 ms in duration and 50-200 I.N. in amplitude are seen, and are evidence of reinnervation.
OTHER CHANGES. Myotonic discharges (in myotonias) consist of high-frequency activity that varies repeatedly to cause a characteristic sound on the loudspeaker. In myasthenia gravis a characteristic decrement in the evoked muscle action potential follows stimulation of the motor nerve. The reverse is seen (an increment in repetitive response) in the rare myasthenic-myopathic syndrome (Eaton-Lambert syndrome), which may accompany carcinoma of the bronchus.Muscle biopsy
Information about muscle fibre types (type 1, slow; type 2, fast), denervation, inflammation, dystrophic changes and muscle histochemistry is obtained by muscle biopsy. Electron microscopy is sometimes necessary. In chronic partial denervation, ‘fibre type grouping’, i.e. groups of atrophic fibres of the same fibre type, is seen. Hypertrophic fibres also occur. In acute denervation, small angulated fibres are seen scattered randomly between normal fibres. In dystrophies and myositis, the muscle fibres are diffusely abnormal, the nuclei become central, and invasion by inflammatory cells and/ornecrosis occurs. Considerable experience is required to assess these changes accurately.
This group of disorders is characterized by non-suppurative inflammation of skeletal muscle. The muscles are weak and usually painful. In many cases there are skin changes (dermatomyositis, see p.404) or other connective tissue diseases.
‘Polymyositis alone’ is a rare disease, most common in the fourth and fifth decades. Symptoms are of difficulty in rising from a chair, climbing stairs or lifting. Weakness is typically proximal. The weak muscles ache and are sometimes tender and indurated.
As the disease progresses there may be widespread weakness and wasting, with dysphagia, respiratory muscle weakness and cardiac involvement.
Preliminary investigations show a raised ESR and a mild normochromic normocytic anaemia. ANF is sometimes positive. The serum creatine phosphokinase is usually (but not always) elevated.
The electromyogram shows myopathic changes. Occasionally fibrillation potentials occur and may cause diagnostic difficulty.
Muscle biopsy shows inflammatory changes with infiltration of the muscle by mononuclear cells.
Muscular dystrophies rarely progress as rapidly as polymyositis and there is no muscle pain. Pseudohypertrophy does not occur in polymyositis and there is no family history.
MND is always eventually accompanied by upper motor neurone signs, and prominent fasciculation is common.
Corticosteroids and/or azathioprine or cyclophosphamide reduce the symptoms in about 75% of cases. Only rarely does the disease progress to cause grave disability or death from respiratory failure or cardiac involvement. Other inflammatory myopathies Muscle pain and weakness occur in trichinosis due to the ingestion of pork infected with Trichinella spiralis. Acute myositis also occurs with Coxsackievirus infections(see p. 51) and in several other infections. Tropical pyomyositis of Central Africa is suppurative inflammation of muscle caused by staphylococci and other organisms.
An inflammatory myopathy may occur in sarcoidosis.
METABOLIC AND ENDOCRINE
Corticosteroids and Cushing’s syndrome Proximal muscle weakness occurs with prolonged highdose steroid therapy (particularly with 9a-fluorinated steroids such as dexamethasone and triamcinolone) and in Cushing’s syndrome. Selective type-2 fibre atrophy is seen on muscle biopsy. Thyroid disease (see p. 800) Several muscle diseases may occur:
THYROTOXICOSIs is sometimes accompanied by a severe proximal myopathy. There is also an association between thyrotoxicosis and myasthenia gravis, and between thyrotoxicosis and hypokalaemic periodic paralysis. Both associations are seen more frequently in South East Asia.
IN OPHTHALMIC GRAVES’ DISEASE, there is swelling and lymphocytic infiltration of the extraocular muscles (see p. 807).
HYPOTHYROIDISM is sometimes associated with uscle pain and stiffness, resembling myotonia. A true proximal myopathy also occurs.
Disorders of calcium metabolism Proximal myopathy may occur in osteomalacia of any cause .
Acute hypokalaemia (e.g. in diuretic therapy) causes a severe flaccid paralysis (periodic paralysis, see p. 510) that s reversed by correcting the electrolyte disturbance. Chronic mild hypokalaemia (also commonly caused by diuretics) gives rise to a mild, mainly proximal, weakness. Alcohol
Severe my pathy with muscle pain, necrosis and myoglobinuriaoccurs in acute alcoholic excess. (A similar syndrome occurs in diamorphine and amphetamine addicts.) A subacute proximal myopathy occurs with chronic alcohol abuse. Drugs Many drug-induced muscle disorders have
described . Most respond to withdrawal.
DISORDERS OF THE NEUROMUSCULAR JUNCTION
This acquired condition is characterized by weakness and fatiguability of proximal limb, ocular and bulbar muscles. The heart is not affected.
The cause is unknown. IgG antibodies to ac tylcholine receptor protein are found. Immune complexes (IgG and complement) are deposited at the postsynaptic membranes causing interference with and later destruction of the acetylcholine receptor.
Thymic hyperplasia is found in 70% of myasthenic patients below the age of 40 years. In 10% of patients a thymic tumour is found, the incidence increasing with age; antibodies to striated muscle can be demonstrated in these patients. Young patients without a thymoma havean increased association with HLA-B8, DR3.
There is an association between myasthenia gravis and thyroid disease, rheumatoid disease, pernicious anaemia and SLE. Myasthenia gravis is sometimes caused by Dpenicillamine treatment in rheumatoid disease.
The prevalence is about 4 in 100000. It is twice as common in women as in men, with a peale incidence around the age of 30 years.
Fatiguability is the single most important feature. The proximal limb muscles, the extraocular muscles, and the muscles of mastication, speech and facial expression are those commonly affected in the early stages. Respiratory difficulties may occur.
Complex extraocular palsies, ptosis and a typical fluctuating roximal weakness are found. The reflexes are initially preserved but may be fatiguable. Muscle wasting is sometimes seen late in the disease.
The clinical picture of fluctuating weakness may be diagnostic but many cases are initially diagnosed as ‘hysterical’ .
Tensilon (edrophonium) test Edrophonium (an anticholinesterase) 10 mg i.v. is injected as a bolus after a test dose of 1-2 mg. Improvement in weakness occurs within seconds and lasts for 2-3 min when the test is positive. To be certain it is wise to have an observer present and to perform a control test using an injection of saline.
Occasionally the test itself causes bronchial constriction and syncope. It should not therefore be carried out where there are no facilities for resuscitation. Serum acetylcholine receptor antibodies These are present in 90% of cases of generalized myasthenia gravis. The antibodies are found in no other condition.
There is a characteristic decrement in the evoked muscle action potential following stimulation of the motor nerve. Other tests
Preliminary tests may show a mediastinal mass on chest X-ray that can be confirmed by mediastinal CT scanning. Routine peripheral blood studies are normal (the ESR is not raised). Autoantibodies to striated muscle, intrinsic factor or thyroid may be found. Rheumatoid factor and
antinuclear antibody tests may be positive. Muscle biopsy is usually not performed but ultrastructural abnormalities can be seen.
COURSE AND MANAGEMENT
The severity of myasthenia gravis fluctuates but most cases have a protracted course. It is important to recognize respiratory impairment, dysphagia and nasal regurgitation; emergency assisted ventilation may be required in myasthenic crises.
Exacerbations are usually unpredictable but may be brought on by infections, by aminoglycosides or other drugs. Enemas (magnesium sulphate) may provoke severe weakness.
Pyridostigmine (60 mg tablet) is the most widely used drug. Its duration of action is 3-4 hours. The dose (usually 4-16 tablets daily) is determined by the patient’s esponse. This drug prolongs the action of acetylcholine by inhibiting th e action of the enzyme cholinesterase. Overdose of anticholinesterase causes severe weakness (cholinergic crisis). Colic and diarrhoea may occur with antich linesterases. Oral atropine 0.5 mg with each dose may reduce his.
Although anticholinesterases are of value in treating the weakness, they do not alter the natural history of the disease.
Thymectomy offers long-term benefit, though the reason is uncertain. It improves the prognosis, particularly in patients below 40 years with positive receptor antibodies and in those who have had the disease for less than 10 years.
Following thymectomy, some 60% of non-thymoma cases improve. If a thymoma is present, surgery is necessary to remove a potentially malignant tumour, but it is unusual for the myasthenia to improve.
Immunosuppressant drugs Corticosteroids are used when there is an incomplete response to anticholinesterases. There is improvement in70% of cases, although this may be preceded by anin itial relapse.
Azathioprine (and sometimes plasmapheresis) is co bined with prednisolone in steroid-resistant cases.