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.

[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.

[Blood-brain barrier breakdown and autoimmune cerebellar ataxia].

Autoimmune cerebellar ataxia is a disease entity that affects the cerebellum and is induced by autoimmune mechanisms. The disease is classified into several etiologies, including gluten ataxia, anti-glutamate decarboxylase (GAD) ataxia, paraneoplastic cerebellar degeneration, primary autoimmune cerebellar ataxia and postinfectious cerebellar ataxia. The autoimmune response in the periphery cross-reacts with similar antigens in the cerebellum due to molecular mimicry. Breakdown of the blood‒brain barrier (BBB) could potentially explain the vulnerability of the cerebellum during the development of autoimmune cerebellar ataxia, as it gives rise to the entry of pathogenic autoantibodies or lymphocytes into the cerebellum. In this review, the maintenance of the BBB under normal conditions and the molecular basis of BBB disruption under pathological conditions are highlighted. Next, the pathomechanism of BBB breakdown in each subtype of autoimmune cerebellar ataxia is discussed. We recently identified glucose-regulated protein (GRP) 78 antibodies in paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome, and GRP78 antibodies induced by cross-reactivity with tumors can disrupt the BBB and penetrate anti-P/Q type voltage-gated calcium channel (VGCC) antibodies into the cerebellum, thus leading to cerebellar ataxia in this disease.

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 .

[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.

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.

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.

[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.

Paraneoplastic Lambert-Eaton myasthenic syndrome: a diagnostic challenge.

Lambert-Eaton myasthenic syndrome (LEMS) is a rare neuromuscular junction disorder. Underlying small cell lung cancer is found in more than half of patients. Proximal muscle weakness, autonomic features and areflexia are typical manifestations. However, LEMS is often misdiagnosed. We report a rare case of paraneoplastic LEMS, identified amid admission due to a different diagnosis. Our patient was initially admitted due to aspiration pneumonia. Further investigation revealed clinical and electrophysiological manifestations of LEMS. High clinical suspicion and early diagnostic workup were paramount in the patient outcome. Nevertheless, paraneoplastic aetiology was difficult to confirm and revealed itself a difficult challenge. Clinical awareness is crucial to diagnose LEMS and urge cancer screening and early treatment.

SOX1 antibody-related paraneoplastic neurological syndromes: clinical correlates and assessment of laboratory diagnostic techniques.

OBJECTIVE: To describe the clinical associations of SOX1 antibodies (SOX1-Abs), determine the accuracy of various detection techniques, and propose laboratory criteria to identify definite paraneoplastic neurological syndromes (PNS) associated with SOX1-Abs. METHODS: Single-center, retrospective study of patients referred to the French Reference Center between 2009 and 2019 for confirmation of SOX1-Ab positivity, without concurrent neural antibodies. Patients were classified according to the updated diagnostic PNS criteria; biological samples were systematically retested with three distinct techniques (line blot, cell-based assay, indirect immunofluorescence). RESULTS: Among 77 patients with isolated SOX1-Ab positivity, 23 (29.9%) fulfilled the criteria for definite PNS; all of them had lung cancer (mostly small-cell) and presented mainly with Lambert-Eaton myasthenic syndrome (10/23) and rapidly progressive cerebellar ataxia (6/23). SOX1-Ab positivity varied depending on the laboratory methods which were used, and a single technique was not sufficient to draw conclusions about the PNS diagnosis. The combination of an antigen-specific test (line blot and/or cell-based assay) and immunofluorescence showed the highest accuracy (81.5%, 95% CI 70.0-90.1) in identifying definite PNS. Moreover, when the PNS-Care score was recalculated assigning three points at the laboratory-level only to patients with positive "antigenic-specific test + immunofluorescence" and 0 points to the remaining cases, a higher certainty for definite and non-PNS was achieved (from 41/77, 53.2%, to 60/77, 77.9%; p < 0.001). CONCLUSION: SOX1-Abs should be considered high-risk antibodies only when detected with a positive antigenic-specific test and immunofluorescence. Other laboratory results and clinical associations different from Lambert-Eaton myasthenic syndrome and rapidly progressive cerebellar ataxia should be carefully reassessed to rule out false positivity and alternative diagnoses.

A MIDDLE-AGED PATIENT WITH BILATERAL VISION LOSS AND NYCTALOPIA.

PURPOSE: To report a case of nonparaneoplastic autoimmune retinopathy in a patient with a diagnosis of Lambert-Eaton myasthenic syndrome. METHODS: Case report. Main outcome measures included findings on retinal examination and analysis of fundus autofluorescence, spectral-domain optical coherence tomography, and full-field electroretinogram. Vitamin A levels and results of antiretinal antibody testing and paraneoplastic workup are also presented. RESULTS: A 47-year-old male presented with a 1-year history of bilateral vision loss and nyctalopia. Past medical history was significant for Lambert-Eaton myasthenic syndrome, confirmed by positive voltage-gated calcium channel antibodies, and thymectomy reported as thymic follicular hyperplasia. Optical coherence tomography showed bilateral diffuse outer retinal atrophy and ellipsoid zone loss. Fundus autofluorescence displayed a bull's pattern of hyperautofluorescence around each fovea. Full-field electroretinogram showed an extinguished rod response and a severely depressed cone response in each eye. CONCLUSION: We describe a case of nonparaneoplastic autoimmune retinopathy in a patient with Lambert-Eaton myasthenic syndrome. Multimodal retinal imaging and electroretinogram confirmed the presence of autoimmune retinopathy with severe rod-cone degeneration. The association of this myasthenic syndrome with AIR is novel.

SOX-1 antibodies in a patient with Crohn's disease: a case report.

BACKGROUND: The anti-SOX-1 antibodies have been mainly associated with Lambert-Eaton Myasthenic Syndrome (LETMS) and Small-Cell Lung Cancer (SCLC). In this report, we describe the interesting case of a patient with serum anti-SOX-1 antibodies and Crohn's Disease (CD) with ensuing neurological symptoms. CASE PRESENTATION: A Caucasian 67-year-old female was admitted to the Emergency Department with seizures, vertigo, emesis, nausea, postural instability and recurrent falls, over a period of 10 days. She had been affected by Crohn's Disease since 1991. A CT scan failed to detect any ischemic or haemorrhagic lesion. A brain MRI revealed signs of leukoencephalopathy. Western blot analysis of her serum revealed a high titre of the onconeural antibody anti-SOX1, consistent with a neurological, cerebellar type, paraneoplastic syndrome. In spite of multiple efforts to unmask a possible underlying malignancy, no neoplastic lesion cropped up during hospitalization. Her clinical conditions progressively deteriorated, up to respiratory failure; a few days later she died, due to ensuing septic shock and Multiple Organ Failure. CONCLUSIONS: Our experience may usher and reveal a new role of anti-neural antibodies, so far reckoned an early indicator of associated malignancy, suggesting that neurological syndromes associated with such antibodies may complicate also chronic Gastrointestinal (GI) diseases. As of now, testing for anti-neuronal antibodies appeared unnecessary within the diagnostic assessment of gastroenterological disorders, which may lead to overlooking incident neurologic autoimmune diseases. Further exploration of such research hypothesis in clinical grounds appears intriguing.

[Diagnostics and treatment of clinically relevant paraneoplastic syndromes]. / Diagnostik und Therapie klinisch relevanter paraneoplastischer Syndrome.

Paraneoplastic syndromes (PS) are rare disorders with often complex clinical manifestations that occur in association with a tumor without being triggered by direct tumor invasion or compression. They arise from tumor secretions of hormones, peptides or cytokines or from immune cross-reactivity between malignant and healthy tissue. They are categorized into endocrine, neurological, dermatological, rheumatological, and hematological PS. The PS most commonly occurs in small cell lung carcinoma but also in association with other respiratory tract tumors, gynecological tumors, and hematological malignancies. The PS can precede a tumor diagnosis, therefore timely diagnosis can improve the prognosis of a malignant disease. The diagnostics are based on the clinical presentation as well as diagnostic methods depending on the underlying pathogenesis. The most important treatment approach involves the best possible treatment of the tumor and a targeted treatment is only sometimes possible. This review focuses on the clinically most frequently encountered PS.

Progressive motor quadriparesis with wasting: a diagnostic conundrum.

The case of a man in his early 30s, presenting with slowly progressive, asymmetrical onset, pure motor quadriparesis over 9 months with bulbar involvement, absence of upper motor neuron features and significant weight loss, is reported. In view of presentation with diffuse lower motor neuron involvement of short duration, the diagnostic possibilities are discussed. Apart from motor neuron disease, its mimics including muscle and neuromuscular junction disorders were also considered and evaluated for. Carefully assessed clinical and electrophysiological markers which finally clinched the diagnosis of the rare disorder Lambert-Eaton myasthenic syndrome are elaborated. In the present context, recognition of the oddities on clinical and laboratory evaluation is of paramount importance to rule in causes of pure motor quadriparesis.

Lambert-Eaton Myasthenic Syndrome in Lung Cancer.

The aim is to study lung cancer with Lambert-Eaton myasthenic syndrome (LEMS) with clinical and electrical characteristics of physiology and prognosis. Fourteen LEMS patients with lung cancer were studied retrospectively. The data including demographics, clinical presentation, treatments, and prognosis from the medical records were analyzed. Lung cancer coexisting with LEMS is more common in men (10/14). The median age was 67.1 years. Eleven (78.6%) patients experienced gradual onset of disease. Most patients presented nervous system lesions prior to occult tumors. The most common symptoms reported were proximal muscle weakness (92.9%), decreased or absent tendon reflexes (50%), and autonomic dysfunction (71.4%). All the patients showed reduction in action potential amplitude after repetitive peripheral never stimulation at low frequency and increased amplitude at high frequency. LEMS usually occurs prior to lung cancer with complicated and various clinical manifestations in our centers. We should improve awareness and knowledge of such disease to shorten the diagnostic delay and lead to few misdiagnoses.

Autonomic dysfunction detected by skin sympathetic response in Lambert-Eaton myasthenic syndrome: a case report.

BACKGROUND: Lambert-Eaton myasthenic syndrome (LEMS) is a type of paraneoplastic syndrome that may initially manifest itself with proximal weakness and gait abnormalities. Approximately up to 50% of LEMS patients have a primary autonomic dysfunction. CASE PRESENTATION: We present here a case of a 75-year-old male with symmetric proximal muscle weakness, dry mouth and constipation. The cutaneous response to scratch and upright tilt-table testing were positive. A repetitive nerve stimulation test showed that there was a decremental response of compound muscle action potential (CMAP) amplitude at 3 Hz while an incremental response at 20 Hz. The presence of antibodies against voltage-gated calcium channels (VGCC) confirmed the diagnosis. Because of the prominent symptom of autonomic disorder, the patient further underwent the test of skin sympathetic response (SSR). Lower amplitude and longer response duration were found in palms, while it evoked no response in soles. CONCLUSIONS: In this case, we present the detailed results of SSR test on a patient suffering LEMS with autonomic disorder. Since autonomic dysfunction has a significant impact on clinical management and SSR test is an effective detection method, we recommend that SSR test be performed on patients with LEMS regularly.

Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders.

Autoimmune neuromuscular junction disorders are rare. However, myasthenia gravis is being increasingly recognised in people older than 50 years. In the past 5-10 years, epidemiological studies worldwide suggest an incidence of acetylcholine receptor antibody-positive myasthenia gravis of up to 29 cases per 1 million people per year. Muscle-specific tyrosine kinase antibody-positive myasthenia gravis and Lambert-Eaton myasthenic syndrome are about 20 times less common. Several diagnostic methods are available for autoimmune neuromuscular junction disorders, including serological antibody, electrophysiological, imaging, and pharmacological tests. The course of disease can be followed up with internationally accepted clinical scores or patient-reported outcome measures. For prognostic purposes, determining whether the disease is paraneoplastic is of great importance, as myasthenia gravis can be associated with thymoma and Lambert-Eaton myasthenic syndrome with small-cell lung cancer. However, despite well defined diagnostic parameters to classify patients into subgroups, objective biomarkers for use in the clinic or in clinical trials to predict the course of myasthenia gravis and Lambert-Eaton myasthenic syndrome are needed.

Anti-SOX1 Antibody-Positive Paraneoplastic Syndrome Presenting with Subacute Cerebellar Degeneration and Lambert-Eaton Myasthenic Syndrome: A Case Report.

PURPOSE: Paraneoplastic neurological disorders associated with autoantibodies are rare diseases, causing abnormal manifestations in the central or peripheral nervous system separately or simultaneously. Early recognizing the occurrence of paraneoplastic syndrome can lead to prompt and effective management. CASE REPORT: We presented a patient of subacute cerebellar degeneration with cachectic and bed-ridden status, who was proven to have positive SOX1 antibody. A coexisting Lambert-Eaton myasthenic syndrome was also documented by electrophysiological study. CONCLUSION: Intensive and regular follow up for an occult malignancy is crucial in patients with SOX1 antibody. Coadministration of therapies for underlying malignancy and LEMS improve the functional disability.