Paraneoplastic neurologic manifestations of neuroendocrine tumors.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors arising from the transformation of neuroendocrine cells in several organs, most notably the gastro-entero-pancreatic system and respiratory tract. The classification was recently revised in the 5th Edition of the WHO Classification of Endocrine and Neuroendocrine Tumors. NENs can rarely spread to the central or peripheral nervous systems. Neurologic involvement is determined by the rare development of paraneoplastic syndromes, which are remote effects of cancer. Mechanisms depend on immunologic response to a tumor, leading to the immune attack on the nervous system or the production of biologically active ("functioning") substances, which can determine humoral (endocrine) effects with neurologic manifestations. Paraneoplastic neurologic syndromes (PNS) are immunologically mediated and frequently detected in small cell lung cancer but rarely seen in other forms of NEN. PNS and Merkel cell carcinoma is increasingly reported, especially with Lambert Eaton myasthenic syndrome. Endocrine manifestations are found in a wide spectrum of NENs. They can develop at any stage of the diseases and determine neurologic manifestations. Patient outcomes are influenced by tumor prognosis, neurologic complications, and the severity of endocrine effects.

Brief Communication: Lambert-Eaton Myasthenic Paraneoplastic Syndrome Associated With Merkel Cell Carcinoma Successfully Treated by Immune Checkpoint Inhibitors: 2 Cases.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cutaneous tumor with high metastatic potential. In rare cases, it can be associated with paraneoplastic syndromes (PNS), which result from an antitumor immunity against antigens produced by the tumor itself. Lambert-Eaton Myasthenic Syndrome (LEMS) is a neurological autoimmune PNS characterized by an impairment of the neuromuscular junction, leading to proximal muscle weakness and fatigability. Although the development of immune checkpoint inhibitors (ICI) is a breakthrough in the management of many cancers, onset or worsen of immune diseases has been described. Thereby, in patients with previous neurological PNS like LEMS, the ICI therapy for cancer may aggravate neurological symptoms and lead to irreversible impairment. We report here 2 cases of patients with metastatic MCC associated with a LEMS at the diagnosis. Both successfully received ICI therapies (anti-PDL1 avelumab and anti-PD1 pembrolizumab) without worsening of LEMS and any major immune-related adverse effects. Their neurological condition improved and disappeared concomitantly with the efficacy of immunotherapy, and we did not observe relapse of both MCC and LEMS after treatment discontinuation. Finally, we performed a complete review of the literature, which confirmed that ICI treatment could be discussed for patients with paraneoplastic LEMS, and emphasized the need for multidisciplinary management.

Paraneoplastic syndromes in ophthalmology.

Paraneoplastic syndromes consist on systemic manifestations associated with certain cancers which are not a direct consequence of tumor invasion or its metastases. It is known that autoimmunity and autoantibody synthesis play an important role in its pathophysiology due to a process of molecular mimicry. Paraneoplastic syndromes in ophthalmology are rare, but it is important to recognize them clinically because in some cases symptoms preceded the diagnosis of an underlying neoplasia. Most frequently involved cancer is small cell lung carcinoma, but there is also a relationship with other tumor etiologies such as thymoma, gynecological tumors or neuroblastoma in children. Paraneoplastic syndromes with ocular involvement can be divided into those that affect the afferent visual pathway, such as cancer-associated retinopathy, melanoma-associated retinopathy, or paraneoplastic optic neuropathy; and the ones that affect the efferent visual pathway, such as bilateral tonic pupils, Myasthenia Gravis, Lambert-Eaton syndrome or paraneoplastic cerebellar degeneration. The presence of autoantibodies is helpful in clinical practice but negativity does not exclude this diagnosis. Although evolution and prognosis is linked to primary disease, in some cases specific treatment, usually immunosuppressive therapy, can help improving patients quality of life.

Síndrome miasteniforme de Lambert-Eaton / Lambert-Eaton myasthenic syndrome

Introducción: El síndrome miasteniforme de Lambert-Eaton (LEMS) es una patología paraneoplásica (T-LEMS) o idiopática autoinmunitaria (NT-LEMS) ocasionada por autoanticuerpos contra los canales de calcio dependientes del voltaje presinápticos de la unión neuromuscular. El 60% de los T-LEMS se asocia a carcinoma de pulmón de células pequeñas. Una puntuación Dutch-English LEMS Tumor Association Prediction (DELTA-P) mayor de 3 denota un riesgo elevado de dicha asociación. El diagnóstico precoz fundado en los hallazgos clínicos, estudios neurofisiológicos y dosificación de títulos de anticuerpos en el suero permite iniciar tempranamente el tratamiento sintomático y la búsqueda oncológica. Son escasos los informes de pacientes con LEMS en Latinoamérica. Objetivo: Describir las características de pacientes con LEMS de un centro privado de Buenos Aires, Argentina, y compararlas con las de otras series publicadas. Pacientes y métodos: Se revisaron historias clínicas de 13 pacientes con LEMS con hallazgos clínicos, electromiograma compatible y/o anticuerpos positivos. Se realizó seguimiento hasta descartar o confirmar una neoplasia asociada de acuerdo con los algoritmos recomendados. Resultados: Cuatro pacientes presentaron diagnóstico de T-LEMS, dos de ellos con carcinoma de pulmón de células pequeñas. De los nueve pacientes con NT-LEMS, cinco presentaron una puntuación DELTA-P de 3 y 4. Nueve pacientes presentaron la tríada clínica clásica desde el inicio. Todos los pacientes presentaron en el electromiograma hallazgos compatibles con defecto de placa neuromuscular presináptico. El 70% mejoró sintomáticamente con piridostigmina. Conclusiones: Los hallazgos clínicos, junto con los estudios neurofisiológicos compatibles, resultan suficientes para el diagnóstico de LEMS. No pudo replicarse la relación entre puntuación DELTA-P y riesgo de carcinoma de pulmón de células pequeñas...(AU)

Introduction: Early diagnosis based on clinical findings, neurophysiological studies and serum antibody titres allows early initiation of symptomatic treatment and oncological screening. Reports of patients with LEMS in Latin America are scarce. Aim: This article aims to describe the characteristics of patients with LEMS from a private centre in Buenos Aires, Argentina, and to compare them with those of other series that have been published. Patients and methods: The medical records of 13 patients with LEMS with clinical findings, compatible electromyogram and/or positive antibodies were reviewed. Follow-up was performed until associated neoplasia was ruled out or confirmed according to the recommended algorithms. Results: Four patients were diagnosed with T-LEMS, two of them with small-cell lung carcinoma. Of the nine patients with NT-LEMS, five had a DELTA-P score of 3 and 4. Nine patients presented with the classic clinical triad from the onset of the disease. All patients had electromyogram findings compatible with presynaptic neuromuscular plaque defect. Of the total, 70% improved symptomatically with pyridostigmine. Conclusions: The clinical findings, together with compatible neurophysiological studies, are sufficient for the diagnosis of LEMS. The relationship between the DELTA-P score and the risk of small-cell lung carcinoma could not be replicated. Symptomatic treatment with pyridostigmine represents an effective therapeutic alternative.(AU)

[Lambert-Eaton myasthenic syndrome]. / Síndrome miasteniforme de Lambert-Eaton.

INTRODUCTION: Early diagnosis based on clinical findings, neurophysiological studies and serum antibody titres allows early initiation of symptomatic treatment and oncological screening. Reports of patients with LEMS in Latin America are scarce. AIM: This article aims to describe the characteristics of patients with LEMS from a private centre in Buenos Aires, Argentina, and to compare them with those of other series that have been published. PATIENTS AND METHODS: The medical records of 13 patients with LEMS with clinical findings, compatible electromyogram and/or positive antibodies were reviewed. Follow-up was performed until associated neoplasia was ruled out or confirmed according to the recommended algorithms. RESULTS: Four patients were diagnosed with T-LEMS, two of them with small-cell lung carcinoma. Of the nine patients with NT-LEMS, five had a DELTA-P score of 3 and 4. Nine patients presented with the classic clinical triad from the onset of the disease. All patients had electromyogram findings compatible with presynaptic neuromuscular plaque defect. Of the total, 70% improved symptomatically with pyridostigmine. CONCLUSIONS: The clinical findings, together with compatible neurophysiological studies, are sufficient for the diagnosis of LEMS. The relationship between the DELTA-P score and the risk of small-cell lung carcinoma could not be replicated. Symptomatic treatment with pyridostigmine represents an effective therapeutic alternative.

TITLE: Síndrome miasteniforme de Lambert-Eaton.Introducción. El síndrome miasteniforme de Lambert-Eaton (LEMS) es una patología paraneoplásica (T-LEMS) o idiopática autoinmunitaria (NT-LEMS) ocasionada por autoanticuerpos contra los canales de calcio dependientes del voltaje presinápticos de la unión neuromuscular. El 60% de los T-LEMS se asocia a carcinoma de pulmón de células pequeñas. Una puntuación Dutch-English LEMS Tumor Association Prediction (DELTA-P) mayor de 3 denota un riesgo elevado de dicha asociación. El diagnóstico precoz fundado en los hallazgos clínicos, estudios neurofisiológicos y dosificación de títulos de anticuerpos en el suero permite iniciar tempranamente el tratamiento sintomático y la búsqueda oncológica. Son escasos los informes de pacientes con LEMS en Latinoamérica. Objetivo. Describir las características de pacientes con LEMS de un centro privado de Buenos Aires, Argentina, y compararlas con las de otras series publicadas. Pacientes y métodos. Se revisaron historias clínicas de 13 pacientes con LEMS con hallazgos clínicos, electromiograma compatible y/o anticuerpos positivos. Se realizó seguimiento hasta descartar o confirmar una neoplasia asociada de acuerdo con los algoritmos recomendados. Resultados. Cuatro pacientes presentaron diagnóstico de T-LEMS, dos de ellos con carcinoma de pulmón de células pequeñas. De los nueve pacientes con NT-LEMS, cinco presentaron una puntuación DELTA-P de 3 y 4. Nueve pacientes presentaron la tríada clínica clásica desde el inicio. Todos los pacientes presentaron en el electromiograma hallazgos compatibles con defecto de placa neuromuscular presináptico. El 70% mejoró sintomáticamente con piridostigmina. Conclusiones. Los hallazgos clínicos, junto con los estudios neurofisiológicos compatibles, resultan suficientes para el diagnóstico de LEMS. No pudo replicarse la relación entre puntuación DELTA-P y riesgo de carcinoma de pulmón de células pequeñas. El tratamiento sintomático con piridostigmina representa una alternativa terapéutica eficaz.

Successful treatment of advanced lung adenocarcinoma complicated with Lambert-Eaton myasthenic syndrome: A case report and literature review.

Lambert-Eaton myasthenic syndrome (LEMS) is a rare disease characterized by involvement of the neuromuscular junction. Most cases have an underlying malignancy, especially small-cell lung cancer (SCLC), while adenocarcinoma is less common. Here, we report a rare case of metastatic lung adenocarcinoma complicated with LEMS. In this case, L858R mutation was detected in the 21st exon of the EGFR gene. First-line treatment with gefitinib was given, and the patient has survived for more than six years. Early diagnosis of LEMS and timely and effective treatment can result in a good prognosis. We also searched for "lung cancer", or "carcinoma of lung", or "adenocarcinoma of lung", or "Lambert-Eaton myasthenic syndrome" in PubMed until 1 December 2019. Seven cases of lung adenocarcinoma complicated with LEMS were found, most of which had a poor prognosis. KEY POINTS: This article reports a rare case of metastatic lung adenocarcinoma with EGFR mutation, complicated with LEMS. Gefitinib was given as first-line treatment, and resulted in a good prognosis.

Lambert-Eaton myasthenic syndrome and merkel cell carcinoma.

Lambert-Eaton myasthenic syndrome (LEMS) is an antibody-mediated disorder of the neuromuscular junction that is most commonly diagnosed in association with small cell lung carcinoma (SCLC). Small cell lung carcinoma is histologically similar to the aggressive cutaneous neuroendocrine malignancy Merkel cell carcinoma (MCC). We provide a full report and longitudinal clinical follow-up of a case of LEMS occurring with MCC. We also review the literature on paraneoplastic syndromes associated with MCC and other nonpulmonary small cell carcinomas.

Clinical characteristics and long term follow-up of Lambert-Eaton myasthenia syndrome in patients with and without small cell lung cancer.

In order to describe the clinical characteristics, treatment response and long-term follow up in Lambert-Eaton myasthenic syndrome (LEMS) patients with and without small cell lung cancer (SCLC) in East China, patients seen in Huashan Hospital from January 1997 to December 2017 were included. Clinical information was collected retrospectively and quantitative MG (QMG) score, manual muscle testing (MMT), activities of daily living (ADL) scale were evaluated when the patients were followed up. Of 50 patients, 23 (46%) were SCLC-LEMS and 20 (40%) were nontumor LEMS (NT-LEMS). The median onset age was 55.5 (18-86) years old and the gender ratio was about 1.8:1. It took less time to make the diagnosis (median time: 6 vs 22.5 months, p = 0.0003) and there were more patients with other paraneoplastic syndromes in SCLC-LEMS group than in NT-LEMS group (8/23 vs 0/20, p = 0.0042). Electrophysiologically, the peroneal compound motor action potential (CMAP) of rest showed difference between SCLC-LEMS and NT-LEMS (0.8 vs 1.6 mV, p = 0.0499). The median survival time of 19 SCLC-LEMS patients since the diagnosis of SCLC was 30 months. According to their survival time, SCLC patients with LEMS showed a more favorable prognosis than those without LEMS. In the time of follow-up, most NT-LEMS showed improvement or obtained status of CSR/PR/MM after immunosuppressive therapy and no significant difference in proportion of achieving CSR/PR/MM was found between SCLC-LEMS and NT-LEMS patients (0/5 vs 6/13, p = 0.114).

Paraneoplastic Lambert-Eaton syndrome in a patient with disseminated metastatic cancer. / Síndrome paraneoplásico de Lambert-Eaton en paciente con cáncer metastásico diseminado

Background: Neurological paraneoplastic syndromes are rare, occur in 0.01% of all cancer patients; like part of them, the Lambert-Eaton syndrome is an autoimmune presynaptic disorder of neuromuscular transmission characterized by muscle weakness and neurovegetative dysfunction, and often associated with small cell lung cancer. Case report: A 72 years old female with a family history of lung cancer and leukemia, with 7 months of dry cough and 3 months with waist and pelvic muscle weakness, oropharyngeal dysphagia, dry mouth, chronic constipation and weight loss of 10 kg. Physical examination: patient prostrated; clinical muscle examination: pelvic muscles waist -3/5 and -4/5 the rest; diminished reflexes. Laboratory normal parathormone and hypercalcemia. With electrophysiological study and positive anti-voltage-gated calcium channel antibodies, confirming Lambert-Eaton syndrome and imaging studies with neoplastic condition in brain, liver and kidney, with unspecified primary origin.

Antecedentes: Los síndromes paraneoplásicos neurológicos son poco frecuentes; se presentan en el 0.01% de todos los pacientes con cáncer. Uno de ellos es el síndrome de Lambert-Eaton, correspondiendo a un trastorno presináptico autoinmunitario de transmisión neuromuscular caracterizado por debilidad muscular y disfunción neurovegetativa, y asociado con frecuencia al carcinoma microcítico de pulmón. Caso clínico: Mujer de 72 años, con antecedentes heredofamiliares de cáncer de pulmón y leucemia, con tos seca de 7 meses, 3 meses con debilidad de los músculos de cintura pélvica, disfagia al inicio de la deglución, xerostomía, estreñimiento crónico y pérdida de peso de 10 kg. A la exploración física: paciente postrada; examen clínico muscular: músculos de cintura pélvica en −3/5, resto en −4/5; reflejos disminuidos. Pruebas de laboratorio indicando hipercalcemia y paratohormona normal. Estudio electrofisiológico y anticuerpos anticanales de calcio positivos, demostrando síndrome de Lamber-Eaton, y estudios de imagen con afectación neoplásica en cerebro, hígado y riñón, sin lograr especificar el origen primario.

Lambert-Eaton Myasthenic Syndrome Associated with Synchronous Double Cancer: A Combination of Small Cell Carcinoma of the Cervix and Breast Carcinoma.

Lambert-Eaton myasthenic syndrome (LEMS) is most commonly associated with small cell lung carcinoma, while it is rarely associated with gynecological and breast carcinoma. We herein report a case of LEMS associated with synchronous double cancer, which was a combination of small cell carcinoma of the cervix and breast carcinoma. The early diagnosis and treatment of LEMS are important for achieving a good outcome. The possibility of accompanying paraneoplastic neurological syndrome must be sufficiently considered in gynecology and breast cancer patients. To our knowledge, this is the first report of LEMS associated with synchronous double cancer.

Paraneoplastic Cerebellar Degeneration and Lambert-Eaton Myasthenic Syndrome Associated with Neuroendocrine Carcinoma of the Oropharynx.

Paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome (PCD-LEMS) are usually associated with small-cell lung carcinoma (SCLC). PCD-LEMS with extrapulmonary non-SCLC tumors; however, has not been previously reported. A 78-year-old man presented with dysarthria, dysphagia, staggering gait, and lower extremity muscle fatigue. He was diagnosed with PCD-LEMS associated with neuroendocrine carcinoma of the oropharynx, based on the histological findings of the biopsy, the existence of antibodies against P/Q-type voltage-gated calcium channels, and an incremental response of the compound muscle action potentials during repetitive nerve stimulation tests. Thus, PCD-LEMS should be included in the differential diagnosis of neurological dysfunction, even in extrapulmonary non-SCLC patients.

Lambert-Eaton myasthenic syndrome: mouse passive-transfer model illuminates disease pathology and facilitates testing therapeutic leads.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder caused by antibodies directed against the voltage-gated calcium channels that provide the calcium ion flux that triggers acetylcholine release at the neuromuscular junction. To study the pathophysiology of LEMS and test candidate therapeutic strategies, a passive-transfer animal model has been developed in mice, which can be created by daily intraperitoneal injections of LEMS patient serum or IgG into mice for 2-4 weeks. Results from studies of the mouse neuromuscular junction have revealed that each synapse has hundreds of transmitter release sites but that the probability for release at each one is likely to be low. LEMS further reduces this low probability such that transmission is no longer effective at triggering a muscle contraction. The LEMS-mediated attack reduces the number of presynaptic calcium channels, disorganizes transmitter release sites, and results in the homeostatic upregulation of other calcium channel types. Symptomatic treatment is focused on increasing the probability of release from dysfunctional release sites. Current treatment uses the potassium channel blocker 3,4-diaminopyridine (DAP) to broaden the presynaptic action potential, providing more time for calcium channels to open. Current research is focused on testing new calcium channel gating modifiers that work synergistically with DAP.

Paraneoplastic Inverse Myasthenic Syndrome as a Presentation of Bronchogenic Carcinoma.

Tumours may produce growth factors and cytokines responsible for signs and symptoms distant to the primary or metastatic site. This may be the first sign of a malignancy and its recognition may be critical for early cancer detection. Moreover, proper diagnosis spares the patient of extensive and expensive search for an alternate cause of the neurological dysfunction. In neurological paraneoplastic syndromes like Lambert Eaton Myasthenic syndrome associated with small cell lung cancer, evidence of autoimmunity against presynaptic neuro-muscular junction by anti voltage gated calcium channel anti bodies is well documented. 60% of patients with LEMS are associated with an underlying cancer, usually SCLC. We report a 49 year old male, with over thirty pack years of smoking, who presented with dysautonomia, constitutional symptoms and weakness of all four limbs. Investigations confirmed axonal motor neuropathy with limited stage SCLC with fibro nodular lesions right upper lobe and mediastinal lymphadenopathy. He improved dramatically following chemotherapy and radiotherapy.

Relapse of both small cell lung cancer and Lambert-Eaton myasthenic syndrome after a 13-year disease-free survival period.

Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic syndrome and only 3% of small cell lung carcinoma (SCLC) patients have LEMS. Moreover, the recurrence of SCLC after a disease-free survival (DFS) of more than 10 years is rare. We report a patient who had a recurrence of both SCLC and LEMS after a 13-year DFS period. A 69-year-old man was diagnosed with LEMS and SCLC (cT0N2M0, stage IIIA) 13 years ago. Chemoradiotherapy was performed and a complete response was achieved. With anticancer treatment, the LEMS symptoms was alleviated. At the age of 82 years, gait disturbance appeared followed by left supraclavicular lymphadenopathy and further examination revealed the recurrence of SCLC. Careful screening for the recurrence of SCLC might be needed when the patient has recurrent or secondary paraneoplastic neurological syndrome even after a long DFS period.

Paraneoplastic syndromes in patients with laryngeal neuroendocrine carcinomas: clinical manifestations and prognostic significance.

Paraneoplastic syndromes are associated with a variety of malignant neoplasms and are systemic and non-metastatic manifestations that develop in a minority of cancer patients. This review examines all published cases of paraneoplastic syndromes associated with neuroendocrine carcinomas of the larynx. There are a total of ten patients reported with paraneoplastic syndromes associated with laryngeal neuroendocrine carcinomas in the literature. Of these, nine died and the tenth is alive with liver metastases. There were five cases of small-cell neuroendocrine carcinoma, four cases of moderately differentiated neuroendocrine carcinoma, and one case of well-differentiated neuroendocrine carcinoma associated with paraneoplastic syndromes. As these syndromes have significant clinical relevance, physicians should be aware of the possible presence of paraneoplastic syndromes in the diagnostic process of patients with neuroendocrine carcinoma of the larynx.

Lambert-Eaton myasthenic syndrome in patients with small cell lung cancer: Report of five cases.

OBJECTIVE: To further evaluate the clinical characteristics of small cell lung cancer (SCLC) with Lambert-Eaton syndrome. METHODS: We reviewed the patient database of our hospital from 2001 to 2013 to evaluate and analyze the patients of SCLC with Lambert-Eaton syndrome. The clinical characteristics and prognosis of the patients were analyzed in this retrospective study. RESULTS: From reviewing our hospital database, we included 5 SCLC patients with Lambert-Eaton syndrome from 202 SCLC subjects with an incidence rate of 2.5%. The median age of the 5 patients was 52 (41-71) with 4 male and 1 female. The myasthenia symptom can be detected in 2-20 months before the pathology confirmation for small cell lung carcinoma. The general electromyography characteristics of Lambert-Eaton syndrome was reduction in action potential amplitude after repetitive peripheral never stimulation at low frequency and increased amplitude at high frequency. CONCLUSION: Lambert-Eaton syndrome was sometimes found in patients with SCLC which was useful for diagnosis of non-small cell lung carcinoma in a relatively early stage.