Vitamin D3 mediates spatial memory improvement through nitric oxide mechanism in demyelinated hippocampus of rat

Abstract Studies have revealed beneficial role of vitamin D3 in neuro-cognitive function. There is also supporting evidence on the involvement of nitric oxide (NO) in the neuro-protective action. However, its over production could contribute to brain disorders. In this study, demyelination was induced by ethidium bromide (EB) injection into the right side of the hippocampus area of male rats. Vitamin D3 was administered to rats for 7 and 28 days prior to behavioral experiments using Morris water maze (MWM). Travelled distance, time spent to reach the platform, and time spent in target zone, were considered for learning and spatial memory evaluation. Nitrite oxide (NO2-) concentration was measured as an indicator for nitric oxide production. The time spent to reach the platform and the travelled distance were decreased significantly by 28 days of vitamin D3 administration (compared to 7 days experiment). Time spent in target quadrant was significantly lowered by administered vitamin on day 28. Therefore, considering a number of studies that have shown the effect of vitamin D3 on cognition, these findings could support their potential effect. Besides, nitric oxide concentration significantly differed in 28 days of vitamin D3 treated group compared with the groups treated with EB or 7 days of vitamin D3.

Comparison of Spinal Cord Magnetic Resonance Imaging Features Among Children With Acquired Demyelinating Syndromes.

Importance: The recognition of magnetic resonance imaging (MRI) features associated with distinct causes of myelitis in children is essential to guide investigations and support diagnostic categorization. Objective: To determine the clinical and MRI features and outcomes associated with spinal cord involvement in pediatric myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), multiple sclerosis (MS), and seronegative monophasic myelitis. Design, Setting, and Participants: In this cohort study, participants were recruited between 2004 and 2017 through the multicenter Canadian Pediatric Demyelinating Disease Study, which enrolled youth younger than 18 years presenting within 90 days of an acquired demyelinating syndrome. Of the 430 participants recruited, those with lesions on available spine MRI and anti-MOG testing performed on archived samples obtained close to clinical presentation were selected. Participants with poor-quality images and final diagnoses of nondemyelinating disease, anti-aquaporin 4 antibody positivity, and relapsing seronegative myelitis were excluded. Data analysis was performed from December 2019 to November 2020. Main Outcomes and Measures: Spinal cord involvement was evaluated on 324 MRI sequences, with reviewers blinded to clinical, serological, and brain MRI findings. Associated clinical features and disability scores at 5 years of follow-up were retrieved. Results were compared between groups. Results: A total of 107 participants (median [IQR] age at onset, 11.14 [5.59-13.39] years; 55 girls [51%]) were included in the analyses; 40 children had MOGAD, 21 had MS, and 46 had seronegative myelitis. Longitudinally extensive lesions were very common among children with MOGAD (30 of 40 children [75%]), less common among those with seronegative myelitis (20 of 46 children [43%]), and rare in children with MS (1 of 21 children [5%]). Axial gray matter T2-hyperintensity (ie, the H-sign) was observed in 22 of 35 children (63%) with MOGAD, in 14 of 42 children (33%) with seronegative myelitis, and in none of those with MS. The presence of leptomeningeal enhancement was highly suggestive for MOGAD (22 of 32 children [69%] with MOGAD vs 10 of 38 children [26%] with seronegative myelitis and 1 of 15 children [7%] with MS). Children with MOGAD were more likely to have complete lesion resolution on serial images (14 of 21 children [67%]) compared with those with MS (0 of 13 children). Conclusions and Relevance: These findings suggest that several features may help identify children at presentation who are more likely to have myelitis associated with MOGAD. Prominent involvement of gray matter and leptomeningeal enhancement are common in pediatric MOGAD, although the pathological underpinning of these observations requires further study.

Schwann Cell and the Pathogenesis of Charcot-Marie-Tooth Disease.

Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy and genetically heterogeneous. CMT1 and CMTX are autosomal dominant and X-linked demyelinating neuropathies, respectively. CMT1A, CMT1B, and CMTX1 are the common forms of CMT, which are attributed to the genes encoding the myelin or gap junction proteins expressed in the myelinating Schwann cells. CMT4 is a rare autosomal recessive demyelinating neuropathy that usually shows an early-onset severe phenotype. Twelve genes have been described as CMT4, which encodes many kinds of proteins including mitochondrial proteins, phosphatases in the endosomal pathway, endocytic recycling proteins, and trafficking proteins. The genes responsible for CMT4 are expressed in Schwan cells and necessary for the development and maintenance in the peripheral nervous system. However, CMT1, CMT4, and CMTX1 are primarily demyelinating neuropathies, axonal degeneration is necessary for symptoms to develop. Schwann cell-axon interactions are impaired in the pathogenesis of demyelinating CMT.

Atypical inflammatory demyelinating lesions and atypical multiple sclerosis.

Atypical idiopathic inflammatory demyelinating disorders (IIDDs) of the brain have long been known to be disorders closely related to multiple sclerosis (MS), despite having distinctive clinical and radiological characteristics. Originally, they mostly corresponded to acute-onset variants of MS that classically had poor prognoses, such as Baló's concentric sclerosis, Marburg variant of MS and Schilder's disease, and their relationship with MS was based on their shared pathological findings and the co-occurrence of these variants in patients with typical MS. More recently, other atypical disorders, such as solitary sclerosis, have also been described as belonging to the MS spectrum, raising the question of their links with MS. Meanwhile, multiple MS mimics have been described and need to be considered in the differential diagnosis of MS. In addition, thorough characterization of these atypical entities, including advanced MRI and biological studies, is now warranted to further improve their management.

Classification and diagnostic criteria for demyelinating diseases of the central nervous system: Where do we stand today?

The diagnosis of multiple sclerosis (MS) and other demyelinating diseases of the central nervous system is challenging, and although the currently available biological and imaging tools offer considerable support to physicians, these tools often fail to provide a simple and final answer at the time of a first event. Thus, sets of diagnostic criteria have been published and tested on patient cohorts, and are now used in clinical trials and in daily clinical practice. These criteria have evolved over time to take into account physicians' and patients' needs, along with emerging paraclinical tests. The different presentations of MS have given rise to the use of a common classification system to identify patient profiles and adapt care protocols accordingly. This article reviews the various classifications of the forms and diagnostic criteria of MS and related syndromes, including neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSDs), acute disseminated (demyelinating) encephalomyelitis (ADEM) and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Also discussed is their validity in the light of the currently available literature.

Clinically isolated syndromes or clinically isolated patients? A patient and clinician perspective on the utility of CIS as a diagnosis.

BACKGROUND: The term "Clinically Isolated Syndrome" (CIS) was introduced to describe a first clinical neurologic episode suggestive of an inflammatory demyelinating CNS disorder. Thereafter, the risk of developing clinically definite multiple sclerosis ranges from 20% to 80%, depending on a number of prognostic factors. Although the concept of CIS has been an important component in improving our understanding of risk levels in Multiple Sclerosis and prognosis, communicating uncertainty in this context remains a challenge for both patients and their clinicians. We therefore wished to explore both the patients understanding of the concept of CIS and the subsequent impact of a diagnosis. We also explored the concept of CIS from the clinician's perspective. METHODS: The study uses a qualitative descriptive design involving both a semi-structured interview of patients with CIS as well as a short questionnaire sent to practising clinicians in the Republic of Ireland. Narrative data was coded onto themes. RESULTS: Thirty CIS patients were interviewed. The majority of patients understood the term "CIS" but not the link between CIS and MS. Two themes were identified: emotional reactions following CIS diagnosis; and terminology and communication. Confusion and anxiety among patients due to inconsistent communication of CIS was identified. Of the thirty-three clinicians surveyed, only thirty-nine per cent found the term "CIS" clinically useful. Eighteen per cent of clinicians diagnosed MS from the CIS case vignette provided. CONCLUSION: In the diagnosis of a first demyelinating event, use of the term "CIS" is confusing to patients and inconsistent among clinicians. We suggest that the term "CIS" be abandoned in favour of terminology that reflects both its pathogenesis and inherent risk of subsequent MS.

Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms.

Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic resonance imaging pattern recognition and next generation sequencing. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin- or oligodendrocyte-specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels. We here propose a novel classification of leukodystrophies that takes into account the primary involvement of any white matter component. Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin (hypomyelinating and demyelinating leukodystrophies, leukodystrophies with myelin vacuolization); astrocytopathies; leuko-axonopathies; microgliopathies; and leuko-vasculopathies. Following this classification, we illustrate the neuropathology and disease mechanisms of some leukodystrophies taken as example for each category. Some leukodystrophies fall into more than one category. Given the complex molecular and cellular interplay underlying white matter pathology, recognition of the cellular pathology behind a disease becomes crucial in addressing possible treatment strategies.

Central and peripheral nervous system immune-mediated demyelinating disease after allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: We aimed to evaluate clinical and diagnostic features of central and peripheral immune-mediated demyelinating disease (CPID) in allogeneic hematopoietic stem cell transplantation (aHSCT) recipients. BACKGROUND: CPID refers to the late-onset, immune-mediated neurological complications following aHSCT, when other frequent differential diagnoses have been ruled out, and when symptoms and signs of systemic GvHD manifestations are absent. METHODS: Case records at the University of Tuebingen, between 2001 and 2015, were screened to identify patients with CPID after aHSCT. RESULTS: Seven patients who developed CPID after aHSCT were identified. The average time interval from aHSCT until onset of CPID was 2.6 (±2.8) years (mean±SD). The most prevalent manifestations of CPID were optic neuritis and/or myelitis and polyneuropathy. Cerebrospinal fluid analyses involved elevated protein concentration and lymphocytic pleocytosis, while oligoclonal bands in CSF, but not in serum, were detected in 28% of cases. Aquaporin-4-antibodies were consistently absent. MRI studies showed features suggestive of demyelination processes, with cerebral and/or spinal cord white-matter involvement, and features compatible with cerebral vasculitis. Corticosteroids, Immunoglobulins, Cyclophosphamide, Rituximab and Interferon beta-1a showed marginal treatment responses, whereas plasma exchange resulted in marked clinical improvement in two treated patients. A chronic disease-course with persisting neurological deficits was prevalent. CONCLUSIONS: CPID may comprise a rare complication of aHSCT, which manifests as optic neuritis and/or myelitis and is accompanied by sensorimotor polyneuropathy. A concomitant systemic manifestation of GvHD is not mandatory for CPID diagnosis. Usually, CPID exhibits a chronic, persisting disease course. Thus, clinical awareness is required, as early diagnosis and aggressive treatment may be prognostically advantageous.

Childhood leukodystrophies: A literature review of updates on new definitions, classification, diagnostic approach and management.

Childhood leukodystrophies are a growing category of neurological disorders in pediatric neurology practice. With the help of new advanced genetic studies such as whole exome sequencing (WES) and whole genome sequencing (WGS), the list of childhood heritable white matter disorders has been increased to more than one hundred disorders. During the last three decades, the basic concepts and definitions, classification, diagnostic approach and medical management of these disorders much have changed. Pattern recognition based on brain magnetic resonance imaging (MRI), has played an important role in this process. We reviewed the last Global Leukodystrophy Initiative (GLIA) expert opinions in definition, new classification, diagnostic approach and medical management including emerging treatments for pediatric leukodystrophies.

A nationwide survey of pediatric acquired demyelinating syndromes in Japan.

OBJECTIVE: To investigate the clinical and epidemiologic features of pediatric acquired demyelinating syndromes (ADS) of the CNS in Japan. METHODS: We conducted a nationwide survey and collected clinical data on children with ADS aged 15 years or younger, who visited hospitals between 2005 and 2007. RESULTS: Among 977 hospitals enrolled, 723 (74.0%) responded to our inquiries and reported a total of 439 patients as follows: 244 with acute disseminated encephalomyelitis (ADEM), 117 with multiple sclerosis (MS), 14 with neuromyelitis optica (NMO), and 64 with other ADS. We collected and analyzed detailed data from 204 cases, including those with ADEM (66), MS (58), and NMO (10). We observed the following: (1) the estimated annual incidence rate of pediatric ADEM in Japan was 0.40 per 100,000 children (95% confidence interval [CI], 0.34-0.46), with the lowest prevalence in the north; (2) the estimated prevalence rate of MS was 0.69 per 100,000 children (95% CI, 0.58-0.80), with the lowest prevalence in the south; (3) NMO in Japan was rare, with an estimated prevalence of 0.06 per 100,000 children (95% CI, 0.04-0.08); and (4) the sex ratio and mean age at onset varied by ADS type, and (5) male/female ratios correlated with ages at onset in each ADS group. CONCLUSIONS: Our results clarify the characteristic clinical features of pediatric ADS in the Japanese population.

Interleukin 17 alone is not a discriminant biomarker in early demyelinating spectrum disorders.

BACKGROUND: Radiologically isolated syndrome (RIS) is a sub clinical demyelinating neurological disorder and to date no biomarker that triggers the seminal event has been identified. As for multiple sclerosis (MS), disease activity and clinical course are unpredictable. In MS, exploratory studies reported increased IL-17 levels in CSF but results in detecting IL-17 in serum at different stage of the disease are controversial. OBJECTIVES: We investigate levels of IL-17 in serum and CSF in patients diagnosed at different stages of demyelinating diseases (RIS, CIS, relapsing remitting (RR) or active multiple sclerosis patients:AMS) as a marker of inflammatory condition. METHODS: 1417 sera has been tested for IL-17A (1177 from active MS, 80 RRMS, 35 RIS, 35 CIS, 10 IIH: idiopathic intracranial hypertension, and 80 controls) and 240 CSF from RIS, CIS, IIH and controls. RESULTS: No difference has been found between RIS who early clinically converted and CIS patients who rapidly evolve in McDonald or clinically definite MS, nor active MS. No correlation was found with usual MRI or CSF criteria. CONCLUSION: Our results do not confirm that IL-17 can be considerate as a reliable marker of inflammation in the demyelinating spectrum disorders, either in blood or CSF.

Differential diagnosis and evaluation in pediatric inflammatory demyelinating disorders.

Major advances have been made in the clinical and radiologic characterization of children presenting with the different forms of an acquired inflammatory demyelinating syndrome (ADS) such as acute disseminating encephalomyelitis, neuromyelitis optica spectrum disorders, and clinically isolated syndromes. Nevertheless, a proportion of cases that present with similar symptoms are due to a broad spectrum of other inflammatory disorders affecting the white matter, primary CNS tumors, or neurometabolic diseases. The clinician therefore has to be aware of the different forms of ADS, the risk factors for a chronic-relapsing course, and features that indicate an alternative diagnosis. The goal of this article is therefore to provide an outline of a pathway for evaluating pediatric patients with a presumed inflammatory demyelinating disorder and discussing the spectrum of the more common differential diagnoses.

A Novel Approach to Discriminate Subgroups in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of central nervous system. Since different types of immune cells are involved in MS pathogenesis, in this study we aimed to evaluate serum levels of several immunological components including soluble CD4 (sCD4), sCD8, sCD163, and immunoglobulins as markers of activity of T-cells, macrophages, and B-cells in different types of MS. Serum levels of sCD4, sCD8, and sCD163 of patients with relapsing-remitting MS (RRMS, n=61), primary progressive MS (PRMS, n=31), secondary progressive MS (SPMS, n=31), clinical isolated syndrome (CIS, n=31) and neuromyelitis optica (NMO, n=31), and healthy controls (n=49) were measured using enzyme-linked immunosorbent assay (ELISA). Serum levels of Ig-G, Ig-M, and Ig-A were determined using nephelometric technique. Serum levels of sCD4, sCD8, sCD163, Ig-G, Ig-M, and Ig-A were significantly different in five groups of cases (p<0.05). Furthermore, application of stepwise method of discriminant analysis yielded 4 significant discriminant functions of classification due to the presence of six levels of categorical variables in the analysis. The most important function explained 85.5% of the total variance with the correlation value of 0.79. Taken together, our preliminary analysis suggests that although we found some functions to discriminate most of the patients, further studies will be required to individuate immunological markers characterizing the different type of MS including RRMS, PPMS, SPMS, CIS and NMO as proved by the data on sCD4, sCD163, Ig-M, and Ig-G in blood.

Case definition and classification of leukodystrophies and leukoencephalopathies.

OBJECTIVE: An approved definition of the term leukodystrophy does not currently exist. The lack of a precise case definition hampers efforts to study the epidemiology and the relevance of genetic white matter disorders to public health. METHOD: Thirteen experts at multiple institutions participated in iterative consensus building surveys to achieve definition and classification of disorders as leukodystrophies using a modified Delphi approach. RESULTS: A case definition for the leukodystrophies was achieved, and a total of 30 disorders were classified under this definition. In addition, a separate set of disorders with heritable white matter abnormalities but not meeting criteria for leukodystrophy, due to presumed primary neuronal involvement and prominent systemic manifestations, was classified as genetic leukoencephalopathies (gLE). INTERPRETATION: A case definition of leukodystrophies and classification of heritable white matter disorders will permit more detailed epidemiologic studies of these disorders.

Demyelinating CMT--what's known, what's new and what's in store?

Inherited neuropathies known collectively as Charcot-Marie-Tooth disease are one of the most common inherited neurological conditions affecting ∼1 in 2500 people. A heterogenous disorder, CMT is divided into subtypes based on the pattern of inheritance and also by neurophysiological studies. Despite the clinical similarities among patients with demyelinating CMT, it is recognized that this group of disorders is both genetically and phenotypically heterogenous. Understanding the pathogenesis of these disorders requires an intimate knowledge of normal myelin development and homeostasis. Improvements in genetic testing techniques over the last 20 years have contributed majorly to the identification of specific genes, proteins, and molecular pathways that are providing the basis for understanding the disease processes and developing rational approaches to therapy.

Adult-onset leukodystrophy: review of 3 clinicopathologic phenotypes and a proposed classification.

Adult-onset leukodystrophies are clinically and pathologically heterogeneous diseases, and the overlapping morphologic features among these disorders can lead to confusion in pathologic classification. We report 3 recent autopsy cases that illustrate the clinicopathologic distinction between the 3 entities. The first, autosomal dominant leukodystrophy, is characterized clinically by early autonomic dysfunction and genetically by LMNB1 (lamin B1 gene) duplication. Recently, another clinical subtype emerged without the early autonomic dysfunction but with a similar genetic abnormality documented in 1 family. We reviewed the reported autopsy cases and show that both clinical subtypes share distinctive pathologic features. Other forms of adult-onset leukodystrophy can be classified based on the histologic evidence of the primary pathologic processes. A case of axonopathy with secondary demyelination serves as a prototype for adult-onset leukoencephalopathy/leukodystrophy with axonal spheroids; the genetic mutation of CSF1R (colony stimulating factor 1R) was recently discovered in patients with this disorder. A case of a primary demyelinating disease with no other distinctive pathologic features is designated as orthochromatic leukodystrophy. Pigmented glia can be present in both of the latter two categories and should not be used as a differentiating diagnostic feature. Based on the observations of our cases and literature review, we propose an algorithm for a practical diagnostic approach to adult-onset leukodystrophies.

Sensory Guillain-Barré syndrome and related disorders: an attempt at systematization.

The possibility that some patients diagnosed with an acute sensory neuropathy could actually have Guillain-Barré syndrome (GBS) has been repeatedly advanced in the literature, but the number of cases reported is small. The reports have shown different clinical presentations and electrophysiological findings and are variously named, thus generating terminological and nosological confusion. We operatively defined sensory GBS as an acute, monophasic, widespread neuropathy characterized clinically by exclusive sensory symptoms and signs that reach their nadir in a maximum of 6 weeks without related systemic disorders and other diseases or conditions. We reviewed the literature through searches of PubMed from 1980 to March 2011 and our own files. On the basis of the size of fibers involved and the possible site of primary damage, we propose tentatively classifying sensory GBS and related disorders into three subtypes: acute sensory demyelinating polyneuropathy; acute sensory large-fiber axonopathy-ganglionopathy; and acute sensory small-fiber neuropathy-ganglionopathy.