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Background: Fatigue is a common and debilitating feature of multiple sclerosis (MS) that remains without reliably effective treatment. Transcranial direct current stimulation (tDCS) is a promising option for fatigue reduction. We developed a telerehabilitation protocol that delivers tDCS to participants at home using specially designed equipment and real-time supervision (remotely supervised transcranial direct current stimulation (RS-tDCS))., Objective: To evaluate whether tDCS can reduce fatigue in individuals with MS., Methods: Dorsolateral prefrontal cortex left anodal tDCS was administered using a RS-tDCS protocol, paired with 20 minutes of cognitive training. Here, two studies are considered. Study 1 delivered 10 open-label tDCS treatments (1.5 mA; n = 15) compared to a cognitive training only condition ( n = 20). Study 2 was a randomized trial of active (2.0 mA, n = 15) or sham ( n = 12) delivered for 20 sessions. Fatigue was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue Short Form., Results and Conclusion: In Study 1, there was modest fatigue reduction in the active group (-2.5 ± 7.4 vs -0.2 ± 5.3, p = 0.30, Cohen's d = -0.35). However, in Study 2 there was statistically significant reduction for the active group (-5.6 ± 8.9 vs 0.9 ± 1.9, p = 0.02, Cohen's d = -0.71). tDCS is a potential treatment for MS-related fatigue.

Objective: Cognitive impairment is a common symptom of multiple sclerosis (MS) that can lead to declines in daily functioning. Timed instrumental activities of daily living (TIADLs) have been useful to bridge between cognitive testing and real-world functioning in disorders such as Alzheimer's disease and other dementias. However, these have not been standardized for general use, and the tasks that are typically employed have not been sensitive to the detection of milder forms of cognitive deficits. We developed a test of ten TIADLs tasks to measure a broader range of functioning, entitled the "Test of Everyday Cognitive Ability" or TECA, and tested its utility in a diverse sample of participants with MS., Method: TECA performance was characterized in n = 177 participants with MS and compared to healthy controls (n = 49). A subset from each group received repeated administration. In addition, all participants completed a standard battery of neuropsychological measures., Results: TECA performances were significantly different between MS and control participants. Further, MS participants with cognitive impairment performed significantly slower relative to those MS participants without impairment., Conclusions: The TECA is a TIADLs assessment appropriate for use in those with MS as it includes a broad range of task difficulties, requires minimum motor involvement, and is sensitive to MS-related cognitive impairment. The TECA is a brief and repeatable test of TIADLs and its ease of administration makes it suitable for both clinical practice and research settings., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Cognitive impairment is a common and troubling feature of pediatric-onset multiple sclerosis (POMS). Brief cognitive assessment in the outpatient setting can identify and longitudinally monitor cognitive involvement so that early intervention is possible., Objectives: The goal of this study was to measure the sensitivity of two cognitive assessment approaches that are brief, repeatable, and suitable for clinical practice and for multicenter investigation., Methods: Participants with POMS ( n = 69) were consecutively evaluated as part of outpatient neurologic visits and compared to healthy control participants (HC, n = 66) using the Brief International Cognitive Assessment for MS (BICAMS) approach and timed information processing measures from Cogstate, a computer-based assessment., Results: There was strong agreement in the detection rate of impairment between both assessments, with 26% for the BICAMS and 27% for Cogstate. Two of the Cogstate tasks were the most sensitive individual measures., Conclusion: Both the BICAMS and Cogstate timed processing measures offer practical, sensitive, and standardized approaches for cognitive screening assessment in POMS.

[This corrects the article DOI: 10.1371/journal.pone.0177177.].

The neuropsychological aspects of multiple sclerosis (MS) have evolved over the past three decades. What was once thought to be a rare occurrence, cognitive dysfunction is now viewed as one of the most disabling symptoms of the disease, with devastating effects on patients' quality of life. This selective review will highlight major innovations and scientific discoveries in the areas of neuropathology, neuroimaging, diagnosis, and treatment that pertain to our understanding of the neuropsychological aspects of MS. Specifically, we focus on the recent discovery that MS produces pathogical lesions of gray matter (GM) that have consequences for cognitive functions. Methods for imaging these GM lesions in MS are discussed along with multimodal imaging studies that integrate structural and functional imaging methods to provide a better understanding of the relationship between cognitive test performance and functional reserve. Innovations in the screening and comprehensive assessment of cognitive disorders are presented along with recent research that examines cognitive dysfunction in pediatric MS. Results of innovative outcome studies in cognitive rehabilitation are discussed. Finally, we highlight trends for potential future innovations over the next decade. (JINS, 2017, 23, 832-842).

Background: Adverse childhood experiences (ACEs) exert a psychological and physiological toll that increases risk of chronic conditions, poorer social functioning, and cognitive impairment in adulthood., Objective: To investigate the relationship between childhood adversity and clinical disease features in multiple sclerosis (MS)., Methods: Sixty-seven participants with MS completed the ACE assessment and neuropsychological assessments as part of a larger clinical trial of cognitive remediation., Results: Adverse childhood experience scores, a measure of exposure to adverse events in childhood, significantly predicted age of MS onset ( r  = -0.30, p  = 0.04). ACEs were also linked to reading recognition (a proxy for premorbid IQ) ( r  = -0.25, p  = 0.04). ACE scores were not related to age, current disability, or current level of cognitive impairment measured by the Symbol Digit Modalities Test (SDMT)., Conclusion: Childhood adversity may increase the likelihood of earlier age of onset and poorer estimated premorbid IQ in MS.

Cognitive impairment affects more than half of all individuals living with multiple sclerosis (MS). We hypothesized that training at home with an adaptive online cognitive training program would have greater cognitive benefit than ordinary computer games in cognitively-impaired adults with MS. This was a double-blind, randomized, active-placebo-controlled trial. Participants with MS were recruited through Stony Brook Medicine and randomly assigned to either the adaptive cognitive remediation (ACR) program or active control of ordinary computer games for 60 hours over 12 weeks. Training was remotely-supervised and delivered through a study-provided laptop computer. A computer generated, blocked stratification table prepared by statistician provided the randomization schedule and condition was assigned by a study technician. The primary outcome, administered by study psychometrician, was measured by change in a neuropsychological composite measure from baseline to study end. An intent-to-treat analysis was employed and missing primary outcome values were imputed via Markov Chain Monte Carlo method. Participants in the ACR (n = 74) vs. active control (n = 61) training program had significantly greater improvement in the primary outcome of cognitive functioning (mean change in composite z score±SD: 0·25±0·45 vs. 0·09±0·37, p = 0·03, estimated difference = 0·16 with 95% CI: 0·02-0·30), despite greater training time in the active control condition (mean±SD:56·9 ± 34·6 vs. 37·7 ±23 ·8 hours played, p = 0·006). This study provides Class I evidence that adaptive, computer-based cognitive remediation accessed from home can improve cognitive functioning in MS. This telerehabilitation approach allowed for rapid recruitment and high compliance, and can be readily applied to other neurological conditions associated with cognitive dysfunction., Trial Registration: Clinicaltrials.gov NCT02141386.

Background: Genetic ancestry, sex, and individual alleles have been associated with multiple sclerosis (MS) susceptibility., Objective: To determine whether established risk factors for disease onset are associated with relapse rate in pediatric MS., Methods: Whole-genome genotyping was performed for 181 MS or high-risk clinically isolated syndrome patients from two pediatric MS centers. Relapses and disease-modifying therapies were recorded as part of continued follow-up. Participants were characterized for 25-hydroxyvitamin D serum status. Ancestral estimates (STRUCTURE v2.3.1), human leukocyte antigen (HLA)-DRB1*15 carrier status (direct sequencing), sex, and a genetic risk score (GRS) of 110 non-HLA susceptibility single-nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate with Cox and negative binomial regression models., Results: Over 622 patient-years, 408 relapses were captured. Girls had greater relapse rate than boys (incident rate ratio (IRR) = 1.40, 95% confidence interval (CI) = 1.04-1.87, p = 0.026). Participants were genetically diverse; ~40% (N = 75) had <50% European ancestry. HLA-DRB1*15 status modified the association of vitamin D status (p ixn  = 0.022) with relapse rate (per 10 ng/mL, in DRB1*15+ hazard ratio (HR) = 0.72, 95% CI = 0.58-0.88, p = 0.002; in DRB1*15- HR = 0.96, 95% CI = 0.83-1.12, p = 0.64). Neither European ancestry nor GRS was associated with relapse rate., Conclusion: We demonstrate that HLA-DRB1*15 modifies the association of vitamin D status with relapse rate. Our findings emphasize the need to pursue disease-modifying effects of MS genes in the context of environmental factors., (© The Author(s), 2016.)

In comparison with the large body of evidence on cognitive functioning in adults with multiple sclerosis (MS), there is limited information on cognition in pediatric-onset MS (POMS). Unique vulnerabilities in POMS can derive from having a disease that occurs during key periods of age-expected brain growth, active myelination in the CNS, and maturation of neural networks during the learning curve and key formative years in the academic career of the patient. Therefore, the consequences of MS on developing cognitive faculties can be assessed only in the pediatric population and cannot be simply extrapolated from studies carried on in the adult population. Until the last decade, research in the pediatric population was mainly represented by small clinical series, often limited by the narrow scope of neuropsychological assessment and lack of adequate control groups. Over the last decade, however, cognitive functioning and mood-related difficulties have become an increasing concern as awareness of this population has grown. A few specialized MS centers have begun performing more systematic research in the field in order to assess the prevalence of cognitive impairments and mood-related difficulties in patients with POMS, to better characterize the neuropsychological pattern and determine the functional consequences of these problems. This chapter summarizes our current understanding of cognitive and mood-related difficulties in POMS and highlights perceived gaps in knowledge and priorities for future research., (© 2016 American Academy of Neurology.)

In light of the published 2012 International Pediatric Multiple Sclerosis Group definitions for pediatric multiple sclerosis (MS) and related disorders and given that pediatric-onset MS is now formally included in the 2010 McDonald criteria for MS, we sought to review these criteria and summarize their application in children with acquired CNS demyelination. In addition, proposals are made for definitions of no evidence of disease activity and inadequate treatment response that are important because of new therapeutic options and trials., (© 2016 American Academy of Neurology.)

Supporting young people with pediatric multiple sclerosis can be challenging for families and health care providers. Adolescents may be more resilient than adults in reaction to the diagnosis but can have more difficulty planning for their futures. Appropriate, sensitive, and focused health provision should include consideration of the perspective of both the patient and parents. Multidisciplinary management strategies are often effective, as are referrals to programs that enhance individual and family coping and strengthen a sense of community., (© 2016 American Academy of Neurology.)

The International Pediatric Multiple Sclerosis Study Group held its inaugural educational program, "The World of Pediatric MS: A Global Update," in September 2014 to discuss advances and challenges in the diagnosis and management of pediatric multiple sclerosis (MS) and other neuroinflammatory CNS disorders. Highlights included a discussion on the revised diagnostic criteria, which enable the differentiation of MS, acute disseminated encephalomyelitis, neuromyelitis optica, and other neuroinflammatory disorders. While these criteria currently identify clinical and MRI features for a particular diagnosis, advances in biomarkers may prove to be useful in the future. An update was also provided on environmental factors associated with pediatric MS risk and possibly outcomes, notably vitamin D deficiency. However, optimal vitamin D intake and its role in altering MS course in children have yet to be established. Regarding MS outcomes, our understanding of the cognitive consequences of early-onset MS has grown. However, further work is needed to define the course of cognitive function and its long-term outcome in diverse patient samples and to develop strategies for effective cognitive rehabilitation specifically tailored to children and adolescents. Finally, treatment strategies were discussed, including a need to consider additional drug treatment options and paradigms (escalation vs induction), although treatment should be tailored to the individual child. Of critical importance, clinical trials of newer MS agents in children are required. Although our understanding of childhood MS has improved, further research is needed to have a positive impact for children and their families., (© 2016 American Academy of Neurology.)

The emotional and behavioral problems associated with pediatric multiple sclerosis remain unclear. Participants with pediatric multiple sclerosis or clinically isolated syndrome (n = 140; ages 5-18 years) completed self- and parent ratings using the Behavioral Assessment System for Children, Second Edition, neurologic exam, the Fatigue Severity Scale, and neuropsychological assessment. Mean self- and parent-ratings on the Behavioral Assessment System for Children, Second Edition, were in the typical range across all scales. However, 33.1% indicated a clinically significant problem on a least 1 scale. Although the type of clinical problems varied across participants, attention problems, somatization, and anxiety were found to be most common. Disease features including duration, age of onset, neurologic disability, and fatigue did not distinguish those with and without clinical problems. However, cognitive functioning significantly predicted the presence of a clinical problem (P =02). Pediatric multiple sclerosis is associated with a range of nonspecific emotional and behavioral clinical problems, occurring more frequently in those patients with cognitive involvement., (© The Author(s) 2016.)

Objectives: To describe the demographic and clinical characteristics of pediatric multiple sclerosis (MS) in the United States., Methods: This prospective observational study included children and adolescents with MS. Cases were evaluated across 9 geographically diverse sites as part of the US Network of Pediatric MS Centers., Results: A total of 490 children and adolescents (324 girls, 166 boys) were enrolled; 28% developed symptoms before 12 years of age. The proportion of girls increased with age from 58% (<12 years) to 70% (≥12 years). Race and ethnicity as self-identified were: white, 67%; African American, 21%; and non-Hispanic, 70%. Most (94%) of the cases were born in the United States, and 39% had 1 or both foreign-born parents. Fifty-five percent of cases had a monofocal presentation; 31% had a prodrome (most frequently infectious), most often among those aged <12 years (P < .001). Children aged <12 years presented more commonly with encephalopathy and coordination problems (P < .001). Sensory symptoms were more frequently reported by older children (ie, those aged ≥12 years) (P < .001); 78% of girls had MS onset postmenarche. The initial Expanded Disability Status Scale score for the group was <3.0, and the annualized relapse rate was 0.647 for the first 2 years. Interval from symptom onset to diagnosis and from diagnosis to initiation of disease-modifying therapy was longer among those <12 years of age., Conclusions: Pediatric MS in the United States is characterized by racial and ethnic diversity, a high proportion of children with foreign-born parents, and differences in clinical features and timing of treatment among those <12 years of age compared with older children., (Copyright © 2016 by the American Academy of Pediatrics.)

Background: To further understand management of pediatric patients with multiple sclerosis (MS), we examined disease features, clinical practice patterns, and response to treatment in the United States (US) and seven other countries ('rest of World'; ROW)., Methods: Anonymized data, recorded as part of routine clinical practice, were obtained from medical records (1997-2009) of study participants (who received subcutaneous interferon β-1a before age 18 years) from the US and ROW. Samples were stratified by age (preadolescents [<12 years] and adolescents [12-17 years])., Results: US adolescents had a higher mean body mass index versus ROW adolescents (BMI; 27.2 versus 22.5 kg/m(2)), started disease-modifying therapy (DMT) earlier after the first relapse, were more likely to have received a DMT before initiating subcutaneous interferon β-1a, had a higher relapse rate, and were more likely to switch from subcutaneous interferon β-1a to another DMT before the end of the observation period., Conclusions: This retrospective analysis of a multinational sample of pediatric MS patients who received subcutaneous interferon β-1a found that those from the US had higher BMI, relapsed more frequently, and were managed differently, compared with ROW patients. Future prospective studies are needed to confirm these observations and ascertain their clinical significance., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: High salt intake may be associated with pro-inflammatory changes in the immune response, and increased clinical and MRI activity in adults with relapsing-remitting multiple sclerosis., Objective: We sought to determine if dietary salt intake is associated with pediatric-onset MS risk in a multicenter, case-control study., Methods: Pediatric-onset CIS/MS cases within four years of onset and controls less than 22 years old recruited from 14 pediatric-MS centers were studied. Dietary sodium intake was assessed using the validated Block Kids Food Screener (NutritionQuest). Sodium intake, excess sodium, and sodium terciles were compared between cases and controls. Logistic regression models were adjusted for age, gender, ethnicity, body mass index, and socioeconomic status., Results: Among 170 cases (mean age=15.2±3.5) and 331 controls (mean age=14.0±3.7), no significant difference in unadjusted mean sodium intake was found between cases (2044mg/d) and controls (2030mg/d, p=0.99). The proportion of subjects consuming excess sodium, based on the adequate intake for age and gender, was similar between cases and controls (65% versus 69%, p=0.34). There were no increased odds of higher sodium intake among cases as compared to controls (for each 100mg/d increase in sodium, OR=1.00, 95% CI 0.98, 1.02; p=0.93, for excess sodium intake, OR=1.05, 95% CI 0.67, 1.64; p=0.84)., Conclusions: Our results show no strong association between dietary salt intake and pediatric-onset MS risk, suggesting that salt intake may not play a prominent role in susceptibility to MS in children., (Copyright © 2016. Published by Elsevier B.V.)

Fatigue is a severe problem for many people living with Parkinson's disease (PD). Best estimates suggest that more than 50% of patients experience this debilitating symptom. Little is known about its etiology or treatment, making the understanding of fatigue a true unmet need. As part of the Parkinson's Disease Foundation Community Choice Research Program, patients, caregivers, and scientists attended a symposium on fatigue on 16 and 17 October 2014. We present a summary of that meeting, reviewing what is known about the diagnosis and treatment of fatigue, its physiology, and what we might learn from multiple sclerosis (MS), depression, and cancer-disorders in which fatigue figures prominently too. We conclude with focused recommendations to enhance our understanding and treatment of this prominent problem in PD.

Multiple sclerosis can adversely affect cognitive functioning whether the disease has an adult or pediatric onset. The research thus far suggests that pediatric MS shares many features with adult MS but is also unique in several respects. One particular characteristic of pediatric MS is that, while physical disability develops more slowly as compared with adult patients, the impact of cognitive deficits in children may be more substantial as they are in a period of life during which they acquire many skills that are needed to transition into independently functioning adults. Our review takes a lifespan approach to MS, comparing and contrasting the neuropsychology (i.e., cognitive, psychological, and psychosocial factors) of these two populations. Understanding how MS manifests across the lifespan has important implications for tailoring assessment and treatment for individuals with MS as they transition from childhood to adulthood, and later life., (© The Author(s), 2015.)

Objective: To evaluate the Symbol Digit Modalities Test (SDMT) as a tool for identifying pediatric-onset MS patients at risk for cognitive impairment., Background: The SDMT is a brief measure of cognitive processing speed that is often used in adult MS patients. Approximately one-third of pediatric-onset MS patients have cognitive impairment and there is a need for an effective screening instrument., Design/methods: Seventy (70) consecutive outpatients with pediatric-onset MS underwent clinical evaluations including the SDMT and were compared to those with other pediatric neurological diagnoses (OND, n=40) and healthy controls (HC, n=32). A subset of the MS group and all healthy controls completed neuropsychological evaluation within one year of SDMT administration., Results: The MS group performed worse on the SDMT compared to the HC group (p=0.02). Thirty-seven percent (37%) of the MS, 20% of the OND, and 9% of HC groups scored in the impaired range. For MS participants who underwent neuropsychological testing (n=31), the SDMT showed 77% sensitivity and 81% specificity for detecting neuropsychological impairment when administered within one year and reached 100% sensitivity when the interval was under two months (n=17). Overall, older age and increased disability predicted poorer SDMT performance (age r=-0.26, p=0.03) and the Expanded Disability Status Scale score or EDSS (r=-0.47, p<0.001), while a history of optic neuritis predicted better performance (p=0.04). Optical coherence tomography measures were not related to SDMT performance., Conclusion: In this preliminary study, the SDMT was an effective brief screen for detecting cognitive impairment in pediatric-onset MS., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Proton magnetic resonance spectroscopy ((1)H-MRS) is capable of noninvasively detecting metabolic changes that occur in the brain tissue in vivo. Its clinical utility has been limited so far, however, by analytic methods that focus on independently evaluated metabolites and require prior knowledge about which metabolites to examine. Here, we applied advanced computational methodologies from the field of metabolomics, specifically partial least squares discriminant analysis and orthogonal partial least squares, to in vivo (1)H-MRS from frontal lobe white matter of 27 patients with relapsing-remitting multiple sclerosis (RRMS) and 14 healthy controls. We chose RRMS, a chronic demyelinating disorder of the central nervous system, because its complex pathology and variable disease course make the need for reliable biomarkers of disease progression more pressing. We show that in vivo MRS data, when analyzed by multivariate statistical methods, can provide reliable, distinct profiles of MRS-detectable metabolites in different patient populations. Specifically, we find that brain tissue in RRMS patients deviates significantly in its metabolic profile from that of healthy controls, even though it appears normal by standard MRI techniques. We also identify, using statistical means, the metabolic signatures of certain clinical features common in RRMS, such as disability score, cognitive impairments, and response to stress. This approach to human in vivo MRS data should promote understanding of the specific metabolic changes accompanying disease pathogenesis, and could provide biomarkers of disease progression that would be useful in clinical trials., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: There has been tremendous growth in research in pediatric multiple sclerosis (MS) and immune mediated central nervous system demyelinating disorders since operational definitions for these conditions were first proposed in 2007. Further, the International Pediatric Multiple Sclerosis Study Group (IPMSSG), which proposed the criteria, has expanded substantially in membership and in its international scope., Objective: The purpose of this review is to revise the 2007 definitions in order to incorporate advances in delineating the clinical and neuroradiologic features of these disorders., Methods: Through a consensus process, in which input was sought from the 150 members of the Study Group, criteria were drafted, revised and finalized. Final approval was sought through a web survey., Results: Revised criteria are proposed for pediatric acute disseminated encephalomyelitis, pediatric clinically isolated syndrome, pediatric neuromyelitis optica and pediatric MS. These criteria were approved by 93% or more of the 56 Study Group members who responded to the final survey., Conclusions: These definitions are proposed for clinical and research purposes. Their utility will depend on the outcomes of their application in prospective research.

To expand current knowledge, we examined the safety and tolerability of subcutaneous interferon β-1a in patients with pediatric-onset multiple sclerosis. Records from 307 patients who had received at least 1 injection of subcutaneous interferon β-1a for demyelinating events when aged younger than 18 years were reviewed. Overall, 168 (54.7%) patients had at least 1 prespecified medical event related to or under close monitoring with subcutaneous interferon β-1a or specific to pediatric patients, 184 (59.9%) had nonserious medical events related to treatment or of unknown causality, and 12 (3.9%) had serious medical events irrespective of causality. The most common laboratory abnormalities were increased alanine (74/195; 37.9%) and aspartate aminotransferase levels (59/194; 30.4%). Annualized relapse rates were 1.79 before treatment and 0.47 during treatment. In conclusion, adult doses of subcutaneous interferon β-1a (44 and 22 μg, 3 times weekly) were well tolerated in pediatric patients and were associated with reduced relapse rates.

In the largest sample studied to date, we measured cognitive functioning in children and adolescents with pediatric multiple sclerosis (n = 187) as well as those with clinically isolated syndrome (n = 44). Participants were consecutively enrolled from six United States Pediatric Multiple Sclerosis Centers of Excellence. Participants had a mean of 14.8 ± 2.6 years of age and an average disease duration of 1.9 ± 2.2 years. A total of 65 (35%) children with multiple sclerosis and 8 (18%) with clinically isolated syndrome met criteria for cognitive impairment. The most frequent areas involved were fine motor coordination (54%), visuomotor integration (50%), and speeded information processing (35%). A diagnosis of multiple sclerosis (odds ratio = 3.60, confidence interval = 1.07, 12.36, P = .04) and overall neurologic disability (odds ratio = 1.47, confidence interval = 1.10, 2.10, P = .03) were the only independent predictors of cognitive impairment. Cognitive impairment may occur early in these patients, and prompt recognition is critical for their care.

Multiple Sclerosis (MS), an autoimmune mediated disease of the central nervous system, has historically been considered a disease of young adulthood. However, there has been increasing recognition that the disease can occur in adolescence and even early childhood and recent years have witnessed a surge of studies documenting the clinical features of the disease as it pertains to this young population. The purpose of this article is to review the literature on MS in childhood and adolescence, including the clinical presentation of the disease in this group, neuropathology and pathogenesis, magnetic resonance imaging findings, as well as neuropsychological and psychosocial considerations.

Parainfectious disorders of the nervous system encompass those meningo-encephalo-radiculomyelitic conditions that are temporally associated with a systemic infection, antigenic stimuli, or toxin exposure, in the absence of evidence of direct neuronal infection or invasion of the central nervous system (CNS) or peripheral nervous system (PNS). Pathogenetic mechanisms can be due to immune-mediated processes (such as bystander activation, molecular mimicy) or the inciting insult can be due to toxic factors, as in the case of botulism. A myriad of clinical manifestations can occur including headache, seizures, and mental status changes, ranging from mood and behavioral disturbances to varying levels of alteration in consciousness. Focal neurological deficits can include aphasia, hemiparesis, or paraparesis. The PNS can also be affected leading to cranial nerve involvement, focal or multifocal neuropathies, and dysfunction of the autonomic nervous system. Diagnosis is based not only on the history, examination, laboratory, and neuroimaging data but also on epidemiological factors. The parainfectious disorders covered in this review are cat scratch disease, Lyme borreliosis, legionellosis, brucellosis, botulism, pertussis, and mycoplasma. Each is associated with a distinct organism, has both systemic and neurological manifestations, and has a different epidemiological profile., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Multiple sclerosis (MS) is the leading cause of neurological disability among young and middle-aged adults. One of the most devastating consequences of MS in this relatively young population group is unemployment. Although certain demographic and disease factors have been associated with employment, few studies have examined the contribution of person-specific factors, such as personality., Objective: The goal of this study was to determine the extent to which personality, demographics, and clinical measures contribute to unemployment in MS., Method: A total of 101 individuals with MS who were enrolled in a clinical trial on cognition underwent a brief neuropsychological battery and completed questionnaires related to vocation, mood, fatigue, and personality. Neurological impairment was measured with the Expanded Disability Status Scale (EDSS)., Results: Employment status was related with disease duration, MS subtype, level of neurological impairment, fatigue, performance on measures assessing information processing speed (Symbol Digit Modalities Test (SDMT)), learning and memory (Selective Reminding Test), and the personality characteristic of persistence. Based on a forward logistic regression analysis, EDSS, SDMT, and persistence were the strongest predictors of employment status., Conclusions: These findings underscore the importance of personality on outcomes in MS and point to the need for more clinical attention and research in this area.

Diffusion tensor imaging (DTI) is a sensitive tool for detecting microstructural tissue damage in vivo. In this study, we investigated DTI abnormalities in individuals with relapsing remitting multiple sclerosis (RRMS) and examined the relations between imaging-based measures of white matter injury and cognitive impairment. DTI-derived metrics using tract-based spatial statistics (TBSS) were compared between 37 individuals with RRMS and 20 healthy controls. Cognitive impairment was assessed with three standard tests: the Symbol Digit Modalities Test (SDMT), which measures cognitive processing speed and visual working memory, the Rey Auditory Verbal Learning Test (RAVLT), which examines verbal memory, and the Paced Auditory Serial Addition Test (PASAT), which assesses sustained attention and working memory. Correlations between DTI-metrics and cognition were explored in regions demonstrating significant differences between the RRMS patients and the control group. Lower fractional anisotropy (FA) was found in RRMS participants compared to controls across the tract skeleton (0.40 ± 0.03 vs. 0.43 ± 0.01, p<0.01). In areas of reduced FA, mean diffusivity was increased and was dominated by increased radial diffusivity with no significant change in axial diffusivity, an indication of the role of damage to CNS myelin in MS pathology. In the RRMS group, voxelwise correlations were found between FA reduction and cognitive impairment in cognitively-relevant tracts, predominantly in the posterior thalamic radiation, the sagittal stratum, and the corpus callosum; the strongest correlations were with SDMT measures, with contributions to these associations from both lesion and normal-appearing white matter. Moreover, results using threshold-free cluster enhancement (TFCE) showed more widespread white matter involvement compared to cluster-based thresholding. These findings indicate the important role for DTI in delineating mechanisms underlying MS-associated cognitive impairment and suggest that DTI could play a critical role in monitoring the clinical and cognitive effects of the disease., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The relative contribution and interaction of risk factors for multiple sclerosis (MS) have not been evaluated., Objectives: To determine whether vitamin D status is associated with antibody levels to common viruses in pediatric-onset MS or clinically isolated syndrome (CIS) patients and controls., Methods: We assessed whether vitamin D status was associated with viral antibody levels to Epstein-Barr virus, cytomegalovirus (CMV), and herpes simplex virus (HSV)-1 or -2 in subjects who demonstrated evidence of remote infection with these viruses and whether these associations differed depending on disease status., Results: In 140 subjects, vitamin D status was weakly associated with antibody levels to CMV but not to the other viruses. However, there were some interactions between vitamin D status and disease state. Among those with vitamin D sufficiency (≥30 ng/ml), MS/CIS patients had higher antibody levels to Epstein-Barr nuclear antigen-1 than controls. Vitamin D sufficiency was associated with higher CMV antibody levels in MS/CIS subjects but lower CMV antibody levels in controls. Higher vitamin D levels appeared to be associated with higher titers to HSV-2 in MS/CIS patients but not controls., Conclusions: Vitamin D status may be differentially associated with antibody levels to common childhood viruses among seropositive subjects.

The Brief Visuospatial Memory Test - Revised (BVMTR) and the Symbol Digit Modalities Test (SDMT) oral-only administration are known to be sensitive to cerebral disease in adult samples, but pediatric norms are not available. A demographically balanced sample of healthy control children (N = 92) ages 6-17 was tested with the BVMTR and SDMT. Multiple regression analysis (MRA) was used to develop demographically controlled normative equations. This analysis provided equations that were then used to construct demographically adjusted z-scores for the BVMTR Trial 1, Trial 2, Trial 3, Total Learning, and Delayed Recall indices, as well as the SDMT total correct score. To demonstrate the utility of this approach, a comparison group of children with acute disseminated encephalomyelitis (ADEM) or multiple sclerosis (MS) were also assessed. We find that these visual processing tests discriminate neurological patients from controls. As the tests are validated in adult multiple sclerosis, they are likely to be useful in monitoring pediatric onset multiple sclerosis patients as they transition into adulthood.

Background: Children with multiple sclerosis (MS) can suffer significant cognitive deficits. This study investigates the sensitivity and validity in pediatric MS of two visual processing tests borrowed from the adult literature, the Brief Visuospatial Memory Test-Revised (BVMTR) and the Symbol Digit Modalities Test (SDMT)., Objective: To test the hypothesis that visual processing is disproportionately impacted in pediatric MS by comparing performance with that of healthy controls on the BVMTR and SDMT., Methods: We studied 88 participants (43 MS, 45 controls) using a neuropsychological assessment battery including measures of intelligence, language, visual memory, and processing speed. Patients and demographically matched controls were compared to determine which tests are most sensitive in pediatric MS., Results: Statistically significant differences were found between the MS and control groups on BVMTR Total Learning (t (84) = 4.04, p  <  0.001, d  =  0.87), BVMTR Delayed Recall (t (84) = 4.45, p < 0.001, d = 0.96), and SDMT (t (38) = 2.19, p = 0.035, d = 0.69). No significant differences were found between groups on confrontation naming or general intellectual ability. Validity coefficients exploring correlation between BVMTR, SDMT, and disease characteristics were consistent with the adult literature., Conclusions: This study found that BVMTR and SDMT may be useful in assessing children and adolescents with MS.

Background: Currently available disease-modifying therapies (DMTs) are known to be only partially effective in adults with multiple sclerosis (MS). Little is known about pediatric patients with MS who experience refractory disease while receiving first-line DMTs., Objective: To assess the occurrence and management of refractory disease in a group of pediatric patients with MS treated with first-line DMTs approved for adult patients within a network of pediatric MS centers in the United States., Design, Setting, and Patients: A multicenter, retrospective, longitudinal, open-label study design involving record review of 258 patients with pediatric-onset MS (68.6% female; mean [SD] age at disease onset, 13.2 [3.5] years; range of age at onset, 2.0-17.9 years) who were seen at 6 pediatric MS centers in the United States., Intervention: We evaluated medication changes owing to refractory disease in cases of pediatric-onset MS., Main Outcome Measure: Disease stability as represented by lack of medication change for breakthrough disease., Results: Records of 258 children with a confirmed diagnosis of MS and exposure to DMTs were reviewed. Interferon beta (prescribed to 200 of 258 children [77.5%]) and glatiramer acetate (prescribed to 53 of 258 children [20.5%]) were the 2 most frequently used first-line DMTs. Overall, 144 children (55.8%) continued receiving 1 therapy, while 65 (25.2%), 29 (11.2%), and 20 (7.8%) received 2, 3, or 4 or more sequential therapies, respectively, during a mean (SD) observation period of 3.9 (2.8) years. Second-line DMT use was restricted to interferon beta and glatiramer acetate in 203 children (78.7%), whereas other treatments such as broad-spectrum chemotherapies (cyclophosphamide, mitoxantrone hydrochloride), natalizumab, corticosteroids (monthly), and daclizumab were used at some point during the observation period for disease management in 55 children (21.3%). Hispanic children were more likely to experience breakthrough disease while receiving first-line DMTs than non-Hispanic children., Conclusion: Although switching between first-line DMTs may be effective in pediatric patients with disease that is refractory to initial treatment, a subset of patients may require second-line therapeutic interventions.

Objective: A previous phase 3 study showed significant improvement in walking ability in multiple sclerosis (MS) patients treated with oral, extended-release dalfampridine (4-aminopyridine) 10mg twice daily. The current study was designed to confirm efficacy and further define safety and pharmacodynamics., Methods: This was a 39-center, double-blind trial in patients with definite MS of any course type. Participants were randomized to 9 weeks of treatment with dalfampridine (10mg twice daily; n = 120) or placebo (n = 119). Response was defined as consistent improvement on the Timed 25-Foot Walk, with percentage of timed walk responders (TWRs) in each treatment group as the primary outcome. The last on-treatment visit provided data from 8 to 12 hours postdose, to examine maintenance of effect., Results: One patient from each group was excluded from the modified Intention to Treat population. The proportion of TWRs was higher in the dalfampridine group (51/119 or 42.9%) compared to the placebo group (11/118 or 9.3%, p < 0.0001). The average improvement in walking speed among dalfampridine-treated TWRs during the 8-week efficacy evaluation period was 24.7% from baseline (95% confidence interval, 21.0-28.4%); the mean improvement at the last on-treatment visit was 25.7%, showing maintenance of effect over the interdosing period. There were no new safety findings., Interpretation: This interventional study provides class 1 evidence that dalfampridine extended-release tablets produce clinically meaningful improvement in walking ability in a subset of people with MS, with the effect maintained between doses.

Fatigue is an extremely prevalent issue for multiple sclerosis (MS) patients. Fatigue can affect quality of life, depression, anxiety, motor function and sleep patterns. There are a number of available rating scales designed to detect and assess fatigue. However, the pathophysiology of fatigue is still not completely understood and the treatment of this symptom remains difficult. A number of clinical trials for fatigue in MS have shown some benefit with different interventions, including medication, physical activity and cognitive-behavioral therapy. Nonetheless, further research and the development of more targeted therapies are needed to improve the management of fatigue.

Objective: We sought to determine if vitamin D status, a risk factor for multiple sclerosis, is associated with the rate of subsequent clinical relapses in pediatric-onset multiple sclerosis., Methods: This is a retrospective study of patients with pediatric-onset multiple sclerosis or clinically isolated syndrome who were consecutively recruited into a prospective cohort at their clinical visit at the pediatric multiple sclerosis center of University of California, San Francisco or State University of New York at Stony Brook. Of 171 eligible patients, 134 (78%) with multiple sclerosis/clinically isolated syndrome were included in the cohort; a further 24 were excluded from this analysis due to lack of available serum (n = 7) or lack of follow-up (n = 17). Serum 25-hydroxyvitamin D(3) levels were measured and were adjusted to reflect a deseasonalized value. The adjusted serum 25-hydroxyvitamin D(3) level was the primary predictor in a multivariate negative binomial regression model in which the main outcome measure was the number of subsequent relapses., Results: Among the 110 subjects, the mean unadjusted 25-hydroxyvitamin D(3) level was 22 +/- 9 ng/ml. After adjustment for age, gender, race, ethnicity, disease duration, disease-modifying therapy, and length of follow-up, every 10 ng/ml increase in the adjusted 25-hydroxyvitamin D(3) level was associated with a 34% decrease in the rate of subsequent relapses (incidence rate ratio, 0.66; 95% confidence interval, 0.46-0.95; p = 0.024)., Interpretation: Lower serum 25-hydroxyvitamin D(3) levels are associated with a substantially increased subsequent relapse rate in pediatric-onset multiple sclerosis or clinically isolated syndrome, providing rationale for a randomized controlled trial of vitamin D supplementation.

Little is known about psychiatric aspects of pediatric demyelinating conditions. A total of 23 youths (6-17 years) with demyelinating conditions underwent semistructured psychiatric interviews using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. Adolescents and parents completed the Child Symptom Inventory-4 and the Youth's Inventory-4. Fears and conceptions of their neurological problems were elicited. In all, 48% (n = 11) met criteria for current psychiatric diagnoses, including 27% (n = 3) with depressive disorders and 64% (n = 7) with anxiety disorders. Fears and conceptions of the illness were severe and diverse. Depressive and anxiety disorders are common in pediatric demyelinating disease. Clinicians should therefore screen for psychiatric comorbidity symptoms as part of the routine evaluation of such patients.

Fatigue and quality of life are significant concerns in adult multiple sclerosis (MS) but little is known about these factors in pediatric MS. The present investigation evaluates fatigue and quality of life in 51 pediatric MS patients to determine the rate of fatigue and reduced quality of life and assesses the relations between these variables and clinical factors. Fatigue and quality of life were assessed by self- and parent-report via the PedsQL Multidimensional Fatigue Scale and the PedsQL Quality of Life Scale. One-sample t-tests determined if scores were below published data for healthy individuals. Moreover, scores falling one standard deviation from norms were considered mildly affected, with severe difficulties being defined as scores falling two or more standard deviations from norms. Associations between self- and parent-reported difficulties and clinical factors were examined via Pearson correlation analyses. In comparison with healthy samples, pediatric MS patients reported greater difficulties with respect to fatigue, sleep, cognition, physical limitations, and academics. In addition to significant difficulties on these factors, parents reported problems with respect to emotional functioning, and tended to report greater fatigue, sleep, and cognitive difficulties than were self-reported. Expanded Disability Status Scale score was the only neurologic variable significantly related to fatigue or quality of life scores. Fatigue was significantly correlated with reports of sleep difficulties, cognitive problems, and quality of life variables. These findings suggest that fatigue and poorer quality of life is a clear concern in pediatric MS, and is related to overall physical disability.

The diagnosis of pediatric multiple sclerosis (MS) is challenging due to its low frequency and the overlap with other acquired childhood demyelinating disorders of the central nervous system. To identify potential protein biomarkers which could facilitate the diagnosis, we used two-dimensional gel electrophoresis (2-DE) in combination with mass spectrometry to identify proteins associated with pediatric MS. Plasma samples from nine children with MS and nine healthy subjects, matched in aggregate by age and gender, were analyzed for differences in their patterns of protein expression. We found 12 proteins that were significantly up regulated in the pediatric MS group: alpha-1-acid-glycoprotein 1, alpha-1-B-glycoprotein, transthyretin, apoliprotein-C-III, serum amyloid P component, complement factor-I, clusterin, gelsolin, hemopexin, kininogen-1, hCG1993037-isoform, and vitamin D-binding protein. These results show that 2-DE in combination with mass spectrometry is a highly sensitive technique for the identification of blood-based biomarkers. This proteomic approach could lead to a new panel of diagnostic and prognostic markers in pediatric MS.

Background: Clinical studies suggested that fampridine (4-aminopyridine) improves motor function in people with multiple sclerosis. This phase III study assessed efficacy and safety of oral, sustained-release fampridine in people with ambulatory deficits due to multiple sclerosis., Methods: We undertook a randomised, multicentre, double-blind, controlled phase III trial. We randomly assigned 301 patients with any type of multiple sclerosis to 14 weeks of treatment with either fampridine (10 mg twice daily; n=229) or placebo (n=72), using a computer-generated sequence stratified by centre. We used consistent improvement on timed 25-foot walk to define response, with proportion of timed walk responders in each treatment group as the primary outcome. We used the 12-item multiple sclerosis walking scale to validate the clinical significance of the response criterion. Efficacy analyses were based on a modified intention-to-treat population (n=296), which included all patients with any post-treatment efficacy data. The study is registered with ClinicalTrials.gov, number NCT00127530., Findings: The proportion of timed walk responders was higher in the fampridine group (78/224 or 35%) than in the placebo group (6/72 or 8%; p<0.0001). Improvement in walking speed in fampridine-treated timed walk responders, which was maintained throughout the treatment period, was 25.2% (95% CI 21.5% to 28.8%) and 4.7% (1.0% to 8.4%) in the placebo group. Timed walk responders showed greater improvement in 12-item multiple sclerosis walking scale scores (-6.84, 95% CI -9.65 to -4.02) than timed walk non-responders (0.05, -1.48 to 1.57; p=0.0002). Safety data were consistent with previous studies., Interpretation: Fampridine improved walking ability in some people with multiple sclerosis. This improvement was associated with a reduction of patients' reported ambulatory disability, and is a clinically meaningful therapeutic benefit.

Objective: To determine the predictors of longitudinal changes in fatigue based on pain, mood, and neurological impairment across multiple sclerosis (MS) subtypes., Background: Fatigue is the most common symptom of MS but remains poorly understood. The New York State Multiple Sclerosis Consortium (NYSMSC) database offers a unique opportunity to longitudinally assess a variety of potential fatigue correlates in a very large and diverse MS sample., Design/methods: This study examined baseline and 1-year follow-up data on 2768 patients drawn from the NYSMSC database regarding fatigability, pain, depressive symptoms, MS subtype, and expanded disability status scale (EDSS). Correlates and predictors of fatigue were assessed in correlational and multiple regression analyses., Results: Baseline fatigue, pain, and depression accounted for 34.6% of the variance in 1-year follow-up fatigue scores. Fatigue was lower in relapsing-remitting subjects than in other MS subtypes. Fatigue consistently correlated at baseline and follow-up with depressive symptoms, pain severity, and EDSS. Changes in fatigue correlated with changes in other variables., Conclusions: Predictors of fatigue at 1 year include baseline fatigue, pain, mood, and EDSS. These symptoms are also correlated at baseline, follow-up, and in change scores. Identifying predictors of fatigue may facilitate patient management.

Baseline predictors of cognitive change were explored in a sample of persons with multiple sclerosis (MS). Potential predictors included demographic features, baseline clinical characteristics, and psychological state. Participants were 38 individuals diagnosed with either relapsing remitting or secondary progressive MS who did not meet criteria for a current major depressive episode. Subjects were tested at baseline and approximately 1 year in an ongoing longitudinal study of cognition in MS. Participants completed neuropsychological tests sensitive to impairment in MS. They also completed self-report measures of depression, anxiety, fatigue, apathy, and positive and negative affect. Baseline measures of negative affect (e.g., depressed mood, state anxiety, and negative affective state) consistently predicted cognitive change over the course of the study. Higher baseline levels of negative affect were associated with greater relative declines in cognitive performance. This longitudinal relation occurred in the absence of a cross-sectional relation between negative affect and overall cognition. High baseline negative affect particularly predicted a relative decline in episodic memory for newly learned verbal and visuospatial information. The negative affect measures were unique in their predictive value among all the baseline measures assessed. (JINS, 2009, 15, 53-61.).

Objective: To examine the efficacy and safety of three different doses of sustained-release fampridine in people with multiple sclerosis (MS)., Method: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study recruited 206 participants at 24 centers in the United States and Canada. After a single-blind, 2-week placebo run-in, participants were randomly assigned to receive fampridine (10, 15, or 20 mg twice daily) or placebo for 15 weeks. The primary efficacy variable was percent change in walking speed based on the timed 25-foot walk., Results: Trends for increased walking speed were consistent across dose groups vs placebo, but not significant, on the prospective analysis. An increase from baseline in lower extremity strength during the 12-week stable-dose period was seen in the groups receiving 10- and 15-mg doses, compared with placebo (p = 0.018 and 0.003). There were no significant changes in other secondary assessments. Post hoc analysis revealed subsets of participants in each dose group with walking speeds during the treatment period that were consistently faster than during the nontreatment period. There were significantly more "consistent responders" in the drug-treated groups than in the placebo group (36.7% compared with 8.5%). Consistent responders showed significantly greater improvement in self-assessed ambulation on the 12-Item MS Walking Scale than did nonresponders. Fampridine was generally well tolerated. Severe and serious adverse events were more frequent at the highest dose., Conclusions: This phase 2 study suggests that a subgroup of patients, when treated with fampridine, experiences a clinically relevant improvement in walking ability, which is sustained for at least 14 weeks.

Background: we sought to assess how impairment (physiological/psychological) and disability (social/environmental) are associated with physical and leisure/recreation activity levels and quality of life (QOL) in people with moderate/severe multiple sclerosis (MS). We conducted a cross-sectional survey at the MS Comprehensive Care Center, Stony Brook University Hospital, Stony Brook, NY, of a convenience sample of 43 people (50 eligible) with MS and Expanded Disability Status Scale scores of 6.0 to 8.0. The main outcome measures were QOL measured by MSQOL-54, physical activity measured by Physical Activity Disability Scale, and leisure/recreation activity measured by Nottingham Leisure Questionnaire. We analyzed the canonical correlations among physical and leisure/recreation activity levels and (1) impairment and (2) QOL., Results: higher levels of physical and leisure/recreation activity were associated with lower levels of apathy and depression and higher levels of cognition, self-efficacy, and QOL (physical and mental). Major barriers reported included fatigue, lack of motivation, and cost., Conclusion: impairments and social/environmental disabilities create barriers to physical and leisure/recreation activity. Additional research is needed to determine, for people with MS, what supports might increase participation in physical and leisure/recreation activities and whether this increase yields improved QOL.

Objectives: Pediatric-onset multiple sclerosis offers a unique window into early targets and mechanisms of immune dysregulation. It is unknown whether heightened T-cell reactivities documented in adult patients, to both target-organ and environmental antigens, emerge in parallel or develop as early or late events. Our objectives were to determine the presence, pattern, and specificity of abnormal T-cell reactivities to such antigens in the earliest stages of the multiple sclerosis process., Methods: Peripheral T-cell proliferative responses to self-, dietary, and control antigens were blindly evaluated in a large cohort of well-characterized children (n = 172) with central nervous system (CNS) inflammatory demyelination (n = 63), recent-onset type 1 (insulin-dependent) diabetes mellitus (T1D; n = 41), nonautoimmune neurological conditions (n = 39), and healthy children (n = 29)., Results: Children with inflammatory demyelination, CNS injury, and T1D exhibited heightened T-cell reactivities to self-antigens, and these responses were not strictly limited to the disease target organs. Children with autoimmune disease and CNS injury also exhibited abnormal T-cell responses against multiple cow-milk proteins. Responses to specific milk epitopes distinguished T1D from inflammatory demyelination and other neurological diseases., Interpretation: Abnormal T-cell reactivities to self- and environmental antigens manifest in the earliest clinical stages of inflammatory demyelination and T1D. The pattern of heightened T-cell reactivities implicates both shared and distinct mechanisms of immune dysregulation in the different autoimmune diseases. Abnormal T-cell responses in children with tissue injury challenge the prevailing view that CNS autoreactive cells inherently mediate the disease in early multiple sclerosis.

Although psychological distress and cognitive dysfunction are well documented in adults with multiple sclerosis (MS), they are poorly understood in children with the disease. Psychosocial difficulty experienced by children and adolescents with MS involves factors common to all chronic illnesses in children, as well as MS-specific factors. The psychosocial manifestations of the disease may affect the patient's self-image, role functioning, mood, and cognition to adversely affect schooling, interpersonal relationships, and treatment compliance. Furthermore, the impact of having a family member with MS may affect overall family functioning. Assessment and interventions for psychosocial and cognitive problems in pediatric MS should be multidisciplinary in nature and address the child's functioning at home, school, and among peers, as well as the effect on the family.

Background: The CNS inflammatory demyelinating disorders of childhood include both self-limited and lifelong conditions, which can be indistinguishable at the time of initial presentation. Clinical, biologic, and radiographic delineation of the various monophasic and chronic childhood demyelinating disorders requires an operational classification system to facilitate prospective research studies., Methods: The National Multiple Sclerosis Society (NMSS) organized an International Pediatric MS Study Group (Study Group) composed of adult and pediatric neurologists and experts in genetics, epidemiology, neuropsychology, nursing, and immunology. The group met several times to develop consensus definitions regarding the major CNS inflammatory demyelinating disorders of children and adolescents., Results: Clinical definitions are proposed for pediatric multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), recurrent ADEM, multiphasic ADEM, neuromyelitis optica, and clinically isolated syndrome. These definitions are considered operational and need to be tested in future research and modified accordingly., Conclusion: CNS inflammatory demyelinating disorders presenting in children and adolescents can be defined and distinguished. However, prospective research is necessary to determine the validity and utility of the proposed diagnostic categories.

Fatigue is a common problem in Parkinson's disease (PD), often the most troubling of all symptoms. It is poorly understood, generally under-recognized, and has no known treatment. This article reviews what is known about the symptom, putting it into the context of fatigue in other disorders, and outlines a program for developing better understanding and therapy.

Although Multiple Sclerosis (MS) occurring in childhood and adolescence has received increasing attention in recent years, the impact of the disease on cognitive function in this subgroup remains poorly understood. It has been posited that children and adolescents with MS may be particularly susceptible to cognitive dysfunction because the pathological processes, including inflammation, blood brain barrier breakdown, and demyelination, occur concurrently with ongoing myelination. Early work has documented that a number of these children present with cognitive deficits. However, there is no available information on the progression of these deficits, or on what clinical factors may predict further decline. The current article reviews what is currently known about pediatric MS and follows a cohort of pediatric MS patients and assesses cognitive function longitudinally. Participants were evaluated with a brief neuropsychological test battery on two separate occasions and correlational analyses assessed the relations between changes in cognition and several clinical variables including level of neurologic impairment, number of relapses prior to baseline assessment, number of interim relapses, age of disease onset, and disease length. The results indicate that a number of these patients experience further cognitive decline over time, or decline from previously normal functioning. Baseline level of neurologic disability was significantly correlated with changes in cognition. The number of interim relapses (i.e., relapses occurring between baseline assessment and re-evaluation) showed a modest relationship to changes in cognitive function, but this did not reach statistical significance.

Acetylcholinesterase inhibitors are used to treat dementia associated with Alzheimer's disease, but their cognitive benefits may extend to additional disorders such as multiple sclerosis (MS). A single-center double-blind placebo-controlled randomized clinical trial evaluated the effectiveness of donepezil in a sample of 69 MS persons selected for initial memory difficulties. Subjects received neuropsychological assessment at baseline and after 24 weeks of treatment. The primary outcome was change in total recall on the Selective Reminding Test, a measure of verbal learning and memory. Secondary outcomes included other neuropsychological tests from the Brief Repeatable Battery, patient-reported change in memory, and physician-reported impression of cognitive change. Donepezil improved memory performance on the SRT compared to placebo. This benefit remained significant after controlling for various covariates including Expanded Disability Status Scale (EDSS), MS subtype, interferon beta use, treatment group beliefs, gender, baseline selected reminding test (SRT) score, and reading ability. Subjects on donepezil were more likely to report memory improvement (65.7%) than those on placebo (32.4%). The clinician also reported cognitive improvement in more donepezil (54.3%) than placebo (29.4%) subjects. No serious adverse events related to study medication occurred. However, more donepezil (34.3%) than placebo (8.8%) subjects reported unusual/abnormal dreams. Donepezil improved learning and memory in MS patients with initial cognitive difficulties in a single-center clinical trial. Replication of results in a larger multi-center investigation is warranted in order to more definitively assess the efficacy of this intervention.