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In the present study, one-dimensional advection-dispersion equation with variable coefficients is solved numerically with help of PDEPE in a finite porous domain. The pollutant is entering from the left end of the domain along the direction of the flow. Two different types of groundwater velocities have been considered, one rapidly decreasing with position and time and the other one being of sinusoidal nature over position and time. The dispersion coefficient is taken proportional to the groundwater velocity. Transport is included the first order decay and zero-order production parameters being proportional to the exponentially decreasing function with position and time and also being of sinusoidal nature over position and time. The nature of pollutant and porous medium are considered chemically non-reactive. Initially, porous domain is considered not to be solute free. Numerical solutions are obtained for uniform and varying type point sources. In heterogeneous porous media, variations in the parameters of solute transport such as: seepage velocities, dispersion coefficients etc. can be easily deal through numerical models. The effects of various physical parameters on solute concentration profiles are illustrated graphically.

We describe the case of a 33-year-old pre-eclamptic Bhutanese woman who presented with postpartum hallucinations. We discuss our concern for postpartum psychosis versus a culturally appropriate phenomenon, with her diagnostic picture complicated by the use of interpreters and the intersection of culture and medicine. Top experts in the consultation-liaison (CL) field provide guidance for this clinical scenario based on their experience and a review of the available literature. This case highlights both the impact of language barriers and the challenges of interpreting psychiatric symptoms within a cultural context. Key teaching points include differential diagnoses for postpartum hallucinations, the importance of interpreting patient presentations within their unique cultural contexts and identities, and the impact of language interpretation on patient care. Specifically, we offer guidance on differentiating postpartum psychosis from a culturally appropriate phenomenon.

Management of multiple sclerosis and neuroimmunologic disorders has become increasingly complex because of the expanding number of recognized neuroimmune disorders, increased number of therapeutic options, and multidisciplinary care management needs of people with multiple sclerosis and neuroimmunologic disorders. More subspecialists are needed to optimize care of these patients, and many fellowship programs have been created or expanded to increase the subspecialty workforce. Consequently, defining the scope and standardizing fellowship training is essential to ensure that trainees receive high-quality training. A workgroup was created to develop a consensus fellowship curriculum to serve as a resource for all current and future training programs. This curriculum may also serve as a basis for future accreditation efforts.

ObjectiveIllustrate that some neuroinflammatory diseases may respond best to antiproliferative therapies rather than immunomodulatory therapies.BackgroundGenomics are increasingly employed in the diagnostic armamentarium of refractory neuro-inflammatory diseases. Metagenomic next-generation sequencing is used to detect pathogens and germline genetic testing is used to detect inborn errors of the immune system. Genetic testing of tissue can identify somatic mutations for targeted treatment. MEK-inhibitors are an emerging treatment for RAS/MAPK pathway mutated diseases which include some neuro-inflammatory mimics like neuro-histiocytoses.Design/MethodsNA.ResultsPreviously healthy 12-year-old girl presented with 1 month of diplopia and headaches. Her brother has clinically diagnosed NF1 (café-au-lait macules, cutaneous neurofibromas). Exam notable for right third nerve palsy. MRI showed T2/FLAIR hyperintense lesions of the right temporal lobe, basal ganglia, and cervical through thoracic cord, nodular leptomeningeal enhancement along the entire spinal cord, and right middle cerebral artery vessel wall enhancement. CSF: WBC 6/mm3(62% lymphocytes 37% monocytes), protein 133 mg/dL. She improved with pulse methylprednisolone and maintenance steroids. At 5 months, she developed malignant elevated intracranial pressure with CSF OP >50 cm water, bradycardia, and encephalopathy requiring weekly LPs. Brain biopsy showed astrocytic and microglial activation without significant inflammation. No histiocytes were noted. There was no evidence of neoplasia or infection. She was tried on anakinra. At 6 months, she developed left third nerve palsy and seizures. For weeks, she required daily LPs for intracranial hypertension despite placement of ventriculoperitoneal shunt. Additional treatments included infliximab, steroids, and siltuximab. NGS from brain biopsy identified 2 NF1 mutations (nonsense, splicing). Allele fractions: 6% and 9%. Her mental status and need for frequent LP improved dramatically with trametinib.ConclusionsThis case illustrates the importance of considering somatic genomic testing of neural tissue even when the neuropathology is not suggestive of a malignancy or histiocytosis as this can inform newer molecularly targeted therapeutic options.

Case Summary: While multiple sclerosis (MS) disease activity declines during pregnancy, there are situations where MS relapses in pregnant women do occur. Mild relapses may be managed with close observation, but severe refractory relapses may require more aggressive management. We describe two cases of rituximab used for severe, refractory multiple sclerosis relapses during pregnancy. Rituximab did not appear to complicate either pregnancy and there were no further relapses for either women. Rituximab should not be overlooked in rare refractory cases, such as the rebound relapses sometimes seen following the discontinuation of lymphocyte-sequestering disease-modifying therapies.

Spinal adhesive arachnoiditis (SAA) is a rare, but often devastating, cause of compressive myelopathy. We report a patient with SAA resulting in a longitudinally extensive T2-hyperintense spinal cord lesion with initial nodular pial and dural enhancement mimicking neurosarcoidosis. Neurologists should be aware of this entity, especially in patients who have pertinent risk factors, such as prior meningitis, spinal cord trauma, or surgery.

BackgroundThere are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis.MethodsWe enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.ResultsOf 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.ConclusionsIn a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Background: Evidence supports that cannabinoids reduce self-reported spasticity and neuropathic pain in people with MS (PwMS), and legal access to cannabis for medical and recreational use continues to rise. However, there are limited data regarding patterns of cannabis use and perceived benefits of cannabis among PwMS in the US. This study describes the prevalence of cannabis use, routes of administration, perceived benefit of cannabis for MS, and characteristics associated with cannabis use and perception of benefit among a population of PwMS living in two states where cannabis is legal for both medical and recreational use. Methods: A survey about treatments used by PwMS, focusing on complementary and alternative medicine (CAM), was sent to PwMS living in Oregon and Southwest Washington. This survey included questions about current and past cannabis use, route of cannabis administration, and perceived benefits, as well as personal demographics. Results: Of the 1188 returned surveys, 1000 had at least 75% complete survey responses and also completed the questions about current and past cannabis use. Thirty percent (n=303) of respondents reported currently using cannabis, 21% (n=210) used in the past but not currently, and 49% (n=487) had never used cannabis. Among current users, rates of use by smoking, vaping, topicals, tinctures and oils, or edibles were similar (35-46%), and most (59%) reported using multiple routes of administration. Most (64-78%, varying by route) current and past users reported cannabis being very or somewhat beneficial for their MS. The odds of current cannabis use were higher in PwMS who: 1) were younger (OR 2.24 [95% CI 1.39-3.61] for those age 18-40 compared with age >60]; 2) had lower household income (OR 3.94 [95% CI 2.55-6.09] with annual income $100k); 3) had secondary progressive MS (OR 1.77 [95% CI 1.07-2.92]); and 4) had more than minimal MS disability (OR 2.05 [95% CI 1.03-4.10] for those using a walker compared to those with none/minimal disability). The odds of perceiving cannabis as beneficial for MS were higher in: 1) younger individuals (OR 5.61 [95% CI 2.62-11.98] for those age 18-40 compared with age >60); 2) those with lower household income (OR 3.35 [95% CI 1.65-6.80] with annual income $100k), 3) those not currently using disease modifying therapies (OR 2.32 [95% CI 1.30-4.13]), and 4) those with the greatest disability (OR 17.96; [95% CI 2.00-161.22]). Conclusion: In this survey, 30% of PwMS reported currently using cannabis for their MS, mostly by multiple routes of administration, and most of these people report this being helpful for their MS. People who were younger, had lower household income, had progressive disease, and had more than minimal disability were more likely to use cannabis and report it was beneficial for their MS. People who were not using disease modifying therapies were also more likely to report benefit from cannabis use.

Background:TNFi are effective treatments for multiple immune-mediated inflammatory diseases. There are five TNFi’s approved for clinical use. Despite their acceptable safety/efficacy profile, serious side effects have been reported, including central and peripheral nervous system demyelinating diseases (DD).ͥ Causation remains controversial and there is a paucity of data on the long-term outcomes in these patients.Objectives:To assess long term outcomes in patients with DD related to TNFi use.Methods:We conducted a database search and then retrospective chart review to identify patients with potential TNFi related neurologic events at a university medical center between 2006 and 2016. 15 total patients (13 living, 2 deceased) were ultimately identified. Six were able to be contacted by phone to assess their current status. Four of these patients were able to attend a one time-visit to complete a neurologic assessment and musculoskeletal examination. Interviews over the phone or in person were used to complete multiple assessments for disability.Results:15 patients with DD were identified from among 4600 patients on TNFi’s for various indications (0.3%). Mean duration of follow-up was 6.8 years. Neurologic symptoms occurred >12 months after starting a TNFi in 8/15 (53%) patients. 47% of patients had been exposed to two or more TNFi’s. 40% received some form of treatment for their DD, including MS disease modifying therapies, IVIG and immunosuppression. No patients experienced worsening DD after stopping their TNFi except for one patient with MS who experienced a repeat flare. Two of three patients diagnosed with MS after TNFi had a first degree relative with MS. 3/15 (20%) experienced complete resolution of their symptoms. Two patients were deceased; cause of death was thought not directly related to DD on chart review.Conclusion:Prevalence of DD after TNFi exposure was low at our center, consistent with previously published data. Presentations included both central and peripheral demyelinating events. With the exception of one patient who developed MS, withdrawal of TNFi’s appeared to halt further progression or development of new neurologic symptoms. It is unclear if treatment for DD is beneficial after diagnosis and TNFi withdrawal.Patient Data:Table.Baseline characteristics and 6-month outcome of patients who have switched from originator to ABP 501AgeSexIndicationTNFi at time of eventNeurologic Presentation/DiagnosisDuration of follow-up, yearsDD status at last follow-up32FJIAEAtaxia, paresthesias, dysarthria, nystagmus, tetraparesis11Persistent despite tx58MPsAGParesthesias9Improved no tx38FASANumbness and weakness5Resolved, no tx54MPsAEParesthesias, cognitive impairment10Persistent, no tx51FASAIncontinence, paresthesias10Persistent, no tx26FCrohn’sAOptic neuritis11Resolved, no tx49MPsAAMultifocal motor neuropathy3Resolved after tx37MPsAAWeakness, spasticity, paresthesias, optic neuritis9Persistent, on tx33FPsAAOptic neuritis, transverse myelitis (MS)5Flared, no tx59FPsAETransverse myelitis (MS)9Deceased45FASITransverse myelitis7Deceased70MRAACIDP1Received treatment but lost to follow-up34FCrohn’sASmall fiber neuropathy11Persistent, no tx62FRAEOptic neuritisLost to follow-up after initial visit42MUveitis, retinal vasculitisAParesthesias (MS)1Persistent, on txJuvenile idiopathic arthritis (JIA), Psoriatic arthritis (PsA), Ankylosing spondylitis (AS), Rheumatoid Arthritis (RA)Adalimumab (A), Etanercept (E), Golimumab (G), Infliximab (I)Treatment (tx)References:[1]ͥKemanetzoglou E, Andreadou E. CNS Demyelination with TNF-α Blockers.Curr Neurol Neurosci Rep. 2017;17(4):36. doi:10.1007/s11910-017-0742-1Disclosure of Interests:Nicholas Stienstra: None declared, Michael Lane: None declared, Joel Horton: None declared, Anand Kumthekar: None declared, Nishad Sathe: None declared, Christy Sunny: None declared, Vijayshree Yadav Consultant of: Alexion (one time consulting fee), Atul Deodhar Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB

Background The role that dietary interventions can play in multiple sclerosis (MS) management is of huge interest amongst patients and researchers but data evaluating this is limited. Possible effects of a very-low-fat, plant-based dietary intervention on MS related progression and disease activity as measured by brain imaging and MS related symptoms have not been evaluated in a randomized-controlled trial. Despite use of disease modifying therapies (DMT), poor quality of life (QOL) in MS patients can be a significant problem with fatigue being one of the common disabling symptoms. Effective treatment options for fatigue remain limited. Emerging evidence suggests diet and vascular risk factors including obesity and hyperlipidemia may influence MS disease progression and improve QOL. Objectives To evaluate adherence, safety and effects of a very-low-fat, plant-based diet (Diet) on brain MRI, clinical [MS relapses and disability, body mass index (BMI)] and metabolic (blood lipids and insulin) outcomes, QOL [Short Form-36 (SF-36)], and fatigue [Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS)], in relapsing-remitting MS (RRMS). Methods This was a randomized-controlled, assessor-blinded, one-year long study with 61 participants assigned to either Diet (N=32) or wait-listed (Control, N=29) group. Results The mean age (years) [Control−40.9±8.48; Diet−40.8±8.86] and the mean disease duration (years) [Control −5.3±3.86; Diet−5.33±3.63] were comparable between the two groups. There was a slight difference between the two study groups in the baseline mean expanded disability status scale (EDSS) score [Control−2.22±0.90; Diet−2.72±1.05]. Eight subjects withdrew (Diet, N=6; Control, N=2). Adherence to the study diet based on monthly Food Frequency Questionnaire (FFQ) was excellent with the diet group showing significant difference in the total fat caloric intake compared to the control group [total fat intake/total calories averaged ~15% (Diet) versus ~40% (Control)]. The two groups showed no differences in brain MRI outcomes, number of MS relapses or disability at 12 months. The diet group showed improvements at six months in low-density lipoprotein cholesterol (Δ=−11.99mg/dL; p =0.031), total cholesterol (Δ=−13.18mg/dL; p =0.027) and insulin (Δ=−2.82mg/dL; p =0.0067), mean monthly reductions in BMI (Rate=−1.125kg/m2 per month; p p =0.0010); MFIS (Rate=−0.233 points/month; p =0.0011)] during the 12-month period. Conclusions While a very-low fat, plant-based diet was well adhered to and tolerated, it resulted in no significant improvement on brain MRI, relapse rate or disability as assessed by EDSS scores in subjects with RRMS over one year. The diet group however showed significant improvements in measures of fatigue, BMI and metabolic biomarkers. The study was powered to detect only very large effects on MRI activity so smaller but clinically meaningful effects cannot be excluded. The diet intervention resulted in a beneficial effect on the self-reported outcome of fatigue but these results should be interpreted cautiously as a wait-list control group may not completely control for a placebo effect and there was a baseline imbalance on fatigue scores between the groups. If maintained, the improved lipid profile and BMI could yield long-term vascular health benefits. Longer studies with larger sample sizes are needed to better understand the long-term health benefits of this diet.

Background In 2001, we conducted a survey on use of complementary and alternative medicine (CAM) in people with multiple sclerosis (pwMS) in Oregon and Southwest Washington to treat their disease. Objectives, Methods In 2018, we administered a revised survey in the same region to describe updated patterns of CAM use in pwMS and to compare changes in use, perceived benefit, and patterns of communication between participants and providers regarding CAM over the past 17 years. Results 81% of respondents in 2018 (n = 1014) used a CAM supplement (vitamins, minerals, herbs), 39% used mind-body therapies (mindfulness, massage), 41% used specific diet, and 81% used exercise to treat their multiple sclerosis. Since 2001, use of supplements, exercise, and mind-body therapies have increased (65% to 81%, 67 to 81%, and 14% to 39%). Participants were also nine times more likely to speak to their neurologists about CAM use (6.7% to 55.4%). In 2018, factors associated with CAM use included female sex, progressive disease, and longer time since multiple sclerosis diagnosis. Conclusion These findings highlight the high and increasing prevalence of CAM use in pwMS and factors associated with CAM use, and underscore the importance of research to investigate safety and efficacy of these therapies.

Background Lipoic acid, an antioxidant, has beneficial effects in experimental acute optic neuritis and autoimmune encephalomyelitis. Optical coherence tomography can detect retinal nerve fiber layer thinning, representing axonal degeneration, approximately 3–6 months after acute optic neuritis. Objective To determine whether lipoic acid is neuroprotective in acute optic neuritis. Methods A single-center, double-blind, randomized, placebo controlled, 24-week trial. Intervention included 6 weeks of once daily lipoic acid (1200 mg) or placebo within 14 days of acute optic neuritis diagnosis. The primary outcome was the mean difference in affected eye retinal nerve fiber layer (RNFL) thickness from baseline to 24 weeks. Results We enrolled 31 subjects (placebo n=16; lipoic acid n=15; average age 38.6 years (standard deviation (SD) 10.3)). Affected eye mean global RNFL thickness (µm) in the lipoic acid group decreased from 108.47 (SD 26.11) at baseline to 79.31 (SD 19.26) at 24 weeks. The affected eye RNFL in the placebo group decreased from 103.67 (SD 18.04) at baseline to 84.43 (SD 20.94) at 24 weeks. Unaffected eye RNFL thickness did not significantly change in either group over 24 weeks. Conclusion Six weeks of oral lipoic acid supplementation after acute optic neuritis is safe and well tolerated; however, because of insufficient recruitment, we could not conclude that lipoic acid treatment was neuroprotective in acute optic neuritis.

BACKGROUND: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses.METHODS: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18-58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0-6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0-5·5 vs 6·0-6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181.FINDINGS: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66-1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74-1·53; nominal p=0·753) or the T25FW (0·98, 0·74-1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40-0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108-221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred.INTERPRETATION: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components.FUNDING: Biogen.

Little is known about mechanisms that drive the development of progressive multiple sclerosis (MS), although inflammatory factors, such as macrophage migration inhibitory factor (MIF), its homolog D-dopachrome tautomerase (D-DT), and their common receptor CD74 may contribute to disease worsening. Our findings demonstrate elevated MIF and D-DT levels in males with progressive disease compared with relapsing-remitting males (RRMS) and female MS subjects, with increased levels of CD74 in females vs. males with high MS disease severity. Furthermore, increased MIF and D-DT levels in males with progressive disease were significantly correlated with the presence of two high-expression promoter polymorphisms located in the MIF gene, a −794CATT5–8 microsatellite repeat and a −173 G/C SNP. Conversely, mice lacking MIF or D-DT developed less-severe signs of experimental autoimmune encephalomyelitis, a murine model of MS, thus implicating both homologs as copathogenic contributors. These findings indicate that genetically controlled high MIF expression (and D-DT) promotes MS progression in males, suggesting that these two factors are sex-specific disease modifiers and raising the possibility that aggressive anti-MIF treatment of clinically isolated syndrome or RRMS males with a high-expresser genotype might slow or prevent the onset of progressive MS. Additionally, selective targeting of MIF:CD74 signaling might provide an effective, trackable therapeutic approach for MS subjects of both sexes.

Multiple Sclerosis (MS) is a chronic, disabling neurologic disease that has its onset in young adulthood. While the knowledge about underlying pathogenesis of MS has improved significantly over the last few decades, the exact cause still eludes us. Despite the availability of several United States Food and Drug Administration-approved disease-modifying therapies (DMT) for MS in the last two decades, the disease remains disabling for many. DMT use is limited by its partial effectiveness, significant side effects in many cases, and high cost that leads people with MS (PwMS) to look for alternative management options. Dietary intervention as a possible mode to help MS seems very appealing to PwMS; however, scientific data supporting this notion remains sparse. New information on the role of various non-MS health factors, especially vascular disease risk factors such as hypertension, hyperlipidemia, salt intake, and obesity, that may play a role in MS pathogenesis appears very intriguing as it may partly explain the heterogeneity seen in MS activity and disability. This review will highlight the emerging information on various dietary approaches that may affect MS and their possible underlying mechanism.

Stressful life events are associated with worsening neurological symptoms and decreased quality of life in multiple sclerosis (MS). Mindful consciousness can alter the impact of stressful events and has potential to improve health outcomes in MS. This study evaluated the relationship between trait mindfulness and perceived stress, coping, and resilience in people with MS. Quality of life was assessed as a secondary outcome. One hundred nineteen people with confirmed MS completed the Five-Facet Mindfulness Questionnaire, Perceived Stress Scale, Brief Coping Orientation for Problem Experiences, Connor-Davidson Resilience Scale, and Medical Outcome Study Short Form–36. Greater trait mindfulness was significantly associated with decreased psychological stress, better coping skills, increased resilience, and higher quality of life. After investigators controlled for confounders, mindfulness accounted for 25% of the variation in perceived stress scores and 44% of the variation in resilience scores. Results support further investigation of mindfulness training to enhance psychological resilience and improve well-being for those living with MS.

Lipoic acid (LA) exhibits antioxidant and anti-inflammatory properties; supplementation reduces disease severity and T lymphocyte migration into the central nervous system in a murine model of multiple sclerosis (MS), and administration in secondary progressive MS (SPMS) subjects reduces brain atrophy compared to placebo. The mechanism of action (MOA) of LA's efficacy in suppression of MS pathology is incompletely understood. LA stimulates production of the immunomodulator cyclic AMP (cAMP) in vitro. To determine whether cAMP could be involved in the MOA of LA in vivo, we performed a clinical trial to examine whether LA stimulates cAMP production in healthy control and MS subjects, and whether there are differences in the bioavailability of LA between groups. We administered 1200 mg of oral LA to healthy control, relapsing remitting MS (RRMS) and SPMS subjects, and measured plasma LA and cAMP levels in peripheral blood mononuclear cells (PBMCs). There were no significant differences between the groups in pharmacokinetic (PK) parameters. Healthy and SPMS subjects had increased cAMP at 2 h and 4 h post LA treatment compared to baseline, while RRMS subjects showed decreases in cAMP. Additionally, plasma concentrations of prostaglandin E2 (PGE(2), a known cAMP stimulator) were significantly lower in female RRMS subjects compared to female HC and SPMS subjects 4 h after LA ingestion. These data indicate that cAMP could be part of the MOA of LA in SPMS, and that there is a divergent response to LA in RRMS subjects that may have implications in the efficacy of immunomodulatory drugs. This clinical trial, “Defining the Anti-inflammatory Role of Lipoic Acid in Multiple Sclerosis,” NCT00997438, is registered at https://clinicaltrials.gov/ct2/show/record/NCT00997438

Objective: To characterize patients misdiagnosed with multiple sclerosis (MS). Methods: Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS. Results: Of 110 misdiagnosed patients, 51 (46%) were classified as “definite” and 59 (54%) “probable” misdiagnoses according to study definitions. Alternate diagnoses included migraine alone or in combination with other diagnoses 24 (22%), fibromyalgia 16 (15%), nonspecific or nonlocalizing neurologic symptoms with abnormal MRI 13 (12%), conversion or psychogenic disorders 12 (11%), and neuromyelitis optica spectrum disorder 7 (6%). Duration of misdiagnosis was 10 years or longer in 36 (33%) and an earlier opportunity to make a correct diagnosis was identified for 79 patients (72%). Seventy-seven (70%) received disease-modifying therapy and 34 (31%) experienced unnecessary morbidity because of misdiagnosis. Four (4%) participated in a research study of an MS therapy. Leading factors contributing to misdiagnosis were consideration of symptoms atypical for demyelinating disease, lack of corroborative objective evidence of a CNS lesion as satisfying criteria for MS attacks, and overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms. Conclusions: Misdiagnosis of MS leads to unnecessary and potentially harmful risks to patients. Misinterpretation and misapplication of MS clinical and radiographic diagnostic criteria are important contemporary contributors to misdiagnosis.

Signs and symptoms of multiple sclerosis are usually attributed to demyelinating lesions in the spinal cord or cerebral cortex. The hypothalamus is a region that is often overlooked yet controls many important homeostatic functions, including those that are perturbed in multiple sclerosis. In this review we discuss how hypothalamic dysfunction may contribute to signs and symptoms in people with multiple sclerosis. While dysfunction of the hypothalamic-pituitary-adrenal axis is common in multiple sclerosis, the effects and mechanisms of this dysfunction are not well understood. We discuss three hypothalamic mechanisms of fatigue in multiple sclerosis: (1) general hypothalamic-pituitary-adrenal axis hyperactivity, (2) disordered orexin neurotransmission, (3) abnormal cortisol secretion. We then review potential mechanisms of weight dysregulation caused by hypothalamic dysfunction. Lastly, we propose future studies and therapeutics to better understand and treat hypothalamic dysfunction in multiple sclerosis. Hypothalamic dysfunction appears to be common in multiple sclerosis, yet current studies are underpowered and contradictory. Future studies should contain larger sample sizes and standardize hormone and neuropeptide measurements.

Multiple sclerosis (MS) is a chronic disabling disease of the CNS that affects people during early adulthood. Despite several US FDA-approved medications, the treatment options in MS are limited. Many people with MS explore complementary and alternative medicine (CAM) treatments to help control their MS and treat their symptoms. Surveys suggest that up to 70% of people with MS have tried one or more CAM treatment for their MS. People with MS using CAM generally report deriving some benefit from the therapies. The CAM therapies most frequently used include diet, omega-3 fatty acids and antioxidants. There is very limited research evaluating the safety and effectiveness of CAM in MS. The most promising among CAM therapies that warrant further investigation are a low-fat diet, omega-3 fatty acids, lipoic acid and vitamin D supplementation as potential anti-inflammatory and neuroprotective agents in both relapsing and progressive forms of MS. There is very limited research evaluating the safety and effectiveness of CAM in MS. However, in recent years, the NIH and the National MS Society have been actively supporting the research in this very important area.

Background Neurogenic stunned myocardium is an increasingly recognized cause of left ventricular apical ballooning, or takotsubo cardiomyopathy. We report the first case of neurogenic stunned myocardium as a result of limbic encephalitis. Methods This 73-year-old woman with anterograde and retrograde amnesia was investigated using electrocardiography, magnetic resonance imaging, and left ventricular angiography. Results Electrocardiography showed deep T-wave inversions in multiple leads, magnetic resonance imaging demonstrated increased signal on fluid-attenuated inversion recovery images symmetrically within the medial temporal lobes consistent with limbic encephalitis. Left ventricular angiography showed apical ballooning. Conclusions Because the insula has extensive interconnections with limbic structures, limbic encephalitis could lead to alterations in the sympathetic regulation of the insular cortex resulting in neurogenic stunned myocardium.

Complementary and alternative medicine (CAM) use is high in people with multiple sclerosis (MS), yet there are limited reports on safety and effectiveness of CAM in MS. Naturopathic medicine encompasses a broad range of CAM modalities and may improve quality of life in patients with MS.To assess quality of life in MS subjects who received interventions designed to "model" the "whole practice" of naturopathy.A pilot, randomized, controlled study with a 6-month intervention period.Participants who met criteria for clinically definite MS.The 3 intervention arms were usual care, naturopathic medicine plus usual care, and MS education plus usual care.The primary outcome measure was quality of life (36-item short form health survey [SF-36]). Secondary outcome measures included fatigue (Modified Fatigue Impact Scale); depression (Beck Depression Inventory); cognition battery (Stroop test and Paced Auditory Serial Addition Test 3), and neurologic impairment (Expanded Disability Status Scale [EDSS] and Multiple Sclerosis Functional Composite). Adverse event reporting and laboratory measures were used to assess safety.Forty-five (45) participants (15 per group) were randomized and all completed the 6-month intervention. There were no significant differences between groups on any outcome measure. There was a trend in favoring the naturopathic group in the General Health subscale of the SF-36 (p = 0.11), Timed Walk (p = 0.11), and neurologic impairment (EDSS) (p = 0.07). There was a trend favoring the Education group in the Stroop attention test (p = 0.07). There was no difference between groups in adverse events or laboratory changes.Naturopathic medicine combined with usual care for MS showed a trend in improvement in the General Health subscale of the SF-36, Timed Walk, and neurologic impairment. Evaluation of naturopathic medicine, as a multimodality regimen, warrants further investigation.

Several randomized trials have demonstrated potential benefit of cannabis derivatives in the symptomatic treatment of multiple sclerosis (MS) patients. These provide class 1 and 2 evidence for cannabinoid product use for spasticity and pain in these patients. The precise best ratio or doses are not yet clear. The safety and potential long-term effects of these products on cognitive function in people with MS have not been evaluated. Since short-term memory and processing speed can be significantly impaired in many people with MS, the concern of potential cognitive impairment related to cannabis products needs consideration in clinical care and should be addressed in longer, prospective studies.

Complementary and alternative medicine (CAM) use is high among people with multiple sclerosis (MS), yet there are no reports on the association between CAM use and health-related quality of life (HRQL) in MS. To examine this relationship, a cross-sectional survey and SF-12 was used to collect demographic and HRQL data from 1667 survey respondents. Factors examined for their association with CAM use included, age, gender, race, self-reported disease severity, disease-modifying drug (DMT) use, MS duration, MS type, education level, physical and mental well-being. Multiple regression analysis revealed that female gender, high education level, longer MS duration, lower physical well-being and not using DMT were independent factors associated with both ‘ever’ and ‘current’ CAM use. The finding that a drop in physical component score (PCS) of the SF-12 is independently associated with an increased odds of ‘ever’ CAM use, ‘current’ CAM use, and ‘past’ CAM reflect an association of CAM use with PCS regardless of time of use. Although, temporality of this relationship cannot be established, as this was a cross-sectional study, a longitudinal study is warranted so that we can establish if HRQL is predictive for CAM use in MS.

We conducted a survey to study the prevalence and types of complementary and alternative medicine (CAM) therapies used by multiple sclerosis (MS) patients in Oregon and southern Washington. We mailed questionnaires to 5316 people using the mailing list of the Oregon Chapter of the National Multiple Sclerosis Society (NMSS). The survey enquired about demographic and clinical characteristics, use of various CAM and conventional therapies for MS by the respondents, and the respondents' self-perceived benefit ratings for the various therapies. We received 2026 responses (38%). Eighty-four percent of the respondents reported using one or more CAM therapies at some time after diagnosis of MS (CAM users), the most common being diet (59%), nutritional supplements (46%), herbal treatments (36%), and mind-body therapies (32%). CAM therapies rated as very beneficial included yoga; meditation; Swank, vegetarian and low-fat/low-cholesterol diets; and vitamin B12. Respondents also used conventional exercise (86%) and disease-modifying therapies (77%). Our survey confirms the common use of various CAM therapies by MS patients. CAM therapies such as low-fat diets, essential fatty acid supplements, yoga, and meditation appear to be frequently used and considered very beneficial by a significant number of MS patients and may warrant further exploration.

To describe the perceived benefit and satisfaction from complementary and alternative medicine (CAM) and conventional therapies and providers in MS.Cross-sectional mailed survey.One thousand nine hundred and thirteen respondents who were members of the Oregon Chapter of the National MS Society.The benefit rating of both conventional therapies and providers was significantly higher than for CAM therapies and providers (p0.001 and0.001). When stratifying satisfaction rating by MS disease severity, significant differences were found between CAM providers and neurologists, favoring CAM providers in those with moderate disease severity (p = 0.014) and favoring neurologists in those with severe disease severity (p = 0.032). CAM providers were rated significantly higher than MDs on the following: listening skills (p0.001), care and concern (p0.001), and patient empowerment (p0.001).Although MS patients report significant benefit from conventional therapies and providers; they may seek CAM providers for emotional support. The impact of emotional support gained from providers on quality of life in MS warrant further investigation.

The availability of the second-generation therapies for relapsing multiple sclerosis (MS), natalizumab and fingolimod, provides new treatment options for MS but also presents new challenges. Both natalizumab and fingolimod appear to be more effective than the interferon beta products and glatiramer acetate, but both have more safety problems than do the first-generation therapies. Treatment with natalizumab is associated with a significant risk of patients developing progressive multifocal leukoencephalopathy (PML), which the JC virus causes. We now are able to risk stratify MS patients into high- and low-risk groups for developing PML on the basis of the presence or absence of antibodies to the JC virus, history of prior use of immunosuppressants, and duration of therapy with natalizumab. Fingolimod appears to be associated with a risk of asystole and sudden death. It may also increase the risk of serious herpes infections and paradoxical activation of MS. More information is needed about these serious side effects from fingolimod to allow us to use it safely in patients.

Objective:To determine whether lipoic acid (LA), an endogenously produced antioxidant, slowed the whole-brain atrophy rate and was safe in secondary progressive MS (SPMS).Methods:Patients with SPMS aged 40–70 years enrolled in a single center, 2-year, double-blind, randomized trial of daily oral 1,200 mg LA vs placebo. Primary outcome was change in annualized percent change brain volume (PCBV). Secondary outcomes were changes in rates of atrophy of segmented brain, spinal cord, and retinal substructures, disability, quality of life, and safety. Intention-to-treat analysis used linear mixed models.Results:Participation occurred between May 2, 2011, and August 14, 2015. Study arms of LA (n = 27) and placebo (n = 24) were matched with mean age of 58.5 (SD 5.9) years, 61% women, mean disease duration of 29.6 (SD 9.5) years, and median Expanded Disability Status Score of 6.0 (interquartile range 1.75). After 2 years, the annualized PCBV was significantly less in the LA arm compared with placebo (−0.21 [standard error of the coefficient estimate (SEE) 0.14] vs −0.65 [SEE 0.10], 95% confidence interval [CI] 0.157–0.727, p = 0.002). Improved Timed 25-Foot Walk was almost but not significantly better in the LA than in the control group (−0.535 [SEE 0.358] vs 0.137 [SEE 0.247], 95% CI −1.37 to 0.03, p = 0.06). Significantly more gastrointestinal upset and fewer falls occurred in LA patients. Unexpected renal failure (n = 1) and glomerulonephritis (n = 1) occurred in the LA cohort. Compliance, measured by pill counts, was 87%.Conclusions:LA demonstrated a 68% reduction in annualized PCBV and suggested a clinical benefit in SPMS while maintaining favorable safety, tolerability, and compliance over 2 years.ClinicalTrials.gov identifier:NCT01188811.Classification of evidence:This study provides Class I evidence that for patients with SPMS, LA reduces the rate of brain atrophy.

To develop evidence-based recommendations for complementary and alternative medicine (CAM) in multiple sclerosis (MS).We searched the literature (1970-March 2011; March 2011-September 2013 MEDLINE search), classified articles, and linked recommendations to evidence.Clinicians might offer oral cannabis extract for spasticity symptoms and pain (excluding central neuropathic pain) (Level A). Clinicians might offer tetrahydrocannabinol for spasticity symptoms and pain (excluding central neuropathic pain) (Level B). Clinicians should counsel patients that these agents are probably ineffective for objective spasticity (short-term)/tremor (Level B) and possibly effective for spasticity and pain (long-term) (Level C). Clinicians might offer Sativex oromucosal cannabinoid spray (nabiximols) for spasticity symptoms, pain, and urinary frequency (Level B). Clinicians should counsel patients that these agents are probably ineffective for objective spasticity/urinary incontinence (Level B). Clinicians might choose not to offer these agents for tremor (Level C). Clinicians might counsel patients that magnetic therapy is probably effective for fatigue and probably ineffective for depression (Level B); fish oil is probably ineffective for relapses, disability, fatigue, MRI lesions, and quality of life (QOL) (Level B); ginkgo biloba is ineffective for cognition (Level A) and possibly effective for fatigue (Level C); reflexology is possibly effective for paresthesia (Level C); Cari Loder regimen is possibly ineffective for disability, symptoms, depression, and fatigue (Level C); and bee sting therapy is possibly ineffective for relapses, disability, fatigue, lesion burden/volume, and health-related QOL (Level C). Cannabinoids may cause adverse effects. Clinicians should exercise caution regarding standardized vs nonstandardized cannabis extracts and overall CAM quality control/nonregulation. Safety/efficacy of other CAM/CAM interaction with MS disease-modifying therapies is unknown.

Background Complementary and alternative medicine (CAM) use in individuals with multiple sclerosis (MS) is common, but its use has been limited by a lack of evidence-based guidance. Methods In March 2014, the American Academy of Neurology published the most comprehensive literature review and evidence-based practice guidelines for CAM use in MS. The guideline author panel reviewed and classified articles according to the American Academy of Neurology therapeutic scheme, and recommendations were linked to the evidence strength. Findings Level A recommendations were found for oral cannabis extract effectiveness in the short term for spasticity-related symptoms and pain and ineffectiveness of ginkgo biloba for cognitive function improvement in MS. Key level B recommendations included: Oral cannabis extract or a synthetic cannabis constituent, tetrahydrocannabinol (THC) is probably ineffective for objective spasticity improvement in the short term; Nabiximols oromucosal cannabinoid spray is probably effective for spasticity symptoms, pain, and urinary frequency, but probably ineffective for objective spasticity outcomes and bladder incontinence; Magnetic therapy is probably effective for fatigue reduction in MS; A low-fat diet with fish oil supplementation is probably ineffective for MS-related relapses, disability, fatigue, magnetic resonance imaging lesions, and quality of life. Several Level C recommendations were made. These included possible effectiveness of gingko biloba for fatigue; possible effectiveness of reflexology for MS-related paresthesias; possible ineffectiveness of the Cari Loder regimen for MS-related disability, symptoms, depression, and fatigue; and bee sting therapy for MS relapses, disability, fatigue, magnetic resonance imaging outcomes, and health-related quality of life. Implications Despite the availability of studies evaluating the effects of oral cannabis in MS, the use of these formulations in United States may be limited due to a lack of standardized, commercial US Food and Drug Administration–regulated preparations. Additionally, significant concern about prominent central nervous system–related adverse effects with cannabis was emphasized in the review.

Current US Food and Drug Administration (FDA)-approved disease-modifying therapies (DMTs) for multiple sclerosis (MS) require either self-injection (the interferon-β products and glatiramer acetate) or intravenous infusion (natalizumab and mitoxantrone). MS patients and their physicians have long wanted an effective oral DMT. That wait soon may be over. Earlier this year, the results of phase 3 clinical trials of two oral immunosuppressants for MS, fingolimod (AKA FTY720) and cladribine, were published, and both agents were found to be effective [1-3]. FDA approval of these oral agents for the treatment of MS will be a historic landmark in MS therapeutics. This review focuses on fingolimod. Fingolimod has a novel mechanism of action. It is a sphingosine 1-phosphate receptor modulator and inhibits lymphocyte egress from lymph nodes [4]. Previously, fingolimod showed beneficial effects on clinical and MRI parameters in a 3-year phase 2 study involving patients with relapsing MS [5]. This report reviews the results from the two phase 3 clinical trials of fingolimod in MS, one comparing two different doses of fingolimod with placebo [1] and the other comparing two different doses of fingolimod with interferon-β-1a [2]. First we discuss the results of the double-blind, placebo-controlled phase 3 trial of fingolimod called FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis) that compared two different doses of fingolimod with placebo [1]. We then discuss the 12-month double-blind, double-dummy study called TRANSFORMS (Trial Assessing Injectable Interferon Versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis) [2].

Background. Recombinant T-cell receptor ligand 1000 (RTL1000) is a single-chain protein construct containing the outer two domains of HLA-DR2 linked to myelin-oligodendrocyte-glycoprotein- (MOG-) 35–55 peptide. Analogues of RTL1000 induce T-cell tolerance, reverse clinical and histological disease, and promote repair in experimental autoimmune encephalomyelitis (EAE) in DR2 transgenic, C57BL/6, and SJL/J mice.Objective. Determining the maximum tolerated dose, safety, and tolerability of RTL1000 in multiple sclerosis (MS) subjects.Methods. This was a multicenter, Phase I dose-escalation study in HLA-DR2+MS subjects. Consecutive cohorts received RTL1000 doses of 2, 6, 20, 60, 200, and 100 mg, respectively. Subjects within each cohort randomly received a single intravenous infusion of RTL1000 or placebo at a 4 : 2 ratio. Safety monitoring included clinical, laboratory, and brain magnetic resonance imaging (MRI) evaluations.Results. Thirty-four subjects completed the protocol. All subjects tolerated the 2–60 mg doses of RTL1000. Doses ≥100 mg caused hypotension and diarrhea in 3 of 4 subjects, leading to discontinuation of further enrollment.Conclusions. The maximum tolerated dose of RTL1000 in MS subjects is 60 mg, comparable to effective RTL doses in EAE. RTL1000 is a novel approach for MS treatment that may induce immunoregulation without immunosuppression and promote neural repair.

The current understanding regarding the therapeutic potential of statins in central nervous system (CNS) autoimmune diseases evolved from studies in mice with experimental autoimmune encephalomyelitis (EAE). Migration of leukocytes from the blood into the CNS involves multiple steps, including chemo-attraction, cell adhesion, extravasation, and proteolytic degradation of biological membranes. Statin-mediated immunomodulation observed in mice may translate to humans. In vitro, statins inhibit the expression of intracellular adhesion molecule (ICAM)-1 and various chemokine receptors on activated peripheral mononuclear cells from both patients with multiple sclerosis (MS) and controls. Although statins are considered safe and well-tolerated drugs, they have side effects that should be considered. Statins have been shown to target key elements of the immunological cascade associated with glial and neural tissue damage in MS. In a recent placebo-controlled trial in patients with early MS, Statin treatment reduced development of newly occurring CNS inflammatory lesions.

Introduction: Cognitive impairment can be a significant disabling symptom in many people with multiple sclerosis (MS) leading to poor quality of life and social and economic burdens [1–3]. Prevalence of cognitive impairment in MS varies from 40% to 65% [1] and can affect people even in early MS [4–6]. The cognitive domains commonly affected in MS include short-term memory, information processing speed, and attention [1, 7]. Despite availability of disease-modifying therapies (DMTs) such as interferon β, glatiramer acetate, natalizumab, and fingolimod for relapsing forms of MS, the beneficial effect on cognitive improvement of these therapies remains far from being clear. In theory, controlling the MS disease activity with use of such therapies should slow the cognitive impairment but this has not been studied well in the completed clinical trials of the DMTs. In addition, none of these therapies seem effective at reversing established cognitive impairment, and symptomatic therapies for this MS problem are needed. In recent years, researchers have tested several therapies aimed specifically at improving cognition in MS. These therapies have included dietary supplements, such as gingko biloba [8, 9], and drugs used in treatment of cognitive dysfunction in Alzheimer’s disease (AD) such as the cholinesterase inhibitors donepezil hydrochloride [10, 11] and rivastigmine [12–14], in which the preliminary studies showed mixed results. We describe here two recent large trials that tested memantine and donepezil for treatment of MS-related cognitive dysfunction and showed them to be ineffective [15, 16]. Donepezil hydrochloride (marketed in the United States as Aricept®; Eisai, Tokyo, Japan) is a centrally acting cholinesterase inhibitor that is US Food and Drug Administration (FDA) approved for symptomatic treatment of mild to moderate dementia in AD [17]. Donepezil’s mechanism of action involves increasing acetylcholine in the neuronal pathways affected in AD. Donepezil is administered in a dose of 5 to 10 mg per day. Memantine (marketed in United States as Namenda®; Forest Pharmaceuticals, St. Louis, MO), conversely, is an N-methyl-Daspartate (NMDA) receptor antagonist that is FDA approved for symptomatic treatment of moderate to severe dementia in AD [18] and can be given in doses up to 5 to 20 mg per day. NMDA receptors with glutamate as their key neurotransmitter have an important role in learning and memory function of the brain; and by blocking the actions of glutamate, memantine is thought to improve some aspects of cognitive dysfunction in AD. This editorial revisits the limitations that exist currently in the treatment of cognitive dysfunction in MS. The first study that we discuss here was conducted by Krupp et al. [16] studying the effects of donepezil on memory function in MS. The second study was conducted by Lovera et al. V. Yadav (*) :D. N. Bourdette Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, UHS-42, Portland, OR 97239, USA e-mail: yadavv@ohsu.edu

In multiple sclerosis (MS), compromised blood-brain barrier (BBB) integrity contributes to inflammatory T cell migration into the central nervous system. Matrix metalloproteinase-9 (MMP-9) is associated with BBB disruption and subsequent T cell migration into the CNS. The aim of this paper was to evaluate the effects of omega-3 fatty acids on MMP-9 levels and T cell migration. Peripheral blood mononuclear cells (PBMC) from healthy controls were pretreated with two types of omega-3 fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Cell supernatants were used to determine MMP-9 protein and activity levels. Jurkat cells were pretreated with EPA and DHA and were added to fibronectin-coated transwells to measure T cell migration. EPA and DHA significantly decreased MMP-9 protein levels, MMP-9 activity, and significantly inhibited human T cell migration. The data suggest that omega-3 fatty acids may benefit patients with multiple sclerosis by modulating immune cell production of MMP-9.

Background: Memantine, an NMDA antagonist, is effective for moderate to severe Alzheimer’s disease. Objective: Determine whether memantine improves cognitive performance (CP) among subjects with multiple sclerosis (MS) and cognitive impairment (CI). Methods: This double-blind, randomized, placebo-controlled trial (Clinicaltrials.gov NCT00300716) compared memantine 10 mg twice a day (4 week titration followed by 12 weeks on the highest tolerated dose) with placebo. The primary outcome was the change from baseline to exit on the Paced Auditory Serial Addition Test (PASAT) and the California Verbal Learning Test-II (CVLT-II) Long Delay Free Recall (LDFR). Secondary outcomes included additional neuropsychological tests; self-report measures of quality of life, fatigue, and depression; and family/caregiver reports of subjects’ CI and neuropsychiatric symptoms. Results: The differences between the groups on the change on the PASAT (placebo—memantine = 0.0 correct responses, 95% CI 3.4, 3.4; p = 0.9) and on CVLT-II LDFR (placebo—memantine =—0.6 words, 95% CI —2.1, 0.8; p = 0.4) as well as on the other cognitive tests were not significant. Subjects on memantine had no serious adverse events (AEs) but had more fatigue and neurological AEs as well as, per family members’ reports, less cognitive improvement and greater neuropsychiatric symptoms than subjects on placebo. Conclusion: Memantine 10 mg twice a day does not improve CP in subjects with MS, ages 18—65, without major depression, who have subjective cognitive complaints and perform worse than one SD below the mean on the PASAT or on the California Verbal Learning Test-II (total recall or delayed free recall).

Fatigue: Take Control is a novel program to teach fatigue management to people with multiple sclerosis (MS) following recommendations in the Fatigue and Multiple Sclerosis guideline. Fatigue: Take Control includes six 2-hour group sessions with DVD viewing, discussion and homework and accompanying participant and leader workbooks. While many people have participated in Fatigue: Take Control programs, its efficacy has not been determined. The objective of this study was to determine whether participation in Fatigue: Take Control reduces fatigue and increases self-efficacy in people with MS. Thirty participants were randomly assigned to a group who immediately participated in the program (FTC) or a wait-list group (WL). The primary outcome was the Modified Fatigue Impact Scale (MFIS) and secondary outcomes were the Multiple Sclerosis Self-Efficacy Scale (MSSE) and the Fatigue Severity Scale (FSS). The MFIS was administered on 10 occasions. Other measures were administered on four occasions. A mixed model tested the effects using all observations. Compared with the WL, the FTC group had significantly more improvement on the MFIS [F(1, 269) = 7.079, p = 0.008] and the MSSE [F(1, 111) = 5.636, p = 0.019]. No significant effect was found for the FSS. Across all visits, fatigue was significantly lower and self-efficacy was significantly higher for the FTC group compared with the WL group. This pilot study demonstrated significant effects in fatigue and self-efficacy among subjects taking the Fatigue: Take Control program, suggesting that this comprehensive program based on the Fatigue and Multiple Sclerosis guideline may be beneficial in MS.

Lipoic acid is a natural anti-oxidant available as an oral supplement from a number of different manufacturers. Lipoic acid administered subcutaneously is an effective therapy for murine experimental autoimmune encephalomyelitis, a model of multiple sclerosis. The aim of this study was to compare serum lipoic acid levels with oral dosing in patients with multiple sclerosis with serum levels in mice receiving subcutaneous doses of lipoic acid. We performed serum pharmacokinetic studies in patients with multiple sclerosis after a single oral dose of 1200 mg lipoic acid. Patients received one of the three different racemic formulations randomly: tablet (Formulation A) and capsules (Formulations B and C). Mice pharmacokinetic studies were performed with three different subcutaneous doses (20, 50 and 100 mg/kg racemic lipoic acid). The pharmacokinetic parameters included Maximum Serum Concentrations (Cmax in μg/ml) and area under the curve 0—infinity (AUC 0—infinity in μg*min/ml). We found mean Cmax and AUC 0—infinity in patients with multiple sclerosis as follows: group A ( N = 7) 3.8 ± 2.6 and 443.1 ± 283.9; group B ( N = 8) 9.9 ± 4.5 and 745.2 ± 308.7 and group C ( N = 8) 10.3 ± 3.8 and 848.8 ± 360.5, respectively. Mean Cmax and AUC 0—infinity in the mice were: 100 mg/kg lipoic acid: 30.9 ± 2.9 and 998 ± 245; 50 mg/kg lipoic acid: 7.6 ± 1.4 and 223 ± 20; 20 mg/kg lipoic acid: 2.7 ± 0.7 and 119 ± 33. We conclude that patients taking 1200 mg of lipoic acid from two of the three oral formulations achieved serum Cmax and AUC levels comparable to that observed in mice receiving 50 mg/kg subcutaneous dose of lipoic acid, which is a highly therapeutic dose in experimental autoimmune encephalomyelitis. A dose of 1200 mg oral lipoic acid can achieve therapeutic serum levels in patients with multiple sclerosis.

The naturally occurring antioxidant lipoic acid (LA) was first described as an essential cofactor for the conversion of pyruvate to Acetyl-CoA, a critical step in respiration. LA is now recognized as a compound that has many biological functions. Along with its reduced form dihydrolipoic acid (DHLA), LA reduces and recycles cellular antioxidants such as glutathione, and chelates zinc, copper and other transition metal ions in addition to heavy metals. LA can also act as a scavenger of reactive oxygen and nitrogen species. By acting as an insulin mimetic agent, LA stimulates glucose uptake in many different cell types and can also modulate insulin signaling. The p38 and ERK MAP kinase pathways, AKT and NFkappaB are all regulated by LA. In addition, LA activates the prostaglandin EP2 and EP4 receptors to stimulate the production of the small molecule cyclic adenosine 5' monophosphate (cAMP). These diverse actions suggest that LA may be therapeutically effective in treating oxidative stress associated diseases. This review discusses the known biochemical properties of LA, its antioxidant properties, its ability to modulate signal transduction pathways, and the recent progress made in the utilization of LA as a therapeutic alternative for multiple sclerosis, Alzheimer's disease and diabetic neuropathy.

Therapeutic vaccination using T-cell receptor (TCR) peptides from V genes commonly expressed by potentially pathogenic T cells remains an approach of interest for treatment of multiple sclerosis (MS) and other autoimmune diseases. We developed a trivalent TCR vaccine containing complementarity determining region (CDR) 2 peptides from BV5S2, BV6S5 and BV13S1 emulsified in incomplete Freund's adjuvant that reliably induced high frequencies of TCR-specific T cells. To evaluate induction of regulatory T-cell subtypes, immunological and clinical parameters were followed in 23 treatment-naive subjects with relapsing-remitting or progressive MS who received 12 monthly injections of the trivalent peptide vaccine over 1 year in an open-label study design. Prior to vaccination, subjects had reduced expression of forkhead box (Fox) P3 message and protein, and reduced recognition of the expressed TCR repertoire by TCR-reactive cells compared with healthy control donors. After three or four injections, most vaccinated MS subjects developed high frequencies of circulating interleukin (IL)-10-secreting T cells specific for the injected TCR peptides and significantly enhanced expression of FoxP3 by regulatory T cells present in both 'native' CD4+ CD25+ and 'inducible' CD4+ CD25- peripheral blood mononuclear cells (PBMC). At the end of the trial, PBMC from vaccinated MS subjects retained or further increased FoxP3 expression levels, exhibited significantly enhanced recognition of the TCR V gene repertoire apparently generated by perturbation of the TCR network, and significantly suppressed neuroantigen but not recall antigen responses. These findings demonstrate that therapeutic vaccination using only three commonly expressed BV gene determinants can induce an expanded immunoregulatory network in vivo that may optimally control complex autoreactive responses that characterize the inflammatory phase of MS.