Transcript diseases of the neuromuscular junction

DISEASES OF THE NEUROMUSCULAR JUNCTION
Myasthenia gravis:
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.
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 musclespecific 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 :
12345-
chest infection.
rapid withdrwal of steroid and other immunomodulators.
surgical operation.
physical stress.
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.