Long-term safety and efficacy of zilucoplan in patients with generalized myasthenia gravis: interim analysis of the RAISE-XT open-label extension study.

Background: Generalized myasthenia gravis (gMG) is a chronic, unpredictable disease associated with high treatment and disease burdens, with a need for more effective and well-tolerated treatments. Objectives: To evaluate the long-term safety, tolerability, and efficacy of zilucoplan in a mild-to-severe, acetylcholine receptor autoantibody-positive (AChR+) gMG population. Design: Ongoing, multicenter, phase III open-label extension (OLE) study. Methods: Eligible patients had completed a qualifying randomized, placebo-controlled phase II or phase III zilucoplan study and received daily, self-administered subcutaneous 0.3 mg/kg zilucoplan. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy endpoints included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Results: In total, 200 patients enrolled. At the cut-off date (8 September 2022), median (range) exposure to zilucoplan in RAISE-XT was 1.2 (0.11-4.45) years. Mean age at OLE baseline was 53.3 years. A total of 188 (94%) patients experienced a TEAE, with the most common being MG worsening (n = 52, 26%) and COVID-19 (n = 49, 25%). In patients who received zilucoplan 0.3 mg/kg in the parent study, further improvements in MG-ADL score continued through to Week 24 (least squares mean change [95% confidence interval] from double-blind baseline -6.06 [-7.09, -5.03]) and were sustained through to Week 60 (-6.04 [-7.21, -4.87]). In patients who switched from placebo in the parent study, rapid improvements in MG-ADL score were observed at the first week after switching to zilucoplan; further improvements were observed at Week 24, 12 weeks after switching (-6.46 [-8.19, -4.72]), and were sustained through to Week 60 (-6.51 [-8.37, -4.65]). Consistent results were observed in other efficacy endpoints. Conclusion: Zilucoplan demonstrated a favorable long-term safety profile, good tolerability, and sustained efficacy through to Week 60 with consistent benefits in a broad AChR+ gMG population. Additional long-term data will be available in future analyses. Trial registration: ClinicalTrials.gov identifier: NCT04225871 (https://clinicaltrials.gov/ct2/show/NCT04225871).

MicroRNAs as biomarkers of brain injury in neonatal encephalopathy: an observational cohort study.

Neonatal Encephalopathy (NE) is a major cause of lifelong disability and neurological complications in affected infants. Identifying novel diagnostic biomarkers in this population may assist in predicting MRI injury and differentiate neonates with NE from those with low-cord pH or healthy neonates and may help clinicians make real-time decisions. To compare the microRNA (miRNA) profiles between neonates with NE, healthy controls, and neonates with low cord pH. Moreover, miRNA concentrations were compared to brain injury severity in neonates with NE. This is a retrospective analysis of miRNA profiles from select samples in the biorepository and data registry at the University of Florida Health Gainesville. The Firefly miRNA assay was used to screen a total of 65 neurological miRNA targets in neonates with NE (n = 36), low cord pH (n = 18) and healthy controls (n = 37). Multivariate statistical techniques, including principal component analysis and orthogonal partial least squares discriminant analysis, and miRNA Enrichment Analysis and Annotation were used to identify miRNA markers and their pathobiological relevance. A set of 10 highly influential miRNAs were identified, which were significantly upregulated in the NE group compared to healthy controls. Of these, miR-323a-3p and mir-30e-5p displayed the highest fold change in expression levels. Moreover, miR-34c-5p, miR-491-5p, and miR-346 were significantly higher in the NE group compared to the low cord pH group. Furthermore, several miRNAs were identified that can differentiate between no/mild and moderate/severe injury in the NE group as measured by MRI. MiRNAs represent promising diagnostic and prognostic tools for improving the management of NE.

Improvement of fatigue in generalised myasthenia gravis with zilucoplan.

BACKGROUND: Fatigue is a debilitating symptom of myasthenia gravis (MG). The impact of fatigue on MG can be assessed by Quality of Life in Neurological Disorders (Neuro-QoL) Short Form Fatigue scale. Transformation of raw Neuro-QoL fatigue scores to T-scores is a known approach for facilitating clinical interpretation of clinically meaningful and fatigue severity thresholds. METHODS: In the Phase 3, double-blind, placebo-controlled RAISE study (NCT04115293), adults with acetylcholine receptor autoantibody-positive generalised MG (MG Foundation of America Disease Class II-IV) were randomised 1:1 to daily subcutaneous zilucoplan 0.3 mg/kg or placebo for 12 weeks. Patients completing RAISE could opt to receive zilucoplan 0.3 mg/kg in an ongoing, open-label extension study, RAISE-XT (NCT04225871). In this post-hoc analysis, we evaluated the long-term effect of zilucoplan on fatigue in RAISE patients who entered RAISE-XT. We report change in Neuro-QoL Short Form Fatigue T-scores and fatigue severity levels from RAISE baseline to Week 60. RESULTS: Mean Neuro-QoL Short Form Fatigue T-scores improved from baseline to Week 12 in the zilucoplan group (n = 86) with a clinically meaningful difference versus placebo (n = 88; least squares mean difference: - 3.61 (nominal p-value = 0.0060]), and these improvements continued further to Week 60. At Week 12, more patients on zilucoplan (n = 34, 47.2%) experienced improvements in ≥ 1 fatigue severity level from baseline versus placebo (n = 23, 28.4%; p = 0.017). At Week 60, most (n = 55, 65.5%) patients had mild fatigue or none. CONCLUSION: Treatment with zilucoplan demonstrated statistical and clinically meaningful improvements in fatigue scores and severity versus placebo during RAISE, which were sustained to Week 60 in RAISE-XT.

NRBC concentrations over time in neonates with moderate to severe neonatal encephalopathy with and without sentinel events.

OBJECTIVE: To study the serum concentrations of nucleated red blood cells (NRBC) over time in neonates with moderate to severe neonatal encephalopathy (NE). STUDY DESIGN: A retrospective cohort study with subjects subdivided into three groups: definite sentinel events (n = 52), probable sentinel events (n = 20) and no history of sentinel events (n = 63). Peak absolute NRBC and NRBC/100 WBC were compared between groups and with MRI Injury score, cord and admission pH/base deficit. RESULTS: Absolute NRBC peaked at 24.05 h after birth (CI: 15.30-32.79), 17.56 h after birth (CI: 7.35-27.77), and 39.81 h after birth (CI: 28.73-50.89) in each respective group. The peak in absolute NRBC correlated with the severity of injury in the grey matter in group 2 and white matter in groups 1 and 2. Higher peak absolute NRBC value correlated to a lower admission ABG pH. CONCLUSION: NRBC peak at 24 h after birth in neonates with sentinel events.

MiR-126 and miR-146a as Melatonin-Responsive Biomarkers for Neonatal Brain Ischemia.

Despite advances in obstetric and neonatal care, challenges remain in early identification of neonates with encephalopathy due to hypoxia-ischemia who are undergoing therapeutic hypothermia. Therefore, there is a deep search for biomarkers that can identify brain injury. The aims of this study were to investigate the serum and brain expressions of two potential biomarkers, miR-126/miR-146a, in a preclinical model of hypoxia-ischemia (HI)-induced brain injury, and to explore their modulation during melatonin treatment. Seven-day-old rats were subjected to permanent ligation of the right carotid artery followed by 2.5 h hypoxia (HI). Melatonin (15 mg/kg) was administered 5 min after HI. Serum and brain samples were collected 1, 6 and 24 h after HI. Results show that HI caused a significant increase in the circulating levels of both miR-126 and miR-146a during the early phase of ischemic brain damage development (i.e. 1 h), with a parallel and opposite pattern in the ischemic cerebral cortex. These effects are not observed 24 h later. Treatment with melatonin restored the HI-induced effects on miR-126/miR-146a expressions, both in the cerebral cortex and in serum. We conclude that miR-126/miR-146a are promising biomarkers of HI injury and demonstrate an associated change in concentration following melatonin treatment.

Therapeutic targeting of ALS pathways: Refocusing an incomplete picture.

Numerous potential amyotrophic lateral sclerosis (ALS)-relevant pathways have been hypothesized and studied preclinically, with subsequent translation to clinical trial. However, few successes have been observed with only modest effects. Along with an improved but incomplete understanding of ALS as a neurodegenerative disease is the evolution of more sophisticated and diverse in vitro and in vivo preclinical modeling platforms, as well as clinical trial designs. We highlight proposed pathological pathways that have been major therapeutic targets for investigational compounds. It is likely that the failures of so many of these therapeutic compounds may not have occurred because of lack of efficacy but rather because of a lack of preclinical modeling that would help define an appropriate disease pathway, as well as a failure to establish target engagement. These challenges are compounded by shortcomings in clinical trial design, including lack of biomarkers that could predict clinical success and studies that are underpowered. Although research investments have provided abundant insights into new ALS-relevant pathways, most have not yet been developed more fully to result in clinical study. In this review, we detail some of the important, well-established pathways, the therapeutics targeting them, and the subsequent clinical design. With an understanding of some of the shortcomings in translational efforts over the last three decades of ALS investigation, we propose that scientists and clinicians may choose to revisit some of these therapeutic pathways reviewed here with an eye toward improving preclinical modeling, biomarker development, and the investment in more sophisticated clinical trial designs.

Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants.

Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterized by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS). In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS. We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and three benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar's classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G>A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness [change in CMTES (ΔCMTES) = 1.3 ± 2.6, P = 0.00016, SRM = 0.50]. Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0-7; 3-year ΔCMTES = 2.3 ± 2.5, P = 0.001, SRM = 0.90). Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials.

Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Generalised myasthenia gravis is a chronic, unpredictable, and debilitating rare disease, often accompanied by high treatment burden and with an unmet need for more efficacious and well tolerated treatments. Zilucoplan is a subcutaneous, self-administered macrocyclic peptide complement C5 inhibitor. We aimed to assess safety, efficacy, and tolerability of zilucoplan in patients with acetylcholine receptor autoantibody (AChR)-positive generalised myasthenia gravis. METHODS: RAISE was a randomised, double-blind, placebo-controlled, phase 3 trial that was done at 75 sites in Europe, Japan, and North America. We enrolled patients (aged 18-74 years) with AChR-positive generalised myasthenia gravis (Myasthenia Gravis Foundation of America disease class II-IV), a myasthenia gravis activities of daily living (MG-ADL) score of least 6, and a quantitative myasthenia gravis score of at least 12. Participants were randomly assigned (1:1) to receive subcutaneous zilucoplan 0·3 mg/kg once daily by self-injection, or matched placebo, for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in MG-ADL score in the modified intention-to-treat population (all randomly assigned patients who received at least one dose of study drug and had at least one post-dosing MG-ADL score). Safety was mainly assessed by the incidence of treatment-emergent adverse events (TEAEs) in all patients who had received at least one dose of zilucoplan or placebo. This trial is registered at ClinicalTrials.gov, NCT04115293. An open-label extension study is ongoing (NCT04225871). FINDINGS: Between Sept 17, 2019, and Sept 10, 2021, 239 patients were screened for the study, of whom 174 (73%) were eligible. 86 (49%) patients were randomly assigned to zilucoplan 0·3 mg/kg and 88 (51%) were assigned to placebo. Patients assigned to zilucoplan showed a greater reduction in MG-ADL score from baseline to week 12, compared with those assigned to placebo (least squares mean change -4·39 [95% CI -5·28 to -3·50] vs -2·30 [-3·17 to -1·43]; least squares mean difference -2·09 [-3·24 to -0·95]; p=0·0004). TEAEs occurred in 66 (77%) patients in the zilucoplan group and in 62 (70%) patients in the placebo group. The most common TEAE was injection-site bruising (n=14 [16%] in the zilucoplan group and n=8 [9%] in the placebo group). Incidences of serious TEAEs and serious infections were similar in both groups. One patient died in each group; neither death (COVID-19 [zilucoplan] and cerebral haemorrhage [placebo]) was considered related to the study drug. INTERPRETATION: Zilucoplan treatment showed rapid and clinically meaningful improvements in myasthenia gravis-specific efficacy outcomes, had a favourable safety profile, and was well tolerated, with no major safety findings. Zilucoplan is a new potential treatment option for a broad population of patients with AChR-positive generalised myasthenia gravis. The long-term safety and efficacy of zilucoplan is being assessed in an ongoing open-label extension study. FUNDING: UCB Pharma.

Melatonin in Newborn Infants Undergoing Surgery: A Pilot Study on Its Effects on Postoperative Oxidative Stress.

Surgery is frequently associated with excessive oxidative stress. Melatonin acts as an antioxidant and transient melatonin deficiency has been described in neonatal surgical patients. This randomized, blinded, prospective pilot study tested the hypothesis that oral melatonin supplementation in newborn infants undergoing surgery is effective in reducing perioperative oxidative stress. A total of twenty-three newborn infants requiring surgery were enrolled: 10 received a single dose of oral melatonin 0.5 mg/kg in the morning, before surgery (MEL group), and 13 newborns served as the control group (untreated group). Plasma concentrations of melatonin, Non-Protein-Bound Iron (NPBI), Advanced Oxidation Protein Products (AOPP), and F2-Isoprostanes (F2-IsoPs) were measured. Both in the pre- and postoperative period, melatonin concentrations were significantly higher in the MEL group than in the untreated group (preoperative: 1265.50 ± 717.03 vs. 23.23 ± 17.71 pg/mL, p < 0.0001; postoperative: 1465.20 ± 538.38 vs. 56.47 ± 37.18 pg/mL, p < 0.0001). Melatonin significantly increased from the pre- to postoperative period in the untreated group (23.23 ± 17.71 vs. 56.47 ± 37.18 pg/mL; pg/mL p = 0.006). In the MEL group, the mean blood concentrations of NPBI, F2-IsoPs, and AOPP significantly decreased from the pre- to the postoperative period (4.69 ± 3.85 vs. 1.65 ± 1.18 micromol/dL, p = 0.049; 128.40 ± 92.30 vs. 50.25 ± 47.47 pg/mL, p = 0.037 and 65.18 ± 15.50 vs. 43.98 ± 17.92 micromol/dL, p = 0.022, respectively). Melatonin concentration increases physiologically from the pre- to the postoperative period, suggesting a defensive physiologic response to counteract oxidative stress. The administration of exogenous melatonin in newborn infants undergoing surgery reduces lipid and protein peroxidation in the postoperative period, showing a potential role in protecting babies from the deleterious consequences of oxidative stress.

Combined GFAP, NFL, Tau, and UCH-L1 panel increases prediction of outcomes in neonatal encephalopathy.

BACKGROUND: Neuroprognostication in neonates with neonatal encephalopathy (NE) may be enhanced by early serial measurement of a panel of four brain-specific biomarkers. METHODS: To evaluate serum biomarkers, 40 NE samples and 37 healthy neonates from a biorepository were analyzed. Blood samples were collected at 0-6, 12, 24, 48, and 96 h of life. MRI provided a short-term measure of injury. Long-term outcomes included death or a Bayley III score at 17-24 months of age. RESULTS: Glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase-L1 (UCH-L1), and Tau peaked at 0-6 h of life, while neurofilament light chain (NFL) peaked at 96 h of life. These four marker concentrations at 96 h of life differentiated moderate/severe from none/mild brain injury by MRI, while GFAP and Tau showed early discrimination. For long-term outcomes, GFAP, NFL, Tau, and UCH-L1 could differentiate a poor outcome vs good outcome as early as 0-6 h of life, depending on the Bayley domain, and a combination of the four markers enhanced the sensitivity and specificity. Machine learning trajectory analyses identified upward trajectory patients with a high concordance to poor outcomes. CONCLUSION: GFAP, NFL, Tau, and UCH-L1 may be of neuroprognostic significance after NE. IMPACT: Serial measurements of GFAP, NFL, Tau, and UCH-L1 show promise in aiding the bedside clinician in making treatment decisions in neonatal encephalopathy. The panel of four neuroproteins increased the ability to predict neurodevelopmental outcomes. The study utilized a trajectory analysis that enabled predictive modeling. A panel approach provides the bedside clinician with objective data to individualize care. This study provides the foundation to develop a point of care device in the future.

Concentration of Serum Biomarkers of Brain Injury in Neonates With a Low Cord pH With or Without Mild Hypoxic-Ischemic Encephalopathy.

Objective: To determine the concentrations of four neuroprotein biomarkers and 68 miRNAs in neonates with low cord pH and/or mild hypoxic-ischemic encephalopathy (HIE). Study Design: A prospective cohort study enrolled neonates with low cord pH (n = 18), moderate-severe HIE (n = 40), and healthy controls (n = 38). Groups provided serum samples at 0-6 h of life. The concentrations of biomarkers and miRNAs were compared between cohorts. Result: The low cord pH and moderate-severe HIE groups had increased concentrations of GFAP, NFL and Tau compared to controls (P < 0.05, P < 0.001, respectively). NFL concentrations in mild HIE was higher than controls (P < 0.05) but less than moderate-severe HIE (P < 0.001). Of 68 miRNAs, 36 in low cord pH group and 40 in moderate-severe HIE were upregulated compared to controls (P < 0.05). Five miRNAs in low cord pH group (P < 0.05) and 3 in moderate-severe HIE were downregulated compared to controls (P < 0.05). Conclusion: A biomarker panel in neonates with low cord pH may help clinicians make real-time decisions.

Human-rat integrated microRNAs profiling identified a new neonatal cerebral hypoxic-ischemic pathway melatonin-sensitive.

Neonatal encephalopathy (NE) is a pathological condition affecting long-term neurodevelopmental outcomes. Hypothermia is the only therapeutic option, but does not always improve outcomes; hence, researchers continue to hunt for pharmaceutical compounds. Melatonin treatment has benefitted neonates with hypoxic-ischemic (HI) brain injury. However, unlike animal models that enable the study of the brain and the pathophysiologic cascade, only blood is available from human subjects. Therefore, due to the unavailability of neonatal brain tissue, assumptions about the pathophysiology in pathways and cascades are made in human subjects with NE. We analyzed animal and human specimens to improve our understanding of the pathophysiology in human neonates. A neonate with NE who underwent hypothermia and enrolled in a melatonin pharmacokinetic study was compared to HI rats treated/untreated with melatonin. MicroRNA (miRNA) analyses provided profiles of the neonate's plasma, rat plasma, and rat brain cortexes. We compared these profiles through a bioinformatics tool, identifying Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways common to HI brain injury and melatonin treatment. After evaluating the resulting pathways and the literature, to validate the method, the key proteins expressed in HI brain injury were investigated using cerebral cortexes. The upregulated miRNAs in human neonate and rat plasma helped identify two KEGG pathways, glioma and long-term potentiation, common to HI injury and melatonin treatment. A unified neonatal cerebral melatonin-sensitive HI pathway was designed and validated by assessing the expression of protein kinase Cα (PKCα), phospho (p)-Akt, and p-ERK proteins in rat brain cortexes. PKCα increased in HI-injured rats and further increased with melatonin. p-Akt and p-ERK returned phosphorylated to their basal level with melatonin treatment after HI injury. The bioinformatics analyses validated by key protein expression identified pathways common to HI brain injury and melatonin treatment. This approach helped complete pathways in neonates with NE by integrating information from animal models of HI brain injury.

Management of Spinal Muscular Atrophy in the Adult Population.

Spinal muscular atrophy (SMA) is a group of neurodegenerative disorders resulting from the loss of spinal motor neurons. 95% of patients share a pathogenic mechanism of loss of survival motor neuron (SMN) 1 protein expression due to homozygous deletions or other mutations of the SMN1 gene, with the different phenotypes influenced by variable copy numbers of the SMN2 gene. Advances in supportive care, disease modifying treatment and novel gene therapies have led to an increase in the prevalence of SMA, with a third of SMA patients now represented by adults. Despite the growing number of adult patients, consensus on the management of SMA has focused primarily on the pediatric population. As the disease burden is vastly different in adult SMA, an approach to treatment must be tailored to their unique needs. This review will focus on the management of the adult SMA patient as they age and will discuss proper transition of care from a pediatric to adult center, including the need for continued monitoring for osteoporosis, scoliosis, malnutrition, and declining mobility and functioning. As in the pediatric population, multidisciplinary care remains the best approach to the management of adult SMA. Novel and emerging therapies such as nusinersen and risdiplam provide hope for these patients, though these medications are of uncertain efficacy in this population and require additional study.

Neonatal Transplant in Hypoxic Injury.

Even with therapeutic hypothermia as standard of care, hypoxic-ischemic encephalopathy in neonates often causes long-term disabilities. Stem cell therapy may be a successful treatment for HIE both in the acute and chronic time periods post-injury. Neurogenic astrocytes with characteristics of neural stem cells can be cultured as adherent monolayers and be induced to generate neuronal progeny in vitro and in vivo following reintroduction into the neural stem cell niche of both neonatal and adult hosts. Thus, these neurogenic astrocytes represent promising candidates for cell replacement therapy in HIE. Such an approach requires optimized cell cultivation protocols as well as extensive testing of donor cells to assess their capacity for engraftment, survival, and integration in the HIE animal models. In this chapter, we will describe methods of generating the HIE model, generating and culturing monolayer neurogenic astrocytes, and transplanting these cells into HIE animal models.

Sporadic inclusion body myositis and primary Sjogren's syndrome: an overlooked diagnosis.

Sporadic inclusion body myositis (sIBM) has been reported to occur in association with autoimmune diseases and in particular, primary Sjogren's syndrome (pSS). This brief report describes patients identified with a positive SSA antibody and diagnosis of sIBM at a large academic medical center over a 13.5-year period. A cohort identification tool was used to identify patients with positive SSA antibody and a diagnosis of sIBM between January 1, 2006 and June 1, 2019. All cases of sIBM had diagnostic confirmation by a neuromuscular specialist. Demographics, clinical features, autoantibodies, MRI and EMG findings, and muscle biopsy features were reviewed for each identified case. Eight patients were found to carry the diagnosis of pSS and sIBM. Two additional sIBM patients were SSA antibody positive without other pSS features. The mean time from initial symptom onset of muscle weakness to diagnosis was 5.4 years (range 1-15 years). All patients had alternative diagnoses offered for their myopathic symptoms prior to sIBM identification. The NT5c1A antibody was positive in 7 of 8 patients tested. No patient had a durable response to immunosuppressive therapy. The diagnosis of sIBM went unrecognized for over 5 years in our cohort of SSA antibody-positive patients with myopathy. The patients in this cohort were treated with a variety of immunosuppressive agents prior to diagnosis without benefit. Recognizing the clinical features of sIBM in patients with pSS is crucial in instituting appropriate therapy and avoiding unnecessary immunosuppression. Key Points • Sporadic inclusion body myositis (sIBM) can be associated with Sjogren's syndrome. • In this case series, prevalence of the NT5c1A antibody was higher among patients with associated Sjogren's syndrome compared to the cited prevalence of the NT5c1A antibody in patients with isolated sIBM. • It is crucial to consider sIBM in patients with Sjogren's syndrome presenting with motor weakness in order to avoid unnecessary immunosuppression and institute appropriate therapy.

Long-standing Multifocal Motor Neuropathy Presenting With Delayed Clinical Features of Anti-Myelin-Associated Glycoprotein Neuropathy and Elevated Anti-Myelin-Associated Glycoprotein Antibody Titers.

ABSTRACT: Multifocal motor neuropathy with conduction block (MMN) and anti-myelin-associated glycoprotein (MAG) neuropathy are rare chronic acquired demyelinating neuropathies with distinct clinical and electrophysiological characteristics. These neuropathies are generally not known to coexist. This report describes a patient with long-standing MMN who subsequently developed clinical features of anti-MAG neuropathy. This suggests that subtypes of chronic inflammatory neuropathies may not be sharply defined. In addition, a presentation of MMN with anti-MAG titers may be a prognostic indicator of poor response to standard MMN treatment.

Endocannabinoids and related lipids in serum from patients with amyotrophic lateral sclerosis.

BACKGROUND: The goals of this study were to determine whether serum concentrations of endocannabinoids (eCB) and related lipids predict disease status in patients with amyotrophic lateral sclerosis (ALS) relative to healthy controls, and whether concentrations correlate with disease duration and severity. METHODS: Serum concentrations of the eCBs 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA), and related lipids palmitoylethanolamine (PEA), oleoylethanolamine (OEA), and 2-oleoylglycerol (2-OG), were measured in samples from 47 patients with ALS and 19 healthy adults. Hierarchical binary logistic and linear regression analyses assessed whether lipid concentrations predicted disease status (ALS or healthy control), duration, or severity. RESULTS: Binary logistic regression revealed that, after controlling for age and gender, 2-AG, 2-OG and AEA concentrations were unique predictors of the presence of ALS, demonstrating odds ratios of 0.86 (P = .039), 1.03 (P = .023), and 42.17 (P = .026), respectively. When all five lipids and covariates (age, sex, race, ethnicity, body mass index, presence of a feeding tube) were included, the resulting model had an overall classification accuracy of 92.9%. Hierarchical linear regression analyses indicated that in patients with ALS, AEA and OEA inversely correlated with disease duration (P = .030 and .031 respectively), while PEA demonstrated a positive relationship with disease duration (P = .013). None of the lipids examined predicted disease severity. CONCLUSIONS: These findings support previous studies indicating significant alterations in concentrations of circulating lipids in patients with ALS. They suggest that arachidonic and oleic acid containing small lipids may serve as biomarkers for identifying the presence and duration of this disease.

Effects of mexiletine on hyperexcitability in sporadic amyotrophic lateral sclerosis: Preliminary findings from a small phase II randomized controlled trial.

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.

Comparing head ultrasounds and susceptibility-weighted imaging for the detection of low-grade hemorrhages in preterm infants.

OBJECTIVE: Intraventricular hemorrhage (IVH) is a complication of prematurity. Grades III and IV IVH lead to significant morbidity, but mounting evidence shows low-grade IVH (grades I-II) may be associated with adverse sequelae. Head ultrasounds (HUS) are used to screen infants for IVH but may miss low-grade IVH. Our study compared the results of HUS around 7 days of age to susceptibility-weighted imaging (SWI) obtained at term-corrected age in infants born at <30 wGA. STUDY DESIGN: Infants <30 weeks gestational age (GA) with an HUS and MRI at admission to UF Health were identified by a retrospective chart review. Images were re-read by a pediatric neuroradiologist. RESULTS: Ninety-four infants with a mean GA of 25.8 weeks were identified. Of those with normal HUS, 50% had low-grade IVH on the term-corrected MRI. CONCLUSIONS: HUS are effective for screening for high-grade IVH. SWI is more sensitive in identifying low-grade IVH.