Distinguishing Lambert-Eaton Myasthenic Syndrome From Myasthenia Gravis: Ocular and Systemic Clues

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Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction in which patients produce autoantibodies against presynaptic P/Q-type voltage-gated calcium channels (VGCCs) on motor nerve terminals. By limiting calcium entry when a nerve impulse arrives, these antibodies reduce vesicular acetylcholine release and weaken muscle contraction. Antibodies may also bind N-type channels, which govern transmitter release from autonomic nerve terminals.¹

Because myasthenia gravis (MG) also targets the neuromuscular junction, the 2 conditions are frequently confused, particularly when patients present with ptosis or diplopia. LEMS classically presents with a triad of proximal limb weakness, reduced or absent tendon reflexes, and autonomic dysfunction.^1,2 The disease occurs in 2 forms: paraneoplastic LEMS, in which the immune response is thought to begin against VGCCs expressed by a tumor, most often small cell lung cancer (SCLC), and nontumoral LEMS, which behaves as a primary autoimmune condition.¹

How LEMS Differs From MG

The core distinction is anatomic: LEMS autoantibodies target molecules on the presynaptic membrane, whereas MG autoantibodies target the postsynaptic membrane.^1,3 That difference produces several clinically useful contrasts.

Pattern of weakness. MG usually begins in the extraocular muscles and spreads downward, whereas LEMS begins in the legs and ascends, reaching the oculobulbar muscles later in the disease course.^1,4 In a Dutch comparison, ocular weakness was the first symptom in 59% of patients with MG and in none with LEMS.⁴

Response to effort. Weakness in MG worsens with sustained activity. In LEMS, strength and reflexes may briefly improve after maximal contraction, and ptosis may lessen rather than worsen after sustained upgaze.^1,5

Reflexes and autonomic function. Reduced or absent tendon reflexes and autonomic symptoms such as dry mouth are hallmarks of LEMS.^1,2

Testing. The resting compound muscle action potential (CMAP) is low in LEMS and often more than doubles after brief exercise. P/Q-type VGCC autoantibodies are detected in 80% to 90% of patients with LEMS vs fewer than 5% of patients with MG.¹

Cancer and treatment response. More than half of LEMS cases are associated with SCLC, so the diagnosis should prompt a tumor search. Acetylcholinesterase inhibitors help many patients with MG but usually produce little improvement in LEMS, for which amifampridine is the first-line symptomatic therapy.^1,6,7

Epidemiology and Cancer Association

The annual incidence of LEMS is roughly one-10th to one-14th that of MG, and its prevalence is approximately 46 times lower.¹ A nationwide Turkish database study confirmed 159 cases, with a median age at diagnosis of 60 years (range, 16-88). Women made up 55% of the cohort, and approximately 60% of patients had the paraneoplastic form, with SCLC accounting for 56% of those tumors.⁸ A Japanese nationwide survey estimated prevalence at 2.7 per million and identified a tumor in 47% of patients, most often SCLC; men predominated in the paraneoplastic group and women in the autoimmune group.³

Demographics differ by subtype. In SCLC-associated LEMS, median age at onset is approximately 60 years, and 65% to 75% of patients are men. Nontumoral LEMS can begin at any age, with a smaller peak around age 35 years and a larger one near 60 years, and most of these patients are women.¹

Smoking, weight loss, and male sex raise the likelihood of an underlying cancer.¹ Neurologic symptoms usually precede tumor detection; in an analysis of 227 published cases, cancer was diagnosed anywhere from 5 years before to 6 years after LEMS onset.^1,9 As a result, neurologists and eye care professionals evaluating new weakness, ptosis, or diplopia may encounter these patients before a cancer is found.

Clinical Features, Diagnosis, and Tumor Screening

Leg weakness is the most common initial complaint, reported by 60% of patients in one large review, whereas diplopia was the presenting symptom in only 4%.⁹ Weakness typically spreads from proximal to distal muscles and from the legs upward, the reverse of the craniocaudal pattern seen in MG, and progresses faster when SCLC is present.^1,2 Autonomic dysfunction affects 80% to 96% of patients. Dry mouth is the most frequent complaint, followed by erectile dysfunction, constipation, orthostatic symptoms, altered sweating, and dry eyes.¹

Diagnosis rests on clinical features confirmed by serology and electrodiagnostic testing. On repetitive nerve stimulation, the resting CMAP is low, decrements at slow stimulation rates, and rises, often by more than 100%, after 10 seconds of maximal voluntary contraction or high-rate stimulation. Antibodies to SOX1 favor an associated SCLC.¹

Once LEMS is confirmed, chest CT or PET imaging is recommended, with repeat screening every 3 to 6 months for at least 2 years.¹ The DELTA-P score can help stratify risk, assigning 1 point each for 50 years and older, smoking, weight loss of 5% or more, bulbar involvement, erectile dysfunction, and a Karnofsky performance score below 70; higher scores indicate greater SCLC risk.^1,10

Ocular Manifestations

Ocular involvement in LEMS differs from that in MG in both timing and severity. In the Dutch comparison of 38 patients with LEMS and 101 with MG, 59% of patients with MG first noticed eye symptoms vs none with LEMS, leading the authors to conclude that ocular-onset weakness makes LEMS very unlikely.⁴ Eye findings nonetheless become common as disease evolves: in a large cohort, about half of patients developed ocular symptoms within 12 months of onset, particularly those with SCLC.^1,2 At the Lahey Clinic in Burlington, Massachusetts, 78% of 23 patients had oculobulbar symptoms or signs and 65% had ptosis, diplopia, or both; investigators cautioned that these findings should not be used to rule out LEMS.¹¹

A Mayo Clinic retrospective review focused on ophthalmic findings reported ptosis (23%), diplopia (20.5%), decreased vision (14%), and dry eye (7%) as symptoms. Examination signs included ptosis (26%), abnormal ocular motility (8.5%), strabismus (8%), pupillary dysfunction (7%), and dry eye (2%).^1,12 Overall, ocular weakness in LEMS tends to be milder than in MG, and frank ophthalmoplegia is very unusual.¹

Several examination findings may point toward LEMS. In an early neuro-ophthalmic series, 3 of 5 patients had mild, unilateral ptosis of no more than 2 to 3 mm.¹³ Whereas ptosis in MG typically worsens with prolonged upgaze, ptosis in LEMS may transiently improve, a paradoxical lid elevation described in case reports.^5,14 Enhanced ptosis, in which manually lifting one lid worsens ptosis of the fellow lid, occurs in both conditions and therefore does not exclude LEMS.¹⁴ Eye-movement recordings have also shown subclinical increases in saccadic velocity after repeated saccades, the opposite of the fatigue expected in MG.¹³

Isolated ocular presentations are rare but documented.¹⁵ In one report, a 59-year-old woman with bilateral ptosis and diplopia was initially diagnosed with seronegative ocular MG. Brief exercise testing showed a CMAP increment of more than 100%, P/Q-type VGCC antibodies were markedly elevated, and chest CT revealed a mediastinal mass; biopsy confirmed small cell carcinoma.¹⁶

Clinical Red Flags

Features that should raise suspicion for LEMS in a patient presenting with ocular symptoms include:

• Ptosis or diplopia accompanied by difficulty climbing stairs, rising from a chair, or proximal fatigue
• Autonomic symptoms such as dry mouth, dry eye, constipation, or erectile dysfunction
• Ptosis that improves, rather than worsens, after sustained upgaze
• Suspected ocular MG that is antibody-negative or responds poorly to pyridostigmine¹
• SCLC risk factors, including 50 years and older, smoking, and unexplained weight loss¹⁰

These patients warrant prompt antibody and electrodiagnostic testing. Before surgery under general anesthesia, the anesthesia team should be aware of the diagnosis, because respiratory failure in LEMS, although uncommon, is often related to paralytic agents.¹

Treatment and Prognosis

In paraneoplastic LEMS, treating the underlying cancer is the priority and often improves neuromuscular symptoms.¹

Amifampridine (3,4-diaminopyridine; Firdapse; Catalyst Pharmaceuticals) blocks presynaptic potassium channels, prolonging nerve terminal depolarization so that VGCCs stay open longer and more acetylcholine is released.^6,17 In a phase 3 randomized withdrawal trial of 38 patients, amifampridine phosphate was significantly better than placebo on the Quantitative Myasthenia Gravis score and Subject Global Impression; the most common adverse events were oral and digital paresthesias, nausea, and headache.¹⁸ A trial of the base formulation showed that strength was maintained with treatment,¹⁷ and a Cochrane review found moderate- to high-quality evidence that the drug improves muscle strength and CMAP amplitude.¹⁹ Typical daily doses range from 30 to 80 mg in divided doses, and seizures have been reported at daily doses above 100 mg.¹ The FDA has approved amifampridine for adults and pediatric patients 6 years and older, and Australian guidance recommends it as first-line symptomatic therapy.^6,20

Acetylcholinesterase inhibition is less helpful in LEMS than in MG. In a randomized crossover trial, adding pyridostigmine to 3,4-diaminopyridine provided no further benefit, and pyridostigmine alone did not differ from placebo.⁷

For rapidly progressive disease, intravenous immunoglobulin at 1 g/kg daily for 2 days improved limb strength in a randomized crossover trial, with an effect that peaked at 2 to 4 weeks and declined over up to 8 weeks alongside falling VGCC antibody levels.²¹ Plasma exchange may help patients with severe weakness.¹

When symptoms persist despite symptomatic therapy, prednisolone combined with azathioprine is commonly used, mainly in nontumoral LEMS. Among 47 such patients followed at 1 center, approximately 90% required combination therapy and 43% achieved sustained clinical remission within 3 years, although only 14% reached both clinical and pharmacologic remission.²² Because immunosuppression could theoretically weaken the antitumor immune response, aggressive immunotherapy is used more often in patients without cancer.¹

In paraneoplastic LEMS, outcome depends largely on the cancer. Notably, patients with both SCLC and LEMS survive longer than those with SCLC alone, an advantage that persisted after adjustment for known prognostic factors in a prospective comparison.²³

Clinical Implications

Because LEMS is rare and its eye signs are usually mild and late, they are easily attributed to MG or aging. Still, ptosis, diplopia, dry eye, and pupillary changes occur in a meaningful share of patients, and in a few, the eye is where disease first manifests.^12,15,16 Pairing an ocular finding with a history of proximal weakness or autonomic symptoms, and recognizing ptosis that improves with sustained upgaze, can prompt testing that leads to both a neuromuscular diagnosis and earlier detection of an associated lung cancer.

Price Wooldridge, founder and board president of the LEMS Family Association and a patient with LEMS, noted that because the patient population is so small, “clinical experience is often lacking due to the scarcity of patients.” He described frequent misdiagnosis stemming from symptom overlap with MG and other autoimmune disorders. Although proximal weakness and inability to walk were his first symptoms, he has also experienced blurry and double vision, with severity that fluctuates unpredictably. Woolridge emphasized that greater physician awareness gives patients a better chance at a correct diagnosis and effective treatment.

Information about the LEMS Family Foundation can be accessed at the website: lemsfamily.org

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