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Background: Persons with MS (PwMS) ≥ 55 years are underrepresented in therapy studies leading to a lack of evidence., Objective and Methods: To study the subgroup of PwMS ≥ 55 years in the German MS registry in comparison with PwMS < 55 years. Endpoints of interest were the grade of disability, leading symptoms, clinical and magnetic resonance imaging activity, and use of disease modifying therapy., Results: At the time of analysis, data from 40,428 PwMS were available for analysis. In PwMS aged ≥ 65 and PwMS aged ≥ 55 to 64 years, compared with PwMS aged < 55 years, the mean Expanded Disability Status Scale Scores were higher (5.3, 4.2 and 2.7, respectively), while the proportion of individuals with current use of disease modifying therapy was lower (42.6%, 60.9% and 76.7%, respectively). The older patient groups were more likely to be labeled with progressive MS and the frequency of occupational invalidity was high (38.8% in PwMS aged ≥ 55 to 64 years). Gait disorder, fatigue, bladder dysfunction, and spasticity were among the leading symptoms in PwMS aged ≥ 55 years., Conclusion: PwMS ≥ 55 years have a high degree of disability, but a large proportion do not receive disease modifying therapy, exposing an unmet need., (© 2024. The Author(s).)

Background: Depression has a major impact on the disease burden of multiple sclerosis (MS). Analyses of overlapping MS and depression risk factors [smoking, vitamin D (25-OH-VD) and Epstein-Barr virus (EBV) infection] and sex, age, disease characteristics and neuroimaging features associated with depressive symptoms in early MS are scarce., Objectives: To assess an association of MS risk factors with depressive symptoms within the German NationMS cohort., Design: Cross-sectional analysis within a multicenter observational study., Methods: Baseline data of n  = 781 adults with newly diagnosed clinically isolated syndrome or relapsing-remitting MS qualified for analysis. Global and region-specific magnetic resonance imaging (MRI)-volumetry parameters were available for n  = 327 patients. Association of demographic factors, MS characteristics and risk factors [sex, age, smoking, disease course, presence of current relapse, expanded disability status scale (EDSS) score, fatigue (fatigue scale motor cognition), 25-OH-VD serum concentration, EBV nuclear antigen-1 IgG (EBNA1-IgG) serum levels] and depressive symptoms (Beck Depression Inventory-II, BDI-II) was tested as a primary outcome by multivariable linear regression. Non-parametric correlation and group comparison were performed for associations of MRI parameters and depressive symptoms., Results: Mean age was 34.3 years (95% confidence interval: 33.6-35.0). The female-to-male ratio was 2.3:1. At least minimal depressive symptoms (BDI-II > 8) were present in n  = 256 (32.8%), 25-OH-VD deficiency (<20 ng/ml) in n  = 398 (51.0%), n  = 246 (31.5%) participants were smokers. Presence of current relapse [coefficient ( c ) = 1.48, p  = 0.016], more severe fatigue ( c  = 0.26, p  < 0.0001), lower 25-OH-VD ( c  = -0.03, p  = 0.034) and smoking ( c  = 0.35, p  = 0.008) were associated with higher BDI-II scores. Sex, age, disease course, EDSS, month of visit, EBNA1-IgG levels and brain volumes at baseline were not., Conclusion: Depressive symptoms need to be assessed in early MS. Patients during relapse seem especially vulnerable to depressive symptoms. Contributing factors such as fatigue, vitamin D deficiency and smoking, could specifically be targeted in future interventions and should be investigated in prospective studies., (© The Author(s), 2023.)

Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P < 5 × 10-8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10-16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187-0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (>90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10-4, OR = 2.5, 95%CI = 1.499-4.157) and DRB1*04:01 allele (P = 8.3 × 10-5, OR = 2.4, 95%CI = 1.548-3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: To assess seizure characteristics in antibody (ab)-associated autoimmune encephalitis (ab + AE) with the 3 most prevalent abs against N-methyl-d-aspartate receptor (NMDAR), leucine-rich glioma-inactivated protein 1 (LGI1), and glutamic acid decarboxylase (GAD)., Methods: Multicenter nationwide prospective cohort study of the German Network for Research in Autoimmune Encephalitis., Results: Three hundred twenty patients with ab + AE were eligible for analysis: 190 NMDAR+, 89 LGI1+, and 41 GAD+. Seizures were present in 113 (60%) NMDAR+, 69 (78%) LGI1+, and 26 (65%) GAD+ patients and as leading symptoms for diagnosis in 53 (28%) NMDAR+, 47 (53%) LGI+, and 20 (49%) GAD+ patients. Bilateral tonic-clonic seizures occurred with almost equal frequency in NMDAR+ (38/51, 75%) and GAD+ (14/20, 70%) patients, while being less common in LGI1+ patients (27/59, 46%). Focal seizures occurred less frequently in NMDAR+ (67/113; 59%) than in LGI1+ (54/69, 78%) or in GAD+ patients (23/26; 88%). An aura with déjà-vu phenomenon was nearly specific in GAD+ patients (16/20, 80%). Faciobrachial dystonic seizures (FBDS) were uniquely observed in LGI1+ patients (17/59, 29%). Status epilepticus was reported in one-third of NMDAR+ patients, but only rarely in the 2 other groups. The occurrence of seizures was associated with higher disease severity only in NMDAR+ patients., Discussion: Seizures are a frequent and diagnostically relevant symptom of ab + AE. Whereas NMDAR+ patients had few localizing semiological features, semiology in LGI1+ and GAD+ patients pointed toward a predominant temporal seizure onset. FBDS are pathognomonic for LGI1 + AE. Status epilepticus seems to be more frequent in NMDAR + AE., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Newly approved, drug-modifying therapies are associated with still unknown adverse events, although clinical trials leading to approval have strict inclusion and exclusion criteria and analyse safety and efficacy., Objectives: The aim of this study was to analyse the eligibility of multiple sclerosis (MS) patients treated in routine care into the phase III clinical trial of the respective drug., Methods: In total, 3577 MS patients with 4312 therapies were analysed. Patients with primary-progressive MS were excluded. Inclusion and exclusion criteria of phase III clinical trials in relapsing-remitting MS were adopted and subsequently applied. A comparison in clinical and sociodemographic characteristics was made between patient who met the criteria and those who did not., Results: 83% of registered patients would not have been eligible to the respective phase III clinical trial. Relapse was the single most frequent criterion not fulfilled (74.7%), followed by medication history (21.2%)., Conclusion: The majority of MS patients treated in routine care would not have met clinical trials criteria. Thus, the efficacy and safety of therapies in clinical trials can differ from those in the real world. Broader phase III inclusion criteria would increase their eligibility and contribute to a better generalizability of the results in clinical trials.

Objective: To determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS)., Methods: Serum samples were collected from 901 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16 163) from Berlin/Northern Germany., Results: EBNA-1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS. Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA. In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot. Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive. EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts., Conclusion: The complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS. It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS., Competing Interests: Competing interests: SA reports no disclosures. BE reports no disclosures. M-MH received travel expenses from Bayer Health Care and honoraria for an advisory board from Merck Serono GmbH. LA reports no disclosures. FL serves as an advisory board member for Roche Pharma and has received travel grants from Teva Pharma. SG reports no disclosures. LK received compensation for serving on scientific advisory boards (Genzyme, Novartis Pharma); speaker honoraria and travel support (CSL Behring, Merck Serono, Roche, Novartis Pharma); research support (Biogen, Novartis Pharma). SGM receives honoraria for lecturing, and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Bundesinstitut für Risikobewertung (BfR), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, Gemeinsamer Bundesausschuss (G-BA), German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and Alexion, Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, HERZ Burgdorf, Merck Serono, Novartis, ONO Pharma, Roche, and Teva.CS reports no disclosures.TG received travel reimbursement from Biogen Idec; not related to this work. BT received personal speaker honoraria and consultancy fees as a speaker and advisor from Bayer Healthcare, Biogen, CSL Behring, GRIFOLS, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, TEVA und UCB Pharma. His University received unrestricted research grants from Biogen-idec, Novartis, TEVA, Bayer Healthcare, CSL-Behring, GRIFOLS, Octapharma, Sanofi Genzyme und UCB Pharma; none related to this work.FP serves on the scientific advisory board for Novartis; received speaker honoraria and travel funding from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is an academic editor for PLoS ONE; is an associate editor for Neurology® Neuroimmunology & Neuroinflammation; consulted for SanofiGenzyme, Biogen Idec, MedImmune, Shire, and Alexion; and received research support from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis/Genzyme, Alexion, Merck Serono, German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Guthy Jackson Charitable Foundation, and National Multiple Sclerosis of the USA; none related to this work. FTB received personal compensation for speaking and attending advisory boards from Actelion, Bayer, Biogen, Genzyme, Merck, Novartis, Teva and Roche; financial support, through his institution, to attend scientific meetings or for investigator initiated studies from Actelion, Bayer, Biogen, Genzyme, Merck, Novartis and Teva. TK received travel expenses and personal compensations from Bayer Healthcare, Teva Pharma, Merck-Serono, Novartis, Sanofi-Aventis/Genzyme, Roche and Biogen, as well as grant support from Bayer-Schering AG, Novartis and Chugai Pharma; and none related to this work. FW received honoraria from Genzyme, Novartis, TEVA, Bayer and Biogen for speaking or for serving on a scientific advisory board, a travel grant for the attention of a scientific meeting from Merck-Serono and Novartis and grant support from Merck-Serono, Novartis and from the Federal Ministry of Education and Research (BMBF, Projects Biobanking and Omics in ControlMS as part of the Competence Network Multiple Sclerosis). MS received honoraria for scientific lectures or consultancy from Bayer Healthcare, Biogen, Baxter/Baxalta, CSL Behring, Euroimmune, Grifols, Merck-Serono, Novartis, Roche, Sanofi-Aventis, and Teva. His institution received research support from Bayer Healthcare, Biogen Idec, Genzyme, Merck-Serono, Novartis, and Teva; and none related to this work. AB received personal compensation from Merck Serono, Biogen, Bayer, Novartis, TEVA, Roche, Sanofi/Genzyme, Celgene, Alexion and grants for congress trips and participation from Biogen, TEVA, Novartis, Sanofi/Genzyme, Merck Serono, Celgene; none related to this work. BW reports grants from Deutsche Forschungsgemeinschaft, grants from Bundesministerium für Forschung und Technologie, grants from Dietmar Hopp Stiftung, grants from Klaus Tschira Stiftung, grants and personal fees from Merck Serono, personal fees from Biogen, personal fees from Bayer Healthcare, personal fees from TEVA, grants and personal fees from Novartis, grants and personal fees from Sanofi Genzyme, personal fees from Roche, outside the submitted work. CH received research grants and speaker honoraria from Biogen, Genzyme, Roche, and Merck; none related to this work. UKZ received speaker fees from Aventis, Almirall, Biogen, Bayer, Merck, Novartis, Roche, and Teva. CW has received institutional fees for consultancy, speaking, or research from Novartis, Biogen, Sanofi-Genzyme and Roche. GA reports no disclosures.NH reports no disclosures.HW receives honoraria for acting as a member of scientific advisory boards and as a consultant for Biogen, Evgen, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, as well as speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche Ltd, Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, TEVA, and WebMD Global. Professor Wiendl is acting as a paid consultant for Abbvie, Actelion, Biogen, IGES, Novartis, Roche, Sanofi-Genzyme, and the Swiss Multiple Sclerosis Society. His research is funded by the BMBF, DFG, Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children’s Foundation, Biogen GmbH, GlaxoSmithKline GmbH, and Roche Pharma AG, Sanofi-Genzyme. SB has received honoria and compensation for travel from Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme and Roche. BH served on scientific advisory boards for F. Hoffmann-La Roche Ltd, Novartis, Bayer AG, and Genentech; he has served as DMSC member for Allergy Care and TG Therapeutics; he or his institution have received speaker honoraria from Biogen Idec, Teva Neuroscience, Merck Serono, Medimmune, Novartis, Desitin, and F. Hoffmann-La Roche Ltd; his institution has received research support from Chugai Pharmaceuticals; holds part of two patents; one for the detection of antibodies and T cells against KIR4.1 in a subpopulation of patients with MS and one for genetic determinants of neutralizing antibodies to interferon β during the last 3 years. RG serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd, Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis; none related to this work. AS received speaker honoraria and/or travel compensation for activities with Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme; none related to this work. KR received research support from Novartis, Merck Serono, German Ministry of Education and Research, European Union, Stiftung Charité (BIH Clinical Fellow), Arthur Arnstein Stiftung Berlin, as well as speaking fees and travel grants from Bayer Healthcare, Biogen Idec, Merck Serono, Sanofi-Aventis/Genzyme, Teva Pharmaceuticals, Roche, Novartis, and Guthy Jackson Charitable Foundation., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate if patients with neuromyelitis optica spectrum disorder (NMOSD) develop subclinical visual pathway impairment independent of acute attacks., Methods: A total of 548 longitudinally assessed full-field visual evoked potentials (VEP) of 167 patients with NMOSD from 16 centers were retrospectively evaluated for changes of P100 latencies and P100-N140 amplitudes. Rates of change in latencies (RCL) and amplitudes (RCA) over time were analyzed for each individual eye using linear regression and compared using generalized estimating equation models., Results: The rates of change in the absence of optic neuritis (ON) for minimal VEP intervals of ≥3 months between baseline and last follow-up were +1.951 ms/y (n = 101 eyes; SD = 6.274; p = 0.012) for the P100 latencies and -2.149 µV/y (n = 64 eyes; SD = 5.013; p = 0.005) for the P100-N140 amplitudes. For minimal VEP intervals of ≥12 months, the RCL was +1.768 ms/y (n = 59 eyes; SD = 4.558; p = 0.024) and the RCA was -0.527 µV/y (n = 44 eyes; SD = 2.123; p = 0.111). The history of a previous ON >6 months before baseline VEP had no influence on RCL and RCA. ONs during the observational period led to mean RCL and RCA of +11.689 ms/y (n = 16 eyes; SD = 17.593; p = 0.003) and -1.238 µV/y (n = 11 eyes; SD = 3.708; p = 0.308), respectively., Conclusion: This first longitudinal VEP study of patients with NMOSD provides evidence of progressive VEP latency delay occurring independently of acute ON. Prospective longitudinal studies are needed to corroborate these findings and help to interpret the clinical relevance., (© 2019 American Academy of Neurology.)

After years of low incidence, a large increase of new tuberculosis (TB) cases has been reported in Germany since 2015. New immunotherapies for the treatment of multiple sclerosis (MS) are associated with a reduced immune competence and a potential increased risk for infections. Most neurologists lack specific experiences with TB infections. This article summarizes specific recommendations for the diagnostics and treatment of TB under MS immunotherapies with a focus on the situation in Germany. Due to low case numbers and little experience with the risk of TB under the new immunotherapies, the clinical competence network for MS (KKNMS) consensus recommendations have a low grade of evidence.

Objective: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR)., Methods: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody-seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome., Results: Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04-144.91, p = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89-0.99, p = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76-631.17, p = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03-21.62, p = 0.046)., Conclusions: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques., Classification of Evidence: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.

Background: In neurological diseases presenting with a plethora of symptoms, the value of bodily functions for a given patient might be a guide for clinical management. Multiple sclerosis (MS) is paradigmatic in this respect, and little is known about the value of different bodily functions of patients and their physicians' perceptions., Methods: In a multicenter study, 171 patients with relapsing-remitting multiple sclerosis (RRMS), 61% with a clinically active disease within the last 2 years were followed over up to 3 years and yearly patients and their study physician rated on the perceived value of 13 bodily functions via a priority list. Differences between patients and physicians as well as modulating disease demographic factors were analyzed., Results: Patients with RRMS rated visual function followed by thinking and memory and walking highest while physicians stressed mobility, followed by thinking and memory and alertness most. Ratings were independent from disease duration or disability. Strongest value judgment differences were seen in swallowing regarded more relevant by patients and hand function regarded more relevant by physicians. In general, patients' and physicians' ratings through time were quite stable. Collapsing physical items into a physical functioning scale and mental items in a mental function scale, both dimensions were regarded equally important by patients while physicians underscored physical functioning (P = .016)., Conclusion: There are differences between patients and physicians in value statements of bodily functions in MS. In particular, visual functioning is under-recognized by physicians., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To analyse predictors for relapses and number of attacks under different immunotherapies in patients with neuromyelitis optica spectrum disorder (NMOSD)., Design: This is a retrospective cohort study conducted in neurology departments at 21 regional and university hospitals in Germany. Eligible participants were patients with aquaporin-4-antibody-positive or aquaporin-4-antibody-negative NMOSD. Main outcome measures were HRs from Cox proportional hazard regression models adjusted for centre effects, important prognostic factors and repeated treatment episodes., Results: 265 treatment episodes with a mean duration of 442 days (total of 321 treatment years) in 144 patients (mean age at first attack: 40.9 years, 82.6% female, 86.1% aquaporin-4-antibody-positive) were analysed. 191 attacks occurred during any of the treatments (annual relapse rate=0.60). The most common treatments were rituximab (n=77, 111 patient-years), azathioprine (n=52, 68 patient-years), interferon-β (n=32, 61 patient-years), mitoxantrone (n=34, 32.1 patient-years) and glatiramer acetate (n=17, 10 patient-years). Azathioprine (HR=0.4, 95% CI 0.3 to 0.7, p=0.001) and rituximab (HR=0.6, 95% CI 0.4 to 1.0, p=0.034) reduced the attack risk compared with interferon-β, whereas mitoxantrone and glatiramer acetate did not. Patients who were aquaporin-4-antibody-positive had a higher risk of attacks (HR=2.5, 95% CI 1.3 to 5.1, p=0.009). Every decade of age was associated with a lower risk for attacks (HR=0.8, 95% CI 0.7 to 1.0, p=0.039). A previous attack under the same treatment tended to be predictive for further attacks (HR=1.5, 95% CI 1.0 to 2.4, p=0.065)., Conclusions: Age, antibody status and possibly previous attacks predict further attacks in patients treated for NMOSD. Azathioprine and rituximab are superior to interferon-β., Competing Interests: Competing interests: AB has received honoraria for consultancy or lectures and travel reimbursement from Bayer HealthCare, Biogen, Merck Serono, Mylan, Roche, Novartis and Teva, and grant support from Bayer HealthCare and Chugai. AG has received travel reimbursement from Sanofi Genzyme. BH reports grants from Chugai, grants, personal fees and non-financial support from Roche, personal fees and non-financial support from Biogen, personal fees and non-financial support from Novartis, personal fees and non-financial support from Merck, and personal fees and non-financial support from Bayer. BW has received grants from the German Ministry of Education and Research, Dietmar Hopp Foundation, Biogen, Biotest, Merck, Novartis Pharmaceuticals and Teva Pharma, personal fees from Biogen, Merck, Novartis Pharmaceuticals, Teva Pharma, Bayer HealthCare and Genzyme. CG received honoraria for lectures, travel reimbursement and grant support from Merck Serono, Teva, Novartis and CSL Behring. CT has received honoraria for consultation and expert testimony from Bayer Vital GmbH, Biogen Idec/Biogen GmbH, Genzyme GmbH and Novartis Pharmaceuticals/Pharma GmbH. FL reports travel expenses from Teva Pharma. FlP reports grants from BIH‐Charité Clinical Scientist Program funded by the Charité–Universitätsmedizin Berlin and the Berlin Institute of Health and non-financial support from ECTRIMS-Travel grant 2014. FrP reports grants and personal compensations from Alexion, Bayer, Biogen, Shire, Novartis, Medimmune, Merck and Genzyme. FTB reports grants and others from Bayer, personal fees and others from Biogen Idec, grants and personal fees from CSL Behring, grants from Fresenius, personal fees and others from Genzyme Sanofi, others from Merck Serono, grants, personal fees and others from Novartis, grants, personal fees and others from Teva, grants and others from Actelion, and grants from the German Ministry of Education and Research. HPH received, with approval of the Rector of Heinrich-Heine-University and the CEO of University of Düsseldorf Hospital, honoraria for consulting, serving on steering committees and speaking from Biogen, Geneuro, Genzyme, Medimmune, Merck, Novartis, Opexa, Receptos/Celgene, Roche, Sanofi and Teva. IK has received honoraria for consultancy or lectures and travel reimbursement from Bayer HealthCare, Biogen Idec, Chugai, Novartis, Shire and Roche, and grant support from Biogen Idec, Novartis, Chugai and Diamed. JHF received grant support and honoraria from Novartis, Bayer Vital, Merck, Biogen, Sanofi-Genzyme and Roche. JH reports personal fees and non-financial support from Sanofi Genzyme, Bayer HealthCare, Merck and Novartis Pharma. JPS received honoraria for consultancy or lectures, travel reimbursement and grant support from Biogen, Merck Serono, Novartis, Genzyme and Medimmune. KH reports grants and personal fees from Bayer HealthCare, grants and personal fees from Biogen, grants and personal fees from Teva, grants and personal fees from Merck Serono, grants and personal fees from Novartis, grants and personal fees from Almirall. KLY has nothing to disclose. KR has received research support from the German Ministry of Education and Research (BMBF/KKNMS, Competence Network Multiple Sclerosis) and Novartis, as well as speaking fees and travel grants from Guthy Jackson Charitable Foundation, Bayer HealthCare, Biogen Idec, Merck Serono, Sanofi-Aventis/Genzyme, Teva Pharmaceuticals, Roche and Novartis. LZ has nothing to disclose. MK received grant support, travelling expenses and scientific advisory board honoraria from Novartis, Novartis Foundation, Genzyme, Bayer, Roche and Biogen. MM has received grants from Biogen, Novartis; personal fees from Bayer Vital, Biogen, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Teva; and non-financial support from Biogen. MR received speaker honoraria from Novartis and Bayer Vital GmbH, and travel reimbursement from Bayer Schering and Biogen Idec. MSch has nothing to disclose. MSt reports grants and personal fees from Bayer HealthCare, personal fees from Baxter/Baxalta, grants and personal fees from Biogen, personal fees from CSL Behring, grants and personal fees from Genzyme, personal fees from Grifols, personal fees from Merck, personal fees from Roche, grants and personal fees from Novartis, personal fees from Sanofi, and grants and personal fees from Teva. NB has received grants from Alexion Pharmaceuticals, Inc. ON has nothing to disclose. RAL reports grants and personal fees from Biogen, personal fees from Bayer, grants and personal fees from Novartis, grants and personal fees from Merck, personal fees from TEVA, personal fees from Roche, personal fees from Genzyme. SJ has received a research grant from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). MR received speaker honoraria from Novartis and Bayer Vital GmbH, and travel reimbursement from Bayer Schering and Biogen Idec. TF received honoraria for consultancies (including data monitoring committees and advisoryboards) from Novartis, Biogen, Bayer, AstraZeneca, Janssen, SGS and Pharmalog. TK reports personal fees from Biogen, grants from Novartis, personal fees from Genzyme and from Merck-Serono. UHO reports grants from Genzyme, grants from Zambon, and others from Merck Serono, Bayer, Biogen, Teva and Novartis. UZe has patents, whether planned, pending or issued, broadly relevant to the work. UZi reports personal fees from Biogen Idec GmbH, grants from Biogen Idec GmbH, personal fees from Bayer Vital GmbH, personal fees from Bristol Myers Squibb GmbH, personal fees from CorTec GmbH, personal fees from Medtronic GmbH, grants from Servier, grants from Janssen Pharmaceuticals NV and personal fees from Takeda., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Evidence exists for a potential modulation of inflammasome activity by interferon beta. Here, we investigated the roles of inflammasomes [absent in melanoma 2 (AIM2); NLR family, CARD domain containing 4 (NLRC4); NLR family, pyrin domain containing 1 and 3 (NLRP1 and NLRP3)] and related cytokines (IL1B, IL10, IL18) in the response to interferon beta in patients with relapsing-remitting multiple sclerosis. Ninety-seven patients treated with interferon beta were classified into responders and non-responders according to clinical criteria after 24 months and clinical-radiological criteria after 12 months of treatment. Messenger RNA expression levels of inflammasomes and cytokines were determined by real-time polymerase chain reaction in peripheral blood mononuclear cells collected before treatment with interferon beta. In a subgroup of patients, NLRP3 and IL1B expression was also determined after 3 months (n = 32) and 12 months (n = 20) of interferon beta treatment. A polymorphism located in the NLRP3 gene, rs35829419, was genotyped in 789 multiple sclerosis patients treated with interferon beta. Baseline mRNA expression levels for NLRP3 and IL1B were increased in peripheral blood mononuclear cells from non-responders compared to responders classified according to clinical criteria after 24 months (P = 0.02 and P = 0.001, respectively). No significant differences were observed for other inflammasomes and related cytokines. Differences in NLRP3 and IL1B expression remained significant following a clinical-radiological classification after 12 months (P = 0.007 and P = 0.02, respectively). After treatment with interferon beta, NLRP3 and IL1B expression was increased in responders but unchanged in non-responders. A trend for association was observed between rs35829419 and interferon beta response (pM-H = 0.08). These results point to a role of the NLRP3 inflammasome and its related cytokine IL1B in the response to interferon beta in patients with relapsing-remitting multiple sclerosis., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Inflammatory disorders of the peripheral nervous system (PNS) and central nervous system (CNS) are common, and contribute substantially to physical and emotional disability of affected individuals. Often, the afflicted are young and in their active years. In the past, physicians and scientists often had very little to offer in terms of diagnostic precision and therapeutic effectiveness. During the past two decades, both of these relative shortcomings have clearly improved. Some of the recent developments in clinical neuroimmunology are illustrated in this special edition of Clinical and Experimental Immunology., (© 2014 British Society for Immunology.)

Recently, the disappearance of oligoclonal bands (OCBs) from the cerebrospinal fluid (CSF) of a few natalizumab-treated patients with multiple sclerosis (MS) has been reported. This is interesting since CSF-restricted OCB are believed to persist in MS. We pooled CSF data from 14 MS centers to obtain an adequate sample size for investigating the suspected changes in central nervous system (CNS)-restricted humoral immune activities in the context of natalizumab therapy. In a retrospective chart analysis, CSF parameters of blood-CSF barrier integrity and intrathecal IgG production from 73 natalizumab-treated MS patients requiring a diagnostic puncture for exclusion of progressive multifocal leukoencephalopathy were compared with CSF data obtained earlier in the course of disease before natalizumab therapy. At the time of repeat lumbar puncture, local IgG production (according to Reibergram) was significantly reduced (p < 0.0001) and OCB had disappeared in 16% of the patients. We therefore conclude that natalizumab therapy interferes with intrathecal antibody production at least in a significant number of patients.

Patients with immunodeficiency and patients under immunosuppressive therapy have an increased risk of infectious diseases. Vaccination strategies are needed to protect them from preventable diseases. The underlying disease and severity of the immune impairment may have influence on indications and contra-indications of vaccines. Inactivated vaccines can be administered safely according to the current recommendations of the Permanent Commission on Vaccinations of the Robert-Koch-Institut in Berlin, Germany (STIKO). Depending on the severity of the immune dysfunction, antibody response to vaccinations varies. Where possible, the antibody response following vaccinations should be tested. Previously, attenuated live vaccines were considered to be strictly contra-indicated in immunocompromised patients. Today, the administration of attenuated live vaccines is thought to be possible, depending on the degree and type of immunodeficiency or immunosuppression of the individual., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The incidence of therapy-related acute leukaemia (TRAL) in mitoxantrone treatment in multiple sclerosis (MS) is controversially discussed., Methods and Results: In a retrospective meta-analysis from six centres, we observed six cases of acute myeloid leukaemia (AML) (incidence 0.41% for patients with mean follow up after end of treatment of 3.6 years, n = 1.156; incidence 0.25% for all patients, n = 2.261). Potential influencing factors such as myelotoxic or glucocorticosteroid pretreatment/cotreatment were present in all but one case of TRAL. Between 1990 and 2010, 11 cases of TRAL were reported to the Drug Commission of the German Medical Association (estimated risk of 0.09-0.13%)., Conclusions: Regional differences in reported TRAL incidence may point to confounding cofactors such as administration protocols and cotreatments.

Recent years have broadened the spectrum of therapeutic strategies and specific agents for treatment of multiple sclerosis (MS). While immune-modulating drugs remain the first-line agents for MS predominantly due to their benign safety profile, our growing understanding of key processes in initiation and progression of MS has pioneered development of new agents with specific targets. One concept of these novel drugs is to hamper migration of immune cells towards the affected central nervous system (CNS). The first oral drug approved for MS therapy, fingolimod inhibits egress of lymphocytes from lymph nodes; the monoclonal antibody natalizumab prevents inflammatory CNS infiltration by blocking required adhesion molecules. The second concept is to deplete T cells and/or B cells from the peripheral circulation using highly specific monoclonal antibodies such as alemtuzumab (anti-CD52) or rituximab/ocrelizumab (anti-CD20). All of these novel, highly effective agents are a substantial improvement in our therapeutic armamentarium; however, they have in common to potentially lower the abundance of immune cells within the CNS, thereby collaterally affecting immune surveillance within this well-controlled compartment. In this review, we aim to critically evaluate the risk/benefit ratio of therapeutic strategies in treatment of MS with a specific focus on infectious neurological side effects.

Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting., Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators., Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm)., Conclusions: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.

We discuss the manner in which the dynamics of tracer polystyrene chains varies with the concentration of matrix polystyrene chains dissolved in toluene. Using fluorescence correlation spectroscopy and theory, it is shown that the cooperative diffusion coefficient of the matrix polystyrene chains can be measured by fluorescence correlation spectroscopy in the semidilute entangled concentration regime. In addition the self-diffusion coefficient of the tracer polystyrene chains can be detected for arbitrary concentrations. The measured cooperative diffusion coefficient is independent of the molecular weight of the tracer polystyrene chains because it is a characteristic feature of the transient entanglement network.

Over the past 2 decades, enormous progress has been made with regard to pharmacotherapies for patients with multiple sclerosis. There is perhaps no other subspecialty in neurology in which more agents have been approved that substantially alter the clinical course of a disabling disorder. Many of the pharmaceuticals that are currently approved, in clinical trials, or in preclinical development were initially evaluated in an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis. Two Food and Drug Administration-approved agents (glatiramer acetate and natalizumab) were developed using the experimental autoimmune encephalomyelitis model. This model has served clinician-scientists for many decades to enable understanding the inflammatory cascade that underlies clinical disease activity and disease surrogate markers detected in patients.

We report on the swelling behavior and the corresponding morphological behavior of cylinder-forming polystyrene-b-polybutadiene diblock copolymers, which are confined to several layers of structures. The equilibration of thin films has been done under controlled atmosphere of a nonselective solvent. In situ spectroscopic ellipsometry measurements revealed more than 10% increase of the solvent uptake with decreasing film thickness. With scanning force microscopy of the microphase separated patterns in quenched films, the correlation between the degree of the long-range order of cylinder domains and the degree of the macroscopic swelling has been established. In the case of spontaneously formed micrometer-sized topographic features with discreet film thickness (terraces), the increased solvent uptake by thinner films holds true even for isolated terraces on the mesoscale. The observation of nonhomogeneous swelling of the films on the micrometer scale brings novel insights into the properties of confined soft matter, and suggests new approaches toward the fabrication of polymer-based nanostructured responsive materials.

Monoclonal antibodies are of growing interest as treatment options for immune-mediated diseases in neurology. As our knowledge of immunological principals increases, we learn to modulate specifically mechanisms of pathogenesis by the use of monoclonal antibodies. It is clearly desirable to improve efficacy in disease treatment without increasing toxicity by using drugs with more specific modes of action. Natalizumab was the first monoclonal antibody approved in the field of neurology for treatment of relapsing remitting multiple sclerosis (MS). Several other monoclonal antibodies are currently under investigation. Alemtuzumab, a monoclonal antibody targeting CD52, is a highly promising agent currently being studied in two phase III clinical trials. In this review, data from the recently published phase II clinical trial in the treatment of early relapsing remitting MS is summarized and analyzed in light of the development of alemtuzumab for MS and its potential role in treating this disease is discussed.

Based on the results of two phase III clinical trials, the humanized recombinant monoclonal antibody natalizumab was approved for the treatment of relapsing forms of multiple sclerosis (MS). Since its initial approval in November 2004, it has been announced that six patients who received natalizumab in the context of clinical studies acquired an infection with the human polyoma virus JC and were diagnosed with progressive multifocal leukoencephalopathy (PML). Two of these individuals had a fatal outcome. Our groups recently showed that natalizumab therapy results in a reduction of CD4(+) T cells within the cerebrospinal fluid (CSF) that is ten-fold more pronounced than the reduction in the number of CD8(+) T lymphocytes. Interestingly, it appears that the effect of natalizumab on cell numbers in the CSF persists for at least 6 months after cessation of treatment. More recently, we studied the expression of major histocompatibility complex (MHC) I and II, and the number and phenotypes of leukocytes in cerebral perivascular spaces (CPVS). We observed that natalizumab therapy was associated with a significant decrease in the cell surface expression of MHC class II molecules, and the numbers of dendritic cells in CPVS. In addition, no CD4(+) T cells were detectable in this compartment. Our observations may explain the differential and prolonged effects of natalizumab therapy on different leukocyte subsets in the central nervous system. They also suggest that natalizumab treatment may result in prolonged immunosuppression in peripheral organs, and the delayed onset of adverse events.

We report on a novel lithography-free method for obtaining chemical submicron patterns of macromolecules on flat substrates. The approach is an advancement of the well-known microcontact printing scheme: While for classical microcontact printing lithographically produced masters are needed, we show that controlled wrinkling can serve as an alternative pathway to producing such masters. These can even show submicron periodicities. We expect upscaling to larger areas to be considerably simpler than that for existing techniques, as wrinkling results in a macroscopic deformation process that is not limited in terms of substrate size. Using this approach, we demonstrate successful printing of aqueous solutions of polyelectrolytes and proteins. We study the effectiveness of the stamping process and its limits in terms of periodicities and heights of the stamps' topographical features. We find that critical wavelengths are well below 355 nm and critical amplitudes are below 40 nm and clarify the failure mechanism in this regime. This will permit further optimization of the approach in the future.

We determine the mobility of dye-labeled polystyrene molecules in solution by fluorescence correlation spectroscopy (FCS) over a wide range of concentrations and molecular weights (ranging from 3.9 x 10{3} to 1550 x 10{3} g/mol ). In order to obtain absolute values of the diffusion coefficient, which can be compared to diffusion coefficients determined by other methods, the size of the focal volume has been determined by independent experiments and theoretical calculations. All data demonstrate that FCS is uniquely suited to explore polymer dynamics in solution. The mobility of the chains as expressed through the self-diffusion coefficient is significantly slowed down above the overlap concentration c{*}. The dependence of c{*} on molecular weight is well described by the power law c{*} proportional, variant M{w};{1-3nu} ( nu: Flory exponent). A comparison with the data taken from the literature demonstrates that the overlap concentration presents a robust concept that holds for a wide range of molecular weights.

The contribution of leukocyte apoptosis to the resolution of meningeal inflammation in bacterial meningitis was studied in the cerebrospinal fluid (CSF) and in meningeal infiltrates of humans and rabbits by in situ tailing, flow cytometry, agarose gel electrophoresis, and electron microscopy. In humans, the rate of apoptotic granulocytes was 21.0+/-20.8% (n=11) in cytocentrifuge preparations and 3.3+/-3.4 (n=14) in putrid infiltrates of autopsy cases (P=0.02). In rabbits, CSF pleocytosis peaked 8 h after the initiation of antibiotic treatment (5311+/-3122/microl). At this time, the rate of apoptotic granulocytes was 15.2+/-7.3% in CSF and 1.8+/-1.4% in the meningeal infiltrates (each group n=6, P=0.007). Thereafter, the rate of apoptotic granulocytes in CSF declined below 10%. In humans and rabbits, bands representing internucleosomal fragments of approximately 180 base pairs and multiples thereof were documented on agarose gels. Phagocytosis of apoptotic granulocytes by macrophages was visualized by light and electron microscopy. In conclusion, during resolution of subarachnoid space inflammation in bacterial meningitis, a substantial fraction of granulocytes undergoes apoptosis. These granulocytes are removed by phagocytosis by macrophages. Apoptosis is more frequent in granulocytes floating in the CSF than in adherent cells.

Macrophages are important effector cells involved in the pathogenesis of demyelination in multiple sclerosis (MS). Macrophage differentiation was studied in a series of 158 MS plaques from 43 patients obtained at different stages of the disease. Macrophages were identified by immunocytochemistry using a panel of antibodies recognizing different formalin- and paraffin-resistant macrophage activation antigens. The number of cells stained with each antibody was related to the demyelinating activity of the lesions as detected by the presence of myelin degradation products as well as to the category of MS tissue. Highest numbers of macrophages were observed in actively demyelinating and early remyelinating lesions using immunocytochemistry for the panmacrophage marker Ki-M1P. Lower numbers were encountered in inactive, demyelinated or late remyelinated lesions. The acute stage inflammatory macrophage markers MRP14 and 27E10 were selectively expressed in early and late active lesions, thus allowing the identification of actively demyelinating lesions. The chronic stage inflammatory macrophage marker 25F9, in contrast, showed a continuous expression also in inactive lesions. The different types of MS tissue revealed significant differences in their macrophage response. The most intense macrophage infiltration was seen in acute MS cases whereas lesions of early and late chronic MS showed lower macrophage levels. These findings indicate a differentiated pattern of macrophage activation in MS depending on the stage of the demyelinating activity as well as on the category of MS tissue. Furthermore, these macrophage markers give new parameters for staging the inflammatory and demyelinating activity of MS lesions.

The role of quantitative proton magnetic resonance imaging (MRI) for the evaluation of immunopathological lesions in the CNS was studied in adoptively transferred experimental allergic encephalomyelitis (AT-EAE). We utilized a recently established treatment model, inhibition of the cell adhesion molecule ICAM-1 by the monoclonal antibody 1A-29. The animals were scanned on days 3, 5 and 7 after injection of encephalitogenic T-cells, before and after bolus injection of Gd-DTPA by performing T1-measurements to assess the integrity of the blood-brain barrier (BBB). On day 7, immunohistochemistry was performed looking for T-cells, activated macrophages, and albumin staining. There was clinical evidence of partial inhibition of AT-EAE in rats treated with antibodies against ICAM-1. This finding was in line with a significantly reduced number of T-cells in the medulla. However, the number of activated macrophages and the distribution of albumin did not differ from untreated AT-EAE animals. The histological findings are in agreement with the MRI data before and after Gd-DTPA injection which were similar in treated and untreated AT-EAE rats on day 3 and 5. On day 7 after Gd-DTPA injection there was evidence of a delayed breakdown of the BBB in the treated rats. The observation of a dissociation of clinical and MRI findings, especially evidence of Gd-enhancement despite clinical improvement, may be important in the context of interpreting MRI studies in MS patients in treatment trials.

In vivo proton MRI was carried out on a 7 Tesla system at 2-3 day intervals over 10 days in rats with adoptive transfer experimental allergic encephalomyelitis (AT-EAE), an animal model of some aspects of multiple sclerosis. In order to assess the integrity of the blood-brain barrier (BBB), MRI was performed by acquiring quantitative MR-relaxation time T1 images of the AT-EAE rat brain before and after i.v. injection gadolinium-diethylene triaminepentaacetic acid (Gd-DTPA) using an ultrafast MRI technique. The MRI findings were compared with the immunohistochemical stain of T cells, macrophages and albumin and, in addition, apoptosis of T cells was assessed using in situ nick translation (ISNT). Prior to injection of Gd-DTPA, an increase of T1 times in the brain of the AT-EAE rats was observed, which paralleled the time course of albumin in histological sections. These were MRI findings observed well before the onset of major cellular infiltration and before the onset of clinical signs. After i.v. injection of Gd-DTPA the observed decrease of T1 times paralleled macrophage activation, and less closely T-cell infiltration. Our results provide evidence that using MRI, it is possible to assess quantitatively the breach of the BBB and to distinguish in vivo between two components of the early phase of the lesion, inflammatory infiltrates and vasogenic oedema.