The impact of HLA-DRB1 alleles in a Hellenic, Pediatric-Onset Multiple Sclerosis cohort: Implications on clinical and neuroimaging profile.

BACKGROUND: Pediatric-Onset Multiple Sclerosis (POMS) is considered a complex disease entity and several genetic, hormonal, and environmental factors have been associated with disease pathogenesis. Linkage studies in Caucasians have consistently suggested the human leukocyte antigen (HLA) polymorphisms, as the genetic locus most strongly linked to MS, with the HLA-DRB1*15:01 allele, being associated with both adult and pediatric MS patients. Here we aim to investigate the prevalence of the HLA-DRB1 alleles among a Hellenic POMS cohort and any possible associations with clinical and imaging disease features. MATERIALS AND METHODS: 100 POMS patients fulfilling the IPMSSG criteria, 168 Adult-Onset MS (AOMS) patients, and 246 Healthy Controls (HCs) have been enrolled. HLA genotyping was performed with a standard low-resolution sequence-specific oligonucleotide (SSO) technique. RESULTS: POMS patients display a significantly increased HLA-DRB1*03 frequency compared to both HCs [24% vs. 12.6%, OR [95%CI]: 2.19 (1.21-3.97), p=0.016) and AOMS (24% vs. 13.1%, OR [95%CI]: 2.1 (1.1-3.98), p=0.034] respectively. HLA-DRB1*03-carriers display reduced risk for brainstem lesion development (OR [CI 95%]:0.19 (0.06-0.65), p=0.011). A significantly lower frequency of HLA-DRB1*07 (4% vs 13.4%, OR (95% CI): 0.27 (0.09-0.78), p= 0.017) and HLA-DRB1*11 (37% vs 52%, OR [95% CI]: 0.54 (0.34-0.87), p= 0.016) was observed in POMS compared to HCs. CONCLUSION: The HLA-DRB1*03 allele was associated with a higher risk for POMS, replicating our previous findings, and with a lower risk for brainstem lesion development, a common clinical and neuroimaging feature in POMS, while HLA-DRB1*07 and HLA-DRB1*11 display a protective role. These findings expand the existing knowledge of HLA associations and POMS.

Macrophages and HLA-Class II Alleles in Multiple Sclerosis: Insights in Therapeutic Dynamics.

Antigen presentation is a crucial mechanism that drives the T cell-mediated immune response and the development of Multiple Sclerosis (MS). Genetic alterations within the highly variable Major Histocompatibility Complex Class II (MHC II) have been proven to result in significant changes in the molecular basis of antigen presentation and the clinical course of patients with both Adult-Onset MS (AOMS) and Pediatric-Onset MS (POMS). Among the numerous polymorphisms of the Human Leucocyte Antigens (HLA), within MHC II complex, HLA-DRB1*15:01 has been labeled, in Caucasian ethnic groups, as a high-risk allele for MS due to the ability of its structure to increase affinity to Myelin Basic Protein (MBP) epitopes. This characteristic, among others, in the context of the trimolecular complex or immunological synapsis, provides the foundation for autoimmunity triggered by environmental or endogenous factors. As with all professional antigen presenting cells, macrophages are characterized by the expression of MHC II and are often implicated in the formation of MS lesions. Increased presence of M1 macrophages in MS patients has been associated both with progression and onset of the disease, each involving separate but similar mechanisms. In this critical narrative review, we focus on macrophages, discussing how HLA genetic alterations can promote dysregulation of this population's homeostasis in the periphery and the Central Nervous System (CNS). We also explore the potential interconnection in observed pathological macrophage mechanisms and the function of the diverse structure of HLA alleles in neurodegenerative CNS, seen in MS, by comparing available clinical with molecular data through the prism of HLA-immunogenetics. Finally, we discuss available and experimental pharmacological approaches for MS targeting the trimolecular complex that are based on cell phenotype modulation and HLA genotype involvement and try to reveal fertile ground for the potential development of novel drugs.

First-line disease modifying treatments in pediatric-onset multiple sclerosis in Greece: therapy initiation at more advanced age is the main cause of treatment failure, in a retrospective observational study, with a cohort from a single Multiple Sclerosis Center.

OBJECTIVES: Long-term immunomodulatory therapy of pediatric onset-multiple sclerosis (POMS) is based mainly on published case series and internationally agreed guidelines. Relevant studies in the Greek population are absent from the literature. The purpose of this study is to present data on the efficacy and safety of the 1st line immunomodulatory drugs in the treatment of POMS patients. MATERIALS AND METHODS: The present study included 27 patients meeting the IPMSSG criteria for POMS and who are monitored at the outpatient clinic of the Multiple Sclerosis and Demyelinating Diseases Unit (MSDDU), of the 1st Neurological Department, University Hospital of Aeginition. All patients received 1st line immunomodulatory drugs as initial therapy. Clinical, laboratory, and imaging parameters of the disease were recorded before and after treatment. RESULTS: Post-treatment, a significant reduction of the relapse number (mean ± SD: 2.0 ± 1.0 vs 1.2 ± 1.6, p = 0.002), EDSS progression (mean ± SD: 1.5 ± 0.8 vs 0.9 ± 0.7, p = 0.005) and ARR (mean ± SD: 1.5 ± 0.7 vs 0.4 ± 0.5, p = 0.0001) was observed, while no changes were observed in the EDSS score, (mean ± SD: 1.8 ± 0.6 vs 1.9. 0.6, p = 0.60). Advanced age at treatment initiation increased the risk for drug discontinuation before 24 months of therapy (HR = 0.6, 95% CI (0.35-0.99), p = 0.04). CONCLUSIONS: Most pediatric patients are forced to switch to either more efficacious 1st line or 2nd line drugs. Additionally, our study suggests that older age at the time of the 1st line treatment initiation, contributes to earlier drug discontinuation.

Cortical involvement and leptomeningeal inflammation in myelin oligodendrocyte glycoprotein antibody disease: A three-dimensional fluid-attenuated inversion recovery MRI study.

BACKGROUND: Cortical demyelination and meningeal inflammation have been detected neuropathologically in multiple sclerosis (MS) and recently in myelin oligodendrocyte glycoprotein antibody disease (MOGAD). OBJECTIVES: To assess in vivo cortical and leptomeningeal involvement in MOGAD. METHODS: We prospectively evaluated 11 MOGAD and 12 relapsing-remitting MS (RRMS) patients combining three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) and 3D-T1-weighted (3D-T1w) sequences at 3-Tesla magnetic resonance imaging (MRI). Leptomeningeal contrast enhancement (LMCE) was assessed on 3D-FLAIR post-gadolinium (3D-FLAIRGd). Cerebral cortical lesions (CCLs) were classified as either intracortical-subpial (IC-SP) or leukocortical (LC). RESULTS: CCLs were present in 8/11 MOGAD and 12/12 RRMS patients, with the number of CCLs being significantly lower in MOGAD (median (interquartile range (IQR)) 3 (0.5-4) vs 12 (4.75-19), p = 0.0032). In MOGAD, IC-SP lesions were slightly more prevalent than LC lesions (2 (0-2.5) vs 1 (0-2), p = 0.6579); whereas in RRMS, IC-SP lesions were less prevalent than LC lesions (3.5 (2.75-5.5) vs 9 (2-12.75), p = 0.27). LMCE was observed in 3/11 MOGAD and 1/12 RRMS patients; MOGAD with LMCE showed an increased median number of CCLs compared with MOGAD without LMCE (8 (4-9) vs 2.5 (0.75-3.25), p = 0.34). No correlation was observed between MOGAD MRI findings and (a) MOGAD duration, (b) serum MOG-immunoglobulin G1 titers, and (c) oligoclonal band presence. CONCLUSION: We described cortical lesion topography and detected for the first time LMCE using 3D-FLAIRGd sequences in MOGAD patients.

Psychosocial and Trauma-Related Stress and Risk of Dementia: A Meta-Analytic Systematic Review of Longitudinal Studies.

Stress has deleterious effects on brain health and yet, the prognostic value of psychosocial stress regarding the most common types of dementias, including Alzheimer disease, is still unclear. The primary aim of this systematic review was to explore the association between psychosocial stress and late onset dementia. We classified 24articles from Medline, PsycINFO, CINAHL, and Web of Science, as pertaining toxic categories of psychosocial and trauma-related stress (low socio-economic status [SES] related inequalities, marital status, posttraumatic stress disorder, work stress, "vital exhaustion" [VE], and, combined stressors). Using the Quality of Prognosis Studies in Systematic Reviews tool, we judged the quality of evidence to be low. This systematic review provided some non-robust, yet suggestive evidence that the above psychosocial types of stress are associated with increased risk of dementia in later life. Future robust, longitudinal studies with repeated validated measures of psychosocial stress and dementiaare required to strengthen or refute these findings.

Fingolimod as a first- or second-line treatment in a mini-series of young Hellenic patients with adolescent-onset multiple sclerosis: focus on immunological data.

BACKGROUND: Pediatric onset multiple sclerosis(POMS) is characterized by a highly active profile, often warranting treatment with high efficacy disease-modulating therapies (DMTs). Fingolimod, an oral sphingosine-1-phosphate receptor modulator, is the first Food and Drug Administration (FDA)- and European Medicines Agency (EMA)-approved DMT for the treatment of POMS. OBJECT: Our aim is to present real-world data of seven fingolimod-treated POMS-patients, recruited in a single MS center in Greece. METHODS: Clinical and imaging/laboratory data from 7 Hellenic patients fulfilling the International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria for POMS diagnosis, who have received fingolimod treatment, were selected. Human leukocyte antigen (HLA) genotyping was performed with standard low-resolution sequence-specific oligonucleotide techniques. RESULTS: Three patients were treatment-naïve adolescents who received fingolimod as first-line treatment. Two experienced ongoing clinical and radiological disease activity and have been switched to natalizumab. The remaining cases were post-adolescent adults with POMS, where the vast majority experienced total/near-total disease remission. Fingolimod was generally well-tolerated. Two patients with high disease activity carried the HLA-DRB1*03 allele, while five patients were carriers of at least one of the HLA-DRB1*04, HLA-DRB1*13, and HLA-DRB1*14 alleles, which when not combined with HLA-DRB1*03 showed a trend towards a more favorable clinical course. Fingolimod responders showed a trend towards increased CD(16-56)+NK cell counts in immunophenotyping assays. CONCLUSIONS: Our preliminary results support that response of POMS patients to fingolimod may be partially dependent on age and previous DMT, with younger and treatment-naïve patients presenting worse outcomes. The role of immunogenetics and immunophenotyping in personalized treatment warrants investigation in larger and more diverse populations.

Myasthenia gravis, atypical polyneuropathy and multiple autoimmune phenomena in the same patient, with HLA-immunogenetic profile expectable for Greek chronic inflammatory demyelinating polyneuropathy: a case report.

PURPOSE: The comorbidity of myasthenia gravis (MG), with other autoimmune disorders like systemic lupus erythematosus (SLE), is relatively frequent but the co-occurrence with chronic inflammatory demyelinating polyneuropathy (CIDP) along with various autoimmune manifestations in the absence of thymoma is of extreme rarity. Our aim is to report a case of a woman who presented the concomitant appearance of MG, axonal sensory-motor polyneuropathy and hepatitis that may indicate an underlying pathogenetic link among the different autoimmune disorders. MATERIALS AND METHODS/RESULTS: We present a case of a 54-year-old woman, with a generalized MG and a chronic sensory-motor polyneuropathy, hypothyroidism, anaemia, hepatitis, livedo reticularis and facial flush, of assumed autoimmune background, like SLE, although with persistent negative ANA antibodies, from the beginning and through the whole following years. The Human Leukocyte Antigen (HLA)-DRB1 genotyping showed a profile of alleles (DRB1*11:01/11:04) compatible with CIDP of mainly female gender in Greece and frequencies close to those of Sjogren's syndrome and scleroderma's in the Greek population. The diagnostic problems, the atypical clinical, electrophysiological and immunological features are discussed, along with the rarity of the case, with this exceptional combination of autoimmune manifestations, which could be truly associated under the clinical umbrella of a systemic disease, like SLE. However, our patient did not ever fulfil the SLE criteria. CONCLUSIONS: To raise awareness among clinicians about the exceptional combination of autoimmune manifestations driven by a specific HLA background.

The mTOR Signaling Pathway in Multiple Sclerosis; from Animal Models to Human Data.

This article recapitulates the evidence on the role of mammalian targets of rapamycin (mTOR) complex pathways in multiple sclerosis (MS). Key biological processes that intersect with mTOR signaling cascades include autophagy, inflammasome activation, innate (e.g., microglial) and adaptive (B and T cell) immune responses, and axonal and neuronal toxicity/degeneration. There is robust evidence that mTOR inhibitors, such as rapamycin, ameliorate the clinical course of the animal model of MS, experimental autoimmune encephalomyelitis (EAE). New, evolving data unravel mechanisms underlying the therapeutic effect on EAE, which include balance among T-effector and T-regulatory cells, and mTOR effects on myeloid cell function, polarization, and antigen presentation, with relevance to MS pathogenesis. Radiologic and preliminary clinical data from a phase 2 randomized, controlled trial of temsirolimus (a rapamycin analogue) in MS show moderate efficacy, with significant adverse effects. Large clinical trials of indirect mTOR inhibitors (metformin) in MS are lacking; however, a smaller prospective, non-randomized study shows some potentially promising radiological results in combination with ex vivo beneficial effects on immune cells that might warrant further investigation. Importantly, the study of mTOR pathway contributions to autoimmune inflammatory demyelination and multiple sclerosis illustrates the difficulties in the clinical application of animal model results. Nevertheless, it is not inconceivable that targeting metabolism in the future with cell-selective mTOR inhibitors (compared to the broad inhibitors tried to date) could be developed to improve efficacy and reduce side effects.

Genes, brain dynamics and art: the genetic underpinnings of creativity in dancing, musicality and visual arts.

Creativity, art and artistic creation in music, dance and visual arts are brain activities specific to humans. Their genetic background remained unexplored for years, but many recent studies have uncovered significant associations with cognition-related genes and loci. These studies are summarized in the present article. Creativity is a trait with heavy genetic influences, which are also associated with mental disorders and altruism. Associated genes include dopaminergic, serotoninergic and other genes (a1-antitrypsin, neuregulin, Brain-derived neurotrophic factor). Music is another complex phenotype with important genetic background. Studies in musicians and their families have highlighted the contribution of loci (e.g., 4q22) and specific genes (vasopressin receptor 1α and serotonin transporter). The latter two are also associated with dancing. Although few studies have investigated visual arts, they appear to be influenced by genetic differences, which could explain the increased prevalence of synesthesia in artists and individuals with autism. Lastly, although genes play an important role in creativity and art, epigenetics and the environment should not be overlooked. The genetic exploration of artistic creativity may provide useful knowledge on cognition, behavior and brain function. It may also enable targeted and personalized art therapy in health and disease.

The role of melatonin in Multiple Sclerosis.

Melatonin is a neurohormone mainly produced by the pineal gland following a circadian rhythm. It is characterized as a pleiotropic factor because it not only regulates the wake-sleep rhythm but also exerts antinociceptive, antidepressant, anxiolytic, and immunomodulating properties. Recent studies suggest that dysregulation of melatonin secretion is associated with the pathogenesis of various autoimmune diseases, such as, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS). MS is an autoimmune disorder characterized by an abnormal immune response directed against the myelin sheath in the central nervous system, demyelination, oligodendrocyte death, and axonal degeneration. Recent evidence reveals that melatonin secretion is dysregulated in MS patients, suggesting that melatonin could be a potential target for therapeutic intervention. Here, we summarize the available literature regarding the role of melatonin in immune processes relevant for experimental autoimmune encephalomyelitis (EAE), MS, and the current clinical trials of melatonin supplementation in MS patients.

Recurrent myelitis and asymptomatic hypophysitis in IgG4-related disease: case-based review.

IgG4-related disease (IgG4-RD) is a disorder with various clinical manifestations. Central nervous system (CNS) involvement is well recognized, with hypertrophic pachymeningitis and hypophysitis being the most common manifestations. Spinal cord involvement is an extremely rare manifestation. We present the first case of an IgG4-RD patient with spinal cord parenchymal disease and concurrent hypophysitis. We review also the current literature about CNS parenchymal involvement in the context of IgG4-RD. A young female presented with clinical symptoms of myelitis. Cervical spinal cord magnetic resonance imaging (MRI) displayed features of longitudinally extensive transverse myelitis (LETM). Brain MRI showed a small number of high-intensity lesions in the deep white matter and enlargement of hypophysis with homogeneous gadolinium enhancement (asymptomatic hypophysitis). Diagnostic workup revealed elevated IgG4 serum levels (146 mg/dL). Our patient fulfilled the organ-specific diagnostic criteria of IgG4-hypophysitis. Treatment with intravenous glucocorticoids led to rapid clinical response, and to the substantial resolution of imaging findings. Azathioprine was used as a maintenance treatment. One relapse occurred 2 years after the initial diagnosis and patient was re-treated with glucocorticoids. Three years after relapse, patient is in remission with azathioprine. We present the first case of myelitis with radiological features of LETM associated with increased IgG4 serum levels and the simultaneous presence of asymptomatic IgG4-related hypophysitis.

New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disorder. Two forms are recognized, familial (FALS) that accounts for 5-10% of ALS cases, and sporadic (SALS) that accounts for the rest. Early diagnosis of ALS is important because it improves their therapeutic efficacy. Current diagnosis is based on clinical assessment and requires approximately 12 months, leading to a significant delay in drug administration. Therefore, new methods are required for the earlier diagnosis of ALS. Screening for pathogenic variants in known ALS-associated genes is already exploited as a diagnostic tool in ALS but cannot be applied for population-based screening. New circulating biomarkers (proteins or small molecules) are needed for initial screening, whereas specific diagnostic methods can be applied to confirm the presence of pathogenic variants in the selected population subgroup. Lipids appear as promising biomarkers for population-based screening and for monitoring disease progression. Genetic analysis can also assist in the prediction of disease progression by analyzing disease-modifying genes, for example, EPHA4 and CHGB. Furthermore, molecular diagnosis will aid the stratification of ALS patients for improved pharmacological approaches. Here, we discuss current and novel diagnostic strategies and how they can be applied to revolutionize the field of ALS molecular diagnosis.

X linked Charcot-Marie-Tooth disease and multiple sclerosis: emerging evidence for an association.

OBJECTIVE: X linked Charcot-Marie-Tooth disease (CMTX) is a hereditary neuropathy caused by mutations in GJB1 coding for connexin-32, a gap junction protein expressed in Schwann cells, but also found in oligodendrocytes. Four patients with CMTX developing central nervous system (CNS) demyelination compatible with multiple sclerosis (MS) have been individually published. We presently sought to systematically investigate the relationship between CMTX and MS. METHODS: Over 20 years, 70 consecutive patients (36 men) with GJB1 mutations were identified at our Neurogenetics Unit, Athens, Greece, and assessed for clinical features suggestive of MS. Additionally, 18 patients with CMTX without CNS symptoms and 18 matched controls underwent brain MRI to investigate incidental findings. Serum from patients with CMTX and MS was tested for CNS immunoreactivity. RESULTS: We identified three patients with CMTX who developed clinical features suggestive of inflammatory CNS demyelination fulfilling MS diagnostic criteria. The resulting 20-year MS incidence (4.3%) differed significantly from the highest background 20-year MS incidence ever reported from Greece (p=0.00039). The search for incidental brain MRI findings identified two CMTX cases (11%) with lesions suggestive of focal demyelination compared with 0 control. Moreover, 10 cases in the CMTX cohort had hyperintensity in the splenium of the corpus callosum compared with 0 control (p=0.0002). No specific CNS-reactive humoral factors were identified in patients with CMTX and MS. CONCLUSIONS: We have demonstrated a higher than expected frequency of MS in patients with CMTX and identified incidental focal demyelinating lesions on brain MRI in patients with CMTX without CNS symptoms. This provides circumstantial evidence for GJB1 mutations acting as a possible MS risk factor.

Determinants of stigma in a cohort of hellenic patients suffering from multiple sclerosis: a cross-sectional study.

BACKGROUND: Patients suffering from several neurologic disorders may bear the "stigma" of their disease, being disqualified from full social acceptance. Although stigma is considered to be present in Multiple Sclerosis (MS), the factors that influence its levels are ambiguous. Aim of our study was to examine, for the first time in the literature, the basic determinants of stigma in a Hellenic MS-patients cohort, as well as how stigma affects their Quality-of-Life (QoL) profiles. METHODS: Three hundred forty two patients were recruited in this study. Data collected concerned sociodemographic and disease-related variables, mental illness assessment, Multiple-Sclerosis-QoL-54 (MSQoL-54) and Stigma-Scale-for-Chronic-Illness-24 (SSCI-24) questionnaires. Potential determinants were evaluated with univariate statistical analyses for their contribution to total, internalized (inner-self derived) and externalized (society derived) stigma. Important findings were further evaluated on hierarchical regression models. RESULTS: Disability levels were found to be the most powerful predictor in all stigma categories, followed by the presence of mental illness. Working and caregiving status were also ascertained as determinants of internalized stigma. Stigma levels displayed strong negative correlation with all composites of MSQoL-54. CONCLUSIONS: Stigma is present in the social environment of MS patients and was confirmed as a barrier (according to the International Classification of Functioning, Disability and Health), with detrimental effects on their QoL levels and functioning performances. Disability and mental illness were shown as the principal determinants of stigma, while financial characteristics were not as equally involved. Further validation of these results in other MS populations may provide safer conclusions, towards more efficacious patient-centered care outcomes.

Clinical and cognitive implications of cerebrospinal fluid oligoclonal bands in multiple sclerosis patients.

The presence of cerebrospinal fluid oligoclonal bands (CSF-OCB) in Caucasian patients with multiple sclerosis (MS) is supportive of diagnosis, though the relation with patients' clinical and specifically cognitive features has never been established or thoroughly examined. Thus, we investigated the clinical and for the first time the cognitive profile of MS patients in relation to CSF-OCB. We studied 108 patients with and without OCB and recorded demographic characteristics and detailed clinical data. A comprehensive neuropsychological battery covering different cognitive domains (attention/processing speed, memory, perception/constructions, reasoning, executive functions) was administered to MS patients and 142 demographically related healthy controls (HC). We did not find any significant differences between patients with and without OCB on demographic and clinical parameters (p > 0.05), including subtype and brain neuroimaging findings. Results revealed significantly higher cognitive scores in HC compared to both OCB subgroups, with more widespread cognitive changes in patients with OCB. Analysis between OCB subgroups showed significantly worse performance in patients with OCB on visual memory (Rey's complex figure test-recall; p = 0.006). Concluding, the presence of CSF-OCB in our MS patients tends to be related to more widespread cognitive changes, specifically worse visual memory. Future longitudinal studies in different populations are warranted to better clarify the clinical and cognitive characteristics related to CSF-OCB which could serve as early biomarker in disease monitoring.

Assessing the Impact of the Mindfulness-Based Body Scan Technique on Sleep Quality in Multiple Sclerosis Using Objective and Subjective Assessment Tools: Single-Case Study.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system, often leading to poor sleep quality and diminished quality of life (QoL) for affected patients. Sleep disturbances in MS do not always correlate linearly with other symptoms such as anxiety, depression, fatigue, or pain. Various approaches, including stress reduction techniques such as mindfulness-based interventions, have been proposed to manage MS-related sleep issues. OBJECTIVE: The aim of this study was to evaluate the effects of the mindfulness-based body scan technique on sleep quality and QoL in patients with MS using both subjective (questionnaires) and objective (electronic portable device) measures. METHODS: A single-case study was performed involving a 31-year-old woman diagnosed with relapsing-remitting MS. The patient practiced the mindfulness-based body scan technique daily before bedtime and outcomes were compared to measures evaluated at baseline. RESULTS: The mindfulness-based body scan intervention demonstrated positive effects on both sleep quality and overall QoL. Biometric data revealed a notable dissociation between daily stress levels and sleep quality during the intervention period. Although self-report instruments indicated significant improvement, potential biases were noted. CONCLUSIONS: While this study is limited to a single patient, the promising outcomes suggest the need for further investigation on a larger scale. These findings underscore the potential benefits of the mindfulness-based body scan technique in managing sleep disturbances and enhancing QoL among patients with MS.

Implication of Apolipoprotein E gene variants in pediatric-onset multiple sclerosis: Possible association with disease susceptibility and its clinical characteristics, in a Hellenic cohort.

BACKGROUND: Apolipoprotein E (ApoE) plays a major role in lipid homeostasis and myelination in the central nervous system. Although ApoE gene variants have been linked with cognitive impairment in the setting of Multiple sclerosis (MS), no association with disease susceptibility was found, while similar studies in pediatric-onset MS (POMS) are limited. OBJECTIVE: This study aims to explore the role of ApoE gene variants in the POMS susceptibility of a Hellenic cohort and any association with disease features. METHODS: 112 POMS, fulfilling the revised IPMSSG 2013 criteria, 391 adult-onset MS (AOMS) and 200 healthy controls (HCs), were enrolled. After DNA extraction, ApoE genotyping was performed by a polymerase chain reaction and sequence-specific-oligonucleotide technique. RESULTS: ApoE2/E3 genotype and ApoE2 allele were found to be significantly more frequent among POMS patients compared to HCs [(20.5% vs 11 %, OR [95 %]: 2.1 (1.1-4.0), p = 0.03)], and [(11% vs 5.3 %, OR [95 %]: 2.3 (1.2-4.1), p = 0.01)], respectively. Additionally, significantly lower frequencies of the ApoE3/E3 genotype and the ApoE3 allele were observed in POMS patients compared to HCs (59.8% vs 79 %, OR [95 %]:0.40 (0.24-0.65), p = 0.0005 and 79% vs 89 % 0.46, OR [95 %]: (0.30-0.73), p = 0.001)], respectively. CONCLUSIONS: The ApoE2 allele may represent a novel risk factor for POMS development.

Myelin Oligodendrocyte Glycoprotein Antibody Disease (MOGAD)-Monophasic Optic Neuritis and Epstein-Barr Virus (EBV): A Case Report of Rare Comorbid Diagnoses in an Adolescent From a Remote Greek Island.

A unique case of a female adolescent diagnosed with myelin oligodendrocyte glycoprotein (MOG) monophasic optic neuritis with Epstein-Barr virus (EBV) reactivation antibody profile on a remote Greek island is presented, highlighting the challenges of diagnosing rare conditions in rural settings and the importance of connecting centers of expertise with regional hospitals. The 16-year-old patient presented with progressive vision loss, headache, and retrobulbar pain in the right eye. Initial ophthalmological examinations showed decreased visual acuity and color vision deterioration. Magnetic resonance imaging (MRI) revealed optic perineuritis and edema. Cerebrospinal fluid (CSF) analysis excluded oligoclonal bands, and blood analysis was positive for both anti-MOG antibodies and EBV reactivation. Expert opinion and blood immunophenotyping confirmed the neuroimmunological condition. This case not only underscores the value of telemedicine in overcoming diagnostic challenges in rural settings but also contributes to the scientific discussion on neuroimmunological aspects and the potential role of EBV as an underlying factor in acquired demyelinating syndromes (ADS), beyond multiple sclerosis (MS).