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BackgroundThe specificity of the aquaporin-4 antibody to predict recurrent inflammatory central nervous system disease has led to the design of the 2015 neuromyelitis optica spectrum disorder criteria which capture all aquaporin-4 antibody seropositive patients.ObjectiveThe purpose of this study was to compare treatment outcomes in aquaporin-4 antibody seropositive patients who met the previous 2006 clinical criteria for neuromyelitis optica with patients who meet the 2015 neuromyelitis optica spectrum disorder criteria.MethodsThe study involved a three-center retrospective chart review of clinical outcomes among aquaporin-4 patients diagnosed with neuromyelitis optica and neuromyelitis optica spectrum disorder.ResultsHazard ratios of relapse during immunosuppressive therapy, relative to pre-therapy, were not significantly different for patients who met the 2006 criteria of neuromyelitis optica versus the 2015 neuromyelitis optica spectrum disorder criteria among those treated with azathioprine ( p = 0.24), mycophenolate mofetil ( p = 0.63), or rituximab ( p = 0.97).ConclusionReductions in the hazard of relapse during treatment with immunosuppressive therapies, relative to average pre-treatment, were not different for aquaporin-4 antibody seropositive patients categorized using the 2006 criteria of neuromyelitis optica and the 2015 neuromyelitis optica spectrum disorder criteria. These therapeutic findings support the design of the 2015 neuromyelitis optica spectrum disorder criteria which capture all aquaporin-4 antibody seropositive patients.

Background: Glial fibrillary acid protein (GFAP) astrocytopathy is an autoimmune central nervous system disorder that rarely affects children. We describe a case of GFAP astrocytopathy with associated rhabdomyolysis in a pediatric patient., Methods: We report a case report from a tertiary care university hospital., Results: An 11-year-old girl developed subacute progressive neurological symptoms, beginning with vision changes and later followed by gait instability and lower extremity weakness over 2 months. On the day of presentation, she experienced new-onset upper extremity weakness. Examination revealed severe weakness of all 4 limbs and areflexia. She also had hematuria, with markedly elevated creatine kinase level of 64,408 U/L. Magnetic resonance imaging showed T2 hyperintensity in the optic chiasm and tract, a longitudinally extensive cord lesion, and cauda equina enhancement. Cerebrospinal fluid analysis revealed pleocytosis, elevated protein, and GFAP antibodies detected by cell-based assay. An electromyogram/nerve conduction study suggested peripheral nervous system involvement. Treatment with intravenous methylprednisolone, plasmapheresis, intravenous immunoglobulin, and rituximab led to partial clinical improvement., Conclusion: This case highlights a rare presentation of GFAP astrocytopathy with subacute visual loss, severe weakness, areflexia, and rhabdomyolysis. Clinicians should consider GFAP astrocytopathy in pediatric patients presenting with combined central and peripheral nervous system involvement., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Background: This study evaluated the clinical characteristics of neuronal ceroid lipofuscinosis type 7 or CLN7 disease spectrum to characterize the clinical, electrophysiologic and neuroimaging phenotypes., Methods: We performed a single-center cross sectional data collection along with retrospective medical chart review in patients with a genetic diagnosis of CLN7. This study received ethical approval by the University of Texas Southwestern Medical Center Institutional Review Board. A total of 8 patients were included between the ages of 4 to 6 years. All patients had a genetic diagnosis of CLN7 with homozygous or compound heterozygous mutations in the MFSD8 gene. The information collected includes patient demographics, developmental history, neurological events including seizures and neurodevelopmental regression along with further evaluation of brain magnetic resonance imaging and electrophysiological findings. The clinical phenotype is described through cross sectional and retrospective data collection and standardized tools assessing quality of life and functional skills., Results: Our findings in this cohort of CLN7 patients indicated that development is initially normal with onset of clinical symptoms as early as two years of age. Language problems were noted prior to or at the onset of seizures in all cases. Gait problems were noted prior to seizure onset in 3 of 8 patients, and at or within 6 months after the onset of seizures in 5 of 8 patients. All patients followed a progressive course of language, motor, and neurocognitive deterioration. Congruent with the medical history, our patients had significantly low scores on adaptive abilities. Natural history data such as this can be used to support future clinical trial designs., Conclusions: This study provides a comprehensive description of CLN7 disease, highlighting clinical data alongside standardized neuropsychological assessments, neuroimaging, and electrophysiologic data. It emphasizes the value of importance of standardized tools for understanding disease phenotype and their potential use as endpoints in future clinical trials. The findings established can provide a baseline for developing future prospective natural history studies and potential therapeutic clinical trials., Competing Interests: Declarations. Ethics approval and consent to participate: Ethical approval was obtained from the University of Texas Southwestern Medical Center Institutional Review Board prior to commencing this research study (STU 2020-0916, STU 2020-0640). An informed consent waiver was obtained for all participants. Consent for publication: This is a retrospective data collection for which a consent waiver was obtained to conduct this research. Competing interests: The authors have no competing interests to declare., (© 2024. The Author(s).)

Introduction: The transformative feature of Artificial Intelligence (AI) is the massive capacity for interpreting and transforming unstructured data into a coherent and meaningful context. In general, the potential that AI will alter traditional approaches to student research and its evaluation appears to be significant. With regard to research in global health, it is important for students and research experts to assess strengths and limitations of GenAI within this space. Thus, the goal of our research was to evaluate the information literacy of GenAI compared to expectations that graduate students meet in writing research papers., Methods: After completing the course, Fundamentals of Global Health (INTH 401) at Case Western Reserve University (CWRU), Graduate students who successfully completed their required research paper were recruited to compare their original papers with a paper they generated by ChatGPT-4o using the original assignment prompt. Students also completed a Google Forms survey to evaluate different sections of the AI-generated paper (e.g., Adherence to Introduction guidelines, Presentation of three perspectives, Conclusion) and their original papers and their overall satisfaction with the AI work. The original student to ChatGPT-4o comparison also enabled evaluation of narrative elements and references., Results: Of the 54 students who completed the required research paper, 28 (51.8%) agreed to collaborate in the comparison project. A summary of the survey responses suggested that students evaluated the AI-generated paper as inferior or similar to their own paper (overall satisfaction average = 2.39 (1.61-3.17); Likert scale: 1 to 5 with lower scores indicating inferiority). Evaluating the average individual student responses for 5 Likert item queries showed that 17 scores were < 2.9; 7 scores were between 3.0 to 3.9; 4 scores were ≥ 4.0, consistent with inferiority of the AI-generated paper. Evaluation of reference selection by ChatGPT-4o (n = 729 total references) showed that 54% (n = 396) were authentic, 46% (n = 333) did not exist. Of the authentic references, 26.5% (105/396) were relevant to the paper narrative; 14.4% of the 729 total references., Discussion: Our findings reveal strengths and limitations on the potential of AI tools to assist in understanding the complexities of global health topics. Strengths mentioned by students included the ability of ChatGPT-4o to produce content very quickly and to suggest topics that they had not considered in the 3-perspective sections of their papers. Consistently presenting up-to-date facts and references, as well as further examining or summarizing the complexities of global health topics, appears to be a current limitation of ChatGPT-4o. Because ChatGPT-4o generated references from highly credible biomedical research journals that did not exist, our findings conclude that ChatGPT-4o failed an important component in using information effectively. Moreover, misrepresenting trusted sources of public health information is highly concerning, particularly given recent experiences from the COVID-19 pandemic and more recently in reporting on the impact of, and response to natural disasters. This is a significant limitation of GenAI's ability to meet information literacy standards expected of graduate students., Competing Interests: Declarations. Ethics approval and consent to participate: Based on discussions with faculty colleagues who presented module content and the Senior Associate Dean of Graduate Studies, this study did not qualify as human subjects research and therefore did not require Institutional Review Board approval. All students agreed with the project protocol and consented to participate. Consent for publication: All authors have read and agreed to the published version of the manuscript. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) is a relatively new disease entity in the field of demyelinating disorders. Its first diagnostic criteria have recently been published., Objectives: We evaluated the positive predictive value (PPV) for MOG-IgG testing and report the clinical and radiologic features with respect to the recently published criteria., Methods: A retrospective study was conducted at three centers in Dallas, Texas. Patients with positive MOG-IgG testing on cell-based assays at any time were included. Positive cases were reviewed by at least two neuroimmunologists for fulfillment of the criteria., Results: We included 235 patients. The PPV of seropositivity at any time was 78.3% overall, 52.6% for low titer, and 90.1% for high titer. Children had a higher PPV than adults (93.9% versus 67.2%). Positive predictive value was 6.3% in those without a core clinical demyelinating attack. Children more often have the typical imaging features of MOGAD in optic neuritis than adults., Conclusions: We report a PPV of 78.3% for MOG-IgG testing using the 2023 MOGAD diagnostic criteria. Children had higher PPV and frequency of supporting imaging features. Careful consideration is necessary when assigning patients with no core demyelinating event and low titers a MOGAD diagnosis., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2024.)

There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disease by establishing a gene replacement therapy developed for a single patient with hereditary spastic paraplegia type 50 (SPG50). Through a multicenter collaboration, an adeno-associated virus-based gene therapy product carrying the AP4M1 gene was created and successfully administered intrathecally to a 4-year-old patient within 3 years of diagnosis as part of a single-patient phase 1 trial. Primary endpoints were safety and tolerability, and secondary endpoints evaluated efficacy. At 12 months after dosing, the therapy was well tolerated. No serious adverse events were observed, with minor events, including transient neutropenia and Clostridioides difficile gastroenteritis, experienced but resolved. Preliminary efficacy measures suggest a stabilization of the disease course. Longer follow-up is needed to confirm the safety and provide additional insights on the efficacy of the therapy. Overall, this report supports the safety of gene therapy for SPG50 and provides insights into precision therapy development for rare diseases. Clinical trial registration: NCT06069687 ., (© 2024. The Author(s).)

Background: Pediatric acute transverse myelitis (ATM) accounts for 20-30% of children presenting with a first acquired demyelinating syndrome (ADS) and may be the first clinical presentation of a relapsing ADS such as multiple sclerosis (MS). B cells have been strongly implicated in the pathogenesis of adult MS. However, little is known about B cells in pediatric MS, and even less so in pediatric ATM. Our lab previously showed that plasmablasts (PB), the earliest B cell subtype producing antibody, are expanded in adult ATM, and that these PBs produce self-reactive antibodies that target neurons. The goal of this study was to examine PB frequency and phenotype, immunoglobulin selection, and B cell receptor reactivity in pediatric patients presenting with ATM to gain insight to B cell involvement in disease., Methods: We compared the PB frequency and phenotype of 5 pediatric ATM patients and 10 pediatric healthy controls (HC) and compared them to previously reported adult ATM patients using cytometric data. We purified bulk IgG from the plasma samples and cloned 20 recombinant human antibodies (rhAbs) from individual PBs isolated from the blood. Plasma-derived IgG and rhAb autoreactivity was measured by mean fluorescence intensity (MFI) in neurons and astrocytes of murine brain or spinal cord and primary human astrocytes. We determined the potential impact of these rhAbs on astrocyte health by measuring stress and apoptotic response., Results: We found that pediatric ATM patients had a reduced frequency of peripheral blood PB. Serum IgG autoreactivity to neurons in EAE spinal cord was similar in the pediatric ATM patients and HC. However, serum IgG autoreactivity to astrocytes in EAE spinal cord was reduced in pediatric ATM patients compared to pediatric HC. Astrocyte-binding strength of rhAbs cloned from PBs was dependent on somatic hypermutation accumulation in the pediatric ATM cohort, but not HC. A similar observation in predilection for astrocyte binding over neuron binding of individual antibodies cloned from PBs was made in EAE brain tissue. Finally, exposure of human primary astrocytes to these astrocyte-binding antibodies increased astrocytic stress but did not lead to apoptosis., Conclusions: Discordance in humoral immune responses to astrocytes may distinguish pediatric ATM from HC., (© 2024. The Author(s).)

Background: Prognostic markers for relapse and neurological disability following the first clinical event in children with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) remain lacking. We investigated the clinical profiles and early prognostic factors associated with relapsing disease or impaired functional outcome in a large single-center cohort of pediatric MOGAD., Methods: We retrospectively analyzed the clinical and paraclinical data and treatment outcomes of children with MOGAD seen at Children's Health in Dallas, Texas from 2009 to 2022. Univariate analyses were used to evaluate factors from initial event associated with relapsing disease course and impaired functional outcome (modified Rankin scale [mRS] >1) at final follow-up., Results: Our cohort comprised of 87 children of diverse race/ethnicity. Presentation with acute disseminated encephalomyelitis (ADEM) was more frequent in children aged ≤8 years and Caucasian background, whereas presentation with optic neuritis was more common in children aged >8 years and other race/ethnicity. 44.3 % (27/61) had relapsing disease course, of whom 48.0 % had multiple relapses. 30.3 % (23/76) had final mRS >1. Children with abnormal electroencephalogram had reduced relapse risk. Children with ADEM presentation, severe disease, low MOG-IgG titer, and central and systemic inflammation (represented by cerebrospinal fluid pleocytosis and serum leukocytosis, respectively) at onset had higher likelihood of final mRS >1., Conclusion: Abnormal electroencephalogram at the first event was associated with reduced relapse risk while disease severity and peripheral inflammation significantly contributed to final neurological disability. Further studies are needed to validate these findings as early risk factors for disability and relapse and to identify optimal treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) can cause significant disability to patients via relapse-associated worsening and progression independent of relapses. The causes of neuronal and myelin damage can include lymphocyte-mediated inflammation and microglial activation. Bruton's tyrosine kinase (BTK) is an enzyme that mediates B cell activation and the proinflammatory phenotype of microglia. Inhibiting BTK provides a novel therapeutic target for MS but also has a complicated pharmacology based on binding specificity, CNS penetration, half-life, and enzyme inhibition characteristics. Multiple agents are being studied in phase 3 trials, and each agent will have unique efficacy and safety profiles that must be considered individually., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Impaired brain energy metabolism has been observed in many neurodegenerative diseases, including Parkinson's disease (PD) and multiple sclerosis (MS). In both diseases, mitochondrial dysfunction and energetic impairment can lead to neuronal dysfunction and death. CNM-Au8® is a suspension of faceted, clean-surfaced gold nanocrystals that catalytically improves energetic metabolism in CNS cells, supporting neuroprotection and remyelination as demonstrated in multiple independent preclinical models. The objective of the Phase 2 REPAIR-MS and REPAIR-PD clinical trials was to investigate the effects of CNM-Au8, administered orally once daily for twelve or more weeks, on brain phosphorous-containing energy metabolite levels in participants with diagnoses of relapsing MS or idiopathic PD, respectively., Results: Brain metabolites were measured using 7-Tesla 31 P-MRS in two disease cohorts, 11 participants with stable relapsing MS and 13 participants with PD (n = 24 evaluable post-baseline scans). Compared to pre-treatment baseline, the mean NAD + /NADH ratio in the brain, a measure of energetic capacity, was significantly increased by 10.4% after 12 + weeks of treatment with CNM-Au8 (0.584 units, SD: 1.3; p = 0.037, paired t-test) in prespecified analyses of the combined treatment cohorts. Each disease cohort concordantly demonstrated increases in the NAD + /NADH ratio but did not reach significance individually (p = 0.11 and p = 0.14, PD and MS cohorts, respectively). Significant treatment effects were also observed for secondary and exploratory imaging outcomes, including β-ATP and phosphorylation potential across both cohorts., Conclusions: Our results demonstrate brain target engagement of CNM-Au8 as a direct modulator of brain energy metabolism, and support the further investigation of CNM-Au8 as a potential disease modifying drug for PD and MS., (© 2023. The Author(s).)

Background and Objectives: Elevated intracranial pressure (ICP) in myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) has been largely unexplored. The objectives of this study were to determine the frequency of increased ICP in MOGAD and its association with disease course and outcomes and to highlight cases requiring medical and/or surgical management of increased ICP., Methods: In this retrospective, single-center cohort study, we examined the clinical and paraclinical data from the initial presentation and follow-up data of children diagnosed with MOGAD. In those with opening pressure (OP) measurements, univariate analyses were used to evaluate factors associated with increased ICP, which was defined as OP > 28 cm H 2 O. We also present a case series of patients with or without OP measurement who required medical and/or surgical management of increased ICP., Results: Of 86 children with MOGAD, 43 (50.0%) had an OP recorded and 7 (8.1%) required ICP management. In those with OP recorded, the median (interquartile range) OP for the different MOGAD phenotypes were: 30.0 (22.8-41.6) (acute disseminated encephalomyelitis, ADEM), 20.5 (16.1-23.6) (optic neuritis), 17.0 (17.0-22.5) (myelitis), and 19.5 (16.5-29.3) (other) cm H 2 0. Overall, 20.9% had increased ICP based on an OP > 28 cm H 2 O, of whom 77.8% presented with ADEM. In a subgroup analysis of those presenting with ADEM, those with an elevated ICP had longer hospital stay ( p = 0.007) and neurologic disability (defined as modified Rankin Scale >1) ( p = 0.049). In those with or without OP recorded, 7 (6 with ADEM, one with cerebral cortical encephalitis) required ICP-directed therapies. Findings on brain MRI in these 7 children revealed extensive disease burden with bilateral cerebral involvement and evidence of restricted diffusion. While neuropsychological data in this small subset revealed significant variability, all sustained identifiable deficits after discharge, including attention-deficit hyperactivity disorders and language and learning disorders., Discussion: In pediatric MOGAD, increased OP and ADEM at initial presentation were associated with longer hospital stays and greater long-term morbidity. Although invasive ICP monitoring has not been specifically advocated in the management of MOGAD, it is important to recognize signs and symptoms of increased ICP in these patients and consider ICP monitoring and management strategies based on clinical and radiologic findings, especially in those presenting with ADEM and with OP > 28 cm H 2 O., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by reactivation of the human polyomavirus 2 (HPyV-2). PML is associated with a high morbidity and mortality rate and there is currently no standard curative therapy. We report short-term immunologic response and long-term clinical outcomes in a patient diagnosed with follicular lymphoma (FL) who developed PML. Diagnosis of PML was established conclusively based on findings from a brain biopsy. The patient was treated with recombinant interleukin 2 (IL-2) and showed rapid clinical improvement. HPyV-2-specific T-cells were tracked longitudinally and correlation with clinical status, viral load, and radiographic imaging was documented. After the progression of the patient's FL, which required an allogeneic bone marrow transplant, the patient prophylactically received human leukocyte antigen-matched donor-derived HPyV-2 T-cells to prevent the recurrence of the PML as part of a clinical trial. Twelve years after the initial diagnosis of PML, he did not develop a relapse of his PML, supporting data that therapies that increase HPyV-2-specific T-cells, including IL-2, may be effective in the management of PML., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Benjamin M. Greenberg, MD, MHS has received consulting fees or honoraria from EMD Serono, Novartis, and Alexion., (© The Author(s), 2023.)

Background and Objectives: The clinical spectrum of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is heterogenous and has evolved over time since the commercial availability of the anti-MOG antibody assay. Subclinical disease activity has been previously reported in the visual pathway, but prevalence data remains limited. We investigated subclinical optic neuritis (ON) based on changes on retinal nerve fiber layer (RNFL) thickness on optic coherence tomography (OCT) in pediatric patients who tested positive for the anti-MOG antibody., Methods: In this retrospective, single-center cohort study, we examined children with MOGAD with at least one complete assessment of the anterior visual pathway. Subclinical ON was defined by structural visual system disease in the absence of a subjective complaint of vision loss, pain (particularly with eye movement), or color desaturation., Results: Records were reviewed from 85 children with MOGAD, 67 of whom (78.8%) had complete records for review. Eleven children (16.4%) had subclinical ON on OCT. Ten had significant reductions in RNFL, of which one had two distinct episodes of decreased RNFL, and one had significant elevations in RNFL. Of the eleven children with subclinical ON, six (54.5%) had a relapsing disease course. We also highlighted the clinical course of three children with subclinical ON detected on longitudinal OCT, including two who had subclinical ON outside of clinical relapses., Conclusion: Children with MOGAD can have subclinical ON events that can manifest as significant reductions or elevations in RNFL on OCT. OCT should be used routinely in the management and monitoring of MOGAD patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Excessive daytime sleepiness (EDS) in multiple sclerosis (MS) can be a significant source of disability. Despite this, its prevalence as a patient-reported outcome in this condition has not been well established, and its causes are not well understood., Methods: We prospectively assessed EDS as part of an observational study for patients referred for diagnostic neuro-ophthalmological testing. EDS was evaluated by the Epworth Sleepiness Scale (ESS), and visual data were also collected as part of a research protocol. Analysis with patient data was performed following the exclusion of patients with known primary sleep disorders., Results: A total of 69 patients with MS were included in the analysis. The mean ESS was 6.5 with a SD of 4.3. ESS ≥ 10 was present in 23% of the cohort even in the presence of minimal mean neurological disability (Patient Determined Disease Steps (PDDS) = 1.5). The ESS score was not associated with age, sex, disease-related disability, retinal nerve fiber layer (RNFL), or optic neuritis (ON), but displayed an association with visual dysfunction., Conclusions: There is an increased prevalence of EDS in MS. The increased values of the ESS are not explained by other sleep disorders, suggesting separate mechanisms. Further study of the underlying mechanisms is warranted., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2023.)

Objective: The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among patients with pediatric-onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG-IgG-associated disease (MOGAD), and identify clinical features associated with final diagnosis., Methods: Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case-control study on POMS risk factors. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays., Results: AQP4-IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG-IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty-five of 30 patients positive with MOG-IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re-review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p = 0.044), younger age (mean = 8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p = 0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p = 0.002), serum Epstein-Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001)., Interpretation: MOG-IgG and AQP4-IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4-IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2023;93:271-284., (© 2022 American Neurological Association.)

Over the past four decades, ATP, the obligatory energy molecule for keeping all cells alive and functioning, has been thought to contribute only one set of signals in brain 31 P MR spectra. Here we report for the first time the observation of two separate β-ATP peaks in brain spectra acquired from patients with myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGADs) using 3D MRSI at 7 T. In voxel spectra with β-ATP line splitting, these two peaks are separated by 0.46 ± 0.18 ppm (n = 6). Spectral lineshape analysis indicates that the upper field β-ATP peak is smaller in relative intensity (24 ± 11% versus 76 ± 11%), and narrower in linewidth (56.8 ± 10.3 versus 41.2 ± 10.3 Hz) than the downfield one. Data analysis also reveals a similar line splitting for the intracellular inorganic phosphate (P i ) signal, which is characterized by two components with a smaller separation (0.16 ± 0.09 ppm) and an intensity ratio (26 ± 7%:74 ± 7%) comparable to that of β-ATP. While the major components of P i and β-ATP correspond to a neutral intracellular pH (6.99 ± 0.01) and a free Mg 2+ level (0.18 ± 0.02 mM, by Iotti's conversion formula) as found in healthy subjects, their minor counterparts relate to a slightly acidic pH (6.86 ± 0.07) and a 50% lower [Mg 2+ ] (0.09 ± 0.02 mM), respectively. Data correlation between β-ATP and P i signals appears to suggest an association between an increased [H + ] and a reduced [Mg 2+ ] in MOGAD patients., (© 2022 John Wiley & Sons Ltd.)

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20 dim CD8 + T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20 dim CD8 + T cells had a greater contribution to treatment-associated changes in the CD8 + T cell pool than was the case for CD4 + T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20 dim CD8 + T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19 + CD24 high CD38 high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20 dim CD8 + T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8 + T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

Background: Immunocompromised (IC) patients show diminished immune response to COVID-19 mRNA vaccines (Co-mV). To date, there is no 'empirical' evidence to link the perturbation of translation, a rate-limiting step for mRNA vaccine efficiency (VE), to the dampened response of Co-mV., Materials and Methods: Impact of immunosuppressants (ISs), tacrolimus (T), mycophenolate (M), rapamycin/sirolimus (S), and their combinations on Pfizer Co-mV translation were determined by the Spike (Sp) protein expression following Co-mV transfection in HEK293 cells. In vivo impact of ISs on SARS-CoV-2 spike specific antigen (SpAg) and associated antibody levels (IgG Sp ) in serum were assessed in Balb/c mice after two doses (2D) of the Pfizer vaccine. Spike Ag and IgG Sp levels were assessed in 259 IC patients and 50 healthy controls (HC) who received 2D of Pfizer or Moderna Co-mV as well as in 67 immunosuppressed solid organ transplant (SOT) patients and 843 non-transplanted (NT) subjects following three doses (3D) of Co-mV. Higher Co-mV concentrations and transient drug holidays were evaluated., Results: We observed significantly lower IgG SP response in IC patients (p<0.0001) compared to their matched controls in 2D and 3D Co-mV groups. IC patients on M or S showed a profound dampening of IgG SP response relative to those that were not on these drugs. M and S, when used individually or in combination, significantly attenuated the Co-mV-induced Sp expression, whereas T did not exert significant influence. Sirolimus combo pretreatment in vivo significantly attenuated the Co-mV induced IgM Sp and IgG Sp production, which correlated with a decreasing trend in the early levels (after day 1) of Co-mV induced Sp immunogen levels. Neither higher Co-mV concentrations (6μg) nor withholding S for 1-day could overcome the inhibition of Sp protein levels. Interestingly, 3-days S holiday or using T alone rescued Sp levels in vitro., Conclusions: This is the first study to demonstrate that ISs, sirolimus and mycophenolate inhibited Co-mV-induced Sp protein synthesis via translation repression. Selective use of tacrolimus or drug holiday of sirolimus can be a potential means to rescue translation-dependent Sp protein production. These findings lay a strong foundation for guiding future studies aimed at improving Co-mV responses in high-risk IC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2022 Kim, Narasimhan, Mahimainathan, Zhang, Araj, Kim, Tharpe, Greenberg, Greenberg, Li, Cheng, Sarode, Malladi and Muthukumar.)

Demyelinating diseases of the central nervous system (CNS) often have neuro-ophthalmological manifestations, and retinal examination can be helpful in making the diagnosis. The latest iteration of optical coherence tomography (OCT)-based criteria for optic neuritis in multiple sclerosis has been developed in the research realm, but its application to clinical practice, and to the more uncommon demyelinating diseases requires further study. The ability to use OCT data to distinguish between various CNS demyelinating disorders could provide additional paraclinical tools to accurately diagnose patients. Furthermore, neuro-ophthalmological testing can define the extent of inflammatory damage in the CNS, independent of patient-reported history. New referrals for OCT at a tertiary multiple sclerosis and neuro-immunology referral centre ( n  = 167) were analysed retrospectively for the self-reporting of optic neuritis, serological test results, and diagnosis. Only approximately 30% of patients with a clinical history of unilateral optic neuritis solely had a unilateral optic neuropathy, nearly 40% of those subjects actually having evidence of bilateral optic neuropathies. Roughly 30% of patients reporting a history of bilateral optic neuritis did not have any evidence of structural disease, with 20% of these patients having a separate, intervenable diagnosis noted on macular scans. OCT is a useful adjunct diagnostic tool in the evaluation of demyelinating disease and has the ability to aid in a more accurate diagnosis for patients. Application of the international interocular difference thresholds to a clinical patient population generally reproduces the original results, emphasising their appropriateness. The analysis distinguishing the demyelinating diseases needs to be replicated in a blinded, multi-centre setting., Competing Interests: Peter Sguigna has no disclosures related to this publication. He has received grant support from the NMSS, CTM, PSTP, and the PRC. He has received consulting fees from Medical Logix LLC, Genentech, and Bristol Myers Squibb. Research reported in this publication was supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001105. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Lauren Tardo has nothing to declare. Kyle Blackburn has nothing to declare. Lindsay Horton has nothing to declare. Darrel Conger has nothing to declare. Robert “Nick” Hogan has nothing to declare. Morgan McCreary has nothing to declare. Benjamin Greenberg has received grant support from the NIH, NMSS, Transverse Myelitis Association, PCORI, Guthy Jackson Charitable Foundation, Chugai, MedImmune, Medday, and Genentech. He has received consulting fees from Alexion, Novartis, EMD Serono, Genentech, and Celgene; he is an unpaid board member of the Transverse Myelitis Association., (© 2022 Taylor & Francis Group, LLC.)

Background: Depression is one of the most common symptoms experienced by multiple sclerosis patients and may be secondary to the disease itself as well as other variables such as age, disease severity and side effects of treatment., Objective: To determine if there is an association between disease modifying therapies and depression rates based on PHQ9 scores in multiple sclerosis., Methods: This was a retrospective chart review. Patients followed at the University of Texas Southwestern Multiple Sclerosis and Neuroimmunology Clinic from 2017 to 2020 were included in this study. Patients' most recent PHQ-9 scores were used. The following data was extracted from patient charts: disease modifying therapy, age, disease duration, gender, antidepressant use and ambulatory status., Results: Data from our study included 2611 individual PHQ-9 scores. The majority of our patients were female and the mean age across all treatment groups was 50.37 years old. The median disease duration across all treatment groups was 12.74 years. Most patients in this cohort required no ambulatory assistance. 43.86% of patients were on antidepressants and use was correlated with a higher PHQ9 score. The median PHQ 9 score across all treatment groups was 4 (Interquartile range = 7). Across treatment groups, patients on interferon therapy had the lowest PHQ 9 scores with a median of 2., Conclusions: Our study demonstrated that there were lower PHQ-9 scores among interferon treatment group as compared to other disease modifying therapies and non-treatment groups., Competing Interests: Declaration of conflicting interest: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Benjamin Greenberg has received consulting fees from Alexion, Novartis, EMD Serono, Viela Bio, Genentech/Roche, Greenwhich Biosciences, Axon Advisors, Rubin Anders, ABCAM, and PRIME Education. He has received grant funding from PCORI, NIH, NMSS, The Siegel Rare Neuroimmune Association, Clene Nanomedicine and the Guthy Jackson Charitable Foundation for NMO. He serves as an unpaid member of the board of the Siegel Rare Neuroimmune Association., (© The Author(s) 2022.)

Background: Recombinant human immunoglobulin M22 (rHIgM22) has promoted remyelination in animal models and was well tolerated in people with clinically stable multiple sclerosis., Objective: Safety/tolerability of a single rHIgM22 dose was investigated following an acute relapse and to determine whether this enhanced CNS/CSF concentrations., Methods: Adults (N = 27) with acute relapse were assigned to rHIgM22 (0.5 or 2.0 mg/kg) or placebo. Study included screening/steroid administration periods and 10 study visits over 6 months. rHIgM22 CSF concentrations were assessed on days 2 and 29. Pharmacokinetic and safety samples were taken for up to 60 days. Assessments included adverse events and other clinical measures. Brain magnetic resonance imaging was performed with/without gadolinium., Results: rHIgM22 CSF levels were consistent with dose-dependent concentration on both days 2 and 29. Infusion was generally well tolerated during an acute relapse. Immunogenicity was mild. Most adverse events did not appear to be dose dependent, were mild/moderate, and were events often associated with multiple sclerosis., Conclusion: Although limited by high variability and small sample size, the data suggest enhanced CNS uptake associated with a drop in CSF levels. This study demonstrated safety of an antibody directed to myelin and oligodendrocytes in the course of active demyelinating disease. Further research into rHIgM22 is warranted. ClinicalTrials.gov : NCT02398461 https://clinicaltrials.gov/ct2/show/study/NCT02398461?term=M22&draw=2&rank=8., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Xxxxxxx. B.M. Greenberg has received consulting fees from Alexion, Novartis, EMD Serono, Viela Bio, Genentech/Roche, Greenwich Biosciences, Axon Advisors, Rubin Anders, ABCAM, Signant, IQVIA, Sandoz, Druggability Technologies, Genzyme, Immunovant, and PRIME Education. He has received grant funding from PCORI, NIH, NMSS, The Siegel Rare Neuroimmune Association, Clene Nanomedicine, and the Guthy Jackson Charitable Foundation for NMO. He serves as an unpaid member of the board of the Siegel Rare Neuroimmune Association. He receives royalties from UpToDate. J.D. Bowen has received compensation for activities such as advisory boards, lectures, and consultancy with the following companies and organizations: AbbVie, Alkermes, Biogen IDEC, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, Genzyme, Novartis, and Roche. E. Alvarez has received compensation for activities such as advisory boards, lectures, and consultancy with the following companies and organizations: Actelion/Janssen, Alexion, Bayer, Biogen, Celgene/BMS, EMD Serono/Merck, Genentech/Roche, Genzyme, Novartis, and TG Therapeutics. He has also received research support from Biogen, Genentech/Roche, Novartis, TG Therapeutics, Patient-Centered Outcomes Research Initiative, National Multiple Sclerosis Society, National Institutes of Health, and Rocky Mountain MS Center. M.R. Rodriguez and A.E.W. Warrington: The Mayo Clinic owns patents and has licensed rHIgM22 to Acorda Therapeutics. If the antibody proves to be effective, then royalties may be received. A. Caggiano, Ping Zhao and A. Eisen were employees of Acorda Therapeutics at the time of the study, and A. Caggiano and A. Eisen own stock in Acorda., (© The Author(s), 2022.)

Neuromyelitis optica spectrum disorder is an inflammatory condition of the central nervous system typically manifesting as myelitis, optic neuritis, and/or area postrema syndrome. Here, we present a pediatric patient who developed symptoms consistent with area postrema syndrome with positive anti-aquaporin-4 (AQP4) antibodies who was also found to have an ovarian teratoma. Pathological specimens revealed the presence of aquaporin-4. This was felt to be the antigenic trigger that led to the patient's condition. She suffered no further clinical attacks and seroconverted to negative AQP4 status upon teratoma removal. This case varies from others, in that the paraneoplastic presentation occurred in a pediatric patient and in that the patient has not required maintenance immunotherapy after teratoma removal.

Background and Objectives: A descriptive analysis of COVID-19 infection in patients with multiple sclerosis (MS) receiving fingolimod or siponimod., Methods: We reviewed the cases of COVID-19 from postmarketing or ongoing clinical trials reported to Novartis through December 27, 2020., Results: As of December 27, 2020, 283 cases had been reported in fingolimod-treated patients. The mean age was 44 years (from n = 224; range 11-69 years), and 190 were women. Of 161 cases with available information, 138 were asymptomatic (6), mild (100), or moderate (32); 50 cases required hospitalization. At the last follow-up, 140 patients were reported as recovered/recovering, condition was unchanged in 22, and deteriorated in 3 patients; 4 patients had a fatal outcome. Information was not available for 114 patients. Of the 54 cases of COVID-19 reported in siponimod-treated patients, 45 were from the postmarketing setting and 9 from an ongoing open-label clinical trial. The mean age was 54 years (from n = 45; range 31-70), and 30 were women. Of 28 cases with available information, 24 were asymptomatic (2), mild (17), or moderate (5); 9 cases required hospitalization. At the last follow-up, 27 patients were reported as recovered/recovering, condition remained unchanged for 1, and 3 patients had a fatal outcome. Information was not available for 23 patients., Discussion: Based on a review of available information, the risk of more severe COVID-19 in patients receiving fingolimod or siponimod seems to be similar to that reported in the general population and the MS population with COVID-19. However, limitations of spontaneous reporting, especially missing data, should be considered in the interpretation of these observations., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: As phase III trials have shown interest in innovative but expensive drugs in the treatment of neuromyelitis optica spectrum disorder (NMOSD), data are needed to clarify strategies in the treatment of neuromyelitis optica (NMO). This meta-analysis compares the efficacy of first-line strategies using rituximab (RTX), mycophenolate mofetil (MMF), or azathioprine (AZA), which are still widely used., Methods: Studies identified by the systematic review of Huang et al. (2019) were selected if they considered at least two first-line immunosuppressants among RTX, MMF, and AZA. We updated this review. The Medline, Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials databases were queried between November 2018 and April 2020. To be included, the hazard ratio (HR) [95% CI] for the time to first relapse after first-line immunosuppression had to be available, calculable, or provided by the authors., Results: We gathered data from 919 NMO patients (232 RTX-, 294 MMF-, and 393 AZA-treated patients). The risk of first relapse after first-line immunosuppression was 1.55 [1.04, 2.31] (p = 0.03) for MMF compared with RTX, 1.42 [0.87, 2.30] (p = 0.16) for AZA compared with RTX, and 0.94 [0.58, 1.54] (p = 0.08) for MMF compared with AZA., Interpretation: The findings suggest that RTX is more efficient than MMF as a first-line therapy. Even if the results of our meta-analysis cannot conclude that RTX has a better efficacy in delaying the first relapse than AZA, the observed effect difference between both treatments combined with the results of previous studies using as outcome the annualized relapse rate may be in favor of RTX., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Objectives: Opsoclonus-myoclonus syndrome (OMS) is a rare autoimmune disorder associated with neuroblastoma in children, although idiopathic and postinfectious etiologies are present in children and adults. Small cohort studies in homogenous populations have revealed elevated rates of autoimmunity in family members of patients with OMS, although no differentiation between paraneoplastic and nonparaneoplastic forms has been performed. The objective of this study was to investigate the prevalence of autoimmune disease in first-degree relatives of pediatric patients with paraneoplastic and nonparaneoplastic OMS., Methods: A single-center cohort study of consecutively evaluated children with OMS was performed. Parents of patients were prospectively administered surveys on familial autoimmune disease. Rates of autoimmune disease in first-degree relatives of pediatric patients with OMS were compared using Fisher exact t test and χ 2 analysis: (1) between those with and without a paraneoplastic cause and (2) between healthy and disease (pediatric multiple sclerosis [MS]) controls from the United States Pediatric MS Network., Results: Thirty-five patients (18 paraneoplastic, median age at onset 19.0 months; 17 idiopathic, median age at onset 25.0 months) and 68 first-degree relatives (median age 41.9 years) were enrolled. One patient developed systemic lupus erythematosus 7 years after OMS onset. Paraneoplastic OMS was associated with a 50% rate of autoimmune disease in a first-degree relative compared with 29% in idiopathic OMS ( p = 0.31). The rate of first-degree relative autoimmune disease per OMS case (14/35, 40%) was higher than healthy controls (86/709, 12%; p < 0.001) and children with pediatric MS (101/495, 20%; p = 0.007)., Discussion: In a cohort of pediatric patients with OMS, there were elevated rates of first-degree relative autoimmune disease, with no difference in rates observed between paraneoplastic and idiopathic etiologies, suggesting an autoimmune genetic contribution to the development of OMS in children., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objective: The objective of this study was to determine whether family members of patients with pediatric multiple sclerosis (MS) have an increased prevalence of autoimmune conditions compared with controls., Methods: Data collected during a pediatric MS case-control study of risk factors included information about various autoimmune diseases in family members. The frequency of these disorders was compared between cases and controls., Results: There was an increased rate of autoimmune diseases among family members of pediatric MS cases compared with controls with first-degree history of MS excluded (OR = 2.27, 95% CI 1.71-3.01, p < 0.001). There was an increased rate of MS among second-degree relatives of pediatric MS cases compared with controls (OR = 3.47, 95% CI 1.36-8.86, p = 0.009). The OR for MS was 2.64 when restricted to maternal relatives and 6.37 when restricted to paternal relatives., Discussion: The increased rates of autoimmune disorders, including thyroid disorders and MS among families of patients with pediatric MS, suggest shared genetic factors among families with children diagnosed with pediatric MS., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To determine whether distinct aquaporin-4 (AQP4)-IgG lineages play a role in neuromyelitis optica spectrum disorder (NMOSD) pathogenesis, we profiled the AQP4-IgG polyclonal serum repertoire and identified, quantified, and functionally characterized distinct AQP4-IgG lineages circulating in 2 patients with NMOSD., Methods: We combined high-throughput sequencing and quantitative immunoproteomics to simultaneously determine the constituents of both the B-cell receptor (BCR) and the serologic (IgG) anti-AQP4 antibody repertoires in the peripheral blood of patients with NMOSD. The monoclonal antibodies identified by this platform were recombinantly expressed and functionally characterized in vitro., Results: Multiple antibody lineages comprise serum AQP4-IgG repertoires. Their distribution, however, can be strikingly different in polarization (polyclonal vs pauciclonal). Among the 4 serum AQP4-IgG monoclonal antibodies we identified in 2 patients, 3 induced complement-dependent cytotoxicity in a model mammalian cell line ( p < 0.01)., Conclusions: The composition and polarization of AQP4-IgG antibody repertoires may play an important role in NMOSD pathogenesis and clinical presentation. Here, we present a means of coupling both cellular (BCR) and serologic (IgG) antibody repertoire analysis, which has not previously been performed in NMOSD. Our analysis could be applied in the future to clinical management of patients with NMOSD to monitor disease activity over time as well as applied to other autoimmune diseases to facilitate a deeper understanding of disease pathogenesis relative to autoantibody clones., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Purpose of Review: To explore the elements that are typically considered when determining physician compensation in the United States and to examine if the compensation of neurologists with expertise in multiple sclerosis (MS) care is commensurate with that for other neurological specialists and medical specialists that also employ complex therapies, e.g., oncology., Recent Findings: The complexity in the diagnosis and management of MS requires increasing specialization. Additionally, changing models for the delivery of MS care has resulted in the MS neurologist generating significant contribution margins. In fact, the revenue to compensation ratio for the MS neurologist may be significantly higher than that of any other discipline in neuroscience service lines. However, while the contribution margin is often a key justification of compensation of interventional and intensive care practitioners in neuroscience service lines, it is generally not considered in the MS neurologist's compensation. Compensation models for MS neurologists typically depend heavily on the absolute number of relative value units associated with evaluation and management (E&M) codes making other fields of neurology financially more attractive to trainees., Summary: In considering the shortage of MS specialists, the demands of their discipline, and the revenue to compensation ratios, the MS neurologist is significantly undercompensated relative to other neurological specialists and to physicians in other disciplines. Compensating the MS neurologist appropriately and supporting the necessary infrastructure for MS care will likely attract more trainees to this discipline and help reverse the current scarcity of MS neurologists in the United States., (Copyright © 2021. Published by Elsevier B.V.)