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Myasthenia gravis

Overview

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction caused by antibodies that attack components of the postsynaptic membrane, impair neuromuscular transmission, and lead to weakness and fatigue of skeletal (voluntary) muscles. This can be generalised or localised to certain muscle groups, and involvement of the bulbar and respiratory muscles can be life threatening.

The exact cause of myasthenia gravis is unknown. In some cases, it is linked to tumours of the thymus.

Myasthenia gravis can affect people at any age. It is most common in young women and older men. Current estimates place the prevalence at a high value of about 20 per 100,000.

Myasthenia gravis can affect people at any age. It is most common in young women and older men. Current estimates place the prevalence at a high value of about 20 per 100,000.

Myasthenia gravis can be classified according to the type, age of onset, antibody specificity and thymus histology.

1. course type:

  • ocular (in approximately 15-20% of MG patients)
  • oropharyngeal or generalized

 2. age of onset:

  • start before puberty
  • early onset before the age of 50 years
  • late onset after the age of 50 years

 3. antibody specificity:

  • anti-AChR
  • anti-muscle-specific receptor tyrosine kinase (MuSK)
  • anti-low-density lipoprotein receptor-related protein 4 (LRP4)
  • seronegative MG

 4. pathology of the thymus

  • normal/atrophic thymus pathology
  • thymitis
  • paraneoplastic occurrence associated with thymoma

Symptoms - Myasthenia gravis

The most common symptoms are ptosis (weak, drooping eyelids), diplopia (weak eye muscles, which cause double vision) and muscle weakness after use of the affected muscle. Weakness resolves when the affected muscles are rested but recurs when they are used again.

The disease generally begins with ocular symptoms and extends to other muscles in 80% of cases. If generalized myasthenia is going to develop after ocular symptoms, it usually does so within the first 3 yr. Ocular muscles are affected initially in 40% of patients and eventually in 85%.

Hand grip may alternate between weak and normal (milkmaid’s grip). Neck muscles may become weak. Proximal limb weakness is common. Some patients present with bulbar symptoms (eg, altered voice, nasal regurgitation, choking, dysphagia). Sensation and deep tendon reflexes are normal. Manifestations fluctuate in intensity over minutes to hours to days.

Myasthenic crisis, a severe generalized quadriparesis or life-threatening respiratory muscle weakness, occurs in about 15 to 20% of patients at least once in their life. It is often due to a supervening infection that reactivates the immune system. Once respiratory insufficiency begins, respiratory failure may occur rapidly.

Causes - Myasthenia gravis

MG is caused by antibodies that attack components of the postsynaptic membrane, with acetylcholine receptor (AChR) being the most common target. The other targets include the muscle-specific kinase (MuSK) or lipoprotein-related protein 4 (LRP4).

Only about 10 to 20% of patients with generalized myasthenia have no antibodies to acetylcholine receptors in serum; up to 50% of these AChR antibody‒negative patients have antibodies to muscle-specific receptor tyrosine kinase (MuSK), a surface membrane enzyme that helps AChR molecules aggregate during development of the neuromuscular junction. However, anti-MuSK antibodies do not occur in most patients with AChR antibodies or with isolated ocular myasthenia.

There are several clinically important differences between the anti-MuSK antibody-positive MG and the anti-AChR antibody-positive type: only rarely is muscular weakness limited to the eye muscles, which are affected predominately in the majority of patients with anti-AChR antibody-positive MG. However, it is not possible to differentiate both types based only on clinical presentation. Anti-MuSK-positive MG occurs predominately in middle-aged women. Patients with anti-MuSK antibodies may have atypical presentations characterized by prominent oropharyngeal, facial, neck and respiratory muscle weakness. Facial and tongue atrophy may be present by clinical examination and by magnetic resonance imaging (MRI). The risk of myasthenic crisis is particularly high, and the chances of achieving complete stable remission are significantly lower than in anti-AChR MG.

Prevention - Myasthenia gravis

Currently, there is no known method of preventing myasthenia gravis. However, people who develop the disorder can take steps to prevent complications or exacerbations of their conditions.

Diagnosis - Myasthenia gravis

1.     Bedside testing

The traditional anticholinesterase test, done at bedside and using the short-acting (< 5 min) drug edrophonium, is positive in most patients who have myasthenia with overt weakness. However, this test should only be done in patients with obvious ptosis or ophthalmoparesis; these deficits must be present to be able to clearly see improvement to normal strength and thus provide unequivocal objective evidence of a positive test result. For the test, patients are asked to exercise the affected muscle until fatigue occurs (eg, to hold the eyes open until ptosis occurs); then, edrophonium 2 mg IV is given. If no adverse reaction (eg, bradycardia, atrioventricular block) occurs within 30 sec, another 8 mg is given. Rapid (< 2 min) recovery of muscle function is a positive result. However, this test is not ideal for the following reasons:

  • A positive result is not definitive for myasthenia gravis because such improvement may occur in other neuromuscular disorders.
  • Results may be equivocal, particularly if the test is done in patients without obvious ptosis or ophthalmoparesis.
  • During the test, weakness due to cholinergic crisis may worsen; thus, resuscitation equipment and atropine (as an antidote) must be available during the test.

Because weakness due to myasthenia lessens in cooler temperature, patients with ptosis can be tested using the ice pack test. For this test, an icepack is applied to a patient's closed eyes for 2 min, then removed. A positive result is full or partial resolution of ptosis. The ice pack test usually does not work if patients have ophthalmoparesis.

Patients with opthalmoparesis can be tested using the rest test. For this test, patients are asked to lie quietly in a dark room for 5 min with their eyes closed. If ophthalmoparesis resolves after this rest, the result is positive.

2.     Antibody testing and electromyography

Even if a bedside test is unequivocally positive, one or both of the following are required to confirm the diagnosis:

  • Serum AChR antibody levels
  • Electromyography (EMG)

AChR antibodies are present in 80 to 90% of patients with generalized myasthenia but in only 50% with the ocular form. Antibody levels do not correlate with disease severity. Up to 50% of patients without AChR antibodies test positive for anti-MuSK antibodies.

EMG using repetitive stimuli (2 to 3/sec) shows a > 10% decrease in amplitude of the compound muscle action potential response in 60% of patients. Single-fiber EMG can detect abnormal neuromuscular transmission in > 95%.

3.     Further testing

After confirmation of the diagnosis it is essential to identify comorbidities associated frequently with MG. Due to the possibility of a paraneoplastic aetiology, the search for a thymoma is mandatory. CT or MRI of the thorax should be done. Thymoma-associated MG is generally associated with anti-AChR antibodies and not with anti-MuSK antibodies.

Other tests should be done to screen for autoimmune disorders frequently associated with myasthenia gravis (eg, pernicious anemia, autoimmune hyperthyroidism, RA, SLE).

Patients in myasthenic crisis should be evaluated for an infectious trigger. Bedside pulmonary function tests (eg, forced vital capacity) help detect impending respiratory failure.

Prognosis - Myasthenia gravis

Many myasthenic patients require life-long immunosuppressive therapy. However, using the spectrum of treatment options available nowadays, the majority of them can have largely normal lives. Even complete stable remission can be achieved in nearly every fourth patient suffering from anti-AChR or double-negative MG, respectively. Unfortunately, treatment response is much less favourable in anti-MuSK MG, with a significantly increased risk of myasthenic crisis.

Treatment - Myasthenia gravis

Symptomatic treatment with acetylcholine esterase inhibition is usually combined with immunosuppression. Azathioprine still remains the first choice for long-term immunosuppressive therapy. Alternative immunosuppressive options to azathioprine include cyclosporin, cyclophosphamide, methotrexate, mycophenolate mofetil and tacrolimus. Rituximab is a promising new drug for severe generalized MG.

 The current standard treatment of MG is hardly proven by controlled studies. It is largely based on serendipity and retrospective studies. Well-designed clinical trials comparing currently available therapeutic options are lacking. The choice of treatment modalities seems to rely mainly on institutional preferences and the personal experiences of the respective neurologist. However, conducting controlled trials on the therapy of rare and heterogeneous diseases, such as MG, is extremely difficult or even impossible.

1.     Symptomatic treatment

Anticholinesterase drugs are the mainstay of symptomatic treatment but do not alter the underlying disease process. The aim is to improve the neuromuscular transmission. They rarely relieve all symptoms, and myasthenia may become refractory to these drugs.

Pyridostigmine is begun at 60 mg po q 3 to 4 h and titrated up to a maximum of 120 mg/dose based on symptoms. When parenteral therapy is necessary (eg, because of dysphagia), neostigmine (1 mg = 60 mg of pyridostigmine) may be substituted.

Acetylcholinesterase inhibitors are often poorly tolerated due to abdominal cramps and diarrhea, which are treated with oral atropine 0.4 to 0.6 mg (given with pyridostigmine or neostigmine) or propantheline 15 mg tid to qid.

Patients who have been responding well to treatment and then deteriorate require respiratory support because they may have cholinergic crisis, and anticholinesterase drugs must be stopped for several days.

2.     Immunomodulating treatment

Immunosuppressants interrupt the autoimmune reaction and slow the disease course, but they do not relieve symptoms rapidly. After being given IVIG 400 mg/kg once/day for 5 days, 70% of patients improve in 1 to 2 wk. Effects may last 1 to 2 mo. Plasma exchange (eg, 5 exchanges of 3 to 5 L plasma over 7 to 14 days) can have similar effects.

Corticosteroids are necessary as maintenance therapy for many patients but have little immediate effect in myasthenic crisis. Over half of patients worsen acutely after starting high-dose corticosteroids. Initially, prednisone 10 mg po once/day is given; dose is increased by 10 mg weekly up to 60 mg, which is given for about 2 mo, then tapered slowly. Improvement may take several months; then, the dose should be reduced to the minimum necessary to control symptoms.

Azathioprine 2.5 to 3.5 mg/kg po once/day may be as effective as corticosteroids, although significant benefit may not occur for many months. Cyclosporine 2 to 2.5 mg/kg po bid may allow the corticosteroid dose to be reduced. These drugs require the usual precautions.

Other drugs that may be beneficial include methotrexate, cyclophosphamide, and mycophenolate mofetil. For patients with refractory disease, monoclonal antibodies (eg, rituximab, eculizumab) may be beneficial but are costly.

Administration of the anti-CD20 antibody rituximab often results in a long-lasting, outstandingly good therapeutic effect. However, controlled prospective study-collected data on the use of rituximab in MG are not yet available.

3.     Treatment of acute exacerbations

Apheresis (plasma exchange) or IVIG (intravenous immunoglobulins) is useful for myasthenic crisis and, for patients unresponsive to drugs, before thymectomy.

4.     Thymectomy

Thymectomy may be indicated for patients with generalized myasthenia if they are < 80 yr; it should be done in all patients with a thymoma. Subsequently, in 80%, remission occurs or the maintenance drug dose can be lowered.

Resources - Myasthenia gravis

[1] https://medlineplus.gov/ency/article/000712.htm

[2] Phillips WD, Vincent A – Pathogenesis of myasthenia gravis: update on disease types, models and mechanisms. Published online 2016 Jun 27. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926737/

[3] http://www.merckmanuals.com/professional/neurologic-disorders/peripheral-nervous-system-and-motor-unit-disorders/myasthenia-gravis

[4] Gilhus NE, Verschuuren JJ – Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol. 2015 Oct;14(10):1023-36. doi: 10.1016/S1474-4422(15)00145-3.

[5] Berrih-Aknin S, Frenkian-Cuvelier M, Eymard B – Diagnostic and clinical classification of autoimmune myasthenia gravis. J Autoimmun. 2014 Feb-Mar;48-49:143-8. doi: 10.1016/j.jaut.2014.01.003. Epub 2014 Feb 13.

[6] Sieb JP – Myasthenia gravis: an update for the clinician. Clin Exp Immunol. 2014 Mar;175(3):408-18. doi: 10.1111/cei.12217.

[7] Phillips LH 2nd – The epidemiology of myasthenia gravis. Ann N Y Acad Sci. 2003 Sep;998:407-12.

[8] https://www.sharecare.com/health/immune-lymphatic-system-health/can-myasthenia-gravis-be-prevented

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