Fatigue and depression predict quality of life in patients with early multiple sclerosis: a longitudinal study.

BACKGROUND AND PURPOSE: The clinical predictors of health-related quality of life (HRQoL) in multiple sclerosis (MS) have mainly been studied in patients with long-standing disease. The objective of this study was to investigate the longitudinal association among HRQoL and clinical characteristics in early MS. METHODS: Relapsing MS patients within 12 months of clinical onset were enrolled in a neuroprotection trial of riluzole versus placebo as an add-on to weekly interferon with up to 36 months of follow-up. Serial clinical measures included Short Form-36 (SF-36) as the measure of HRQoL, MS Functional Composite (as a measure of disability), Modified Fatigue Impact Scale, Patient Health Questionnaire-9 (as a measure of depression) and a cognitive battery. Multivariable linear regression analyses assessed cross-sectional associations. Mixed model regressions with mutual adjustments were used to assess the longitudinal association of HRQoL components and clinical, cognitive and demographic variables. RESULTS: Forty-three patients were enrolled within 7.5 ± 4.9 months of clinical onset (72% female, mean age 36 years). The baseline severity of fatigue and depression predicted subsequent changes in SF-36 Physical Component Summary (PCS) (P values of 0.001 and 0.021, respectively). In longitudinal analyses, changes in disability and depression were associated with changes in SF-36 PCS (P values of 0.002 and 0.009, respectively), whereas changes in cognitive function and fatigue were associated with changes in SF-36 Mental Component Summary (P values of 0.037 and 0.001, respectively). A 1-unit increase in MS Functional Composite was associated with a 7.1-point increase in SF-36 PCS (95% CI, 2.6-11.6). CONCLUSIONS: Fatigue, depression, cognition and disability are independently associated with HRQoL in early MS.

Vitamin D in clinically isolated syndrome: evidence for possible neuroprotection.

BACKGROUND AND PURPOSE: Vitamin D status has been associated with inflammatory activity in multiple sclerosis (MS), but it is not known if it is associated with gray matter volume, the loss of which predicts long-term disability in MS. The association of vitamin D levels with brain volume measures and inflammatory activity in patients with clinically isolated syndrome (CIS) was investigated. METHODS: In the phase 2 CIS trial of atorvastatin, 25-hydroxyvitamin D levels were evaluated for their age-adjusted associations with normalized gray matter and brain parenchymal volumes on brain magnetic resonance imaging (MRI). The relationships between 25-hydroxyvitamin D levels and clinical and MRI measures of inflammatory activity were also assessed. RESULTS: In 65 patients in this substudy, each 25 nmol/l higher 25-hydroxyvitamin D level was associated with 7.8 ml higher gray matter volume (95% confidence interval 1.0, 14.6, P = 0.025). There was a tendency for an inverse association of average 25-hydroxyvitamin D levels and the composite end-point of ≥3 new brain T2 lesions or ≥1 relapse within a year (odds ratio per 25 nmol/l higher 25-hydroxyvitamin D level 0.66, 95% confidence interval 0.41, 1.08, P = 0.096). CONCLUSIONS: Vitamin D status may impact neurodegeneration after CIS, although these results should be replicated in a second study. If confirmed in clinical trials, vitamin D supplementation may reduce long-term disability.

Retinal axonal loss in very early stages of multiple sclerosis.

BACKGROUND AND PURPOSE: The lack of surrogates of clinical progression has limited the design of neuroprotection trials in multiple sclerosis (MS). Our aim was to study the association between time-domain optical coherence tomography measures and clinical and magnetic resonance imaging outcomes in early MS. METHODS: Forty-three relapsing-remitting MS patients within 1 year of onset were followed for up to 3 years. RESULTS: The peripapillary retinal nerve fiber layer (RNFL) decreased annually by 2 µm (95% confidence interval -3.89, -0.11; P = 0.038). The RNFL tended to be associated with normalized normal appearing white matter volume in cross-sectional (P = 0.08) and longitudinal analyses (P = 0.06). CONCLUSIONS: There is substantial RNFL loss even in very early MS. Our data suggest that retinal axonal atrophy is associated with atrophy in global white matter volume in early MS.

Composite end points to assess delay of disability progression by MS treatments.

BACKGROUND: The Expanded Disability Status Scale (EDSS) has low sensitivity and reliability for detecting sustained disability progression (SDP) in multiple sclerosis (MS) trials. OBJECTIVE: This study evaluated composite disability end points as alternatives to EDSS alone. METHODS: SDP rates were determined using 96-week data from the Olympus trial (rituximab in patients with primary progressive MS). SDP was analyzed using composite disability end points: SDP in EDSS, timed 25-foot walk test (T25FWT), or 9-hole peg test (9HPT) (composite A); SDP in T25FWT or 9HPT (composite B); SDP in EDSS and (T25FWT or 9HPT) (composite C); and SDP in any two (EDSS, T25FWT, and 9HPT) (composite D). RESULTS: Overall agreements between EDSS and other disability measures in defining SDP were 66%-73%. Composite A showed similar treatment effect estimate versus EDSS alone with much higher SDP rates. Composite B, C, and D all showed larger treatment effect estimate with different or similar SDP rates versus EDSS alone. Using composite A (24-week confirmation only), B, C, or D could reduce sample sizes needed for MS trials. CONCLUSION: Composite end points including multiple accepted disability measures could be superior to EDSS alone in analyzing disability progression and should be considered in future MS trials.

Longitudinal evaluation of cognitive functioning in pediatric multiple sclerosis: report from the US Pediatric Multiple Sclerosis Network.

BACKGROUND: Approximately one-third of those with pediatric-onset multiple sclerosis (MS) experience cognitive impairment. Less is known concerning their change in cognitive functioning over time. OBJECTIVE: Changes in cognitive function over time were measured in the largest pediatric cohort to date through the US Network of Pediatric MS Centers. METHODS: A total of 67 individuals with pediatric MS (n=62) or clinically isolated syndrome (CIS, n=5), ranging from 8-17 years of age (mean age ± standard deviation (SD)=14.37 ± 2.02) completed initial and follow-up neuropsychological testing after an average of 1.64 ± 0.63 years apart. The nine tests administered measure general intellect, attention and working memory, verbal memory, visuomotor integration, language, and executive functioning. RESULTS: Rate of impairment (having one-third or more scores in the impaired range) was 37% at baseline and 33% at follow-up. Tests commonly impaired were measures of visuomotor integration, speeded processing, and attention. Most tested did not decline over two years. There was no clear pattern of change on any specific measure. CONCLUSION: Findings suggest that, over short timeframes, stable or even improved performances on measures of cognitive ability can occur. Pediatric MS may instead prevent expected age-related cognitive gains.

Copy number variation in pediatric multiple sclerosis.

BACKGROUND: Pediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions. OBJECTIVES AND METHODS: The objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array. RESULTS AND DISCUSSION: We identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS. CONCLUSIONS: This is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient's disease course and prognosis.

Systematic review of disease-modifying therapies to assess unmet needs in multiple sclerosis: tolerability and adherence.

Reviews of therapeutic drugs usually focus on the highly selected and closely monitored patient populations from randomized controlled trials. The objective of this study was to review systematically the tolerability and adherence of multiple sclerosis disease-modifying therapies, using data from both randomized controlled trials and observational settings. Relevant literature was identified using predefined search terms, and adverse event and study discontinuation data were extracted and categorized according to study type (randomized controlled trial or observational) and study duration. A total of 151 papers were selected for analysis; 33% were classified as randomized controlled trials and 62% as observational studies. Most of the papers concerned interferon preparations and glatiramer acetate; the limited available information on mitoxantrone and natalizumab precluded extensive examination of these. The most common adverse events were flu-like symptoms (interferon therapies only) and injection-site reactions. Mean discontinuation rates ranged from 16% to 27%. There were no marked differences in tolerability or adherence data from randomized controlled trials and observational studies, but the incidence of adverse events remained high in lengthy studies and discontinuations accumulated with time. The present systematic review of randomized clinical trial and observational data highlights the tolerability and adherence issues associated with commonly used first-line multiple sclerosis treatments.

Central vein sign: A diagnostic biomarker in multiple sclerosis (CAVS-MS) study protocol for a prospective multicenter trial.

The specificity and implementation of current MRI-based diagnostic criteria for multiple sclerosis (MS) are imperfect. Approximately 1 in 5 of individuals diagnosed with MS are eventually determined not to have the disease, with overreliance on MRI findings a major cause of MS misdiagnosis. The central vein sign (CVS), a proposed MRI biomarker for MS lesions, has been extensively studied in numerous cross sectional studies and may increase diagnostic specificity for MS. CVS has desirable analytical, measurement, and scalability properties. "Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS)" is an NIH-supported, 2-year, prospective, international, multicenter study conducted by the North American Imaging in MS Cooperative (NAIMS) to evaluate CVS as a diagnostic biomarker for immediate translation into clinical care. Study objectives include determining the concordance of CVS and McDonald Criteria to diagnose MS, the sensitivity of CVS to detect MS in those with typical presentations, and the specificity of CVS among those with atypical presentations. The study will recruit a total of 400 participants (200 with typical and 200 with atypical presentations) across 11 sites. T2*-weighted, high-isotropic-resolution, segmented echo-planar MRI will be acquired at baseline and 24 months on 3-tesla scanners, and FLAIR* images (combination of FLAIR and T2*) will be generated for evaluating CVS. Data will be processed on a cloud-based platform that contains clinical and CVS rating modules. Imaging quality control will be conducted by automated methods and neuroradiologist review. CVS will be determined by Select6* and Select3* lesion methods following published criteria at each site and by central readers, including neurologists and neuroradiologists. Automated CVS detection and algorithms for incorporation of CVS into McDonald Criteria will be tested. Diagnosis will be adjudicated by three neurologists who served on the 2017 International Panel on the Diagnosis of MS. The CAVS-MS study aims to definitively establish CVS as a diagnostic biomarker that can be applied broadly to individuals presenting for evaluation of the diagnosis of MS.

Genotype-Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures.

Genetic susceptibility to multiple sclerosis (MS) is associated with the human leukocyte antigen (HLA) DRB1*1501 allele. Here we show a clear association between DRB1*1501 carrier status and four domains of disease severity in an investigation of genotype-phenotype associations in 505 robust, clinically well characterized MS patients evaluated cross-sectionally: (i) a reduction in the N-acetyl-aspartate (NAA) concentration within normal appearing white matter (NAWM) via (1)HMR spectroscopy (P = 0.025), (ii) an increase in the volume of white matter (WM) lesions utilizing conventional anatomical MRI techniques (1,127 mm(3); P = 0.031), (iii) a reduction in normalized brain parenchymal volume (nBPV) (P = 0.023), and (iv) impairments in cognitive function as measured by the Paced Auditory Serial Addition Test (PASAT-3) performance (Mean Z Score: DRB1*1501+: 0.110 versus DRB1*1501-: 0.048; P = 0.004). In addition, DRB1*1501+ patients had significantly more women (74% versus 63%; P = 0.009) and a younger mean age at disease onset (32.4 years versus 34.3 years; P = 0.025). Our findings suggest that DRB1*1501 increases disease severity in MS by facilitating the development of more T2-foci, thereby increasing the potential for irreversible axonal compromise and subsequent neuronal degeneration, as suggested by the reduction of NAA concentrations in NAWM, ultimately leading to a decline in brain volume. These structural aberrations may explain the significant differences in cognitive performance observed between DRB1*1501 groups. The overall goal of a deep phenotypic approach to MS is to develop an array of meaningful biomarkers to monitor the course of the disease, predict future disease behaviour, determine when treatment is necessary, and perhaps to more effectively recommend an available therapeutic intervention.

Neurite Orientation Dispersion and Density Imaging for Assessing Acute Inflammation and Lesion Evolution in MS.

BACKGROUND AND PURPOSE: MR imaging is essential for MS diagnosis and management, yet it has limitations in assessing axonal damage and remyelination. Gadolinium-based contrast agents add value by pinpointing acute inflammation and blood-brain barrier leakage, but with drawbacks in safety and cost. Neurite orientation dispersion and density imaging (NODDI) assesses microstructural features of neurites contributing to diffusion imaging signals. This approach may resolve the components of MS pathology, overcoming conventional MR imaging limitations. MATERIALS AND METHODS: Twenty-one subjects with MS underwent serial enhanced MRIs (12.6 ± 9 months apart) including NODDI, whose key metrics are the neurite density and orientation dispersion index. Twenty-one age- and sex-matched healthy controls underwent unenhanced MR imaging with the same protocol. Fifty-eight gadolinium-enhancing and non-gadolinium-enhancing lesions were semiautomatically segmented at baseline and follow-up. Normal-appearing WM masks were generated by subtracting lesions and dirty-appearing WM from the whole WM. RESULTS: The orientation dispersion index was higher in gadolinium-enhancing compared with non-gadolinium-enhancing lesions; logistic regression indicated discrimination, with an area under the curve of 0.73. At follow-up, in the 58 previously enhancing lesions, we identified 2 subgroups based on the neurite density index change across time: Type 1 lesions showed increased neurite density values, whereas type 2 lesions showed decreased values. Type 1 lesions showed greater reduction in size with time compared with type 2 lesions. CONCLUSIONS: NODDI is a promising tool with the potential to detect acute MS inflammation. The observed heterogeneity among lesions may correspond to gradients in severity and clinical recovery after the acute phase.

The onset location of multiple sclerosis predicts the location of subsequent relapses.

BACKGROUND: Demyelinating events in relapsing-remitting multiple sclerosis (RRMS) can involve several locations in the central nervous system. We sought to determine if initial clinical demyelinating event (IDE) location predicts subsequent clinical relapse locations in early RRMS. METHODS: We identified all RRMS patients from two large MS clinics who were seen within 1 year of disease onset. Logistic regression was performed with the outcome defined as the second or third exacerbation location and the predictor defined as IDE+/-second event location. RESULTS: 195 patients with at least two clinical exacerbations were identified. There was an increased odds of a patient's second relapse occurring in the spinal cord if the IDE was in the spinal cord (odds ratio (OR) = 3.79, 95% CI 2.06 to 7.00, p<0.001). There was more than a sixfold increase in the odds of a patient's second relapse occurring in the optic nerve if the IDE was in the optic nerve (OR = 6.18, 95% CI 2.90 to 13.18, p<0.001). These associations remained similar after adjusting for treatment and patient characteristics. If the IDE and second event were both in the same location (spinal cord, optic nerve or brainstem/cerebellum), the third event was likely to remain in that location. CONCLUSION: Patients with RRMS have relatively localised clinical relapses. It remains to be determined if genetic or biological processes are responsible for this pattern.

Predictors of the location of multiple sclerosis relapse.

BACKGROUND: While clinical relapses are the defining feature of relapsing-remitting multiple sclerosis (RRMS), their characteristics vary widely from patient to patient. This study sought to identify predictors of MS relapse location. Based on the current literature, two potential predictors were identified: treatment with interferon beta (IFNB) and location of previous relapse. METHODS: Patients with RRMS were identified from the UCSF MS Center database who underwent at least 3 months of treatment with IFNB or glatiramer acetate (GA). The relapse immediately preceding the initiation of treatment (pretreatment relapse) and the first relapse occurring after the initiation of treatment (on-treatment relapse) were coded as affecting the spinal cord (SC), optic nerve (ON), brainstem/cerebellum (BC) or cerebrum. Logistic regression was performed to identify independent predictors of on-treatment relapse location. RESULTS: The 134 IFNB and 56 GA patients did not differ in gender, race, age at symptom onset (30.3 years) or disease duration at the start of treatment (5.7 years). Patients with pretreatment SC relapses had increased odds of having on-treatment SC compared with non-SC relapses (OR 2.31, p = 0.013); the same tendency for localisation occurred with BC (OR 3.05, p = 0.013) and ON (OR 3.63, p = 0.011) relapses. Additionally, patients who relapsed on treatment had a higher SC (but not ON or BC) relapse risk when they were receiving IFNB compared with GA (OR 2.05, p = 0.041), independent of pretreatment relapse location. CONCLUSION: These results show a tendency for patients to have localised exacerbations, which could be mediated by genetic or immunological factors. In addition, and to be confirmed in subsequent studies, IFNB treatment may influence SC relapse risk.

Multiple sclerosis onset after granulocyte macrophage colony-stimulating factor withdrawal.

A 51-year old woman with stage III melanoma participated in a phase II clinical trial in which she received subcutaneous rhGM-CSF injections for 3 years. She was in remission by the end of the trial. Seven months after discontinuing GM-CSF she had her first MS event. The unique timeline of rh-GM-CSF injections in a melanoma trial, during which yearly MRI scans showed subtle stable demyelination followed by RRMS onset shortly after discontinuation of treatment, may provide some insight on the role of GM-CSF in MS.

Emerging therapies for MS.

Immune modulators, such as interferon beta (IFNB) and glatiramer acetate (GA), have focused on T cells as the primary therapeutic target. In the past few year several novel therapeutic strategies have emerged that will be reviewed here. These include treatments that modify the immune balance in general, others that inhibit more specifically various key players of the immune response such as antibody-dependent, and antibody-independent B cell responses in MS, but also some that inhibit migration of inflammatory cells to the central nervous system (CNS). At this time, there are several phase III trials in relapsing-remitting MS with promising agents, including intravenous agents administered once or twice a year (alemtuzumab, rituximab) and oral agents (FTY720, fumaric acid, laquinomod). Finally, new therapeutic approaches are now also addressing neuroprotection and CNS repair.

Evaluating the association of allergies with multiple sclerosis susceptibility risk and disease activity in a pediatric population.

BACKGROUND: Multiple sclerosis (MS) and allergies are both considered to be related to imbalanced Th1 and Th2 immune responses. Previous studies evaluating the relationship between MS and allergies provide conflicting results. OBJECTIVE: To assess allergies and asthma as risk factors for MS and as predictors of MS relapses in a pediatric cohort. METHODS: The environment and genetic risk factors for pediatric MS study is a national case-control project with 16 participating US sites. An environmental questionnaire is used that includes history of allergies in the first five years of life. Case-control data are entered in the pediatric MS Network database and cases at 12 of the 16 sites enter relapse data prospectively. Annualized relapse rate was calculated for patients with follow-up and adjusted for age at disease onset, gender, race, ethnicity, and use of disease-modifying therapy (DMT). RESULTS: We included 271 cases (mean age at disease onset of 15.7years and 62% female) and 418 controls. Relapse data were available for 193 cases. There was no difference in prevalence of allergies or asthma between cases and controls. Patients with food allergies had fewer relapses compared to patients without food allergies (0.14 vs 0.48, p=0.01). CONCLUSIONS: While allergies and asthma are not associated with pediatric MS, cases with food allergies have fewer relapses compared to those without food allergies.

IFN-beta1a may increase serum levels of TIMP-1 in patients with relapsing-remitting multiple sclerosis.

Serum levels of matrix metalloprotease-9 (MMP-9) and tissue inhibitor of MMP-1 (TIMP-1) were measured monthly in 7 patients with relapsing-remitting multiple sclerosis (MS) 6 months before and 6 months during treatment with weekly intramuscular (i.m.) injections of interferon-beta1a (IFN-beta1a) 30 microg. Within-patient median MMP-9 levels were unchanged on treatment. Within-patient median TIMP-1 levels were higher during months 1-6 (771.5 ng/ml) and during months 4, 5, and 6 of treatment (793 ng/ml) compared with 6 months pretreatment (414 ng/ml) (respectively, p = 0.10, p = 0.047; Wilcoxon signed-rank test). These preliminary data suggest that IFN-beta1a therapy may increase TIMP-1 levels.

Multiple sclerosis that is progressive from the time of onset: clinical characteristics and progression of disability.

OBJECTIVE: To use the new consensus definitions of primary progressive multiple sclerosis (PPMS) and progressive relapsing multiple sclerosis (PRMS) to report the demographic, clinical, and natural history characteristics of multiple sclerosis (MS) that is progressive from the time of onset. DESIGN: Retrospective study by database/chart review and telephone interview. SETTING: Multiple sclerosis clinic at a university teaching hospital. PATIENTS: Eighty-three patients (prevalence, 6.9%) with PPMS and 12 patients (prevalence, 1.0%) with PRMS were studied. RESULTS: Fifty-nine percent of the patients with PPMS (n=49) and 67% of the patients with PRMS (n=8) were women. Mean +/- SD ages at the time of onset were 41.2 +/- 10.5 and 38.0 +/- 7.3 years, respectively; mean disease duration was 14.2 +/- 8.8 and 12.2 +/- 6.5 years, respectively. The initial symptoms involved leg weakness in 94% of the patients with PPMS (n = 78) and 100% of the patients with PRMS (n= 12). For the PPMS cohort, a syndrome consistent with isolated myelopathy was found in 36% of patients (n = 30) and arm weakness without leg weakness did not occur. Mean +/- SEM time of progression to a score of 6.0 on the Expanded Disability Status Scale was 10.2 +/- 1.0 years for patients with PPMS and 10.9 +/- 2.6 years for patients with PRMS. CONCLUSIONS: The clinical characteristics and disability progression of these MS subtypes were indistinguishable, with the exception of 1 or 2 relapses in patients with PRMS that occurred 8 months to 9 years after the onset of symptoms. We see little reason to consider PPMS and PRMS separate clinical entities; however, whether they can be better distinguished by radiological, histopathological, or immunological markers of disease activity remains unknown.

A pilot study of MRI activity before and during interferon beta-1a therapy.

We compared the number of new gadolinium-enhancing and T2-weighted lesions on six monthly MRI scans in eight patients with relapsing multiple sclerosis before and during treatment with weekly intramuscular interferon beta-1a (Avonex; 30 microg). MRI activity was modestly reduced during treatment (p = 0.016). The treatment effect was also significant after adjusting pretreatment lesion frequency for regression to the mean. Based on this pilot study, Avonex, as approved for treatment of relapsing forms of MS in the United States, reduces new MRI activity.

Magnetization transfer ratio in new MS lesions before and during therapy with IFNbeta-1a.

OBJECTIVE: The authors examined the effect of 6.0 MIU interferon beta-1a (IFNbeta-1a) administered IM each week on the evolution of monthly magnetization transfer ratio (MTR) within new gadolinium-enhancing (Gd+) lesions in patients with very early relapsing-remitting (RR) MS. BACKGROUND: IFNbeta is an effective disease-modifying treatment for patients with RRMS. Among other effects, it has been shown to decrease the number of new Gd+ and T2-weighted lesions. MTR is a putative marker for irreversible tissue damage and evolution of MTR within a lesion may reflect recovery of tissue damage. It is not known whether IFNbeta-1a affects the recovery phase of lesions. METHODS: Eight untreated patients with RRMS who completed up to 14 monthly brain MRI sessions elected to initiate treatment with IFNbeta-1a. Four out of eight patients developed new Gd+ lesions during treatment. MTR of lesions at the time of appearance and subsequent rate of change of monthly MTR were compared before and after treatment (stratified Mann-Whitney test). RESULTS: The difference between MTR at appearance of 47 new Gd+ lesions before treatment versus 23 new Gd+ lesions during treatment was not significant. Twenty-two of 47 new Gd+ lesions before treatment and 11 of 23 new Gd+ lesions after treatment were monitored for up to 6 months. After appearance of new Gd+ lesions, the rate of increase in MTR was faster during therapy (p = 0.037). CONCLUSION: MTR abnormalities within new Gd+ lesions evolve at a faster rate during treatment with IFNbeta-1a than before initiating therapy. This is consistent with the hypothesis that IFNbeta-1a promotes resolution of new Gd+ lesions.