Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular junction disease characterized by presynaptic autoantibodies against voltage-gated calcium channels (VGCC) at motor nerve terminals. It has the paradoxical feature of temporary improvement in muscle strength after repeated voluntary muscle contractions.
Neurological signs associated with malignant tumors were first reported in 1953. In 1956, Lambert and Eaton described electrophysiological abnormalities, and in 1957, it was established as a clinical syndrome7).
The annual incidence is estimated at 0.6 per million, and the prevalence at 2.8 per million7). This is 10 to 14 times less common than MG in incidence, and 46 times less common in prevalence. Cancer is found in 47–62% of LEMS patients8).
The average age of onset for SCLC-associated LEMS (SCLC-LEMS) is about 60 years, with 65–75% being male. Non-tumor LEMS (NT-LEMS) shows a bimodal peak at ages 35 and 60, and is more common in women. Childhood LEMS is extremely rare, with only 13 cases reported in the literature5).
MG is caused by antibodies against postsynaptic acetylcholine receptors (AChR), with ocular symptoms and bulbar palsy appearing early. LEMS is caused by antibodies against presynaptic VGCC, and ocular symptoms appear later in the disease and are often mild. The progression also differs: MG progresses from head to tail, while LEMS progresses from tail to head. For details, see the “Diagnosis and Testing Methods” section.
Limb muscle weakness is the most common chief complaint. It is symmetric and fluctuates throughout the day, worsening with warmth. The legs are more affected than the arms, making it difficult to stand up from a chair or climb stairs.
Symptoms progress over weeks to months from proximal to distal muscles and from caudal to cranial, eventually involving ocular and bulbar symptoms.
Autonomic dysfunction is present in 80–96% of patients. Dry mouth is the most common (75%), along with erectile dysfunction, constipation, dry eyes, orthostatic hypotension, anhidrosis, and urinary retention. Rarely, pain or stiffness associated with muscle weakness is reported.
Ocular symptoms are reported in 49–78% of LEMS patients. A retrospective review of 167 patients at the Mayo Clinic documented the following:
Frequency reported as subjective symptoms:
Clinical findings confirmed on examination:
Dry eye and pupillary dysfunction are ocular signs of autonomic neuropathy. Ocular symptoms and bulbar palsy are generally milder than in MG and tend to be underestimated.
Rarely, cases present with isolated ocular symptoms. A case has been reported where the patient presented with right eye pain, eyelid edema, and bilateral ptosis, and later was found to have pulmonary large cell neuroendocrine carcinoma (LCNEC)4). Additionally, ICI-induced LEMS presenting with bilateral ptosis, diplopia, and dysarthria has been documented8).
The main differentiating points between MG and LEMS are shown below.
| Item | MG | LEMS |
|---|---|---|
| Antibody target | Postsynaptic AChR | Presynaptic VGCC |
| Associated tumor | Thymoma | SCLC |
| Timing of ocular symptoms | Common in early stage | Late stage, severe cases |
| Direction of disease progression | Cranial to caudal | Caudal to cranial |
| Muscle strength after exercise | Worsens | Improves |
| Deep tendon reflexes | Rarely decreased | Often absent, enhanced after contraction |
| Autonomic dysfunction | Rare | Common |
| Response to pyridostigmine | Marked | Minimal |
In LEMS, ocular and bulbar symptoms appear late in the disease course, reported in 49–78% of cases, but are often underestimated. Muscle weakness in LEMS progresses from caudal (lower limbs) to cranial (eyes), so ocular symptoms take time to develop. Additionally, unlike MG, the effect of pyridostigmine is limited, which also contributes to diagnostic delay.
LEMS occurs either as a paraneoplastic syndrome or as an acquired autoimmune disease associated with autoimmune disorders.
Approximately 60% of LEMS cases have an underlying tumor, with SCLC being the most common. Smoking is a risk factor for SCLC-related LEMS. Associations with tumors other than SCLC have also been reported.
As a rare associated tumor, the second case in the literature of laryngeal neuroendocrine carcinoma (PD-NEC) has been reported2), and only three cases of association with LCNEC have been reported in the literature4).
Associated with underlying autoimmune diseases (such as thyroid disease), approximately 65% have the HLA-B8-DR3 haplotype. In pediatric NT-LEMS, an association with autoimmune predisposition (anti-TPO antibodies, ANA positivity) is observed5).
ICIs such as pembrolizumab, nivolumab, and atezolizumab have been reported to induce LEMS as an irAE1,6,8). With the widespread use of ICIs, this form of LEMS may increase in the future.
Repetitive nerve stimulation (RNS) shows high sensitivity and specificity for confirming the diagnosis of LEMS.
Specific values include a recorded increase from resting CMAP 0.7 mV to 4.3 mV after maximal voluntary contraction in PCD-LEMS cases3). In ICI-induced LEMS cases, a 16.3-fold increase with 50 Hz stimulation6) and a 688.5% increase8) have been reported.
It is a useful biomarker for identifying SCLC-LEMS.
SOX-1 antibody positivity with paraneoplastic cerebellar degeneration (PCD) strongly suggests the presence of SCLC. Cases have been reported where an 18 mm SCLC was only found at autopsy 3), and tumors are often difficult to detect on imaging.
The following score is used as a tool to predict the probability of SCLC.
Factors of DELTA-P
D — Dysarthria: Presence or absence of dysarthria
E — Erectile dysfunction: Erectile dysfunction (females excluded)
L — Loss of weight: Weight loss of 5% or more
T — Tobacco use: Smoking at onset
A — Age ≥ 50: Age 50 or older
P — Performance status: Karnofsky performance status < 70
Score and Predicted Probability
Score 0–1: SCLC probability 0–2.6%
Score 4: SCLC probability 93.5%
Score 5: SCLC probability 96.6%
Score 6: SCLC probability 100%
After LEMS diagnosis, tumor screening with PET or chest MRI should be performed every 3–6 months for at least 2 years 7). Particularly aggressive screening is important in patients with a high DELTA-P score.
The misdiagnosis rate of LEMS reaches approximately 58% 7). The following diseases should be considered in the differential diagnosis.
Tumor screening with PET or chest MRI every 3–6 months for at least 2 years is recommended. It is desirable to stratify the risk of SCLC using the DELTA-P score and determine the intensity of screening. Long-term vigilance is necessary because there have been case reports where tumors were only detected at autopsy, especially in SOX-1 antibody-positive cases or when tumors are difficult to detect on imaging.
If an underlying tumor is present, tumor treatment management is the highest priority. Tumor treatment also improves LEMS symptoms.
3,4-Diaminopyridine (amifampridine): FDA-approved first-line drug. There are two formulations: for ages 17 and older, and for ages 6 to 17. It blocks presynaptic voltage-gated potassium channels, prolonging depolarization and thereby extending the time VGCCs are open, increasing ACh release. Side effects include transient paresthesias, gastrointestinal symptoms, and seizures at high doses. History of seizures is a contraindication. As of 2022, it is not approved in Japan 6).
Pyridostigmine: Acetylcholinesterase (AChE) inhibitor. Its effect in LEMS is limited compared to MG. In one case, pyridostigmine 180 mg/day for 5 days was ineffective 8).
Guanidine: Used in combination with pyridostigmine. High doses carry risks of renal failure and bone marrow suppression.
IVIG (intravenous immunoglobulin): Reports of improvement in LEMS relapse with 20 g/day for 5 days1). Improvement reported with 25 g/day for 5 days plus steroid pulse8). There is a report of improvement after adding IVIG in a case where steroid pulse alone was ineffective6).
Steroid pulse therapy (mPSL): 1 g/day for 3 days6,8)
Plasmapheresis: Used for severe and rapidly progressive cases
In Japan, since 3,4-diaminopyridine is not approved, alternatives include pyridostigmine (limited efficacy), immunosuppressive therapy (prednisolone, azathioprine), IVIG, and plasma exchange. For ICI-induced LEMS, a combination of steroid pulse and IVIG has been reported effective.
In normal neuromuscular transmission, an action potential in the motor nerve opens P/Q-type voltage-gated calcium channels (VGCCs), allowing Ca²⁺ influx that causes acetylcholine (ACh)-containing vesicles to fuse with the nerve terminal membrane and release their contents. This ACh release triggers muscle contraction.
In LEMS, autoantibodies against VGCCs (mainly P/Q-type, and some N-type) inhibit Ca²⁺ influx, reducing ACh release. This is the fundamental mechanism of muscle weakness 7). The temporary improvement in muscle strength after repetitive stimulation is thought to be due to Ca²⁺ accumulation in the terminal, partially restoring ACh release.
SCLC tumor cells express VGCCs. It is hypothesized that anti-VGCC antibodies produced as an immune response to SCLC cross-react with VGCCs on motor nerve terminals, leading to LEMS through a paraneoplastic autoimmune mechanism.
Approximately 65% of NT-LEMS cases carry the HLA-B8-DR3 haplotype, suggesting a genetic autoimmune predisposition contributes to its development.
SOX-1 is a transcription factor involved in the differentiation of airway epithelial cells and is expressed in SCLC. SOX-1 antibodies also react with Bergmann glial cell nuclei in the cerebellum and can induce cerebellar ataxia (paraneoplastic cerebellar degeneration; PCD) 3).
Approximately 10% of LEMS patients have concurrent PCD (PCD-LEMS). In PCD-LEMS patients, a positive SOX-1 antibody test strongly suggests the presence of SCLC. Cases have been reported where the tumor was difficult to detect on CT but SCLC was only identified at autopsy 3), making SOX-1 antibody an important biomarker for early tumor detection.
ICI-induced immune activation is thought to stimulate the production of VGCC antibodies, leading to LEMS. When LEMS develops during complete tumor remission, it strongly suggests an irAE and requires differentiation from paraneoplastic neurological syndrome (PNS) 1,6,8).
Yamazoe et al. (2023) reviewed 7 cases of ICI-induced LEMS in the literature8). The underlying diseases included SCLC in 4 cases, neuroendocrine tumor in 1 case, squamous cell carcinoma in 1 case, and squamous cell carcinoma plus large cell NEC in 1 case. The causative drugs were atezolizumab in 2 cases, pembrolizumab in 2 cases, nivolumab in 2 cases, and nivolumab plus ipilimumab in 1 case. Treatment outcomes were inconsistent8).
In the report by Yamazoe et al. (2023), an ES-SCLC patient who developed LEMS after 5 cycles of atezolizumab maintenance therapy improved with steroid pulse plus IVIG, and showed no neurological recurrence or tumor progression 18 months after discontinuing atezolizumab8). This finding suggests that the antitumor effect may persist even after ICI discontinuation.
Takigawa et al. (2023) reported a case of irAE in which LEMS recurred after pembrolizumab administration for NSCLC in a 73-year-old woman who had achieved complete remission of SCLC-associated LEMS 22 years earlier 1). The anti-P/Q-type VGCC antibody titer at initial onset was 2,472.9 pmol/L, whereas at recurrence it was low at 124.9 pmol/L, and improvement was achieved with IVIG alone (20 g/day for 5 days). The edrophonium test showed no change in ptosis, confirming differentiation from MG 1).
Approximately 93% of LEMS cases develop before SCLC diagnosis, and the timing of LEMS onset and tumor status provide clues to distinguish PNS from irAE. ICI-induced LEMS as an irAE occurs at a median of 5.5 cycles of ICI 8).
Amifampridine is not approved in Japan, and unavailability has been reported even in cases of ICI-induced LEMS 6). With the expansion of ICI indications for SCLC treatment through trials such as IMpower133, an increase in ICI-induced LEMS is a concern for the future 6,8).
Takigawa Y, Watanabe H, Omote Y, et al. Lambert-Eaton myasthenic syndrome recurrence induced by pembrolizumab in a patient with non-small-cell lung cancer. Intern Med. 2023;62:1055-1058.
Mesolella M, Allosso S, Buono S, et al. Neuroendocrine carcinoma of the larynx with Lambert-Eaton myasthenic syndrome: a rare case report and literature review. J Int Med Res. 2021;49(5):1-7.
Wada S, Kamei M, Uehara N, et al. Paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome with SOX-1 antibodies. Intern Med. 2021;60:1607-1610.
Hernandez-Arriaga P, Gonzalez-Urquijo M, López Altamirano DF, et al. Pulmonary large cell neuroendocrine carcinoma associated with Lambert-Eaton syndrome. Clin Pathol. 2021;14:1-4.
Moor SE, Gardin T. Lambert-Eaton myasthenic syndrome in a young girl. BMJ Case Rep. 2022;15:e245773.
Kunii E, Owaki S, Yamada K, et al. Lambert-Eaton myasthenic syndrome caused by atezolizumab in a patient with small-cell lung cancer. Intern Med. 2022;61:1739-1742.
Viveiros L, Martins SR, Pires SX, et al. Paraneoplastic Lambert-Eaton myasthenic syndrome: a diagnostic challenge. BMJ Case Rep. 2023;16:e250947.
Yamazoe M, Hatakeyama T, Furukawa K, et al. Atezolizumab-induced Lambert-Eaton myasthenic syndrome in a patient with small-cell lung cancer. Cureus. 2023;15(1):e33557.
