What is the differential diagnosis for ocular myasthenia gravis?

Differential Diagnosis for Ocular Myasthenia Gravis

The differential diagnosis for ocular myasthenia gravis includes any pupil-sparing ocular motility disorder, with the most critical distinctions being third nerve palsy, thyroid eye disease, chronic progressive external ophthalmoplegia, Lambert-Eaton syndrome, botulism, brainstem lesions, and orbital pathology. 1, 2

Key Distinguishing Feature: Pupil-Sparing Pattern

Pupils are characteristically not affected in myasthenia gravis, which serves as the most important distinguishing feature from other causes of ophthalmoplegia and ptosis. 2 If pupils are abnormal, immediately prioritize evaluation for third nerve palsy, Horner syndrome, or other neurologic causes over myasthenia gravis. 2 This pupil-sparing pattern occurs because myasthenia affects nicotinic receptors at the neuromuscular junction of voluntary skeletal muscles, not the autonomic nervous system responsible for pupillary function. 2

Primary Differential Diagnoses

Third Nerve Palsy

• Most critical distinction: Third nerve palsy can present with ptosis and ophthalmoplegia but typically involves pupillary abnormalities (though pupil-sparing variants exist). 1, 2
• Requires immediate neuroimaging and vascular workup given risk of aneurysm or ischemia. 1
• Unlike myasthenia, weakness pattern follows anatomic distribution of third nerve rather than variable, fatigable pattern. 3

Thyroid Eye Disease (TED)

• Second most common mimic: TED causes restrictive myopathy with mechanical limitation rather than neuromuscular junction dysfunction. 1
• Key distinguishing features include proptosis (measured by exophthalmometry), eyelid retraction, and fixation duress (brow elevation with attempted upgaze). 1
• Forced duction testing confirms mechanical restriction in TED versus fatigable weakness in myasthenia. 1
• Inferior rectus most commonly affected, followed by medial rectus, causing hypotropia with esotropia. 1
• Orbital imaging shows tendon-sparing muscle enlargement in TED. 1
• Critical pitfall: Myasthenia incidence is increased in TED patients, so assess for coexistence if clinical examination suggests both. 1

Chronic Progressive External Ophthalmoplegia (CPEO)

• Presents with slowly progressive, symmetric ophthalmoplegia and ptosis without fluctuation or fatigability. 3
• Lacks the variability and fatigue pattern characteristic of myasthenia. 4, 3
• Mitochondrial disorders should be considered with family history or systemic features. 3

Lambert-Eaton Myasthenic Syndrome (LEMS)

• Autoimmune disorder affecting presynaptic calcium channels rather than postsynaptic acetylcholine receptors. 4, 3
• Weakness typically improves with repeated muscle contraction (opposite of myasthenia). 3
• More commonly affects proximal limb muscles; ocular involvement less prominent than in myasthenia. 4
• Associated with small cell lung cancer in 50-60% of cases. 3

Botulism

• Acute onset of descending paralysis with pupillary involvement (dilated, poorly reactive pupils). 4, 3
• History of contaminated food, wound infection, or infant exposure. 3
• Autonomic dysfunction prominent (unlike myasthenia's pupil-sparing pattern). 2, 3

Brainstem Lesions

• Stroke, demyelination, or tumor affecting midbrain/pons can mimic ocular myasthenia. 3
• Associated with other brainstem signs (sensory changes, ataxia, altered consciousness). 3
• Neuroimaging (MRI brain with contrast) essential to exclude. 3

Orbital Pathology

• Orbital tumors, inflammation (orbital myositis), or infiltrative processes can restrict eye movements. 3
• Orbital imaging distinguishes these from myasthenia. 1, 3
• Pain more common with orbital inflammation than myasthenia. 3

Secondary Considerations

Congenital Myasthenic Syndromes

• Not immune-mediated; present in childhood with lifelong symptoms. 1
• Genetic testing confirms diagnosis. 1

Oculopharyngeal Muscular Dystrophy

• Progressive ptosis and dysphagia without fluctuation. 3
• Positive family history in autosomal dominant inheritance pattern. 3

Systemic Conditions Causing Fluctuating Symptoms

• Encephalopathy, sepsis, or metabolic derangements can produce fluctuating ptosis or eye movements. 3
• However, myasthenia is almost never found when weakness or fatigue symptoms lack objective neurological correlate. 3

Diagnostic Approach to Differentiate

Clinical Examination Priorities

• Assess pupillary function first as part of initial examination in patients with ptosis and ophthalmoplegia. 2
• Document variability and fatigability: symptoms worsen with sustained upgaze or at end of day. 1, 4
• Perform ice pack test: apply ice over closed eyes for 2 minutes; highly specific for myasthenia if symptoms improve. 2, 5
• Forced duction testing distinguishes mechanical restriction (TED, orbital pathology) from neuromuscular weakness. 1

Laboratory and Electrodiagnostic Testing

• Anti-AChR antibodies present in only 40-77% of ocular myasthenia (versus nearly all generalized cases). 1, 5
• Single-fiber EMG has >90% sensitivity for ocular myasthenia; repetitive nerve stimulation only 33% sensitive. 5
• Anti-MuSK antibodies should be tested when AChR antibodies negative. 5

Imaging Studies

• Orbital CT/MRI differentiates TED (tendon-sparing muscle enlargement) from myasthenia. 1
• Brain MRI with contrast excludes brainstem lesions. 3
• Chest CT with contrast mandatory after myasthenia diagnosis to evaluate for thymoma. 5

Critical caveat: Approximately 50-80% of patients presenting with isolated ocular symptoms will develop generalized myasthenia within a few years, making accurate diagnosis essential for preventing life-threatening respiratory failure. 1, 5