Relapsing-remitting Multiple Sclerosis Cases Research Articles

Prediction of Retinal Loss Based on Lesion of the Optic Nerve in Acute Stage of Optic-Neuritis

Aim: To assess the predictive features of optic neuritis in retinal loss through optic nerve lesion identification. Study design: Prospectively longitudinal study Place and duration of study: Ghulam Muhammad Mahar Medical College Sukkur and Shaheed Mohtarma Benazir Bhutto Medical University Larkana from 1st January 2021 to 30th June 2022. Methodology: One hundred and ten patients suffering from acute optic neuritis ≤8 weeks were enrolled. Retinal optical-coherence tomography was performed in all patients. Fifty five patients in the whole cohort while clinically isolated syndrome (CIS) 25 patients and relapsing remitting multiple sclerosis (RRMS) as well as neuromyelitis-optica spectrum disorders (NMOSD) and isolated optic neuritis as 20, 3 and 7 respectively. Brain optic nerve magnetic resonance imaging which included three-dimensional double inversion recovery sequence was also conducted at acute phase (M0) and then post 12 months (M12). Results: The mean age of the cases was 30.85±8.9 years. There was a higher frequency of males then females. The duration of the disease was found highest in RRMS cases with 50.31±77.45 months. The variance in estimated and standard error of the ganglion cell-inner plexiform layer volume change was significantly different in whole acute optic neuritis cases as well as the one with CIS and multiple sclerosisat cohort. Conclusion: Optic nerve-lesion length in prediction of retinal-neuroaxonal loss in cases of optic neuritis. The optic-nerve lesion length can also be considered as a biomarker for the process of retinal remodeling as well as visual impairment. Key words: Optic nerve lesion, Acute phase, Optic neuritis (ON), Retinal neuronal loss

Predicting cognitive impairment and psycho-emotional disorders in Multiple Sclerosis patients according to MRI findings

Objectives. The aim of our study was to assess the probability of cognitive impairment (CI) in general and in separate domains, depression, anxiety and sleep disorders onset depending on their association with MRI findings in patients with multiple sclerosis (MS). Materials and methods. 137 patients with MS were enrolled into the study. All participants were divided into two groups: group A included study subjects with relapsing remitting multiple sclerosis (RRMS) and B consisted of patients with secondary progressive multiple sclerosis (SPMS). Results. Participants with progressive forms of MS had a higher risk of CI development compare to the patients with RRMS (p=0,0361). Memory decline onset depended on the presence of the brain atrophy in combination with lesions of the parietal lobe (OR=2.74 (0.85-8.77), p <0.0001) in RRMS cases, furthermore, on presence of combined demyelination in temporal lobe with corpus callosum (OR=17.33 (2.92-103.02), p=0.0006) and parietal lobe separately (OR=7.5 (1.14-49.26), p=0.0239) in patients with SPMS. Conclusions. CI and psycho-emotional disorders can be predicted by means of MRI findings and potentially prevented.

Brain functional connectivity analysis in patients with relapsing-remitting multiple sclerosis: A graph theory approach of EEG resting state.

Multiple sclerosis (MS) is an autoimmune disease related to the central nervous system (CNS). This study aims to investigate the effects of MS on the brain's functional connectivity network using the electroencephalogram (EEG) resting-state signals and graph theory approach. Resting-state eyes-closed EEG signals were recorded from 20 patients with relapsing-remitting MS (RRMS) and 18 healthy cases. In this study, the prime objective is to calculate the connectivity between EEG channels to assess the differences in brain functional network global features. The results demonstrated lower cortical activity in the alpha frequency bands and higher activity for the gamma frequency bands in patients with RRMS compared to the healthy group. In this study, graph metric calculations revealed a significant difference in the diameter of the functional brain network based on the directed transfer function (DTF) measure between the two groups, indicating a higher diameter in RRMS cases for the alpha frequency band. A higher diameter for the functional brain network in MS cases can result from anatomical damage. In addition, considerable differences between the networks' global efficiency and transitivity based on the imaginary part of the coherence (iCoh) measure were observed, indicating higher global efficiency and transitivity in the delta, theta, and beta frequency bands for RRMS cases, which can be related to the compensatory functional reaction from the brain. This study indicated that in RRMS cases, some of the global characteristics of the brain's functional network, such as diameter and global efficiency, change and can be illustrated even in the resting-state condition when the brain is not under cognitive load.

Disability Progression in Multiple Sclerosis Patients using Early First-line Treatments.

Background and purposeTherapeutic management of relapsing–remitting multiple sclerosis (RRMS) has evolved towards early treatment. The objective was to assess the impact of early treatment initiation on disability progression amongst RRMS first‐line‐treated patients.MethodsThis study included all incident RRMS cases starting interferon or glatiramer acetate for the first time from 1 January 1996 to 31 December 2012 (N = 5279) from 10 MS expert Observatoire Français de la Sclérose en Plaques centres. The delay from treatment start to attaining an irreversible Expanded Disability Status Scale (EDSS) score of 3.0 was compared between the early group (N = 1882; treated within 12 months following MS clinical onset) and the later group using propensity score weighted Kaplan–Meier methods, overall and stratified by age.ResultsOverall, the restricted mean time before reaching EDSS 3.0 from treatment start was 11 years and 2 months for patients treated within the year following MS clinical onset and 10 years and 7 months for patients treated later. Thus, early treated patients gained 7 months (95% confidence interval [CI] 4–11 months) in the time to reach EDSS 3.0 compared to patients treated later (treatment start delayed by 28 months). The difference in restricted mean time was respectively 6 months (95% CI 1–10 months) and 14 months (95% CI 4–24 months) in the ≤40 years age group and in the >40 years age group, in favour of the early group.ConclusionsEarly treatment initiation resulted in a significant reduction of disability progression amongst patients with RRMS, and also amongst older patients.

Differentiation of relapsing-remitting and secondary progressive multiple sclerosis: a magnetic resonance spectroscopy study based on machine learning.

Magnetic resonance imaging (MRI) is the most important tool for diagnosis and follow-up in multiple sclerosis (MS). The discrimination of relapsing-remitting MS (RRMS) from secondary progressive MS (SPMS) is clinically difficult, and developing the proposal presented in this study would contribute to the process. This study aimed to ensure the automatic classification of healthy controls, RRMS, and SPMS by using MR spectroscopy and machine learning methods. MR spectroscopy (MRS) was performed on a total of 91 participants, distributed into healthy controls (n=30), RRMS (n=36), and SPMS (n=25). Firstly, MRS metabolites were identified using signal processing techniques. Secondly, feature extraction was performed based on MRS Spectra. N-acetylaspartate (NAA) was the most significant metabolite in differentiating MS types. Lastly, binary classifications (healthy controls-RRMS and RRMS-SPMS) were carried out according to features obtained by the Support Vector Machine algorithm. RRMS cases were differentiated from healthy controls with 85% accuracy, 90.91% sensitivity, and 77.78% specificity. RRMS and SPMS were classified with 83.33% accuracy, 81.81% sensitivity, and 85.71% specificity. A combined analysis of MRS and computer-aided diagnosis may be useful as a complementary imaging technique to determine MS types.

Latency of Multifocal Visual Evoked Potential in Multiple Sclerosis: A Visual Pathway Biomarker for Clinical Trials of Remyelinating Therapies.

Acute focal demyelination is the characteristic feature of multiple sclerosis, with the majority of damaged axons undergoing limited remyelination and forming chronic lesions. Potential remyelinating agents are currently under development and there is therefore an urgent need for reliable in vivo biomarkers of remyelination. This study aimed to investigate potential changes in multifocal visual evoked potentials' (mfVEPs) latency in a cohort of relapsing-remitting multiple sclerosis (RRMS) patients. The potential sample size required for a remyelination-based clinical trial using different treatment effect sizes and the mfVEP latency as an outcome measure was also estimated. A total of 50 RRMS consecutive patients with no previous history of optic neuritis in at least one eye and 15 normal controls of similar age and gender composition were prospectively enrolled. Fifteen patients had a history of unilateral ON more than 12 months earlier, whereas 41 patients demonstrated optic radiations lesions on MRI at baseline. Most patients were on disease modifying therapy. A mfVEP was recorded at baseline and 12 months later. At baseline, the mfVEP latency in RRMS patients was delayed compared with normal controls in both optic neuritis and nonoptic neuritis eyes. Latency delay was significantly correlated to optic radiation lesion volume (R2 = 0.38, P < 0.001). There was no significant latency change in multiple sclerosis patients' eyes or optic neuritis and nonoptic neuritis eyes over the follow-up period with latency remaining remarkably constant. This was despite the fact that 46 of 50 patients were on disease-modifying therapies, implying current treatments do not affect myelination in chronic RRMS cases. Sample size calculations to evaluate an additional or alternative remyelinating agent, based on a 40% treatment effect, revealed that a relatively small sample size (78 patients) would be required to demonstrate efficacy in future trials of remyelination therapies. Given its known sensitivity for latency changes and the stability found in this RRMS population, the mfVEP represents an ideal biomarker to assess the degree of latency recovery that may be achieved by remyelination in multiple sclerosis.

Impact of cytomegalovirus infection on B cell differentiation and cytokine production in multiple sclerosis

BackgroundHuman cytomegalovirus (HCMV) infection has been recently associated with a low risk of multiple sclerosis (MS), yet the basis behind this observation remains uncertain. In this study, we aimed to determine in MS patients whether HCMV induces modifications in the peripheral B cell compartment.MethodsHCMV serostatus was determined in 73 MS patients (55 relapsing-remitting MS (RRMS); 18 progressive MS (PMS)) and 30 healthy controls, assessing their B cell immunophenotype and cytokine production (GM-CSF, IL-6, IL-10, and TNFα) by flow cytometry.ResultsHCMV seropositivity in untreated MS patients (n = 45) was associated with reduced switched memory B cells, contrasting with an opposite effect in PMS. Expansions of transitional B cells were observed in HCMV(+) IFNβ-treated RRMS patients but not in HCMV(−) cases (p < 0.01), suggesting that HCMV may influence the distribution of B cell subsets modulating the effects of IFNβ. Considering the B cell functional profile, HCMV(−) PMS displayed an increased secretion of proinflammatory cytokines (IL-6, TNFα) as compared to HCMV(+) PMS and RRMS cases (p < 0.001).ConclusionsOur study reveals an influence of HCMV infection on the phenotype and function of B cells, promoting early differentiation stages in RRMS and reducing the proinflammatory cytokine profile in advanced MS forms, which might be related with the putative protective role of this virus in MS.

Myelin Water Fraction and Intra/Extracellular Water Geometric Mean T2 Normative Atlases for the Cervical Spinal Cord from 3T MRI

Acquiring and interpreting quantitative myelin-specific MRI data at an individual level is challenging because of technical difficulties and natural myelin variation in the population. To overcome these challenges, we used multiecho T2 myelin water imaging (MWI) to create T2 metric healthy population atlases that depict the mean and variation of myelin water fraction (MWF), and intra- and extracellular water mobility as described by geometric mean T2 (IEGMT2 ). Cervical cord MWI was performed at 3T on 20 healthy individuals (10M/10F, mean age: 36 years) and 3 relapsing remitting multiple sclerosis (RRMS) participants (1M/2F, age: 39/42/37 years). Anatomical data were collected for the purpose of image segmentation and registration. Atlases were created by coregistering and averaging T2 metrics from all controls. Voxel-wise z-score maps from 3 RRMS participants were produced to demonstrate the preliminary utility of the MWF and IEGMT2 atlases. The average MWF atlas provides a representation of myelin in the spinal cord consistent with well-known spinal cord anatomical characteristics. The IEGMT2 atlas also depicted structural variations in the spinal cord. Z-score analysis illustrated distinct abnormalities in MWF and IEGMT2 in the 3 RRMS cases. Our findings highlight the potential for using a quantitative T2 relaxation metric atlas to visualize and detect pathology in spinal cord. Our MWF and IEGMT2 atlases (URL: https://sourceforge.net/projects/mwi-spinal-cord-atlases/) can serve as normative references in the cervical spinal cord for other studies.

IL12B gene polymorphisms have sex-specific effects in relapsing-remitting multiple sclerosis.

IL-12-family cytokines play a pivotal role in neuroinflammation and neurodegeneration in relapsing-remitting multiple sclerosis (RRMS). The aim of the study was to evaluate whether two polymorphisms in IL12B gene, rs17860508 and rs3212227, are associated with RRMS, and to define their function effect on serum level of IL-12p40 and IL-23 and degree of disability in RRMS cases. In total 156 Bulgarian patients with Expanded Disability Status Scale score ranging from 1.0 to 3.5 in remission of the disease and 379 controls were genotyped by polymerase chain reaction-based methods. The IL-12p40 and IL-23 serum levels were determined by enzyme-linked immunosorbent assay. We have found substantially higher IL-12p40 and IL-23 serum levels in cases than in controls (p < 0.01) in a sex-dependent manner. Women with RRMS had significantly higher IL-12р40 and IL-23 than men. Gender-stratified association analyses showed a significant impact of rs3212227 polymorphism on RRMS susceptibility in men. The carriers of rs3212227*CC-genotype (OR 3.390, 95% CI 1.007-11.545, p = 0.023) and haplotype rs17860508*2-allele/rs3212227*C-allele (OR 3.740; 95% CI 1.36-10.32, p = 0.007), showed higher risk of RRMS in men, in contrast to women. In women, both IL12B polymorphisms influencing the course, rather than genetic predisposition of RRMS. The rs17860508*22-genotype was associated with significantly lower disability (OR 0.208; 95% CI 0.055-0.725; pc = 0.01) and lower IL-23 serum levels (p = 0.0345), while rs3212227*AA-genotype was associated with early onset of the disease (OR 2.368; 95% CI 1.007-5.608; p = 0.03). Our results suggest that sex-specific effects of IL12B polymorphisms, rs17860508 and rs3212227, on genetic predisposition and disease course of RRMS, is probably mediated by their gender-dependent functional effect on IL-12p40-containing cytokines.

Adipokines in Multiple Sclerosis Patients with and without Optic Neuritis as the First Clinical Presentation

ABSTRACTBackground: Adipocytokines have been implied to be involved in multiple sclerosis (MS) pathogenesis. MS patients whose first clinical episode is optic neuritis (ON) have been reported to display a milder disease course. In this study, we aimed to show whether this milder disease course is related to reduced adipokine production.Methods: A total of 55 (24 with ON as the first clinical episode) relapsing-remitting MS (RRMS) patients and 40 healthy individuals were recruited. Concentrations of adipokines were measured in sera by ELISA.Results: The levels of adiponectin, leptin, resistin, monocyte chemoattractant protein-1 (MCP-1) and IL-8 were significantly higher in RRMS patients compared with healthy controls. RRMS cases starting with ON had lower expanded disability status scale scores. Serum adiponectin, leptin, resistin and MCP-1 levels were significantly lower in MS patients, whose first clinical episode was ON.Conclusions: MS patients with ON as the first manifestation display both lower disability scores and reduced serum adipokine levels implying that adipocytokine production is associated with MS progression. Exact mechanisms of this association in MS patients with first episode ON need to be further studied.

Preclinical disease activity in multiple sclerosis: A prospective study of cognitive performance prior to first symptom.

To prospectively investigate potential signs of preclinical multiple sclerosis (MS) activity and when they are present prior to first symptom using data from a historical cohort. We linked the cognitive performance of all Norwegian men born 1950-1995 who underwent conscription examination at age 18 to 19 years to the Norwegian MS registry to identify those later developing MS, and randomly selected controls frequency-matched on year of birth from the Norwegian Conscript Service database. In this nested case-control study, cognitive test scores were available for 924 male cases and 19,530 male controls. We estimated mean score differences among cases and controls (Student t test) and the risk of developing MS comparing lower to higher scores (Cox regression) in strata of years to clinical onset. Men developing first clinical MS symptoms up to 2 years after the examination scored significantly lower than controls (Δ = 0.80, p = 0.0095), corresponding to a 6 intelligence quotient (IQ)-point difference. Those scoring lowest, that is, >1 standard deviation below the controls' mean, had an increased MS risk during the 2 following years (relative risk = 2.81, 95% confidence interval = 1.52-5.20). Whereas results were similar for relapsing-remitting MS cases (RRMS), those developing primary-progressive MS (PPMS) scored a significant 4.6 to 6.9 IQ points lower than controls up to 20 years prior to first progressive symptoms. RRMS may start years prior to clinical presentation, and disease processes in PPMS could start decades prior to first apparent progressive symptoms. Cognitive problems could be present in both MS forms before apparent symptoms. Apart from potential implications for clinical practice and research, these findings challenge our thinking about the disease. Ann Neurol 2016;80:616-624.

A comparison of multiple sclerosis clinical disease activity between patients treated with natalizumab and fingolimod

Background: Natalizumab and fingolimod were approved for treatment of active relapsing-remitting multiple sclerosis (RRMS) in Denmark in 2006 and 2011, respectively. There have been no randomized head-to-head studies comparing the two drugs. Objective: To compare the clinical efficacy of natalizumab and fingolimod. Methods: Data on all Danish RRMS patients who started their first second-line treatment with natalizumab or fingolimod from July 2011 to March 2015 were prospectively recorded in the Danish Multiple Sclerosis (MS) Treatment Register. The two treatment arms were 1:1 propensity score matched by baseline covariates using ‘nearest neighbour’ method. Results: Propensity score matching left 928 of 1309 RRMS cases, 464 in each treatment group. The on-treatment annualized relapse rate was 0.296 (95% confidence interval (CI): 0.26–0.34) for natalizumab and 0.307 (95% CI: 0.27–0.35) for fingolimod. The adjusted relapse rate ratio was 0.93 (95% CI: 0.74–1.17; p = 0.53). Mean time to first relapse was 2.55 and 2.56 years, respectively (p = 0.76). There was no difference in change of Expanded Disability Status Scale (EDSS). Conclusion: We found no differences in clinical disease activity between natalizumab- and fingolimod-treated RRMS patients in this real-life observational study. However, the lack of magnetic resonance imaging (MRI) data for the propensity score matching may conceal a higher efficacy of natalizumab.

Sudden hearing loss as the initial symptom in Japanese patients with multiple sclerosis and seropositive neuromyelitis optica spectrum disorders

Sudden hearing loss may occur in rare cases of relapsing-remitting multiple sclerosis (RRMS). There have also been reports of idiopathic sudden sensorineural hearing loss (SNHL) in patients with neuromyelitis optica spectrum disorders (NMOSD), but the frequency of such cases is unclear.We conducted a retrospective analysis of the medical records of 173 consecutive patients with multiple sclerosis (MS) and 101 consecutive patients with NMOSD who tested positive for anti-aquaporin-4 antibodies in addition to 37 consecutive patients with clinically isolated syndromes (CIS) to investigate the frequency and onset timing of SNHL. SNHL was observed in six (3.5%) of the RRMS cases, one (1.0%) of the seropositive NMOSD cases, and three (8.1%) of the CIS cases. SNHL occurred ahead of onset in 4/6 MS patients and in all of 3 CIS patients. Patient with NMOSD exhibited SNHL 6years after the onset of NMOSD. Although SNHL is rare, these results suggest the risk of developing demyelinating lesions in the central nervous system and further conversion to MS in the future.

Gut microbiota in early pediatric multiple sclerosis: a case-control study.

Alterations in the gut microbial community composition may be influential in neurological disease. Microbial community profiles were compared between early onset pediatric multiple sclerosis (MS) and control children similar for age and sex. Children ≤18 years old within 2 years of MS onset or controls without autoimmune disorders attending a University of California, San Francisco, USA, pediatric clinic were examined for fecal bacterial community composition and predicted function by 16S ribosomal RNA sequencing and phylogenetic reconstruction of unobserved states (PICRUSt) analysis. Associations between subject characteristics and the microbiota, including beta diversity and taxa abundance, were identified using non-parametric tests, permutational multivariate analysis of variance and negative binomial regression. Eighteen relapsing-remitting MS cases and 17 controls (mean age 13 years; range 4-18) were studied. Cases had a short disease duration (mean 11 months; range 2-24) and half were immunomodulatory drug (IMD) naïve. Whilst overall gut bacterial beta diversity was not significantly related to MS status, IMD exposure was (Canberra, P < 0.02). However, relative to controls, MS cases had a significant enrichment in relative abundance for members of the Desulfovibrionaceae (Bilophila, Desulfovibrio and Christensenellaceae) and depletion in Lachnospiraceae and Ruminococcaceae (all P and q < 0.000005). Microbial genes predicted as enriched in MS versus controls included those involved in glutathione metabolism (Mann-Whitney, P = 0.017), findings that were consistent regardless of IMD exposure. In recent onset pediatric MS, perturbations in the gut microbiome composition were observed, in parallel with predicted enrichment of metabolic pathways associated with neurodegeneration. Findings were suggestive of a pro-inflammatory milieu.

Interferon-β therapy and risk of thrombocytopenia in multiple sclerosis patients.

Thrombocytopenia is a well-described adverse event of several disease-modifying therapies (DMT) in multiple sclerosis (MS). On the other hand, an increased prevalence of MS has been reported in patients with immune thrombocytopenia. In this retrospective, cross-sectional, case-control study we evaluated in a heterogeneous MS cohort: (1) the prevalence of thrombocytopenia in comparison with sex- and age-matched controls; (2) the relationship between thrombocytopenia and patients' demographic, clinical characteristics; (3) the risk for thrombocytopenia in relation to DMT. 187 consecutive MS patients [51 males, mean age (±SD) 44.5 ± 10.7 years] and 200 controls (56 males, mean age 45.5 ± 12 years) were included. Thrombocytopenia was defined as platelet count lower than normal laboratory values (130-400 × 10(9)/L). The prevalence of thrombocytopenia was significantly higher in MS patients than in controls (7 vs. 2.5 %, p = 0.04). Thrombocytopenia was present only in relapsing-remitting MS cases, and significantly associated with lower EDSS (p = 0.002) and with a trend for shorter disease duration (p = 0.06). It was more frequent in patients on high-dose interferon-β therapy compared with those on low-dose interferon-β therapy, other therapies or untreated patients (p = 0.02). High-dose interferon-β therapy was associated with more than eightfold increase in the risk for thrombocytopenia (odds ratio 8.60, 95 % confidence interval: 1.01-74.48 adjusted for EDSS, disease duration and type of disease). The prevalence of thrombocytopenia was increased in MS patients treated with DMT. High-dose interferon-β therapy is the variable most strongly associated with thrombocytopenia.

Clinical Parameters to Predict Response to Interferon in Relapsing Multiple Sclerosis

Background: To identify clinical parameters of response to β-interferon (IFN-β) in relapsing-remitting multiple sclerosis (RRMS) from an East France cohort. Methods: Data from 2,645 patients, identified by Burgundy and Lorraine multiple sclerosis (MS) networks, were computerized by a neurologist using the European Database for MS software. Patient inclusion criteria were: clinically or laboratory-supported definite RRMS according to Poser’s diagnostic criteria and treatment with IFN-β for at least 6 months. Four criteria were chosen to predict a response to IFN-β. The first criterion was any patient who had a lower annualized relapse rate under IFN-β therapy than during the year preceding treatment; the second criterion was a lower relapse rate than during the 2 years preceding treatment. The third was any patient free of relapse during the first 2 years of IFN-β therapy. The last criterion concerned the variation in the degree of disability measured by the Disability Status Scale during the first year of treatment. Multivariate logistic regression analyses were performed. Results: 751 RRMS cases were included. A higher relapse rate in the year preceding IFN-β onset, an older age at MS onset and having a polysymptomatic onset of MS were significantly associated with a response for the first criterion. With the 3 other criteria, no parameter predicting response was identified. Conclusion: Only the relapse rate in the year before initiation of IFN-β treatment appears to be able to predict response to treatment but not the one of 2 years before.

Altered Glutamate Reuptake in Relapsing-Remitting and Secondary Progressive Multiple Sclerosis Cortex: Correlation With Microglia Infiltration, Demyelination, and Neuronal and Synaptic Damage

Cortical involvement in multiple sclerosis (MS) is emerging as an important determinant of disease progression. The mechanisms responsible for MS cortical pathology are not fully characterized. The objective of this study was to assess the role of excitotoxicity in MS cortex, evaluating excitatory amino acid transporter (EAAT) expression and its relationship with demyelination, inflammation, gliosis, and neuronal and synaptic pathology. EAATs are essential in maintaining low extracellular glutamate concentrations and preventing excitotoxicity. Ten MS brains (3 relapsing-remitting MS cases and 7 secondary progressive MS cases) were evaluated by immunohistochemistry for myelin basic protein, CD68, HLA-DR, EAAT1, EAAT2, glial fibrillary acidic protein, phosphorylated c-Jun N-terminal kinase (pJNK), synaptophysin, and neurofilaments. Cortical lesions were frequently observed in MS brains in variable numbers and extensions. In cortical lesions, activated microglia infiltration correlated with focal loss of EAAT1, EAAT2, and synaptophysin immunostaining, and with neuronal immunostaining for pJNK, a protein involved in response to excitotoxic injury. No reduction of EAATs or synaptophysin immunostaining was observed in demyelinated cortex in the absence of activated microglia. Alterations of the mechanisms of glutamate reuptake are found in cortical MS lesions in the presence of activated microglia and are associated with signs of neuronal and synaptic damage suggestive of excitotoxicity. Excitotoxicity may be involved in the pathogenesis of demyelination and of neuronal and synaptic damage in MS cortex.