Lambert-Eaton myasthenic syndrome.

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disease characterized by proximal muscle weakness, loss of tendon reflexes, and autonomic dysfunction. Muscle weakness usually starts in the upper legs and can progress to oculobulbar and in severe cases respiratory muscles. P/Q-type voltage-gated calcium channels (VGCCs) localized in the presynaptic motor nerve terminal and in the autonomic nervous system are targeted by antibodies in LEMS patients. These antibodies can be detected in about 90% of patients, and the presence of decrement and increment upon repetitive nerve stimulation is also a highly sensitive diagnostic test. Rapid diagnosis is important because of the association with SCLC in 50%-60% of patients, which stresses the need for vigorous tumor screening after diagnosis. Clinical parameters can predict tumor probability and guide frequency of tumor screening. Treatment of the tumor as well as symptomatic treatment and immunosuppression can effectively control symptoms in the majority of patients.

Overview of treatment strategies in paraneoplastic neurological syndromes.

Treatment strategies in paraneoplastic neurological syndromes rely on the three pillars of tumor treatment, immunotherapy, and symptomatic treatment, the first one being by far the most important in the majority of patients and syndromes. Classically, antibodies against extracellular antigens are directly pathogenic, and patients with these syndromes are more responsive to immunomodulatory or immunosuppressive treatments than the ones with antibodies against intracellular targets. This chapter first discusses some general principles of tumor treatment and immunotherapy, followed by a closer look at specific treatment options for different clinical syndromes, focusing on symptomatic treatments.

SOX-1 antibodies positive Lambert-Eaton myasthenic syndrome with occult small cell lung cancer: A case report.

Lambert-Eaton myasthenic syndrome (LEMS) is a rare paraneoplastic neurological syndrome of the neuromuscular transmission. The symptoms often progress slowly and can be misdiagnosed in early stage. Seropositive SOX-1 antibodies are support for the diagnosis of LEMS and have high specificity for small cell lung cancer (SCLC). In this paper, we report a case of a 56-year-old man with smoking history who was admitted to hospital with progressive muscle weakness of the proximal legs. LEMS was diagnosed by repetitive nerve stimulation (RNS) testing and seropositive SOX-1 antibodies. Primary screening with chest computed tomography (CT) and integrated PET/CT did not reveal any tumor. After continuous follow-up, SCLC was found by chest CT and confirmed with pathological examination 10 months after the diagnosis of LEMS. Long-term follow-up and screening for occult SCLC in LEMS patients with positive SOX-1 antibodies are very important.

Efficacy of durvalumab plus chemotherapy in small-cell lung cancer with Lambert-Eaton myasthenic syndrome.

Lambert-Eaton myasthenic syndrome (LEMS) is a rare disease but is often associated with small-cell lung cancer (SCLC). We discuss the case of a 65-year-old man diagnosed with SCLC-LEMS and treated with carboplatin, etoposide, and durvalumab. Lower extremity weakness and high anti-P/Q voltage-gated calcium channel (VGCC) antibody levels were diagnostic and helpful. The patient showed a reduction in neurological symptoms with treatment for SCLC, including an immune checkpoint inhibitor (ICI), without standard treatment for LEMS. This treatment may be a treatment option, although the recurrence of LEMS as an immune-related adverse events (irAEs) should be noted.

Acute onset of Lambert Eaton myasthenic syndrome in prostate adenocarcinoma: a case report.

Lambert Eaton myasthenic syndrome (LEMS) is a rare disorder of the neuromuscular junction. The representative clinical triad consists of proximal muscular weakness, areflexia and autonomic dysfunction. The diagnosis is based on the clinical findings confirmed by voltage-gated calcium channels antibody titer and neurophysiology. We present a 69 year old male with prostate adenocarcinoma and 30 years history of smoking, referred for muscle weakness in the lower limbs and difficulty to climb the stairs.

Burden of disease in Lambert-Eaton myasthenic syndrome: taking the patient's perspective.

BACKGROUND: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune-mediated neuromuscular disorder leading to muscle weakness, autonomic dysregulation and hyporeflexia. Psychosocial well-being is affected. Previously, we assessed burden of disease for Myasthenia gravis (MG). Here, we aim to elucidate burden of disease by comparing health-related quality of life (HRQoL) of patients with LEMS to the general population (genP) as well as MG patients. METHODS: A questionnaire-based survey included sociodemographic and clinical data along with standardized questionnaires, e.g. the Short Form Health (SF-36). HRQoL was evaluated through matched-pairs analyses. Participants from a general health survey served as control group. RESULTS: 46 LEMS patients matched by age and gender were compared to 92 controls from the genP and a matched cohort of 92 MG patients. LEMS participants showed lower levels of physical functioning (SF-36 mean 34.2 SD 28.6) compared to genP (mean 78.6 SD 21.1) and MG patients (mean 61.3 SD 31.8). LEMS patients showed lower mental health sub-scores compared to genP (SF-36 mean 62.7 SD 20.2, vs. 75.7 SD 15.1) and MG patients (SF-36 mean 62.7 SD 20.2, vs. 66.0 SD 18.). Depression, anxiety and fatigue were prevalent. Female gender, low income, lower activities of daily living, symptoms of depression, anxiety and fatigue were associated with a lower HRQoL in LEMS. DISCUSSION: HRQoL is lower in patients with LEMS compared to genP and MG in a matched pair-analysis. The burden of LEMS includes economic and social aspects as well as emotional well-being. TRIAL REGISTRATION INFORMATION: drks.de: DRKS00024527, submitted: February 02, 2021, https://drks.de/search/en/trial/DRKS00024527 .

Guideline for the management of myasthenic syndromes.

Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare chronic diseases. MG and LEMS have an autoimmune-mediated etiology, while CMS are genetic disorders. A (strain dependent) muscle weakness due to neuromuscular transmission disorder is a common feature. Generalized MG requires increasingly differentiated therapeutic strategies that consider the enormous therapeutic developments of recent years. To include the newest therapy recommendations, a comprehensive update of the available German-language guideline 'Diagnostics and therapy of myasthenic syndromes' has been published by the German Neurological society with the aid of an interdisciplinary expert panel. This paper is an adapted translation of the updated and partly newly developed treatment guideline. It defines the rapid achievement of complete disease control in myasthenic patients as a central treatment goal. The use of standard therapies, as well as modern immunotherapeutics, is subject to a staged regimen that takes into account autoantibody status and disease activity. With the advent of modern, fast-acting immunomodulators, disease activity assessment has become pivotal and requires evaluation of the clinical course, including severity and required therapies. Applying MG-specific scores and classifications such as Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Foundation of America allows differentiation between mild/moderate and (highly) active (including refractory) disease. Therapy decisions must consider age, thymic pathology, antibody status, and disease activity. Glucocorticosteroids and the classical immunosuppressants (primarily azathioprine) are the basic immunotherapeutics to treat mild/moderate to (highly) active generalized MG/young MG and ocular MG. Thymectomy is indicated as a treatment for thymoma-associated MG and generalized MG with acetylcholine receptor antibody (AChR-Ab)-positive status. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status. Specific treatment for myasthenic crises requires plasmapheresis, immunoadsorption, or IVIG. Specific aspects of ocular, juvenile, and congenital myasthenia are highlighted. The guideline will be further developed based on new study results for other immunomodulators and biomarkers that aid the accurate measurement of disease activity.

[A 50 year old man with progressive weakness in lower limbs].

Lambert-Eaton Myasthenic Syndrome (LEMS) is a rare neurological disorder caused by autoimmune antibodies attacking the presynaptic neuromuscular junction, in some cases caused by underlying cancer. The main clinical finding is fluctuating weakness of the extremities and a triad of symtoms can help physicians suspect the disease. A key to the diagnosis are the electrophysiological abnormalities seen in this group of diseases. Treatment with symtomatic and/or immunosuppressive therapy is important as well as a workup for possible malignancy. This article identifies the clinical features, diagnosis and treatment of this uncommon disease.

A Rare Case of Lambert-Eaton Myasthenia Syndrome Associated with Non-Hodgkin's Lymphoma: A Case Report and Review of the Literature.

Introduction: Lambert-Eaton myasthenia syndrome (LEMS) is a rare autoimmune disorder characterized by autoantibodies targeting presynaptic neuromuscular junctions. It results in muscle weakness and autonomic dysfunction. LEMS can be idiopathic or associated with neoplastic diseases, often small-cell lung cancer. This case report describes a rare instance of paraneoplastic LEMS in a man with non-Hodgkin lymphoma. Case Presentation: A 57-year-old male with non-Hodgkin lymphoma presented with progressive muscle weakness, diminished reflexes, and autonomic symptoms. Diagnosis revealed LEMS with autoantibodies against voltage-gated calcium channels. Immunosuppressive therapy and lymphoma treatment led to significant improvement in his condition. Conclusion: This case highlights the rare occurrence of paraneoplastic LEMS in a patient with non-Hodgkin lymphoma. Recognition and timely management of LEMS alongside lymphoma treatment can lead to significant clinical improvement, emphasizing the need for increased awareness of such complex associations.

A rare case of concomitant Lambert-Eaton myasthenic syndrome and syndrome of inappropriate antidiuretic hormone secretion in a patient with small cell lung carcinoma.

Small cell lung carcinoma (SCLC) is a neuroendocrine carcinoma with a poor prognosis and is a common cause of paraneoplastic syndromes. Paraneoplastic syndromes are characterized by neurological and endocrinological problems in patients with malignancy and are often associated with difficulty in induction of chemotherapy. Here we report the case of a patient with SCLC concomitant with two paraneoplastic syndromes, syndrome of inappropriate antidiuretic hormone secretion (SIADH) and Lambert-Eaton myasthenic syndrome (LEMS), who was treated with a platinum-doublet chemotherapy regimen. A 66-year-old male patient presented with a 1-month history of progressive proximal muscle weakness, ataxia gait and 5 kg of body weight loss. The laboratory tests revealed hyponatremia due to SIADH and the existence of antibodies against P/Q-type voltage-gated calcium channels. The nerve conduction study showed a low amplitude of compound muscle action potential (0.38 mv), a 34% decrement on 3-Hz stimulation, and a 1939% increment after maximum voluntary contraction in 10 seconds (7.75 mv). The endobronchial ultrasound transbronchial needle aspiration biopsy revealed the pathological findings of SCLC. A 2-cycle chemotherapy regimen of irinotecan plus cisplatin resulted in temporary tumor shrinkage that lasted 2 months, but the improvement of proximal muscle weakness and hyponatremia were maintained over the tumor re-progression period after chemotherapy. Although paraneoplastic syndromes accelerate the decrease in performance status, chemotherapy for SCLC may improve symptoms related to paraneoplastic syndromes and could be considered in similar cases.

Nivolumab-induced Lambert-Eaton myasthenic syndrome: an immune-related adverse event in nonsmall cell lung cancer.

Nivolumab is an anti-programmed cell death protein 1 (anti-PD-1) monoclonal antibody and was the first immune checkpoint inhibitor drug approved for use in advanced non-small cell lung cancer (NSCLC). In this report, we describe a rare case of Lambert-Eaton myasthenic syndrome (LEMS), which developed as a side effect of nivolumab in a patient with metastatic lung squamous cell carcinoma. Our patient, who was previously treated with nivolumab for metastatic squamous cell carcinoma of the lung, appeared with a headache, swollen face, dysarthria, asthenia, xerostomia, and drooping eyelid. Early testing indicated no thymomas or newly developing tumors in whole-body scans, and the blood workup was normal. We came to the conclusion that nivolumab-induced LEMS was the cause of the symptoms after performing nerve conduction investigations ruling out other differentials. We believe our clinical experience of this rare and unexpected adverse event should be shared.

Spontaneous regression of small cell lung cancer associated with Lambert-Eaton Myasthenic Syndrome: Case report.

Spontaneous regression (SR) of cancer is very rare, especially of small cell lung cancer (SCLC). Recently, an association of paraneoplastic neurological syndrome (PNS) has been reported as a cause of SR of cancer, and onconeural antibodies are a possible factor in the SR of cancer associated with PNS. We herein report the first case of SR of SCLC combined with anti-P/Q-type of voltage-gated calcium channel (VGCC) antibody-positive Lambert-Eaton myasthenic syndrome (LEMS), a subtype of PNS. This case report suggests that SCLC may be spontaneously reduced by an autoimmune response induced by VGCC antibodies associated with LEMS. Our finding may help elucidate the mechanisms that inhibit tumor growth and cause the regression of tumors.

Lambert-Eaton Myasthenic Syndrome Complicated by anti-GABAB Receptor Encephalitis.

A 74-year-old man experienced diplopia, generalized muscle weakness, and acute respiratory failure. He was diagnosed with Lambert-Eaton myasthenic syndrome (LEMS) and treated with immunotherapy, but no improvement was observed, and additional symptoms, including central apnea and hallucinations, appeared. Subsequent serum and cerebrospinal fluid (CSF) analyses confirmed the presence of GABAB receptor antibodies, indicating the coexistence of autoimmune encephalitis. Although there were no findings of malignancy, it is highly likely that occult small-cell lung carcinoma was present. When atypical symptoms occur in patients with LEMS, it is important to consider the possibility of concomitant autoimmune encephalitis.

Cancer detection after a 9-year course of Lambert-Eaton myasthenic syndrome complicated by anti-Hu associated limbic encephalitis.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune neuromuscular junction disorder, paraneoplastic in 55% of cases and commonly associated with small-cell lung cancer (SCLC). We report the case of a 61-year-old man presented who with a 3-month history of lower limb proximal weakness, progressing to upper limbs, associated with dysphagia, xerostomia and erectile dysfunction. Electrodiagnostic studies and anti voltage-gated calcium channel (VGCC) antibodies (Abs) detection confirmed LEMS diagnosis. Contrast-enhanced thorax computed tomography (CT) scan and subsequently [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) showed no malignancy. Two years after the onset of LEMS, he was diagnosed with anti-Hu limbic encephalitis (LE). FDG-PET/CT scan remained negative for the following seven years. Nine years after LEMS onset, a hypermetabolic lesion of the left lung hilus was detected. This is a case of a paraneoplastic LEMS where the interval between the onset of neurological disease and tumour detection was as long as nine years.

[A case of Lambert-Eaton myasthenic syndrome with exacerbation of respiratory failure triggered by acute myocardial infarction].

The patient, a 58-year-old man, experienced weakness of the proximal muscles in both lower extremities, and Lambert-Eaton myasthenic syndrome and small cell carcinoma of unknown primary origin were diagnosed. He received symptomatic treatment for myasthenia and radiochemotherapy for small cell carcinoma; once this regimen, the myasthenic symptoms improved. However, acute myocardial infarction occurred, after which type II respiratory failure developed, and the patient required ventilator management with tracheal intubation. Acute-phase treatment, such as plasma exchange, intravenous immune globulin therapy, and methylprednisolone pulse therapy, and intensification of symptomatic treatment allowed for extubation, and eventually the patient was able to walk independently. According to electrophysiological examination, compound muscle action potentials were larger at discharge than at the time of exacerbation.

Lambert-Eaton myasthenic syndrome with primary thymic marginal zone B-cell lymphoma: A case report.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune paraneoplastic syndrome with proximal muscle weakness, that often complicates small cell lung cancer. It is known that neurological symptoms do not improve with malignancy treatment alone in many LEMS patients, therefore treatment is often difficult. Since Lambert-Eaton myasthenic syndrome is a rare disease with a frequency of about 1/100 that of myasthenia gravis, there are only a few case reports on malignancy complications other than small cell lung cancer. We report a LEMS patient in his 40s who was found to have an anterior mediastinal mass. We performed surgical resection and confirmed the diagnosis of primary thymic marginal zone B-cell lymphoma by pathological diagnosis using immunostaining. Thymectomy and malignant lymphoma treatment with rituximab had no effect on neurological symptoms. The neurological symptoms improved only after we provided comprehensive care with the haematology, neurology, and rehabilitation department.

Simulations of active zone structure and function at mammalian NMJs predict that loss of calcium channels alone is not sufficient to replicate LEMS effects.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune-mediated neuromuscular disease thought to be caused by autoantibodies against P/Q-type voltage-gated calcium channels (VGCCs), which attack and reduce the number of VGCCs within transmitter release sites (active zones; AZs) at the neuromuscular junction (NMJ), resulting in neuromuscular weakness. However, patients with LEMS also have antibodies to other neuronal proteins, and about 15% of patients with LEMS are seronegative for antibodies against VGCCs. We hypothesized that a reduction in the number of P/Q-type VGCCs alone is not sufficient to explain LEMS effects on transmitter release. Here, we used a computational model to study a variety of LEMS-mediated effects on AZ organization and transmitter release constrained by electron microscopic, pharmacological, immunohistochemical, voltage imaging, and electrophysiological observations. We show that models of healthy AZs can be modified to predict the transmitter release and short-term facilitation characteristics of LEMS and that in addition to a decrease in the number of AZ VGCCs, disruption in the organization of AZ proteins, a reduction in AZ number, a reduction in the amount of synaptotagmin, and the compensatory expression of L-type channels outside the remaining AZs are important contributors to LEMS-mediated effects on transmitter release. Furthermore, our models predict that antibody-mediated removal of synaptotagmin in combination with disruption in AZ organization alone could mimic LEMS effects without the removal of VGCCs (a seronegative model). Overall, our results suggest that LEMS pathophysiology may be caused by a collection of pathological alterations to AZs at the NMJ, rather than by a simple loss of VGCCs.NEW & NOTEWORTHY We used a computational model of the active zone (AZ) in the mammalian neuromuscular junction to investigate Lambert-Eaton myasthenic syndrome (LEMS) pathophysiology. This model suggests that disruptions in presynaptic active zone organization and protein content (particularly synaptotagmin), beyond the simple removal of presynaptic calcium channels, play an important role in LEMS pathophysiology.

Durvalumab for Extensive-Stage of Small-Cell Lung Cancer With Lambert-Eaton Myasthenic Syndrome.

Durvalumab is an immune checkpoint inhibitor (ICI) of anti-programmed cell death protein 1 ligand antibody. ICI-combined chemotherapy has recently become a standard regimen for extensive-stage of small-cell lung cancer (ES-SCLC). SCLC is well known to be the most likely tumor associated with Lambert-Eaton myasthenic syndrome (LEMS), a rare autoimmune disease of a neuromuscular junction disorder. Although LEMS has been reported to be induced by ICI as immune-mediated adverse events, it remains unknown whether ICI can deteriorate preexisting paraneoplastic syndrome (PNS) of LEMS. Our rare case was successfully treated by durvalumab plus chemotherapy without exacerbation of preexisting PNS of LEMS. We report a 62-year-old female with ES-SCLC and preexisting PNS of LEMS. She started carboplatin-etoposide in combination with durvalumab. This immunotherapy achieved nearly complete response. However, multiple brain metastases were found after two courses of maintenance durvalumab. Her symptoms and physical examinations of LEMS improved despite of no significant change in compound muscle action potential amplitude in the nerve conduction study. The titer of anti-P/Q-type voltage-gated calcium channel (VGCC) antibody decreased from 1,419.2 to 263.5 pmol/L during the immunotherapy. In conclusion, ICI in combination with platinum doublet chemotherapy is still challenging but may be a treatment option for ES-SCLC patients complicated with PNS of LEMS.

Atezolizumab-Induced Lambert-Eaton Myasthenic Syndrome in a Patient With Small-Cell Lung Cancer.

The case of a 70-year-old man who developed Lambert-Eaton myasthenic syndrome (LEMS) while receiving atezolizumab treatment for extensive-stage small-cell lung cancer (SCLC) is presented. He started receiving maintenance immunotherapy with atezolizumab following four cycles of combination therapy with atezolizumab, carboplatin, and etoposide. After five cycles of maintenance atezolizumab therapy, he complained of muscle weakness in the lower limbs and fatigue. Electromyographic findings and positive results for anti-P/Q-type voltage-gated calcium channel antibody made a diagnosis of LEMS. Based on the onset time of LEMS and the state of his underlying cancer at the time of the appearance of neurological symptoms, he was diagnosed with LEMS as an immune-related adverse event (irAE) induced by atezolizumab. After discontinuing atezolizumab treatment and initiating combination therapy with steroid pulse plus intravenous immunoglobulin, his neurological symptoms improved. Although 18 months have passed since the discontinuation of atezolizumab treatment, there has been neither recurrence of neurological symptoms nor a progression of his cancer without salvage chemotherapy. This is a rare case of LEMS as a neurological irAE induced by atezolizumab. Clinicians must be aware of the potential for LEMS to develop in SCLC patients taking atezolizumab treatment.

Lambert-Eaton myasthenic syndrome (LEMS) in a patient with lung cancer under treatment with pembrolizumab: a case study.

Pembrolizumab is an immune checkpoint inhibitor (ICI) against the programmed death-1 receptor. Herein, we introduce a rare adverse effect during using pembrolizumab. We present the case of an 80-year-old man with biopsy-proven unresectable double primary squamous cell carcinoma and large cell neuroendocrine carcinoma of the lung. After using pembrolizumab for 10 months, he complained of muscle weakness of both upper and lower extremities. In a nerve conduction study, the repetitive nerve stimulation test in the abductor digiti minimi was diagnostic of Lambert-Eaton myasthenic syndrome (LEMS): low in the amplitude of compound muscle action potential (1.4 mV), 28.6% decrement in the 5-Hz stimulation, and 579% increment in the 50-Hz stimulation. The disease did not progress after the discontinuation of pembrolizumab, even without any anti-cancer treatment for 12 months. We believe our clinical experience of this rare and unexpected adverse effect should be shared.