Machine Learning EEG to Predict Cognitive Functioning and Processing Speed Over a 2-Year Period in Multiple Sclerosis Patients and Controls.

Event-related potentials (ERPs) show promise to be objective indicators of cognitive functioning. The aim of the study was to examine if ERPs recorded during an oddball task would predict cognitive functioning and information processing speed in Multiple Sclerosis (MS) patients and controls at the individual level. Seventy-eight participants (35 MS patients, 43 healthy age-matched controls) completed visual and auditory 2- and 3-stimulus oddball tasks with 128-channel EEG, and a neuropsychological battery, at baseline (month 0) and at Months 13 and 26. ERPs from 0 to 700 ms and across the whole scalp were transformed into 1728 individual spatio-temporal datapoints per participant. A machine learning method that included penalized linear regression used the entire spatio-temporal ERP to predict composite scores of both cognitive functioning and processing speed at baseline (month 0), and months 13 and 26. The results showed ERPs during the visual oddball tasks could predict cognitive functioning and information processing speed at baseline and a year later in a sample of MS patients and healthy controls. In contrast, ERPs during auditory tasks were not predictive of cognitive performance. These objective neurophysiological indicators of cognitive functioning and processing speed, and machine learning methods that can interrogate high-dimensional data, show promise in outcome prediction.

Effects of vitamin D3 in clinically isolated syndrome and healthy control participants: A double-blind randomised controlled trial.

BACKGROUND: Lowserum vitamin D levels are associated with susceptibility to, and severity of, multiple sclerosis. High dose vitamin D has been proposed as a potential immunomodulator in multiple sclerosis. OBJECTIVES: We performed a single centre, investigator-led, exploratory, double-blind, randomised, placebo controlled, trial of vitamin D3 in clinically isolated syndrome and healthy control participants to assess its immunological effects. Secondary end-points included clinical and magnetic resonance imaging outcomes and safety. METHODS: Clinically isolated syndrome patients and healthy control participants were randomised to: placebo, 5000 IU or 10,000 IU vitamin D3/day (Vigantol oil). Study duration was 24 weeks. RESULTS: The trial did not meet its primary end point, with no difference in the frequency of pro-inflammatory CD4+ T cells (interleukin (IL)-17+/interferon (IFN)-γ+) seen. A higher level of disease freedom (67% versus 50%) was seen in those with serum 1,25 (OH) vitamin D levels>100 nmol/l but this did not reach significance. High dose vitamin D3 was well tolerated with no safety signal. CONCLUSIONS: High dose vitamin D3 over 24 weeks was well tolerated but without immunological, magnetic resonance imaging or clinical evidence of benefit. The hypothesised therapeutic effects in clinically isolated syndrome or multiple sclerosis patients may require longer periods of administration or may only be seen in patients treated with vitamin D3 as an adjunct to established disease modifying therapies.

Delayed P100-Like Latencies in Multiple Sclerosis: A Preliminary Investigation Using Visual Evoked Spread Spectrum Analysis.

Conduction along the optic nerve is often slowed in multiple sclerosis (MS). This is typically assessed by measuring the latency of the P100 component of the Visual Evoked Potential (VEP) using electroencephalography. The Visual Evoked Spread Spectrum Analysis (VESPA) method, which involves modulating the contrast of a continuous visual stimulus over time, can produce a visually evoked response analogous to the P100 but with a higher signal-to-noise ratio and potentially higher sensitivity to individual differences in comparison to the VEP. The main objective of the study was to conduct a preliminary investigation into the utility of the VESPA method for probing and monitoring visual dysfunction in multiple sclerosis. The latencies and amplitudes of the P100-like VESPA component were compared between healthy controls and multiple sclerosis patients, and multiple sclerosis subgroups. The P100-like VESPA component activations were examined at baseline and over a 3-year period. The study included 43 multiple sclerosis patients (23 relapsing-remitting MS, 20 secondary-progressive MS) and 42 healthy controls who completed the VESPA at baseline. The follow-up sessions were conducted 12 months after baseline with 24 MS patients (15 relapsing-remitting MS, 9 secondary-progressive MS) and 23 controls, and again at 24 months post-baseline with 19 MS patients (13 relapsing-remitting MS, 6 secondary-progressive MS) and 14 controls. The results showed P100-like VESPA latencies to be delayed in multiple sclerosis compared to healthy controls over the 24-month period. Secondary-progressive MS patients had most pronounced delay in P100-like VESPA latency relative to relapsing-remitting MS and controls. There were no longitudinal P100-like VESPA response differences. These findings suggest that the VESPA method is a reproducible electrophysiological method that may have potential utility in the assessment of visual dysfunction in multiple sclerosis.

Unmet needs of multiple sclerosis patients in the community.

BACKGROUND: There is no evidence that disease modifying therapies (DMTs) are beneficial in progressive (non-relapsing) MS. However, these patients may benefit from multidiscipliniary interventions, and require financial and community support. Non-pharmacological needs of MS patients may be overlooked during fund allocation, and identification of unmet needs is important to optimise care and inform governmental resource distribution. AIM: To identify unmet needs of MS patients in 3 areas during an Irish epidemiology study. PATIENTS AND METHODS: Observational study in 3 regions in Ireland: South Dublin SCD (an urban area), Donegal DGL and Wexford WEX (rural counties).A validated Needs Assessment Questionnaire (NAQ) was completed by MS patients at research clinics, or by telephone if unable to attend. RESULTS: We identified 632 patients with multiple sclerosis: 23% SCD (urban), 30.8% WEX, and 46.2% DGL.MS subtype was relapsing remitting (RR) in 51.1%, secondary progressive (SP) in 39.7%, and primary progressive (PP) in 9.2%. EDSS was 6.5 in 14%. NAQ was completed by 325 (49.9%).Group A: 155 (47.7%) reported no unmet needs relating to MS.Group B: 170 (52.3%) reported unmet needs relating to MS,including all in a group continuing to use disease-modifying therapy without benefit (EDSS>6.5).Number of unmet needs per patient in group B: 1 need 27%, ≥2 needs 73%, ≥5 24%.Unmet needs overall correlated with EDSS >6.5 (p<0.001),MS subtype: RR 36.4%/SP 69.8%/PP 59.5% (p<0001),increased age (p 0.003) and MS duration (p 0.003). Multivariate analysis: presence of unmet needs related to higher EDSS (p<0.001), rural residence (p<0.05), SPMS (p<0.05).Financial unmet needs frequency differed by county: DGL 23.9%, WEX 17%, SCD 10.4% (p 0.045) and marital status: 24% single, 13.5% married (p 0.03).Multivariate analysis: related to rural residence (p<0.05), being single (p<0.05).Occupational therapy (OT) unmet needs frequency differed by subtype:RR 6%/SP 24.5%/ PP 19% (p 0.001), MS duration: 19.7 v 14.8y (p 0.003)and increasing age: 52.5 v 45.8y (p 0.0006).Multivariate analysis: rural, older age, higher EDSS (p<0.05).Physiotherapy unmet needs frequency differed by subtype: RR 17.2%/SP 43.4%/PP 31.7% (p<0.001), MS duration (p<0.001), and age (p 0.002).Multivariate analysis: related to higher EDSS (p<0.001).Employment unmet needs frequency differed by gender:male 22.9%, female 12.8% (p 0.02).Social unmet needs frequency differed by subtype: RR 12%/SP 39.2%/PP 32.5%, MS duration and age (p 0.001): multivariate analysis: SPMS (p<0.001). DISCUSSION: More than 50% reported unmet needs relating to MS: suggesting non-pharmacological needs are not optimally addressed, particularly in older, single, rural residents, with greater EDSS and progressive non-relapsing MS. Physiotherapy offers significant benefits, but is the most frequently reported unmet need.These findings highlight the need for increased fund allocation, especially for development of community supports and multidisciplinary/ social services.Identifying unmet needs may help inform health service planning, and emphasises particular need for improved resources in a high-risk group of MS patients.

Dose-related effects of vitamin D on immune responses in patients with clinically isolated syndrome and healthy control participants: study protocol for an exploratory randomized double- blind placebo-controlled trial.

BACKGROUND: There is increasing evidence linking vitamin D deficiency to both susceptibility to, and severity of, multiple sclerosis (MS). Patients with the clinically isolated syndrome represent the initial presentation of a demyelinating disorder, and those with asymptomatic lesions on magnetic resonance imaging (MRI) are at risk of progression to clinically definite MS. The aims of this study are to examine the immunologic effects of vitamin D in both healthy individuals and in patients with clinically isolated syndrome, and in the latter group the effects on disease progression assessed by MRI and clinical measures. METHODS/DESIGN: This is a single-center double-blind randomized placebo-controlled clinical trial. The primary endpoint is the immunologic effects of two doses of vitamin D compared with placebo over 24 weeks in both healthy control participants and patients presenting with the clinically isolated syndrome. Healthy control participants (n = 39) and patients with clinically isolated syndrome (n = 45) will be randomized to one of three arms, namely 1) vitamin D 5,000 IU daily, 2) vitamin D 10,000 IU daily, or 3) placebo, and followed up for 24 weeks. In both patients and healthy control participants, the primary outcome will be immunologic measures of the frequency of CD4 T-cell subsets and cytokine responses in peripheral blood mononuclear cells, assessed at baseline, and after 16 and 24 weeks of treatment. Secondary endpoints, in the patients with clinically isolated syndrome, will be relapse activity, and the number of new T2 lesions and gadolinium-enhancing lesions assessed by MRI in the two vitamin D-treated groups compared with the placebo-treated group over the 24 weeks of the study. TRIAL REGISTRATION: EU Clinical Trials Register: EudraCT: 2012-000635-68. ClinicalTrials.gov identifier: NCT01728922.

Symptom overlap in anxiety and multiple sclerosis.

BACKGROUND: The validity of self-rated anxiety inventories in people with multiple sclerosis (pwMS) is unclear. However, the appropriateness of self-reported depression scales has been widely examined. Given somatic symptom overlap between depression and MS, research emphasises caution when using such scales. OBJECTIVE: This study evaluates symptom overlap between anxiety and MS in a group of 33 individuals with MS, using the Beck Anxiety Inventory (BAI). METHODS: Participants underwent a neurological examination and completed the BAI. RESULTS: A novel procedure using hierarchical cluster analysis revealed three distinct symptom clusters. Cluster one ('wobbliness' and 'unsteady') grouped separately from all other BAI items. These symptoms are well-recognised MS-related symptoms and we question whether their endorsement in pwMS can be considered to reflect anxiety. A modified 19-item BAI (mBAI) was created which excludes cluster one items. This removal reduced the number of MS participants considered 'anxious' by 21.21% (low threshold) and altered the level of anxiety severity for a further 27.27%. CONCLUSION: Based on these data, it is suggested that, as with depression measures, researchers and clinicians should exercise caution when using brief screening measures for anxiety in pwMS.

Only low frequency event-related EEG activity is compromised in multiple sclerosis: insights from an independent component clustering analysis.

Cognitive impairment (CI), often examined with neuropsychological tests such as the Paced Auditory Serial Addition Test (PASAT), affects approximately 65% of multiple sclerosis (MS) patients. The P3b event-related potential (ERP), evoked when an infrequent target stimulus is presented, indexes cognitive function and is typically compared across subjects' scalp electroencephalography (EEG) data. However, the clustering of independent components (ICs) is superior to scalp-based EEG methods because it can accommodate the spatiotemporal overlap inherent in scalp EEG data. Event-related spectral perturbations (ERSPs; event-related mean power spectral changes) and inter-trial coherence (ITCs; event-related consistency of spectral phase) reveal a more comprehensive overview of EEG activity. Ninety-five subjects (56 MS patients, 39 controls) completed visual and auditory two-stimulus P3b event-related potential tasks and the PASAT. MS patients were also divided into CI and non-CI groups (n = 18 in each) based on PASAT scores. Data were recorded from 128-scalp EEG channels and 4 IC clusters in the visual, and 5 IC clusters in the auditory, modality were identified. In general, MS patients had significantly reduced ERSP theta power versus controls, and a similar pattern was observed for CI vs. non-CI MS patients. The ITC measures were also significantly different in the theta band for some clusters. The finding that MS patients had reduced P3b task-related theta power in both modalities is a reflection of compromised connectivity, likely due to demyelination, that may have disrupted early processes essential to P3b generation, such as orientating and signal detection. However, for posterior sources, MS patients had a greater decrease in alpha power, normally associated with enhanced cognitive function, which may reflect a compensatory mechanism in response to the compromised early cognitive processing.

A pilot study of the immunological effects of high-dose vitamin D in healthy volunteers.

Although vitamin D deficiency is considered an environmental factor in multiple sclerosis (MS), the immunological and clinical effects of vitamin D supplementation remain unclear. We performed a pilot study of the immunomodulatory effects of vitamin D in healthy individuals (n=4), who took 5000-10,000 IU/day of vitamin D over 15 weeks. After 15 weeks of vitamin D supplementation, serum 25(OH) vitamin D levels rose significantly from baseline, with a corresponding increase in IL-10 production by peripheral blood mononuclear cells and a reduced frequency of Th17 cells. These data provide a strong rationale for randomised trials to assess the clinical effects of vitamin D supplementation in MS.

Using atypical symptoms and red flags to identify non-demyelinating disease.

BACKGROUND: Red flags and atypical symptoms have been described as being useful in suggesting alternative diagnoses to multiple sclerosis (MS) and clinically isolated syndrome (CIS); however, their diagnostic utility has not been assessed. The aim of this study was to establish the predictive value of red flags and the typicality/atypicality of symptoms at presentation in relation to the final diagnosis of patients referred with suspected MS. METHODS: All patients referred with suspected MS over a 3-year period were assessed by the typicality of the clinical presentation and the occurrence of red flags in relation to the eventual diagnosis. The extent of agreement of trainee and consultant neurologists as to typicality of clinical presentations was determined. RESULTS: Of 244 patients referred, 119 (49%) had MS/CIS and 125 (51%) did not. 41 patients were referred because of an abnormal MRI. Of 203 with clinical symptoms, 96 patients had atypical symptoms of whom, 81 (84%) did not have MS and 15 (16%) had MS/CIS. Typical symptoms occurred in 107 patients; 10% did not have MS/CIS. Atypical symptoms had a sensitivity of 84%, specificity of 90% and positive likelihood ratio (PLR) of 8.4, whereas red flags had a sensitivity of 47%, specificity of 88% and PLR of 3.9 for the exclusion of MS/CIS. Mean percentage agreement between consultants and trainees was 73% with a range of 32-96%. CONCLUSIONS: Atypical features at presentation are more sensitive, specific and have a higher PLR than red flags to refute a diagnosis of MS/CIS.

IL-27 mediates the response to IFN-ß therapy in multiple sclerosis patients by inhibiting Th17 cells.

Interferon (IFN)-ß is a commonly used therapy for relapsing remitting multiple sclerosis (RRMS). However its protective mechanism is still unclear and the failure of many patients to respond has not been explained. We have found that IFN-ß suppressed IL-23 and IL-1ß production and increased IL-10 production by human dendritic cells (DC) activated with the TLR2 and dectin-1 agonist zymosan. Furthermore, IFN-ß impaired the ability of DC to promote IL-17 production by CD4(+) T cells, but did not affect IFN-γ production. IFN-ß induced IL-27 expression by DC, and neutralisation of IL-27 abrogated the suppressive effects of IFN-ß on zymosan-induced IL-1 and IL-23 production and the generation of Th17 cells in vitro. Complementary in vivo studies in a mouse model showed that treatment with IFN-ß enhanced expression of IL-27, and reduced IL-17 in the CNS and periphery and attenuated the clinical signs of experimental autoimmune encephalomyelitis (EAE). In addition, the significant suppressive effect of IFN-ß on the ability of DC to promote Th17 cells was lost in cells from IL-27 receptor deficient mice. Finally, we showed that PBMC from non-responder RRMS patients produced significantly less IL-27 in response to IFN-ß than patients who responded to IFN-ß therapy. Our findings suggest that IFN-ß mediates its therapeutic effects in MS at least in part via the induction of IL-27, and that IL-27 may represent an alternative therapy for MS patients that do not respond to IFN-ß.

Discontinuing disease-modifying therapy in progressive multiple sclerosis: can we stop what we have started?

Disease-modifying therapy is ineffective in disabled patients (Expanded Disability Status Scale [EDSS] > 6.5) with secondary progressive multiple sclerosis (MS) without relapses, or in primary progressive MS. Many patients with secondary progressive MS who initially had relapsing MS continue to use disease-modifying therapies. The enormous associated costs are a burden to health services. Regular assessment is recommended to guide discontinuation of disease-modifying therapies when no longer beneficial, but this is unavailable to many patients, particularly in rural areas. The objectives of this study are as follows: 1. To observe use of disease-modifying therapies in patients with progressive multiple sclerosis and EDSS > 6.5. 2. To examine approaches used by a group of international MS experts to stopping-disease modifying therapies in patients with secondary progressive MS without relapses. During an epidemiological study in three regions of Ireland (southeast Dublin city, and Wexford and Donegal Counties), we recorded details of disease-modifying therapies in patients with progressive MS and EDSS > 6.5. An e-questionnaire was sent to 26 neurologists with expert knowledge of MS, asking them to share their approach to stopping disease-modifying therapies in patients with secondary progressive MS. Three hundred and thirty-six patients were studied: 88 from southeast Dublin, 99 from Wexford and 149 from Donegal. Forty-four had EDSS > 6.5: 12 were still using disease-modifying therapies. Of the surveyed neurologists, 15 made efforts to stop disease-modifying therapies in progressive multiple sclerosis, but most did not insist. A significant proportion (12 of 44 patients with progressive MS and EDSS > 6.5) was considered to be receiving therapy without benefit. Eleven of the 12 were from rural counties, reflecting poorer access to neurology services. The costs of disease-modifying therapies in this group (>170,000 euro yearly) could be re-directed towards development of neurology services to optimize their management.

CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis.

Despite the fact that CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg cells) play a central role in maintaining self-tolerance and that IL-17-producing CD4(+) T cells (Th17 cells) are pathogenic in many autoimmune diseases, evidence to date has indicated that Th17 cells are resistant to suppression by human Foxp3(+) Treg cells. It was recently demonstrated that CD39, an ectonucleotidase which hydrolyzes ATP, is expressed on a subset of human natural Treg cells. We found that although both CD4(+)CD25(high)CD39(+) and CD4(+)CD25(high)CD39(-) T cells suppressed proliferation and IFN-gamma production by responder T cells, only the CD4(+)CD25(high)CD39(+), which were predominantly FoxP3(+), suppressed IL-17 production, whereas CD4(+)CD25(high)CD39(-) T cells produced IL-17. An examination of T cells from multiple sclerosis patients revealed a normal frequency of CD4(+)CD25(+)CD127(low)FoxP3(+), but interestingly a deficit in the relative frequency and the suppressive function of CD4(+)CD25(+)CD127(low)FoxP3(+)CD39(+) Treg cells. The mechanism of suppression by CD39(+) Treg cells appears to require cell contact and can be duplicated by adenosine, which is produced from ATP by the ectonucleotidases CD39 and CD73. Our findings suggest that CD4(+)CD25(+)Foxp3(+)CD39(+) Treg cells play an important role in constraining pathogenic Th17 cells and their reduction in multiple sclerosis patients might lead to an inability to control IL-17 mediated autoimmune inflammation.