Distinguishing Lambert-Eaton Myasthenic Syndrome From Ocular Myasthenia Gravis in the Eye Clinic

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction in which antibodies against presynaptic P/Q-type voltage-gated calcium channels impair acetylcholine release. It typically presents with proximal leg weakness, reduced reflexes, and autonomic dysfunction, but ocular symptoms such as ptosis and diplopia can appear and make it easy to mistake for seronegative ocular myasthenia gravis. For that reason, some patients may first present to an eye care practice.

Roughly half of LEMS cases are paraneoplastic, most often tied to small cell lung cancer, which means early recognition can also lead to an earlier cancer diagnosis. Because treatment differs substantially between LEMS and myasthenia gravis, sorting out which disorder is present shapes everything that follows.

To help eye care clinicians recognize the condition, NeurologyLive spoke with Kiril Kiprovski, MD, clinical professor of neurology and director of the Division of Neuromuscular Medicine at NYU Langone. Kiprovski answered questions on the clinical clues that should raise suspicion for LEMS, bedside maneuvers that separate presynaptic from postsynaptic disorders, the role of autonomic symptoms, what testing to start before referral, and how treatment and coordination between neurology and eye care differ across the two conditions.

NeurologyLive: In a patient with fluctuating ptosis or diplopia who tests negative for acetylcholine receptor antibodies, what clinical clues should raise suspicion for LEMS rather than seronegative ocular myasthenia gravis?

Kiril Kiprovski, MD: The key distinction is that Lambert-Eaton myasthenic syndrome (LEMS) is primarily a presynaptic neuromuscular junction disorder that causes proximal limb weakness and autonomic dysfunction. Ocular myasthenia gravis (OMG), in contrast, typically causes fluctuating, fatigable weakness of the extraocular and eyelid muscles, without prominent autonomic symptoms and with or without limb weakness. The clinical features of LEMS are as follows:

• Distribution of weakness: proximal leg weakness, with difficulty rising from a chair, climbing stairs, or walking uphill.
• Reduced or absent deep tendon reflexes, sometimes transiently restored after exercise.
• Autonomic symptoms: dry mouth, constipation, erectile dysfunction, reduced sweating, and orthostatic symptoms.

Are there bedside maneuvers an eye care clinician can perform in the exam lane that help distinguish a presynaptic neuromuscular junction disorder from a postsynaptic one?

Check deep tendon reflexes before and after exercise. This is the best bedside clue for LEMS.

• Test the patellar and Achilles reflexes at rest.
• Ask the patient to perform a brief maximal contraction, such as repeated chair rises or a 10-second quadriceps contraction.
• Immediately retest the reflexes.

Interpretation: Depressed or absent reflexes that transiently return or become brisker after contraction strongly favor LEMS. Reflexes are usually preserved in ocular MG.

• Progressive ptosis on sustained upgaze supports a fatigable disorder but is not specific.
• Ptosis that improves by at least 2 mm after cooling supports MG but does not definitively exclude LEMS.
• Normal reflexes, no autonomic symptoms, and isolated fluctuating ptosis or diplopia are more compatible with ocular MG but are not diagnostic.

How does the timing and progression of ocular involvement in LEMS typically compare with myasthenia gravis, and what does that mean for the rare patient whose first stop is an eye care practice?

Myasthenia gravis (MG) commonly starts in the eyes, with facial and bulbar weakness, whereas LEMS usually starts in the proximal legs and reaches the eyes later if it is untreated or progressive. That distinction is useful in an eye care practice, but it is a clinical pattern rather than an absolute rule.

Which autonomic features of LEMS can surface during a routine eye examination, and how much weight should those findings carry in the diagnostic picture?

Autonomic symptoms are among the most useful clues to LEMS in an eye care practice because patients may not volunteer them unless specifically asked. Dry mouth, dry eyes, constipation, reduced sweating, and lightheadedness on standing are particularly worth screening for. Their diagnostic value is greatest when they occur alongside proximal leg weakness and reduced tendon reflexes.

When a neuromuscular junction disorder is suspected, what testing is reasonable to initiate before referral, and which parts of the workup, such as electrodiagnostic studies, are best left to a neuromuscular specialist?

For an eye care clinician evaluating fluctuating ptosis or diplopia, the most useful approach is to document the phenotype, initiate targeted first-line testing when appropriate, and refer early rather than delaying referral to complete the workup.

• AChR antibodies and MuSK antibodies are reasonable first-line tests for MG.
• P/Q-type voltage-gated calcium channel antibodies are a reasonable first-line test for LEMS.
• A complete blood count, metabolic panel, thyroid testing, and other tests should be guided by the history and examination.
• Document ocular motility, ptosis, pupils, proximal strength, tendon reflexes, autonomic symptoms, and bulbar or respiratory complaints.

What is the relationship between LEMS and underlying malignancy, and how should that relationship shape the urgency of referral when an eye care clinician suspects the diagnosis?

The relationship is clinically important because LEMS is a paraneoplastic neurologic syndrome in approximately half of cases, most often associated with small cell lung cancer (SCLC). In some patients, the immune response triggered by the tumor produces antibodies against presynaptic P/Q-type voltage-gated calcium channels, impairing acetylcholine release at the neuromuscular junction.

For an eye care clinician, this means suspected LEMS is not simply a reason to arrange a routine neurology appointment. It can be the first clue to an otherwise undiagnosed malignancy.

How do current symptomatic and immunomodulatory treatments affect ocular symptoms like ptosis and diplopia, and where does coordination between neurology and eye care add the most value in long-term management?

Treatment differs substantially between LEMS and MG. The first goal is to treat the underlying neuromuscular junction disorder, not simply the visible ptosis or diplopia. The best treatment depends on which disorder is present.

For LEMS:

• Amifampridine (3,4-DAP): This is the principal symptomatic treatment for LEMS. It prolongs presynaptic depolarization, increasing calcium entry and acetylcholine release. It can improve muscle strength and may improve ocular symptoms, but ptosis and diplopia may respond less predictably than limb weakness.
• Pyridostigmine and immunotherapy: Pyridostigmine is sometimes added, although its benefit in LEMS is generally more modest than in MG. For persistent, clinically significant autoimmune LEMS, neurologists may use corticosteroids and steroid-sparing agents such as azathioprine. IVIG can be considered in selected cases.

For MG, particularly ocular MG, treatment often follows a different sequence:

• Pyridostigmine: This is commonly tried first for symptomatic relief. It can help ptosis, but diplopia and extraocular muscle weakness may respond incompletely.
• Corticosteroids: If ocular symptoms remain functionally limiting or troublesome despite symptomatic treatment, low-dose prednisone or another appropriate corticosteroid regimen may be considered under neurologic supervision.
• Steroid-sparing immunotherapy: Agents such as azathioprine or mycophenolate may be used when corticosteroids are ineffective, unsuitable, or poorly tolerated. Benefits can take months to emerge, and treatment requires monitoring for adverse effects.
• Advanced therapies: Selected patients with generalized or difficult-to-control MG may be candidates for IVIG, plasma exchange, or targeted biologic therapies, depending on disease subtype and severity. These are not routine treatments for every patient with isolated ocular MG.

Treatment choices depend on disease severity, adverse effects, and whether the syndrome is cancer-associated. The associated cancer should also be treated.