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.

HLA-DPB1*03 as Risk Allele and HLA-DPB1*04 as Protective Allele for Both Early- and Adult-Onset Multiple Sclerosis in a Hellenic Cohort.

Background: Human Leucocyte Antigens (HLA) represent the genetic loci most strongly linked to Multiple Sclerosis (MS). Apart from HLA-DR and HLA-DQ, HLA-DP alleles have been previously studied regarding their role in MS pathogenesis, but to a much lesser extent. Our objective was to investigate the risk/resistance influence of HLA-DPB1 alleles in Hellenic patients with early- and adult-onset MS (EOMS/AOMS), and possible associations with the HLA-DRB1*15:01 risk allele. Methods: One hundred MS-patients (28 EOMS, 72 AOMS) fulfilling the McDonald-2010 criteria were enrolled. HLA genotyping was performed with standard low-resolution Sequence-Specific Oligonucleotide techniques. Demographics, clinical and laboratory data were statistically processed using well-defined parametric and nonparametric methods and the SPSSv22.0 software. Results: No significant HLA-DPB1 differences were found between EOMS and AOMS patients for 23 distinct HLA-DPB1 and 12 HLA-DRB1 alleles. The HLA-DPB1*03 allele frequency was found to be significantly increased, and the HLA-DPB1*02 allele frequency significantly decreased, in AOMS patients compared to controls. The HLA-DPB1*04 allele was to be found significantly decreased in AOMS and EOMS patients compared to controls. Conclusions: Our study supports the previously reported risk susceptibility role of the HLA-DPB1*03 allele in AOMS among Caucasians. Additionally, we report for the first time a protective role of the HLA-DPB1*04 allele among Hellenic patients with both EOMS and AOMS.

HLA-DRB1 differences in allelic distribution between familial and sporadic multiple sclerosis in a Hellenic cohort.

Objective: Familial Multiple Sclerosis (fMS) is reported to have distinct clinical and imaging characteristics in comparison to the sporadic disease (sMS). Nevertheless, the genetic/immunogenetic profile of fMS has never been investigated in depth, so far. In this study, we examined differences of HLA-DRB1 allelic frequencies between 57 fMS and 141 sMS Hellenic patients, with reference to 246 previously genotyped healthy controls (HCs). Patients and Methods: All patients underwent medical interview and DRB1 genotyping, using a low-resolution SSOP technique. Statistical analyses were performed using SPSS v.21.0 software, with significance set at 0.05, and p value corrected according to the Benjamini-Yekutieli method. Results: 29 fMS cases had at least one 1st degree relative affected (fMS 1st), while the rest had at least one 2nd or 3rd degree relative affected (fMS 2nd/3rd). Parent-of-origin effects were observed, with the prevalence of maternal inheritance. Frequency of DRB1*15 was significantly increased in fMS and sMS, in comparison to HCs (p = 0.002 and <0.001, respectively). After fMS stratification, this result was mainly attributed to the fMS 2nd/3rd subgroup. DRB1*11 frequency was significantly decreased only in sMS (p < 0.001) with fMS approximating HCs' frequency, especially for the fMS 1st subgroup. Heterozygosity was favored over homozygosity in all groups. Conclusion: We propose possible HLA-DRB1 allelic distribution differences between fMS and sMS, which become more apparent as proximity of affected relative/-es in fMS increases, supporting a rather degraded role of DRB1 alleles in fMS HLA/immunogenetics and indicating the concomitant implication of other HLA and non-HLA polymorphisms.

Familial multiple sclerosis in Greece: Distinct clinical and imaging characteristics in comparison with the sporadic disease.

OBJECTIVE: Few studies are available worldwide concerning clinical, imaging and genetic/immunogenetic profile of familial multiple sclerosis (fMS). Recent but not systematic data concerning fMS, without direct comparison to sporadic MS (sMS) drove our aim towards further research in the field, given the total lack of information for the Greek population as well. Thus, in this case-control study we examined the clinical and imaging characteristics of 102 fMS-patients, compared to 282 patients suffering sMS. PATIENTS AND METHODS: Patients recruited underwent medical interview (demographic, clinical and family history data collected). They were also assessed for disability and their MRI-scans were analyzed for lesion distribution. Statistical analyses were performed using SPSS v.21.0 software. RESULTS: 49% of unrelated fMS cases had at least one 1st degree relative affected, while the rest had also at least one relative with MS, 3rd degree or closer. Only the former subgroup (1st degree relative) and not the entire fMS sample, had significantly younger age at onset (AAO) compared to sMS cases (mean AAO 28.08 vs 31.33 years, p = 0.036). AAO anticipation was noted in younger generation fMS patients (mean AAO 24.67 years in younger generation vs 37 years in older generation, p = 0.001). With regard to our MRI findings, subcortical lesions were less frequent in fMS (71% in fMS vs 81.9% in sMS patients, p = 0.028), whereas cervical cord lesions more frequent (93% in fMS vs 79.9% in sMS patients, p = 0.033, only in the 1st degree relative subgroup). Double vision was a less common first symptom in fMS (4.1% in fMS vs 14.8% in sMS patients, p = 0.005). 1st degree relatives of fMS patients were more often diagnosed with Hashimoto's (8.9% in fMS relatives vs 3.3% in sMS relatives, p = 0.033). CONCLUSION: Younger AAO and different lesion distribution in brain and possibly spinal cord was observed in fMS in comparison to sMS patients. The hypothesis of increased genetic burden in fMS could offer some explanation for these differences, which needs though further validation as a next step, through genetic/immunogenetic testing in larger cohorts, of different ethnic groups.

Alemtuzumab as Treatment for Multiple Sclerosis.

Alemtuzumab, the first monoclonal antibody to be used as a therapy and the first to be humanized, was introduced into the treatment of multiple sclerosis in 1991 after its successful use in hematology, oncology, and transplantation medicine. One phase 2 and two phase 3 trials of this lymphocyte-depleting agent have established alemtuzumab's superior efficacy to interferon ß-1a over the short term (2-3 years) with greater relapse rate reduction, reduced accumulation of disability, and more frequent sustained improvement in disability. Longer-term extension studies show durable effects on slowing cerebral atrophy over 6 years and maintained low relapse rates over 10 years, despite roughly half of patients not needing further dosing. Homeostatic proliferation of residual T cells after alemtuzumab-induced lymphopenia is probably responsible for its most common side effects: secondary autoimmunity 1 or 2 years after the last infusion of alemtuzumab affecting the thyroid gland (30% of patients), platelets (1%), or renal glomeruli (0.1%). With the prerequisite of patient and physician adherence to a prolonged safety-monitoring protocol, alemtuzumab offers durable high efficacy from infrequent dosing.

Multiple Sclerosis and Subsequent Human Immunodeficiency Virus Infection: A Case with the Rare Comorbidity, Focus on Novel Treatment Issues and Review of the Literature.

BACKGROUND: The comorbidity between Multiple Sclerosis (MS) and Human Immunodeficiency Virus (HIV) infection is particularly rare. Only a few cases of comorbidity of Clinically Definite(CD)-MS and HIV have been documented worldwide, while the potential beneficial role of antiretroviral therapy regarding MS activity has long been an area of debate. CASE REPORT: We present a 36-year old male, bearing a diagnosis of CD-MS for twelve years. He had been treated for ten years with interferon-beta-1b, when he voluntarily discontinued therapy, claiming clinical stability. One year later he was diagnosed positive for HIV and he started and continued only on efavirenz/emricitabine/tenofovir-disoproxil fumarate (ATRIPLA®), remaining relapse-free until today. CONCLUSION: This fact, in combination with the unique pharmaceutical composition of the drug, which contains a component similar to a newly-approved agent for MS, dimethyl fumarate, prompted us to review the literature regarding this rare comorbidity and to suggest that the role of the antiretroviral therapy should be further explored in MS.

Predicting caregiving status and caregivers' burden in multiple sclerosis. A short report.

OBJECTIVES: Predicting caregiving status (CS) in multiple sclerosis (MS) is of both clinical and health policy-making value. The aim of this cross-sectional study was to assess the clinical predictors of CS, along with factors related to caregivers' stress. METHODS: A sample of 342 clinically definite MS patients (67.5% females, 67.8% relapsing MS, mean age 43.1 ± 11.4 year-old, mean disease duration 147 ± 105.4 months, median Expanded Disability Status Scale -EDSS-3.0) was screened for CS. The Multiple Sclerosis Quality of Life-54 and Zarit Burden Interview were used to measure quality of patients' life and the their caregivers' burden, respectively. RESULTS: In total, 57.9% of patients reported at least one caregiver, 97% of which were relatives or friends. Higher EDSS was associated with higher chance of reporting a caregiver. Two EDSS cut-offs were recognized; 2.0 and 4.5, the former with increased sensitivity (78.8%) and the latter with increased specificity (82.3%) to predict CS. Patients in the mild disability group (EDSS: 0-1.5) needing a caregiver had higher subjective cognitive function, implying presumably a beneficial role of care in cognition. Age and education were showed to affect CS in the moderate disability group (EDSS: 2.0-4.5). Physical and mental disability was more pronounced in patients reporting at least one caregiver in the high disability group (EDSS above 4.5). Caregivers' stress was significantly positively correlated with age, EDSS, and duration of the disease and negatively with cognitive, physical, and mental health. DISCUSSION: In conclusion, the clinical predictors of CS are known to serve well both the researchers and the clinicians.

Vertebral hemangiomas in the thoracic spine of multiple sclerosis patients are connected with fewer demyelinating lesions at the same level. Possible impact on pathophysiology and clinical course.

OBJECTIVES: Mechanisms of angiogenesis regulate multiple sclerosis (MS) lesions' evolution, displaying both neuroprotective and harmful effects. Factors traditionally considered as purely angiogenic, like vascular endothelial growth factor (VEGF), exert complex heterogenous actions on both neural and vascular malformation-derived tissues. Aim of this retrospective study was to examine, for the first time, potential associations between the presence of common vascular malformations, like vertebral hemangiomas (VHs), and several clinico-radiological MS parameters. METHODS: 236 MS patients who were followed in our Outpatient Clinic were recruited in this study. Outcome measures concerned demographics, disease-derived variables, and MS-lesions' distribution in VHs - positive and negative patients. All data were collected retrospectively. Potential correlations were assessed with univariate statistical analyses (p = 0.05), followed by multivariate regression models, for purposes of confounder-effects elimination. RESULTS: VH presence showed significant negative correlations with presence of MS lesions in the thoracic (p = 0.005 for thoracic VHs), but not the cervical cord. Trends towards negative associations of VH presence with subtentorial MS lesions and positive family history for MS were also observed. DISCUSSION: Our observations suggest that VH presence may reduce the risk of thoracic demyelinating lesions in MS patients. They could be explained as part of a multifaceted angiogenic process, concomitantly enhancing neural repair and abnormal hemangioma vascularization.

Cerebrospinal fluid analysis after unprovoked first seizure.

The aim of this study was to determine cerebrospinal fluid (CSF) characteristics after an unprovoked first seizure (UFS). We reviewed the medical records of 71 patients with UFS who underwent lumbar puncture, and examined the CSF parameters. Each CSF parameter was evaluated separately for potential correlations with the other study variables. We observed an overall frequency of CSF abnormalities of 35.2%. CSF protein was the most common abnormal parameter (31%) and showed significant positive correlations with male gender (p=0.037) and older age (p=0.007). Only seven patients (9.9%) had an abnormal cell count (5-40 cells/µl). Higher CSF cell counts were found to predict a longer hospitalization period (p=0.005). No relationship with abnormal EEG findings could be established (p=0.169). This study is one of the few to evaluate postictal CSF parameters in a clinical setting, and to our knowledge the first to investigate these parameters specifically in the emergency department. The development of a rapid, easy-to-use test that does not require extensive laboratory equipment to differentiate UFS from other conditions could be of great value in everyday clinical practice.

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 Imaging Correlations of Generalized Hypersynchronous Alpha Activity in Human EEG Recordings, During Alertness.

PURPOSE: In a considerable percentage of individuals with a detectable alpha rhythm in their EEG, bursts of generalized hypersynchronous alpha activity (GHSAA) may occur, during alertness. The aim of this study was to examine whether appearance of GHSAA, which probably generates from transcortical circuitry, shows any correlation with demographic characteristics, underlying normal or abnormal pathophysiology, or substances in use. METHODS: The authors retrospectively reviewed 441 EEG recordings performed in their laboratory during a 1-year period for presence of GHSAA, concomitantly collecting data that concerned symptoms, diagnosis, imaging, medication, and demographics. Recordings in mental states other than alertness were excluded from the sample. RESULTS: Generalized hypersynchronous alpha activity was found in 22.95% of the study population. Its occurrence was diminished in male gender (P < 0.001), older age (Kendall tau, 0.16; P < 0.0001), and disorders involving structural abnormalities like brain lesions or neurodegeneration (P < 0.02). Dementia, Parkinson disease, and psychoses showed individually a trend towards lower GHSAA presence. CONCLUSIONS: In the sample, the presence of GHSAA was commonly observed in the cohort of patients without abnormalities in their neuroimaging studies. Generalized hypersynchronous alpha activity is a finding of youth and requires a properly functioning cerebral cortex in order to emerge. Female preponderance may signify underlying trangender differences in alpha rhythm generators. These preliminary results indicate that the significance of GHSAA alterations deserves more thorough evaluation in larger groups of patients suffering from a variety of different neuropsychiatric disorders.

Effects of Wind Chill Factor, Temperature and Other Meteorological Parameters on the Incidence of Bell's Palsy: Results Based on a Retrospective, 7-Year Long, Greek Population Study.

BACKGROUND: The etiology of Bell's palsy (BP), the most common type of dysfunction of the facial nerve, remains unclear despite vigorous research. Data concerning the effects of meteorological factors (MFs) on its appearance are inconclusive. The aim of our study was to examine the demographics of a convenience sample of patients with BP and to determine the effects of several MFs in the recorded number of cases per month (cpm). METHODS: We retrospectively reviewed 568 files of BP patients and concomitant data of MFs during an 84-month observation period. Information collected included age, gender, diabetic status, number of cpm (months further categorized as winter or summer), mean daily and monthly temperatures and wind speeds and monthly values of wind chill factor (WCF), a measure dependent on both temperature and wind speed. Potential correlations were estimated by univariate analyses (p = 0.05). RESULTS: Demographics were in line with previous research regarding age and diabetic status, but indicative of slight male preponderance. Summer months and mean monthly temperatures showed significant negative correlations with cpm (p = 0.002 and <0.000, respectively) and strong positive correlation with WCF (p < 0.000). CONCLUSIONS: MFs can substantially influence the possibility for BP appearance. We propose WCF as a novel, reliable estimator of the overall MF-derived risk.

HLA-DRB1 15:01 and Epstein-Barr virus in a multiple sclerosis patient with psoriasis, nasopharyngeal and breast cancers. Lessons for possible hidden links for autoimmunity and cancer.

BACKGROUND: Multiple sclerosis (MS) patients have a low general cancer risk and cases of neoplastic comorbidity are attributed by many researchers in chance, or therapeutical side-effects. Human leucocyte antigen (HLA) class II allele DRB1 15:01 is considered the main genetic factor independently associated with increased susceptibility for MS in Caucasians. Epstein-Barr virus (EBV) has also been proven to be a core triggering factor in MS initiation and progress, mainly in HLA-DRB1 15:01 positive MS patients. CASE REPORT: We present an exceptional case of a Greek-origin woman, carrying a distinct immunogenetic profile (HLA-A 26:01-Cw 06:02-DRB1 15:01), which gradually developed psoriasis, nasopharyngeal carcinoma (NPC), MS, breast cancer, uterine leiomyoma and other neoplasms. DISCUSSION: EBV plays a fundamental role in the pathogenesis of both autoimmunity (i.e. MS) and cancer (i.e. NPC). Our patient's immunogenetic profile included HLA alleles which are associated with psoriasis (Cw 06:02), NPC (A 26:01), MS (DRB1 15:01) and increased risk of MS, in patients carrying EBV (DRB1 15:01). We made a targeted review of the literature finding data supporting an EBV-HLA interaction mechanism behind our patient's unique combination of disorders, suggesting that beyond the standard role of each factor, their combination could act as the hidden link, in initiation or/and comorbidity of autoimmunity and cancer.

Biomarkers in Multiple Sclerosis: An Up-to-Date Overview.

During the last decades, the effort of establishing satisfactory biomarkers for multiple sclerosis has been proven to be very difficult, due to the clinical and pathophysiological complexities of the disease. Recent knowledge acquired in the domains of genomics-immunogenetics and neuroimmunology, as well as the evolution in neuroimaging, has provided a whole new list of biomarkers. This variety, though, leads inevitably to confusion in the effort of decision making concerning strategic and individualized therapeutics. In this paper, our primary goal is to provide the reader with a list of the most important characteristics that a biomarker must possess in order to be considered as reliable. Additionally, up-to-date biomarkers are further divided into three subgroups, genetic-immunogenetic, laboratorial, and imaging. The most important representatives of each category are presented in the text and for the first time in a summarizing workable table, in a critical way, estimating their diagnostic potential and their efficacy to correlate with phenotypical expression, neuroinflammation, neurodegeneration, disability, and therapeutical response. Special attention is given to the "gold standards" of each category, like HLA-DRB1∗ polymorphisms, oligoclonal bands, vitamin D, and conventional and nonconventional imaging techniques. Moreover, not adequately established but quite promising, recently characterized biomarkers, like TOB-1 polymorphisms, are further discussed.