Myasthenia gravis (MG) is a neurological condition characterised by a fatiguing weakness of certain muscle groups, particularly those that control eye opening, eye movements, speech and swallowing When severe the proximal muscles of the limbs and respiratory muscles may be involved. Acquired myasthenia is an autoimmune disease, where antibodies are directed against the post synaptic nicotinic acetyl choline receptors (AChR) of neuromuscular junctions or against other proteins that affect AChR function.
Diagnosis and appropriate management of MG is particularly important because at any time it can transform suddenly from a relatively benign condition of ptosis and diplopia to a crisis with potentially fatal bulbar dysfunction and respiratory failure. These latter symptoms may in turn reverse with prompt emergency supportive care and immunomodulatory treatment.
The discussed review in Lancet Neurology by Gilhus & Vershuuren seeks to provide an insight into the usefulness of the latest antibody assays in predicting in individual patients the clinical course of MG and response to therapy. Evidence was gathered from the literature on the basis of appropriate searches on Medline and the Cochrane library for English language publications from 1995 to 2015.
The review first describes the pathophysiology of the different associated antibodies. AChR antibodies cross link receptors, accelerating their breakdown. Muscle specific kinase (MUSK) and lipoprotein related protein 4 (LRP4) exist as a complex on the post-synaptic membrane. When activated by agrin protein, this complex affects the aggregation of AchR and the morphology of the terminal. Antibodies to MUSK, LRP4 and agrin influence this process and are therefore are likely to be directly pathogenic. Titin and ryanodine receptor antibodies occur in some patients with thymoma related MG, but may be markers of severe disease rather than directly pathogenic.
Comorbidities may be present in MG, and awareness of these is important. Younger onset patients may have other organ specific autoimmune disease , including polymyositis. Thymoma associated MG is associated with increased risk of haematological malignancies and with a severe autoimmune cardiomyopathy.
Classical subtypes include:
- Early onset MG with ACh antibodies. This often has ocular involvement and has a female preponderance. Thymic hyperplasia may be present and in these cases the condition responds to thymectomy.
- Late onset MG with AChR antibodies. This is also often ocular, but there is only rarely thymic hyperplasia.
- Thymoma-associated MG. These patients usually have generalised disease and AChR antibodies. There are also other paraneoplastic associations, such as pure red cell aplasia and neuromyotonia.
- MUSK associated MG. These antibodies are present in 1-4% of MG cases. The condition is usually bulbar or generalised rather than ocular and there is no thymic involvement.
- LRP4 associated MG. This can be ocular or generalised in presentation.
- Antibody negative MG occurs in 5% and is heterogenous, probably reflecting different undiscovered causative factors.
- Ocular MG is defined as being restricted to the ocular muscles; if this remains the case for 2 years, 90% of the time it will remain so. Half of such cases have AChR antibodies, but only very rarely do they have MUSK antibodies.
When symptoms are typical, the review considers neurophysiological testing unnecessary in all cases bar those that are seronegative.
Finally the review discusses treatment options. Immunosuppressive treatment is recommended when symptomatic treatments (anticholinesterases such as pyridostigmine) fail alone to control symptoms. (MUSK antibody associated disease often has a poor response to such treatment.) An extensive review of clinical trials reveals disappointing results in many cases when compared with placebo. Nevertheless a clear treatment plan of steroids combined with immunosuppressive drugs is recommended. Other treatment plans may vary from this. The only information regarding treatment in relation to antibody serology is that rituximab in uncontrolled studies may be particularly effective in MUSK associated MG.
The review concludes with a discussion of new treatments, such as other monoclonal antibody therapies targeting autoantibodies, or antigen specific treatments that encourage the development of immune tolerance.
The review provides a welcome revision of management in an important therapeutic area. However it was felt that there was little specific information on serological-clinical correlations that practically affect management. This was the presumed main hypothesis of the review. The lack of ocular and thymic involvement in MUSK associated disease, and its poor symptomatic response to anticholinesterases, were interesting points.
Other points that arose out of the discussion were:
- The lack of evidence base for treatment compared to the clear benefits observed in practice does point to the limitation of relying solely on evidence based medicine. It was conjectured that in some cases this may reflect patient selection. If for example, all ocular myasthenic patients are started on immunosuppression, in many cases it may be unnecessary and so demonstrating an improved response compared with placebo may prove difficult. Perhaps clinical focus is understandably upon patients with myasthenic crises or who have recently had myasthenic crises, where the response to treatment is more dramatic and clearly in some cases life-saving.
- The indication in the review that neurophysiology was only necessary in seronegative patients was surprising. In our practice, we often have neurophysiology results before serology becomes available. In patients with ocular symptoms only, the differential includes cranial nerve palsy, sympathetic lesions, myopathic processes and even muscle tension related symptoms. Identification by neurophysiology alerts clinicians to the fact that the patient is at risk of life-threatening myasthenic crisis. Patients with bulbar involvement may have motor neurone disease or myopathy. Finally, there is a significant false positive AChR occurrence; in patients with low positive AChR titre in whom we feel that myasthenia is actually unlikely, normal neurophysiology on single fibre EMG jitter study helps to confirm this. While not 100% sensitive and specific, neurophysiology does lend valuable diagnostic support.
This paper was presented to our Journal Club by Dr Salman Haider, Specialist Registrar in Neurology, Queens Hospital, Romford, UK.