Neurology - Neuroimmunology Neuroinflammation

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ISSN / EISSN : 23327812 / 23327812
Current Publisher: Ovid Technologies (Wolters Kluwer Health) (10.1212)
Total articles ≅ 718
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Gilles Brun, Jean-François Hak, Stéphanie Coze, Elsa Kaphan, Julien Carvelli, Nadine Girard, Jan-Patrick Stellmann
Neurology - Neuroimmunology Neuroinflammation, Volume 7; doi:10.1212/nxi.0000000000000777

Abstract:
Since December 2019, a novel coronavirus, also called severe acute respiratory syndrome CoV-2 (SARS-CoV-2), emerged in Wuhan, China, and caused a pandemic disease (COVID-19). Respiratory impairment is the most common symptom in patients with confirmed COVID-19; however, neurologic symptoms were documented in approximately 36%, including headache, disturbed consciousness, and paresthesia.1 The virus can take different pathways to involve the CNS: in one way through hematogenous or lymphatic route and in another way via the cribriform plate close to the olfactory bulb. Very few studies have shown CNS abnormalities related to COVID-19 on MRI. Herein, we report a case of SARS-CoV-2 brain lesions suggesting an acute demyelination.
Pierre Becquart, Jake Johnston, Carles Vilariño-Güell, Jacqueline A. Quandt
Neurology - Neuroimmunology Neuroinflammation, Volume 7; doi:10.1212/nxi.0000000000000745

Abstract:
ObjectiveWe examined expression of aryl hydrocarbon receptor nuclear translocator 2 (ARNT2), a basic-loop-helix transcription factor implicated in neuronal development and axonal health, in oligodendrocyte (OL) cultures and over the course of chronic experimental autoimmune encephalomyelitis (EAE), the murine model of multiple sclerosis (MS).MethodsWe assessed OL ARNT2 expression in EAE compared with sham-immunized controls and also in OL primary cultures and over the course of dibutyryl cyclic adenosine monophosphate (dbcAMP)-mediated maturation of the immortalized Oli-neu cell line. We also tested the functional role of ARNT2 in influencing OL characteristics using small interfering RNA (siRNA).ResultsARNT2 is localized to Olig2+ cells in healthy spinal cord gray and white matter. Despite a significant expansion of Olig2+ cells in the white matter at peak disease, ARNT2 is reduced by almost half in OLs, along with a reduction in the percentage of ARNT2+/Olig2+ cells. Mature OLs in mixed cortical cultures or OLs matured from embryonic progenitors express negligible ARNT2. Similarly, Oli-neu cells express high levels of ARNT2, which are reduced following dbcAMP maturation. siRNA-mediated knockdown of ARNT2 affected OL viability, which led to an enrichment of myelin-producing OLs.ConclusionThe analysis of ARNT2 expression in OLs demonstrates that OL ARNT2 expression is altered in EAE and during OL maturation. Findings point to ARNT2 as an important mediator of OL viability and differentiation and warrant further characterization as a target for intervention in demyelinating disorders such as MS.
Christoph Mahler, Michael Andrews, Sian M. Henson, Sharmilee Gnanapavan
Neurology - Neuroimmunology Neuroinflammation, Volume 7; doi:10.1212/nxi.0000000000000756

Abstract:
Progressive multifocal leukoencephalopathy (PML) secondary to John Cunningham (JC) virus infection remains as yet an untreatable viral infection. Plasmapheresis, adoptive T-cell therapyies, and immune reconstitution strategies have all been used with variable success. Cortese et al.1 showed that pembrolizumab, a programmed cell death protein-1 (PD-1) checkpoint inhibitor, increases CD4+ and CD8+ activities and thereby reduces JC viral load. Five of their 8 patients did well, but the remainder, despite effective PD-1 suppression, failed to establish an anti–JC virus T-cell response. Recently, Kuepper et al.2 published a case of primary immunodeficiency with PML who demonstrated a dramatic reduction in PD-1 expression with pembroluzimab, but the patient still died. The authors would like to thank Professor David Baker, Queen Mary University of London for his helpful comments.
Andrea Ines Ciplea, Annette Langer-Gould, Anna Stahl, Sandra Thiel, Annette Queisser-Wahrendorf, Ralf Gold, Kerstin Hellwig
Neurology - Neuroimmunology Neuroinflammation, Volume 7; doi:10.1212/nxi.0000000000000757

Abstract:
ObjectiveTo determine whether potential breast milk exposure to interferon-beta (IFN-β) or glatiramer acetate (GA) is safe for the infant.MethodsWe identified 74 infants born to 69 women with MS who breastfed under IFN-β (n = 39), GA (n = 34), or both (n = 1). Women had been enrolled into the German Multiple Sclerosis and Pregnancy Registry during pregnancy. Data were obtained from standardized, telephone-administered questionnaires completed by the mother during pregnancy and at 1, 3, 6, and 12 months postpartum and the infant's take-home medical record.ResultsThe median duration of exposed breastfeeding was 8.5 months (wide interquartile range: 4.9–12.7 months). Physical growth curves during the first year of life were consistent with national, sex-specific growth curves. Median body measurements were consistent with national medians. Most children (n = 71, 96%) had normal motor and language development. Gross motor delay was reported in 3 children, of whom 1 remained delayed at last follow-up (3.9 years old) and 2 were normal by 0.9 and 4.1 years old. The proportion of children hospitalized at least once (girls n = 2, 7%, and boys n = 6, 14%) and the proportion of children with at least one episode of systemic antibiotic use during the first year of life (girls n = 7, 23%, and boys n = 8, 18%) are consistent with national averages.ConclusionPotential breast milk exposure to IFN-β or GA did not increase the risk of common adverse infant outcomes in the first year of life. Taken together with the benefits of breastfeeding and low biological plausibility of risk, women with MS who wish to resume IFN-β or GA postpartum can be encouraged to breastfeed.
Eleonora Tavazzi, Dejan Jakimovski, Jens Kuhle, Jesper Hagemeier, Osman Ozel, Murali Ramanathan, Christian Barro, Niels Bergsland, Davorka Tomic, Harald Kropshofer, et al.
Neurology - Neuroimmunology Neuroinflammation, Volume 7; doi:10.1212/nxi.0000000000000737

Abstract:
ObjectiveTo study the association between serum neurofilament light chain (sNfL) and multiple optical coherence tomography (OCT) measures in patients with MS and healthy controls (HCs).MethodsIn this prospective study, 110 patients with MS were recruited, together with 52 age- and sex-matched HCs. Clinical evaluation and spectral domain OCT and sNfL were obtained at baseline and after 5.5 years of follow-up. Nested linear mixed models were used to assess differences between MS vs HC and associations between sNfL and OCT measures. Partial correlation coefficients are reported, and p values were adjusted for the false discovery rate.ResultsAt baseline, peripapillary retinal nerve fiber layer thickness (pRNFLT) and macular ganglion cell and inner plexiform layer thickness (mGCIP) were significantly lower in MS than HC both in MS-associated optic neuritis (MSON) (p = 0.007, p = 0.001) and nonaffected MSON (n-MSON) eyes (p = 0.003, p = 0.018), along with total macular volume (TMV) in n-MSON eyes (p = 0.011). At follow-up, MS showed significantly lower pRNFLT, mGCIP, and TMV both in MSON and n-MSON eyes (p < 0.001) compared with HC. In MS n-MSON eyes, sNfL was significantly associated with baseline pRNFLT and mGCIP (q = 0.019). No significant associations were found in MSON eyes.ConclusionsThis study confirms the ability of sNfL to detect neurodegeneration in MS and advocates for the inclusion of sNfL and OCT measures in clinical trials.Classification of evidenceThis study provides Class III evidence that sNfL levels were associated with MS neurodegeneration measured by OCT.
Joseph R. Berger, Rachel Brandstadter, Amit Bar-Or
Neurology - Neuroimmunology Neuroinflammation, Volume 7; doi:10.1212/nxi.0000000000000761

Abstract:
ObjectiveTo address concerns regarding the effect of MS disease-modifying therapies (DMTs) on the expression of coronavirus 2019 (COVID-19).MethodsReview of the current state of knowledge regarding the viral etiology of COVID-19, mechanisms of injury by SARS-CoV-2 infection, and the effect of individual DMTs on the risk of infection and COVID-19 disease expression.ResultsAlthough data are limited, MS DMTs do not obviously increase the risk of acquiring symptomatic SARS-CoV-2 infection. The severe morbidity and mortality of SARS-CoV-2 appear to be largely the consequence of an overly robust immune response rather than the consequence of unchecked viral replication. The effects of specific MS DMTs on the immune response that may increase the risk of impaired viral clearance and their potential counterbalancing beneficial effects on the development of COVID-19–associated acute respiratory distress syndrome are reviewed.ConclusionAlthough there is currently insufficient real-world experience to definitively answer the question of the effect of a specific MS DMT on COVID-19, registries presently in nascent form should provide these answers. This review provides an approach to addressing these concerns while the data are being accumulated. Early insights suggest that the risk of infection and associated morbidity of COVID-19 in this population is little different than that of the population at large.
Jennifer Lord, M. Mateo Paz Soldan, Jonathan Galli, Karen L. Salzman, Jacob Kresser, Rae Bacharach, L. Dana DeWitt, Julia Klein, John Rose, John Greenlee, et al.
Neurology - Neuroimmunology Neuroinflammation, Volume 7; doi:10.1212/nxi.0000000000000743

Abstract:
ObjectiveTo characterize patients with neurosarcoidosis within the University of Utah healthcare system, including demographics, clinical characteristics, treatment, and long-term outcomes.MethodsWe describe the clinical features and outcomes of patients with neurosarcoidosis within the University of Utah healthcare system (a large referral center for 10% of the continental United States by land mass). Patients were selected who met the following criteria: (1) at least one International Classification of Diseases Clinical Modification, 9th revision code 135 or International Classification of Diseases Clinical Modification, 10th revision code D86* (sarcoidosis) and (2) at least one outpatient visit with a University of Utah clinician in the Neurology Department within the University of Utah electronic health record.ResultsWe identified 56 patients meeting the study criteria. Thirty-five patients (63%) were women, and most patients (84%) were white. Twelve patients (22%) met the criteria for definite neurosarcoidosis, 36 patients (64%) were diagnosed with probable neurosarcoidosis, and 8 patients (14%) were diagnosed with possible neurosarcoidosis. A total of 8 medications were used for the treatment of neurosarcoidosis. Prednisone was the first-line treatment in 51 patients (91%). Infliximab was the most effective therapy, with 87% of patients remaining stable or improving on infliximab. Treatment response for methotrexate and azathioprine was mixed, and mycophenolate mofetil and rituximab were the least effective treatments in this cohort.ConclusionsThis is a comprehensive characterization of neurosarcoidosis within a single healthcare system at the University of Utah that reports long-term response to treatment and outcomes of patients with neurosarcoidosis. Our results suggest the use of infliximab as a first-line therapy for neurosarcoidosis.
Marie-Christine Reinert, Pascal Benkert, Jens Wuerfel, Zuzanna Michalak, Esther Ruberte, Christian Barro, Peter Huppke, Wiebke Stark, Harald Kropshofer, Davorka Tomic, et al.
Neurology - Neuroimmunology Neuroinflammation, Volume 7; doi:10.1212/nxi.0000000000000749

Abstract:
ObjectiveTo investigate serum neurofilament light chain (sNfL) as a potential biomarker for disease activity and treatment response in pediatric patients with multiple sclerosis (MS).MethodsIn this retrospective cohort study, sNfL levels were measured in a pediatric MS cohort (n = 55, follow-up 12–105 months) and in a non-neurologic pediatric control cohort (n = 301) using a high-sensitivity single-molecule array assay. Association of sNfL levels and treatment and clinical and MRI parameters were calculated.ResultsUntreated patients had higher sNfL levels than controls (median 19.0 vs 4.6 pg/mL; CI [4.732, 6.911]), p < 0.001). sNfL levels were significantly associated with MRI activity (+9.1% per contrast-enhancing lesion, CI [1.045, 1.138], p < 0.001; +0.6% per T2-weighted lesion, CI [1.001, 1.010], p = 0.015). Higher values were associated with a relapse p < 0.001) and a higher Expanded Disability Status Scale score (CI [1.001, 1.240], p = 0.048). In patients treated with interferon beta-1a/b (n = 27), sNfL levels declined from 14.7 to 7.9 pg/mL after 6 ± 2 months (CI [0.339, 0.603], p < 0.001). Patients with insufficient control of clinical or MRI disease activity under treatment with interferon beta-1a/b or glatiramer acetate who switched to fingolimod (n = 18) showed a reduction of sNfL levels from 16.5 to 10.0 pg/mL 6 ± 2 months after switch (CI [0.481, 0.701], p < 0.001).ConclusionssNfL is a useful biomarker for monitoring disease activity and treatment response in pediatric MS. It is most likely helpful to predict disease severity and to guide treatment decisions in patients with pediatric MS. This study provides Class III evidence that sNfL levels are associated with disease activity in pediatric MS.
Carolin Otto, Oliver Wengert, Nadine Unterwalder, Christian Meisel, Klemens Ruprecht
Neurology - Neuroimmunology Neuroinflammation, Volume 7; doi:10.1212/nxi.0000000000000725

Abstract:
ObjectiveTo systematically analyze soluble interleukin-2 receptor (sIL-2R) in CSF as a diagnostic and disease activity biomarker in patients with sarcoidosis involving the CNS (neurosarcoidosis).MethodssIL-2R was determined by chemiluminescent immunoassays in CSF/serum samples from patients with neurosarcoidosis (n = 23), MS (n = 19), neurotuberculosis (n = 8), viral (n = 18) and bacterial (n = 9) meningitis, cerebral lymphoma (n = 15), Guillain-Barré syndrome (n = 8), and 115 patients with noninflammatory neurologic diseases (NINDs) as controls. The sIL-2R index was calculated by dividing the CSF/serum sIL-2R quotient (QsIL-2R) through the CSF/serum albumin quotient (QAlb). sIL-2R quotient diagrams were established by plotting QsIL-2R against QAlb. sIL-2R levels were correlated with clinical, MRI, and CSF disease activity markers of neurosarcoidosis.ResultsPatients with neurosarcoidosis had higher CSF sIL-2R, QsIL-2R, and sIL-2R index values than patients with NINDs (p < 0.0001 for all pairwise group comparisons). sIL-2R quotient diagrams demonstrated an intrathecal sIL-2R synthesis in >50% of neurosarcoidosis samples. Similar findings were observed in viral/bacterial meningitis, CNS lymphoma, and, most pronounced, in neurotuberculosis, but not in patients with MS. CSF sIL-2R parameters were associated with clinical disease activity, leptomeningeal gadolinium enhancement, and the CSF white cell count in patients with neurosarcoidosis.ConclusionsCSF sIL-2R parameters are elevated in patients with neurosarcoidosis, but this finding is not specific for neurosarcoidosis. Nevertheless, CSF sIL-2R parameters may help distinguishing neurosarcoidosis from MS and are associated with clinical, radiologic, and CSF disease activity markers of neurosarcoidosis.Classification of evidenceThis study provides Class II evidence that CSF sIL-2R parameters distinguish neurosarcoidosis from NINDs and MS.
Gemma C. Howdle, Yann Quidé, Mustafa S. Kassem, Kate Johnson, Caroline D. Rae, Bruce J. Brew, Lucette A. Cysique
Neurology - Neuroimmunology Neuroinflammation, Volume 7; doi:10.1212/nxi.0000000000000739

Abstract:
ObjectiveTo determine whether virally suppressed HIV neuropathogenesis, a chronic neuroinflammatory state, promotes abnormal brain amyloid deposition.MethodsA total of 10 men with virally suppressed HIV-associated neurocognitive disorder (HAND), aged 46–68 years, underwent 11C-labeled Pittsburgh compound B PET. Data from the Australian Imaging, Biomarkers and Lifestyle (AIBL), including 39 cognitively normal individuals (aged 60–74 years), 7 individuals with mild cognitive impairment (MCI) (aged 64–71 years), and 11 individuals with Alzheimer disease (AD) (aged 55–74 years), were used as reference. Apart from more women, the AIBL cohort was demographically comparable with the HIV sample. Also, the AIBL PET data did not differ by sex. Cerebellum standardized uptake value ratio amyloid values within 22 regions of interest were estimated. In the HIV sample, apolipoprotein E (APOE) was available in 80%, CSF biomarkers in 60%, and 8–10 years of long-term health outcomes in 100%.ResultsHAND and the AIBL group with no cognitive deficits had similar amyloid deposition, which was lower than that in both the MCI and AD groups. At the individual level, one HAND case showed high amyloid deposition consistent with AD. This case also had a CSF-AD–like profile and an E4/E4 for APOE. Clinically, this case declined over 18 years with mild HAND symptoms first, followed by progressive memory decline 8–9 years after the study PET, then progression to severe dementia within 2–3 years, and lived a further 6 years. Another HAND case showed increased amyloid deposition restricted to the hippocampi. Two other HAND cases showed abnormally decreased amyloid in subcortical areas.ConclusionsRelative to cognitively normal older controls, brain amyloid burden does not differ in virally suppressed HAND at the group level. However, individual analyses show that abnormally high and low amyloid burden occur.
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