Adult-onset Multiple Sclerosis Patients Research Articles

Longitudinal Brain Volume Findings in an Outpatient Practice of Young People with MS (P11-3.001)

<h3>Objective:</h3> To assess in an outpatient setting the application of volumetrics with brain MRI among young people with multiple sclerosis (MS). <h3>Background:</h3> Research on brain atrophy in MS has illuminated how inflammation and neurodegenerative processes lead to cognitive and neurologic declines. However, brain volume assessment is rarely used in routine practice. Here, we examined predominantly pediatric onset MS and some younger adult-onset MS patients who underwent routine brain MRI including volumetrics. Our goal was to assess the impact of brain volume change on clinical outcomes including SDMT in this relatively young and stable MS subset. <h3>Design/Methods:</h3> 77 patients with pediatric or adult onset RRMS or CIS, 31 years of age or younger, were evaluated with at least two MRI studies. Volume data was computed on MRI images with icobrain ms software, compared to age- and sex-related norms and adjusted for differences across the various Siemens 3T scanners. Changes in volumes of whole brain (WB), white matter (WM), grey matter (GM), lateral ventricles (LV), and thalamus were calculated as an average annualized percent brain volume change per year. <h3>Results:</h3> The mean patient age was 21.6 years (range 12–31); 70% were female. The annual mean decrease of WB volume: −0.473%, WM: −0.390%, GM: −0.517%, thalamus: −0.552%, and annual LV volume increase: 1.78%. A total of 32.5% of patients had an annual decrease in GM volume &gt;0.8% (the 90% threshold for measurement error). 29.9% of patients had LV volumes increase &gt;3.5%. Whole brain volume loss and lateral ventricle increase was significantly correlated, r=−0.34 (p=0.002). Clinical and demographic features between those whose brain volume declined and those whose brain volumes remained stable will be presented. <h3>Conclusions:</h3> Quantitative MRI is a useful technique which has only begun to be incorporated into clinical practice. A proportion of young otherwise stable patients with RRMS show brain volume loss under computer-assisted analyses. <b>Disclosure:</b> Dr. O’Neill has nothing to disclose. Dr. Couvreur has received personal compensation in the range of $10,000-$49,999 for serving as a Intern Clinical application specialist at icometrix with The Prince Albert Fund. Dr. Hu has nothing to disclose. Mr. Zhang has nothing to disclose. Ms. Pehel has nothing to disclose. Ms. Sosa has nothing to disclose. Ms. Fade has nothing to disclose. Elayne Feld has nothing to disclose. Dr. Chen has received personal compensation for serving as an employee of icometrix. Dr. De Barros has received personal compensation for serving as an employee of Icometrix. Thibo Billiet has received personal compensation for serving as an employee of icometrix. Annemie Ribbens, 9599 has received personal compensation for serving as an employee of icometrix. Annemie Ribbens, 9599 has stock in icometrix. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gerson Lerhman. Dr. Krupp has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for medscape. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuroLive. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Krupp has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for Cleveland Clinic. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for MCIC. The institution of Dr. Krupp has received research support from Biogen. The institution of Dr. Krupp has received research support from National Multiple Sclerosis Society. Dr. Krupp has received intellectual property interests from a discovery or technology relating to health care.

Alemtuzumab following natalizumab is more effective in adult-onset than paediatric-onset multiple sclerosis.

Paediatric-onset multiple sclerosis (POMS) therapeutic approach derives from of adult-onset multiple sclerosis (AOMS) tailored algorithms. To evaluate in a common clinical scenario the efficacy and safety of alemtuzumab (ALZ) in POMS and AOMS. All patients switching from natalizumab (NTZ) to ALZ for safety concerns (high anti-John Cunningham Virus Antibody Index value, anti-JCV Index) were enrolled in this single-centre, retrospective, case-control open-label study. Ten POMS and 27 AOMS were followed up for 51.3 months. After month 12, we found a lower risk of clinical or radiological relapses among AOMS patients and among patients with older age at ALZ (both p < 0.05). Survival analysis revealed an increased risk of relapse in POMS compared with AOMS (logrank p = 0.00498) and patients starting ALZ before age 22.75 years than the elder ones (logrank p = 0.0018). Survival analysis did not disclose any difference between AOMS and POMS (logrank p = 0.27) in terms of progression independent of any relapse activity (PIRA). In addition, no evidence of relapse-associated worsening was observed. Autoimmune events were reported by 5 AOMS and no POMS (29.4% versus 0.0%, p = 0.057), and survival analysis was not significant (logrank p = 0.0786). ALZ seems more effective in AOMS than in POMS following NTZ. These findings underrate ALZ effectiveness when shifting from NTZ in POMS.

Age-related blood transcriptional regulators affect disease progression in pediatric multiple sclerosis

BackgroundPediatric onset multiple sclerosis patients (POMS) are defined as multiple sclerosis with an onset before the age of 18 years. Compared to adult onset multiple sclerosis (AOMS), POMS has more severe disease activity at onset, but better recovery. Little is known about the molecular mechanism responsible for the differences in the clinical presentations. MethodsPeripheral Blood Mononuclear Cells samples were taken from 22 POMS patients (mean age 14.1 ± 2.4 years, 15 females, 7 male), and 16 AOMS patients, (mean age 30.8 ± 6.1 years,10 females, 6 males), and gene-expression were analyzed using Affymetrix Inc. HU-133-A2 microarrays. Differentially Expressed Genes (DEGs) that significantly distinguished between POMS and AOMS with pvalue <0.05 after false discovery rate correction were evaluated using Partek software. Twenty-one matched age and gender control was applied to clarify age-related changes. Clinical assessment was performed by analysis of expanded disability status scale (EDSS) and brain MRI lesion loads. Gene functional analysis was performed by Ingenuity Pathway Analysis software. ResultsCompared to AOMS, POMS had higher EDSS (3.0 IQR 2.0–3.0 and 2.0 IQR 2.0–3.0, p = 0.005), volume of T1 (2.72 mm3, IQR 0.44–8.39 mm3 and 0.5 mm3 IQR 0–1.29 mm3 respectively, p = 0.04) and T2 (3.70 mm3, IQR 1.3–9.6 and 0.96 mm3, IQR 0.24–4.63 respectively, p = 0.02) brain MRI lesions. The POMS transcriptional profile was characterized by 551 DEGs, enriched by cell cycling, B lymphocyte signaling and senescent pathways (p < 0.02). Of these, 183 DEGs significantly correlated with T2 lesions volume. The POMS MRI correlated DEGs (n = 183) and their upstream regulators (n = 718) has overlapped with age related DEGs obtained from healthy subjects (n = 497). This evaluated common DEGs (n = 29) defined as POMS age-related regulators, suggesting to promote effect on disease severity. ConclusionOur finding of higher transcriptional levels of genes involved in cell cycle, cell migration and B cell proliferation that promoted by transcriptional level of age-associated genes and transcription factors allows better understanding of the more aggressive clinical course that defines the POMS.

Early onset multiple sclerosis and the effect of disease onset age on neurological disability in multiple sclerosis

ObjectivesThe incidence of early onset multiple sclerosis (EOMS) is increasing. We therefore aimed to compare the demographic, clinical, and magnetic resonance imaging features of early onset and adult onset multiple sclerosis patients. Furthermore, the effects of age of onset were evaluated for patients who reached an expanded disability status scale (EDSS) scores of six. Patients and methodsThis was a retrospective study of MS patient medical charts between 1977 and 2021, which were registered in the MS database. Only patients with relapsing remitting MS longer than 1 year were included in the study. The patients included in the study were divided into the EOMS and adult onset MS (AOMS) groups. General demographic datas, clinical datas such as the characteristics of the first clinical period, the time between the first two attacks, the attack rate in the first 2 and 3 years, the treatment status, the EDSS at the first evaluation, the EDSS score at 6 month intervals, the time to reach an EDSS score of six, and magnetic resonance imaging features such brain and spinal T2 lesions were recorded. ResultsTotal of 3477 including 353 (10.2 %) EOMS and 3124 (89.8 %) AOMS patients were analyzed. There was no statistically significant difference in symptom patterns between the EOMS and AOMS groups ( p = 0.649). Supratentorial clinical features at first attack were more common in AOMS patients, while optic neuropathy at first attack was more common in EOMS patients. Using univariable analysis, clinical supratentorial features at first attack, clinical optic neuropathy at first attack, clinical spinal cord at fist attack, spinal cord lesions, first EDSS score, relapse in the first 3 years, and onset patterns in terms of age were found to be statistically significant risk factors. In multivariable-adjusted analysis, clinical supratentorial features at first attack, clinical spinal cord lesions at first attack, first EDSS scores relapses in the first 3 years, and onset patterns in terms of age were found to be independent risk factors for EDSS in reaching a score of six. Early treatment start was associated with reduced hazard rate of reaching an EDSS score of 6. ConclusionOnset pattern in terms of age was an independent prognostic factor for neurological disabilities in MS patients.

Assessment of cervical spinal cord volume in pediatric-onset multiple sclerosis

PurposeSeveral studies of adult-onset multiple sclerosis (AOMS) patients have demonstrated that spinal cord volume loss is associated with disease progression and clinical disability. However, complementary studies of young patients with pediatric-onset multiple sclerosis (POMS) are lacking. Our retrospective study aimed to assess spinal cord volume in POMS patients compared with that in healthy controls. MethodsCervical spinal cord magnetic resonance images were evaluated for 20 POMS patients and 20 age- and sex-matched controls. Cross-sectional areas (CSAs) were measured at C2 and C7, along with the spinal cord average segmental area (CASA). The POMS group was further subdivided based on the presence or absence of spinal cord lesions, specifically C2 lesions. Pairwise area and volume comparisons were made across the different groups. ResultsNo significant difference was found in CASA and CSA at C2 and C7 between POMS patients and comparative controls. However, CASA, CSA at C7, and estimated spinal cord volume were significantly lower in a small subset of POMS patients with C2 lesions (3 patients) than in controls (P = 0.001, 0.02, and 0.001, respectively). ConclusionNo significant difference was found in spinal cord areas and volumes between POMS patients and controls. This finding contrasts with spinal cord volume measurements in AOMS patients.

A-70 Differences in Cognition and Disease Characteristics in Adult Vs. Late Onset Multiple Sclerosis

Abstract Objective Cognitive impairment is a common sequelae of multiple sclerosis(MS), however, relatively little is known about cognitive impairment in late-onset MS (LOMS; symptom onset &amp;gt;50 years old). The present study investigated differences in disease characteristics and cognition in LOMS and adult-onset MS (AOMS). Methods Archival medical records and neuropsychological evaluations from an MS specialty center were reviewed. Differences in disease characteristics between 57 LOMS and 124 AOMS patients were compared using chi-square or ANOVA. To investigate differences in cognitive functioning, age-adjusted standardized scores were compared via ANCOVA, using cardiac risk factors and disease duration as covariates. Results Compared to AOMS (age range: 21–88; mean age: 49.66 +/−12.83), LOMS patients (age range 42–82; mean age: 61.88 +/− 8.57) had significantly more cardiac comorbidities (mean: 1.12+/−1.1 vs. 0.6+/−0.9; p &amp;lt; 0.01), shorter disease duration (mean years: 13.14+/−7.9 vs. 21.0+/−12.6; p &amp;lt; 0.001), and shorter time to diagnosis (mean years: 3.0+/−4.2 vs 6.5+/−8.5; p &amp;lt; 0.01). LOMS patients had similar Expanded Disability Status Scale scores and number of prescribed disease-modifying therapy as AOMS. LOMS patients demonstrated greater impairment on Brief Visuospatial Memory Test-Revised learning (F(1,169) = 8.03, p &amp;lt; 0.05; d = 0.36) and delayed recall (F(1,169) = 4.44, p &amp;lt; 0.05; d = 0.27), and on Wechsler Adult Intelligence Scale-4th edition Digit Span Backward (F(1,176) = 5.68, p &amp;lt; 0.05; d = 0.41) and Sequencing (F(1, 176) = 11.90, p &amp;lt; 0.001; d = 0.55) subtests. Conclusion Despite a shorter disease duration and quicker diagnosis, LOMS patients demonstrate similar levels of physical impairment. Moreover, even after accounting for differences in disease duration and cardiac risk, LOMS showed a greater burden of cognitive impairment than AOMS, which taken together, suggests an elevated rate of disease progression in LOMS.

Cognition and disease characteristics in adult onset versus late onset multiple sclerosis

Background: Cognitive impairment is common sequelae of multiple sclerosis (MS); however, relatively little is known about cognitive impairment in late-onset multiple sclerosis (LOMS). Objective: To investigate differences in disease characteristics and cognition in LOMS and adult-onset multiple sclerosis (AOMS) patients. Methods: Archival medical records and neuropsychological evaluations from an MS specialty center were reviewed. Differences in disease characteristics between 53 LOMS and 124 AOMS were compared using chi-square or analysis of variance (ANOVA). To investigate differences in cognitive functioning, age-adjusted standardized scores were compared via analysis of covariance (ANCOVA), using cardiac risk factors and disease duration as covariates. Results: Compared to AOMS, LOMS patients had significantly more cardiac risk factors, shorter disease duration, and shorter time to diagnosis. LOMS patients had similar Expanded Disability Status Scale scores as AOMS patients. LOMS patients demonstrated significantly more impairment on tasks of visual learning and memory, and working memory than AOMS patients. Conclusion: Despite a shorter disease duration, LOMS and AOMS patients had similar levels of physical impairment. However, even after accounting for differences in disease duration and cardiac risk, LOMS patients showed a greater burden of cognitive impairment than AOMS patients, suggesting MS diagnosed later in life may progress faster due to the interaction between MS neuropathology and aging.

Outcomes on Social and Classic Cognition in adults with Pediatric-onset Multiple Sclerosis

Cognitive impairment affecting classic and social domains has been consistently reported in patients with Multiple Sclerosis (MS). However, little is known about the cognitive outcomes, particularly on social cognition, in adults with pediatric-onset multiple sclerosis (POMS). To compare the performance in classic and social cognitive domains between adults with POMS and adult-onset MS (AOMS). A group of 30 patients with POMS (age onset <18 years) was compared with age-matched (AOAMS, n=30) and disease duration-matched (AODMS, n= 30) patients who developed MS after the age of 18 years. Cognitive performance was assessed using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and Theory of Mind (ToM) tests. Cognitive impairment was more prevalent in POMS patients (40% vs. 16.7%, p=0.045), independently of age or disease duration, affecting more severely information-processing speed and visual memory domains. No statistically significant differences were found in ToM performance between patients with POMS and AOMS. When analyzing ToM performance according to age of disease onset (≤15 years; 15-20 years; ≥20 years), patients with disease onset ≤15 years old had significantly lower scores on ToM tests when compared to the other groups. Patients with POMS were more prone to develop impairment on classic cognitive domains than on ToM ability, when compared with AOMS patients. The interference of POMS with critical neurodevelopmental periods, specific for each cognitive domain, may explain different outcomes at adulthood on social and classic cognition.

Predictors of treatment outcome in patients with paediatric onset multiple sclerosis

Background: Disease-modifying therapies (DMT) are increasingly used for children with multiple sclerosis (MS) even though most double-blinded randomized controlled trials evaluating efficacy, safety and dosing strategy of a specific drug have included adults. Objective: To investigate predictors of treatment outcomes in patients with paediatric onset MS treated with DMTs. Methods: Prospective cohort study from the nationwide Danish Multiple Sclerosis Registry including all patients with a MS diagnosis who initiated treatment with an approved DMT before the age of 18 (N = 137) and followed until their 25th birthday. Selected baseline predictors were tested in univariate and multivariate regression models. Results: Multivariate analyses showed that being female and having disease duration for 2 or more years prior to DMT initiation predicted a higher relapse rate. In addition, disease duration and baseline expanded disability status scale (EDSS) predicted both confirmed disability worsening and improvement. We found no difference in treatment outcome between children with MS onset before and after the age of 13 years. Conclusions: The efficacy of DMT in paediatric onset MS patients is comparable to that seen in adult onset MS patients. Earlier treatment start is associated with a beneficial prognosis in the paediatric cohort.

Investigating the Role of MicroRNA and Transcription Factor Co-regulatory Networks in Multiple Sclerosis Pathogenesis.

MicroRNAs (miRNAs) and transcription factors (TFs) play key roles in complex multifactorial diseases like multiple sclerosis (MS). Starting from the miRNomic profile previously associated with a cohort of pediatric MS (PedMS) patients, we applied a combined molecular and computational approach in order to verify published data in patients with adult-onset MS (AOMS). Six out of the 13 selected miRNAs (miR-320a, miR-125a-5p, miR-652-3p, miR-185-5p, miR-942-5p, miR-25-3p) were significantly upregulated in PedMS and AOMS patients, suggesting that they may be considered circulating biomarkers distinctive of the disease independently from age. A computational and unbiased miRNA-based screening of target genes not necessarily associated to MS was then performed in order to provide an extensive view of the genetic mechanisms underlying the disease. A comprehensive MS-specific miRNA-TF co-regulatory network was hypothesized; among others, SP1, RELA, NF-κB, TP53, AR, MYC, HDAC1, and STAT3 regulated the transcription of 61 targets. Interestingly, NF-κB and STAT3 cooperatively regulate the expression of immune response genes and control the cross-talk between inflammatory and immune cells. Further functional analysis will be performed on the identified critical hubs. Above all, in our view, this approach supports the need of multidisciplinary strategies for shedding light into the pathogenesis of MS.

Adult brain volume in multiple sclerosis: The impact of paediatric onset

BackgroundPaediatric onset multiple sclerosis (POMS) is associated with reduced brain and deep grey matter volume in comparison with that in healthy controls and individuals with adult onset multiple sclerosis (AOMS). The aim of our study was to evaluate the impact of POMS on adult brain volume with adjustment for other parameters, such as disease duration. Patients and methodsWe recruited 20 POMS and 40 AOMS patients and 20 healthy controls matched for age and sex. All study participants were adults at the time of inclusion in the study. All study subjects underwent brain magnetic resonance imaging (MRI) to evaluate whole brain, white matter, grey matter, cortical, and deep grey matter volumes. Clinical features, such as the Expanded Disability Status Scale (EDSS) score and disease duration, were also assessed. ResultsBrain (p = 0.01), grey matter (p = 0.01), and deep grey matter volume (p = 0.03) was significantly lower in POMS patients than in AOMS patients, while no differences were detected in the volume of white matter or cortical grey matter. A multiple linear regression analysis showed a relationship between brain volume (dependent variable) and the independent variables age (p < 0.000) and paediatric onset (p < 0.001), while other independent variables, including disease duration, sex, and disability, were not significantly different among groups. There were significant differences in thalamic volume among POMS and AOMS patients and healthy controls. ConclusionOur data support the previous findings that POMS patients have reduced brain and deep grey matter volume, particularly thalamic volume, compared with sex- and age-matched AOMS patients and healthy controls. These findings appear to be independent of disease duration and other clinical features.

Patients with paediatric-onset multiple sclerosis are at higher risk of cognitive impairment in adulthood: An Italian collaborative study

Background: Patients with paediatric-onset multiple sclerosis (POMS) could be at an increased risk for cognitive impairment (CI), given the potential harmful effects of disease activity in neurodevelopment. However, there is scarce information on their long-term cognitive outcomes. Objective: To compare the prevalence and profile of CI between adults with a history of POMS and those with classic, adult-onset multiple sclerosis (AOMS). Methods: Cognitive performance was assessed through the Brief Repeatable Battery (BRB) and the Stroop Test in consecutive patients referred to six Italian MS centres. CI was defined as impairment in ⩾2 cognitive domains. Results: In all, 119 patients with POMS and 712 with AOMS were included in this analysis. The prevalence of CI was 48.0% in AOMS, 44.5% in POMS; with similar neuropsychological profile between the two groups. However, when adjusting for current age, we found a significantly increased risk for CI (odds ratio (OR) = 1.71; p = 0.02) and for impairment in information processing speed (OR = 1.86; p < 0.01) in patients with POMS. A higher Expanded Disability Status Scale (EDSS) was also identified in POMS (p = 0.03) compared with AOMS patients. Conclusion: Patients with a history of POMS appear to be at higher risk of physical and cognitive disability than AOMS patients, after correcting for age effects, with particular involvement of information processing speed.

HLA-DRB1* Allele Frequencies in Pediatric, Adolescent and Adult-Onset Multiple Sclerosis Patients, in a Hellenic Sample. Evidence for New and Established Associations

HLA-DRB1* Allele Frequencies in Pediatric, Adolescent and Adult-Onset Multiple Sclerosis Patients, in a Hellenic Sample. Evidence for New and Established Associations

Elevated relapse rates in pediatric compared to adult MS persist for at least 6 years

ObjectiveTo compare relapse rates in pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (AOMS) over the first 6-years of disease. MethodsPatients with relapsing-remitting disease onset were identified from the Partners Pediatric MS Center, Massachusetts General Hospital and Partners MS Center, Brigham and Women's Hospital. 84 POMS and 258 AOMS patients were included. Annualized relapse rates (ARR) for each individual year from year 1 to year 6, after first attack were compared using Poisson regression, as was expanded disability status scale (EDSS) score at the visit closest to each year interval. ResultsARR was significantly higher in POMS compared to AOMS at individual years (except year 4), and was not significantly affected by adjustment for gender, race and proportion of time on treatment. Despite a 2.30 times higher relapse rate over 6-years, EDSS between groups did not differ. ARR in years 1–5 did not impact year 5 disability measured by EDSS in POMS. ConclusionsOur findings demonstrate that higher ARR in POMS relative to AOMS is sustained over 6-years, suggesting a more inflammatory nature and potential disconnect between relapses and disability measured by EDSS early in POMS. This data may be useful when designing clinical trials for POMS.

Comparative clinical characteristics of early- and adult-onset multiple sclerosis patients with seizures

Multiple sclerosis (MS) and epilepsy are common disorders, the co-occurrence of which has been of considerable interest. This study aimed to evaluate the prevalence and clinical features of epileptic seizures in patients with definite MS including those with pediatric onset (≤16 years of age). Out of 2,300 patients with definite MS followed in our outpatient clinic, 36 with epileptic seizures were identified. In this cohort, 8 out of 146 pediatric cases had seizures. The clinical and demographic features of the patients were recorded. Multiple logistic regression model with the occurence of seizures as the dependent variable was performed to identify the risk factors for seizure occurrence in MS patients. The prevalence of epileptic seizures was 1.5% in definite MS patients, 1.3% in adult-onset (comparable to seizure prevalence in the general population) and 5.5% in pediatric MS patients (≤16 years old). Twenty-six of 36 (72%) patients with MS and epilepsy developed recurrent seizures after the first epileptic seizure. Mean annual relapse rate (p ≤ 0.001), mean expanded disability status scale (EDSS) score (p = 0.004) and the ratio of patients with pediatric onset (p = 0.01) were higher in MS patients with seizures. In the multiple logistic regression analysis, age at MS onset and EDSS at the last examination were found to be predictors of seizure occurrence. Occurrence of seizures during the clinical course of MS appears to be associated with early-onset and increased disease severity and might be coincidental in adults.

HLA-DRB1* Allele Frequencies in Pediatric, Adolescent and Adult-Onset Multiple Sclerosis Patients, in a Hellenic Sample. Evidence for New and Established Associations

Studies in many populations consistently have showed that the human leukocyte antigens (HLA) and especially the DRB1*15 allele has by far the strongest genetic association with multiple sclerosis (MS). The aim of this study was to investigate the role of HLA-DRB1* alleles in MS risk/resistance and onset. A sample of 165 Hellenic MS patients (18 with pediatric-, 24 with adolescent- and 123 with adult-onset MS) and 107 healthy volunteers were examined with molecular techniques. Comparisons were made according to the Benjamini-Yekutieli method for p value correction. Both adult-onset MS patients and early-onset MS patients (age at onset below 20 years-old) had a significantly higher frequency of the DRB1*15 allele and a significantly lower frequency of the DRB1*11 allele compared to controls. For the early-onset vs. healthy group comparison, subgroup analyses revealed that both the pediatric- and the adolescent-onset MS groups contributed to the aforementioned DRB1*15 significant difference, while the DRB1*11 difference was ascribed solely to the adolescent-MS onset vs. healthy group comparison. Within MS patients comparisons revealed that early-onset MS patients had a tendency for higher DRB1*03 allele and a lower DRB1*16 allele frequency frequencies compared to adult-onset MS patients, although both non-significant. Notably, pediatric-onset MS patients showed complete absence of the DRB1*16 allele, along with a non-significant tendency for higher DRB1*15 allele frequency relative to the adult-onset group. Finally, the adolescent-onset MS group was presented with a lower DRB1*11 allele frequencies compared both to the pediatric- and the adult-onset MS group. Our findings confirm previous studies on the role of HLA-DRB1* in MS. New findings that need to be confirmed by further studies are the pathogenetic role of DRB1*03 for early-onset MS and the putative protective role of the DRB1*16 allele in the pediatric-onset MS.

Early Onset Multiple Sclerosis Has Worse Prognosis Than Adult Onset Multiple Sclerosis Based on Cognition and Magnetic Resonance Imaging

Objectives. In the present study, we aimed to compare the childhood and adult onset multiple sclerosis patients prospectively in their adulthood on the basis of clinical and magnetic resonance imaging (MRI) findings and cognitive impairment, which have not been performed before. Patients and Methods. Forty-six patients in whom the disease onset occurred before 16 years of age were included in the present study. Study subjects were compared with 64 randomly included adult onset patients. Results. Mean disease duration, clinical course, and female to male ratio did not differ in the groups. Cerebellar/brainstem and spinal involvement at onset were significantly higher in EOMS than in AOMS. Difference in MSFC between baseline and at the end of the 5th year was significantly worse in EOMS population (P = 0.02). The most significant difference was found in Paced Auditory Serial Addition Test (PASAT) (P = 0.008). Differences between baseline and at the end of the 5th year on the basis of T1 hypointense lesions were significantly higher in early onset MS than in adult onset MS patients (P = 0.02). Conclusions. Early onset MS seems to have worse prognosis than that of adult onset MS on the basis of clinical manifestation, cognitive impairment, and MRI parameters.

Multiple Sclerosis in the Elderly Patient

Multiple sclerosis (MS) is an acquired inflammatory demyelinating disease of the CNS that is typically diagnosed in the second or third decade of life. It is generally believed that over the last few decades the life expectancy of patients with adult onset MS (AOMS) has approached that of the general population as a result of better medical and nursing care. Thus, an increasing number of MS patients are entering or have reached senescence. A second group of elderly patients with MS that may be very different in terms of disease pathogenesis are patients with late onset MS (LOMS). The diagnosis in LOMS patients can be challenging because of a large number of age-associated MS differential diagnoses, atypical presentations, a low index of suspicion and the lack of diagnostic criteria specific to this age group. Also, specific problems these patients encounter have only recently become a focus of attention. Changes in renal and hepatic function with age, in addition to the coexistence of medical co-morbidities, require special attention in the management of elderly patients with MS. In this review we outline the characteristics of senescent AOMS and LOMS patients. In addition, we discuss therapeutic strategies in elderly patients with MS based on our knowledge of immunosenescence and age-associated characteristics of this disorder. Given the overall aging of the population, focusing on these two patient groups appears highly relevant.

A comparative assessment of cerebral white matter by magnetization transfer imaging in early- and adult-onset multiple sclerosis patients matched for disease duration

A more favorable clinical course in early-onset (EO) multiple sclerosis (MS) than adult-onset (AO) disease is reported. Our aim was to assess white matter with/without lesions by magnetization transfer (MT) imaging in EO and AO MS patients matched for duration of the disease. Relapsing-remitting MS patients with disease onset at age < or =18 years and >18 years (n = 11 for each) were matched according to sex, age, disease duration, and 22 sex-and age-matched healthy subjects were studied with MT imaging. MT ratios (MTR) of manually outlined ROIs from T1-hypointense, T1-isointense lesions and perilesional normal appearing white matter (NAWM) as well as NAWM of the left frontal lobe of the patients and healthy subjects were calculated. MTR differences between two patient groups and control subjects, and correlation of MTR with EDSS, disease onset age, disease duration and relapse rate were analyzed statistically. In comparison with NAWM of the patients and healthy subjects, the greatest MTR reductions were observed in T1-hypointense lesions followed by T1-isointense lesions and perilesional NAWM, respectively, in EO and AO MS. Both groups' NAWM MTR were reduced; greater and more significantly in EO patients. No correlation was found between MTR of any ROI and EDSS, duration of the disease, disease onset age, or relapse rate. Although normalization does not occur, abnormality of white matter in MS decreases as distance from the lesions increases. Greater NAWM abnormality in EO MS may relate to inherent myelin abnormalities and different repair/reorganization processes in this particular group.

Intrathecal antibody production against Epstein-Barr and other neurotropic viruses in pediatric and adult onset multiple sclerosis

Epstein-Barr virus (EBV) has been implicated in the pathogenesis of multiple sclerosis (MS). Recent reports proposed an increased EBV-targeted humoral immune response in MS, which appears to be more pronounced in pediatric patients. However, little is known about the CNS-derived antibody production against EBV in patients with MS. The objective of this study was to assess the frequency and intensity of intrathecal antibody production against EBV as compared to other neurotropic viruses in pediatric and adult onset MS. In cohorts of 43 childhood, 50 adult onset MS patients, 20 children and 12 adults with other CNS disorders, paired CSF and serum samples were studied. Frequency and intensity of intrathecal antibody production against EBV as compared to measles, rubella, varicella zoster (VZV) and herpes simplex virus (HSV) were analyzed by determination of virus-specific CSF-to-serum Antibody Indices (AI). Intrathecally synthesized EBV antibodies were detectable in 26% pediatric and 10% adult onset MS patients, compared to frequencies ranging in both groups from 10 to 60% for the other viruses. Median AIs for EBV were lower than those for all other viruses, with more than twofold higher median AI for measles, rubella and VZV. The EBV-targeted humoral immune response in the CNS is only part of the intrathecal polyspecific antibody production in MS, directed against various neurotropic viruses. Our results do not rule out the possibility that EBV is involved in the pathogenesis of MS by triggering diverse cellular immune mechanisms, but they argue against a direct pathogenic role of EBV-targeted humoral immune response within the CNS.