Worldwide prevalence of neuromyelitis optica spectrum disorder (NMOSD) and neuromyelitis optica (NMO): a systematic review and meta-analysis.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a progressive demyelinating disease of the central nervous system that has overlapping symptoms with multiple sclerosis (MS) but differs from it in a variety of ways. Previous studies have reported conflicting results trying to estimate the number of individuals affected by them which is why we designed this systematic review and meta-analysis to estimate the worldwide prevalence and incidence of NMOSD/NMO based on current evidence. METHODS: We searched PubMed, Scopus, EMBASE, Web of Science, and gray literature including references from the identified studies, review studies, and conference abstracts which were published up to February 1, 2022. We used all MeSH terms pertaining to "NMOSD," "NMO," and all the terms on "prevalence," "incidence," and "epidemiology" to identify the search components. Pooled effect sizes were measured using random-effect model by DerSimonian-Laird. RESULTS: The prevalence and incidence rates of NMOSD/NMO ranged from 0.07 to 10 and 0.029 to 0.880 per 100,000 population, respectively. The overall pooled prevalence of NMO per 100,000 population was 1.54 (I2: 98.4%, 95% CI: 1.13-1.96, P< 0.001) based on the 2006 criteria, 1.51 (I2: 99.4%, 95% CI: 1.21-1.81, P < 0.001) based on the 2015 criteria and 2.16 (I2: 89.4%, 95% CI: 1.46-2.86, P < 0.001) based on the 2006/2015 criteria. The overall annual incidence of NMO per 100,000 population was 0.155 (I2: 95%, 95% CI: 0.115-0.195, P < 0.001) based on the 2006 criteria and 0.278 (I2: 100%, 95% CI: 0.135-0.420, P < 0.001) based on the 2015 criteria. The prevalence rates were highest in French West Indies and South Korea, and lowest in Cuba and Australia, based on the 2006 and 2015 criteria, respectively. Also, the highest annual incidence rates were obtained for Sweden and Slovak republic and the lowest for Cuba and Australia based on the 2006 and 2015 criteria, respectively. All estimated rates were higher among females compared to males. CONCLUSION: Although rare, NMOSD/NMO impact affected individuals in devastating ways. Several large-scale prospective studies are required to reach a comprehension of the epidemiological aspects of these notorious demyelinating conditions.

Long-term efficacy and safety of inebilizumab in neuromyelitis optica spectrum disorder: Analysis of aquaporin-4-immunoglobulin G-seropositive participants taking inebilizumab for ⩾4 years in the N-MOmentum trial.

BACKGROUND: Efficacy and safety of inebilizumab for treatment of neuromyelitis optica spectrum disorder in adults seropositive for aquaporin-4 (AQP4)-immunoglobulin (Ig) G were demonstrated in the 28-week randomized controlled period of the N-MOmentum study. OBJECTIVE: To assess efficacy and safety of long-term inebilizumab treatment. METHODS: Post hoc analysis was performed in 75 AQP4-IgG-seropositive participants receiving inebilizumab for ⩾4 years in the randomized controlled period and open-label extension of the N-MOmentum study. RESULTS: Eighteen attacks occurred in 13 participants during inebilizumab treatment (annualized attack rate, 0.052 attacks/person-year). Twelve attacks occurred during the first year of treatment, and two each occurred in years 2-4. Disability scores remained stable throughout ⩾4 years of treatment. Inebilizumab was well tolerated, with two (2.7%) serious treatment-emergent adverse events related to inebilizumab and no deaths. Immunoglobulin G levels decreased over time; however, correlation between severe infections and low IgG levels could not be determined because of their small numbers. CONCLUSION: These results from the N-MOmentum study continue to support use of inebilizumab for treatment of neuromyelitis optica spectrum disorder. Furthermore, the findings suggest that efficacy of inebilizumab may be enhanced after the first year of treatment, warranting additional long-term investigation.

An assessment on the use of infra-scanner for the diagnosis of the brain hematoma in head trauma.

PURPOSE: Timely identification and treatment of intracranial hematomas in patients with brain injury is essential for successful treatment. This study evaluates Infra-scanner as a handy medical screening tool for diagnosing, on-site, cerebral hematomas in patients with head injury. MATERIALS AND METHODS: Patients referred to the emergency department of university hospitals with mild to moderate brain trauma, up to 12 h from injury were included. NIR sensors of infra-scan device were placed on the right and left frontal, temporal, peritoneal and occipital parts of the head and light absorption was recorded. Positive or negative cerebral hemorrhage cases were compared with contrast-enhanced CT scan results as the gold standard. Diagnostic parameters of the device and cases related to bleeding were analyzed and reported. RESULTS: A total of 300 patients were studied. Sensitivity of the infrasound scanner in the Iranian study population was 94.8 (95% CI: 88% -100) and its specificity was 86.9 (95% CI: 79% -99% 99). Negative predictive value (NPV) was 90.3% and positive predictive value (PPV) was 92.9%. Sensitivity in men (95.7%) (95%CI, 90% -1) was more than women (95% CI, 81% -99%)90%. At the ages of less than 36 years, sensitivity (95.3%) and specificity (87.1%) were more than sensitivity (94.4%) and specificity (86.5%) over 36 years old. If the test had been performed in less than / equal to two hours from trauma, the sensitivity (94.9%) and the specificity (92%) were greater than the sensitivity (94.6%) and the specificity (75%) during when the scan had been performed in more than two hours from trauma. In general, in extra-axial bleeding including EDH, SAH, SDH, the sensitivity was 95.1% and the specificity was 84.5%, while in intra-axial bleeding, including ICH and IVH, the sensitivity was lower (93.9%) and the specificity was 91.7. The sensitivity of the device in detecting bleeding in the occipital lobe (95.8%) was higher than other brain lobes. CONCLUSION: This study shows that Infra-scanner is useful in initial examination and screening of patients with head injury and can be used as an adjunct to a CT scan or when not available and may allow earlier treatment which reduce the secondary damage to the hematoma.

A case of fatal invasive aspergillosis in a patient with neurosarcoidosis treated with infliximab.

INTRODUCTION: CNS involvement in sarcoidosis is seen in 5-10% of cases. Long term treatment involves steroids and other immunomodulatory agents, including infliximab. Chronic immunosuppression can result in increased patient susceptibility to opportunistic infections. We present a case of fatal aspergillosis in a patient with neurosarcoidosis treated with infliximab. CASE REPORT: A 55-year-old woman with neurosarcoidosis on infliximab (started 4 months prior) and dexamethasone, presented with progressive cognitive decline. Exam revealed impaired attention and disorientation with preserved language. Brain MRI showed multiple, bilateral cortical and subcortical ring-enhancing lesions. We held immunosuppression due to suspicion of infection; empiric Amphotericin B was given early in the hospital course. The patient rapidly deteriorated from a neurological and respiratory standpoint, requiring intubation. CSF analysis showed elevated protein of 511 and normal glucose of 104 (67% serum), with lymphocytic pleocytosis (25 cells, 96% lymphocytes). Systemic and CNS microbiological studies were negative. On hospital day 13, bronchial fluid grew Aspergillus fumigatus, prompting a switch to voriconazole. Despite early empiric antifungal treatment, she died from respiratory failure; autopsy revealed systemic and CNS aspergillosis with multiple brain abscesses. DISCUSSION: This case represents an example of a fatal complication of infliximab therapy, which was recently shown to be effective in neurosarcoidosis in one study. It also serves to highlight the challenges faced in diagnosing ring-enhancing lesions, especially in patients with pre-existing brain disorders. Finally, it highlights the difficulty in treating invasive aspergillosis. Further studies are needed to identify risks associated with infliximab therapy and potential early interventions to improve outcomes.

Neurological efficacy and safety of mesenchymal stem cells (MSCs) therapy in people with multiple sclerosis (pwMS): An updated systematic review and meta-analysis.

BACKGROUND: Current therapeutic strategies for multiple sclerosis (MS) aim to suppress the immune response and reduce relapse rates. As alternative treatments, mesenchymal stem cells (MSCs) are being explored. MSCs show promise in repairing nerve tissue and reducing autoimmune responses in people with MS (pwMS). OBJECTIVE: This review delves into the literature on the efficacy and safety of MSC therapy for pwMS. METHODS: A comprehensive search strategy was employed to identify relevant articles from five databases until January 2024. The inclusion criteria encompassed interventional studies. Efficacy and safety data concerning MSC therapy in relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS) groups were extracted and analyzed. RESULTS: A comprehensive analysis encompassing 30 studies revealed that individuals who underwent intrathecal (IT) protocol-based transplantation of MSCs experienced a noteworthy improvement in their expanded disability status scale (EDSS) compared to the placebo group. Weighted mean difference (WMD) was -0.28; 95 % CI -0.53 to -0.03, I2 = 0 %, p-value = 0.028); however, the intravenous (IV) group did not show significant changes in EDSS scores. The annualized relapse rate (ARR) did not significantly decrease among pwMS (WMD = -0.34; 95 % CI -1.05 to 0.38, I2 = 98 %, p-value = 0.357). Favorable results were observed in magnetic resonance imaging (MRI), with only 19.11 % of pwMS showing contrast-enhanced lesions (CEL) in the short term and no long-term MRI activity. The most common complications in both short-term and long-term follow-ups were infection, back pain, and gastrointestinal symptoms. CONCLUSIONS: The study highlights the safety potential of MSC therapy for pwMS. While MRI-based neural regeneration shows significant treatment potential, the effectiveness of MSC therapy remains uncertain due to study limitations and ineffective outcome measures. Further research is needed to establish efficacy and optimize evaluation methods for MSC therapy on pwMS.

Effectiveness of BBIBP-CorV vaccine in preventing SARS-CoV2 infection and severe outcomes in people living with multiple sclerosis: A population-based study.

BACKGROUND: The objective of the present study was to estimate the effectiveness of the BBIBP-CorV vaccine (VE) in preventing SARS-CoV-2 infection, related hospitalization, and death among people living with multiple sclerosis (PLWMS). METHODS: In this population-based retrospective observational study, data on all PLWMS, vaccination, SARS-CoV-2 tests, hospitalization, and deaths were collected in Isfahan, Iran between February 9, 2021, and November 4, 2021. We estimated the hazard ratio between vaccinated (partially and fully) and unvaccinated groups using the Andersen-Gill extension of the Cox proportional hazards model. We also performed Cox proportional hazards analysis to identify risk factors for breakthrough infection and COVID-19-related hospitalization in fully-immunized group. RESULTS: Of the 9869 PLWMS, 1368 were in partially-vaccinated group, 4107 were in the fully-vaccinated group, and 3794 were in the unvaccinated group. In the partially-vaccinated group, the estimated VE against COVID-19 infection was 39.3% (16%, 56.1%), hospitalization was 64.9% (1.3%, 87.5%), and mortality was 92.7% (88.8%, 100%). The respective results for the fully-vaccinated group were 63.9% (56%, 70.3%), 75.7% (57.5%, 86.1%), and 100%. Progressive MS was independently associated with a greater risk of breakthrough infection (HR=1.952, 95%CI: 1.174-3.246, p = 0.010). Older adults (≥50 years vs. 18-49 years, HR=3.115, 95%CI: 1.145-8.470, p = 0.026) and those on rituximab (HR=7.584; 95% CI: 1.864-30.854; p = 0.005) were at an increased risk of COVID-19-related hospitalization. CONCLUSION: This study showed that two doses of the BBIBP-CorV vaccine can effectively prevent COVID-19 infection and hospitalization among PLWMS. Old PLWMS and those who treating with rituximab are at increased risk of hospitalization after receiving two doses of the vaccine.

Autologous Hematopoietic Stem-Cell Transplantation in Multiple Sclerosis: A Systematic Review and Meta-Analysis.

INTRODUCTION: In 1995, the use of autologous hematopoietic stem-cell transplantation (AHSCT), which was previously used to treat hematological tumors, was introduced for severe autoimmune diseases such as multiple sclerosis (MS). AHSCT has proven its safety over the past few years due to technical advances and careful patient selection in transplant centers. While most studies have reported that AHSCT led to decreased Expanded Disability Status Scale (EDSS) scores, some patients reported increased EDSS scores following the procedure. Given the contradictory results, we aimed to conduct a comprehensive systematic review and meta-analysis to investigate the efficacy and safety of AHSCT. METHODS: PubMed, Web of Science, and Scopus were searched in March 2022 using a predefined search strategy. We included cohort studies, clinical trials, case-control studies, and case series that investigated the efficacy or safety of AHSCT in patients with MS. PICO in the present study was defined as follows: problem or study population (P): patients with MS; intervention (I): AHSCT; comparison (C): none; outcome (O): efficacy and safety. RESULTS: After a two-step review process, 50 studies with a total of 4831 patients with MS were included in our study. Our analysis showed a significant decrease in EDSS score after treatment (standardized mean difference [SMD]: -0.48, 95% CI -0.75, -0.22). Moreover, the annualized relapse rate was also significantly reduced after AHSCT compared to the pretreatment period (SMD: -1.58, 95% CI -2.34, -0.78). The pooled estimate of progression-free survival after treatment was 73% (95% CI 69%, 77). Furthermore, 81% of patients with MS who received AHSCT remained relapse-free (95% CI 76%, 86%). Investigating event-free survival, which reflects the absence of any disease-related event, showed a pooled estimate of 63% (95% CI 54%, 73%). Also, the MRI activity-free survival was 89% (95% CI 84%) among included studies with low heterogeneity. New MRI lesions seem to appear in nearly 8% of patients who underwent AHSCT (95% CI 4%, 12%). Our meta-analysis showed that 68% of patients with MS experience no evidence of disease activity (NEDA) after AHSCT (95% CI 59%, 77). The overall survival after transplantation was 94% (95% CI 91%, 96%). In addition, 4% of patients died from transplant-related causes (95% CI 2%, 6%). CONCLUSION: Current data encourages a broader application of AHSCT for treating patients with MS while still considering proper patient selection and transplant methods. In addition, with increasing knowledge and expertise in the field of stem-cell therapy, AHSCT has become a safer treatment approach for MS.

Association of Disease-Modifying Therapies with COVID-19 Susceptibility and Severity in Patients with Multiple Sclerosis: A Systematic Review and Network Meta-Analysis.

Background: We conducted this study to assess the effect of disease-modifying therapies (DMTs) on coronavirus disease (COVID-19) susceptibility and severity in people with multiple sclerosis (MS). Methods: Available studies from PubMed, Scopus, EMBASE, Web of Science, and gray literature, including reference lists and conference abstracts, were searched from December 1, 2019, to July 26, 2021. We included cross-sectional, case-control, and cohort studies assessing the association of DMTs with risk of contracting COVID-19 or its outcomes in MS patients on univariate or multivariate regression analyses. We conducted a network meta-analysis (NMA) to compare the risk of COVID-19 and developing severe infection across DMTs. Results: Out of the initial 3893 records and 1883 conference abstracts, a total of 10 studies were included. Pairwise comparisons showed that none of the DMTs meaningfully affect the risk of acquiring infection. There was significant total heterogeneity and inconsistency across this NMA. In comparison with no DMT, dimethyl fumarate (0.62 (0.42, 0.93)), fingolimod (0.55 (0.32, 0.94)), natalizumab (0.50 (0.31, 0.81)), and interferon (0.42 (0.22, 0.79)) were associated with a decreased risk of severe COVID-19; but, rituximab was observed to increase the risk (1.94 (1.20, 3.12)). Compared to rituximab or ocrelizumab, all DMTs were associated with a decreased risk. Pairwise comparisons showed no differences across other DMTs. Interferon and rituximab were associated with the lowest and highest risks of severe COVID-19. Conclusion: Our study showed an increased risk of severe COVID-19 in patients on rituximab and ocrelizumab. No association with COVID-19 severity across other DMTs was observed.

Inebilizumab for treatment of neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease characterized by recurrent optic neuritis and transverse myelitis often resulting in severe disability. Anti-AQP4-immunoglobulin G (IgG) is a pathogenic product of CD19-positive plasma cells found in most, but not all, individuals with NMOSD and is associated with immune-mediated neurologic injury. Inebilizumab, an afucosylated humanized IgG1κ, anti-CD19 monoclonal antibody, may target pathogenic CD19-expressing B cells. In a Phase II/III trial, inebilizumab significantly reduced the proportion of participants experiencing an NMOSD attack and was well tolerated versus placebo. Fewer treated participants had worsening disability than those receiving placebo. Inebilizumab was approved in 2020 by the US FDA for treatment of anti-AQP4 antibody positive NMOSD.

Lay abstract Neuromyelitis optica spectrum disorder (NMOSD) is a rare nervous system disease. People with NMOSD experience 'attacks' of the brain, spinal cord and an important nerve that sends visual signals to the brain, and they may experience severe disability. NMOSD is thought to be caused by an imbalanced immune system response. In a portion of patients with NMOSD, immune cells produce antibodies which may lead to inflammation in the nervous system and cause brain injury leading to attacks. Inebilizumab is a medication that directly targets these immune cells, reducing the likelihood of a person having an NMOSD attack.

Progressive myelopathy in myelin oligodendrocyte glycoprotein antibody-associated disease: A new mimicker of progressive multiple sclerosis?

Background MOG-IgG-associated disease (MOGAD) in adults typically presents as a monophasic or relapsing optic, spinal, or opticospinal neuroinflammatory syndrome. Current recommendations discourage testing for MOG-IgG in patients with clinical or paraclinical findings more typical of MS, or in patients with a progressive clinical course. However, this approach may impede identification of the full phenotypic spectrum of this recently described disorder. Methods We retrospectively reviewed charts of 39 MOG-IgG-seropositive patients from two Ohio-based neuroimmunology centers to identify unusual disease patterns. Those with a progressive course were included in this case series. Results We describe five cases of progressive myelopathy associated with MOG-IgG. Most patients had features suggestive of MS, including typical MRI and cerebrospinal fluid findings. However, MOG-IgG positive patients with progressive myelopathy showed poor response to MS disease modifying therapy and better response to intravenous immunoglobulins similar to previous reports on MOGAD patients. Conclusion MOG-IgG-seropositive patients may present with progressive myelopathy and may have a clinical and radiologic phenotype suggestive of primary progressive or secondary progressive MS, or progressive solitary sclerosis. MOG-IgG testing should be considered in patients with progressive myelopathy, especially if clinically worsening on MS therapy.

Safety evaluation of shorter infusion for ocrelizumab in a substudy of the Phase IIIb CHORDS trial.

The CHORDS trial evaluated ocrelizumab (OCR) in patients with relapsing-remitting multiple sclerosis who had a suboptimal response to previous disease-modifying treatment. The objective of the present study was to assess the safety of shorter OCR infusions in a substudy of CHORDS. After completing four doses of OCR per initial US prescribing recommendations in the main study, participants in the substudy (N = 129) received a fifth dose over a 2-h duration (vs. 3.5 h). Infusion-related reactions occurred in 12.4% of patients. None were severe, life-threatening or led to treatment discontinuation. Shorter infusion time did not change the safety profile of OCR. Clinicaltrials.gov (NCT0237856).

The functional polymorphism of the hemoglobin-binding protein haptoglobin influences susceptibility to idiopathic Parkinson's disease.

Oxidative stress and iron have been widely implicated in the etiology of Parkinson's disease (PD). Hemoglobin is the richest source of iron in the body. The human Haptoglobin (Hp) protein is a plasma alpha-2 glycoprotein that removes free Hemoglobin from the circulation and tissues and is important in protection from oxidative stress, in immune system regulation, and angiogenesis. A common genetic polymorphism of Hp exists in the population, where the Hp 1-1, Hp 2-1, and Hp 2-2 forms exhibit profound functional differences. In this study, the Hp genotype corresponding to phenotypes Hp 1-1, 2-1 and 2-2 was determined in 312 idiopathic PD patients and 420 normal control subjects. A significant increase in the number of subjects carrying the Hp 2-1 genotype was present among PD patients. The distribution of Hp genotypes among PD patients (16.0% Hp 1-1, 56.4% Hp 2-1, 27.6% Hp 2-2) was significantly different from the distribution in controls (15.2% Hp 1-1, 48.1% Hp 2-1, 36.7% Hp 2-2) (chi(2) = 6.99, P = 0.030). The odds ratios for PD risk for Hp 2-1 and Hp 1-1 versus Hp 2-2 genotype were 1.51 (1.07-2.12) and 1.36 (0.86-2.15), respectively. Overall, the association of Hp-1 allele with PD resulted stronger among subjects who were never-smokers as compared to ever-smokers. Also, among ever-smokers, Hp genotypes were significantly associated with PD only among women, but not men, indicating the presence of a gene x gender x smoking interaction. To our knowledge, this is the first study that investigates the association of Hp genotypes with the risk of PD.

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis.

BACKGROUND: Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. METHODS: SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96weeks. Imaging is conducted every 24weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. RESULTS: A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. CONCLUSION: SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.

Identification of proteins in human substantia nigra.

Characterization of the human brain proteome is a critical area of research. While examination of the human cortex has provided some insight, very little is known about the proteome of the human midbrain, which demonstrates substantial loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) in Parkinson's disease (PD). Therefore, characterization of this region is essential to a better understanding of the pathogenesis of PD. This dataset paper reports two separate studies, where human SNpc was collected from PD and control subjects and 1263 proteins were identified using MALDI-TOF/TOF as well as linear ion trap MS platforms. With gene ontology analysis, the proteins were categorized according to their biological processes, as well as cellular components. These data were also compared with previous proteomic characterization of the human frontal and temporal cortex, and cerebrospinal fluid to establish shared proteins of relevance. The present dataset is the most extensive survey of the human SNpc proteome, to date. Further characterization of the SNpc proteome will significantly facilitate our understanding of the function and expression of proteins involved in PD, as well as provide potential proteins that may be utilized as biomarkers.