DISORDERS OF THE NEUROMUSCULAR JUNCTION AND MUSCLE

NEUROMUSCULAR JUNCTION

1 MYASTHENIA GRAVIS

1.1 Epidemiology.

Seen twice as frequently in women; there is a peak incidence in the 2nd and 3rd decades and a second in the 6th and 7th.

1.2 Pathophysiology and Aetiology

The disease is idiopathic but there are HLA associations and other auto- immune diseases, notably thyrotoxicosis, are associated. The disorder is a result of antibodies to the acetylcholine receptor. This is the nicotinic type of acetylcholine receptor, found in striated muscle. The antibodies are associated with:

i) Hyperplasia of the thymus gland
ii) Neoplasms of the thymus gland (thymoma)

The antibodies bind the to the receptors and also cause destruction of the endplate region by inducing a complement cascade.

1.3 Symptoms:

Characteristically there is a fluctuating weakness of voluntary muscles, particularly affecting the cranial nerves. Thus common symptoms are double vision, dysphagia and ptosis. Since the proximal muscles, in particular, are affected there is often difficulty with combing hair, getting up from a chair etc. The onset is usually subacute, but acute onset(with respiratory failure) does occur. Note that only striated muscle is affected and that therefore myasthenia does not involve the pupils or sphincters.

Common presentations include

i) involvement of facial and bulbar muscles and proximal weakness;
ii) diplopia and ptosis alone(ocular myasthenia);
iii) complaints of fluctuating weakness, particularly of proximal muscles;
iv) patients may present in respiratory failure, particularly if there has been an associated infection or physical stress.

Note that it is uncommon for a patient who is suspected of having myasthenia and complains of weakness to have normal strength on physical examination. Also, note that fatigueability is a non-specific symptom and may be found in a wide range of nerve and muscle diseases.

1.4 Signs:

Signs are of motor weakness: ptosis, ocular palsies, gaze palsies, facial and jaw weakness, bulbar palsy.Myasthenia classically has fatigueability of muscle strength: eg on repeated muscle contraction strength becomes less and less. This is best examined in the most affected muscles: if there is ocular weakness, ask the patient to look upwards and observe to see if ptosis develops; if there is proximal weakness test repeated shoulder abduction. Note that reflexes are normal, there is no muscle wasting or fasciculations and sensory examination is normal.

1.5 Tests:

The diagnosis is often clinically obvious in which case tests merely confirm what is already known. What is more difficult is in doubtful cases (diplopia without obvious ocular palsies or complaints of slight weakness with nothing to find on examination) when a definitive test is required to establish or reject the diagnosis.

i) Tensilon Test (Edrophonium): This is an anticholinesterase inhibitor which therefore raises levels of acetylcholine in the synaptic cleft. Administered intravenously: Test-dose of 1 mg followed by further 9 mg: there are muscarinic side effects (tears, abdominal cramps and nausea). Beware of bradycardia: atropine is a muscarinic blocker and will counteract this effect. Test works best if there is weakness which you can actually see improving in front of you after Tensilon: eg ocular palsies or facial weakness; testing strength is more unreliable, since the injection may act as a placebo.
ii) Anti-acetylcholine receptor antibodies: the most sensitive test
iii) Electrophysiology: repetitive stimulation:this is the electrical equivalent of testing for fatigueability: repeated shocks are given and if myasthenia is present, there may be a decline in the amplitude of the muscle response.
iv) CT scan of the thorax: may show a thymoma.

1.6 Treatment.

Mestinon (Pyridostigmine): dose is often limited by side effects, such as diarrhoea. Excessive doses may result in a cholinergic crisis. Usual dose is 30-120mg five or six times a day.

Steroids (Prednisone): required if pyridostigmine does not relieve symptoms. This should always be started in low doses, as high doses may lead to worsening of signs. Steroids may be the only effective therapy for ocular myasthenia.

Other immunosuppressive agents (azathioprine): these are useful in themselves and because they enable lower doses of steroids to be used, thus avoiding steroid side effects. Blood counts and liver function tests need to be carried out regularly.

Thymectomy may be indicated in all patients under the age of 50 and in all patients with thymoma.

Plama exchange: alleviates symptoms for several weeks. This is used during acute exacerbations of the disease.


2. EATON-LAMBERT SYNDROME:

This is a disorder caused by antibodies to the calcium channel in the nerve terminal, resulting in decreased release of quanta of acetylcholine. There is a very strong association with neoplasms, particularly with bronchus carcinoma. Syrntoms are proximal weakness, often with autonomic features (blurred vision and dry mouth); reflexes are absent.


3. OTHER DISORDERS OF THE NEURO-MUSCULAR JUNCTION:

i) Botulinum toxin prevents release of quanta.
ii) Aminoglycosides and excess Magnesium interfere with calcium-mediated release of quanta.
iii) Black widow spider venom: causes a complete depletion of acetylcholine:there is initial spasms and then paralysis.
iv) Cobratoxins bind specifically to the acetylcholine receptor.


MUSCLE DISEASE

There are three major groups of muscle disease:

1) Acquired inflammatory.
2) Acquired metabolic/endocrine.
3) Inherited: dystrophies and enzyme defects of glycogen and lipid utilisation,

1. ACQUIRED INFLAMMATORY

1.1 Polymyositis:

A subacute or slow (rarely acute) disorder of proximal muscle weakness, more common in young females. Underlying pathophysiology is related to a disorder of cell mediated immunity. Symptoms are prominent weakness of neck flexion and extension and of the shoulder and hip girdle. Pain is often a prominent feature and dysphagia is also sometimes present.

Usually reflexes are intact and there is no muscle atrophy, but if the disease progresses mild to severe atrophy may develop and there may be reflex loss in wasted muscles.

1.2 Dermatomyositis:

This disorder is related to immune complex deposition in intramuscular blood vessels with a resultant vasculitis: a disorder of humoral (antibody mediated) immunity.

The disorder may affect children in particular. There are skin changes, notably a heliotrope (violet coloured rash around the eyes); splinter haemorrhages in the nail-folds; scaly, erythematous rash over the upper chest and extensor surfaces of the limbs and similar patches over the knuckles (Gottron's papules).

There is an association with various malignancies.

Diagnosis in polymyositis and dermatomyositis:

i) Elevated creatine kinase: usually significantly elevated.
ii) Electromyography: shows rnyopathic changes on needle examination
iii) Muscle Biopsy: there is necrosis of muscle fibers with an inflammatory infiltrate.

Treatment

The major concern is that inflammation in the muscle is followed by fibrosis and permanent muscle damage: an intensive effort must be made to prevent this happening.

High dose steroids are therefore used, usually in conjunction with other immunosuppressive agents.

1.3 Overlap Myositis:

This is a condition in which an inflammatory myositis is associated with a connective tissue disorder. It is particularly common in mixed connective tissue disorder and is also seen with SLE, Rheumatoid Arthritis, Seleroderma and Sjogrens syndrome.

1.4 Inclusion Body Myositis:

This is a chronic form of myositis seen in older people and affecting distal and proximal muscles. There are specific inclusion bodies seen on muscle biopsy.

1.5 Granulomatous Myositis:

This may occur in sarcoidosis and is then associated with a chronic progressive myopathy. Sarcoid granulomas are found on muscle biopsy.


2. ACQUIRED METABOLIC/ENDOCRINE

2.1 Hyperthyroidism may present with a proximal myopathy. CK is normal. Hypothyroidism may present with myalgia, cramps, stiffness and proximal myopathy Cushing's Syndrome and steroid induced myopathy. CK is normal.

2.2 Acromegaly

2.3 Osteomalacia: associated with renal failure and coeliac disease and other states of

2.4 Vitamin D deficiency.

2.5 Hyperparathyoidism

2.6 Drugs and Toxins: may produce an acute or subacute necrotizing myopathy. Muscle necrosis causes myoglobinuria.

The two important offending agents are alcohol and drugs which cause hypokalaemia.


3. INHERITED

3.1 Muscle Dystrophy.

These are usually disorders of slow onset with weakness and muscle wasting in specific patterns. History should pay careful attention to minor symptoms of weakness, which are often unnoticed by the patient or family, but which indicate the chronicity of the problem eg motor milestones, particular difficulty with sports at school. An accurate family history is very important. The disorders will be classified here according to pattern of inheritance, since the family history will often indicate the particular mode of inheritance.

3.1.1 X-Linked

i) Duchenne's muscular dystrophy. Although starting in utero, this disorder presents in early childhood with delayed motor milestones.

30% arise from spontaneous mutations, the remainder are inherited. Note that in X- linked conditions, half the male offspring are affected and all female children are carriers, although in Duchenne's the affected individuals die before they are able to have children.

Typically the affected boy is in a wheelchair by the age of 10 and dies by the age of 20. Clinically there is progressive proximal weakness with pseudohypertrophy of muscles due to replacement with fat and fibrous tissue. Reflexes are lost and there is cardiac involvement. One classic sign is Gower's sign: the affected patient has to "climb up" themselves in order to stand.

Investigation: CK is raised to very high levels

EMG shows myopathic changes

Muscle Biopsy shows groups of fibers undergoing segmental necrosis and phagocytosis.

ECG has tall R waves in Vl.

ii) Becker's Muscular dystrophy. This is similar to Duchenne's except it presents later (teenagers) and is only slowly progressive. (The "older brother" to Duchenne's). There is also psedohypertrophy, but unlike Duchenne's the face is not involved. Cardiac involvement is less frequent.

In both conditions there is an abnormality of the protein, dystrophin, coded for by the X chromosome. Patients may be identified by examining the amount of dystrophin present in muscle. Specific probes are also available to look for deletions in the DNA of the dystrophin gene.

3.1.2 Autosomal dominant

i) Facioscapulobumeral (FSH). The name describes the distribution of weakness and wasting. Onset is usually in the late teens or early twenties. Note that there is usually a clear family history and that every child of an affected parent has a 50% chance of getting the disease.

Profound facial weakness is an early feature of the disease and causes a transverse smile: the corners of the patients mouth do not turn up when smiling.

Scapular winging is prominent and the scapulae ride up high, becoming visible from the front.

With progression there is involvement of the pelvic girdle and pseudohypertrophy in the legs. The course is benign and most patients have a normal life expectancy.

Investigation: since the disease is of slow onset CK and EMG may both be normal.

ii) Scapulo-Peroneal. Presents with foot drop and involvement of the scapular muscles.

3.1.3 Autosomal Recessive.

This accounts for most of the sporadic cases seen.

Patients present from teen years until their thirties or later.

There is weakness of the shoulder girdle followed later by weakness of the hip girdle. converse also occurs.

Investigation: mild elevation of CK; myopathic muscle biopsy.

3.2 Disorders of membrane excitability

3.2.1 Myotonic Dystrophy.

The commonest muscular dystropy presenting in adulthood. This is characterised by myotonia: this is a delayed relaxation of voluntary muscle following contraction. The disorder is autosomal dominant and is the commonest muscle dystrophy. Patients present in adult life with particular symptoms:

Myotonic: Difficulty with releasing grip

Dystrophic: Weakness of the distal muscles of the arms and legs.

Signs: there is ptosis, facial weakness, atrophy of the sternocieidomastoid muscles, cataracts, and decreased intelligence.

Males have frontal balding and testicular atrophy.

The disease is progressive and cardiac failure may occur.

3.2.2 Myotonia Congenita.

This autosomal dominant disease presents in childhood with widespread myotonia and diffuse muscular hypertrophy, the "Infant Hercules". There is normal life expectancy.

3.3 Disorders of fuel utilisation

Vigorous excercise requires phosphocreatine and then glycogen for ATP production. Prolonged low intensity exercise relies on free fatty acids.

Thus enzymatic disoders of either carbohydrate or lipid utilisation give rise to symptoms, usually related to the level of exercise.

Symptoms are muscle cramps, stiffness and myoglobinuria, because of muscle fiber necrosis. In carbohydrate storage disorders these are seen intermittently after intense exercise; in lipid storage disorders usually after starvation or illness. Some patients may present with easy fatigueability or fixed proximal weakness.

These disorders include McArdle's disease (deficiency of glycogen phosphorylase) and other enzymes of the glycolytic pathway.

Diagnosis is by measuring lactate levels after ischaemic exercise: in disorders of carbohydrate use there will not be a significant rise in lactate. Frequently on muscle biopsy there will be evidence of carbohydrate or llipid storage.