Myasthenic Syndrome Research Articles

Paraneoplastic Neurologic Syndromes Associated With Merkel Cell Carcinoma.

To define the clinical and immunologic profile of patients with paraneoplastic neurologic syndromes (PNSs) associated with Merkel cell carcinoma (MCC). Retrospective analysis was conducted on patients with suspected MCC-related PNS assessed at the French Reference Center, and cases were identified by a systematic review of the literature (MEDLINE, Embase) following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 17 patients were identified in our center and 30 in the systematic review, resulting in an overall cohort of 47 patients. The median age was 65 years (range 41-90), and 30 of 46 (65%) were men. Lambert-Eaton myasthenic syndrome (LEMS) (14/47, 29%), rapidly progressive cerebellar syndrome (11/47, 23%), and encephalomyelitis (EM) (8/47, 17%) were the most common associated clinical phenotypes. The most frequently associated neural antibodies (Abs) were voltage-gated calcium channel (VGCC)-Abs (14/45, 31%), followed by Hu-Abs (8/45, 17%) and neurofilament (NF)-Abs (8/45, 17%). Patients with NF-Abs only exhibited CNS disorders (8/8, 100%) and often had antibodies against >1 NF subunit (6/8, 75%). At onset, 26 of 43 patients (60%) had no identifiable primary skin tumor but had lymph node metastasis; these patients were more frequently men (21/26, 80%, vs 7/17, 41%; p = 0.007), had more frequently VGCC-Abs (12/26, 46%, vs 2/17, 11%, p = 0.02) predominantly among those with LEMS, and presented reduced mortality than patients with a known primary tumor (5/25, 20%, vs 8/15, 53%; p = 0.02). MCC-related PNSs present as a heterogeneous clinical spectrum including central and/or peripheral nervous system disorders such as LEMS, RCPS, and EM, mainly associated with VGCC-Abs, NF-Abs, and Hu-Abs. NF-Abs were only seen among patients with CNS disorders. At onset, the absence of a primary skin tumor but presence of lymph node metastasis is frequently observed, and this particular clinical presentation is linked to reduced mortality, highlighting distinctive clinical and immunologic features of MCC-related PNS.

Limb-Girdle Type Congenital Myasthenic Syndrome Anticipated With Scoliosis: A Case Report

Limb-Girdle Type Congenital Myasthenic Syndrome Anticipated With Scoliosis: A Case Report

First-In-Human Dose-Escalation Study of Fianlimab, an Anti-Lymphocyte Activation Gene-3 Antibody, with Cemiplimab in patients with advanced malignancies.

Preclinical data indicate that fianlimab (anti-lymphocyte activation gene-3) plus cemiplimab (anti-programmed cell death-1) enhances antitumor activity. Here, we report prespecified final analyses of the dose-escalation part of a first-in-human, phase 1 study (NCT03005782) of fianlimab as monotherapy and in combination with cemiplimab in patients with advanced malignancies. Adult patients received fianlimab 1-40 mg/kg ± cemiplimab 350 mg every 3 weeks (Q3W) across various dose-escalation schedules. Primary objectives were rate of dose-limiting toxicities, adverse events (including immune-mediated), deaths, laboratory abnormalities, and pharmacokinetics. Secondary outcomes were objective response rate, best overall response, duration of response, and antidrug antibody variables. Seventy-eight patients were enrolled (fianlimab + cemiplimab, n = 47; fianlimab monotherapy, n = 31). One patient treated with 3 mg/kg fianlimab + cemiplimab experienced dose-limiting toxicities, including increased blood creatine phosphokinase and myasthenic syndrome. No maximum tolerated dose was reached. Any-grade treatment-emergent adverse events occurred in 90% of patients with fianlimab monotherapy, 87% with fianlimab + cemiplimab, and 87% who transitioned from monotherapy to combination therapy. Fianlimab pharmacokinetics were dose-proportional, and similar in monotherapy and combination therapy. Across patients who received fianlimab + cemiplimab, five achieved a partial response; three of whom experienced a response after transitioning from monotherapy to combination therapy. Fianlimab 1600 mg Q3W (20 mg/kg in an 80 kg individual) is the selected dose for phase 2 and 3 studies. Fianlimab as monotherapy and in combination with cemiplimab demonstrated acceptable safety and preliminary antitumor activity, which is generally consistent with previous reports of cemiplimab.

Diaphragmatic Palsy Due to a Paraneoplastic Autoimmune Syndrome Revealed by Checkpoint Inhibitors

Background and Clinical Significance: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but may underlie diverse and potentially life-threatening immune-related adverse events (irAEs). They may cause various conditions leading to respiratory failure, including myasthenic syndromes and myositis. However, diaphragmatic paralysis (DP) has rarely been reported. To describe patients with diaphragmatic paralysis in a pharmacovigilance registry, we searched the prospective REISAMIC registry at the Gustave Roussy Cancer Center (Villejuif, France) for cases of diaphragmatic palsy (DP) occurring from September 2014 to December 2021. Case Presentation: We identified three patients, in whom DP was confirmed by diaphragmatic ultrasonography, pulmonary function tests, and/or diaphragmatic electroneuromyogram. Diaphragmatic palsy was life-threatening in all patients, as it caused respiratory failure requiring mechanical ventilation. In all cases, a pre-existing subclinical paraneoplastic syndrome was detected. Onconeural antibodies (anti-titin and anti-VGCC) were detected in these patients before and after the initiation of ICI therapy, suggesting a mixed paraneoplastic syndrome with features overlapping those of myasthenic syndrome (myasthenia gravis in one patient and Lambert–Eaton syndrome in another) and myositis. Conclusions: Diaphragmatic palsy is a severe irAE potentially resulting from different mechanisms, including myositis and neuromuscular junction involvement (myasthenia gravis, Lambert–Eaton). Antineuronal antibodies associated with such conditions were already present in our patients prior to immunotherapy initiation, suggesting ICIs could trigger flare-ups of pre-existing silent paraneoplastic autoimmune conditions.

A Deficiency in Glutamine-Fructose-6-Phosphate Transaminase 1 (Gfpt1) in Skeletal Muscle Results in Reduced Glycosylation of the Delta Subunit of the Nicotinic Acetylcholine Receptor (AChRδ).

The neuromuscular junction (NMJ) is the site where the motor neuron innervates skeletal muscle, enabling muscular contraction. Congenital myasthenic syndromes (CMS) arise when mutations in any of the approximately 35 known causative genes cause impaired neuromuscular transmission at the NMJ, resulting in fatigable muscle weakness. A subset of five of these CMS-causative genes are associated with protein glycosylation. Glutamine-fructose-6-phosphate transaminase 1 (Gfpt1) is the rate-limiting enzyme within the hexosamine biosynthetic pathway (HBP), a metabolic pathway that produces the precursors for glycosylation. We hypothesized that deficiency in Gfpt1 expression results in aberrant or reduced glycosylation, impairing the proper assembly and stability of key NMJ-associated proteins. Using both in vitro and in vivo Gfpt1-deficient models, we determined that the acetylcholine receptor delta subunit (AChRδ) has reduced expression and is hypo-glycosylated. Using laser capture microdissection, NMJs were harvested from Gfpt1 knockout mouse muscle. A lower-molecular-weight species of AChRδ was identified at the NMJ that was not detected in controls. Furthermore, Gfpt1-deficient muscle lysates showed impairment in protein O-GlcNAcylation and sialylation, suggesting that multiple glycan chains are impacted. Other key NMJ-associated proteins, in addition to AChRδ, may also be differentially glycosylated in Gfpt1-deficient muscle.

Blood-Brain Barrier Disruption in Neuroimmunological Disease.

The blood-brain barrier (BBB) acts as a structural and functional barrier for brain homeostasis. This review highlights the pathological contribution of BBB dysfunction to neuroimmunological diseases, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), autoimmune encephalitis (AE), and paraneoplastic neurological syndrome (PNS). The transmigration of massive lymphocytes across the BBB caused by the activation of cell adhesion molecules is involved in the early phase of MS, and dysfunction of the cortical BBB is associated with the atrophy of gray matter in the late phase of MS. At the onset of NMOSD, increased permeability of the BBB causes the entry of circulating AQP4 autoantibodies into the central nervous system (CNS). Recent reports have shown the importance of glucose-regulated protein (GRP) autoantibodies as BBB-reactive autoantibodies in NMOSD, which induce antibody-mediated BBB dysfunction. BBB breakdown has also been observed in MOGAD, NPSLE, and AE with anti-NMDAR antibodies. Our recent report demonstrated the presence of GRP78 autoantibodies in patients with MOGAD and the molecular mechanism responsible for GRP78 autoantibody-mediated BBB impairment. Disruption of the BBB may explain the symptoms in the brain and cerebellum in the development of PNS, as it induces the entry of pathogenic autoantibodies or lymphocytes into the CNS through autoimmunity against tumors in the periphery. GRP78 autoantibodies were detected in paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome, and they were associated with cerebellar ataxia with anti-P/Q type voltage-gated calcium channel antibodies. This review reports that therapies affecting the BBB that are currently available for disease-modifying therapies for neuroimmunological diseases have the potential to prevent BBB damage.

Anti-CD19 CAR-T cells are effective in severe idiopathic Lambert-Eaton myasthenic syndrome.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoantibody-mediated disease of the neuromuscular junction characterized by muscular weakness. Autoantibodies to presynaptic P/Q-type voltage-gated calcium channels (VGCCs) induce defective neuromuscular function. In severe cases, current immunosuppressive and immunomodulatory treatment strategies are often insufficient. First reports show beneficial effects of anti-CD19 chimeric antigen receptor (CAR)-T cell therapy in patients with autoantibody-mediated myasthenia gravis. We report a patient with isolated idiopathic LEMS treated with autologous anti-CD19-CAR-T cells. In this patient, CAR-T infusion leads to expansion of predominantly CD4+ CAR-T cells with a terminally differentiated effector memory cells re-expressing CD45RA (TEMRA)-like phenotype indicating cytotoxic capabilities and subsequent B cell depletion. VGCC antibody titers decrease, resulting in a clinical improvement of LEMS symptoms, e.g., 8-fold increase in walking distance. The patient does not show relevant side effects except for cytokine release syndrome grade 2 and intermittent neutropenia suggesting that anti-CD19 CAR-T cell therapy may be a treatment option in patients with LEMS.

Myasthenia gravis Lambert-Eaton overlap syndrome: Recommended modification for the diagnostic criteria.

In 2016, MLOS (myasthenia gravis Lambert-Eaton overlap syndrome) was coined to represent an entity of overlap syndrome of myasthenia gravis and Lambert-Eaton myasthenic syndrome. Fifty-five MLOS patients have been identified. Modification of the diagnostic criteria for MG by adding MuSK positive antibody testing is recommended. Two MuSK positive MLOS patients were identified by the new diagnostic criteria.

209P Custom orthosis improves mobility and caregiver experience in an adolescent with congenital myasthenic syndrome and myofibrillar myopathy

209P Custom orthosis improves mobility and caregiver experience in an adolescent with congenital myasthenic syndrome and myofibrillar myopathy

507P Late-onset and milder phenotypes in a DOK7 myasthenic syndrome cohort to rethink the natural history of a perceived severe disease

507P Late-onset and milder phenotypes in a DOK7 myasthenic syndrome cohort to rethink the natural history of a perceived severe disease

498P Neuromuscular centre effect on prevalence of congenital myasthenic syndrome (CMS) in the UK

498P Neuromuscular centre effect on prevalence of congenital myasthenic syndrome (CMS) in the UK

511P Blood biomarkers in a cohort of patients with CHRNE-associated congenital myasthenic syndrome

511P Blood biomarkers in a cohort of patients with CHRNE-associated congenital myasthenic syndrome

241P Long term follow-up of CHRNE congenital myasthenic syndrome (CMS) – a retrospective multi-centre cohort study

241P Long term follow-up of CHRNE congenital myasthenic syndrome (CMS) – a retrospective multi-centre cohort study

CHRNE-related Congenital Myasthenic Syndrome in Iran: Clinical and Molecular Insights

Variants in the CHRNE gene can lead to a condition called congenital myasthenic syndrome (CMS), which affects the neuromuscular junction (NMJ). CHRNE mutations are the most common cause of CMS. Seventy-seven patients with a possible diagnosis of CMS were referred to the neuromuscular clinic of Shariati Hospital affiliated with the Tehran University of Medical Sciences. We performed whole-exome sequencing (WES) to determine the underlying defect in a group of individuals with a possible diagnosis of CMS. Clinical features and morphological and molecular data on 33 patients with mutations in CHRNE were described. Age of onset, age at diagnosis, consanguinity, family history, motor milestone delay, ophthalmoparesis, generalized fatigue, dysphagia, neurophysiologic findings, and response to treatment of the patients were assessed. Nineteen CHRNE variants including 10 novel ones were identified. The most common mutations were c.1327del; (p.Glu443LysfsTer64) in four different families and c.1252-1267dup; (p.Cys423SerfsTer38) in three families. Clinical onset was mostly at birth or under one year with bilateral fatigable ptosis, ophthalmoplegia, bulbar weakness, and proximal muscle weakness. All patients were treated with pyridostigmine ± salbutamol, which resulted in improvement of motor function, dysphagia, and breathing.

245P Exploring the relationship between an instrumented walking test and community physical activity in individuals with congenital myasthenic syndrome

245P Exploring the relationship between an instrumented walking test and community physical activity in individuals with congenital myasthenic syndrome

234P Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis

234P Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis

244P A natural history study of congenital myasthenic syndromes, to establish reliable outcome measures suitable for clinical and research assessment

244P A natural history study of congenital myasthenic syndromes, to establish reliable outcome measures suitable for clinical and research assessment

237P Advancing the understanding of VAMP1-related congenital myasthenic syndrome: phenotypic insights, favorable response to 3,4-diaminopyridine, and clinical characterization of five new cases

237P Advancing the understanding of VAMP1-related congenital myasthenic syndrome: phenotypic insights, favorable response to 3,4-diaminopyridine, and clinical characterization of five new cases

500P The 6-minute walk test in a small group of patients with congenital myasthenic syndromes

500P The 6-minute walk test in a small group of patients with congenital myasthenic syndromes

AntiSox-1 Limbic Encephalitis: When A Movement Disorder Evolves Oddly And Delirium Just Does Not Feel Right

Abstract Background A 74year old male presented to a Movement Disorder service with a 15year history of a parkinsonian syndrome with asymmetric, akinetic rigidity and prominent axial features. Motor features were stable for almost 13years. Neuropsychiatric features rapidly emerged over several months including: multimodality perceptual hallucinosis, upside down and tilt illusion, akinetopsia, intractable insomnia, emotional incontinence and Othello syndrome. A marked motor, mysaesthenic pattern, deterioration occurred in conjunction with hypoactive delirium, dysphagia, pyrexias, raised inflammatory markers and weight loss, necessitating hospitalisation. Computed tomography (CT) of chest, abdomen and pelvis did not demonstrate infective or neoplastic aetiology. CT brain did not demonstrate cerebellar atrophy. Positron emission tomography did not demonstrate a vasculitis. Drg regimen alterations brought about minor improvements, but he remained very severely frail and discharged to hospice care. Unexpectedly, cognition then markedly improved and neuropsychiatric symptoms resolved over months, and he returned home, albeit now severely frail. There was persistence of hemiparkinsonian symptoms, contralateral to which, dystonia had emerged with new bilateral upper limb ataxia and nystagmus. No mysaesthenic features persisted. Methods Cerebrospinal fluid analysis and electroencephalography were not undertaken. MRI brain was not undertaken. Results Anti Sox-1 positive. Anti Zic-4 and Recoverin were equivocal. Neuronal antibodies were negative. Conclusion Limbic encephalitis as a result of AntiSox-1 onconeural antibodies is most commonly associated with small cell cancer of the lung (prevalence of 36.5% of cases). Lambert-Eaton Mysaesthenic Syndrome is a more common presentation than paraneoplastic cerebellar degeneration. Hindsight raises the possibility of non-convulsive status epilepticus as an explanation for abrupt hypoactive delirium presentation on the background of deteriorating neuropsychiatric features. Oncological or immunotherapeutic intervention was not considered appropriate by respiratory or neurology teams respectively; nor did the patient wish for these to be pursued. Case reports indicate that an underlying neoplasm is not always identified. Non-paraneoplastic autoimmune encephalitis can have a better prognosis.