AIF translocation into nucleus caused by Aifm1 R450Q mutation: generation and characterization of a mouse model for AUNX1.

Mutations in AIFM1, encoding for apoptosis-inducing factor (AIF), cause AUNX1, an X-linked neurologic disorder with late-onset auditory neuropathy (AN) and peripheral neuropathy. Despite significant research on AIF, there are limited animal models with the disrupted AIFM1 representing the corresponding phenotype of human AUNX1, characterized by late-onset hearing loss and impaired auditory pathways. Here, we generated an Aifm1 p.R450Q knock-in mouse model (KI) based on the human AIFM1 p.R451Q mutation. Hemizygote KI male mice exhibited progressive hearing loss from P30 onward, with greater severity at P60 and stabilization until P210. Additionally, muscle atrophy was observed at P210. These phenotypic changes were accompanied by a gradual reduction in the number of spiral ganglion neuron cells (SGNs) at P30 and ribbons at P60, which coincided with the translocation of AIF into the nucleus starting from P21 and P30, respectively. The SGNs of KI mice at P210 displayed loss of cytomembrane integrity, abnormal nuclear morphology, and dendritic and axonal demyelination. Furthermore, the inner hair cells and myelin sheath displayed abnormal mitochondrial morphology, while fibroblasts from KI mice showed impaired mitochondrial function. In conclusion, we successfully generated a mouse model recapitulating AUNX1. Our findings indicate that disruption of Aifm1 induced the nuclear translocation of AIF, resulting in the impairment in the auditory pathway.

Transforming growth factor-ß1 protects against white matter injury and reactive astrogliosis via the p38 MAPK pathway in rodent demyelinating model.

In central nervous system (CNS), demyelination is a pathological process featured with a loss of myelin sheaths around axons, which is responsible for the diseases of multiple sclerosis, neuromyelitis optica, and so on. Transforming growth factor-beta1 (TGF-ß1) is a multifunctional cytokine participating in abundant physiological and pathological processes in CNS. However, the effects of TGF-ß1 on CNS demyelinating disease and its underlying mechanisms are controversial and not well understood. Herein, we evaluated the protective potential of TGF-ß1 in a rodent demyelinating model established by lysophosphatidylcholine (LPC) injection. It was identified that supplement of TGF-ß1 evidently rescued the cognitive deficit and motor dysfunction in LPC modeling mice assessed by novel object recognition and balance beam behavioral tests. Besides, quantified by luxol fast blue staining, immunofluorescence, and western blot, administration of TGF-ß1 was found to significantly ameliorate the demyelinating lesion and reactive astrogliosis by suppressing p38 MAPK pathway. Mechanistically, the results of in vitro experiments indicated that treatment of TGF-ß1 could directly promote the differentiation and migration of cultured oligodendrocytes. Our study revealed that modulating TGF-ß1 activity might serve as a promising and innovative therapeutic strategy in CNS demyelinating diseases.

Microglia-derived exosomes modulate myelin regeneration via miR-615-5p/MYRF axis.

Demyelination and failure of remyelination in the central nervous system (CNS) characterize a number of neurological disorders. Spontaneous remyelination in demyelinating diseases is limited, as oligodendrocyte precursor cells (OPCs), which are often present in demyelinated lesions in abundance, mostly fail to differentiate into oligodendrocytes, the myelinating cells in the CNS. In addition to OPCs, the lesions are assembled numbers of activated resident microglia/infiltrated macrophages; however, the mechanisms and potential role of interactions between the microglia/macrophages and OPCs are poorly understood. Here, we generated a transcriptional profile of exosomes from activated microglia, and found that miR-615-5p was elevated. miR-615-5p bound to 3'UTR of myelin regulator factor (MYRF), a crucial myelination transcription factor expressed in oligodendrocyte lineage cells. Mechanistically, exosomes from activated microglia transferred miR-615-5p to OPCs, which directly bound to MYRF and inhibited OPC maturation. Furthermore, an effect of AAV expressing miR-615-5p sponge in microglia was tested in experimental autoimmune encephalomyelitis (EAE) and cuprizone (CPZ)-induced demyelination model, the classical mouse models of multiple sclerosis. miR-615-5p sponge effectively alleviated disease progression and promoted remyelination. This study identifies miR-615-5p/MYRF as a new target for the therapy of demyelinating diseases.

Myelin oligodendrocyte glycoprotein antibody and N-methyl-d-aspartate receptor antibody overlapping syndrome: insights from the recent case reports.

The overlapping of two or more types of neural autoantibodies in one patient has increasingly been documented in recent years. The coexistence of myelin oligodendrocyte glycoprotein (MOG) and N-methyl-d-aspartate receptor (NMDAR) antibodies is most common, which leads to a unique condition known as the MOG antibody and NMDAR antibody overlapping syndrome (MNOS). Here, we have reviewed the pathogenesis, clinical manifestations, paraclinical features, and treatment of MNOS. Forty-nine patients with MNOS were included in this study. They were young males with a median onset age of 23 years. No tumors were observed in the patients, and 24 of them reported prodromal symptoms. The most common clinical presentations were psychiatric symptoms (35/49) and seizures (25/49). Abnormalities on magnetic resonance imaging involved the brainstem (11/49), cerebellum (9/49), and parietal lobe (9/49). Most patients mostly responded to immunotherapy and had a good long-term prognosis. However, the overall recurrence rate of MNOS was higher than that of mono antibody-positive diseases. The existence of concurrent NMDAR antibodies should be suspected in patients with MOG antibody-associated disease having psychiatric symptoms, seizures, movement disorders, or autonomic dysfunction. Similarly, serum MOG antibody testing should be performed when patients with anti-NMDAR encephalitis present with atypical clinical manifestations, such as visual impairment and limb weakness, and neuroradiological findings, such as optic nerve, spinal cord, or infratentorial involvement or meningeal enhancement. Early detection of the syndrome and prompt treatment can be beneficial for these patients, and maintenance immunosuppressive therapy is recommended due to the high overall recurrence rate of the syndrome.

Identifying high-risk neurological phenotypes in adult-onset classic monogenic autoinflammatory diseases: when should neurologists consider testing?

BACKGROUND: Monogenic autoinflammatory disorders result in a diverse range of neurological symptoms in adults, often leading to diagnostic delays. Despite the significance of early detection for effective treatment, the neurological manifestations of these disorders remain inadequately recognized. METHODS: We conducted a systematic review searching Pubmed, Embase and Scopus for case reports and case series related to neurological manifestations in adult-onset monogenic autoinflammatory diseases. Selection criteria focused on the four most relevant adult-onset autoinflammatory diseases-deficiency of deaminase 2 (DADA2), tumor necrosis factor receptor associated periodic fever syndrome (TRAPS), cryopyrin associated periodic fever syndrome (CAPS), and familial mediterranean fever (FMF). We extracted clinical, laboratory and radiological features to propose the most common neurological phenotypes. RESULTS: From 276 records, 28 articles were included. The median patient age was 38, with neurological symptoms appearing after a median disease duration of 5 years. Headaches, cranial nerve dysfunction, seizures, and focal neurological deficits were prevalent. Predominant phenotypes included stroke for DADA2 patients, demyelinating lesions and meningitis for FMF, and meningitis for CAPS. TRAPS had insufficient data for adequate phenotype characterization. CONCLUSION: Neurologists should be proactive in diagnosing monogenic autoinflammatory diseases in young adults showcasing clinical and laboratory indications of inflammation, especially when symptoms align with recurrent or chronic meningitis, small vessel disease strokes, and demyelinating lesions.

Intranasal Resveratrol Nanoparticles Enhance Neuroprotection in a Model of Multiple Sclerosis.

PURPOSE: Resveratrol is a natural polyphenol which has a very low bioavailability but whose antioxidant, anti-inflammatory and anti-apoptotic properties may have therapeutic potential for the treatment of neurodegenerative diseases such as multiple sclerosis (MS). Previously, we reported the oral administration of resveratrol nanoparticles (RNs) elicited a neuroprotective effect in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS, at significantly lower doses than unconjugated resveratrol (RSV) due to enhanced bioavailability. Furthermore, we demonstrated that the intranasal administration of a cell-derived secretome-based therapy at low concentrations leads to the selective neuroprotection of the optic nerve in EAE mice. The current study sought to assess the potential selective efficacy of lower concentrations of intranasal RNs for attenuating optic nerve damage in EAE mice. METHODS: EAE mice received either a daily intranasal vehicle, RNs or unconjugated resveratrol (RSV) for a period of thirty days beginning on the day of EAE induction. Mice were assessed daily for limb paralysis and weekly for visual function using the optokinetic response (OKR) by observers masked to treatment regimes. After sacrifice at day 30, spinal cords and optic nerves were stained to assess inflammation and demyelination, and retinas were immunostained to quantify retinal ganglion cell (RGC) survival. RESULTS: Intranasal RNs significantly increased RGC survival at half the dose previously shown to be required when given orally, reducing the risk of systemic side effects associated with prolonged use. Both intranasal RSV and RN therapies enhanced RGC survival trends, however, only the effects of intranasal RNs were significant. RGC loss was prevented even in the presence of inflammatory and demyelinating changes induced by EAE in optic nerves. CONCLUSIONS: The intranasal administration of RNs is able to reduce RGC loss independent of the inflammatory and demyelinating effects on the optic nerve and the spinal cord. The concentration of RNs needed to achieve neuroprotection is lower than previously demonstrated with oral administration, suggesting intranasal drug delivery combined with nanoparticle conjugation warrants further exploration as a potential neuroprotective strategy for the treatment of optic neuritis, alone as well as in combination with glucocorticoids.

MRI Markers of Degenerative Disc Disease in Young Patients With Multiple Sclerosis.

Background and Purpose: Evidence has emerged for an association between degenerative disc disease (DDD) and multiple sclerosis (MS). The purpose of the current study is to determine the presence and extent of cervical DDD in young patients (age <35) with MS, an age cohort that is less well studied for these changes. Methods: Retrospective chart review of consecutive patients aged <35 referred from the local MS clinic who were MRI scanned between May 2005 and November 2014. 80 patients (51 female and 29 male) with MS of any type ranging between 16 and 32 years of age (average 26) were included. Images were reviewed by 3 raters and assessed for presence and extent of DDD, as well as cord signal abnormalities. Interrater agreement was assessed using Kendall's W and Fleiss' Kappa statistics. Results: Substantial to very good interrater agreement was observed using our novel DDD grading scale. At least some degree of DDD was found in over 91% of patients. The majority scored mild (grade 1, 30-49%) to moderate (grade 2, 39-51%) degenerative changes. Cord signal abnormality was seen in 56-63%. Cord signal abnormality, when present, occurred exclusively at degenerative disc levels in only 10-15%, significantly lower than other distributions (P < .001 for all pairwise comparisons). Conclusions: MS patients demonstrate unexpected cervical DDD even at a young age. Future study is warranted to investigate the underlying etiology, such as altered biomechanics. Furthermore, cord lesions were found to occur independently of DDD.

Glial progenitor cell-based repair of the dysmyelinated brain: Progression to the clinic.

Demyelinating disorders of the central white matter are among the most prevalent and disabling conditions in neurology. Since myelin-producing oligodendrocytes comprise the principal cell type deficient or lost in these conditions, their replacement by new cells generated from transplanted bipotential oligodendrocyte-astrocyte progenitor cells has emerged as a therapeutic strategy for a variety of primary dysmyelinating diseases. In this review, we summarize the research and clinical considerations supporting current efforts to bring this treatment approach to patients.

AXL+SIGLEC6+ dendritic cells in cerebrospinal fluid and brain tissues of patients with autoimmune inflammatory demyelinating disease of CNS.

Inflammatory demyelinating disease of the CNS (IDD) is a heterogeneous group of autoimmune diseases, and multiple sclerosis is the most common type. Dendritic cells (DCs), major antigen-presenting cells, have been proposed to play a central role in the pathogenesis of IDD. The AXL+SIGLEC6+ DC (ASDC) has been only recently identified in humans and has a high capability of T cell activation. Nevertheless, its contribution to CNS autoimmunity remains still obscure. Here, we aimed to identify the ASDC in diverse sample types from IDD patients and experimental autoimmune encephalomyelitis (EAE). A detailed analysis of DC subpopulations using single-cell transcriptomics for the paired cerebrospinal fluid (CSF) and blood samples of IDD patients (total n = 9) revealed that three subtypes of DCs (ASDCs, ACY3+ DCs, and LAMP3+ DCs) were overrepresented in CSF compared with their paired blood. Among these DCs, ASDCs were also more abundant in CSF of IDD patients than in controls, manifesting poly-adhesional and stimulatory characteristics. In the brain biopsied tissues of IDD patients, obtained at the acute attack of disease, ASDC were also frequently found in close contact with T cells. Lastly, the frequency of ASDC was found to be temporally more abundant in acute attack of disease both in CSF samples of IDD patients and in tissues of EAE, an animal model for CNS autoimmunity. Our analysis suggests that the ASDC might be involved in the pathogenesis of CNS autoimmunity.

Distinct features of B cell receptors in neuromyelitis optica spectrum disorder among CNS inflammatory demyelinating diseases.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) stands out among CNS inflammatory demyelinating diseases (CIDDs) due to its unique disease characteristics, including severe clinical attacks with extensive lesions and its association with systemic autoimmune diseases. We aimed to investigate whether characteristics of B cell receptors (BCRs) differ between NMOSD and other CIDDs using high-throughput sequencing. METHODS: From a prospective cohort, we recruited patients with CIDDs and categorized them based on the presence and type of autoantibodies: NMOSD with anti-aquaporin-4 antibodies, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) with anti-myelin oligodendrocyte glycoprotein antibodies, double-seronegative demyelinating disease (DSN), and healthy controls (HCs). The BCR features, including isotype class, clonality, somatic hypermutation (SHM), and the third complementarity-determining region (CDR3) length, were analyzed and compared among the different disease groups. RESULTS: Blood samples from 33 patients with CIDDs (13 NMOSD, 12 MOGAD, and 8 DSN) and 34 HCs were investigated for BCR sequencing. Patients with NMOSD tended to have more activated BCR features compare to the other disease groups. They showed a lower proportion of unswitched isotypes (IgM and IgD) and a higher proportion of switched isotypes (IgG), increased clonality of BCRs, higher rates of SHM, and shorter lengths of CDR3. Notably, advanced age was identified as a clinical factor associated with these activated BCR features, including increased levels of clonality and SHM rates in the NMOSD group. Conversely, no such clinical factors were found to be associated with activated BCR features in the other CIDD groups. CONCLUSIONS: NMOSD patients, among those with CIDDs, displayed the most pronounced B cell activation, characterized by higher levels of isotype class switching, clonality, SHM rates, and shorter CDR3 lengths. These findings suggest that B cell-mediated humoral immune responses and characteristics in NMOSD patients are distinct from those observed in the other CIDDs, including MOGAD. Age was identified as a clinical factor associated with BCR activation specifically in NMOSD, implying the significance of persistent B cell activation attributed to anti-aquaporin-4 antibodies, even in the absence of clinical relapses throughout an individual's lifetime.

Incidence and predictors of demyelinating disease in spondyloarthritis: data from a longitudinal cohort study.

OBJECTIVES: To investigate the incidence of demyelinating disease (DD) among spondyloarthritis (SpA) patients and identify risk factors that predict DD in this patient population. METHODS: Axial SpA (axSpA) and psoriatic arthritis (PsA) patients were identified from a longitudinal cohort database. Each group was analysed according to the presence or absence of DD. Incidence rates (IR) of DD were obtained with competing risk analysis. Cox regression analysis with Fine and Grey's method was used to evaluate predictors of DD development. RESULTS: Among 2260 patients with follow-up data, we identified 18 DD events corresponding to an average IR of 31 per 100 000 persons per year for SpA. The IR of DD at 20 years was higher in axSpA than in PsA (1.30% vs 0.13%, p= 0.01). The risk factors retained in the best predictive model for DD development included ever- (versus never-) smoking (HR 2.918, 95% CI 1.037-8.214, p= 0.0426), axSpA (versus PsA) (HR 8.790, 95% CI 1.242-62.182, p= 0.0294), and presence (versus absence) of IBD (HR 5.698, 95% CI 2.083-15.589, p= 0.0007). History of TNFi therapy was not a predictor of DD. CONCLUSION: The overall incidence of DD in this SpA cohort was low. Incident DD was higher in axSpA than in PsA. A diagnosis of axSpA, the presence of IBD, and ever-smoking predicted the development of DD. History of TNFi use was not found to be a predictor of DD in this cohort.

Progressive motor impairment from "critical" demyelinating lesions of the cervicomedullary junction.

BACKGROUND: Progressive motor impairment anatomically associated with a "critical" lesion has been described in primary demyelinating disease. Most "critical" lesions occur within the spinal cord. OBJECTIVE: To describe the clinical and radiological features of "critical" lesions of the cervicomedullary junction (CMJ). METHODS: Observational study on people presenting with a CMJ lesion associated with primary demyelinating disease-related progressive motor impairment. Clinical data were extracted by chart review. Brain and spinal cord magnetic resonance images were reviewed to characterize the CMJ lesion and determine additional demyelination burden. RESULTS: Forty-one people were included: 29 (71%) had progression from onset and 12 (29%) had a relapse onset (secondary progressive) course. Most had progressive hemiparesis (21 (51%)) or progressive quadriparesis (15 (37%)) with a median Expanded Disability Status Scale (EDSS) of 5.5 (2.0-8.5) at last follow-up. No "critical" CMJ lesion enhanced; most were bilateral (25 (61%)). Brain magnetic resonance images were otherwise normal in 16 (39%) or with a restricted demyelination burden in 15 (37%). Cervical and thoracic cord MRIs were without additional lesions in 25 (61%) and 22/37 (59%), respectively. CONCLUSION: CMJ "critical" lesions can correlate with progressive motor impairment even with few or no additional magnetic resonance imaging (MRI) lesions. Lesion location is an important determinant of progressive motor impairment in demyelinating disease.

Association between age and inflammatory disease activity on magnetic resonance imaging in relapse onset multiple sclerosis during long-term follow-up.

BACKGROUND AND PURPOSE: Inflammatory disease activity in multiple sclerosis (MS) decreases with advancing age. Previous work found a decrease in contrast-enhancing lesions (CELs) with age. Here, we describe the relation of age and magnetic resonance imaging (MRI) measures of inflammatory disease activity during long-term follow-up in a large real-world cohort of people with relapse onset MS. METHODS: We investigated MRI data from the long-term observational Amsterdam MS cohort. We used logistic regression models and negative binomial generalized estimating equations to investigate the associations between age and radiological disease activity after a first clinical event. RESULTS: We included 1063 participants and 10,651 cranial MRIs. Median follow-up time was 6.1 years (interquartile range = 2.4-10.9 years). Older participants had a significantly lower risk of CELs on baseline MRI (40-50 years vs. <40 years: odds ratio [OR] = 0.640, 95% confidence interval [CI] = 0.45-0.90; >50 years vs. <40 years: OR = 0.601, 95% CI = 0.33-1.08) and a lower risk of new T2 lesions or CELs during follow-up (40-50 years vs. <40 years: OR = 0.563, 95% CI = 0.47-0.67; >50 years vs. <40 years: OR = 0.486, 95% CI = 0.35-0.68). CONCLUSIONS: Greater age is associated with a lower risk of inflammatory MRI activity at baseline and during long-term follow-up. In patients aged >50 years, a less aggressive treatment strategy might be appropriate compared to younger patients.

Pediatric Multiple Sclerosis: Changing the Trajectory of Progression.

PURPOSE OF REVIEW: Multiple sclerosis is a chronic inflammatory disease of the central nervous system. When seen in children and adolescents, crucial stages of brain development and maturation may be affected. Prompt recognition of multiple sclerosis in this population is essential, as early intervention with disease-modifying therapies may change developmental trajectories associated with the disease. In this paper, we will review diagnostic criteria for pediatric multiple sclerosis, outcomes, differential diagnosis, and current therapeutic approaches. RECENT FINDINGS: Recent studies have demonstrated the utility of newer structural and functional metrics in facilitating early recognition and diagnosis of pediatric MS. Knowledge about disease-modifying therapies in pediatric multiple sclerosis has expanded in recent years: important developmental impacts of earlier therapeutic intervention and use of highly effective therapies have been demonstrated. Pediatric MS is characterized by highly active disease and high disease burden. Advances in knowledge have led to early identification, diagnosis, and treatment. Lifestyle-related interventions and higher efficacy therapies are currently undergoing investigation.

A Quality Assessment of Aquaporin-4 & Myelin Oligodendrocyte Glycoprotein Antibody Testing.

BACKGROUND: Accurate anti-aquaporin-4 (AQP4) and anti-myelin oligodendrocyte glycoprotein (MOG) autoantibody assays are needed to effectively diagnose neuromyelitis optica spectrum disorder and MOG antibody-associated disease. A proportion of patients at our centre have been tested for anti-AQP4 and anti-MOG autoantibodies locally, followed by an outsourced test as part of real-world practice. Outsourced testing is costly and of unproven utility. We conducted a quality improvement project to determine the value of outsourced testing for anti-AQP4 and anti-MOG autoantibodies. METHODS: All patients seen by Calgary neurological services who underwent cell-based testing for anti-AQP4 and/or anti-MOG autoantibodies at both MitogenDx (Calgary, AB) and Mayo Clinic Laboratories (Rochester, MN, USA) between 2016 and 2020 were identified from a provincial database. The interlaboratory concordance was calculated by pairing within-subject results collected no more than 365 days apart. Retrospective chart review was done for subjects with discordant results to determine features associated with discordance and use of outsourced testing. RESULTS: Fifty-seven anti-AQP4 and 46 anti-MOG test pairs from January 2016 to July 2020 were analyzed. Concordant tests pairs comprised 54/57 (94.7%, 95%CI 88.9-100.0%) anti-AQP4 and 41/46 (89.1%, 95%CI 80.1-98.1%) anti-MOG results. Discordant anti-AQP4 pairs included two local weak positives (negative when outsourced) and one local negative (positive when outsourced). Discordant anti-MOG pairs were all due to local weak positives (negative when outsourced). CONCLUSION: Interlaboratory discordant results for cell-based testing of anti-AQP4 autoantibodies were rare. Local anti-MOG weak positive results were associated with discordance, highlighting the need for cautious interpretation based on the clinical context. Our findings may reduce redundant outsourced testing.

Progressive multifocal leukoencephalopathy in multiple myeloma: a case report of a patient with SARS-CoV-2 infection and an updated systematic literature review.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by a reactivation of the human polyomavirus 2 (HPyV-2, previously known as JCV) in immunosuppressed individuals. Few cases of PML have been described in multiple myeloma (MM) patients. METHODS: We described a case of PML in a patient with MM with fatal worsening that occurred during SARS-CoV-2 infection. We also performed a literature review to update the 16 cases series of MM patients with PML already collected until April 2020. RESULTS: A 79-year-old female patient with refractory IgA lambda MM in Pomalidomide- Cyclophosphamide-Dexamethasone regimen developed gradual lower limbs and left arm paresis along with a decreased consciousness 3.5 years after the MM diagnosis. Symptoms developed shortly after the recognition of hypogammaglobulinemia. After SARS-CoV-2 infection, her neurological status quickly worsened until she deceased. MRI features and JCV-positive PCR on CSF confirmed the PML diagnosis. Our literature review adds sixteen clinical cases of PML in MM published between May 2020 and March 2023 to the 16 cases already collected in the previously published review by Koutsavlis. DISCUSSION: PML has been increasingly described in MM patients. It remains questionable if the HPyV-2 reactivation is determined by the severity of MM itself, by the effect of drugs or by a combination of both. SARS-CoV-2 infection may have a role in worsening PML in affected patients.

Dietary patterns and risk of multiple sclerosis: Results of a double-center case-control study in Iran.

Background: It has been suggested that nutrition might contribute to multiple sclerosis etiology (MS). Aim: This case-control study aimed to determine the role of food habits and dietary patterns in preventing or developing MS in a multicenter study in Iran (Tehran and Shiraz). Methods: In this study, food intake of (106 patients with relapsing/remitting MS (RRMS) and 72 healthy controls in Tehran) and (75 patients with relapsing/remitting MS (RRMS) and 72 healthy controls in Shiraz) were collected using a validated semi-quantitative food frequency questionnaire. Dietary patterns were extracted using factor analysis. The association between dietary patterns and the risk of MS was analyzed by Logistic regression. Results: Two major dietary patterns were extracted: the "healthy" and the "unhealthy" patterns. After adjustment for potential confounders, in Tehran city, subjects in the highest tertile of the unhealthy dietary pattern score had greater odds of having MS, compared with those in the lowest tertile (OR: 2.16; 95% CI: [1.95-2.41]; p for trend = 0.01). In Shiraz city, subjects in the highest tertile of the unhealthy dietary pattern score had greater odds with MS than those in the lowest tertile (OR: 3.08; 95% CI: [1.27-7.38]; p for trend = 0.01). However, in both groups, no significant association was found between healthy dietary pattern and MS risk. Conclusions: Adherence to unhealthy dietary pattern may increase the risk of MS in Iran. The results can be used for developing interventions that aim to promote healthy eating for preventing MS.

Identification of demyelinating lesions and application of McDonald criteria when confronted with white matter lesions on brain MRI.

INTRODUCTION: White matter lesions (WML) on magnetic resonance imaging (MRI) are common in clinical practice. When analyzing WML, radiologists sometimes propose a pathophysiological mechanism to explain the observed MRI abnormalities, which can be a source of anxiety for patients. In some cases, discordance may appear between the patient's clinical symptoms and the identification of the MRI-appearing WML, leading to extensive diagnostic work-up. To avoid misdiagnosis, the analysis of WML should be standardized, and a consensual MRI reading approach is needed. OBJECTIVE: To analyze the MRI WML identification process, associated diagnosis approach, and misinterpretations in physicians involved in WML routine practice. METHODS: Through a survey distributed online to practitioners involved in WML diagnostic work-up, we described the leading causes of MRI expertise misdiagnosis and associated factors: clinical experience, physicians' subspecialty and location of practice, and type of device used to complete the survey. The survey consisted of sixteen T2-weighted images MRI analysis, from which ten were guided (binary response to lesion location identification), four were not shown (multiple possible answers), and two were associated with dissemination in space (DIS) McDonald criteria application. Two independent, experienced practitioners determined the correct answers before the participants' completion. RESULTS: In total, 364 participants from the French Neuro Radiological (SFNR), French Neurological (SFN), and French Multiple Sclerosis (SFSEP) societies completed the survey entirely. According to lesion identification, 34.3% and 16.9% of the participants correctly identified juxtacortical and periventricular lesions, respectively, whereas 56.3% correctly identified non-guided lesions. Application of the 2017 McDonald's DIS criteria was correct for 35.3% of the participants. According to the global survey scoring, factors independently associated with correct answers in multivariate analysis were MS-expert subspecialty (P<0.001), young clinical practitioners (P=0.02), and the use of a computer instead of a smartphone to perform WML analysis (P=0.03). CONCLUSION: Our results highlight the difficulties regarding WML analysis in clinical practice and suggest that radiologists and neurologists should rely on each other to ensure the diagnosis of multiple sclerosis and related disorders and limit misdiagnoses.

Death following rapidly progressive demyelinating disorder in a young female-a case report.

Multiple sclerosis (MS) is a debilitating, demyelinating disease of the central nervous system, with manifestations ranging from numbness and blindness to paralysis. Typical MS is a slowly progressive demyelinating disease, causing significant morbidity spanning over many years. In contrast, "Marburg's disease" is a rare variant of MS which demonstrates a malignant monophasic disease progression leading to death within weeks to months. We present a rapidly fatal demyelinating disease with the clinicopathological findings on par with the handful of reported cases of "Marburg's disease" in the literature. A previously healthy 30-year-old mother of two children was extensively investigated for focal neurological signs succumbing to death 5 weeks after the onset. Antemortem investigations for tuberculosis, autoimmune diseases, and viral studies were negative. Magnetic resonance imaging of the brain showed hyperintense lesions with contrast enhancement compatible with MS. Histopathologic examination confirmed numerous inflammatory and demyelination foci scattered throughout the brain and brain stem predominantly involving the white matter. There were extensive perivascular inflammatory cell cuffs containing lymphocytes admixed with histiocytes. Also, a few foci of vasculitis with fibrinoid necrosis, mediated by lymphocytes and neutrophils were noted associated with parenchymal haemorrhages. Considered a rare variant of MS, the case of Marburg's disease presented here shows an infrequent association with active vasculitis and haemorrhage, described only a few times in the literature. This wide spectrum of rapidly fatal demyelinating diseases consisting of rare variants with overlapping clinicopathological features makes diagnosis challenging. Therefore, it is important to correlate clinical-radiological and histopathological findings to arrive at an accurate final diagnosis.

HIV-Associated Progressive Multifocal Leukoencephalopathy: A Case Study.

Progressive multifocal leukoencephalopathy (PML) is a rare, life-threatening, infectious, lytic, demyelinating disease that results from reactivation of the virulent JC polyomavirus (JCV) "major opportunistic infection" in immunosuppressed individuals. We reported a case of a young girl who presented with new onset focal neurological defect, evaluated, and laboratory and radiological findings in the context of a clinical setting confirmed HIV-related-PML infection. However, remyelination does not occur, the patients may develop complications in the long term including cognitive impairment, sensory deficits, motor deficits, and disturbances in balance. We must increase our knowledge about HIV- related PML in any patient with reduced immunity and who presented with new onset neurological defect.