Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity

Abstract

Acquired myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction in which patients experience fluctuating skeletal muscle weakness that often affects selected muscle groups preferentially. The target of the autoimmune attack in most cases is the skeletal muscle acetylcholine receptor (AChR), but in others, non-AChR components of the neuromuscular junction, such as the muscle-specific receptor tyrosine kinase, are targeted. The pathophysiological result is muscle endplate dysfunction and consequent fatigable muscle weakness. Clinical presentations vary substantially, both for anti-AChR positive and negative MG, and accurate diagnosis and selection of effective treatment depends on recognition of less typical as well as classic disease phenotypes. Accumulating evidence suggests that clinical MG subgroups might respond differently to treatment. In this Review, we provide current information about the epidemiology, immunopathogenesis, clinical presentations, diagnosis, and treatment of MG, including emerging therapeutic strategies.

Figure 1. The normal NMJ and pathophysiology of MG

(A) Components of the NMJ. In the normal NMJ, ACh is released from the nerve terminal following a nerve action potential, and interacts with the AChR on the postsynaptic membrane. Voltage-gated Ca²⁺ channels allow the influx of Ca²⁺ into the nerve terminal, which facilitates the release of ACh. Voltage-gated Na⁺ channels on the postsynaptic membrane serve to propagate the muscle action potential on depolarisation. Acetylcholinesterase scavenges and hydrolyses unbound ACh. MUSK initiates clustering of the cytoplasmic protein rapsyn and AChRs, and is believed to maintain normal postsynaptic architecture. (B) Effect of the loss of functional AChRs in MG. Conceptual representation of EPP amplitudes after repeated nerve stimulation. EPP amplitude is reduced in MG, narrowing the safety factor of neuromuscular transmission. With repeated stimulations, the EPP amplitude falls below threshold (indicated by the dotted line) for muscle fibre activation, resulting in neuromuscular transmission failure. (C) Electron micrographs of endplate regions from mice with experimental MG, showing lysis and altered morphology of the postsynaptic membrane. A normal endplate region is shown in the left panel. An endplate region from a myasthenic mouse showing loss of normal endplate morphology due to complement-mediated lysis is shown in the right panel. Postsynaptic membranes are indicated by the arrows. ACh=acetylcholine. AChR=ACh receptor. EPP=endplate potential. MG=myasthenia gravis. MUSK=muscle-specific receptor tyrosine kinase. NMJ=neuromuscular junction. NT=nerve terminal. Panel C modified with permission from Lippincott Williams & Wilkins.

Figure 2. Diagnostic flowchart

All patients with suspected MG should undergo testing for anti-AChR antibodies. The detection of serum anti-AChR antibodies in a patient with the appropriate clinical presentation essentially confirms the diagnosis of MG, and obviates the need for further testing. Anti-MUSK testing is usually done on patients with generalised MG who are negative for AChR antibodies, but consideration might be given to initial anti-MUSK testing (at the time of anti-AChR testing) in the presence of severe bulbar and facial weakness with marked muscle atrophy. The repetitive nerve stimulation and SFEMG tests are usually done while the results of the antibody tests are awaited; even if electrophysiological tests are positive, the results of antibody tests are still useful to identify patients with particular subsets of MG. The edrophonium and ice-pack tests are used in selected patients to make a bedside confirmation of a suspected diagnosis of MG (indicated by a dashed outline), but more objective confirmation is desirable (anti-AChR antibodies, repetitive nerve stimulation, or SFEMG). AChR=acetylcholine receptor. MG=myasthenia gravis. MUSK=muscle-specific receptor tyrosine kinase. SFEMG=single-fibre electromyography.

Figure 3. Response of ocular myasthenia gravis to moderate dose daily prednisone

(A) Before treatment, obvious left ptosis and prominent symptoms of diplopia, which did not fully respond to treatment with pyridostigmine. (B) 13 days after initiation of prednisone 30 mg daily. Patient is now asymptomatic with marked improvement in left ptosis.

Figure 4. Treatment flowchart

Management of MG must be individualised, but this general approach is suitable for most patients. Thymectomy is usually considered in early-onset, anti-AChR-positive MG. Pre-operative immunosuppression (PE or IVIg with or without steroids) might be required, particularly in patients with oropharyngeal or respiratory weakness, but some patients can successfully undergo thymectomy without prior treatment. If a thymoma is discovered, thymothymectomy is a requisite component of early disease management. A course of PE/IVIg can be considered at initiation of chronic immunosuppression to hasten onset of clinical response. AChR=acetylcholine receptor. IVIg=intravenous immunoglobulin. MG=myasthenia gravis. MUSK=muscle-specific receptor tyrosine kinase. PE=plasma exchange.