T2 Lesion Volume Research Articles

Multiple Sclerosis: White and Gray Matter Damage Associated with Balance Deficit Detected at Static Posturography

To combine two unbiased (ie, without any a priori hypothesis) magnetic resonance (MR) imaging processing approaches, tract-based spatial statistics and voxel-based morphometry, to investigate the relationship between white matter and gray matter damage and computer-based measures of balance impairment assessed at static posturography in patients with multiple sclerosis (MS). Institutional review board approval and written informed consent were obtained. Forty-five ambulatory patients with MS (34 women, 11 men) and 25 sex- and age-matched healthy control subjects were assessed by using a force platform to compute the displacement (in millimeters) of the body center of pressure in 30 seconds. In a separate session, patients underwent MR imaging at 3 T, including a dual-echo fast spin-echo sequence, a T1-weighted volume sequence, and a diffusion-tensor imaging sequence. T2 lesion volumes were assessed by using a semiautomated technique. Tract-based spatial statistics and voxel-based morphometry were used for the white and gray matter analyses, respectively, to correlate force platform measures with diffusion-tensor imaging parameters and regional gray matter volumes, adjusting for the patients' sex, age, disease duration, and lesion volume. Patients with MS had worse postural stability, widespread alterations in most white matter bundles, and gray matter atrophy in several brain regions compared with control subjects. In patients with MS, balance impairment was correlated with worse diffusion-tensor imaging parameters along the cerebellar connections and supratentorial associative white matter bundles (P < .05, threshold-free cluster enhancement corrected). Gray matter atrophy of the superior lobules of the cerebellum (IV, V, VI), and lobules VIII also correlated with worse posturometric values (P < .05, family-wise error corrected). Imbalance due to MS appears to be related to the disconnection between the spinal cord, cerebellum, and cerebral cortex, which in turn produces atrophy of the sensory motor cerebellar regions that are functionally connected with specific cortical areas.

Brain atrophy and lesion load predict long term disability in multiple sclerosis

ObjectiveTo determine whether brain atrophy and lesion volumes predict subsequent 10 year clinical evolution in multiple sclerosis (MS).DesignFrom eight MAGNIMS (MAGNetic resonance Imaging in MS) centres, we retrospectively included 261...

Importance of neutralizing antibody positivity in Tur-kish multiple sclerosis patients

The frequency and the consequences of binding and neutralizing antibodies (BAbs and NAbs) against Interferon beta (IFNbeta) in Turkish multiple sclerosis (MS) patients have not been determined yet, which could differ in such a country which is between Europa and Asia. The aim of the study is to assess the frequency of these antibodies, and to evaluate the impact of NAbs, from the clinical and radiologic aspects in Turkish patients with MS. One hundred and two MS patients were included. BAbs were screened using capture enzyme-linked immunosorbent assay (cELISA), and NAbs were detected via Myxovirus protein A (MxA) messenger RNA (mRNA) induction assay (real-time polymerase chain reaction-PCR) at the beginning and one year later. Relapse rate and expanded disability status scale (EDSS) were used to assess the clinical impact. Gadolinium enhanced lesions and T2 lesion volume were used as magnetic resonance imaging (MRI) parameters. Persistent NAb positivity defines to be positive both at first and then one year later. NAbs were detected in 12.2% (6/49) of IFNbeta-1b treated patients, and in 7.5% (3/40) of IFNbeta-1a SC treated patients, but none of the IFNbeta-1a IM treated patients had detectable NAbs. It was found that the mean relapse rate difference was significantly higher in persistent NAb negative patients (p = 0.024). Persistent NAb positivity had no effect on T2 lesion volume and contrast enhancing lesions. 60% of the persistent NAb positive patients had at least one relapse during one-year of follow-up. On the other hand, 32% of persistent NAb negative patients were detected to have at least one relapse. Data from this study suggest that patients may become unresponsive to IFNbeta therapy even when the frequency of NAbs does not prove to be as high as those in the literature. Nevertheless, one should keep in mind that disease activity is not always equal to NAb positivity.

Effects of early treatment with glatiramer acetate in patients with clinically isolated syndrome

Background: The placebo-controlled phase of the PreCISe study showed that glatiramer acetate delayed onset of clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome and brain lesions on MRI. Objective: To compare the effects of early versus delayed glatiramer acetate treatment in the open-label phase of PreCISe. Methods: Patients with a clinically isolated syndrome suggestive of MS with unifocal manifestation and ≥2 T2-weighted brain lesions were randomized to receive glatiramer acetate 20 mg/d (early-treatment, n=198) or placebo (delayed-treatment, n=211) for 36 months or until conversion to CDMS, followed by open-label glatiramer acetate treatment for two years. Results: Early glatiramer acetate treatment reduced CDMS conversion risk by 41% (hazard ratio 0.59, 95% confidence interval 0.44–0.80; p=0.0005) versus delayed-treatment, and was associated with a 972-day delay (185%) in conversion to CDMS, less brain atrophy (−28%, p=0.0209), fewer new T2 lesions/year (−42%, <0.0001) and lower T2 lesion volume (−22%, p=0.0005) versus delayed treatment. Adverse events were consistent with the established safety profile of glatiramer acetate. Conclusions: Effects of early glatiramer acetate treatment on the rate of conversion to CDMS and on MRI measures of disease activity and lesion burden support initiating glatiramer acetate treatment soon after the first clinical symptoms suggestive of MS and continuing treatment to sustain benefits.

MRI characteristics of familial and sporadic multiple sclerosis patients

Purpose: To investigate the MRI characteristics in a large cohort of multiple sclerosis (MS) patients with and without a family history of MS. Methods: Enrolled in this prospective study were 758 consecutive MS patients (mean age 46.2 ± 10.1 years, disease duration 13.6 ± 9.2 years and EDSS 3.4 ± 2.1), of whom 477 had relapsing–remitting, 222 secondary-progressive, and 30 primary-progressive disease courses and 29 had clinically isolated syndrome. One hundred and ninety-six patients (25.9%) had a positive family history of MS. Patients were assessed using measurements of lesions, brain atrophy, magnetization transfer ratio (MTR) and diffusion-weighted imaging. Results: The familial MS group had greater T1-lesion volume (p=0.009) and a trend for lower MTR of T1-lesion volume (p=0.047) than the sporadic MS group. No clinical differences were found between familial versus sporadic group, or by a degree of affected relative subgroups. Conclusions: While familial MS was associated with more severe T1-lesion volume and its MTR characteristics, there were no clinical status differences between familial and sporadic MS patients. Therefore, a better understanding of the genetic and/or epigenetic influences causing these differences can advance the understanding and management of MS.

Treatment of Severe Relapsing-Remitting Multiple Sclerosis with High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation: 2-Year Follow-up Results of the HALT MS Clinical Trial (Immune Tolerance Network: ITN033AI)

AbstractAbstract ▪962▪This icon denotes a clinically relevant abstractMost patients with relapsing-remitting multiple sclerosis (RRMS) do not achieve a sustained remission after disease-modifying therapy. A phase II clinical trial of high-dose immunochemotherapy (HDIT; BCNU, etoposide, ara-C, melphalan and antithymocyte globulin) and autologous hematopoietic cell transplantation (HCT) was conducted in patients with highly active RRMS who had failed conventional therapy to assess if a high rate of sustained remission could be induced. Eligibility required an EDSS of 3.0 (moderate disability, fully ambulatory) to 5.5(severe disability, ambulatory only 100 meters without aids) and >2 relapses on treatment in previous 18 months. Treatment-failure was defined as a composite endpoint including 1) mortality 2) relapse 3) new MRI lesions or 4) disability increase >0.5 EDSS points. Adverse events (AE) were recorded according to NCI-CTCAE v3.0.25 patients at a median age of 38(27-53) years were treated with G-CSF to mobilize the autograft; prednisone was given at the same time to prevent MS flares. The autograft was CD34-selected (Baxter, Isolex). One patient withdrew after mobilization secondary to HIT/pulmonary embolus. 24 patients had HDIT/HCT according to protocol. Median follow-up was 131 (52, 282) weeks. After initially stabilizing, one patient died from progressive loss of neurological function at 32 months. No patient had delayed recovery of blood counts. In the 1st year after HDIT, there were 42 grade 3 and 6 grade 4 non-hematopoietic AE. Grade 4 AE included: one suicide attempt (with 3 grade 4 AE); hyperuricemia; hypokalemia; and elevated ALT. In the 2ndyear, there were 13 grade 3 and 1 grade 4 non-hematopoietic AE. The 1-year and 2-year probabilities of event-free survival (i.e. without treatment-failure) were 95.8% (90% CI: 80.2%-99.2%) and 82.8% (90% CI: 65.0%-92.0%), respectively. Progression-free and relapse-free survival at 1 year were 100% (90% CI: 100%-100%) and 95.8% (90% CI: 80.2%-99.2%) and at 2 years were 91.7% (90% CI: 75.7%-97.3%) and 91.7% (90% CI: 75.7%-97.3%), respectively. The probability of freedom from disease activity detected by brain MRI was 95.8% (90% CI: 80.2%-99.2%) at both year 1 and 2. In comparison, a randomized clinical trial of placebo vs natalizumab (Havrdova E et al, Lancet Neurology, 2009) showed that 7% and 37% of RRMS patients were free of disease activity (i.e. progression, relapse and MRI) at 2 years, respectively.T2-weighted MRI scans measure disease burden from MS. T2 lesion volume was significantly reduced by 6 months and was sustained at 2 years (Table 1). T1 lesion volume was increased at 1 year. There was a significant loss of brain volume at 6 months but stabilized after this time point.Flow cytometry of peripheral blood was done at baseline and at 1, 2, 6 and 12 months. There was near complete depletion of naïve CD4 and CD8 T cells (CD45RA+) at 1 month. Memory CD4 and CD8 T cells (CD45RO+) were not completely eliminated from the blood after in vivo depletion from HDIT. Within 2 months of transplant, there was rapid expansion of memory CD8 T cells. The numbers of CD4 naïve and memory T cells were not recovered at 1 year. CD4 and CD8 recent thymic emigrants (CD45RA+, CD31+) were increased at 1 year compared to the nadir at 1 month but did not completely recover. Recovery of naïve and memory B cells was complete between months 6 and 12.HDIT/HCT for highly active RRMS resulted in profound immunosuppression and induced a high rate of sustained remissions at 2 years. The small increase in T1-weighted lesion volume in the absence of persistent brain inflammation may have resulted from damage due to previous brain injury. No further loss in brain volume was observed after 6 months. Follow-up is planned through 5 years. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Volumetric MRI Markers and Predictors of Disease Activity in Early Multiple Sclerosis: A Longitudinal Cohort Study

ObjectivesTo compare clinical and MRI parameters between patients with clinically isolated syndrome and those converting to clinically definite multiple sclerosis within 2 years, to identify volumetric MRI predictors of this conversion and to assess effect of early relapses.MethodsThe SET study comprised 220 patients with clinically isolated syndrome treated with interferon beta (mean age, 29 years; Expanded Disability Status Scale, 1.5). Three patients with missing data were excluded from the analysis. Physical disability, time to clinically definite multiple sclerosis and volumetric MRI data were recorded for 2 years.ResultsPatients reaching clinically definite multiple sclerosis showed impaired recovery of neurological function, faster decrease in corpus callosum cross-sectional area, higher T2 lesion volume and more contrast-enhancing lesions. Six-month decrease in corpus callosum cross-sectional area (≥1%) and baseline T2 lesion volume (≥5 cm3) predicted clinically definite multiple sclerosis within 2 years (hazard ratios 2.5 and 1.8, respectively). Of 22 patients fulfilling both predictive criteria, 83% reached clinically definite multiple sclerosis (hazard ratio 6.5). More relapses were associated with poorer recovery of neurological function and accelerated brain atrophy.ConclusionsNeurological impairment is more permanent, brain atrophy is accelerated and focal inflammatory activity is greater in patients converting to clinically definite multiple sclerosis. Six-month corpus callosum atrophy and baseline T2 lesion volume jointly help predict individual risk of clinically definite multiple sclerosis. Early relapses contribute to permanent damage of the central nervous system.

Baseline brain activity changes in patients with clinically isolated syndrome revealed by resting-state functional MRI

A clinically isolated syndrome (CIS) is the first manifestation of multiple sclerosis (MS). Previous task-related functional MRI studies demonstrate functional reorganization in patients with CIS. To assess baseline brain activity changes in patients with CIS by using the technique of regional amplitude of low frequency fluctuation (ALFF) as an index in resting-state fMRI. Resting-state fMRIs data acquired from 37 patients with CIS and 37 age- and sex-matched normal controls were compared to investigate ALFF differences. The relationships between ALFF in regions with significant group differences and the EDSS (Expanded Disability Status Scale), disease duration, and T2 lesion volume (T2LV) were further explored. Patients with CIS had significantly decreased ALFF in the right anterior cingulate cortex, right caudate, right lingual gyrus, and right cuneus (P < 0.05 corrected for multiple comparisons using Monte Carlo simulation) compared to normal controls, while no significantly increased ALFF were observed in CIS. No significant correlation was found between the EDSS, disease duration, T2LV, and ALFF in regions with significant group differences. In patients with CIS, resting-state fMRI demonstrates decreased activity in several brain regions. These results are in contrast to patients with established MS, in whom ALFF demonstrates several regions of increased activity. It is possible that this shift from decreased activity in CIS to increased activity in MS could reflect the dynamics of cortical reorganization.

Natalizumab may reduce cognitive changes and brain atrophy rate in relapsing–remitting multiple sclerosis: a prospective, non‐randomized pilot study

The development of treatment strategies for cognitive impairment in multiple sclerosis (MS) is still in its infancy. The objective of this prospective, non-randomized, pilot study was to assess the possible efficacy of treatment with natalizumab in comparison with interferon beta (IFNB) in a group of relapsing-remitting patients with MS. We included 12 patients treated with natalizumab and 14 with IFNB. At baseline and at follow-up, cognitive functioning was assessed through Rao's Brief Repeatable Battery. All the patients underwent brain MR study with the assessment of T2 lesion volumes, neocortical volume, normalized brain volume and percentage brain volume change (PBVC). Evolution of cognitive performance was assessed using available normative data for the Italian population. Treatment comparisons were assessed through the Mann-Whitney U-test, anova for repeated measures and linear multivariate regression analyses. After a mean follow-up of 1.5 years, the mean number of neuropsychological tests with a deteriorating performance was significantly lower in patients treated with natalizumab (0.7 ± 0.7 vs. 1.7 ± 1.4; P = 0.031). Likewise, PBVC was significantly lower in natalizumab-treated subjects than that observed in patients treated with IFNB (-0.51% ± 0.47% vs. -1.18% ± 0.98%; P = 0.050). Our results suggest a potential beneficial effect of natalizumab therapy on cognitive functioning in MS, possibly mediated by a reduction of brain atrophy.

Differential Cerebellar Functional Interactions during an Interference Task across Multiple Sclerosis Phenotypes

To determine whether modification of the connections between cerebellar and prefrontal areas might vary among multiple sclerosis (MS) phenotypes and might be associated with cognitive failure. Approval of the institutional review boards and written informed consent were obtained from each participant. Stroop-related functional magnetic resonance (MR) imaging activations and effective connectivity abnormalities between the right cerebellum and any other brain regions were assessed by using a psychophysiologic interaction (PPI) analysis from 17 patients with relapsing-remitting (RR), 17 with benign, and 23 with secondary progressive (SP) MS and 18 healthy control subjects (P < .05, corrected at cluster level). Correlations with disease duration, T2 lesion volume, brain volume, and response times (RTs) during the incongruent condition were estimated (P < .001, uncorrected). Activation and PPI analyses showed that, compared with the other groups, RR MS group had abnormal recruitment of regions of the left frontoparietal lobes, whereas compared with RR MS group, SP MS group had abnormal recruitment of the cingulum or precuneus. Benign MS group had increased activation of the right prefrontal cortex, and increased interaction between these regions and the right cerebellum. In healthy controls, RTs inversely correlated with activity of right cerebellum and several frontoparietal regions. In MS, RTs inversely correlated with bilateral cerebellar activity and directly correlated with right precuneus activity. In MS, disease duration inversely correlated with right cerebellar activity and directly correlated with left inferior frontal gyrus and right precuneus activity. Higher T2 lesion volume and lower brain volumes were related to activity in these areas. Patients with MS who have various clinical phenotypes experience different abnormalities in activation and effective connectivity between the right cerebellum and frontoparietal areas, which contribute to inefficient cortical reorganization, with increasing cognitive load. http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120216/-/DC1.

Large-scale neuronal network dysfunction in relapsing-remitting multiple sclerosis

Given that multiple sclerosis (MS) hits diffusely the brain hemispheres, we hypothesized that this should result in a distributed pattern of functional connectivity (FC) abnormalities. To this aim, we assessed, using resting-state (RS) fMRI, intrinsic FC and functional network connectivity (FNC) of brain large-scale neuronal networks from 85 patients with relapsing-remitting MS (RRMS) and 40 matched controls. Independent component analysis was used to analyze RS fMRI data. Intrinsic FC of each cluster of each RS network (RSN) was compared between controls and patients (analysis of variance adjusted for age, gender, and gray matter volume). The FNC toolbox was used to assess interactions among RSNs. Compared to controls, patients with RRMS experienced a decreased RS FC in regions of the salience (SN), executive control (ECN), working memory (WMN), default mode (DMN), sensorimotor, and visual networks. They also had an increased RS FC in regions of the ECN and auditory RSN. Decreased RS FC was significantly correlated with disability and T2 lesion volumes. In patients with RRMS, when compared to controls, FNC analysis showed that the ECN had an increased connectivity with the SN and a decreased connectivity with the DMN. An abnormal connectivity between the WMNs and sensory networks was also found. Functional abnormalities within and between large-scale neuronal networks occur in patients with RRMS and are related to the extent of T2 lesions and the severity of disability. Longitudinal studies should ascertain whether such functional abnormalities confer a systematic vulnerability to disease progression or, conversely, protect against the onset of clinical deficits.

Cine cerebrospinal fluid imaging in multiple sclerosis

To investigate cerebrospinal fluid (CSF) dynamics in the aqueduct of Sylvius in multiple sclerosis (MS) patients and healthy controls (HC) using cine phase contrast imaging. In all, 67 MS patients (48 relapsing-remitting [RR] and 19 secondary-progressive [SP]), nine patients with clinically isolated syndrome (CIS), and 35 age- and sex-matched HC were examined. CSF flow and velocity measures were quantified using a semiautomated method and compared with clinical and magnetic resonance imaging (MRI) disease outcomes. Significantly decreased CSF net flow was detected in MS patients compared to HC (-3.7 vs. -7.1 μL/beat, P = 0.005). There was a trend for increased net positive flow between SP, RR, and CIS patients. Altered CSF flow and velocity measures were associated with more severe T1 and T2 lesion volumes, lateral and fourth ventricular volumes, and third ventricular width in MS and CIS patients (P < 0.01 for all). In CIS patients, conversion to clinically definite MS in the following year was related to decreased CSF net flow (P = 0.007). There was a trend between increased annual relapse rate and altered CSF flow/velocity measures in RRMS patients (P < 0.05). CSF flow dynamics are altered in MS patients. More severe clinical and MRI outcomes in RRMS and CIS patients relate to altered CSF flow and velocity measures.

Reduced R2′ in multiple sclerosis normal appearing white matter and lesions may reflect decreased myelin and iron content

BackgroundR2′ is an MRI measure of microscopic magnetic field inhomogeneity, and is increased by the paramagnetic effect of iron and the diamagnetic effect of myelin. R2′ may detect features of...

Exploration of the relationships between regional grey matter atrophy and cognition in multiple sclerosis

Cognitive impairment may result in significant disability in patients with Multiple Sclerosis (MS). Previous Magnetic Resonance Imaging (MRI) studies on cognition in MS were mainly based on measures of gross brain involvement. This study, using voxel-based morphometry (VBM), aims to investigate associations between the regional distribution of grey matter (GM) damage and cognitive performance in patients with MS. Eighteen MS patients underwent an extensive neuropsychological battery and MRI, including T2-weighted scans and T1-weighted volumes. A group of 18 healthy individuals were also investigated by MRI and served as controls for the VBM. A cross-sectional analysis was first performed, to assess the pattern of regional GM atrophy in MS patients. Then, the impact of regional GM damage on patients' neuropsychological performance was investigated by multiple regression analyses in the patient group. Correlations between global indexes of brain damage and neuropsychological measures were also assessed for comparison with previous literature. The comparison between MS patients and healthy controls revealed a widespread pattern of regional GM atrophy. Consistent with previous studies, associations were found between neuropsychological scores, and global brain atrophy and T2-lesion volumes. Critically, significant associations were found between scores on the Symbol Digit Modalities test and Long Delay Cued Recall on the California Verbal Learning Test, and regional GM volumes in well localized areas of the prefrontal, parietal, temporal, and insular cortex. This study confirms that global assessments of brain damage correlate with measures of cognitive impairment in MS. Interestingly, VBM contributes to clarify those brain regions that more likely determine the cognitive deficits observed in patients. These findings clarify the pathophysiology of cognitive impairment in MS, and propose measures which could be considered for longitudinal monitoring of patients.

Comparison of Standard 1.5 T vs. 3 T Optimized Protocols in Patients Treated with Glatiramer Acetate. A Serial MRI Pilot Study

This study explored the effect of glatiramer acetate (GA, 20 mg) on lesion activity using the 1.5 T standard MRI protocol (single dose gadolinium [Gd] and 5-min delay) or optimized 3 T protocol (triple dose of Gd, 20-min delay and application of an off-resonance saturated magnetization transfer pulse). A 15-month, phase IV, open-label, single-blinded, prospective, observational study included 12 patients with relapsing-remitting multiple sclerosis who underwent serial MRI scans (Days −45, −20, 0; the minus ign indicates the number of days before GA treatment; and on Days 30, 60, 90, 120, 150, 180, 270 and 360 during GA treatment) on 1.5 T and 3 T protocols. Cumulative number and volume of Gd enhancing (Gd-E) and T2 lesions were calculated. At Days −45 and 0, there were higher number (p < 0.01) and volume (p < 0.05) of Gd-E lesions on 3 T optimized compared to 1.5 T standard protocol. However, at 180 and 360 days of the study, no significant differences in total and cumulative number of new Gd-E and T 2 lesions were found between the two protocols. Compared to pre-treatment period, at Days 180 and 360 a significantly greater decrease in the cumulative number of Gd-E lesions (p = 0.03 and 0.021, respectively) was found using the 3 T vs. the 1.5 T protocol (p = NS for both time points). This MRI mechanistic study suggests that GA may exert a greater effect on decreasing lesion activity as measured on 3 T optimized compared to 1.5 T standard protocol.

MRI Characteristics of Malignant Multiple Sclerosis (S50.001)

Objective: To define brain MRI characteristics of MS patients who experience a malignant course in comparison with disease duration (DD) or disability (EDSS) matched non-malignant patients. Background Malignant MS is defined as rapid accumulation of disability: reaching EDSS≥6 in less than five years from first symptoms. Little is known about the MRI characteristics of malignant MS. Design/Methods: Patients meeting criteria for malignant MS who had at least one brain MRI scan after reaching malignant status were selected. Patients were from both relapsing- and progressive-onset disease categories. The first available MRI closest to attainment of EDSS≥6 was assessed. Two comparison groups were matched to the malignant group by age and gender. The first group was matched based on DD ( Results: 27 malignant (16 females), 31 DD-matched and 24 EDSS-matched patients were selected. BPF in malignant MS patients (mean±SD, 0.82±0.06) was significantly lower than the DD-matched group (BPF 0.87±0.04, p 0.05). T2 lesion volume was significantly larger in the EDSS-matched compared to the malignant group (p Conclusions: Malignant MS patients demonstrate increased brain atrophy compared to DD-matched patients, with similar brain atrophy and lower T2 lesion volumes compared to EDSS-matched patients. These results suggest more rapid cerebral neurodegeneration in malignant MS patients. Supported by: Merck Serono (HLW), National MS Society-RG (TC). Disclosure: Dr. Gholipour has received research support from Merck Serono. Dr. Egorova has nothing to disclose. Dr. Sevdalinova has nothing to disclose. Dr. Healy has nothing to disclose. Dr. Bakshi has received personal compensation for activities with Biogen Idec, Novartis, Questcor, and Teva Neuroscience as a consultant. Dr. Bakshi has received personal compensation in an editorial capacity for serving as a Associate Editor for the journal Neurotherapeutics. Dr. Bakshi has received research support from Biogen Idec, EMD Serono, and Teva Neuroscience. Dr. Guttmann has nothing to disclose. Dr. Khoury has received personal compensation for activities with EpiVax, Argos, LifeCycle, TcLand, and Wyeth as a consultant. Dr. Weiner has received personal compensation for activities with Biogen Idec, Novartis, Serono, Inc., Teva Neurosciences, GlaxoSmithKline, Nasvax, Xenoport and Genzyme Corporation as consulting and/or speaking activities. Dr. Weiner has received research support from Merck Serono. Dr. Chitnis has received personal compensation for activities with Teva Neuroscience, Biogen Idec, Sanofi-Aventis Pharmaceuticals, Inc., and Novartis. Dr. Chitnis has received research support from Merck Serono.

Long-Term (7-Year) Data from a Phase 2 Extension Study of Fingolimod in Relapsing Multiple Sclerosis (P01.129)

Objective: To report long-term outcomes and safety of fingolimod in relapsing multiple sclerosis (RMS) patients participating in a phase 2 study. Background After the 6-month (M) placebo controlled study in which fingolimod (1.25mg and 5mg dose groups) significantly reduced MRI and relapse activity compared to placebo all patients were invited to continue on fingolimod. The final analysis after 7 years is presented. Design/Methods: In the extension, placebo patients were re-randomized to fingolimod 1.25mg or 5mg (placebo/fingolimod group); fingolimod patients (1.25 or 5mg) continued with their core phase dose (fingolimod group). After the M24 visit, all patients received open-label, 1.25mg fingolimod and between M24-M60 were converted to 0.5mg. Results: Of 281 initially randomized patients 122 (43.4%) completed up to 7 years on study (core and extension). The overall ARR for the fingolimod group was 0.16 and for placebo/fingolimod 0.21. By study completion, 55-66% of fingolimod and 44% of placebo/fingolimod patients were relapse-free. The KM estimate of the proportion of patients who were free from 6-month confirmed disability progression ranged from 53-70% for both groups. At the end of study, 83% of all remaining patients were free of gadolinium-enhanced lesions. No increase in T2 lesion volume was observed. No chronic effects of fingolimod treatment were observed on heart rate or atrioventricular conduction. No cases of confirmed macular edema were observed. Twelve cases of skin malignancies have been reported (majority within the first 3 years): 5, basal cell carcinoma; 4, squamous cell carcinoma; 3, malignant melanoma. Conclusions: Long-term (>7 years) fingolimod treatment was associated with sustained low MRI and clinical disease activity in those remaining on therapy and was well tolerated with no new safety concerns arising with long-term dosing. Supported by: Novartis Pharma AG, Basel, Switzerland. Disclosure: Dr. Antel has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc., Biogen Idec, Novartis, Serono, Inc., Genzyme Corporation, Teva Neuroscience, and GlaxoSmithKline. Dr. Antel has received personal compensation in an editorial capacity for Multiple Sclerosis. Dr. Antel has received research support from Novartis. Dr. Montalban has received personal compensation for activities with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. Montalban has received research support from Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. O9Connor has received personal compensation for activities with Abbott Labratories, Inc., Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceuticals Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals as a consultant. Dr. O9Connor has received research support from Abbott Labratories, Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceutical Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals. Dr. De Vera has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Cremer has received personal compensation for activities with Novartis. Dr. Sfikas has received personal compensation for activities with Novartis as an employee. Dr. Comi has received personal compensation for activities with Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Merck Serono, Bayer Schering, and Biogen Dompe. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations.

The CombiRx Trial: A Multi-Center, Double-Blind, Randomized Study Comparing the Combined Use of Interferon Beta-1a and Glatiramer Acetate to Either Agent Alone in Participants with Relapsing-Remitting Multiple Sclerosis - Clinical Outcomes (PL02.003)

Objective: To determine if combined use of interferon beta-1a (IFN) 30ug weekly and glatiramer acetate (GA) 20 mg daily is more efficacious than either alone in relapsing remitting multiple sclerosis (RRMS). Background This double-blind, multi-center, randomized RRMS clinical trial compared IFN plus GA versus single agent arms with matching placebo. Entry criteria included: EDSS ≤ 5.5, RRMS, age 18-60, ≥2 relapses in prior 3 years and no prior use of either medication. Design/Methods: 1,008 participants were randomized and underwent quarterly clinical assessments until the last subject enrolled completes 3 years in January 2012. Magnetic resonance imaging (MRI) was done at baseline and 6, 12, 24 and 36 months. The primary MRI variable was change in the Z4 composite MRI score (unweighted sum of the individual Z scores for enhanced tissue, T2-hyperintense and T1-hypointense lesion volumes, and normalized CSF - an inverse measure of atrophy) from baseline to 36 months by treatment cohort using general linear models. Assuming differences between groups on the Z4 composite, selected additional measures will be formally addressed as follows: cumulative sum of the number of enhanced and unique active lesions, differences in the cubed root of the T2 and T1 lesion volumes, and differences in brain atrophy analyzed over the 36 months on intent to treat basis. Results: Recruitment occurred from January 2005-April 2009. At baseline 39.7% of participants had enhancements, a median total T2 lesion volume of 7.48 ml (T1-hypointense component 0.84 ml), and mean Z4 composite = 0. On study MRI data will be provided, with clinical outcome data presented separately. Conclusions: CombiRx was a uniquely sponsored collaboration between NIH, academic institutions, practicing neurologists and pharma/biotech; the largest test thus far of the potential for combining immunotherapies in early RRMS. It provides the longest controlled clinical, MRI and biomarker dataset of any MS trial. Supported by: NIH/NINDS (5U01NS045719). Disclosure: Dr. Wolinsky has received personal compensation for activities with Astellas, Bayer Pharmaceuticals Corporation, Bayer Multiple Sclerosis Council, Celgene Corporation, Eli Lilly & Company, Roche Diagnostics Corporation, Novartis, Sanofi-Aventis Pharmaceuticals and Teva Neuroscience as consultant and participant on monitoring and advisory boards. Dr. Wolinsky has received (royalty or license fee or contractual rights) payments from University of Texas Health Science Center at Houston. Dr. Wolinsky has received research support from Sanofi-Aventis Pharmaceuticals, Inc. Dr. Narayana has received personal compensation for activities with Teva Neuroscience. Dr. Nelson has received personal compensation for activities with Bayer HealthCare, Biogen Idec, EMD Serono, National MS Society, MS Association of America, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, and the University of Massachusetts Medical School. Dr. Nelson has received research support from Novartis and Sanofi-Aventis Pharmaceuticals, Inc. Dr. Datta has nothing to disclose. Dr. Cofield has received personal compensation for activities with GlaxoSmithKline, Inc., Teva Neuroscience, Orthotech Biotech, the Department of Defense, and the American Academy for Orthopedic Surgery. Dr. Cutter has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc., Cleveland Clinic, Daiichi Pharmaceutical Corporation, GlaxoSmithKline, Inc., Genmab Biopharmaceuticals, Eli Lilly & Company, Medivation, Modigenetech, Ono Pharmaceutical, PTC Therapeutics, Teva Neuroscience, Vivus, University of Pennsylvania, NHLBI, NINDS, NMSS, Alexion, Bayhill Therapeutics, Bayer Pharmaceuticals Corporation, Celgene, Novartis, Consortium of MS Centers, Genzyme Corporation, Klein-Buendel Incorporated, Nuron Biotech, Peptimmune, Somnus Pharmaceuticals, Sandoz, University of Texas Southwestern and Visioneering Technologies, Inc. Dr. Cutter has received compensation for serving on the board of Pythagoras, INC. Dr. Cutter has received research support from various pharmaceutical corporations. Dr. Conwit has nothing to disclose. Dr. Gustafson has nothing to disclose. Dr. Lublin has received personal compensation for activities with Bayer HealthCare Pharmaceuticals, Biogen Idec, EMD Serono, Novartis, Pfizer, Teva Neuroscience, Genmab, Medicinova, Actelion, Allozyne, Sanofi, Acorda, Questcor, Avanir, Roche, Celgene, Abbott, MorphoSys, Johnson & Johnson, Revalesio, Coronado Bioscience, Genzyme, and MedImmune as a consultant.Dr. Lublin has received personal compensation in an editorial capacity for Elsevier: Multiple Sclerosis and Related Diseases. Dr. Lublin has received personal compensation for activities with Bayer HealthCare Pharmaceuticals, Biogen Idec, EMD Serono, Novartis, Pfizer, Teva Neuroscience, Genmab, Medicinova, Actelion, Allozyne, Sanofi, Acorda, Questcor, Avanir, Roche, Celgene, Abbott, MorphoSys, Johnson & Johnson, Revalesio, Coronado Bioscience, Genzyme, and MedImmune as a consultant.Dr. Lublin has received personal compensation in an editorial capacity for Elsevier: Multiple Sclerosis and Related Diseases.

Subcortical but Not Cortical Gray Matter Atrophy Predicts Disability Progression over 5 Years in Patients with Early Relapsing-Remitting Multiple Sclerosis (P03.063)

Objective: Investigate the association between long-term subcortical deep gray matter (SDGM) and cortical volume changes and disability progression in early relapsing-remitting multiple sclerosis (RRMS). Background Pathological changes in gray matter are thought to have an important role in MS disease progression. However, no long-term clinical studies of SDGM and cortical changes have been reported in early RRMS. Design/Methods: One hundred eighty RRMS patients who participated in the Avonex-Steroid-Azathioprine study were assessed yearly for clinical and magnetic resonance imaging outcomes over 5 years. Healthy controls (n=48) were also assessed yearly over 2 years. MS patients were divided into those with and without sustained disability progression (SDP), defined as a ≥1.0-point increase in Expanded Disability Status Scale score lasting for ≥12 weeks at any time over the 5-year study period. Results: Of the 180 patients, 90 patients experienced SDP and 90 had stable disease after 5 years. At baseline, SDP patients were older and had longer disease duration, greater T2 lesion volume, and smaller SDGM and cortical volumes ( P ≤0.014). At 2 years, significant differences were seen in T2 and lateral ventricle volumes as well as whole brain, total SDGM, putamen, thalamus, nucleus accumbens, and amygdala volumes across the 2 RRMS groups and healthy controls; SDP patients had larger percentage changes in these same measures except for nucleus accumbens and amygdala when compared with stable MS patients at 2 years. At 5 years, SDP patients had greater percentage change decreases in volumes of whole brain, total SDGM, putamen, and thalamus and a greater increase in lateral ventricle volume than patients with stable disease ( P ≤0.02). No differences in cortical, white matter, or T2 lesion volumes were observed between patients with and without SDP at 5 years. Conclusions: SDP in early RRMS is associated with SDGM atrophy progression, especially in the putamen and thalamus, but not with cortical atrophy. Supported by: Biogen Idec Inc. and Czech Ministry of Education, Research Program MSM 0021620849. Disclosure: Dr. Zivadinov has received personal compensation for activities with Teva Neuroscience, Biogen Idec, EMD Serono, and Questcor Pharmaceuticals as a speaker and/or consultant. Dr. Zivadinov has received research support from Biogen Idec, Teva Neuroscience, Genzyme Corporation, Bracco, Questcor Pharmaceuticals and EMD Serono. Dr. Bergsland has nothing to disclose. Dr. Dolezal has received personal compensation for activities with Merck Serono, Biogen Idec, and Novartis as a consultant. Dr. Hussein has nothing to disclose. Dr. Seidl has received research support from Biogen Idec. Dr. Dwyer has nothing to disclose. Dr. Vaneckova has nothing to disclose. Dr. Krasensky has received research support from Biogen Idec. Dr. Potts has received personal compensation for activities with Biogen Idec. Dr. Havrodova has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Genzyme Corporation, GlaxoSmithKline, Inc., Novartis, Merck, Sanofi-Aventis Pharmaceuticals, Serono, Inc., and Teva as consultant, speaker and/or advisory board participant. Dr. Horakova has received personal compensation for activities with Biogen Idec as a speaker.Dr. Horakova has received research support from Biogen Idec.

A Voxel-Based Assessment of Cervical Cord Atrophy in MS Patients (P03.061)

Objective: To apply a voxel-based method to assess the regional distribution of atrophy in the cervical cord of multiple sclerosis (MS) patients with different clinical phenotypes. Background Cervical cord atrophy in MS, measured at a single anatomical level, has been correlated with clinical disability, especially in the progressive forms of the disease. Design/Methods: Brain dual-echo and sagittal 3D T1-weighted cervical cord scans were acquired from 31 healthy controls (HC) and 77 MS patients (15 clinically isolated syndrome [CIS], 15 relapsing remitting [RR] MS, 19 benign MS [BMS], 15 primary progressive MS [PPMS] and 13 secondary progressive [SPMS]). T2 lesion volume (T2LV) was assessed on dual-echo scans. Cervical cord images were analyzed using an active surface (AS) method, which segmented the cord surface from C1 to C7 and created output images reformatted in planes perpendicularly to the estimated cord centre line. Unfolded cervical cord images were co-registered into a common standard space, and smoothed cord binary masks were used as input images for spatial statistics. Between-group comparisons of regional cervical cord atrophy as well as and correlations with clinical and structural MRI variables were assessed (SPM8). Results: Compared to HC, CIS patients showed no cord atrophy, while PPMS had a diffuse cord atrophy. Several clusters of cord atrophy were found in BMS vs. RRMS, SPMS vs. RRMS, BMS and PPMS patients. Atrophy mainly involved the posterior and lateral cord segments at different levels. In PPMS, regional cord atrophy was correlated (p Conclusions: Voxel-based assessment of cervical cord atrophy allows a precise localization of regional cord tissue loss and may contribute to a better characterization of the clinical heterogeneity of MS patients. Disclosure: Dr. Damjanovic has nothing to disclose. Ms. Rocca has received personal compensation for activities with Bayer Schering Pharma and Biogen Idec as a consultant. Dr. Valsasina has nothing to disclose. Dr. Mesaros has received personal compensation for activities with Merck-Serono and Bayer Schering Pharma. Dr. Horsfield has received compensation for serving as a Director of Xinapse Systems Ltd.Dr. Horsfield holds stock and/or stock options in Xinapsse Systems Ltd. Dr. Stosic-Opincal has nothing to disclose. Dr. Drulovic has received personal compensation for activities with Bayer Schering Pharma and Merck Serono S.A. Dr. Comi has received personal compensation for activities with Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Merck Serono, Bayer Schering, and Biogen Dompe. Dr. Filippi has received personal compensation for activities with ECTRIMS, MSIF, MS Ireland, US NMSS, Bayer-Schering, Biogen-Dompe AG, Genmab, Merck Serono, Pepgen Corporation, Teva, and Sanofi-Aventis. Dr. Filippi has received research support from Teva, Bayer-Schering and Genmab.