DISEASES OF THE NEUROMUSCULAR JUNCTION
This condition is characterised by progressive fatigable weakness particularly of the ocular, neck, facial and bulbar muscles.It is an autoimmune disease and may associated with other autoimmune diseases such as thyroid, pernecious anemia and vetilligo.Myasthenia gravis:
Pathophysiology :
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 reduces the number of acetylcholine receptors and damages the end plate . A minority of patients have other autoantibodies to an antigene on the post-junctional membrane, in particular autoantibodies to a muscle- specific kinase (MuSK) which is involved in the regulation and maintenance of the acetylcholine receptors.About 15% of patients (mainly those with late onset) have a thymoma(benign tumor of the thymus which may become malignant) and the majority of the remainder have thymic follicular hyperplasia. Some drugs, especially aminoglycosides and ciprofloxacin, may exacerbate the neuromuscular blockade and should be avoided in patients with Myasthenia Gravis.
Clinical features :
The disease usually presents between the ages of 15 and 50 years. Women are affected more often than men in the younger age groups while the reverse applies to older age groups. It tends to run a relapsing and remitting course, especially during the early years .The cardinal symptom is fatigable weakness of the muscles, movement is initially strong but rapidly weakens as muscle use continues. Worsening of symptoms towards the end of the day or following exercise is characteristic (diurnal variation). There are no sensory signs or signs of involvement of the CNS, although weakness of the ocular muscles may occur which is presented as 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 become weak and sudden weakness may require ventilatory support.
The prognosis is variable and sometimes remissions 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.
Investigations :
1- Tensilon test: The intravenous injection of the short-acting anticholinesterase, edrophonium bromide, is a valuable diagnostic aid ; 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.2- Nerve conductive study with repetitive nerve stimulation: may show the characteristic decremental response (gradual decrease in the amplitude.
3- Single fiber EMG :is the most sensitive test for myasthenia with special electrode to measure the EMG of a single muscle fiber.
4- Antibodies assay : Anti-acetylcholine receptor antibody 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. Anti striated muscle antibodies suggest the presence of thymoma .
5- Thoracic CT scan : to exclude thymic hyperplasia and thymoma which may not be visible on plain X-ray examination.
6- Screening for associated autoimmune disorders, particularly thyroid disease, is important .
:Treatment
1- acetylcholinesteras inhibitors :The duration of action of acetylcholine is greatly prolonged by inhibiting its catabolism byacetylcholinesterase. The most commonly used anticholinesterase drug is pyridostigmine (mestinon), which is given orally in a dosage of 30-120 mg, usually 6-hourly. Muscarinic side-effects, including diarrhoea and colic, excessive salivation.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.
2- Corticosteroid :Improvement is commonly preceded by marked exacerbation of myasthenic symptoms and treatment should be initiated in hospital It is usually necessary to continue treatment for months or years.
3- immunosuppressant drugs : Treatment with azathioprine 2.5 mg/kg daily is of value in reducing the dosage of steroids necessary and may allow steroids to be withdrawn .The effect of treatment on clinical disease is often delayed for several months.
Methotrexate ,mycophonilate mofital and rituximab are all used in myasthenia to reduce the dose of steroid and lowering its side effect .
• 4- Thymectomy : in thymic hyperplasia ,thymectomy should be considered in any antibody-positive patient under 45 years with symptoms not confined to extraocular muscles,unless the disease has been established for more than 7 years.While in case of thymoma ,thymectomy should be done in all circumstances.
5-Plasma exchange : Removing antibody from the blood may produce marked improvement but, as this is usually brief, such therapy is normally reserved for myasthenic crisis or for pre-operative preparation .
• 6-Intravenous immunoglobulin : An alternative to plasma exchange in the short-term treatment of severe myasthenia .
• Myasthenic Crises :
• It is acute exacerbation of myasthenia graves associated with sever weakness,dysphagia and shortness of breath that sometimes need mechanical ventillator.• Precipating factors :
1- chest infection.
2- rapid withdrwal of steroid and other immunomodulators.
3- surgical operation.
4- physical stress.
5- precipitating drugs:
a-macrolides:erythromycine .
b-aminoglycosides:gentamycine.c-quinolones:ciprofloxacine.
d-botilinium toxins.
e- muscle relaxants:curarines.
f-procaineamide.
g-penicillamine.
h-beta blockers.
• Treatment:
1-Patient should be admitted to the RCU and put on mechanical ventillator if the vital capacity is less than 1 L.2- stop acetylcholineesterase inhibitors because it cause excessive salivation and increase the dyspnoea.
3- start urgently either IVIg or plasma exchange .
4- increase the dose of steroid till the patient is weaned from ventillator.
5- treat the precipitating factor .Lambert Eaton Syndrome :
It is a paraneoplastic manifestation of bronchogenic carcinoma causing antibodies to voltage gated calcium channels which play a role in the secretion of the acetylcholine in the neuromuscular junction.It is also a neuromuscular junction disease causing also flactuating weakness like myasthenia but differ from it by the following:
1-autonomic feature is common so the pupil is affected while in myasthenia it is spared, conestipation ,dry mouth etc…
2-bulbar involvement is less common.
3- the weakness improved with repeatative movement unlike myasthenia in which there is worsenning of the power.
4- the reflexes is affected (hypo or areflexia).
• Investigation:
1-With repeatative nerve stimulation thre is inceament in the amplitude.2- anti voltage gated calcium channel antibodies is positive.
3- CT chest to detect the primary tumor.
• Treatment :
1- treat the underlying malignancy.2- guanidine may improve the power .
3- 3,4 diaminopyridine which is potassium channel blocker is effective treatment.Note :steroid and acetylcholineesterase inhibitors is ineffective.