Ophthalmology – Myasthenia Gravis

Basics

Description

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction characterized by painless, fluctuating, fatigable skeletal-muscle weakness.

The most commonly affected muscles are the extraocular and eyelid muscles, so ophthalmic manifestations are frequently the first sign of disease.

Typical manifestations include:

• Ptosis
• Diplopia
• Variable ophthalmoplegia
• Orbicularis weakness
• Bulbar weakness
• Limb weakness
• Respiratory muscle weakness in severe disease

A characteristic feature is that weakness:

• Worsens with repeated or prolonged muscle use
• Often worsens later in the day
• Improves after rest
• Can vary considerably from one examination to another

Sensation and pupillary function remain normal.

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Clinical Forms

Ocular Myasthenia Gravis

In ocular MG, weakness remains limited to:

• Eyelids
• Extraocular muscles

Patients typically develop:

• Ptosis
• Diplopia
• Variable ocular misalignment

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Generalized Myasthenia Gravis

Generalized disease can involve:

• Ocular muscles
• Bulbar muscles
• Facial muscles
• Neck muscles
• Limb muscles
• Respiratory muscles

Ocular manifestations often precede generalized disease.

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Serologic Forms

MG can also be categorized according to circulating antibodies.

AChR-Antibody Positive MG

Antibodies are directed against the acetylcholine receptor (AChR) on the postsynaptic membrane.

This is the most common form.

MuSK-Antibody Positive MG

Antibodies are directed against muscle-specific receptor tyrosine kinase (MuSK).

These patients are more likely to have prominent:

• Bulbar weakness
• Facial weakness
• Neck weakness
• Respiratory involvement

Pure ocular presentations are uncommon.

Seronegative MG

Some patients have no detectable conventional AChR or MuSK antibodies despite a compatible clinical syndrome.

Additional antibodies such as LRP4 may be detectable in a subset.

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Epidemiology

MG may occur at any age.

A broadly bimodal pattern is recognized.

Earlier-Onset Disease

Usually affects younger adults and is more common in women.

Later-Onset Disease

Usually affects older adults and has a greater male predominance.

The prevalence has increased over time, probably because of:

• Better recognition
• Improved diagnostic testing
• Greater survival

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Risk Factors and Exacerbating Factors

Factors that can worsen myasthenic weakness include:

• Infection
• Fever
• Emotional or physical stress
• Heat
• Sleep deprivation
• Pregnancy
• Menstruation
• Thyroid dysfunction
• Certain medications

Patients should be reviewed carefully for drugs capable of worsening neuromuscular transmission.

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Genetics

MG is not usually inherited in a simple Mendelian fashion.

However:

• Autoimmune susceptibility may cluster in families.
• Relatives of affected individuals have an increased risk of autoimmune disease and MG.
• Congenital myasthenic syndromes are distinct inherited disorders and should not be confused with autoimmune MG.

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Neonatal Myasthenia

Approximately a minority of infants born to mothers with autoimmune MG may develop transient neonatal myasthenia due to transplacental passage of maternal antibodies.

Symptoms may include:

• Poor suck
• Weak cry
• Generalized hypotonia
• Respiratory weakness

The condition usually resolves as maternal antibodies disappear.

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General Prevention

There is no proven method to prevent autoimmune MG.

However, exacerbations may sometimes be reduced by:

• Prompt treatment of infection
• Avoidance of medications known to impair neuromuscular transmission
• Maintaining appropriate vaccinations
• Careful perioperative planning
• Appropriate management during pregnancy

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Drugs That May Worsen MG

Important medications that can exacerbate weakness include selected:

• Aminoglycoside antibiotics
• Fluoroquinolones
• Macrolides
• Magnesium
• Neuromuscular blocking agents
• Beta-blockers
• Some antiarrhythmics

Penicillamine can induce an MG-like autoimmune syndrome.

Medication risks are not absolute in every patient, but potentially aggravating agents should be used carefully.

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Pathophysiology

Normal neuromuscular transmission depends on acetylcholine released from the presynaptic nerve terminal binding to acetylcholine receptors on the postsynaptic muscle membrane.

In autoimmune MG, antibodies interfere with this process.

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AChR Antibodies

Anti-AChR antibodies cause:

• Functional blockade of acetylcholine receptors
• Receptor internalization and degradation
• Complement-mediated postsynaptic membrane injury

This causes simplification of the postsynaptic folds and reduces the safety margin of neuromuscular transmission.

With repetitive stimulation, transmission increasingly fails, producing fatigable weakness.

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MuSK Antibodies

MuSK is important in organizing and maintaining acetylcholine receptors at the neuromuscular junction.

MuSK autoantibodies disrupt receptor clustering and neuromuscular transmission.

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Thymus and Myasthenia Gravis

The thymus plays an important role, particularly in AChR-antibody positive MG.

Abnormalities include:

• Thymic lymphoid hyperplasia
• Germinal-center formation
• Thymoma

Approximately 10–15% of MG patients have a thymoma.

Conversely, a significant proportion of patients with thymoma develop MG.

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Associated Conditions

MG is associated with other autoimmune disorders, particularly:

• Autoimmune thyroid disease
• Rheumatoid disease
• Systemic lupus erythematosus
• Pernicious anemia

Thyroid disease is especially relevant in patients with ocular symptoms because thyroid eye disease can mimic ocular MG.

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Diagnosis

History

Typical complaints include:

• Drooping eyelid
• Intermittent diplopia
• Worsening symptoms late in the day
• Increasing symptoms after reading or prolonged visual effort
• Difficulty chewing
• Difficulty swallowing
• Nasal or weak voice
• Choking during meals
• Liquids regurgitating through the nose
• Limb weakness
• Neck weakness

Respiratory weakness can occur and represents a potentially life-threatening complication.

Sensory symptoms are not characteristic of MG.

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Ophthalmic Examination

Ptosis

Ptosis may be:

• Unilateral
• Bilateral
• Asymmetric
• Alternating
• Highly variable

Fatigability may be demonstrated by asking the patient to maintain prolonged upgaze.

The eyelid may gradually descend.

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Cogan Lid Twitch

After sustained downgaze, the patient rapidly returns the eyes to primary gaze.

The upper lid may:

1. Overshoot upward
2. Briefly retract
3. Then fall into ptosis

This is called Cogan’s lid twitch and supports the diagnosis of ocular MG.

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Frontalis Compensation

Patients may compensate for ptosis by:

• Raising the eyebrows
• Contracting the frontalis
• Adopting a chin-up posture

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Ice-Pack Test

Cooling improves neuromuscular transmission.

For ptosis:

• Ice is placed over the closed eyelid for several minutes.
• Improvement in ptosis supports MG.

An improvement of approximately 2 mm or more is generally considered strongly suggestive in the appropriate clinical context.

The test is particularly useful because it is:

• Rapid
• Noninvasive
• Inexpensive

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Ocular Motility Findings

MG can mimic almost any ocular motility disorder.

Findings may include:

• Variable ophthalmoparesis
• Changing patterns of strabismus
• Horizontal diplopia
• Vertical diplopia
• Oblique diplopia
• Isolated-appearing muscle weakness
• Apparent cranial nerve palsies

A major clue is variability.

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Pseudo-Internuclear Ophthalmoplegia

Medial rectus weakness can produce an apparent internuclear ophthalmoplegia-like pattern.

Unlike a true brainstem INO:

• The lesion is at the neuromuscular junction rather than the MLF.
• Other variable muscle weakness may be present.
• Ptosis frequently supports MG.
• Pupils remain normal.

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Pupils

The pupils are not affected in myasthenia gravis.

Pupillary abnormalities should suggest another diagnosis.

This is an important examination pearl.

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Orbicularis Oculi Weakness

The examiner may be able to open the patient’s forcibly closed eyelids relatively easily.

A peek sign may occur:

• The patient initially closes the eyes completely.
• The eyelids then slowly separate because of orbicularis weakness.

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Other Examination Findings

Generalized MG may produce weakness of:

• Facial muscles
• Jaw closure
• Palatal muscles
• Tongue
• Neck flexors
• Proximal limb muscles

Deep tendon reflexes and sensation are generally preserved.

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Diagnostic Tests

Acetylcholine Receptor Antibodies

Testing commonly includes:

• AChR-binding antibodies
• AChR-blocking antibodies
• AChR-modulating antibodies

Binding antibody testing is usually the initial test.

Sensitivity is substantially higher in generalized MG than in purely ocular MG.

A positive result is highly supportive of the diagnosis.

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MuSK Antibodies

MuSK antibody testing is particularly useful when:

• Generalized MG is suspected
• AChR antibodies are negative
• Bulbar or respiratory weakness is prominent

MuSK-positive disease is uncommon in isolated ocular MG.

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Additional Antibody Testing

In appropriate seronegative patients, additional testing may include antibodies against:

• LRP4
• Other neuromuscular-junction targets

Availability varies.

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Thyroid Testing

Because autoimmune thyroid disease can coexist with MG and thyroid eye disease can mimic ocular MG, testing may include:

• TSH
• Free T4
• Thyroid antibodies when indicated

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Imaging

Chest CT or MRI

Patients with confirmed MG should generally be evaluated for thymoma using imaging of the anterior mediastinum.

CT is commonly used.

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Neurophysiologic Testing

Repetitive Nerve Stimulation

Repetitive nerve stimulation may demonstrate a decremental response.

It is more useful in generalized disease than isolated ocular disease.

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Single-Fiber EMG

Single-fiber electromyography is highly sensitive for abnormal neuromuscular transmission.

It may be especially useful when:

• Antibody testing is negative
• Clinical suspicion remains high

It is sensitive but not completely specific for MG.

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Edrophonium Testing

Historically, intravenous edrophonium (Tensilon) was used to demonstrate transient improvement of ptosis or ophthalmoplegia.

Because of:

• Bradycardia
• Syncope
• Bronchospasm
• Other cholinergic adverse effects

and the availability of safer antibody and electrophysiologic testing, it is now rarely used.

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Differential Diagnosis

Ocular MG Mimics

Important differential diagnoses include:

• Thyroid eye disease
• Cranial nerve III palsy
• Cranial nerve IV palsy
• Cranial nerve VI palsy
• Internuclear ophthalmoplegia
• Chronic progressive external ophthalmoplegia
• Mitochondrial myopathy
• Myotonic dystrophy
• Fisher syndrome
• Orbital disease
• Decompensated strabismus

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Generalized MG Mimics

Consider:

• Lambert–Eaton myasthenic syndrome
• Botulism
• Amyotrophic lateral sclerosis
• Motor neuropathies
• Inflammatory myopathies
• Congenital myasthenic syndromes

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Myasthenia vs Lambert–Eaton Syndrome

MG typically causes:

• Ocular and bulbar weakness
• Worsening with repetitive activity
• Normal or preserved reflexes

Lambert–Eaton syndrome more commonly causes:

• Proximal limb weakness
• Autonomic symptoms
• Reduced reflexes
• Strength that may transiently improve with activity

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Treatment

Treatment depends on:

• Ocular versus generalized disease
• Degree of functional impairment
• Antibody status
• Bulbar or respiratory involvement
• Presence of thymoma
• Patient age
• Associated illnesses

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Medication

Acetylcholinesterase Inhibitors

Pyridostigmine

Pyridostigmine (Mestinon) is the principal symptomatic treatment.

It increases the amount of acetylcholine available at the neuromuscular junction.

It may improve:

• Ptosis
• General muscle strength
• Bulbar symptoms

Its effect on ophthalmoplegia can be less reliable.

Common cholinergic adverse effects include:

• Abdominal cramping
• Diarrhea
• Excessive salivation
• Sweating
• Lacrimation

Dose is individualized according to response and adverse effects.

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Corticosteroids

Corticosteroids may be used when symptomatic treatment is inadequate.

They are particularly useful for:

• Persistent ptosis
• Ophthalmoplegia
• Generalized disease

Prednisone is commonly used.

Treatment usually requires:

• Gradual titration
• Close monitoring
• Slow tapering once disease is controlled

Higher initial doses can occasionally transiently worsen weakness, so treatment strategy should be individualized by a clinician experienced in MG.

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Steroid-Sparing Immunotherapy

When prolonged immunosuppression is required, options may include:

• Azathioprine
• Mycophenolate mofetil
• Tacrolimus
• Cyclosporine
• Methotrexate in selected cases

Monitoring depends on the medication and may include:

• CBC
• Liver function
• Renal function

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Biologic and Targeted Therapy

For selected generalized or refractory MG, modern therapies can include targeted immunologic agents directed against:

• B cells
• Complement
• Neonatal Fc receptor pathways

These are generally managed by neuromuscular specialists.

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Ophthalmic Symptomatic Treatment

Diplopia

Temporary measures include:

• Occlusion of one eye
• Translucent tape over one spectacle lens
• Eye patch

Prisms can help when deviation becomes sufficiently stable, but MG-related ocular misalignment is often too variable for prism correction to remain effective.

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Ptosis

Mechanical ptosis crutches are occasionally used but are often poorly tolerated.

Definitive eyelid surgery should generally be avoided until:

• Disease is stable
• The degree of ptosis has remained consistent
• Medical treatment has been optimized

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Thymectomy

Thymoma

A thymoma generally requires surgical management, usually with:

• Thymectomy
• Additional oncologic treatment when indicated

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MG Without Thymoma

Thymectomy can benefit selected patients with generalized AChR-antibody positive MG, particularly younger adults.

It can reduce:

• Disease severity
• Steroid requirements
• Exacerbations

Its role in purely ocular MG is much less established.

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Myasthenic Crisis

Alert

Difficulty breathing or swallowing in a patient with MG is a medical emergency.

A myasthenic crisis is severe worsening resulting in:

• Respiratory insufficiency
• Bulbar failure
• Inability to protect the airway

Patients may require:

• Intensive care
• Respiratory monitoring
• Mechanical ventilation

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Acute Immunomodulatory Treatment

For severe exacerbations or myasthenic crisis:

• Intravenous immunoglobulin (IVIG)
• Plasma exchange

can produce relatively rapid improvement.

These are also used before surgery or during severe deterioration in selected patients.

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Cholinergic Crisis

Excessive acetylcholinesterase inhibitor use can rarely produce excessive cholinergic activity.

Features may include:

• Weakness
• Salivation
• Diarrhea
• Sweating
• Miosis
• Bradycardia

It should be distinguished from worsening MG.

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In-Patient Considerations

Admission may be required for:

• Myasthenic crisis
• Significant dysphagia
• Respiratory weakness
• Severe infection
• Rapidly progressive generalized weakness
• Plasma exchange
• IVIG

Respiratory parameters should be monitored carefully in patients with generalized deterioration.

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Anesthetic Considerations

Patients with MG may be extremely sensitive to neuromuscular blocking medications.

Anesthesiologists must be informed of the diagnosis before surgery.

Perioperative medication management requires individualized planning.

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Issues for Referral

Patients with confirmed or strongly suspected MG should be managed jointly with a:

Neurologist or neuromuscular specialist

because:

• Ocular disease can generalize
• Respiratory complications can occur
• Immunosuppressive therapy requires monitoring
• Thymic evaluation may be necessary

Neuro-ophthalmology referral is useful for complex ocular presentations.

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Ongoing Care

Follow-Up

Patients should be monitored for:

• Change in ptosis
• Ocular motility
• Diplopia
• Development of bulbar symptoms
• Limb weakness
• Breathing difficulty
• Medication adverse effects

Patients initially presenting with ocular disease should be asked specifically about emerging systemic symptoms.

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Prognosis

The course is variable.

Many patients initially present with ocular symptoms.

When ocular MG generalizes, this most commonly occurs during the first few years after onset, especially early in the disease course.

With modern therapy:

• Most patients achieve substantial disease control.
• Permanent remission without treatment is uncommon.
• Mortality is low when respiratory crises are rapidly recognized and appropriately managed.

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Complications

The most important complication is:

Myasthenic Crisis

This is a neurologic emergency characterized by severe respiratory and/or bulbar weakness.

Management may require:

• ICU admission
• Airway support
• Mechanical ventilation
• IVIG
• Plasma exchange
• Treatment of precipitating infection or other trigger

Other complications arise from:

• Aspiration
• Infection
• Long-term corticosteroid treatment
• Chronic immunosuppression
• Thymoma

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Ophthalmology Pearls

• Fluctuating ptosis + variable diplopia + normal pupils = think myasthenia gravis.
• MG can imitate almost any pattern of ocular motor palsy.
• Ocular findings may change during the same examination.
• Sustained upgaze can bring out fatigable ptosis.
• Cogan lid twitch is a useful bedside clue.
• The ice-pack test is a simple, useful test for myasthenic ptosis.
• Pupils are spared—pupillary involvement points away from MG.
• Medial rectus weakness can mimic an INO, producing a pseudo-INO.
• Orbicularis weakness and the peek sign are helpful supportive findings.
• AChR antibodies are less sensitive in isolated ocular MG than in generalized MG.
• Single-fiber EMG can help when antibody studies are negative.
• Evaluate confirmed MG for thymoma.
• New dysphagia, choking, weak cough, or dyspnea may represent impending myasthenic crisis and requires urgent assessment.