DISORDERS OF THE NEUROMUSCULAR JUNCTION

MYASTHENIA GRAVIS.

• This condition is characterised by progressive fatigable weakness, particularly of the ocular, neck, facial and bulbar muscles

Aetiology and pathology

•The disease is most commonly caused by autoantibodies to acetylcholine receptors in the post-junctional membrane of the neuromuscular junction. These antibodies block neuromuscular transmission and initiate a complement-mediated inflammatory response which reduces the number of acetylcholine receptors and damages the end plate

•A minority of patients have other autoantibodies to epitopes on the post-junctional membrane, in particular autoantibodies to a muscle-specific kinase (MuSK), an agrin receptor which is involved in the regulation and maintenance of the acetylcholine receptors.

•About 15% of patients (mainly those with late onset) have a thymoma, and the majority of the remainder have thymic follicular hyperplasia. There is an increased incidence of other autoimmune diseases, and the disease

is linked with certain HLA haplotypes .

•Nothing is known about factors which trigger the disease itself, but penicillamine can cause an antibody-mediated myasthenic syndrome which may persist even after drug withdrawal. Some drugs, especially aminoglycosides and ciprofloxacin, may exacerbate the neuromuscular blockade and should be avoided in patients with myasthenia

Clinical features

•The disease usually presents between the ages of 15 and 50 years, with women affected more often than men in the younger age groups and the reverse at older ages. It tends to run a relapsing and remitting course, especially during the early years

•The cardinal symptom is abnormal fatigable weakness of the muscles (which is different from a sensation of muscle fatigue); movement is initially strong but rapidly weakens. Worsening of symptoms towards the end of the day or following exercise is

characteristic .

•There are no sensory signs or signs of involvement of the central nervous system, although weakness of the oculomotor muscles may mimic a central eye movement disorder.

•The first symptoms are usually intermittent ptosis or diplopia, but weakness of chewing, swallowing, speaking or limb movement also occurs. Any limb muscle may be affected, most commonly those of the shoulder girdle; the patient is unable to undertake tasks above shoulder level, such as combing the hair,

without frequent rests .

•Respiratory muscles may be involved, and respiratory failure is a not uncommon cause of death. Aspiration may occur if the cough is ineffectual. Sudden weakness from a cholinergic or myasthenic crisis) may require ventilatory support

Investigations

•The intravenous injection of the short-acting anticholinesterase, edrophonium bromide, is a valuable diagnostic aid (the Tensilon test); 2 mg is injected initially, with a further 8 mg given half a minute later if there are no undesirable side-effects. Improvement in muscle power occurs within 30 seconds and usually persists for 2-3 minutes. EMG with repetitive stimulation may

show the characteristic decremental response .

•Anti-acetylcholine receptor antibody (AChRA) is found in over 80% of cases, though less frequently in purely ocular myasthenia (50%). Anti-MuSK antibodies are found especially in AChRA-negative patients with prominent

bulbar involvement .

•Positive anti-skeletal muscle antibodies suggest the presence of thymoma, but all patients should have a thoracic CT to exclude this condition, which may not be visible on plain X-ray examination. Screening for other autoimmune disorders, particularly thyroid disease, is important

Management

•The principles of treatment are:•1 -to maximise the activity of acetylcholine at remaining

receptors in the neuromuscular junctions •2-to limit or abolish the immunological attack on motor end

plates .•The duration of action of acetylcholine is greatly prolonged by

inhibiting its hydrolysing enzyme, acetylcholinesterase. The most commonly used anticholinesterase drug is pyridostigmine, which is given orally in a dosage of 30-120 mg, usually 6-hourly. Muscarinic side-effects, including diarrhoea and colic,

may be controlled by propantheline (15 mg as required) .•.

•Over-dosage of anticholinesterase drugs may cause a cholinergic crisis due to depolarisation block of motor end plates, with muscle fasciculation, paralysis, pallor, sweating, excessive salivation and small pupils. This may be distinguished from severe weakness due to exacerbation of myasthenia (myasthenic crisis) by the clinical features and, if necessary, by the injection of a small dose of edrophonium

Prognosis

•Prognosis is variable.• Remissions sometimes occur spontaneously.

When myasthenia is confined to the eye muscles, the prognosis is excellent and disability slight. Young female patients with generalised disease have high remission rates after thymectomy, whilst older patients are less likely to have a remission despite treatment. Rapid progression of the disease more than 5 years after its onset is uncommon

OTHER MYASTHENIC SYNDROMES

• .The most common of these is the Lambert-Eaton myasthenic syndrome (LEMS), in which transmitter release is impaired, often in association with antibodies to pre-junctional voltage-gated calcium channels

• Patients may have autonomic dysfunction (and a dry mouth) in addition to muscle weakness, but the cardinal clinical sign is absence of tendon reflexes, which can return immediately after sustained contraction of the

relevant muscle .•.

•The condition is associated with underlying malignancy in a high percentage of cases, and investigation must be directed towards

detecting such a cause .•The condition is diagnosed

electrophysiologically by the presence of post-tetanic potentiation of motor response to nerve stimulation at a frequency of 20-50/s.

• Treatment is with 3,4-diaminopyridine

DISEASES OF MUSCLE

•Voluntary muscle is subject to a range of hereditary and acquired disorders affecting either its structure, or the biochemical processes which convert the chemical energy derived from cell metabolism into mechanical energy in a controlled manner. These disorders present in a limited number of ways, most commonly a symmetrical weakness of the large, power-generating proximal muscles (proximal

myopathy)..

•This weakness may be fixed or periodic. Other symptoms and signs of muscle disease include myotonia (an abnormality of muscle relaxation) and muscle pain. Diagnosis depends upon consideration of the clinical picture along with the results of EMG studies and muscle biopsy. In some inherited muscular diseases, diagnosis can be made by identifying the presence of a specific genetic abnormality.

Muscular Dystrophies

•Muscular dystrophies are inherited myopathies characterized by progressive muscle weakness and degeneration and subsequent replacement by fibrous and fatty connective tissue. Historically, muscular dystrophies were categorized by their distribution of weakness, age at onset, and

inheritance pattern .

Myotonic dystrophy

•is an autosomal dominant multisystem disorder that affects skeletal, cardiac, and smooth muscle and other organs, including the eyes, the endocrine system, and the brain. This is the most prevalent muscular dystrophy, with an incidence of 13.5 per 100,000 live births. Myotonic dystrophy can occur at any age, with the usual onset of symptoms in the late second or third decade

•Typical patients exhibit facial weakness with temporalis muscle wasting, frontal balding, ptosis, and neck flexor weakness. Extremity weakness usually begins distally and progresses slowly to affect the proximal limb-girdle muscles. Percussion myotonia can be elicited on examination in most cases, especially in thenar and wrist extensor muscles.

•.

• Associated manifestations include cataracts, testicular atrophy and impotence, intellectual impairment, and hypersomnia associated with both central and obstructive sleep apnea. Respiratory muscle weakness may be severe, with impairment of ventilatory drive. Cardiac conduction defects are common and can produce sudden death. Pacemakers may be necessary, and annual electrocardiograms are recommended. Chronic hypoxia can lead to cor pulmonale

Duchenne dystrophy

•is present at birth, but the disorder usually becomes apparent between ages 3 and 5. The boys fall frequently and have difficulty keeping up with friends when playing. Running, jumping, and hopping are invariably abnormal. By age 5, muscle weakness is obvious by muscle testing. On getting up from the floor, the patient uses his hands to climb up himself [Gowers' maneuver

•Serum CK levels are invariably elevated to between 20 and 100 times normal. The levels are abnormal at birth but decline late in the disease because of inactivity and loss of muscle mass. EMG demonstrates features typical of myopathy. The muscle biopsy shows muscle fibers of varying size as well as small groups of necrotic and regenerating fibers. Connective tissue and fat replace lost muscle fibers. A definitive diagnosis of Duchenne dystrophy can be established on the basis of dystrophin deficiency in a biopsy of muscle tissue or mutation analysis on peripheral blood leukocytes

•Glucocorticoids, administered as prednisone in a dose of 0.75 mg/kg per day, significantly slow progression of Duchenne dystrophy for up to 3 years. Some patients cannot tolerate

glucocorticoid therapy; weight gain and increased risk of fractures in particular represent a significant deterrent for

some boys. As in other recessively inherited dystrophies presumed to arise from loss of function of a critical muscle

gene, there is optimism that Duchenne disease may benefit from novel therapies that either replace the defective gene or

missing protein or implement downstream corrections (e.g., skipping mutated exons or reading through mutations that

introduce stop codons).

•Becker Muscular Dystrophy•This less severe form of X-linked recessive

muscular dystrophy results from allelic defects of the same gene responsible for Duchenne dystrophy. Becker muscular dystrophy is ~10 times less frequent than Duchenne, with an incidence of about 3 per 100,000 live-born males.

•Most patients with Becker dystrophy first experience difficulties between ages 5 and 15 years, although onset in the third or fourth decade or even later can occur. By definition, patients with Becker

dystrophy walk beyond age 15, while patients with Duchenne dystrophy are typically in a wheelchair by the age of 12. Patients with Becker dystrophy have a reduced life expectancy, but most

survive into the fourth or fifth decade.•Mental retardation may occur in Becker dystrophy, but it is not as

common as in Duchenne. Cardiac involvement occurs in Becker dystrophy and may result in heart failure; some patients manifest

with only heart failure. Other less common presentations are asymptomatic hyper-CK-emia, myalgias without weakness, and

myoglobinuria.