Myasthenia gravis (MG) is an autoimmune disease in which autoantibodies against the acetylcholine receptor (AChR) on the postsynaptic membrane of the neuromuscular junction destroy AChR via complement-mediated mechanisms. In anti-AChR antibody-negative cases, anti-MuSK antibodies (muscle-specific receptor tyrosine kinase) may be involved.
MG is classified into ocular myasthenia gravis (OMG), which presents only with ocular symptoms, and generalized MG (GMG), which involves limb and bulbar symptoms. In ocular MG, vigilance for progression to generalized MG is always necessary.
OMG is a subtype of MG in which muscle weakness is limited to the extraocular muscles, levator palpebrae superioris, and orbicularis oculi 1). It can mimic any comitant or incomitant strabismus, oculomotor nerve palsy, gaze palsy, or internuclear ophthalmoplegia, and is therefore called the “great masquerader” 1).
When onset occurs at age 5 years or younger, many cases are considered “latent generalized MG” in which only extraocular muscle symptoms are initially apparent despite being generalized. Ptosis, eye movement disorders, and abnormal eye position are common initial symptoms.
Ocular myasthenia gravis is limited to the extraocular muscles and eyelids, without affecting swallowing or respiratory muscles. Generalized myasthenia gravis involves limb and bulbar symptoms (swallowing difficulty, speech difficulty, respiratory distress). Since 50–80% of ocular myasthenia gravis cases progress to generalized myasthenia gravis within two years of onset, regular systemic evaluation is necessary.
Eyelid findings
Ptosis: Often progresses from unilateral to bilateral.
Cogan’s lid twitch sign: When returning to primary gaze after looking downward, the upper eyelid briefly overshoots upward and then drifts down. Sensitivity 75%, specificity 99% 2).
Peek sign: Sclera is exposed due to orbicularis oculi muscle weakness during eyelid closure 1).
Contralateral eyelid retraction due to Hering’s law: When the ptotic eyelid is manually lifted, ptosis of the contralateral eyelid becomes apparent1).
Extraocular muscle findings
Diplopia: The most commonly affected extraocular muscle is the medial rectus, followed by the superior rectus1).
Pseudo-oculomotor nerve palsy: Presents as vertical strabismus. The pupil is usually normal (a distinguishing feature from third cranial nerve palsy)1).
Pseudo-MLF syndrome: Presents as adduction deficit.
Saccadic abnormalities: Large saccades with low velocity and small saccades with high velocity coexist (CNS adaptation)1).
Comorbid thyroid eye disease: Approximately 15% of MG patients have comorbid thyroid eye disease. Enlargement of extraocular muscles on MRI suggests thyroid eye disease. Extraocular muscle enlargement is never seen in MG (an important distinguishing feature).
Yes. Ptosis in MG often starts in one eye and later becomes bilateral. Diurnal variation (worsening in the evening) is highly suggestive. Cogan’s lid twitch sign (specificity 99%) and the ice pack test can aid diagnosis.
MG is an autoimmune disease in which autoantibodies against the postsynaptic membrane at the neuromuscular junction impair neuromuscular transmission.
Epidemiology:
Antibody-specific positivity rates:
Thymic abnormalities: Thymoma or thymic hyperplasia is seen in about 50–70% of cases. Thymoma is associated in 10–15%1).
Reasons for selective involvement of extraocular muscles1):
In 2014, the Japanese Society of Neurology published diagnostic criteria in its clinical practice guidelines.
The sensitivity and specificity of each diagnostic test are shown below.
| Test | Sensitivity | Specificity | Notes |
|---|---|---|---|
| Cogan’s sign | 75% | 99% | Highest specificity |
| Ice pack test (ptosis) | 80–94% | 97% | Simple, no side effects |
| Ice pack test (diplopia) | 74–77% | 92–99% | Positive if ocular deviation improves by ≥50% |
| Forced eyelid closure test | 94% | 91% | — |
| Edrophonium test (OMG) | 86% | High | Atropine must be available |
| RNS (repetitive nerve stimulation) | 33% (OMG) | High | Approximately 80% in generalized type |
| SFEMG (Single-fiber electromyography) | 85–100% | High | Most sensitive for NMJ disorders |
| Anti-AChR antibody | 40–77% (OMG) | High | Gold standard |
Edrophonium (Tensilon) test, easy fatigability of myasthenic symptoms (waning phenomenon), and evoked electromyography are used. Sleep test and upward gaze fatigue test are useful as diagnostic methods to capture the variability of symptoms.
A cold pack is applied directly to the closed upper eyelid for 2 minutes. The test is positive if ptosis improves by 2 mm or more. It has no side effects, is simple, and shows a sensitivity of 80–94% and specificity of 97%. It is useful as an alternative when the edrophonium test is difficult to perform. Exceeding 2 minutes can cause false negatives, so time management is important.
CT is used to confirm thymoma (or thymic enlargement). If present, extended thymectomy is prioritized. Generalized MG is treated by neurologists, and ocular MG by ophthalmologists.
Pyridostigmine bromide (Mestinon®) is started at 2 tablets per day divided into two doses (morning and noon, taken at least 4 hours apart) and can be increased up to 4 tablets per day. Side effects include diarrhea and abdominal pain (muscarinic effects). If oral intake is not possible, switch to steroids. It is symptomatic treatment, not curative. If the patient can be weaned off over six months or more, the course is mildest and most favorable.
In OMG, the efficacy of pyridostigmine is only about 50%, and ptosis responds better than diplopia1). In the group that used only pyridostigmine without steroids, 36% developed GMG within 2 years4).
Children: Pyridostigmine bromide (Mestinon) eye drops and Mytelase oral are used.
Added when Mestinon® oral is difficult or insufficient alone. There are three methods of steroid use:
During oral steroid therapy, bone density measurement and concomitant use of osteoporosis prophylaxis (alendronate sodium hydrate, Bonaron® 35 mg, once weekly after waking up in the morning) are necessary.
Steroids show a good response in 66–85% of OMG cases5). They reduce the rate of conversion to generalized myasthenia gravis from 36–83% without steroids to 7–17% with steroids5)6).
Steroid therapy in children: To avoid initial exacerbation and side effects, a low-dose long-term maintenance regimen is often chosen. Steroid pulse therapy is also indicated in children.
Added when steroid response is insufficient, steroid tapering is difficult, or side effects are severe. Start at 2 mg once daily after dinner, and regularly monitor tacrolimus blood concentration, glucose tolerance, and renal function. If blood concentration is ≤5 ng/mL and renal function is normal, increase to 3 mg/day, then taper and discontinue steroids at a rate of prednisolone equivalent 5 mg every 1–3 months. Tacrolimus is the only immunosuppressant with insurance coverage for myasthenia gravis in Japan.
Other immunosuppressants:
When thymoma is present, extended thymectomy is prioritized. Clinical improvement is reported in 70–80%, and complete remission in about 35%1)13). Antibodies do not become negative after surgery, but a halving of antibody titers leads to symptom improvement.
In children, thymectomy is considered in cases of steroid resistance or in generalized type with thymic hyperplasia in those aged 10 years or older.
Surgery is considered when symptoms are judged to have stabilized with medical treatment. Strabismus surgery and eyelid surgery are considered after at least 6 months of stability 1). The surgical method for ptosis follows that for congenital ptosis. For paralytic strabismus, recession of the antagonist muscle is the first choice.
As symptomatic treatments, prism glasses or occlusion for diplopia management, and crutch glasses for severe ptosis management are also effective 1).
Prognosis: The rate of progression from ocular type to generalized type in treated patients is less than 10%, making proper treatment of the ocular type extremely important.
Mestinon is a symptomatic treatment, not a curative one. The best course is when symptoms are controlled over six months or more and the drug can be discontinued. Do not stop on your own; taper under the guidance of your primary physician. It is often combined with steroids or tacrolimus to stabilize symptoms.
In normal neuromuscular transmission, a nerve impulse triggers Ca²⁺ influx into the presynaptic terminal, causing exocytosis of acetylcholine (ACh) from synaptic vesicles. ACh binds to AChRs on the postsynaptic membrane, leading to depolarization and muscle contraction.
Three mechanisms of anti-AChR antibodies (IgG1) 1):
Mechanism of anti-MuSK antibodies (IgG4)12): They do not activate complement. They impair neuromuscular transmission by inhibiting MuSK-mediated AChR clustering signals.
Mechanism of anti-LRP4 antibodies12): LRP4 functions as a receptor for agrin. Anti-LRP4 antibodies inhibit AChR clustering and interaction with agrin, impairing neuromuscular transmission.
Reasons for selective involvement of extraocular muscles1):
Approximately 50–70% of patients have thymoma or thymic hyperplasia, suggesting that thymic immune dysregulation is deeply involved in the pathogenesis of MG. Before transition to generalized MG, an increase in anti-AChR antibody titers is known to occur, making serial antibody testing important.
Eculizumab is an anti-C5 monoclonal antibody (complement inhibitor) approved for anti-AChR antibody-positive gMG10). Ravulizumab is a long-acting anti-C5 antibody, and the CHAMPION MG trial confirmed its efficacy and safety in gMG11). Clinical trials in OMG have not been conducted to date.
Efgartigimod is a human IgG1 Fc fragment (FcRn inhibitor) that has shown efficacy in GMG in the ADAPT trial 9). It reduces pathogenic autoantibodies by inhibiting IgG recycling. A key feature is that it can be used regardless of antibody status.
Rituximab is an anti-CD20 monoclonal antibody that is considered promising for refractory MG, especially in anti-MuSK antibody-positive cases. Improvements have also been reported in reviews of antibody-negative MG 12).
Anti-AChR antibody positivity (67% convert), thymoma (10-15%), and positive SFEMG (77% convert) have been reported as risk predictors 2). Population-based studies report that 55% convert, with 50% at 1 year, 72% at 2 years, and 94% at 5 years 3).
Live CBA (cell-based assay) can detect anti-AChR antibodies in up to 65% of RIPA-negative patients 12), and is expected to improve diagnostic accuracy in the future. Currently, it is only available at specialized facilities.
