Anti‐MuSK antibodies in a case of ocular myasthenia gravis

In 10–20% of patients with generalised myasthenia gravis and in up to 50% of patients with ocular myasthenia gravis there are no detectable antibodies to the acetylcholine receptor (AChR). In such cases the disease is commonly referred to as seronegative myasthenia gravis. Seronegative myasthenia gravis has been recognised as an antibody mediated disease, and recently antibodies to muscle specific kinase (MuSK) were demonstrated in the sera of patients with generalised seronegative myasthenia gravis.¹ Anti‐MuSK antibodies were not found in seropositive myasthenia gravis. Myasthenia gravis patients with these antibodies have been described as having more prominent bulbar and neck weakness and more respiratory crises.²,³,⁴ These studies differ in the degree of ocular involvement reported, however, only one previous case of anti‐MuSK antibodies being found in purely ocular myasthenia gravis has been described.⁵ We would like to describe a further case of seronegative ocular myasthenia gravis associated with anti‐MuSK antibodies.

Case report

A 21 year old male student presented with a four month history of variable diplopia and bilateral ptosis. He did not complain of any limb weakness or speech, swallowing, or respiratory problems. He had no past medical history of note and was not taking any regular medication. He is the youngest of eight siblings and there is no family history of neuromuscular disease.

On examination he had bilateral ptosis with fatigue and Cogan's lid twitch sign was positive. Extraocular movements were limited in all directions, and particularly pronounced on eye abduction bilaterally. The ptosis and ophthalmoplegia varied between clinical assessments. He had no facial or neck weakness, and bulbar function and limb power was normal with no evidence of fatigability.

Anti‐AChR antibodies were negative as measured by a standard radioimmunoprecipitation assay using human adult‐type AChR as antigen. Repetitive nerve stimulation revealed no decrementing response in abductor digiti minimi but stimulated single fibre electromyography of orbicularis oculi demonstrated enhanced jitter (mean of 10 single fibres 31 ms; normal range >23 ms) consistent with a defect in neuromuscular transmission. A computed tomography (CT) scan of the head and orbits was normal, and a magnetic resonance scan of the brain was also normal. CT thorax showed normal residual thymic tissue in the anterior mediastinum.

A provisional diagnosis of seronegative ocular myasthenia gravis was made and he was treated with pyridostigmine up to 60 mg four times daily, which had no benefit. Treatment with 3,4‐diaminopyridine (20 mg three times daily) was also ineffective. An edrophonium test was then performed which was negative. A quadriceps muscle biopsy showed mild variation in fibre size with some atrophic fibres (predominantly type II). He was subsequently found to have anti‐MuSK antibodies as detected by immunoprecipitation of ¹²⁵I‐recombinant MuSK extracellular domains.⁶ He was started on treatment with prednisolone 10 mg once daily which resulted in a marked symptomatic improvement.

Discussion

It could be argued that this patient will go on to develop generalised myasthenia gravis since this progression occurs in up to 85% of patients with ocular myasthenia gravis. His symptoms and signs, however, have now remained purely ocular for over a year whereas in the majority of patients the progression of ocular to generalised myasthenia gravis occurs in the first year. The frequency of anti‐MuSK antibodies in generalised but seronegative myasthenia gravis has been reported as between 40% and 70% in Caucasian populations.¹,²,³,⁴,⁶ The frequency of these antibodies in purely ocular myasthenia gravis is likely to be much lower. One recent report has described positive anti‐MuSK antibodies in purely ocular myasthenia gravis.⁵ In other reports anti‐MuSK antibodies were tested in 38 patients with purely ocular seronegative MG with all being negative.²,⁴,⁶

Interestingly, our patient did not respond to treatment with acetylcholinesterase inhibitors and an edrophonium test was negative. Both of these findings have previously been described in the context of MuSK positive generalised myasthenia gravis.²,³ In one study the edrophonium test was unhelpful in 30% of patients with anti‐MuSK antibody positive generalised myasthenia gravis.³ Although our patient did not find treatment with acetylcholinesterase inhibitors beneficial he responded well to a low dose of prednisolone.

MuSK is a tyrosine kinase receptor predominantly located on the postsynaptic membrane of the neuromuscular junction. It is activated upon binding of nerve released agrin and then mediates AChR clustering and formation of the neuromuscular junction. Anti‐MuSK antibodies interfere with agrin induced clustering of AChRs in cultured muscle cell lines.¹ It is unclear what effect anti‐MuSK antibodies will have on the more stable adult neuromuscular junction, and indeed there is some controversy over the pathogenicity of anti‐MuSK antibodies.⁷ In patients with these antibodies there was no substantial loss of AChRs or MuSK on muscle biopsy. Recent studies suggest that sera from seronegative myasthenia gravis patients may have an inhibitory effect on AChRs that is independent of the IgG fraction or the MuSK antibody itself. Despite these uncertainties the presence of anti‐MuSK antibodies is a useful diagnostic marker of myasthenia gravis. Their frequency appears to be low in purely ocular myasthenia gravis. Finding anti‐MuSK antibodies in a patient with purely ocular seronegative myasthenia gravis, however, may be extremely helpful. This report demonstrates their use in particularly challenging diagnostic cases where the edrophonium test is negative and there is no response to acetylcholinesterase inhibitors.