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ABSTRACT Introduction: A subset of regulatory B cells in humans and mice has been defined functionally by their ability to produce interleukin (IL)-10. We characterized IL-10-producing B (B10) cells in myasthenia gravis (MG) patients and correlated them with disease activity and responsiveness to rituximab therapy. Methods: Frequencies of B10 cells from MG patients and healthy controls were monitored by fluorescence-activated cell sorting (FACS). Results: MG patients had fewer B10 cells than controls, which was associated with more severe disease status. Moreover, patients who responded well to rituximab therapy exhibited rapid repopulation of B10 cells, whereas in patients who did not respond well to rituximab, B10 cell repopulation was delayed. The kinetics of B10 cells were related to the responsiveness to rituximab in MG. Conclusions: We have characterized a specific subset of B10 cells in MG patients which may serve as a marker for disease activity and responsiveness to immune therapy. Muscle Nerve 49:487-494, 2014 [ABSTRACT FROM AUTHOR]

In this study, we present two cases of infiltrative, localized amyloidosis involving lumbosacral root and plexus, e.g., isolated amyloidomas. Rare and poorly understood amyloidomas may occur in both neurologic and non-neurologic tissues. The described cases emphasize potential for localized peripheral amyloidomas: (1) potential for associated λ light chain lymphoplasmacytic lymphoma association; (2) e isolated amyloidosis without evidence for systemic plasma cell dyscrasia; (3) features suggestive of potential pathogenesis; and (4) discussion of treatment options including immunotherapy and resection. The limited literature and experience among other cases is described. [ABSTRACT FROM AUTHOR]

Objectives: To report an autoimmune paraneoplastic encephalitis characterized by immunoglobulin G (IgG) antibody targeting synaptic protein calmodulin kinase‐like vesicle‐associated (CAMKV). Methods: Serum and cerebrospinal fluid (CSF) samples harboring unclassified antibodies on murine brain‐based indirect immunofluorescence assay (IFA) were screened by human protein microarray. In 5 patients with identical cerebral IFA staining, CAMKV was identified as top‐ranking candidate antigen. Western blots, confocal microscopy, immune‐absorption, and mass spectrometry were performed to substantiate CAMKV specificity. Recombinant CAMKV‐specific assays (cell‐based [fixed and live] and Western blot) provided additional confirmation. Results: Of 5 CAMKV‐IgG positive patients, 3 were women (median symptom‐onset age was 59 years; range, 53–74). Encephalitis‐onset was subacute (4) or acute (1) and manifested with: altered mental status (all), seizures (4), hyperkinetic movements (4), psychiatric features (3), memory loss (2), and insomnia (2). Paraclinical testing revealed CSF lymphocytic pleocytosis (all 4 tested), electrographic seizures (3 of 4 tested), and striking MRI abnormalities in all (mesial temporal lobe T2 hyperintensities [all patients], caudate head T2 hyperintensities [3], and cortical diffusion weighted hyperintensities [2]). None had post‐gadolinium enhancement. Cancers were uterine adenocarcinoma (3 patients: poorly differentiated or neuroendocrine‐differentiated in 2, both demonstrated CAMKV immunoreactivity), bladder urothelial carcinoma (1), and non‐Hodgkin lymphoma (1). Two patients developed encephalitis following immune checkpoint inhibitor cancer therapy (atezolizumab [1], pembrolizumab [1]). All treated patients (4) demonstrated an initial response to immunotherapy (corticosteroids [4], IVIG [2]), though 3 died from cancer. Interpretation: CAMKV‐IgG is a biomarker of immunotherapy‐responsive paraneoplastic encephalitis with temporal and extratemporal features and uterine cancer as a prominent oncologic association. ANN NEUROL 2024;96:21–33 [ABSTRACT FROM AUTHOR]

Neuroleptic malignant-like syndrome (NMLS) is well described in the treatment of Parkinson's disease. The syndrome is characterized by fever, rigidity, autonomic instability, elevated creatine phosphokinase levels, and altered level of consciousness, which is usually precipitated by levodopa withdrawal. In recent years, patients have used fava beans to treat Parkinson's symptoms, because the beans contain appreciable amounts of levodopa and have been thought to be a safe adjunctive therapy. We describe a case of NMLS, which was precipitated by the abrupt cessation of fava bean ingestion. © 2005 Movement Disorder Society [ABSTRACT FROM AUTHOR]

T 2 ⁎ relaxivity contrast imaging may serve as a potential imaging biomarker for amyotrophic lateral sclerosis (ALS) by noninvasively quantifying the tissue microstructure. In this preliminary longitudinal study, we investigated the Transverse Relaxivity at Tracer Equilibrium (TRATE) in three muscle groups between SOD1-G93A (ALS model) rat and a control population at two different timepoints. The control group was time matched to the ALS group such that the second timepoint was the onset of disease. We observed a statistically significant decrease in TRATE over time in the gastrocnemius, tibialis, and digital flexor muscles in the SOD1-G93A model (p -value = 0.003, 0.008, 0.005; respectively), whereas TRATE did not change over time in the control group (p-value = 0.4777, 0.6837, 0.9682; respectively). Immunofluorescent staining revealed a decrease in minimum fiber area and cell density in the SOD1-G93A model when compared to the control group (p -value = 6.043E-10 and 2.265E-10, respectively). These microstructural changes observed from histology align with the theorized biophysical properties of TRATE. We demonstrate that TRATE can longitudinally differentiate disease associated atrophy from healthy muscle and has potential to serve as a biomarker for disease progression and ultimately therapy response in patients with ALS. [ABSTRACT FROM AUTHOR]

Introduction/Aims: We tested safety, tolerability, and target engagement of tocilizumab in amyotrophic lateral sclerosis (ALS) patients. Methods: Twenty‐two participants, whose peripheral blood mononuclear cell (PBMC) gene expression profile reflected high messenger ribonucleic acid (mRNA) expression of inflammatory markers, were randomized 2:1 to three tocilizumab or placebo treatments (weeks 0, 4, and 8; 8 mg/kg intravenous). Participants were followed every 4 wk in a double‐blind fashion for 16 wk and assessed for safety, tolerability, plasma inflammatory markers, and clinical measures. Cerebrospinal fluid (CSF) was collected at baseline and after the third treatment. Participants were genotyped for Asp358Ala polymorphism of the interleukin 6 receptor (IL‐6R) gene. Results: Baseline characteristics, safety, and tolerability were similar between treatment groups. One serious adverse event was reported in the placebo group; no deaths occurred. Mean plasma C‐reactive protein (CRP) level decreased by 88% in the tocilizumab group and increased by 4% in the placebo group (−3.0‐fold relative change, P <.001). CSF CRP reduction (−1.8‐fold relative change, P =.01) was associated with IL‐6R C allele count. No differences in PBMC gene expression or clinical measures were observed between groups. Discussion: Tocilizumab treatment was safe and well tolerated. PBMC gene expression profile was inadequate as a predictive or pharmacodynamic biomarker. Treatment reduced CRP levels in plasma and CSF, with CSF effects potentially dependent on IL‐6R Asp358Ala genotype. IL‐6 trans‐signaling may mediate a distinct central nervous system response in individuals inheriting the IL‐6R C allele. These results warrant further study in ALS patients where IL‐6R genotype and CRP levels may be useful enrichment biomarkers. [ABSTRACT FROM AUTHOR]

Background: To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double‐blind randomized controlled trial. Methods: Twenty ALS subjects were randomized to placebo and mexiletine 300 or 600 mg daily for 4 wk and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT). Results: RMT was unchanged with 4 wk of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (P =.039). Reductions of motor evoked potential (MEP) amplitude (P =.013) and accommodation half‐time (P =.002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 wk on mexiletine. Conclusions: The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half‐time supports the reduction of cortical and axonal hyperexcitability with mexiletine. [ABSTRACT FROM AUTHOR]

Objective: To investigate neurodegenerative and inflammatory biomarkers in people with amyotrophic lateral sclerosis (PALS), evaluate their predictive value for ALS progression rates, and assess their utility as pharmacodynamic biomarkers for monitoring treatment effects. Methods: De‐identified, longitudinal plasma, and cerebrospinal fluid (CSF) samples from PALS (n = 108; 85 with samples from ≥2 visits) and controls without neurological disease (n = 41) were obtained from the Northeast ALS Consortium (NEALS) Biofluid Repository. Seventeen of 108 PALS had familial ALS, of whom 10 had C9orf72 mutations. Additional healthy control CSF samples (n = 35) were obtained from multiple sources. We stratified PALS into fast‐ and slow‐progression subgroups using the ALS Functional Rating Scale‐Revised change rate. We compared cytokines/chemokines and neurofilament (NF) levels between PALS and controls, among progression subgroups, and in those with C9orf72 mutations. Results: We found significant elevations of cytokines, including MCP‐1, IL‐18, and neurofilaments (NFs), indicators of neurodegeneration, in PALS versus controls. Among PALS, these cytokines and NFs were significantly higher in fast‐progression and C9orf72 mutation subgroups versus slow progressors. Analyte levels were generally stable over time, a key feature for monitoring treatment effects. We demonstrated that CSF/plasma neurofilament light chain (NFL) levels may predict disease progression, and stratification by NFL levels can enrich for more homogeneous patient groups. Interpretation: Longitudinal stability of cytokines and NFs in PALS support their use for monitoring responses to immunomodulatory and neuroprotective treatments. NFs also have prognostic value for fast‐progression patients and may be used to select similar patient subsets in clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: Agrin is essential for the formation and maintenance of neuromuscular junctions (NMJs). NT-1654 is a C-terminal fragment of mouse neural agrin. In this study, we determined the effects of NT-1654 on the severity of experimental autoimmune myasthenia gravis (EAMG).Methods: EAMG was induced in female Lewis rats by immunization with the Torpedo acetylcholine receptor (tAChR) and complete Freund's adjuvant (CFA). NT-1654 was dissolved in phosphate-buffered saline (PBS) and injected daily subcutaneously into tAChR immunized rats during the first 10 days after immunization, and then every other day for the following 20 days.Results: We showed that NT-1654 attenuated clinical severity, effectively promoted the clustering of AChRs at NMJs, and alleviated the impairment of NMJ transmission and the reduction of muscle-specific kinase (MuSK) in EAMG rats.Discussion: We demonstrated that NT-1654 attenuated clinical severity, effectively promoted the clustering of AChRs at NMJs, and alleviated the impairment of NMJ transmission and the reduction of muscle-specific kinase (MuSK) in EAMG rats. Muscle Nerve 57: 814-820, 2018. [ABSTRACT FROM AUTHOR]

Background Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with few therapeutic options. Mild obesity is associated with greater survival in patients with the disease, and calorie-dense diets increased survival in a mouse model. We aimed to assess the safety and tolerability of two hypercaloric diets in patients with amyotrophic lateral sclerosis receiving enteral nutrition. Methods In this double-blind, placebo-controlled, randomised phase 2 clinical trial, we enrolled adults with amyotrophic lateral sclerosis from participating centres in the USA. Eligible participants were aged 18 years or older with no history of diabetes or liver or cardiovascular disease, and who were already receiving percutaneous enteral nutrition. We randomly assigned participants (1:1:1) using a computer-generated list of random numbers to one of three dietary interventions: replacement calories using an isocaloric tube-fed diet (control), a high-carbohydrate hypercaloric tube-fed diet (HC/HC), or a high-fat hypercaloric tube-fed diet (HF/HC). Participants received the intervention diets for 4 months and were followed up for 5 months. The primary outcomes were safety and tolerability, analysed in all patients who began their study diet. This trial is registered with ClinicalTrials.gov, number NCT00983983. Findings Between Dec 14, 2009, and Nov 2, 2012, we enrolled 24 participants, of whom 20 started their study diet (six in the control group, eight in the HC/HC group, and six in the HF/HC group). One patient in the control group, one in the HC/HC group, and two in the HF/HC group withdrew consent before receiving the intervention. Participants who received the HC/HC diet had a smaller total number of adverse events than did those in the other groups (23 in the HC/HC group vs 42 in the control group vs 48 in the HF/HC group; overall, p=0·06; HC/HC vs control, p=0·06) and significantly fewer serious adverse events than did those on the control diet (none vs nine; p=0·0005). Fewer patients in the HC/HC group discontinued their study diet due to adverse events (none [0%] of eight in the HC/HC group vs three [50%] of six in the control group). During the 5 month follow-up, no deaths occurred in the nine patients assigned to the HC/HC diet compared with three deaths (43%) in the seven patients assigned to the control diet (log-rank p=0·03). Adverse events, tolerability, deaths, and disease progression did not differ significantly between the HF/HC group and the control group. Interpretation Our results provide preliminary evidence that hypercaloric enteral nutrition is safe and tolerable in patients with amyotrophic lateral sclerosis, and support the study of nutritional interventions in larger randomised controlled trials at earlier stages of the disease. Funding Muscular Dystrophy Association, National Center for Research Resources, National Institutes of Health, and Harvard NeuroDiscovery Center. [ABSTRACT FROM AUTHOR]

We have examined whether antibodies to myelin-associated glycoprotein (anti-MAG) influence neuropathy occurrence and phenotype in primary (AL IgM) amyloidosis. Anti-MAG and the cross-reacted sulfoglucuronyl paragloboside antibodies (SGPG) were studied in 46 patients with IgM amyloidosis (21 with polyneuropathy), and 21 matched IgM MGUS (monoclonal gammopathies of undetermined significance) controls without neuropathy. We assessed the occurrence, phenotype of neuropathy, and attributes of nerve conduction and their relation to antibody activity. Twenty of 46 patients with IgM amyloidosis (7 with and 13 without polyneuropathy) had elevation of anti-MAG or SGPG by enzyme-linked immunosorbent assay (ELISA). Two of the polyneuropathy patients with IgM amyloidosis had antibodies to MAG based on Western blot (WB) positivity. One of these patients, with the highest anti-MAG titer, had a painful sensory ataxia, with prominent demyelination, and amyloid deposition in sural nerve. The other anti-MAG WB-positive amyloid patient had an axonal neuropathy and dysautonomia. Low levels of anti-MAG antibodies were found in 12 of 21 IgM MGUS controls without neuropathy (mean follow-up, 11 years). We conclude that finding serum anti-MAG antibodies does not exclude the diagnosis of primary amyloidosis. They do not appear to affect the occurrence or expression of polyneuropathy, except possibly in occasional cases with WB positivity. Muscle Nerve, 2007 [ABSTRACT FROM AUTHOR]

A letter to the editor related to the use of atraumatic needles to reduce post-lumbar puncture headache in patients with amyotrophic lateral sclerosis is presented.