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1.  Consensus Management of Gastrointestinal Events Associated with Delayed-Release Dimethyl Fumarate: A Delphi Study 
Neurology and Therapy  2015;4(2):137-146.
Introduction
Delayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF) is indicated for the treatment of patients with relapsing multiple sclerosis. Gastrointestinal (GI) adverse events (AEs) occur with DMF therapy.
Methods
We used a Delphi process to reach consensus among North American clinicians on effective real-world management strategies for GI AEs associated with DMF. Clinicians were asked to complete two rounds of questionnaires developed by a steering committee; consensus in round 2 was attained if ≥70% of respondents agreed on a particular strategy.
Results
Consensus was reached on several strategies to manage GI AEs, including administering DMF with food, slow titration, dose reduction, and use of symptomatic therapies.
Conclusion
These consensus strategies provide clinicians with information on real-world approaches used to address the tolerability of DMF in patients with multiple sclerosis.
Funding
Biogen.
Electronic supplementary material
The online version of this article (doi:10.1007/s40120-015-0037-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s40120-015-0037-x
PMCID: PMC4685868  PMID: 26525536
Delayed-release dimethyl fumarate; Delphi technique; Disease management; Multiple sclerosis; Health care surveys
2.  Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives 
The Lancet. Neurology  2015;14(2):208-223.
Progressive multiple sclerosis is characterized by the gradual accrual of disability independent of relapses and can occur with disease onset (primary progressive) or preceded by a relapsing disease course (secondary progressive). An effective disease modifying treatment for progressive multiple sclerosis has not been identified, and the results of clinical trials to date have been generally disappointing. Ongoing advances in our understanding of pathogenesis, identification of novel targets for neuro-protection, and improved outcome measures have the potential to lead to effective treatments for progressive multiple sclerosis. In this review lessons learned from previous clinical trials and perspectives from current trials in progressive multiple sclerosis are summarized. Promising clinical, imaging, and biological markers will also be reviewed, along with novel clinical trial designs.
doi:10.1016/S1474-4422(14)70264-9
PMCID: PMC4361791  PMID: 25772899
3.  Correlating Function and Imaging Measures of the Medial Longitudinal Fasciculus 
PLoS ONE  2016;11(1):e0147863.
Objective
To test the validity of diffusion tensor imaging (DTI) measures of tissue injury by examining such measures in a white matter structure with well-defined function, the medial longitudinal fasciculus (MLF). Injury to the MLF underlies internuclear ophthalmoparesis (INO).
Methods
40 MS patients with chronic INO and 15 healthy controls were examined under an IRB-approved protocol. Tissue integrity of the MLF was characterized by DTI parameters: longitudinal diffusivity (LD), transverse diffusivity (TD), mean diffusivity (MD) and fractional anisotropy (FA). Severity of INO was quantified by infrared oculography to measure versional disconjugacy index (VDI).
Results
LD was significantly lower in patients than in controls in the medulla-pons region of the MLF (p < 0.03). FA was also lower in patients in the same region (p < 0.0004). LD of the medulla-pons region correlated with VDI (R = -0.28, p < 0.05) as did FA in the midbrain section (R = 0.31, p < 0.02).
Conclusions
This study demonstrates that DTI measures of brain tissue injury can detect injury to a functionally relevant white matter pathway, and that such measures correlate with clinically accepted evaluation indices for INO. The results validate DTI as a useful imaging measure of tissue integrity.
doi:10.1371/journal.pone.0147863
PMCID: PMC4723147  PMID: 26800522
4.  Identifying the Start of Multiple Sclerosis Injury: A Serial DTI Study 
Background
The events leading up to the development of new multiple sclerosis (MS) lesions on conventional imaging is unknown. The purpose of this study is to use diffusion tensor imaging (DTI) to investigate pre-lesional changes in MS to better understand the pathological changes that lead to lesion development.
Methods
Twenty-one patients with relapsing MS starting natalizumab therapy underwent serial DTI for 12–18 months. Regions of interest were outlined within normal-appearing white matter and new gadolinium-enhancing lesions that developed over the course of the study. Images from all time points were coregistered and non-parametric regression was used to assess DTI changes prior to lesion appearance.
Results
31 newly-enhancing lesions were identified. Significant changes in transverse diffusivity (TD) (p<0.001), longitudinal diffusivity (LD) (p=0.025), mean diffusivity (MD) (p<0.001) and fractional anisotropy (FA) (p=0.04) were observed prior to gadolinium-enhancement. A progressive increase in TD and LD occurred up to 10 months prior to lesion development. DTI measures in normal appearing white matter remained unchanged over the study period.
Conclusion
A significant change in diffusion measures can be seen prior to gadolinium enhancement. Changes in TD drove changes in FA and MD, providing evidence for impaired myelin integrity prior to gadolinium enhancement. DTI may be a sensitive measure for early detection of inflammatory disease activity in MS.
doi:10.1111/jon.12082
PMCID: PMC4221810  PMID: 25370339
MRI; DTI; T2 lesions; multiple sclerosis; natalizumab; pre-lesional
5.  Delayed-Release Dimethyl Fumarate and Pregnancy: Preclinical Studies and Pregnancy Outcomes from Clinical Trials and Postmarketing Experience 
Neurology and Therapy  2015;4(2):93-104.
Introduction
Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) is an oral agent for the treatment of relapsing forms of multiple sclerosis (MS). No formal studies of DMF were conducted in pregnant women, although pregnancies have occurred during clinical trials and in the postmarketing setting.
Methods
Preclinical developmental and reproductive toxicology studies were performed with DMF in rats and rabbits. As of March 26, 2014, the DMF clinical development program included a total of 4132 subjects consisting of 2898 patients with MS, 320 psoriasis patients, 101 rheumatoid arthritis patients, and 813 healthy volunteers. Subjects were required to use reliable contraception and immediately discontinue treatment in the event of pregnancy.
Results
Animal studies showed no evidence of impaired fertility or teratogenicity with DMF. Overall as of June 30, 2014, 63 pregnancies were reported in clinical trials. Outcomes are known for 39 of 42 subjects receiving DMF and include 26 live births (67%), three spontaneous abortions (8%), and 10 elective terminations (26%); follow-up is ongoing in 2 cases and one patient was lost to follow-up. The incidence of spontaneous abortion in subjects exposed to DMF was consistent with the expected rate of early pregnancy loss in the general population (12–22%). A total of 135 pregnancies were reported in the postmarketing setting (spontaneous and solicited reports). Outcomes are known for 30 cases and include 10 live births, 13 spontaneous abortions, and 5 elective terminations; follow-up is ongoing in 103 cases and 2 patients have been lost to follow-up.
Conclusion
Although data are limited and all known exposures have occurred in the first trimester, no increased risk of fetal abnormalities or adverse pregnancy outcomes associated with gestational exposure to DMF has been observed.
Funding
Biogen, Inc.
Electronic supplementary material
The online version of this article (doi:10.1007/s40120-015-0033-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s40120-015-0033-1
PMCID: PMC4685863  PMID: 26662361
Clinical trial; Delayed-release dimethyl fumarate; Multiple sclerosis; Postmarketing; Preclinical; Pregnancy; Safety; Women
6.  Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study 
Neurology  2015;84(11):1145-1152.
Objective:
To evaluate the effects of oral delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on MRI lesion activity and load, atrophy, and magnetization transfer ratio (MTR) measures from the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) study.
Methods:
CONFIRM was a 2-year, placebo-controlled study of the efficacy and safety of DMF 240 mg twice (BID) or 3 times daily (TID) in 1,417 patients with relapsing-remitting multiple sclerosis (RRMS); subcutaneous glatiramer acetate 20 mg once daily was included as an active reference comparator. The number and volume of T2-hyperintense, T1-hypointense, and gadolinium-enhancing (Gd+) lesions, as well as whole brain volume and MTR, were assessed in 681 patients (MRI cohort).
Results:
DMF BID and TID produced significant and consistent reductions vs placebo in the number of new or enlarging T2-hyperintense lesions and new nonenhancing T1-hypointense lesions after 1 and 2 years of treatment and in the number of Gd+ lesions at week 24, year 1, and year 2. Lesion volumes were also significantly reduced. Reductions in brain atrophy and MTR changes with DMF relative to placebo did not reach statistical significance.
Conclusions:
The robust effects on MRI active lesion counts and total lesion volume in patients with RRMS demonstrate the ability of DMF to exert beneficial effects on inflammatory lesion activity in multiple sclerosis, and support DMF therapy as a valuable new treatment option in RRMS.
Classification of evidence:
This study provides Class I evidence of reduction in brain lesion number and volume, as assessed by MRI, over 2 years of delayed-release DMF treatment.
doi:10.1212/WNL.0000000000001360
PMCID: PMC4371413  PMID: 25681448
7.  Risk stratification and mitigation in multiple sclerosis 
The increasing availability of new agents to treat multiple sclerosis poses new challenges for clinicians who seek therapies that are both safe and effective for their patients. The introduction of additional effective therapies has been accompanied by the recognition of serious side effects. The clinician now must weigh both the benefits and risks of therapies to help patients decide which treatment best fits each patient’s risk/benefit profile. An optimal selection of therapies relies on a complete understanding of the risks of therapies and the factors that may help evaluate and mitigate those risks. An individualized treatment approach that incorporates patient and disease factors is needed for each patient. In this review we present risk stratification and mitigation strategies of disease modifying agents for multiple sclerosis.
doi:10.1016/j.msard.2014.05.003
PMCID: PMC4159169  PMID: 25221744
risk; mitigation; stratification; benefits; multiple sclerosis
8.  Clinical Significance of Gastrointestinal and Flushing Events in Patients with Multiple Sclerosis Treated with Delayed-Release Dimethyl Fumarate 
International Journal of MS Care  2015;17(5):236-243.
Background: In the phase 3 DEFINE and CONFIRM trials, flushing and gastrointestinal (GI) events were associated with delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) treatment in people with relapsing-remitting multiple sclerosis (MS). To investigate these events, a post hoc analysis of integrated data from these trials was conducted, focusing on the initial treatment period (months 0−3) with the recommended DMF dosage (240 mg twice daily).
Methods: Eligibility criteria included age 18 to 55 years, relapsing-remitting MS diagnosis, and Expanded Disability Status Scale score 0 to 5.0. Patients were randomized and received treatment with placebo (n = 771) or DMF (n = 769) for up to 2 years. Adverse events were recorded at scheduled clinic visits every 4 weeks.
Results: The incidence of GI and flushing events was highest in the first month of treatment. In months 0 to 3, the incidence of GI events was 17% in the placebo group and 27% in the DMF group and the incidence of flushing and related symptoms was 5% in the placebo group and 37% in the DMF group. Most GI and flushing events were of mild or moderate severity and resolved during the study. The events were temporally associated with the use of diverse symptomatic therapies (efficacy not assessed) and infrequently led to DMF discontinuation.
Conclusions: This integrated analysis indicates that in a clinical trial setting, GI and flushing events associated with DMF treatment are generally transient and mild or moderate in severity and uncommonly lead to treatment discontinuation.
doi:10.7224/1537-2073.2014-069
PMCID: PMC4599361  PMID: 26472945
9.  Is Neuromyelitis Optica with Advanced Age of Onset a Paraneoplastic Disorder? 
Background
Neuromyelitis optica (NMO) antibodies are commonly found in patients with NMO, a relapsing CNS inflammatory disorder. Recent evidence suggests that the NMO antibody may be a paraneoplastic marker. We evaluated this possibility using a health systemwide electronic medical record (EMR), allowing assessment of neoplasm both before and after the assessment of NMO seropositivity.
Design/Methods
An automated search of the Cleveland Clinic EMR was performed to identify patients with NMO serology testing (since 2006 ). Demographic, clinical, and imaging data were collected, including malignancy history.
Results
Forty-one patients NMO seropositive subjects were found. Average age at first clinical symptom was 38.7 years (SD 15.1), and 33 (80.5%) patients met formal criteria for NMO. Six malignancies were identified in 5 NMO seropositive patients (12.2%; age 48.7 yrs [SD 12.4] at presentation of NMO). Cancers included breast carcinoma (3 cases), lymphoma, cervical carcinoma, and leiomyosarcoma. The timing of malignancy diagnosis varied from 15 years prior to 14 years after the onset of neurologic symptoms. Among seropositive patients over age 50 years at the time of this review, malignancy was seen in 5/25 patients (20%). All 5 subjects fulfilled NMO clinical criteria.
Conclusions
A high prevalence of malignancy was found in NMO seropositive patients, although the sample size was small. These observations support the possibility of NMO as a paraneoplastic marker. If further studies confirm this relationship, clinicians may consider malignancy screening in individuals seropositive for NMO, particularly those over the age of 48.
doi:10.3109/00207454.2013.854208
PMCID: PMC4007377  PMID: 24111490
Neuromyelitis optica; paraneoplastic; cancer; myelitis; optic neuritis
10.  Efficacy and safety of delayed-release dimethyl fumarate in patients newly diagnosed with relapsing–remitting multiple sclerosis (RRMS) 
Background:
Delayed-release dimethyl fumarate (DMF) demonstrated efficacy and safety in the Phase 3 DEFINE and CONFIRM trials.
Objective:
To evaluate delayed-release DMF in newly diagnosed relapsing–remitting multiple sclerosis (RRMS) patients, in a post-hoc analysis of integrated data from DEFINE and CONFIRM.
Methods:
Patients included in the analysis were diagnosed with RRMS within 1 year prior to study entry and naive to MS disease-modifying therapy.
Results:
The newly diagnosed population comprised 678 patients treated with placebo (n = 223) or delayed-release DMF 240 mg BID (n = 221) or TID (n = 234). At 2 years, delayed-release DMF BID and TID reduced the annualized relapse rate by 56% and 60% (both p < 0.0001), risk of relapse by 54% and 57% (both p < 0.0001), and risk of 12-week confirmed disability progression by 71% (p < 0.0001) and 47% (p = 0.0085) versus placebo. In a subset of patients (MRI cohort), delayed-release DMF BID and TID reduced the mean number of new or enlarging T2-hyperintense lesions by 80% and 81%, gadolinium-enhancing lesion activity by 92% and 92%, and mean number of new non-enhancing T1-hypointense lesions by 68% and 70% (all p < 0.0001 versus placebo). Flushing and gastrointestinal events were associated with delayed-release DMF.
Conclusion:
Delayed-release DMF improved clinical and neuroradiological outcomes relative to placebo in newly diagnosed RRMS patients.
doi:10.1177/1352458514537013
PMCID: PMC4361464  PMID: 24990854
Delayed-release dimethyl fumarate; multiple sclerosis; newly diagnosed; efficacy; safety
11.  Health Literacy Association With Health Behaviors and Health Care Utilization in Multiple Sclerosis: A Cross-Sectional Study 
Background
Low health literacy is generally associated with poor health outcomes; however, health literacy has received little attention in multiple sclerosis (MS).
Objective
The aim of this study was to investigate the health literacy of persons with MS using the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry.
Methods
In 2012, we conducted a cross-sectional study of health literacy among NARCOMS participants. Respondents completed the Medical Term Recognition Test (METER) which assesses the ability to distinguish medical and nonmedical words, and the Newest Vital Sign (NVS) instrument which evaluates reading, interpretation, and numeracy skills. Respondents reported their sociodemographic characteristics, health behaviors, comorbidities, visits to the emergency room (ER), and hospitalizations in the last 6 months. We used logistic regression to evaluate the characteristics associated with functional literacy, and the association between functional literacy and health care utilization.
Results
Of 13,020 eligible participants, 8934 (68.6%) completed the questionnaire and were US residents. Most of them performed well on the instruments with 81.04% (7066/8719) having functional literacy on the METER and 74.62% (6666/8933) having adequate literacy on the NVS. Low literacy on the METER or the NVS was associated with smoking, being overweight or obese (all P<.001). After adjustment, low literacy on the METER was associated with ER visits (OR 1.28, 95% CI 1.10-1.48) and hospitalizations (OR 1.19, 95% CI 0.98-1.44). Findings were similar for the NVS.
Conclusions
In the NARCOMS cohort, functional health literacy is high. However, lower levels of health literacy are associated with adverse health behaviors and greater health care utilization.
doi:10.2196/ijmr.2993
PMCID: PMC3936300  PMID: 24513479
multiple sclerosis; health literacy; health care utilization; comorbidity; health behaviors
12.  Injury to a specific neural pathway detected by ultra-high-field MRI 
Neurology  2014;82(2):182-183.
We present evidence for the potential of ultra-high-field MRI to reveal injury due to multiple sclerosis (MS) not appreciated using lower field imaging. Internuclear ophthalmoplegia (INO) is an eloquent ocular motor syndrome that frequently affects patients with MS. The medial longitudinal fasciculus (MLF) is a periventricular, dorsomedial brainstem tegmentum pathway that yokes the 2 eyes in many types of eye movements.1,2 Further, T2 lesions localized in the region containing the MLF strongly associate with INO.3 However, the small diameter of the MLF and lack of contrast between the MLF and the surrounding neural tissue on conventional MRI hinder direct visualization.4 We recently demonstrated that the MLF is clearly visible on T2*-weighted images at 7T among healthy controls.4 In this contribution, we demonstrate that hallmarks of the MLF are at most weakly evident among patients with MS with chronic INO. Three patients with MS with bilateral chronic INO (as shown in the figure, D–F: aged 43/52/32 years, male/female/female, primary progressive/relapsing-remitting/relapsing-remitting, Expanded Disability Status Scale score 6.0/5.0/6.0) and 3 healthy controls participated in an institutional review board–approved study. Images were acquired on a 7T Philips Achieva (Philips Healthcare, Cleveland, OH). As T2-weighted (as opposed to T2*-weighted) contrast on 7T images was not optimal for lesion detection, images were also acquired on a 3T system to assess conventional T2 lesions. Imaging at 7T included a multiecho fast field echo scan with high spatial resolution and T2* weighting (0.13 × 0.13 × 3 mm voxels, echo time = 12, 16, 20, 24 ms), with scan planes lying perpendicular to the brainstem. Subsequent coregistration with FSL5 put all images in a common space. The MLF is clearly visible on all healthy controls at all echo times over a range of as much as 15 mm in the inferior-superior direction (figure, A–C) but considerably less conspicuous or not visible in any of the patients with MS with INO (figure, D–F). Conventional T2-weighted imaging at 3T indicates, in each patient, bilateral lesions in the pons overlapping with locations expected for the MLF and (figure, G–I) extensive and typical T2 cerebral lesions of MS. Differences in contrast between the MLF and surrounding neural tissue may arise from microscopic changes to myelin structure, readily observed at ultra-high fields, which are inaccessible to technology commonly used in clinical centers. Myelin sheaths result in enhanced contrast in T2*-weighted images.6 The lack of contrast in our MS cohort with INO likely arises from the reduction in myelin content and axons secondary to MS inflammatory injury.
doi:10.1212/WNL.0000000000000016
PMCID: PMC3897439  PMID: 24285615
13.  Treatment Discontinuation and Disease Progression with Injectable Disease-Modifying Therapies 
International Journal of MS Care  2013;15(4):194-201.
Injectable first-line disease-modifying therapies (DMTs) for multiple sclerosis (MS) are generally prescribed for continuous use. Accordingly, the various factors that influence patient persistence with treatment and that can lead some patients to switch medications or discontinue treatment may affect clinical outcomes. Using data from the North American Research Committee on Multiple Sclerosis (NARCOMS) database, this study evaluated participants' reasons for discontinuation of injectable DMTs as well as the relationship between staying on therapy and sustained patient-reported disease progression and annualized relapse rates. Participants selected their reason(s) for discontinuation from among 16 possible options covering the categories of efficacy, safety, tolerability, and burden, with multiple responses permitted. Both unadjusted data and data adjusted for baseline age, disease duration, disability, and sex were evaluated. Discontinuation profiles varied among DMTs. Participants on intramuscular interferon beta-1a (IM IFNβ-1a) and glatiramer acetate (GA) reported the fewest discontinuations based on safety concerns, although GA was associated with reports of higher burden and lower efficacy than other therapies. Difficulties with tolerability were more often reported as a reason for discontinuing subcutaneous (SC) IFNβ-1a than as a reason for discontinuing IM IFNβ-1a, GA, or SC IFNβ-1b. In the persistent therapy cohort, less patient-reported disability progression was reported with IM IFNβ-1a treatment than with SC IFNβ-1a, IFNβ-1b, or GA. These findings have relevance to clinical decision making and medication compliance in MS patient care.
doi:10.7224/1537-2073.2012-034
PMCID: PMC3883017  PMID: 24453783
14.  Efficacy of delayed-release dimethyl fumarate in relapsing-remitting multiple sclerosis: integrated analysis of the phase 3 trials 
Objective
Obtain a more precise estimate of the efficacy of delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) in relapsing multiple sclerosis (MS) and examine the consistency of DMF's effects across patient subgroups stratified by baseline demographic and disease characteristics.
Methods
A prespecified integrated analysis of the randomized, double-blind, placebo-controlled, Phase 3 DEFINE and CONFIRM trials was conducted.
Results
The intent-to-treat population comprised 2301 patients randomized to receive placebo (n = 771) or DMF 240 mg twice daily (BID; n = 769) or three times daily (TID; n = 761). At 2 years, DMF BID and TID reduced the annualized relapse rate by 49% and 49% (both P < 0.0001), risk of relapse by 43% and 47% (both P < 0.0001), risk of 12-week confirmed disability progression by 32% (P = 0.0034) and 30% (P = 0.0059), and risk of 24-week confirmed disability progression by 29% (P = 0.0278) and 32% (P = 0.0177), respectively, compared with placebo. In a subset of patients (MRI cohort), DMF BID and TID reduced the mean number of new/enlarging T2-hyperintense lesions by 78% and 73%, gadolinium-enhancing lesion activity by 83% and 70%, and mean number of new nonenhancing T1-hypointense lesions by 65% and 64% (all P < 0.0001 vs. placebo). Effects were generally consistent across patient subgroups.
Interpretation
The integrated analysis provides a more precise estimate of DMF's efficacy. DMF demonstrated a robust reduction in disease activity and a consistent therapeutic effect across patient subgroups.
doi:10.1002/acn3.148
PMCID: PMC4338952  PMID: 25750916
15.  Preferred Sources of Health Information in Persons With Multiple Sclerosis: Degree of Trust and Information Sought 
Background
Effective health communication is important for informed decision-making, yet little is known about the range of information sources used by persons with multiple sclerosis (MS), the perceived trust in those information sources, or how this might vary according to patient characteristics.
Objective
We aimed to investigate the sources of health information used by persons with MS, their preferences for the source of health information, and levels of trust in those information sources. We also aimed to evaluate how these findings varied according to participant characteristics.
Methods
In 2011, participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry were asked about their sources of health information using selected questions adapted from the 2007 Health Information National Trends (HINTS) survey.
Results
Of 12,974 eligible participants, 66.18% (8586/12,974) completed the questionnaire. Mass media sources, rather than interpersonal information sources, were the first sources used by 83.22% (5953/7153) of participants for general health topics and by 68.31% (5026/7357) of participants for MS concerns. Specifically, the Internet was the first source of health information for general health issues (5332/7267, 73.40%) and MS (4369/7376, 59.23%). In a logistic regression model, younger age, less disability, and higher annual income were independently associated with increased odds of use of mass media rather than interpersonal sources of information first. The most trusted information source was a physician, with 97.94% (8318/8493) reporting that they trusted a physician some or a lot. Information sought included treatment for MS (4470/5663, 78.93%), general information about MS (3378/5405, 62.50%), paying for medical care (1096/4282, 25.59%), where to get medical care (787/4282, 18.38%), and supports for coping with MS (2775/5031, 55.16%). Nearly 40% (2998/7521) of participants had concerns about the quality of the information they gathered.
Conclusions
Although physicians remain the most trusted source of health information for people with MS, the Internet is the first source of health information for most of them. This has important implications for the dissemination of health information.
doi:10.2196/jmir.2466
PMCID: PMC3650929  PMID: 23635393
multiple sclerosis; Internet; social media; trust; health information
17.  Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR-124 and reduced AMPA receptors 
Annals of neurology  2013;73(5):637-645.
Background
Hippocampal demyelination, a common feature of postmortem multiple sclerosis (MS) brains, reduces neuronal gene expression and is a likely contributor to the memory impairment that is found in greater than 40% of individuals with (MS). How demyelination alters neuronal gene expression is unknown.
Methods
To explore if loss of hippocampal myelin alters expression of neuronal microRNAs (miRNA), we compared miRNA profiles from myelinated and demyelinated hippocampi from postmortem MS brains and performed validation studies.
Findings
A network-based interaction analysis depicts a correlation between increased neuronal miRNAs and decreased neuronal genes identified in our previous study. The neuronal miRNA miR-124, was increased in demyelinated MS hippocampi and targets mRNAs encoding 26 neuronal proteins that were decreased in demyelinated hippocampus, including the ionotrophic glutamate receptors, AMPA 2 and AMPA3. Hippocampal demyelination in mice also increased miR-124, reduced expression of AMPA receptors and decreased memory performance in water maze tests. Remyelination of the mouse hippocampus reversed these changes.
Conclusion
We establish here that myelin alters neuronal gene expression and function by modulating the levels of the neuronal miRNA miR-124. Inhibition of miR-124 in hippocampal neurons may provide a therapeutic approach to improve memory performance in MS patients.
doi:10.1002/ana.23860
PMCID: PMC3679350  PMID: 23595422
Multiple sclerosis; myelin; microRNA
18.  MS disease activity in RESTORE 
Neurology  2014;82(17):1491-1498.
Objective:
RESTORE was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab.
Methods:
Eligible patients were relapse-free through the prior year on natalizumab and had no gadolinium-enhancing lesions on screening brain MRI. Patients were randomized 1:1:2 to continue natalizumab, to switch to placebo, or to receive alternative immunomodulatory therapy (other therapies: IM interferon β-1a [IM IFN-β-1a], glatiramer acetate [GA], or methylprednisolone [MP]). During the 24-week randomized treatment period, patients underwent clinical and MRI assessments every 4 weeks.
Results:
Patients (n = 175) were randomized to natalizumab (n = 45), placebo (n = 42), or other therapies (n = 88: IM IFN-β-1a, n = 17; GA, n = 17; MP, n = 54). Of 167 patients evaluable for efficacy, 49 (29%) had MRI disease activity recurrence: 0/45 (0%) natalizumab, 19/41 (46%) placebo, 1/14 (7%) IM IFN-β-1a, 8/15 (53%) GA, and 21/52 (40%) MP. Relapse occurred in 4% of natalizumab patients and in 15%–29% of patients in the other treatment arms. MRI disease activity recurred starting at 12 weeks (n = 3 at week 12) while relapses were reported as early as 4–8 weeks (n = 2 in weeks 4–8) after the last natalizumab dose. Overall, 50/167 patients (30%), all in placebo or other-therapies groups, restarted natalizumab early because of disease activity.
Conclusions:
MRI and clinical disease activity recurred in some patients during natalizumab interruption, despite use of other therapies.
Classification of evidence:
This study provides Class II evidence that for patients with MS taking natalizumab who are relapse-free for 1 year, stopping natalizumab increases the risk of MS relapse or MRI disease activity as compared with continuing natalizumab.
doi:10.1212/WNL.0000000000000355
PMCID: PMC4011468  PMID: 24682966
19.  Advanced MRI in Multiple Sclerosis: Current Status and Future Challenges 
Neurologic clinics  2011;29(2):357-380.
Synopsis
Magnetic resonance imaging (MRI) has rapidly become a leading research tool in the study of multiple sclerosis (MS). Conventional imaging is useful in diagnosis and management of the inflammatory stages of MS, but has limitations in describing the degree of tissue injury as well as the cause of progressive disability seen in the later stages of disease. Advanced MRI techniques hold promise to fill this void. Magnetization transfer imaging is a widely available technique that can characterize demyelination and may be useful in measuring putative remyelinating therapies. Diffusion tensor imaging describes the three-dimensional diffusion of water and holds promise in characterizing neurodegeneration and putative neuroprotective therapies. Spectroscopy measures the imbalance of cellular metabolites and could help unravel the pathogenesis of neurodegeneration in MS. Functional (f) MRI can be used to understand the functional consequences of MS injury, including the impact on cortical function and compensatory mechanisms. These imaging tools hold great promise to increase our understanding of MS pathogenesis and provide greater insight into the efficacy of new MS therapies.
doi:10.1016/j.ncl.2010.12.011
PMCID: PMC3073625  PMID: 21439446
MRI; imaging; magnetization transfer imaging; spectroscopy; functional MRI; diffusion tensor imaging
20.  CORTICAL REMYELINATION: A NEW TARGET FOR REPAIR THERAPIES IN MULTIPLE SCLEROSIS 
Annals of neurology  2012;72(6):918-926.
Objective
Generation and differentiation of new oligodendrocytes in demyelinated white matter is the best described repair process in the adult human brain. However, remyelinating capacity falters with age in patients with multiple sclerosis. (MS). Since demyelination of cerebral cortex is extensive in brains from MS patients, we investigated the capacity of cortical lesions to remyelinate and directly compared the extent of remyelination in lesions that involve cerebral cortex and adjacent subcortical white matter.
Methods
Postmortem brain tissue from 22 patients with MS (age 27 to 77 years) and 6 subjects without brain disease were analyzed. Regions of cerebral cortex with reduced myelin were examined for remyelination, oligodendrocyte progenitor cells, reactive astrocytes, and molecules that inhibit remyelination.
Results
“New” oligodendrocytes that were actively forming myelin sheaths were identified in 30/42 remyelinated subpial cortical lesions, including lesions from three patients in their 70's. Oligodendrocyte progenitor cells were not decreased in demyelinated or remyelinated cortices when compared to adjacent normal-appearing cortex or controls. In demyelinated lesions involving cortex and adjacent white matter, the cortex showed greater remyelination, more actively remyelinating oligodendrocytes and fewer reactive astrocytes. Astrocytes in the white-matter, but not in cortical portions of these lesions, significantly up-regulate CD44, hyaluronan, and versican, molecules that form complexes that inhibit oligodendrocyte maturation and remyelination.
Interpretation
Endogenous remyelination of the cerebral cortex occurs in individuals with MS regardless of disease duration or chronological age of the patient. Cortical remyelination should be considered as a primary outcome measure in future clinical trials testing remyelination therapies.
doi:10.1002/ana.23693
PMCID: PMC3535551  PMID: 23076662
multiple sclerosis; remyelination
21.  Hydration status substantially affects chronic cerebrospinal venous insufficiency assessments 
Neurology: Clinical Practice  2013;3(5):386-391.
Summary
We sought to determine the effect of hydration on the criteria for chronic cerebrospinal venous insufficiency (CCSVI), a proposed hypothesis for the etiology of multiple sclerosis (MS). Sixteen subjects (11 MS and 5 controls) were asked to fast overnight. The following morning, 2 CCSVI ultrasound examinations were performed: 1 in the mildly dehydrated state, and another 30–45 minutes after rehydrating with 1.5 L of Gatorade. Seven subjects fulfilled CCSVI criteria in the dehydrated state. Of these, 5 (71%) no longer fulfilled CCSVI criteria after rehydration. One additional subject met CCSVI criteria only after rehydration. Hydration status has a substantial effect on CCSVI criteria, suggesting that the sonographic findings of CCSVI may represent a physiologic rather than pathologic state.
doi:10.1212/CPJ.0b013e3182a78f15
PMCID: PMC3806929  PMID: 24175155
22.  Clinically feasible MTR is sensitive to cortical demyelination in MS 
Neurology  2013;80(3):246-252.
Objective:
Presently there is no clinically feasible imaging modality that can effectively detect cortical demyelination in patients with multiple sclerosis (MS). The objective of this study is to determine if clinically feasible magnetization transfer ratio (MTR) imaging is sensitive to cortical demyelination in MS.
Methods:
MRI were acquired in situ on 7 recently deceased patients with MS using clinically feasible sequences at 3 T, including relatively high-resolution T1-weighted and proton density–weighted images with/without a magnetization transfer pulse for calculation of MTR. The brains were rapidly removed and placed in fixative. Multiple cortical regions from each brain were immunostained for myelin proteolipid protein and classified as mostly myelinated (MMctx), mostly demyelinated (MDctx), or intermediately demyelinated (IDctx). MRIs were registered with the cortical sections so that the cortex corresponding to each cortical section could be identified, along with adjacent subcortical white matter (WM). Mean cortical MTR normalized to mean WM MTR was calculated for each cortical region. Linear mixed-effects models were used to test if mean normalized cortical MTR was significantly lower in demyelinated cortex.
Results:
We found that mean normalized cortical MTR was significantly lower in cortical tissue with any demyelination (IDctx or MDctx) compared to MMctx (demyelinated cortex: least-squares mean [LSM] = 0.797, SE = 0.007; MMctx: LSM = 0.837, SE = 0.006; p = 0.01, n = 89).
Conclusions:
This result demonstrates that clinically feasible MTR imaging is sensitive to cortical demyelination and suggests that MTR will be a useful tool to help detect MS cortical lesions in living patients with MS.
doi:10.1212/WNL.0b013e31827deb99
PMCID: PMC3589181  PMID: 23269598
23.  Setting a research agenda for progressive multiple sclerosis: The International Collaborative on Progressive MS 
Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS.
doi:10.1177/1352458512458169
PMCID: PMC3573679  PMID: 22917690
multiple sclerosis; progressive multiple sclerosis; neuroprotection; rehabilitation; research agenda
24.  Demyelination Causes Synaptic Alterations in Hippocampi from Multiple Sclerosis Patients 
Annals of neurology  2011;69(3):445-454.
Background
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system. While the clinical impact of gray matter pathology in MS brains is unknown, 30–40% of MS patients demonstrate memory impairment. The molecular basis of this memory dysfunction has not yet been investigated in MS patients.
Method
To investigate possible mechanisms of memory impairment in MS patients, we compared morphological and molecular changes in myelinated and demyelinated hippocampi from postmortem MS brains.
Findings
Demyelinated hippocampi had minimal neuronal loss but significant decreases in synaptic density. Neuronal proteins essential for axonal transport, synaptic plasticity, glutamate neurotransmission, glutamate homeostasis and memory/learning were significantly decreased in demyelinated hippocampi, but not in demyelinated motor cortices from MS brains.
Interpretation
Collectively, these data support hippocampal demyelination as a cause of synaptic alterations in MS patients and establish that the neuronal genes regulated by myelination reflect specific functions of neuronal subpopulations.
doi:10.1002/ana.22337
PMCID: PMC3073544  PMID: 21446020
Multiple Sclerosis; hippocampus; demyelination; memory
25.  Web-Based Self-Management for Patients with Multiple Sclerosis: A Practical, Randomized Trial 
Abstract
Objective
No studies have addressed the use of electronic personal health records (e-PHRs) for self-management in complex neurological disorders. We assessed and tested an Internet-based self-management system that utilized the e-PHR and determined its impact on self-assessed well-being, clinician-assessed well-being, and healthcare utilization in patients with multiple sclerosis (MS).
Materials and Methods
Subjects were randomized to usual care (a secure Web-based messaging system) or active intervention, which included secure messaging, self-monitoring, self-management of MS symptoms, and communication about upcoming clinic visits. Computers and Internet access were provided. Subjects were included if they had MS, lived within the county or region surrounding our MS center, had at least two appointments at our center in the previous 12 months, and demonstrated basic typing and computer skills. Study duration was 12 months.
Results
Of 220 subjects completing informed consent, 206 met the inclusion criteria. At the study's end, 83 subjects remained in the usual care group and 84 in the enhanced care group. Both groups used the available system components. The groups did not significantly differ on the primary endpoints or healthcare utilization.
Conclusions
Self-management support is an emerging aspect of chronic care management. We established the feasibility of conducting a randomized, controlled trial using e-PHRs for patient self-management. We did not find that e-PHR–enabled self-management augmented multidisciplinary MS center-based care, possibly because the differences between interventions were not great enough.
doi:10.1089/tmj.2010.0133
PMCID: PMC3064874  PMID: 21214498
clinical trials randomized controlled (CONSORT agreement); multiple sclerosis; outcome research

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