Dear Editor, Myasthenia gravis (MG) is an autoimmune disorder caused by antibodies impairing neuromuscular transmission. Antibody subtypes include those targeting acetylcholine receptors (AChRs), muscle-specific kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), and seronegative variants. MuSK antibody-positive MG (MuSK-MG) accounts for 5%–10% of cases, is more common in women, and usually begins between the ages of 30 and 40 years.1 Unlike AChR-MG, MuSK-MG rarely presents with isolated ocular symptoms. We report an atypical case of MuSK-MG initially manifesting as ocular myasthenia in an older man, with delayed but severe generalization 3 years later after coronavirus disease 2019 (COVID-19). A 70-year-old man with no major comorbidities presented with 3 weeks of intermittent binocular horizontal diplopia. Examination showed mild esotropia with bilateral abduction limitation, normal eyelid position, and prompt pupillary light reflexes. Fundoscopy showed no disc edema. Brain magnetic resonance imaging revealed no intracranial or orbital lesions. Symptoms resolved spontaneously after 3 weeks. Six months later, he developed recurrent diplopia and bilateral lid drooping with diurnal variation. Enhanced ptosis, fatigability test, and ice test were positive, suggesting MG. AChR antibodies were negative. Pyridostigmine caused severe diarrhea without clinical benefit. As his ocular symptoms persisted, repetitive nerve stimulation (RNS) of the accessory nerve and trapezius muscle showed only a 5% decrement, and single-fiber electromyography (SFEMG) of the orbicularis oculi was normal. The diagnosis remained inconclusive. Four months later, ptosis and diplopia worsened, accompanied by esotropia, left hypertropia, and supraduction and abduction limitation in both eyes. Prednisolone and pyridostigmine were reintroduced but again poorly tolerated and ineffective. His symptoms fluctuated but remained tolerable without treatment. Three years after onset, during acute COVID-19 infection, he developed generalized weakness, neck drop, and respiratory failure within 1 week. Myasthenic crisis was suspected, and he received tracheostomy, plasmapheresis, and prolonged intensive care. Testing revealed MuSK antibodies Figure 1, confirming MuSK-MG. LRP4 antibody testing was not performed, as this assay was not available at our institution. He stabilized on rituximab, corticosteroids, and cyclophosphamide; azathioprine was discontinued due to leukopenia. Rituximab was administered as two 500-mg doses given 2 weeks apart per cycle. He received two cycles 1 month apart, which resulted in marked improvement in symptoms. Subsequent cycles were administered every 6 months. After a total of four cycles over more than 1 year of follow-up, he regained full independence in daily activities with complete resolution of ocular symptoms.Figure 1: Serum fixed cell-based assay results showing negative adult acetylcholine receptor (AChR) antibodies (no reactivity at 1:10 dilution) (a), negative fetal AChR antibodies (no reactivity at 1:10 dilution) (b), and positive muscle-specific kinase antibodies (reactivity at 1:10 dilution) (c)Ocular MG typically presents with diplopia, ophthalmoparesis, and ptosis. Phenotypic differences exist between subtypes: AChR-MG commonly shows asymmetric ptosis, whereas MuSK-MG often produces symmetric ptosis and conjugate gaze palsy, reported in up to 35% of cases.2 Unlike AChR-MG, MuSK-MG rarely presents with isolated ocular disease and usually progresses rapidly with bulbar involvement within 3 months.1,2 Reports of MuSK-ocular MG without generalization are rare, with only 10 cases identified in the literature.3,4 The median age at onset was 35 years (interquartile range, 20.8–59.5 years), and the median duration of isolated ocular symptoms was 33 months (interquartile range, 15–45.5 months). Eighty percent of reported cases occurred in females. Our case was atypical, given the isolated ocular onset, older age, male sex, and delayed generalization beyond 3 years. The delayed generalization is thought to result from two proposed mechanisms: immunosenescence and infection-triggered immune activation. Immunosenescence refers to the age-related decline in immune regulatory capacity, including reduced expression of checkpoint molecules such as CTLA-4 and CD28, which leads to impaired self-tolerance.5 Infection-triggered immune activation is another potential mechanism. Viral infections can induce interferons and other pro-inflammatory cytokines, creating an environment that promotes the production of pathogenic autoantibodies.6 Diagnostic challenges are common in MuSK-ocular MG. In patients with isolated ocular symptoms, RNS has limited sensitivity, and SFEMG of facial muscles is recommended, although the results may still be nondefinitive.7 Our patient’s negative AChR antibodies, normal RNS and SFEMG, and lack of response to pyridostigmine obscured the diagnosis. These limitations support considering MuSK antibody testing in AChR-negative ocular MG with poor treatment response, even in the absence of bulbar features. Treatment of MuSK-MG differs from AChR-MG. In acute exacerbations, plasmapheresis is typically more effective than intravenous immunoglobulin. Acetylcholinesterase inhibitors and complement-targeted therapies are less effective, and conventional immunosuppressants yield variable responses. Thymectomy is not indicated. Rituximab has emerged as a first-line treatment option, offering quick and prolonged clinical improvement in most patients.2,8 Early initiation of rituximab is advised, particularly in patients who respond poorly to initial immunotherapy or who exhibit rapidly progressive symptoms, though dosing regimens vary and the optimal protocol remains undetermined.8 COVID-19 infection may have precipitated disease generalization in our patient. MG exacerbation has been reported in 15%–40% of infected patients, with higher mortality compared with crises of other etiologies.9,10 Vigilance is warranted in high-risk groups, including older patients, previous long-term corticosteroid treatment, and recent immunosuppressive therapy.9 In conclusion, this case broadens the phenotypic spectrum of MuSK-MG by demonstrating late-onset MuSK-ocular MG with delayed generalization after COVID-19. Clinicians should consider MuSK antibody testing in atypical or treatment-refractory ocular MG, counsel patients regarding COVID-19 risk, and maintain vigilance for late generalization. Data availability statement All data generated or analyzed during this study are included in this published article. Ethics statement This study was approved by the Institutional Review Board (IRB) of Cathay General Hospital, Taipei, Taiwan (IRB number: CGH-P114048). Declaration of patient consent This study was performed in accordance with and conforming to the Declaration of Helsinki. The authors certify that they have obtained all appropriate patient consent form. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of Interest The authors declare that there are no conflicts of interests of this paper.
Wong et al. (Fri,) studied this question.