DISORDERS OF THE NEUROMUSCULAR

JUNCTION
MYASTHENIA GRAVIS
Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission
that presents clinically as fluctuating skeletal muscle weakness often affecting
particular muscle groups preferentially. It is characterized by fluctuating weakness
and easy fatigability of voluntary muscles; muscle activity cannot be maintained, and
initially powerful movements weaken readily. There is a predilection for the external
ocular muscles and certain other cranial muscles, including the masticatory, facial,
pharyngeal, and laryngeal muscles. Respiratory and limb muscles may also be
affected. The target of the autoimmune attack is the skeletal muscle acetylcholine
receptor. Weakness is due to a variable block of neuromuscular transmission related
to an immune-mediated decrease in the number of functioning acetylcholine
receptors.
Myasthenia gravis can occur at any age and is sometimes associated with thymic
tumor, thyrotoxicosis, rheumatoid arthritis, or disseminated lupus erythematosus.

CLINICAL FINDINGS
This disease usually presents between the ages 15 and 50 years, with women
affected more than men in the younger age groups and the reverse at older ages.
Although the onset of the disease is usually insidious, the disorder is sometimes
unmasked by a concurrent infection, which leads to an exacerbation of symptoms.
Exacerbations may also occur in pregnancy or before menses. Pregnancy may affect
the course of MG in an unpredictable way. Generally speaking, worsening of
symptoms most frequently occurs in the first trimester, or in the first 3 to 4 weeks
postpartum.
Symptoms may be worsened by medications that may exacerbate myasthenia gravis
which should therefore be avoided in such patients.
Patients present with ptosis, diplopia, difficulty in chewing or swallowing, nasal
speech, respiratory difficulties, or weakness of the limbs. These symptoms often
fluctuate in intensity during the day, and this diurnal variation is superimposed on
longer-term spontaneous relapses and remissions that may last for weeks.
Clinical examination confirms the weakness and fatigability of affected muscles. The
weakness does not conform to the distribution of any single nerve, root, or level of
the central nervous system. In more than 90% of cases the extraocular muscles are
involved, leading to often asymmetric ocular palsies and ptosis. Pupillary responses
are not affected. The characteristic feature of the disorder is that sustained activity of
affected muscles leads to temporarily increased weakness. Thus, sustained upgaze
for 2 minutes can lead to increased ptosis, with power in the affected muscles
improving after a brief rest.
Sensation is normal, and there are usually no reflex changes.
DIAGNOSIS
The major tools used to confirm the clinical diagnosis of a disorder of neuromuscular
transmission may be divided into three main groups: pharmacologic,
electrophysiologic, and immunologic.
The diagnosis of myasthenia gravis can generally be confirmed by the benefit that
follows administration of anticholinesterase drugs; the power of affected muscles is
influenced at a dose that has no effect on normal muscles and slight, if any, effect on
muscles weakened by other causes.
The most commonly used pharmacological test is the edrophonium (Tensilon) test.
Edrophonium is given intravenously in a dose of 10 mg, of which 2 mg is given
initially and the remaining 8 mg about 30 seconds later if the test dose is well
tolerated. In myasthenic patients, there is an obvious improvement in the strength of
weak muscles that lasts for about 5 minutes.
Alternatively, 1.5 mg of neostigmine can be given intramuscularly, with a response
that lasts for about 2 hours; atropine sulfate (0.6 mg) should be available to
counteract the muscarinic cholinergic side effects of increased salivation, diarrhea,
and nausea. Atropine does not affect nicotinic cholinergic function at the
neuromuscular junction. The longer-acting neostigmine reduces the incidence of
false-negative evaluations.
Impaired neuromuscular transmission can be detected electrophysiologically.
Electrophysiologic studies are performed to confirm a defect in neuromuscular
transmission and also to exclude other diseases of the motor unit that may contribute
to the clinical presentation.
Measuring serum acetylcholine receptor antibody levels is often helpful, since
increased values are found in 80–90% of patients with generalized myasthenia
gravis.
X-rays and CT scans of the chest may reveal a coexisting thymoma.
Because MG often coexists with other autoimmune disorders, particularly thyroid
disease, baseline testing of thyroid function should be obtained at the time of MG
diagnosis, and other autoimmune serologics should be considered if clinically
indicated.

TREATMENT
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 plate.

The primary aim of treatment of MG is induction and maintenance of clinical

remission while minimizing adverse effects of therapy.

The treatment of myasthenia gravis includes:

1. Symptomatic (Nonimmune) Treatment: Cholinesterase inhibitors
Treatment with these drugs provides symptomatic benefit without influencing the
course of the underlying disease. The mainstay of treatment is pyridostigmine, at
doses individually determined. Small doses of atropine may attenuate side effects
such as bowel hypermotility or hypersalivation. Overmedication can lead to increased
weakness, which, unlike myasthenic weakness, is unaffected or enhanced by
intravenous edrophonium. Such a cholinergic crisis may be accompanied by pallor,
sweating, nausea, vomiting, salivation, colicky abdominal pain, and miosis.

2. Immune directed therapy of MG may be divided into short-term (rapid onset)

therapies and long-term therapies.
A. Long-term immune-directed therapies.
 Corticosteroids: Corticosteroids are indicated for patients who have responded
poorly to anticholinesterase drugs. Treatment is initiated with the patient in the
hospital, as weakness may initially be exacerbated. An initial high dose of
 prednisone (60–100 mg/d orally) can gradually be tapered to a relatively low
maintenance level (5–15 mg/d) as improvement occurs. Alternate-day
treatment is helpful in reducing the incidence of side effects.
 Thymectomy: Thymectomy usually leads to symptomatic benefit or remission,
but the mechanism by which it confers benefit is unclear, and its beneficial
effect may not be evident immediately.

non-steroidal immune directed therapy.

Azathioprine: This drug can be used in patients with severe or progressive
disease despite thymectomy and treatment with anticholinesterases and
corticosteroids. It can also be given in place of high doses of corticosteroids
to patients who show no sustained benefit with low doses.

Other immunosuppressive drugs: can be used in patients with no or poor

response to Azathioprine.
Cyclosporine, cyclophosphamide, methotrexate, mycophenolate mofetil,
tacrolimus, rituximab.

B. Short-term immune-directed therapies. (immunomodulating and antibody

depleting treatment)
 Plasmapheresis: Plasmapheresis may be used to achieve temporary
improvement in patients deteriorating rapidly or in myasthenic crisis, and in
certain special circumstances, such as prior to surgery that is likely to produce
postoperative respiratory compromise and to overcome dipping in patient with
steroid therapy.
 Intravenous immunoglobulins: Intravenous immunoglobulins have also been
used to provide temporary benefit in circumstances similar to those in which
plasmapheresis is used.

3. Medications that impair neuromuscular transmission should be avoided.

Aminoglycosides (gentamicin, streptomycin), Macrolides (erythromycin,
azithromycin), Fluoroquinolones (ciprofloxacin), Calcium channel blockers, Beta-
blockers, Statin drugs, phenytoin, penicillamine, lithium.
THERAPEUTIC STRATEGY
Treatment decisions must be individualized based on MG severity and coexisting
disease, and patient participation in these decisions is essential to successful
management.
Most patients improve, usually markedly, in response to appropriate treatment.
Myasthenic symptoms should be initially managed with a cholinesterase inhibitor with
dose optimization until it is clear that either complete control of symptoms is not
possible or the required doses are intolerable. Patients with more than mild
weakness affecting oropharyngeal and respiratory muscles should be treated with a
course of Plasmapheresis or Intravenous immunoglobulins in combination with
initiation of steroid therapy to mitigate steroid induced disease worsening. Early
addition of asteroid-sparing agent azathioprine is considered for patients with
moderate or severe disease, particularly those with an incomplete response to high
dose daily prednisone. In patients with milder disease, a steroid-sparing agent may
be added after failure of prednisone tapering. In patients with disease onset prior to
age 50, thymectomy and possibly enrollment in the ongoing multinational
thymectomy trial should be considered as a long-term option for immune modulation.
If the prednisone can eventually be tapered to zero, the dose of the steroid-sparing
agent may be reduced very slowly to determine the minimum required dose.
Improvement induced by immunotherapy rarely persists if all immune-directed
treatments are completely discontinued. As patient response to therapy is variable in
MG, a ladder of treatment choices is necessary in the event that standard drugs are
either ineffective or not tolerated.

SPECIAL THERAPEUTIC SITUATIONS

MYASTHENIC CRISIS.
The classic definition of myasthenic crisis is weakness from MG that is severe
enough to necessitate intubation for ventilator support or airway protection. It is
estimated that one of every five patients with MG will suffer myasthenic crisis at some
point during their illness. All patients with severe MG exacerbations, producing
prominent oropharyngeal and respiratory muscle symptoms, should be managed in
an intensive care setting with frequent and close monitoring.
Indications for intubation generally include evidence of respiratory muscle fatigue
with increasing tachypnea and declining tidal volumes, hypoxemia, hypercapnia, and
difficulty with secretions. In general patients with a forced vital capacity of below 1L
will require mechanical ventilatory support.
A precipitating factor can be identified in most cases of myasthenic crisis and most
commonly include one or more of the following: bronchopulmonary infections,
aspiration, surgical procedures including thymectomy, corticosteroid-induced
worsening, rapid tapering of immune modulators, and exposure to drugs that may
increase myasthenic weakness. Excessive dosing of cholinesterase inhibitors can
potentially increase weakness due to depolarization blockade. In addition to
weakness, signs of cholinergic hyperactivity will be present, such as excessive
salivation, increased bronchial secretions, muscle fasciculations, and abdominal
cramping. It is recommended practice to discontinue the use of cholinesterase
inhibitors following intubations reduce these symptoms, as they may complicate the
management of airway secretions. Because of its rapid onset of action,
plasmapheresis is the favored treatment for myasthenic crisis. Similar efficacy of
Intravenous immunoglobulins compared with plasmapheresis.
Weaning trials should begin after patients demonstrate a clear trend of improved
respiratory muscle strength (usually at a vital capacity greater than15 mL/kg). The
trial should be terminated if the patient exhibits any sign of respiratory fatigue
(tachypnea, tachycardia, diaphoresis, or agitation).

OCULAR MYASTHENIA GRAVIS.

Ocular MG is the designation given to patients who have signs and symptoms solely
in the ocular muscles (eyelid elevators and extraocular muscles). Ptosis and/or
diplopia are the initial symptoms of MG in up to 85% of patients, and almost all
patients have both symptoms within 2 years of disease onset. If weakness remains
limited to the ocular muscles after 2 years, there is a 90% likelihood that the disease
will not generalize. If ocular symptoms are adequately controlled with cholinesterase
inhibitors, these patients may be reassured that immunosuppressive medications and
thymectomy may be avoided.
Treatment of ocular MG requires an accurate assessment of the patient's functional
impairment and its effects on daily life. While cholinesterase inhibitors may control
symptoms adequately in some patients, the benefit is often partial and not long-lived,
and prednisone is often quite effective. Prednisone treatment may delay or reduce
the frequency of progression of ocular MG to generalized disease.
PROGNOSIS
Early in the course of MG, symptoms may fluctuate and remissions lasting months or
longer are not uncommon, although rarely permanent. Maximum disease severity is
reached within 2 years of disease onset in two-thirds of patients. In most patients, the
active stage of disease, characterized by relapses and remission, may last 7 to 8
years. This is followed by a relatively inactive stage lasting approximately 10 years
and a final stage of ‘‘burned out’’ disease. It is important to recognize that during the
‘‘inactive’’stage, disease exacerbations may still be precipitated by intercurrent
illness, exposure to drugs that adversely effect neuromuscular transmission, or
pregnancy.
MG can now be treated effectively in most patients with minimal long-term morbidity.
The amount of fixed weakness experienced in the ultimate stage of disease may be
dependent on the effectiveness of immunotherapy during the active stage. Recent
advances in intensive care and immunotherapy have contributed to a very favorable
prognosis for MG in most patients.
The disease may have a fatal outcome because of respiratory complications such as
aspiration pneumonia.

Treatment Recommendations

1st Line Mestinon

Pyridostigmine
Prednisone
Thymectomy

2nd Line
Azathioprine
Cyclosporine
IVIg

3rd Line
Mycophenolate Mofetil
Plasmapheresis

4th Line
Methotrexate
Rituximab

5th Line
Tacrolimus
Cyclophosphamide