Ocular Myasthenia Gravis Treatment Options Explained

Myasthenia gravis (MG) can occur in 2 forms: a generalized myasthenia gravis (GMG) or purely ocular myasthenia gravis (OMG). Ocular myasthenia gravis is characterized by progressive fatigability of skeletal muscle limited to the orbicularis oculi, levator palpebrae superioris, and the extraocular muscles.¹ Up to half of patients diagnosed with MG present with ocular muscle weakness before showing any other signs of generalized weakness (indicating GMG), while approximately one-third of patients with MG have symptoms confined to the eye muscles (suggesting OMG).² Although ocular myasthenia gravis is relatively rare, anyone presenting with painless, pupil-spared, isolated ophthalmoparesis, ptosis, diplopia, or difficulty closing the eye should be evaluated for MG. 

When OMG is identified, ophthalmologists must act quickly to develop a treatment plan that works for the patient to help prevent progression to GMG. The options include the use of cholinesterase inhibitors, immunosuppressants, and, controversially, thymectomy. Knowing how to navigate contraindicated systemic medications, when to start patients on which pharmaceutical therapy, and when to recommend surgery are all key to combating this rare, but dangerous condition.

Diagnostic Precision

Although OMG is a clinical diagnosis, serologic confirmation with antibody (Ab) titers is recommended.^3-4 Serum autoantibodies (eg, binding, blocking, modulating) against the acetylcholine receptor (AChR) are seen in approximately 50% of patients but other autoimmune antibody assays can be considered for initially seronegative cases (eg, muscle-specific tyrosine kinase (MuSK) and low-density lipoprotein receptor-related protein 4 a [LRP4]).^4-5  Other autoimmune testing (such as thyroid function tests and thyroid antibodies for thyroid eye disease) could also be considered.^4-5 

Electrodiagnostic studies including repetitive nerve stimulation (RNS) and single-fiber electromyography (SF-EMG) could be considered in seronegative cases.⁶ SF-EMG is the most sensitive and specific of the 2 electrophysiologic studies (80% to 100% sensitive).^4,6-7 Researchers recommend examining a jitter response with SF-EMG in the orbicularis oculi muscle first.⁷ Despite its high sensitivity, SF-EMG has limited availability in many areas.⁴ 

Computed tomography (CT) scan of the chest should be performed to exclude thymoma in MG. Thymectomy may be curative in patients with MG with thymoma and may be helpful for MG even after nonthymomatous thymectomy.^8-9 Up to 10% of patients with MG have a thymoma.⁹ Unlike GMG, thymectomy in nonthymomatous patients with ocular myasthenia gravis remains controversial.^4-5,10  

First-Line Therapy: Cholinesterase Inhibitors 

The goal of therapy in MG is to improve vision and quality of life and limit systemic (including potentially life-threatening) manifestations of GMG.^10-11 The first step of therapy is to identify and discontinue any drugs that may exacerbate MG.¹³ Many classes of antibiotics (including aminoglycosides, fluoroquinolones, and macrolides), as well as beta-blockers and statins can exacerbate MG.¹³ A 2008 investigation developed a quantitative myasthenia gravis assessment tool (the ocular-QMG score) to measure response to therapy.¹²

First-line pharmacologic therapy for ocular myasthenia gravis includes cholinesterase inhibitors (ChE-Is) such as pyridostigmine.^1,5 Most drug recommendations for MG include starting with a low dose and slowly increasing the dose or frequency of dosing until maximum tolerated effect and improvement in clinical symptoms. Low initial dose pyridostigmine (30 mg to 60 mg, once a day) and then gradual increases of the dose in 30 mg increments to a maximum dose of 180 mg, is a reasonable starting regimen. 

Alternatively, another dosing regimen might include pyridostigmine starting with 30 mg to 60 mg once a day and increasing the frequency to every 3 to 4 hours as needed.^1-2  

Documenting the clinical symptoms and signs of MG prior to and during treatment is important for documenting response to pyridostigmine or any other pharmacological treatment. Unfortunately, the response to pyridostigmine varies by individual patient and often when used alone it is not sufficient to resolve symptoms of ocular myasthenia gravis.¹⁴ 

Second-Line Therapy: Immunosuppression

When cholinesterase inhibitors alone do not effectively treat OMG, immunosuppressive (IS) agents can be considered an appropriate second-line therapy.¹³ One retrospective cohort study found that OMG manifestations were much more likely to improve with corticosteroids than with ChE-Is.¹²

Variable dosing regimens for oral prednisone have been recommended in OMG.¹⁴ Some potential regimens include either starting at a relatively high dose (prednisone 60 mg) and then tapering down after symptoms/signs improve or resolve, or starting at a low dose and slowly tapering up until symptoms resolve. Starting with a low dose and slowly tapering up may be a superior approach both because it reduces steroid side effects and decreases the chance of unmasking GMG in OMG.^1-2,13,15

In instances where corticosteroids alone are not effective, contraindicated, or poorly tolerated, a steroid-sparing agent may be needed.¹³ Noncorticosteroid immunosuppressive regimens include mycophenolate mofetil, azathioprine, cyclosporine, cyclophosphamide, or tacrolimus.^1,13 Patients taking any of these agents with or without corticosteroids should be closely monitored for the development of adverse side effects. 

The Role of Thymectomy

Although thymectomy is recommended for thymoma in MG, the role of thymectomy in nonthymomatous cases remains controversial for patients with ocular myasthenia gravis.^1,13,16-17 Thymectomy in nonthymomatous GMG is reasonable for patients who fail, are intolerant of, or noncompliant with maximal medical therapy.^4-5,9-10 

The role of the thymus in the pathogenesis of OMG is not fully understood, but researchers have hypothesized that thymectomy improves outcomes by decreasing autoimmune activity.⁹

The thymus expresses AChR on the surface of “muscle-like cells” in the medulla.⁹ The presence of these AChRs in the thymus provides B lymphocytes an opportunity to develop antibodies against them.⁹ Thymectomy may reduce the development of autoantibodies to the AChR.¹⁸ Currently, the evidence for thymectomy in ocular myasthenia gravis is not sufficient to make a strong recommendation based on the majority of studies to date.¹³  

In a meta-analysis of thymectomy in nonthymomatous OMG, a research team found that the pooled rate of complete stable remission was 50% with better outcomes in pediatric patients.¹⁰ The same systematic review concluded that while “Thymectomy clearly represents an effective treatment for patients with nonthymomatous ocular myasthenia gravis…more multicenter, randomized, controlled clinical trials are now required to confirm these conclusions.”¹⁰

The benefits and risks of thymectomy should be discussed with every patient with MG with the understanding that pharmacotherapy or other measures might still be necessary even after the removal of the thymus.⁴ Additional treatment refractory options may still need to be considered before thymectomy is offered.

Treatment Refractory Options

Immunotherapy (eg, rituximab, eculizumab, plasmapheresis, and intravenous immunoglobulin) may also be considered for patients who have failed or are intolerant of conventional pyridostigmine or corticosteroid treatments.^1,13 The evidence base for these treatments for OMG remains limited.⁴

Nonpharmacologic therapies (eg, ptosis props or crutch glasses) may also be used and help reduce ptosis.¹⁹ These mechanical devices and simply wearing an eye patch (to alleviate binocular diplopia) may be considered especially during the initial optimization phase of medical treatment of ocular myasthenia gravis.¹ Additionally, prisms for patients with diplopia especially for stable and comitant residual deviations may be useful.⁴ Patients who have chronic and stable ophthalmoplegia or ptosis may benefit from ptosis or strabismus surgery.¹⁹ 

Although there is no medical cure for OMG, symptomatic medical treatment including pyridostigmine, steroids, or steroid-sparing immunosuppression should be considered. Thymectomy for the treatment of OMG should be performed for thymoma but could be considered for nonthymomatous MG (especially GMG) if first and second-line medical therapy fails. The role of thymectomy in OMG remains controversial.^8-9 Clinicians should be aware of the risks and benefits of the various treatment options for OMG.