Benign Multiple Sclerosis Patients Research Articles

The Peripheral Profile of the Chitinase 3-like-1 in Benign Multiple Sclerosis - A Single Centre's Experience.

A limited subgroup of multiple sclerosis (MS) patients present with a longterm disease evolution characterized by a limited disease progression, known as benign MS (BMS). Chitinase 3-like-1 (CHI3L1) levels are sensitive to inflammatory processes and may play a role in the pathogenesis of MS. In this observational, cross-sectional study, we aimed to evaluate the implications of serum CHI3L1 and inflammatory cytokines in BMS patients treated with interferon β-1b for over a decade. We collected serum samples from 17 BMS patients and 17 healthy controls (HC) to measure serum CHI3L1 levels and a Th17 panel of inflammatory cytokines. Serum levels of CHI3L1 were analysed using the sandwich ELISA method and the Th17 panel was assessed using the multiplex XMap technology on a Flexmap 3D Analyzer. Serum CHI3L1 levels did not differ significantly from HC. We identified a positive correlation between CHI3L1 levels and relapses during treatment. Our findings suggest that there are no differences in serum CHI3L1 levels between BMS patients and HC. However, serum CHI3L1 levels are sensitive to clinical inflammatory activity and may be associated with relapses in BMS patients.

Grey-matter sodium concentration as an individual marker of multiple sclerosis severity

Objective: Quantification of brain injury in patients with variable disability despite similar disease duration may be relevant to identify the mechanisms underlying disability in multiple sclerosis (MS). We aimed to compare grey-matter sodium abnormalities (GMSAs), a parameter reflecting neuronal and astrocyte dysfunction, in MS patients with benign multiple sclerosis (BMS) and non-benign multiple sclerosis (NBMS). Methods: We identified never-treated BMS patients in our local MS database of 1352 patients. A group with NBMS was identified with same disease duration. All participants underwent 23Na magnetic resonance imaging (MRI). The existence of GMSA was detected by statistical analysis. Results: In total, 102 individuals were included (21 BMS, 25 NBMS and 56 controls). GMSA was detected in 10 BMS and 19 NBMS (11/16 relapsing-remitting multiple sclerosis (RRMS) and 8/9 secondary progressive multiple sclerosis (SPMS) patients) (p = 0.05). On logistic regression including the presence or absence of GMSA, thalamic volume, cortical grey-matter volume and T2-weighted lesion load, thalamic volume was independently associated with BMS status (odds ratio (OR) = 0.64 for each unit). Nonetheless, the absence of GMSA was independently associated when excluding patients with significant cognitive alteration (n = 7) from the BMS group (OR = 4.6). Conclusion: Detection of GMSA in individuals and thalamic volume are promising to differentiate BMS from NBMS as compared with cortical or whole grey-matter atrophy and T2-weighted lesions.

Spectral-Domain Optical Coherence Tomography Assessment in Treatment-Naïve Patients with Clinically Isolated Syndrome and Different Multiple Sclerosis Types: Findings and Relationship with the Disability Status.

This study evaluates the peripapillary retinal nerve fiber layer (pRNFL) thickness and total macular volume (TMV) using spectral-domain optical coherence tomography in treatment naïve patients with the clinically isolated syndrome (CIS) and different multiple sclerosis (MS) types. A total of 126 patients (15 CIS, 65 relapsing-remitting MS, 14 secondary progressive MS, 11 primary progressive MS, 21 benign MS) with or without optic neuritis (ON) history and 63 healthy age-similar controls were assessed. Concerning controls’ eyes, pRNFL thickness was significantly reduced in CIS-ON eyes (p < 0.01), while both TMV and pRNFL thickness was decreased in all MS eyes regardless of ON history (p < 0.01). Significant differences in pRNFL thickness and TMV between MS variants were observed for non-ON eyes (p < 0.01), with the lowest values in benign and secondary progressive disease type, respectively. The pRNFL thickness was inversely correlated with Expanded Disability Status Scale (EDSS) score in non-ON subgroups (p < 0.01), whereas TMV was inversely correlated with EDSS score in both ON and non-ON subgroups (p < 0.01). Concluding, pRNFL thinning confirms optic nerve damage in CIS-ON eyes and appears to be disproportionately high with respect to the disability status of benign MS patients. The values of TMV and pRNFL in non-ON eyes significantly correspond to MS course heterogeneity and patients’ disability than in ON eyes.

Cognitive impairment in benign multiple sclerosis: a multiparametric structural and functional MRI study.

The substrates of cognitive impairment in benign MS (BMS) still need to be identified. We investigated whether cognitive impairment in BMS patients is associated with specific patterns of brain structural and functional abnormalities. Thirty-seven BMS patients (EDSS score ≤ 3.0 and disease duration ≥ 15years) and 50 healthy controls (HC) were studied. In BMS patients, a cognitive impairment index (CII) was derived. Gray matter (GM) volumes, white matter (WM) fractional anisotropy (FA) and resting-state (RS) functional connectivity (FC) were investigated for whole-brain relevant regions (cortex, lobes, subcortical nuclei, fiber tracts) and functional networks. Univariate and multivariate analyses identified independent predictors of cognitive impairment. In BMS, median CII was 9 (IQR: 4-16). Compared to HC, BMS patients showed reduced WM FA, GM atrophy and increased RS FC in fronto-temporo-parietal regions. At multivariate analysis, percentage of T2-lesions of the corpus callosum, reduced posterior corona radiata (PCR) FA and caudate nucleus atrophy were independent predictors of worse CII. A multivariate model identified reduced PCR FA (R2 = 0.39; p = 0.001) as the only predictor of CII. Cognitive impairment in BMS is associated with structural damage of relevant brain areas. WM damage of parietal regions was the predominant predictor of worse cognitive performance in these patients.

B Cell Immunophenotyping and Expression Analysis of B Cell Specific Molecules of Patients with Benign Multiple Sclerosis

<strong>Objective</strong>: Multiple Sclerosis (MS) is a progresive and an immune mediated inflammatory central nervous disease. The focus of this study was to determine the possible relationship between B cell immunophenotypes and related gene expressions in the benign MS (BMS) group with disease and cognitive processes. <br> <strong>Material and Method</strong>: Twenty BMS patients, 16 non-BMS and 28 healthy volunteers were included in the study. Gene expression was performed by real-time PCR (RT-PCR). Immunophenotyping of peripheral B cells was also evaluated by flow cytometry. The relationship between cognitive functions and gene expression levels and B cell subtypes was investigated. <br> <strong>Results</strong>: It was observed that naïve (CD19+ IgD+CD27- ) cells were higher in the BMS group compared to the healthy group (HC), and memory B cells showed opposite changes. Un-switched memory B cells(CD19+IgD+CD27+) were found to be higher in the benign group than in the HC. The expression of BANK and BLNK was found to be lower in both MS groups than in the HC. As a result of neuropsychological examinations and cognitive tests; it was observed that motor processes in BMS were better protected than Non-BMS. <br> <strong>Conclusion</strong>: These findings support that B cell functions may have molecular and cellular effects, and may lead to regression in inflammation and clinical progression. Molecules showing significant changes in our study may play a role as prognostic biomarkers in MS.

Neuropsychological characteristics of benign multiple sclerosis patients: A two-year matched cohort study

BackgroundThe definition of benign multiple sclerosis (BMS) is still debated. It is mainly based on physical status, however, there is an attempt to involve cognitive functioning or paraclinical factors in order to avoid unnecessary long-term treatment with disease-modifying therapies and to identify these subjects in the early stages of the disease. Therefore the aim of our two-year follow-up study was to investigate the pattern of cognitive functioning and depression in patients with BMS compared to treated relapsing-remitting MS (RRMS) patients and healthy controls. MethodsA group of 22 BMS patients was tested against matched RRMS patients and healthy controls. All individuals underwent neuropsychological evaluation exploring mood and the cognitive domains most frequently impaired in MS. MS patients were retested at two-year follow-up. ResultsIn terms of cognitive functions there were no differences between BMS and RRMS patients either at baseline or at two-year follow-up. Compared to healthy controls BMS patients showed poorer performance in long-term visuo-spatial memory and information processing speed, whereas, complex attention, working memory, long-term verbal memory – despite slower verbal learning – and executive function were found to be intact. RRMS patients showed significant difference in complex attention, long-term visual memory and information processing speed. Cognitive impairment differed in the patient groups in terms of severity. Both patient groups were depressed compared to controls, but significant differences were found only between BMS and healthy individuals. ConclusionThe results of our study confirm that cognitive functions and mood can be affected in MS independent of disease course and disease modifying treatment. The “benign” label should be treated as only a reference to physical status and non-motor symptoms should be routinely monitored. Without receiving therapy it is an existing entity with longstanding minimal disability.

Structural connectivity in multiple sclerosis and modeling of disconnection

Background: Multiple sclerosis (MS) is characterized by focal white matter damage, and when the brain is modeled as a network, lesions can be treated as disconnection events. Objective: To evaluate whether modeling disconnection caused by lesions helps explain motor and cognitive impairment in MS. Methods: Pathways connecting 116 cortical regions were reconstructed with magnetic resonance imaging (MRI) tractography from diffusion tensors averaged across healthy controls (HCs); maps of pathways were applied to 227 relapse-onset MS patients and 50 HCs to derive structural connectivity. Then, the likelihood of individual connections passing through lesions was used to model disconnection. Patients were grouped according to clinical phenotype (113 relapsing-remitting multiple sclerosis (RRMS), 69 secondary progressive multiple sclerosis (SPMS), 45 benign MS), and then network metrics were compared between groups (analysis of variance (ANOVA)) and correlated with motor and cognitive scores (linear regression). Results: Global metrics differentiated RRMS from SPMS and benign MS patients, but not benign from SPMS patients. Nodal connectivity strength replicated global results. After disconnection, few nodes were significantly different between benign MS and RRMS patients. Correlations revealed nodes pertinent to motor and cognitive dysfunctions; these became slightly stronger after disconnection. Conclusion: Connectivity did not change greatly after modeled disconnection, suggesting that the brain network is robust against damage caused by MS lesions.

Effects of computer-assisted cognitive rehabilitation in benign multiple sclerosis

Background/aim: Benign multiple sclerosis (BMS) patients display preserved somatic neurological functions but nevertheless may develop cognitive dysfunction. Our aim was to explore the impact of computer-assisted cognitive rehabilitation (CCR) on cognitive functions of BMS patients. Materials and methods: Age- and sex-matched BMS patients (n = 21), non-BMS patients (n = 22), and healthy individuals (n = 38) were recruited for evaluation of cognitive functions. CCR was administered to 10 BMS patients and a panel of neuropsychological tests were employed at baseline and 6 months. CCR was based on mental exercise software containing attention, memory, reasoning, visual, and verbal task modules. Results: BMS and non-BMS patients showed impaired selective reminding, spatial recall, symbol digit modalities (SDMTs), controlled oral word association (COWAT), paced auditory serial addition-3 (PASAT-3), and Stroop tests. Timed 25-foot walk and 9-hole peg test results of BMS patients were comparable to those of healthy controls. BMS patients with CCR showed significantly improved SDMTs, COWAT, and Stroop test results compared to those without CCR. Conclusion: Several cognitive domains including memory and executive functions are impaired in BMS patients. CCR has an ameliorating impact particularly on sustained attention, information processing speed, verbal fluency, categorical reasoning, and executive functions of BMS patients.

The dilemma of benign multiple sclerosis: Can we predict the risk of losing the “benign status”? A 12-year follow-up study

BackgroundDefinition of benign multiple sclerosis (BMS) remains controversial. Moreover, a sizeable proportion of classically defined BMS patients may be no longer benign (NLB) when re-assessed in the long-term. In a previous work, we found that after a five-year follow-up, a clinical score was able to identify patients at risk of losing their benign status. ObjectivesIn this 12-year reappraisal of the same cohort, we aimed at assessing the predictive value of the same score in the long-term. MethodsAfter a mean follow-up of 12.6 + 0.4 years, patients still having an EDSS score <3.0 were classified as “still benign” (SB), whereas patients having an EDSS score ≥3.5 were defined as NLB. The predictive value of the mentioned score was re-assessed using survival analysis. ResultsBy the end of the follow-up, 20 (32.8%) were classified as NLB. Patients were grouped on the basis of the above mentioned score. Patients with score 2–3 were at higher risk of NLB status at the follow-up (HR = 3.5; 95%CI 1.5–8.6; p = 0.005, accuracy = 70.5%). ConclusionsIn patients with established BMS, prognostic prediction of longer-term disease course remains of critical value. In this study, a clinical score was able to predict disease evolution in the long term.

Can we predict benign multiple sclerosis? Results of a 20-year long-term follow-up study.

Benign multiple sclerosis (MS) is a discussed clinical entity, with variable reported prevalence (6-64%) requiring at least 5-10years of clinical observation. Moreover, many benign patients progress with time becoming no longer benign (NLB). The objective of this study is to compare benign MS patients (EDSS≤3, 10years from disease onset) who still fulfilled the definition at 20years to those NLB. In our retrospective study based on Ottawa Hospital MS Clinic database, 175 benign patients fulfilled the inclusion criteria (clinically definite MS, EDSS ≤3 at 10 years, disease onset from 1983 to 1993, and clinical assessments performed at 10 ± 1 and 20 ± 1 years from onset). Out of the identified patients, 66.3% remained benign at 20years; however, by changing the definition for benign to EDSS≤2 or≤1 at 10years, they increased to 71.9 and 81.6%, respectively. Female sex, EDSS≤1 at 10years, and a pure sensory onset were associated with a benign course, while a pure motor onset with an NLB condition. According to multivariate analysis, an EDSS≤2 at 10years predicted a long-term benign course. Our study questions the current definition of "benign" MS, suggesting a more stringent EDSS cutoff at 10years to predict long-term benign prognosis.

Factors associated with benign multiple sclerosis in the New York State MS Consortium (NYSMSC).

BackgroundThis retrospective analysis explored prognostic factors associated with a benign multiple sclerosis (BMS) disease course at baseline and over the 4-year follow-up.MethodsPatients from the centralized New York State Multiple Sclerosis Consortium registry were classified as having BMS according to 3 different criteria centered on disease duration and disability. Additional analyses explored prognostic factors associated with BMS using the most conservative disability criteria (Expanded Disability Status Scale ≤2 and disease duration ≥10 years).ResultsAmong 6258 patients who fulfilled eligibility criteria, 19.8 % to 33.3 % were characterized as having BMS, at baseline depending on classification criteria used. Positive prognostic factors for BMS at baseline included female sex (p < 0.0001) and younger age at onset (p < 0.0001); negative prognostic factors included progressive-onset type of MS and African-American race. Of the 1237 BMS patients (per most conservative criteria), 742 were followed for a median of 4 years to explore effect of disease-modifying treatment (DMT) on benign status. DMT (p = 0.009) and longer disease duration (p = 0.007) were the only significant positive predictors of maintaining BMS at follow-up. The protective effect was stronger for patients taking DMT at both enrollment and follow-up (OR = 0.71; p = 0.006).ConclusionsThere is a need for development of more reliable prognostic indicators of BMS. Use of DMT was significantly associated with maintaining a benign disease state.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0623-2) contains supplementary material, which is available to authorized users.

In vivo evidence of hippocampal dentate gyrus expansion in multiple sclerosis.

Using MR-based radial mapping, we assessed morphological alterations of the hippocampal dentate gyrus (DG) in patients with relapse-onset multiple sclerosis (MS). We analyzed different stages of the disease and the association of DG alterations with hippocampal-related cognitive functions. Using high-resolution morphological imaging, hippocampal radial mapping analysis was performed in 28 relapsing-remitting (RR), 34 secondary progressive, and 26 benign MS patients and 28 healthy controls (HC). Between-groups differences of DG radial distance (from surface points to the central core of the hippocampus) and correlations with clinical, neuropsychological, and radiological measures were evaluated using surface-based mesh modeling. Compared with HC, all MS clinical phenotypes revealed a larger radial distance of the DG, which was more marked on the left side. Radial distance enlargement was more pronounced in RRMS patients compared with the other disease clinical phenotypes and was inversely correlated to disease duration. Radial distance enlargement was correlated with higher T2 lesion volume and a better cognitive performance in RRMS and with a poor cognitive performance in secondary progressive and benign MS patients. Surface expansion of the DG might represent an inflammation-induced neurogenic (reactive) process of the subgranular zone of the hippocampus primarily aimed at rescuing the functional competence of hippocampal circuitry.

Global N-acetylaspartate concentration in benign and non-benign multiple sclerosis patients of long disease duration

Background and objectiveTo examine whether clinically benign multiple sclerosis patients (BMS) show similar losses of their global N-acetylaspartate (NAA) neuronal marker relative to more clinically disabled patients of similar disease duration. MethodsThe whole-brain NAA concentration (WBNAA) was acquired with whole-head non-localizing proton MR spectroscopy. Fractional brain parenchymal volume (fBPV), T2 and T1 lesion loads, were obtained from the MRI in: (i) 24 BMS patients: 23.1±7.2 years disease duration, median Expanded Disability Status Scale (EDSS) score of 2.0 (range: 0–3); (ii) 26 non-benign MS patients (non-BMS), 24.5±7.4 years disease duration, median EDSS of 4.0 (range: 3.5–6.5); (iii) 15 healthy controls. ResultsControls’ 12.4±2.3mM WBNAA was significantly higher than the BMS's and non-BMS's 10.5±2.4 and 9.9±2.1mM (both p<0.02), but the difference between the patients’ groups was not (p>0.4). Likewise, the controls’ 81.2±4.5% fBPV exceeded the BMS and non-BMS's 77.0±5.8% and 76.3±8.6% (p<0.03), which were also not different from one another (p>0.7). BMS patients’ T1-hypointense lesion load, 2.1±2.2cm3, was not significantly different than the non-BMS's 4.1±5.4cm3 (p>0.08) and T2-hyperintense loads: 6.0±5.7cm3 and 8.7±7.8cm3, were also not different (p>0.1). ConclusionsWBNAA differentiates normal controls from MS patients but does not distinguish BMS from more disabled MS patients of similar disease duration. Nevertheless, all MS patients who remain RR for 15+ years suffered WBNAA loss similar to the average RR MS population at fourfold shorter disease duration suggesting relative global neuronal sparing or leveling-off of the neurodegeneration rate.

Retinal nerve fiber layer thickness in benign multiple sclerosis

Background/objective: Retinal nerve fiber layer (RNFL) thickness has been linked to brain atrophy in multiple sclerosis (MS). However, little is known about retinal atrophy in ‘benign’ MS. We compared RNFL thickness in benign MS with healthy controls. Methods: Patients with benign MS (Expanded Disability Status Scale (EDSS) ≤ 3; ≥15 years’ disease duration), identified through the British Columbia MS database, along with age-matched healthy controls, were recruited. RNFL thickness was measured using spectral-domain optical coherence tomography. Analysis of variance (ANOVA) was used to compare groups. The association between RNFL thickness and MS patient characteristics was examined via linear mixed-effects models (adjusting for within-patient inter-eye correlations and history of optic neuritis (ON), where appropriate). Results: Overall, 29 benign MS patients and 29 healthy controls were included, totaling 116 eyes. RNFL thickness was lowest for the benign MS eyes, with and then without a history of ON, followed by healthy controls (mean=73.2 µm, SD ± 0.4; 89.9 µm, SD ± 12.5; 96.7 µm, SD ± 10.4; p<0.02). RNFL thickness was associated with a history of ON (p<0.0001), but not EDSS or disease duration (p>0.1). Conclusions: RNFL thickness was lower in patients with benign MS than healthy controls, regardless of the previous history of ON. However, no association was found between RNFL values and disability or MS disease duration.

The evoked potentials score improves the identification of benign MS without cognitive impairment

The presence of cognitive impairments (CI) among Benign MS (BMS) patients has challenged actual BMS criteria. We hypothesized that a low evoked potentials score (EP-score) at first neurological evaluation would help identify BMS patients without CI. The EP-score was retrospectively computed in 29 putative BMS patients who were then tested for CI during 2012. The difference in the prevalence of CI between low EP-score patients and the recent literature was assessed using resampling methods. Among 23 low EP-score patients, only 3 (13%) had CI. This percentage was significantly reduced (P-values 0.05-0.005) compared to recent literature (39-46%). We conclude that a low EP-score at first neurological evaluation successfully helps to identify BMS patients without CI.

Low degree of cortical pathology is associated with benign course of multiple sclerosis

Background: Although a more favorable course of multiple sclerosis is associated with a low degree of cortical pathology, only longitudinal studies could definitely confirm this association. Materials and Methods: We followed 95 early relapsing–remitting MS (RRMS; median Expanded Disability Status Scale (EDSS) = 1.5, mean disease duration = 3.1 ± 1.3 years) and 45 benign MS patients (EDSS ≤ 3.0, disease duration ≥ 15 years, normal cognition) for 6 years, with EDSS evaluations every 6 months and brain magnetic resonance imaging (MRI) at baseline and then yearly. Results: At baseline, we detected 406 cortical lesions (CLs) in 67/95 (70.5%) early RRMS and in 24/45 (53.3%) benign MS patients (p = 0.046). After 6 years, the appearance of new CLs was observed in 80/95 (84.2%; 518 CLs) of our early RRMS and in 25/45 (55.5%; 63 CLs; p < 0.001) benign MS patients. At baseline, after corrections for age and disease duration, we observed a cortical thinning of several frontal and temporal regions in our RRMS study patients, compared to the benign MS patients (p ranging between 0.001–0.05). After 6 years, the cortical thinning had increased significantly in several cortices of RRMS patients, but only in the occipital-temporal (p = 0.036) and superior parietal gyrus (p = 0.035) of those with benign MS. Stepwise regression analysis revealed the CL volume (p = 0.006) and the cortical thickness of the temporal middle (p < 0.001), insular long (p < 0.001), superior frontal (p < 0.001) and middle frontal gyri (p < 0.001) as the most sensitive independent predictors of a favorable disease course. Conclusions: Our data confirmed that a significantly milder cortical pathology characterizes the most favorable clinical course of MS. Measures of focal and diffuse grey matter should be combined to increase the accuracy in the identification of a benign MS course.

Suppressed RNA-Polymerase 1 Pathway Is Associated with Benign Multiple Sclerosis

Benign multiple sclerosis (BMS) occurs in about 15% of patients with relapsing-remitting multiple sclerosis (RRMS) that over time do not develop significant neurological disability. The molecular events associated with BMS are not clearly understood. This study sought to underlie the biological mechanisms associated with BMS. Blood samples obtained from a cohort of 31 patients with BMS and 36 patients with RRMS were applied for gene expression microarray analysis using HG-U133A-2 array (Affymetrix). Data were analyzed by Partek and pathway reconstruction was performed by Ingenuity for the most informative genes (MIGs). We identified a differing gene expression signature of 406 MIGs between BMS patients, mean±SE age 44.5±1.5 years, 24 females, 7 males, EDSS 1.9±0.2, disease duration 17.0±1.3 years, and RRMS patients, age 40.3±1.8 years, 24 females, 12 males, EDSS 3.5±0.2, disease duration 10.9±1.4 years. The signature was enriched by genes related RNA polymerase I (POL-1) transcription, general inflammatory response and activation of cell death. The most significant under-expressed pathway operating in BMS was the POL-1 pathway (p = 4.0*10−5) known while suppressed to activate P53 dependent apoptosis and to suppress NFκB induced inflammation. In accordance, of the 30 P53 target genes presented within the BMS signature, 19 had expression direction consistent with P53 activation. The transcripts within the pathway include POL-1 transcription factor 3 (RRN3, p = 4.8*10−5), POL-1 polypeptide D (POLR1D, p = 2.2*10−4), leucine-rich PPR-motif containing protein (LRPPRC p = 2.3*10−5), followed by suppression of the downstream family of ribosomal genes like RPL3, 6,13,22 and RPS6. In accordance POL-1 transcript and release factor PTRF that terminates POL-1 transcription, was over-expressed (p = 4.4*10−3). Verification of POL-1 pathway key genes was confirmed by qRT-PCR, and RRN3 silencing resulted in significant increase in the apoptosis level of PBMC sub-populations in RRMS patients. Our findings demonstrate that suppression of POL-1 pathway induce the low disease activity of BMS.

Microstructural magnetic resonance imaging of cortical lesions in multiple sclerosis

Background: Pathologic and magnetic resonance imaging (MRI) studies have shown that cortical lesions (CLs) are a frequent finding in multiple sclerosis (MS). Objective: To quantify microstructural damage in CLs and normal appearing (NA) cortex in relapse-onset MS patients at different stages of the disease. Methods: Brain double inversion recovery (DIR), diffusion tensor (DT) MRI and 3D T 1-weighted scans were acquired from 35 relapsing–remitting (RR) patients, 23 secondary progressive (SP) patients, 12 benign (B) MS patients and 41 healthy controls (HC). Diffusivity values in CLs, cortex, white matter (WM) lesions and normal-appearing white matter (NAWM) were assessed. Results: Compared to HC, MS patients had a significantly lower fractional anisotropy (FA) and higher mean diffusivity (MD) in the cortex and NAWM. CLs had higher FA vs HC cortex and vs patients’ cortex. Compared to RRMS patients, SPMS patients had higher WM lesion volume, higher MD in the cortex, and more severe damage to the NAWM and WM lesions. Compared to SPMS patients, BMS patients had lower MD and FA of CLs. Damage in other compartments was similar between SPMS and BMS patients. Damage in CLs had a high power to discriminate BMS from SPMS (area under the curve: 79–91%), with high specificity (85%), sensitivity (100%) and accuracy (90%). Conclusions: Microstructural imaging features of CLs differ from those of WM lesions and are likely to reflect neuronal damage and microglial activation. The nature and extent of CL damage can be used to help distinguish the different MS clinical phenotypes.

Benign Multiple Sclerosis: Does it exist?

Although the definition of benign multiple sclerosis (BMS) remains controversial, it is generally applied to a subgroup of MS patients showing little disease progression, with minimal disability decades after disease onset, and is based mainly on changes in motor function. Recent studies, however, reveal that deterioration of cognitive function, fatigue, pain, and depression also occur in BMS patients, causing negative impact on work and social activities, despite complete preservation of motor function. Using conventional MRI techniques, lesion load observed in BMS is similar to levels in other disease subtypes; however, newer quantitative MRI techniques show less tissue damage, as well as greater repair and compensatory efficiency following MS injury. Currently accepted criteria for BMS diagnosis may cause overestimation of true prevalence, underscoring the need for routine monitoring of nonmotor symptoms and imaging studies. Clearly, the definition of BMS currently applied in clinical practice requires reassessment.

Microstructural MR Imaging of Cortical Lesions in Multiple Sclerosis Phenotypes (S21.001)

Objective: We used double inversion recovery (DIR) and diffusion tensor (DT) MRI to quantify tissue damage in cortical lesions (CLs) and the apparently normal cortical gray matter (GM) in patients with MS at different stages of the disease. Background DIR sequences allow the in vivo visualization of a proportion of CLs in MS and their application has demonstrated that CLs occur in all the major disease clinical phenotypes. Design/Methods: Brain DIR, DT MRI and 3D T 1 -weighted scans were acquired from 35 relapsing remitting (RR), 23 secondary progressive (SP), 12 benign (B) MS patients and 41 healthy controls (HC). Diffusivity values in CLs, skeletonised cortical GM, white matter (WM) lesions and normal-appearing (NA) WM were assessed. Results: Compared to HC, MS patients had a significantly lower fractional anisotropy (FA) and higher axial (AD), radial (RD) and mean diffusivity (MD) in the skeletonized cortical GM and NAWM. CLs had higher FA (p=0.02), AD (p=0.01) and MD (p=0.05) vs . HC skeletonized cortical GM, as well as higher FA (p=0.00002) and lower RD (p=0.01) vs . patients9 skeletonized cortical GM. Compared to RRMS, SPMS patients had higher WM lesion volume and more severe damage to the skeletonized cortical GM, NAWM and WM lesions. Damage in the other compartments was similar between SPMS and BMS patients. Compared to SPMS, BMS patients had lower MD, AD and FA of CLs. Damage in the CLs had a high power to discriminate BMS from SPMS (area under the curve: 77-80%), with high specificity (93%), sensitivity (89%) and accuracy (87%). Conclusions: Microstructural diffusivity features of CLs differ from those of WM lesions and are likely to reflect neuronal damage and microglial activation. Their quantification may help in the early identification of RRMS patients at risk of developing a progressive form of disease. Supported by: Partially supported by a grant from FISM/2008/R/13. Disclosure: Dr. Pagani has nothing to disclose. Ms. Rocca has received personal compensation for activities with Bayer Schering Pharma and Biogen Idec as a consultant. Dr. Preziosa has nothing to disclose. Dr. Copetti has nothing to disclose. Dr. Mesaros has received personal compensation for activities with Merck-Serono and Bayer Schering Pharma. Dr. Colombo has nothing to disclose. 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. Falini has nothing to disclose. Dr. Comi has received personal compensation for activities with Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Merck Serono, Bayer Schering, and Biogen Dompe. Dr. Lassmann has nothing to disclose. 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.