title: Paraneoplastic syndromes of the neuromuscular junction: therapeutic options in myasthenia gravis, lambert-eaton myasthenic syndrome, and neuromyotonia.
abstract: Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS) and neuromyotonia are neuromuscular transmission disorders occurring with or without associated malignancy. Due to the common antibody-mediated pathophysiology, immunosuppression has an important role in the treatment of each of these disorders. Symptomatic treatment is more variable. Pyridostigmine is first-line treatment in generalized MG. Response seems to be better in patients with acetylcholine receptor (AChR) antibodies than in patients with antibodies against muscle-specific tyrosine kinase (MuSK). Pyridostigmine can be sufficient in mild MG, although most patients need additional immunosuppressive therapy. If so, prednisolone is efficient in the majority of the patients, with a relatively early onset of clinical effect. High drug dosage and treatment duration should be limited as much as possible because of serious corticosteroid-related side effects. As long-term treatment is needed in most patients for sustainable remission, adding non-steroid immunosuppressive drugs should be considered. Their therapeutic response is usually delayed and often takes a period of several months. In the meantime, corticosteroids are continued and doses are tapered down over a period of several months. There are no trials comparing different immunosuppressive drugs. Choice is mainly based on the clinician's familiarity with certain drugs and their side effects, combined with patients' characteristics. Most commonly used is azathioprine. Alternatively, tacrolimus, cyclosporine A, mycophenolate mofetil or rituximab can be used. The use of cyclophosphamide is limited to refractory cases, due to serious side effects. Plasma exchange and intravenous immunoglobulin induce rapid but temporary improvement, and are reserved for severe disease exacerbations because of high costs of treatment. It is recommended that computed tomography (CT) of the thorax is performed in every AChR-positive MG patient, and that patients are referred for thymectomy in case of thymoma. In patients without thymoma, thymectomy can be considered as well, especially in younger, AChR-positive patients with severe disease. However, definite proof of benefit is lacking and an international randomized trial to clarify this topic is currently ongoing. When LEMS is suspected, always search for malignancy, especially small cell lung carcinoma with continued screening up to two years. In paraneoplastic LEMS, cancer treatment usually results in clinical improvement of the myasthenic symptoms. 3,4-Diaminopyridine is first-line symptomatic treatment in LEMS. It is usually well tolerated and effective. When immunosuppressive therapy is needed, the same considerations apply to LEMS as described for MG. Peripheral nerve hyperexcitability in neuromyotonia can be treated with anticonvulsant drugs such as phenytoin, valproic acid or carbamazepine. When response in insufficient, start prednisolone in mild disease and consider the addition of azathioprine. Plasma exchange or intravenous immunoglobulin is indicated in severe neuromyotonia and in patients with neuromyotonia combined with central nervous system symptoms, a clinical picture known as Morvan's syndrome.
authors.affiliation: Department of Neurology, Haga Hospital, The Hague, the Netherlands.
authors.forename: Agnes
authors.initials: A
authors.lastname: van Sonderen
authors.forename: Paul W
authors.initials: PW
authors.lastname: Wirtz
authors.forename: Jan J G M
authors.initials: JJ
authors.lastname: Verschuuren
authors.forename: Maarten J
authors.initials: MJ
authors.lastname: Titulaer