Researchers also call attention to the disease when it’s associated with certain cancer therapies, due to greater risk of death from myocarditis (inflammation of the heart muscle).
The study, “Ocular myasthenia gravis: updates on an elusive target,” was published in the journal Current Opinion in Neurology.
The muscles controlling eye and eyelid movement remain the only muscles affected by weakness and fatigue in about 15% of myasthenia gravis (MG) patients — a disease type known as ocular myasthenia gravis (OMG).
This particular form of MG is complex, with symptoms varying from person to person, which results in poorly defined diagnostic criteria. What drives its progression to generalized disease, where several muscle groups across the body are affected, also remains unclear.
MG is an autoimmune disease that occurs when the body starts making autoantibodies that mistakenly attack and destroy certain receptors — ones important for muscle contractions — that are found on the surface of muscle cells, breaking down nerve transmission to muscles.
In approximately 80% to 90% of generalized MG patients, the self-attacking antibodies are directed against acetylcholine receptors (AChR), and are known as anti-AChR. Less frequently, the disease can be caused by a different type of autoantibody against MuSK (Muscle-Specific Kinase), a protein related to acetylcholine receptors. In addition, other autoantibodies targeting different proteins have been associated with the disease.
For unclear reasons, patients with ocular MG are less likely to have anti-AChR or anti-MuSK antibodies, with recent reports showing anti-AChR positivity in 40% to 70%.
When such antibodies are present, however, OMG patients tend to be at greater risk of their disease progressing to generalized MG.
In line with this, patients negative for both anti-AChR or anti-MuSK — known as double-seronegative myasthenia gravis — are more likely to have mild disease. These patients may carry antibodies to other proteins such as LRP4, agrin, or cortactin, which are involved in nerve transmission to muscles.
These antibodies may hold value as biomarkers for disease severity, the researchers wrote. However, more research is needed to clarify their clinical and prognostic significance.
“Although advancements in serology continue to identify a larger proportion of patients with OMG, there remains a large subset who are widely seronegative,” the researchers noted, adding that for these patients, “a skillful clinical assessment is essential to raising diagnostic suspicion.”
Electromyography, ice packs, and acetylcholinesterase inhibitors, such as edrophonium, remain viable options for diagnosis, although such tests can have variable results and tolerability.
About 50% to 60% of patients with isolated OMG are estimated to develop generalized disease within two years of symptom onset.
Progression to generalized MG has significant implications given the potential life-threatening breathing difficulties and the frequent requirement for immunosuppressive therapy.
The researchers believe that future controlled studies with “uniform data collection and inclusion criteria across multiple centers would help clarify these risk factors to guide patient education and treatment options.”
Of note, the researchers also focused on the development of generalized MG as a side effect of cancer therapy with immune checkpoint inhibitors (ICI), including Keytruda (pembrolizumab), or Opdivo (nivolumab).
ICIs work by activating the immune system to target cancer cells and have been associated with a number of immune-related adverse events, including MG. Nearly 50% of these MG cases involve oculomotor symptoms, and many tend to be complicated by heart disease, including myocarditis.
Unlike the typical disease, ICI-induced MG can rapidly progress to life-threatening respiratory or heart disease and lead to high mortality rates, reportedly above 40%.
“Patients presenting with signs of possible OMG and ICI use should undergo a broad diagnostic work up for coexisting myositis [motor muscle inflammation] and myocarditis,” the researchers said.
In terms of treatment options for OMG, the ideal strategy is to “restore normal muscle function, either through pharmacologic enhancement of muscle contractility or suppression of the autoimmune processes” causing neuromuscular muscle junction dysfunction, the study stated.
First-line treatment consists of acetylcholinesterase inhibitors such as Mestinon (pyridostigmine; by Bausch Health Companies), which may be supplemented by oral prednisone (a corticosteroid) if patients are treatment-resistant or risk generalization. Further suppression of the immune system may be best achieved with CellCept (mycophenolate mofetil; by Roche) or azathioprine, if needed.