[Lambert-Eaton Myasthenic Syndrome].

Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune disorder that affects the neuromuscular junction, is characterized by proximal muscle weakness, reduction of tendon reflexes, and autonomic dysfunction. LEMS shows a prevalence of approximately 0.25-0.27 per 100,000 population. The characteristic muscle weakness observed in patients with LEMS is attributed to the role of pathogenic autoantibodies directed against voltage-gated calcium channels (VGCC) present on the presynaptic nerve terminal. Notably, 50-60% of patients with LEMS have an associated tumor, small-cell lung carcinoma (SCLC), which also expresses functional voltage-gated calcium channels (VGCC). The Japanese LEMS diagnostic criteria 2022 recommend documentation of typical electrophysiological abnormalities combined with myasthenic symptoms for accurate diagnosis. P/Q-type VGCC antibody positivity strongly supports the diagnosis. Treatment options are categorized as oncological treatment, immunotherapy, and symptomatic treatments. Effective treatment of the tumor can improve LEMS in patients with SCLC. Most patients benefit from 3,4-diaminopyridine administration for symptomatic treatment. A treatment algorithm is established by the clinical practice guidelines 2022.

Treatment of concomitant myasthenia gravis and Lambert-Eaton myasthenic syndrome with autologous CD19-targeted CAR T cells.

Myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are autoimmune disorders affecting neuromuscular transmission. Their combined occurrence is rare, and treatment remains challenging. Two women diagnosed with concomitant MG/LEMS experienced severe, increasing disease activity despite multiple immunotherapies. Anti-CD19 chimeric antigen receptor (CAR) T cells have shown promise for treating autoimmune diseases. This report details the safe application of anti-CD19 CAR T cells for treating concomitant MG/LEMS. After CAR T cell therapy, both patients experienced rapid clinical recovery and regained full mobility. Deep B cell depletion and normalization of acetylcholine receptor and voltage-gated calcium channel N-type autoantibody levels paralleled major neurological responses. Within 2 months, both patients returned to everyday life, from wheelchair dependency to bicycling and mountain hiking, and remain stable at 6 and 4 months post-CAR T cell infusion, respectively. This report highlights the potential for anti-CD19 CAR T cells to achieve profound clinical effects in the treatment of neuroimmunological diseases.

[A case of myasthenia gravis with coexistence of anti-acetylcholine receptor antibodies and anti-P/Q-type VGCC antibodies].

A 79-year-old woman who presented ptosis and dysphagia were admitted to our hospital. Anti-acetylcholine receptor antibodies and anti-P/Q-type VGCC antibodies were both positive. Electrophysiological examination showed postsynaptic pattern which supported myasthenia gravis. She did not meet the diagnostic criteria for Lambert-Eaton myasthenic syndrome (LEMS). In cases which these antibodies coexist, careful electrophysiological evaluation is required for the diagnosis. In addition, although anti-P/Q-type VGCC antibodies have been specific to LEMS, patients with these antibodies represent various symptoms other than LEMS. Low and middle titer of the antibodies may be not specific to LEMS.

Advances and ongoing research in the treatment of autoimmune neuromuscular junction disorders.

Myasthenia gravis and Lambert-Eaton myasthenic syndrome are antibody-mediated autoimmune diseases of the neuromuscular junction that usually present with weakness in ocular muscles and in proximal muscles of the limb and trunk. Prognosis regarding muscle strength, functional abilities, quality of life, and survival is generally good. However, some patients do not respond to treatment. Symptomatic drugs, corticosteroids, and steroid-sparing immunosuppressive drugs remain the cornerstone of treatment. In the past few years, new biological agents against complement, the FcRn receptor, or B-cell antigens have been tested in clinical trials. These new therapies extend the possibilities for targeted immunotherapies and promise exciting new options with a relatively rapid mode of action. Challenges in their use might occur, with barriers due to an increase in cost of care and additional considerations in the choice of drugs, and potential consequences of infection and vaccination due to the COVID-19 pandemic.

Performance evaluation of a radioimmunoprecipitation assay for the detection of N-type voltage-gated calcium channel antibodies.

BACKGROUND: In this study, we assessed the performance characteristics of a laboratory-developed radioimmunoassay (RIA) to detect N-type voltage-gated calcium channel (N-VGCC) antibodies found in several autoimmune neurologic diseases. METHODS: Four hundred and forty-five (n = 445) sera were evaluated, including 156 sera (50 positive and 106 negative for N-VGCC antibodies) previously tested at Mayo Clinic Laboratories (MCL) and 289 controls (n = 187 disease and n = 102 healthy). Specimens were analyzed with the RIA using N-VGCC labeled with 125I-ω-conotoxin GVIA. The RIA was compared to the predicate MCL assay using a tiered positive predictive value (PPV) approach. Other performance characteristics evaluated included specificity, precision, interference, and stability. RESULTS: Qualitative inter-laboratory agreement based on tiered PPVs was 100% for results >1.00 nmol/L (71% PPV), 48% for results of 0.10-0.99 nmol/L (24% PPV) and 22% for results of 0.04-0.10 nmol/L (19% PPV). Negative results showed 90% agreement (n = 106). Specificity in controls positive for other neural autoantibodies and healthy controls were 87% and 100%, respectively. Acceptable results were observed for other performance characteristics. CONCLUSIONS: Inter-laboratory correlations demonstrate equivalence between assays with some discrepancies between low positive results. Collaborative efforts aimed at assessing the clinical spectrum associated with these antibodies and consensus for harmonizing test performance are required for optimal categorization of patients.

Neuronal antibody detection and improved lung cancer prediction in Lambert-Eaton myasthenic syndrome.

Since approximately 50% of patients with Lambert-Eaton myasthenic syndrome (LEMS) subsequently develop small-cell lung cancer (SCLC), it is important to be able to predict cancer occurrence in these patients at neurological presentation. We aimed to determine whether circulating biomarkers were effective and objective predictors of cancer development in LEMS. We found that the presence of either SOX2, N-type voltage gated calcium channel or GABAb antibodies at LEMS diagnosis was highly sensitive (84%) and specific (87%) for the detection of SCLC. Screening for SOX2 and neuronal antibodies is a useful adjunct to clinical predictive scoring tools in predicting SCLC in LEMS.

Anti-SOX1 antibody-positive paraneoplastic neurological syndrome presenting with Lambert-Eaton myasthenic syndrome and small cell lung cancer: A case report.

Paraneoplastic neurological syndromes (PNS) are rare disorders affecting any part of the central, peripheral or autonomic nervous system that occur in association with cancer. Among cancer patients, less than 1% overall develop PNS. Anti-SOX1 antibodies' positive paraneoplastic neurological disorders are rare and are usually associated with small cell lung cancer (SCLC). Here, we report a case of a 61-year-old male patient who presented with an unusual anti-SOX1 positive PNS. The right tibialis anterior showed noticeable low-amplitude motor unit potentials and high amplitude motor potentials in electrodiagnostic study, suggesting the presence of Lambert-Eaton myasthenic syndrome (LEMS). Typical MRI and PET-CT found a hyperintense lesion with contrast enhancement in the thorax in front of 5-6 centrum of vertebrae, and thoracoscopic biopsy revealed pathological findings for SCLC. The patient underwent several lines of chemotherapy and radiotherapy and survived for 15 months after the diagnosis of SCLC.

Long-term follow-up, quality of life, and survival of patients with Lambert-Eaton myasthenic syndrome.

OBJECTIVE: To study survival and to characterize long-term functional impairments and health-related quality of life (HRQOL) of patients with Lambert-Eaton myasthenic syndrome (LEMS). METHODS: In this observational study, survival of patients with LEMS, separately for nontumor (NT) and small cell lung cancer (SCLC), was compared to that of the Dutch general population and patients with SCLC. Disease course in patients with LEMS was recorded retrospectively. Several scales for functional impairments and health-related quality of life were assessed. RESULTS: We included 150 patients with LEMS. Survival was similar to that of the general population in 65 patients with NT-LEMS. Tumor survival was significantly longer in 81 patients with SCLC-LEMS compared to patients with non-LEMS SCLC (overall median survival 17 vs 7.0 months, p < 0.0001). At diagnosis, 39 (62%) of 63 patients with complete follow-up data were independent for activities of daily living, improving to 85% at the 1-year follow-up. The physical HRQOL composite score (55.9) was significantly lower than in the general population (76.3, p < 0.0001) and comparable to that of patients with myasthenia gravis (60.5). The mental HRQOL composite score was 71.8 in patients with LEMS, comparable to that of the general population (77.9, p = 0.19) and patients with myasthenia gravis (70.3). CONCLUSIONS: This study shows that patients with NT-LEMS have normal survival. Patients with SCLC-LEMS have an improved tumor survival, even after correction for tumor stage. A majority of patients with LEMS report a stable disease course and remain or become independent for self-care after treatment.

A Case of Triple-Negative Myasthenia Gravis Lambert-Eaton Overlap Syndrome With Negative Agrin and LRP-4 Antibodies.

A case of triple-negative myasthenia gravis Lambert-Eaton overlap syndrome with negative Agrin and LRP-4 antibodies. Myasthenia gravis (MG) is an autoimmune disorder that shares similar features with Lambert-Eaton myasthenic syndrome. The combined clinical and electrophysiological findings of MG and Lambert-Eaton myasthenic syndrome have been reported, these cases represent the so-called "myasthenia gravis Lambert-Eaton overlap syndrome" (MLOS). A total of 55 MLOS cases have been identified, 13 cases were reported before the acetylcholine receptor (AChR) antibody (ab) testing era, 14 during the AChR-ab era, 26 during the voltage-gated calcium channel (VGCC)-ab era, and 2 cases have been reported during the muscle-specific kinase (MuSK)-ab era, of these; only 1 patient tested negative for all 3 antibodies. New immunological markers have been identified in the study of MG [Agrin and the low-density lipopro-tein receptor-related protein 4 (LRP-4)]. We present a patient with MLOS who tested negative for all 5 (AChR, MuSK, VGCC, Agrin, and LRP-4) serologic markers.

GRP78 antibodies damage the blood-brain barrier and relate to cerebellar degeneration in Lambert-Eaton myasthenic syndrome.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease of the neuromuscular junction caused by autoantibodies binding to P/Q-type voltage-gated calcium channels. Breakdown of the blood-brain barrier and diffusion of cerebellar granule/Purkinje cell-reactive autoantibodies into the CNS are critical for the pathogenesis of paraneoplastic cerebellar degeneration (PCD) with Lambert-Eaton myasthenic syndrome. We recently found evidence that glucose-regulated protein 78 (GRP78) autoantibodies in the plasma of patients with neuromyelitis optica promote the CNS access of AQP4 autoantibodies. In the present study, we investigated whether the GRP78 autoantibodies in PCD-LEMS IgG boost the brain uptake of cerebellar cell-reactive antibodies across the blood-brain barrier and facilitate cerebellar dysfunction. We first evaluated the effects of purified IgG from PCD-LEMS or PCD patients on the blood-brain barrier function in human brain microvascular endothelial cells using a high content imaging system with nuclear factor κB p65 and intracellular adhesion molecule 1 (ICAM1) immunostaining. Next, we identified GRP78 autoantibodies causing blood-brain barrier permeability in PCD-LEMS IgG by co-immunoprecipitation and the living cell-based antibody binding assays. Exposure of brain microvascular endothelial cells to IgG from PCD-LEMS patients induced nuclear factor κB p65 nuclear translocation, ICAM1 upregulation, reduced claudin-5 expression, increased permeability and increased autocrine IL-1ß and IL-8 secretion; the IgG from patients with Lambert-Eaton myasthenic syndrome did not have these effects. We detected GRP78 autoantibodies in the IgG of LEMS-PCD (83.3%, n = 18), but observed fewer in patients with LEMS (6.6%, n = 15) and none were observed in the control subjects (n = 8). The depletion of GRP78 autoantibodies reduced the biological effect of LEMS-PCD IgG on brain microvascular endothelial cells. These findings suggest that GRP78 autoantibodies play a role beyond neuromyelitis optica and that they have direct implications in the phenotypic differences between PCD-LEMS and LEMS.

Pathogenic Mechanisms and Clinical Correlations in Autoimmune Myasthenic Syndromes.

Autoimmune myasthenic syndromes are antibody-mediated disorders of the neuromuscular junction. Common antigenic targets are the acetylcholine receptor or muscle specific kinase (MuSK) in myasthenia gravis (MG) and the voltage-gated calcium channel in Lambert-Eaton myasthenic syndrome. There is evidence that antibodies directed against other antigens such as low-density lipoprotein receptor-related protein 4 (LRP4) are also involved in MG. The mechanisms by which various antibodies exert their pathogenic effect depend on the IgG subclass and also the epitope location on the antigens. These mechanisms are partly heterogeneous and include antigen degradation, complement activation, direct functional blocking, or disruption of protein-protein interactions. The neuromuscular junction is characterized by a structural and functional plasticity that is able to compensate for some of the neuromuscular junction defects. Here, we discuss the underlying pathogenic mechanisms of the different autoantibodies and correlate them with phenotypic features. The understanding of these elements should help guide the clinical management of patients with autoimmune myasthenic syndromes.

Low specificity of voltage-gated calcium channel antibodies in Lambert-Eaton myasthenic syndrome: a call for caution.

As testing for neuronal antibodies become more readily available, the spectrum of conditions potentially associated with these autoantibodies has been widening. Voltage-gated calcium channel antibodies (VGCC-Ab) are no exception to this trend. The significance of an elevated VGCC-Ab titer beyond its original clinicopathological correlate, Lambert-Eaton myasthenic syndrome (LEMS) remains undetermined. We sought to determine the diagnostic significance of an elevated serum VGCC-Ab titer in a large single-center cohort of 100 patients. The majority of patients (58%) with elevated VGCC-Ab levels lacked an inflammatory or autoimmune etiology of their neurologic diagnosis. Only six cases (6%) of LEMS and two cases (2%) of SCLC (without LEMS) were identified. No significant differences in antibody titers were seen between the autoimmune and non-autoimmune groups. These findings support the notions that: (a) elevated VGCC-Ab titers without clinical correlation must be interpreted with caution, and (b) the clinical and electrodiagnostic criteria for LEMS should remain the mainstay in the diagnosis of LEMS.

Coexistence of Lambert-Eaton myasthenic syndrome and autoimmune encephalitis with anti-CRMP5/CV2 and anti-GABAB receptor antibodies in small cell lung cancer: A case report.

RATIONALE: Autoimmune encephalitis and Lambert-Eaton myasthenic syndrome are classic paraneoplastic neurological conditions common in patients with small cell lung cancer. PATIENT CONCERNS: The patient complained of tiredness, fluctuating recent memory loss, and inability to find his home. His family members reported a change in character, irritability, and paranoia. One month later, the patient had 1 grand mal seizure lasting 5 minutes. DIAGNOSIS: The patient was diagnosed with limbic encephalitis combined with Lambert-Eaton myasthenic syndrome. The gamma-aminobutyric acid B (GABAB) receptor and collapsin response mediator protein 5 (CRMP5, also called CV2) antibody test results were positive. Nine months after the onset of symptoms, the patient was diagnosed with small cell lung cancer. INTERVENTIONS: The patient was administered intravenous immunoglobulin for 5 days. He was then treated with 60 mg prednisone once per day. The prednisone dose was gradually reduced by 1 tablet every 2 weeks. After the diagnosis, the patient underwent 6 courses of chemotherapy with cisplatin combined with sequential chemoradiation therapy. OUTCOMES: The patient was able to take care of himself. Neurological examination revealed a lower limb proximal muscle strength level of 4 and a reduced limb tendon reflex. The patient had deficits in short-term memory, a Mini-Mental State Examination score of 26, Montreal Cognitive Assessment score of 24, Self-rating Depression Scale score of 54 (mild depression), and Self-Rating Anxiety Scale score of 42 (normal). LESSONS: Autoimmune diseases of the peripheral and central nervous systems can be observed at the same time in patients with small cell lung cancer, even when magnetic resonance imaging findings are negative and immune therapy is effective.

[P/Q-type Calcium Channel Antibodies in Lambert-Eaton Myasthenic Syndrome].

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease of the neuromuscular junction. Approximately 50-60% of patients with LEMS have a tumor, most often small cell lung cancer (SCLC), making LEMS a paraneoplastic neurological syndrome. In Japan, the clinical picture is a male: female ratio of 3:1; mean age, 62 years (17-80 years); and 61% of LEMS patients have SCLC (SCLC-LEMS), with the remainder of patients having no cancer. Patients with LEMS develop a unique set of clinical characteristics, which include proximal muscle weakness, depressed tendon reflexes with post-tetanic potentiation, and autonomic symptoms. Interestingly, less than 10% of patients with LEMS have cerebellar ataxia (LEMS with paraneoplastic cerebellar degeneration). Considering its pathomechanisms, LEMS is a presynaptic disorder of neuromuscular transmission in which quantal release of acetylcholine is impaired by autoantibodies against P/Q-type voltage-gated calcium channels (P/Q-VGCCs) at active zones reducing quantal release of acetylcholine, although an animal model using immunization with purified P/Q-VGCCs has not yet been established. The diagnosis can be confirmed by finding a reduced compound muscle action potential amplitude that increases by over 60% following maximum voluntary activation or 50 Hz nerve stimulation. Approximately 90% of patients who satisfy the above electrophysiological diagnostic criteria are positive for P/Q-VGCC antibodies have their diagnosis confirmed. Specific tumor therapy in SCLC-LEMS will often improve the neurologic deficit. Tumor removal is the primary treatment for LEMS. If primary tumor screening is negative, screening should be repeated after 3-6 months, followed by screening every 6 months until 2 years post diagnosis. Most patients benefit from 3,4-diaminopyridine being administered with pyridostigmine. In those with severe weakness, high-dose intravenous gamma-globulin (IVIg) or plasmapheresis confers short-term benefits. Prednisone, alone or combined with immunosuppressive drugs, can achieve long-term control of the disorder. The results of a prospective cohort study showed that the presence of LEMS with SCLC had a significant survival advantage independent of other prognostic factors including disease extent, age, sex, performance status, and serum sodium values.

Myasthenia gravis seronegative for acetylcholine receptor antibodies in South Korea: Autoantibody profiles and clinical features.

Acquired myasthenia gravis (MG) is a prototype autoimmune disease of the neuromuscular junction, caused in most patients by autoantibodies to the muscle nicotinic acetylcholine receptor (AChR). There seem to be ethnic and regional differences in the frequency and clinical features of MG seronegative for the AChR antibody. This study aimed to describe the autoantibody profiles and clinical features of Korean patients with generalized MG seronegative for the AChR antibody. A total of 62 patients with a high index of clinical suspicion of seronegative generalized MG were identified from 18 centers, and we examined their sera for antibodies to clustered AChR, muscle-specific tyrosine kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (LRP4) by cell-based assays (CBA) and to MuSK by radioimmunoprecipitation assay (RIPA). We also included 8 patients with ocular MG, 3 with Lambert-Eaton myasthenic syndrome, 5 with motor neuron disease, and 9 with other diagnoses as comparators for the serological testing. Antibodies were identified in 25/62 (40.3%) patients: 7 had antibodies to clustered AChR, 17 to MuSK, and 2 to LRP4. Three patients were double seropositive: 1 for MuSK and LRP4, and 2 for MuSK and clustered AChR. The patients with MuSK antibodies were mostly female (88.2%) and characterized by predominantly bulbar involvement (70%) and frequent myasthenic crises (58.3%). The patients with antibodies to clustered AChR, including 2 with ocular MG, tended to have a mild phenotype and good prognosis.

Amifampridine phosphate (Firdapse(®)) is effective and safe in a phase 3 clinical trial in LEMS.

OBJECTIVE: We evaluated the efficacy and safety of amifampridine phosphate (Firdapse(®)) for symptomatic treatment in Lambert-Eaton myasthenic syndrome (LEMS). METHODS: Phase 3, randomized, double-blind, study. Patients were treated initially with amifampridine phosphate for 7-91 days, followed by randomization to continue amifampridine phosphate for 14 days or placebo (7-day taper, 7-day placebo). The primary efficacy endpoints were changes from baseline at day 14 in Quantitative Myasthenia Gravis and Subject Global Impression scores. RESULTS: The coprimary efficacy end points and 1 of the secondary efficacy end points were met, showing a significant benefit of aminfampridine phosphate over placebo at Day 14. All 5 primary, secondary, and tertiary endpoints achieved statistical significance at Day 8. Amifampridine phosphate was well tolerated; the most common adverse events were oral and digital paresthesias, nausea, and headache. CONCLUSIONS: This study provides Class I evidence of efficacy of amifampridine phosphate as a symptomatic treatment for LEMS.