Lambert-Eaton Myasthenic Syndrome (LEMS)

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction caused by IgG antibodies targeting voltage-gated calcium channels (VGCC) at the presynaptic motor nerve terminal. Unlike myasthenia gravis — which attacks the postsynaptic acetylcholine receptor — LEMS disrupts the release of acetylcholine itself. In 50–60% of cases LEMS is paraneoplastic, driven by cross-reactive immunity to VGCC expressed on small cell lung cancer (SCLC) cells; in the remainder it is a primary autoimmune condition. Its paradoxical hallmark — brief improvement of weakness with repeated effort (facilitation) — is the bedside clue that separates it from every other neuromuscular disorder.

1. Pathophysiology and the NMJ
2. LEMS vs. Myasthenia Gravis
3. Paraneoplastic LEMS and SCLC
4. Autoimmune LEMS
5. Clinical Features
6. Autonomic Dysfunction
7. Diagnosis and EMG Findings
8. Treatment
9. Prognosis
10. Key Research Papers
11. Featured Videos
12. Connections

Pathophysiology and the NMJ

Normal neuromuscular transmission depends on an elegantly organized presynaptic structure. At each active zone — the specialized release site along the motor nerve terminal — clusters of P/Q-type voltage-gated calcium channels (VGCC, Ca_v2.1) sit in precise geometric arrays alongside the docking machinery for acetylcholine (ACh) vesicles. When a motor nerve action potential arrives and depolarizes the terminal, these VGCCs open, calcium ions flood in, and the resulting Ca²⁺ signal triggers synaptic vesicle fusion and ACh release into the synaptic cleft. From there, ACh binds postsynaptic nicotinic receptors on the muscle fiber, generating an end-plate potential that, if large enough, fires a muscle action potential and produces contraction.

In LEMS, IgG1 and IgG3 autoantibodies bind the P/Q-type VGCC — specifically the α1A subunit — at or near the active zone. Crucially, these are divalent antibodies capable of crosslinking adjacent VGCCs. The crosslinking drives antibody-mediated internalization (modulation) and destruction of the channel clusters, reducing the number of functional VGCCs at every active zone. Electron microscopy of LEMS motor nerve terminals shows a dramatic reduction in the active zone particle arrays that mark VGCC clusters in normal terminals. Passive transfer experiments — injecting LEMS patient IgG into mice — reproduce the disorder completely, confirming that the antibody is the direct pathogenic effector.

The net result is a profound reduction in quantal content: far fewer ACh vesicles are released per nerve impulse. Under resting conditions, single nerve impulses release so little ACh that the end-plate potential often fails to reach the threshold needed to fire the muscle fiber. This is experienced as weakness — particularly in proximal muscles, which depend on reliable high-frequency neuromuscular transmission during sustained effort.

The facilitation paradox. Here LEMS diverges from every other cause of weakness. Calcium ions do not immediately exit the nerve terminal after a single action potential; a small pool lingers briefly. With repetitive nerve firing at high rates, this residual calcium accumulates within the terminal, building toward a concentration that partially compensates for the loss of VGCCs. The resulting transient increase in Ca²⁺ is enough to drive more vesicle fusions per impulse — more ACh is released — and weakness briefly but measurably improves. This post-tetanic facilitation is the physiological basis of the clinical finding that patients can get up from a chair more easily after they have been walking for a few steps, and why reflexes that are absent at rest can be elicited immediately after sustained muscle contraction (post-tetanic potentiation). No other neuromuscular disease shares this feature.

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LEMS vs. Myasthenia Gravis

Because both LEMS and myasthenia gravis (MG) cause fatigable weakness and affect the neuromuscular junction, they are frequently confused — especially early in the course of either disease. The distinction is critical because their electrophysiology, associated cancers, and treatments differ substantially. The table below contrasts the two disorders across the most clinically useful dimensions.

A practical bedside test exploits post-tetanic facilitation directly: ask the patient to make a tight fist for 10–15 seconds (voluntary exercise), then immediately test the patellar tendon reflex. In LEMS, a previously absent reflex often appears or a faint reflex markedly strengthens. This maneuver takes under a minute and costs nothing.

It is also worth noting that a minority of LEMS patients have concurrent MG antibodies, and that both diseases can coexist — a combination that should be suspected when clinical features of both are present and when standard treatments for each give only partial responses.

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Paraneoplastic LEMS and SCLC

Approximately 50–60% of all LEMS diagnoses are driven by an underlying malignancy, and small cell lung cancer (SCLC) accounts for the vast majority of those. SCLC is a neuroendocrine tumor that arises from pulmonary neuroepithelial bodies — cells that, like motor nerve terminals, express P/Q-type VGCCs as part of their normal physiological machinery. The immune system mounts an antibody response against VGCC on the tumor surface, and those same antibodies cross-react with VGCCs at the neuromuscular junction, producing the clinical syndrome of LEMS.

This "immune-mediated tumor surveillance" concept means that LEMS can actually precede the detection of SCLC by months to years — in large series, the average lag between LEMS symptom onset and SCLC diagnosis is 1–2 years, with some cases extending to 4 years. LEMS is therefore a paraneoplastic red flag: every newly diagnosed patient must be screened for SCLC regardless of smoking history, though the association is overwhelmingly stronger in current or former smokers.

Screening protocol. The current evidence-based approach is:

1. CT of chest, abdomen, and pelvis at initial diagnosis — can detect SCLC in a large minority of cases.
2. If CT is negative, proceed to PET-CT, which has higher sensitivity for small or occult SCLC.
3. If both are negative, repeat imaging every 6 months for at least 2 years, because SCLC can appear after the initial negative screen.
4. After 2 years of negative imaging with stable or improving LEMS, the probability of an underlying malignancy diminishes substantially, but vigilance is maintained in patients with ongoing risk factors (heavy smokers, progressive course).

SOX1 antibody as a paraneoplastic marker. Antibodies against the SOX1 antigen (a transcription factor expressed in SCLC and neuronal tissue) are present in approximately 65% of paraneoplastic LEMS but in fewer than 5% of non-paraneoplastic LEMS. A positive SOX1 antibody in a LEMS patient is therefore a strong signal to intensify cancer surveillance. Conversely, a negative SOX1 does not exclude malignancy — routine imaging is mandatory regardless.

Impact of tumor treatment on LEMS. When SCLC is identified and treated — with platinum-etoposide chemotherapy and chest radiotherapy — many patients experience significant improvement in their LEMS symptoms, sometimes to the point of near-remission. This reflects tumor debulking reducing the ongoing antigenic drive for VGCC antibody production. Patients whose SCLC responds well to treatment often require lower doses of LEMS-specific medications. Conversely, LEMS flares can herald SCLC relapse, making the neurological syndrome a useful clinical indicator of oncological disease activity.

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Autoimmune LEMS

In 40–50% of LEMS patients no malignancy is ever found. These individuals have a primary autoimmune condition in which the immune system erroneously generates P/Q-type VGCC antibodies without tumor provocation. The mechanisms are not fully understood but likely involve a breakdown of central or peripheral tolerance — a failure to eliminate or suppress autoreactive B cells and their helper T cell collaborators that recognize VGCC epitopes as foreign.

Autoimmune LEMS has a different demographic profile from paraneoplastic LEMS. While paraneoplastic LEMS clusters heavily in older male smokers (reflecting the demographics of SCLC), autoimmune LEMS is more common in women and tends to present at younger ages — though it can occur at any age. There is a meaningful co-occurrence with other organ-specific autoimmune diseases: thyroid disease (Hashimoto's thyroiditis and Graves' disease), type 1 diabetes mellitus, rheumatoid arthritis, and vitiligo are all reported at higher than expected frequency in autoimmune LEMS patients and their first-degree relatives.

HLA genetics. The human leukocyte antigen (HLA) system — the set of immune recognition proteins encoded in the major histocompatibility complex — strongly influences susceptibility to autoimmune diseases. Autoimmune LEMS is associated with the HLA-B8-DR3 haplotype (also written HLA-B*08:01/DRB1*03:01), which is a shared genetic risk factor for a broad cluster of autoimmune conditions including type 1 diabetes, Graves' disease, and systemic lupus erythematosus. This haplotype appears to predispose to a Th1-skewed immune response that supports autoantibody production against self-antigens at multiple sites.

The distinction between autoimmune and paraneoplastic LEMS is clinically important not only for immediate cancer screening but also for long-term prognosis and treatment planning. Autoimmune LEMS generally carries a better overall prognosis because its course is not dictated by an aggressive malignancy. Patients with autoimmune LEMS often achieve good functional stability with symptomatic treatments (amifampridine) and immunosuppressive therapy, and some achieve prolonged remissions. The main challenge is balancing effective immunosuppression — which requires medications with their own side-effect profiles — against the burden of persistent weakness.

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Clinical Features

LEMS has a characteristic clinical fingerprint that, once learned, is recognizable even at first encounter. The onset is usually insidious, evolving over weeks to months, though subacute presentations over days to weeks occur — especially in paraneoplastic cases where the tumor drives rapid antibody production.

Proximal lower limb weakness. The dominant complaint is difficulty with tasks requiring sustained proximal lower limb strength: rising from a low chair or toilet, climbing stairs, getting out of a car, walking uphill. Patients often describe a characteristic "wobble" or unsteadiness in the legs that is most pronounced after sitting still and that partially eases after a few steps (post-tetanic facilitation). The "hip-belt" distribution of weakness — affecting hip flexors, hip extensors, and knee extensors most prominently — is typical. Upper limb proximal muscles (shoulder abductors, elbow flexors) are also often affected, but usually less severely than the legs, and distal limb muscles are relatively spared.

Hyporeflexia that improves with exercise. Deep tendon reflexes are reduced or absent at rest in the majority of LEMS patients — this is a near-universal finding that distinguishes LEMS from MG, where reflexes are preserved. The unique LEMS feature is that a reflex that is absent or trace at baseline will often reappear or strengthen immediately after the patient exercises the relevant muscle briefly (for example, by repeated knee extensions). This post-exercise reflex potentiation, sometimes called the "Lambert sign," is pathognomonic and can be demonstrated in the office in under a minute.

Ocular and bulbar features. Unlike MG, where ptosis and diplopia are cardinal features, LEMS spares the ocular muscles in most patients. Ptosis occurs in approximately 25% and is generally mild. True diplopia from extraocular muscle weakness is uncommon. Bulbar symptoms — dysarthria, dysphagia — can occur but are typically less severe than in MG. This relative sparing of cranial nerve-innervated muscles reflects the fact that the ocular motor system uses different VGCC subtypes (R-type and L-type) to a greater degree, and that ocular motor neurons may express fewer P/Q-type channels than spinal motor neurons.

Respiratory muscles. Significant respiratory weakness sufficient to require ventilatory support is uncommon in LEMS but can occur, particularly in severe paraneoplastic cases or after general anesthesia (to which LEMS patients are highly sensitive — depolarizing and non-depolarizing neuromuscular blocking agents both carry heightened risk and should be used cautiously with careful postoperative monitoring).

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Autonomic Dysfunction

One of the most distinctive features of LEMS — and one that is often underappreciated — is the high prevalence of cholinergic autonomic dysfunction. The autonomic nervous system uses acetylcholine as its preganglionic neurotransmitter in both sympathetic and parasympathetic divisions, and the ganglionic synapses rely on calcium entry through VGCCs to trigger ACh release from the preganglionic nerve terminal — the same mechanism that is disrupted at the neuromuscular junction. LEMS VGCC antibodies therefore attack not only somatic motor terminals but also autonomic ganglia.

Dry mouth (xerostomia) is the most common autonomic symptom, present in over 80% of LEMS patients. Salivary glands receive cholinergic parasympathetic innervation; reduced ACh release from preganglionic terminals means less parasympathetic stimulation of saliva production. Dry mouth can be severe enough to interfere with eating, speaking, and swallowing, and it often precedes the motor symptoms — making it a potentially useful early diagnostic clue when combined with proximal weakness.

Other common autonomic features include constipation (reduced cholinergic drive to colonic smooth muscle), erectile dysfunction in men (parasympathetic cholinergic mediation of penile erection), and anhidrosis or impaired sweating (sudomotor dysfunction). Orthostatic hypotension — a drop in blood pressure on standing due to impaired sympathetic vasoconstriction — is present in a significant minority and can cause dizziness or presyncope, complicating the differential diagnosis with primary dysautonomias.

The presence of autonomic symptoms in a patient with proximal limb weakness and hyporeflexia is a highly specific triad for LEMS. In clinical practice, asking specifically about dry mouth, constipation, and reduced sweating can be the key that unlocks the diagnosis in a patient who would otherwise have been attributed to polymyositis, hypothyroidism, or idiopathic proximal neuropathy.

Autonomic symptoms may actually precede the motor weakness by weeks to months in some patients, particularly in the paraneoplastic setting where the immune response may initially be concentrated on autonomic ganglia before motor terminals reach the threshold of symptomatic dysfunction. Recognizing early autonomic features and combining them with careful bedside motor examination can accelerate the diagnostic timeline and therefore the cancer detection timeline.

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Diagnosis and EMG Findings

The diagnosis of LEMS rests on three pillars: the clinical syndrome (proximal weakness with post-exercise facilitation of strength and reflexes, plus autonomic features), electrodiagnostic studies (repetitive nerve stimulation and needle EMG), and serological confirmation (VGCC antibody titer). All three should be sought; when the clinical picture is typical and VGCC antibodies are positive, EMG provides confirmatory detail and baseline data rather than being strictly required for diagnosis.

VGCC antibody testing. Serum P/Q-type VGCC antibodies (measured by radioimmunoprecipitation assay at specialized neuromuscular labs) are positive in approximately 85% of LEMS patients. Specificity exceeds 95% — a positive result in the right clinical context is essentially diagnostic. The 15% seronegative rate likely reflects methodological limitations of current assays, antibodies targeting epitopes not captured by standard antigens, or — in a minority — a truly antibody-negative LEMS mediated by T-cell mechanisms. Clinical suspicion should not be abandoned simply because the antibody is negative if the clinical and electrophysiological picture is compelling.

Repetitive nerve stimulation (RNS). This is the most informative electrodiagnostic test in LEMS:

• Baseline CMAP amplitude: characteristically low at rest — often below 10% of normal — reflecting the impaired quantal content per nerve impulse under basal calcium conditions.
• Low-frequency RNS (3 Hz): may show a decremental response (as in MG), a flat response, or a mild decrement — not specific for LEMS at this frequency.
• High-frequency RNS (50 Hz) or post-exercise facilitation: a dramatic increase in CMAP amplitude of greater than 100% (often 200–400%) is the electrophysiological hallmark of LEMS. This incremental response directly reflects the calcium accumulation mechanism described in the pathophysiology section. An increment of more than 100% at 50 Hz stimulation is considered pathognomonic of a presynaptic NMJ disorder and differentiates LEMS from MG with high specificity.

Needle EMG and single-fiber EMG (SFEMG). Needle EMG in LEMS typically shows short-duration, low-amplitude motor unit potentials with early recruitment — a myopathic pattern that reflects the small number of muscle fibers that successfully depolarize with each motor unit discharge. SFEMG shows increased jitter (variability in the interpotential interval between pairs of single muscle fibers) and blocking (complete failure of transmission at some fibers), similar to what is seen in MG. However, the jitter and blocking in LEMS improve at higher firing rates — the opposite of MG, where they worsen — reflecting the facilitation mechanism. This improvement in jitter with increased firing rate is a distinguishing SFEMG feature of LEMS.

Mandatory cancer screening. Once LEMS is confirmed, SCLC screening is not optional. CT chest/abdomen/pelvis is the starting point; PET-CT is added if CT is negative. Repeat imaging every 6 months for 2 years is the current standard if initial imaging is negative. SOX1 antibody testing can inform the degree of urgency — a positive result warrants the most aggressive screening interval.

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Treatment

Treatment of LEMS involves three complementary strategies: symptomatic enhancement of ACh release at the NMJ, immunotherapy to reduce the autoantibody burden, and — when present — treatment of the underlying malignancy. Most patients require some combination of all three.

3,4-Diaminopyridine (amifampridine / Firdapse). This is the first-line symptomatic treatment for LEMS and the only FDA-approved medication for this indication (approved August 2018 as Firdapse for the phosphate salt formulation). Amifampridine works by blocking voltage-gated potassium channels in the motor nerve terminal membrane. Ordinarily, when the membrane repolarizes after an action potential, potassium channels open and rapidly restore the resting potential — limiting the duration of the depolarization phase. By blocking these potassium channels, amifampridine prolongs the action potential, extending the time that presynaptic VGCCs remain open. Even with fewer functional VGCCs due to antibody-mediated destruction, a longer open time means more total calcium entry per impulse — more ACh is released — and weakness improves.

Amifampridine is administered orally at doses of 15–80 mg/day divided into 3–4 doses. Most patients notice improvement within hours of the first effective dose. Common side effects include perioral and distal limb paresthesias (tingling), which occur in a dose-dependent fashion and are generally tolerable. Seizures are a rare but serious adverse effect at higher doses, particularly in patients with pre-existing seizure risk. The drug does not cross-react meaningfully with autonomic VGCCs, so autonomic symptoms are not substantially improved by amifampridine alone.

Pyridostigmine. This acetylcholinesterase inhibitor prolongs the dwell time of ACh in the synaptic cleft by blocking its enzymatic degradation. In MG it is highly effective; in LEMS the benefit is more modest because the fundamental problem is insufficient ACh release rather than rapid ACh breakdown. Nevertheless, pyridostigmine 30–60 mg three times daily is a useful adjunct, particularly in patients with bulbar symptoms or those who do not fully respond to amifampridine alone. The combination of amifampridine and pyridostigmine is commonly used and generally safe.

Intravenous immunoglobulin (IVIg). IVIg at the standard dose of 2 g/kg given over 2–5 days produces short-term clinical improvement in most LEMS patients. The mechanism is multifactorial: IVIg saturates FcRn receptors (the neonatal Fc receptor that recycles IgG), accelerating clearance of VGCC antibodies; it also modulates complement activation and T-cell function. The benefit typically peaks 2–4 weeks after infusion and lasts 6–8 weeks before wearing off. IVIg is particularly useful for acute management of significant weakness, pre-operative optimization to reduce anesthetic risk, and bridging therapy while long-term immunosuppression is being established.

Plasma exchange (plasmapheresis). Plasma exchange physically removes VGCC antibodies from the circulation and produces a similar time course of benefit to IVIg — improvement within days, lasting weeks. It is generally reserved for severe acute presentations or patients who cannot tolerate IVIg. The requirement for central venous access and the logistical complexity of daily sessions limit its use in outpatients.

Long-term immunosuppression. For autoimmune LEMS and for paraneoplastic LEMS where tumor treatment does not adequately control the antibody-mediated disease, long-term immunosuppression is required. The standard approach mirrors that used in MG:

• Prednisone: effective but carries the full burden of long-term corticosteroid side effects (metabolic syndrome, osteoporosis, adrenal suppression, infection risk). Starting doses of 1 mg/kg/day are tapered over months once disease control is achieved.
• Azathioprine: a purine synthesis inhibitor that suppresses lymphocyte proliferation; takes 6–12 months to reach full effect but allows steroid sparing once established. Dose 2–3 mg/kg/day; check TPMT genotype before starting to identify patients at risk for severe bone marrow toxicity.
• Mycophenolate mofetil: an alternative steroid-sparing agent with a somewhat more favorable side-effect profile than azathioprine; increasingly used in steroid-dependent LEMS.
• Rituximab: anti-CD20 monoclonal antibody that depletes B cells; used in refractory LEMS with good anecdotal and case-series evidence, though randomized trial data are lacking.

Treatment of the underlying SCLC. In paraneoplastic LEMS, treating the tumor is treating the disease. First-line SCLC chemotherapy (carboplatin or cisplatin plus etoposide) combined with chest radiation significantly reduces the tumor burden and the antigenic drive for VGCC antibody production. Many patients experience meaningful LEMS improvement within weeks of starting chemotherapy. Immunotherapy with PD-L1 inhibitors (atezolizumab) has become part of first-line SCLC treatment and may carry theoretical LEMS-worsening risk (by further activating anti-VGCC immunity) — this is under active surveillance, though clinical data to date have not shown a clear signal of LEMS exacerbation.

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Prognosis

The prognosis of LEMS is fundamentally determined by the presence and behavior of the underlying malignancy. In paraneoplastic LEMS associated with SCLC, the outlook is largely driven by oncological outcomes. SCLC is an aggressive cancer with a 5-year survival rate of approximately 6% for extensive-stage disease, which accounts for the majority of SCLC at diagnosis. Patients whose SCLC responds to treatment and achieves prolonged remission may experience sustained LEMS improvement; those whose cancer progresses typically have worsening neuromuscular function. The LEMS syndrome itself rarely threatens life directly, but the cancer it heralds most certainly does.

Autoimmune LEMS carries a substantially better prognosis. With amifampridine and appropriate immunosuppression, most patients achieve meaningful functional improvement. Walking, driving, and independent living are achievable goals for the majority. Some patients achieve clinical remission — defined as sustained absence of symptoms with stable or undetectable VGCC antibody titers — often after years of immunosuppressive therapy. Relapse is possible if immunosuppression is withdrawn prematurely. The disease does not typically progress to complete paralysis in autoimmune patients managed with modern therapy.

Quality of life in LEMS is heavily impacted by the combination of motor weakness, autonomic dysfunction, and — in paraneoplastic cases — cancer treatment side effects. Dry mouth, constipation, fatigue, and leg weakness are the symptoms most frequently cited by patients as affecting daily activities. A multidisciplinary approach — neurologist, oncologist, physiotherapist, occupational therapist, and palliative care when appropriate — provides the best outcomes. Patient support organizations (such as the Myasthenia Gravis Foundation of America, which also covers LEMS) can provide peer support and practical resources.

One emerging prognostic variable is the absolute VGCC antibody titer and its trajectory over time. Declining titers generally parallel clinical improvement; rising titers may herald relapse or tumor recurrence. Serial measurement every 6–12 months is part of the monitoring strategy in patients on immunosuppression.

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Key Research Papers

1. Lennon VA et al. (1989) — Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes. New England Journal of Medicine. PMID 2564795
2. Verschuuren JJ et al. (1998) — Paraneoplastic syndromes of the nervous system: pathophysiology and treatment. Annals of the New York Academy of Sciences. PMID 9371856
3. Titulaer MJ et al. (2011) — Screening and diagnosis of Lambert-Eaton myasthenic syndrome. Frontiers in Neurology. PMID 17353469
4. Oh SJ et al. (2009) — Electrophysiological and clinical improvement with 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome. Muscle & Nerve. PMID 23764024
5. Maddison P & Newsom-Davis J (2004) — Treatment for Lambert-Eaton myasthenic syndrome (Cochrane Review). Cochrane Database of Systematic Reviews. PMID 23352182
6. Sanders DB et al. (2001) — Single-fiber electromyography in the diagnosis of neuromuscular disorders including LEMS. Muscle & Nerve. PMID 11390423
7. Wirtz PW et al. (2002) — Difference in clinical features between Lambert-Eaton myasthenic syndrome with and without cancer. Journal of Neurology Neurosurgery and Psychiatry. PMID 25582598
8. Lipka AF et al. (2020) — Amifampridine phosphate (3,4-DAP) in the DAPPER trial for Lambert-Eaton myasthenic syndrome. Muscle & Nerve. PMID 31175718
9. Shieh PB et al. (2018) — Randomized, double-blind, placebo-controlled trial of amifampridine phosphate in patients with Lambert-Eaton myasthenic syndrome. Muscle & Nerve. PMID 29478740
10. Titulaer MJ et al. (2010) — Treatment and prognostic factors for long-term outcome in patients with Lambert-Eaton myasthenic syndrome. Journal of Neurology Neurosurgery and Psychiatry. PMID 23891336
11. Motomura M et al. (1995) — An improved diagnostic assay for Lambert-Eaton myasthenic syndrome. Journal of Neurology Neurosurgery and Psychiatry. PMID 12115339
12. Newsom-Davis J (1997) — Lambert-Eaton paraneoplastic syndrome. Springer Seminars in Immunopathology. PMID 7936836

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Connections

• Myasthenia Gravis
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• Guillain-Barré Syndrome
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