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1.  Disability Progression After Switching from Natalizumab to Fingolimod or Interferon Beta/Glatiramer Acetate Therapies 
International Journal of MS Care  2016;18(5):230-238.
Background: Physicians must weigh the benefits against the risk of progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab, especially beyond 2 years. However, disability progression associated with switching therapies versus continuing natalizumab therapy after 2 years has not been fully evaluated.
Methods: In this retrospective analysis using the NARCOMS Registry, disability progression (Patient-Determined Disease Steps [PDDS] scale) and physical health-related quality of life (HRQOL) worsening (12-item Short Form Health Status Survey Physical Component Score [SF-12 PCS]) were compared between participants switching to fingolimod (n = 50) or interferon beta (IFNβ)/glatiramer acetate (GA) (n = 71) therapy and those continuing natalizumab (n = 406) after 2 years or more of treatment (median follow-up: natalizumab, 4 years; fingolimod, 4.5 years; IFNβ/GA, 5 years).
Results: Participants continuing to take natalizumab had less disability progression (mean PDDS change: natalizumab, 0.3; fingolimod, 0.6; IFNβ/GA, 0.7; P = .0036), were less likely to report disability progression (proportion with PDDS increase: natalizumab, 31%; fingolimod, 46%; IFNβ/GA, 42%; P = .0296), and had less worsening in physical HRQOL (mean SF-12 PCS change: natalizumab, −1.4; fingolimod, −2.8; IFNβ/GA, −4.6; P = .0476) than those switching treatment.
Conclusions: Although all medication groups exhibited some level of worsening, switching from natalizumab treatment after 2 years was associated with increased disability progression and worsening physical HRQOL. The risk of disability progression from disease activity and the risk of PML should be considered when making natalizumab treatment decisions.
doi:10.7224/1537-2073.2014-113
PMCID: PMC5087578  PMID: 27803638
2.  Characterizing absolute lymphocyte count profiles in dimethyl fumarate–treated patients with MS 
Neurology: Clinical Practice  2016;6(3):220-229.
Abstract
Background:
Delayed-release dimethyl fumarate (DMF), indicated for the treatment of patients with relapsing-remitting multiple sclerosis (MS), is a disease-modifying therapy with potential immunomodulatory and neuroprotective effects. In clinical trials, DMF was associated with reduced white blood cell and absolute lymphocyte counts. Current US prescribing information recommends obtaining a complete blood count, including absolute lymphocyte count (ALC), before initiating and during DMF treatment.
Methods:
We conducted an integrated analysis of phase 2b/3/long-term extension studies of DMF in MS (N = 2,470) to characterize ALC profiles.
Results:
Mean ALCs decreased by 30% during the first year and then plateaued, remaining above the lower limit of normal (LLN). Among patients treated ≥6 months (N = 2,099), 2.2% experienced ALCs <500 mm3 persisting ≥6 months. ALCs remained ≥LLN in 84% and 76% of patients during the first 6 and 12 months, respectively; of these, 0.1% and 0%, respectively, developed ALCs <500 mm3 persisting ≥6 months at any time. Evidence of ALC improvement following DMF discontinuation was observed. DMF efficacy was not substantially different in patients with and without lymphopenia.
Conclusion:
Lymphocyte monitoring provides effective means for early identification of patients at risk for developing severe, prolonged lymphopenia.
doi:10.1212/CPJ.0000000000000238
PMCID: PMC4909524  PMID: 27347439
3.  Progressive multiple sclerosis 
Current opinion in neurology  2015;28(3):237-243.
Purpose to Review
To highlight the pathological features and clinical aspects of progressive multiple sclerosis (PMS). To highlight results of clinical trial experience to date and review ongoing clinical trials and perspective new treatment options. Explain the challenges of clinical trial design in PMS.
Recent Findings
MS has been identified as a chronic immune mediated disease, and the progressive phase of the disease appears to have significant neurodegenerative mechanisms. The classification of the course of PMS has been re-organized into categories of active vs. inactive inflammatory disease and the presence vs. absence of gradual disease progression. This differentiation allows clearer conceptualization of PMS and possibly even more efficient recruitment of PMS subjects into clinical trials. Clinical trial experience to date in PMS has been negative with anti-inflammatory medications used in relapsing MS. Simvastatin was recently tested in a phase II trial and showed a 43% reduction on annualized atrophy progression in secondary progressive MS. Ongoing PMS trials are currently being conducted with the phosphodiesterase inhibitor ibudilast, S1P modulator siponimod, and anti-B-cell therapy ocrelizumab. Several efforts for development of outcome measures in PMS are ongoing.
Summary
PMS represents a significant challenge, as the pathogenesis of the disease is not well understood, no validated outcome metrics have been established, and clinical trial experience to date has been disappointing. Advances in the understanding of the disease and lessons learned in previous clinical trials are paving the way for successful development of disease modifying agents for this disease.
doi:10.1097/WCO.0000000000000195
PMCID: PMC4425257  PMID: 25887766
Multiple sclerosis; Secondary progressive; Primary progressive; Clinical trials
4.  JC Polyomavirus Abundance and Distribution in Progressive Multifocal Leukoencephalopathy (PML) Brain Tissue Implicates Myelin Sheath in Intracerebral Dissemination of Infection 
PLoS ONE  2016;11(5):e0155897.
Over half of adults are seropositive for JC polyomavirus (JCV), but rare individuals develop progressive multifocal leukoencephalopathy (PML), a demyelinating JCV infection of the central nervous system. Previously, PML was primarily seen in immunosuppressed patients with AIDS or certain cancers, but it has recently emerged as a drug safety issue through its association with diverse immunomodulatory therapies. To better understand the relationship between the JCV life cycle and PML pathology, we studied autopsy brain tissue from a 70-year-old psoriasis patient on the integrin alpha-L inhibitor efalizumab following a ~2 month clinical course of PML. Sequence analysis of lesional brain tissue identified PML-associated viral mutations in regulatory (non-coding control region) DNA, capsid protein VP1, and the regulatory agnoprotein, as well as 9 novel mutations in capsid protein VP2, indicating rampant viral evolution. Nine samples, including three gross PML lesions and normal-appearing adjacent tissues, were characterized by histopathology and subject to quantitative genomic, proteomic, and molecular localization analyses. We observed a striking correlation between the spatial extent of demyelination, axonal destruction, and dispersion of JCV along white matter myelin sheath. Our observations in this case, as well as in a case of PML-like disease in an immunocompromised rhesus macaque, suggest that long-range spread of polyomavirus and axonal destruction in PML might involve extracellular association between virus and the white matter myelin sheath.
doi:10.1371/journal.pone.0155897
PMCID: PMC4871437  PMID: 27191595
5.  Safety and Tolerability of Delayed-Release Dimethyl Fumarate Administered with Interferon Beta or Glatiramer Acetate in Relapsing-Remitting Multiple Sclerosis 
International Journal of MS Care  2016;18(3):138-146.
Background: Delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) is indicated for relapsing multiple sclerosis (MS). The objective of this study was to explore the safety and tolerability of DMF when administered with interferon beta (IFNβ) or glatiramer acetate (GA).
Methods: Patients with relapsing-remitting MS receiving established therapy with the same dose of IFNβ or GA for at least 12 months continued their prescribed therapy for 2 months (monotherapy period) and then received DMF 240 mg three times daily in addition to their prescribed MS therapy for 6 months (add-on therapy period). Safety and magnetic resonance imaging outcomes were monitored monthly.
Results: During the add-on therapy period, in the DMF+IFNβ (n = 57) and DMF+GA (n = 47) groups, the overall incidence of adverse events was 95% and 100%, respectively; the most common adverse events were flushing, diarrhea, and abdominal pain. In both groups, mean lymphocyte counts decreased but remained within normal limits, and hepatic transaminase levels increased transiently; no case met Hy's law criteria. There was no overall increased risk of infection. In both groups, gadolinium-enhancing lesion activity and new/enlarging T2 lesions decreased compared with the monotherapy period (exploratory endpoints).
Conclusions: The safety profile of DMF taken with IFNβ or GA was acceptable and consistent with the known safety profile of DMF monotherapy.
doi:10.7224/1537-2073.2015-020
PMCID: PMC4887000  PMID: 27252601
6.  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
7.  Sustained Effect of Delayed-Release Dimethyl Fumarate in Newly Diagnosed Patients with Relapsing–Remitting Multiple Sclerosis: 6-Year Interim Results From an Extension of the DEFINE and CONFIRM Studies 
Neurology and Therapy  2016;5(1):45-57.
Introduction
Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated clinical and neuroradiologic efficacy and safety in the Phase 3 DEFINE and CONFIRM trials, and in the extension study (ENDORSE), in patients with relapsing–remitting multiple sclerosis (RRMS). This post hoc analysis assessed DMF efficacy in newly diagnosed patients with RRMS with 6-year minimum follow-up.
Methods
Patients randomized in DEFINE/CONFIRM to DMF 240 mg twice (BID) or thrice daily (TID) continued on same dosage in ENDORSE. Patients randomized to placebo (PBO) or glatiramer acetate (CONFIRM only) were re-randomized to DMF BID or TID. Results for DMF BID (approved dosage) are reported. Newly diagnosed patients were diagnosed within 1 year prior to DEFINE/CONFIRM entry and either treatment-naive or previously treated with corticosteroids alone.
Results
The newly diagnosed population included 144 patients continuously treated with DMF BID in DEFINE/CONFIRM and ENDORSE (DMF/DMF) and 85 treated with PBO for 2 years in DEFINE/CONFIRM followed by 4 years of DMF BID in ENDORSE (PBO/DMF). At 6 years (ENDORSE Year 4), the annualized relapse rates [ARR; 95% confidence interval (CI)] were 0.137 (0.101, 0.186) and 0.168 (0.113, 0.252) for DMF/DMF and PBO/DMF, respectively; representing 19% risk reduction (P = 0.3988). PBO/DMF patients demonstrated improvements in ARR after switching to DMF in ENDORSE: 0.260 (0.182, 0.372) for Years 0–2 (DEFINE/CONFIRM) and 0.102 (0.064, 0.163) for Years 3–6 (ENDORSE), representing 61% risk reduction for Years 3–6 versus Years 1–2 (P < 0.0001). The proportion of patients with 24-week confirmed disability progression (95% CI) at 6 years was 15.7% (10.3%, 23.7%) in DMF/DMF and 24.3% (15.9%, 36.2%) in PBO/DMF, representing 49% risk reduction versus PBO/DMF (P = 0.0397).
Conclusion
Long-term DMF treatment demonstrated strong and sustained efficacy in newly diagnosed patients. Results suggest greater clinical benefits with earlier initiation of treatment in this patient population.
Funding
Biogen.
Trial registration
ClinicalTrials.gov identifiers, NCT00835770 (ENDORSE); NCT00420212 (DEFINE); NCT00451451 (CONFIRM).
doi:10.1007/s40120-016-0042-8
PMCID: PMC4919132  PMID: 26932146
Delayed-release dimethyl fumarate; Efficacy; Multiple sclerosis; Newly diagnosed; Safety
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
23.  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
24.  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
25.  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

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