Adult-onset myasthenia gravis (ORPHA:391490)
A rare autoimmune disorder of the neuromuscular junction characterized by fatigable muscle weakness with frequent ocular signs and/or generalized muscle weakness, and occasionally associated with thymoma.
Epidemiology
Estimated prevalence varies geographically: 1/5,000 in the USA, about 1/3,000 in the UK in adults. Adult-onset represents 85-90% of MG forms in Europe and USA. The male:female sex ratio is 1:3 in patients below 40 years of age, equal in those aged 40 to 50, and about 1.5:1 in elderly patients.
Clinical description
Patients typically present with ocular symptoms, specifically diplopia and unilateral or bilateral ptosis. About 15% of patients with ocular signs do not progress to generalized myasthenia. Within 2 to 3 years of initial manifestations, a majority of patients (about 80%) develop generalized fluctuating muscle weakness, worsening with exertion and improving with rest. Symptoms, often exacerbated at the end of the day, include fatigue, dysphagia, dysphonia, exertional dyspnea or orthopnea; in severe cases difficulty chewing, choking, and nasal regurgitation may be observed. Upper limb weakness is more common than lower limb weakness. Head drop, expressionless face, and neck pain may also be found. In severe cases, a myasthenic crisis may develop, involving acute respiratory failure requiring mechanical ventilation and nasogastric tube feeding. Myasthenic crisis occurs in about 20% of affected patients, mainly in the absence of treatment. 10-15% of patients have associated thymoma, which is malignant in most cases, and more than 50% of young patients (especially females) present a thymic follicular hyperplasia.
Etiology
The exact pathogenesis is not known, but MG is mediated by circulating antibodies to various muscle receptors, including acetylcholine receptor (AChR), muscle-specific receptor tyrosine kinase (MuSK), and low density lipoprotein receptor-related protein 4 (LRP4). The thymus is thought to trigger antibody production in the form with anti-AChR antibodies. The disorder can also be drug-induced.
Diagnostic methods
The diagnosis is suspected on the basis of fluctuating muscle weakness. A thorough history to identify this pattern is essential. Easy fatigability is a classic sign. Applying ice to the eye in patients with ptosis (ice test) leads to improvement of the condition in most patients. The diagnosis can be confirmed through specific laboratory tests for antibodies to AChR or to MuSK, present in 85% and about 6% of patients, respectively. Some patients display antibodies to LRP4. Antibody-negative cases are however found. Radiography, computed tomography (CT) or magnetic resonance imaging (MRI) are required to detect thymoma or thymic follicular hyperplasia.
Differential diagnosis
Differential diagnoses include congenital MG, Lambert-Eaton myasthenic syndrome, ALS, mitochondrial myopathy, botulism and polymyositis (see these terms).
Management and treatment
The vast majority of MG patients respond well to treatment. A wide range of drugs can be used to control the disease symptoms and to suppress autoimmune response. These include acetylcholinesterase inhibitors (patients with AChR antibodies), immunosuppressants such as oral steroids, azathioprine, mycophenolate mofetil, methotrexate, and tacrolimus. Ciclosporin and cyclophosphamide have been used, as well as rituximab in severe cases. Myasthenic crisis and rapid deterioration can be treated with intravenous immunoglobulins (IVIg) and plasmapheresis. Thymectomy is indicated for young patients with anti-AChR antibodies, and for patients with thymoma.
Prognosis
The natural course of MG is gradual improvement but rare severe cases may be life-threatening. The overall prognosis with treatment is however excellent.

                            Last update: 
                            November 2014


                            - Expert reviewer(s): 
                            Dr Sonia BERRIH-AKNIN  - Pr Bruno EYMARD