Jan Dörr

Treatment of Relapsing Paralysis in Experimental Encephalomyelitis by Targeting Th1 Cells through Atorvastatin

Statins, known as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, exhibit numerous functions related to inflammation, such as MHC class II down-regulation, interference with T cell adhesion, and induction of apoptosis. Here we demonstrate that both subcutaneous and oral administration of atorvastatin inhibit the development of actively induced chronic experimental autoimmune encephalomyelitis in SJL/J mice and significantly reduce the inflammatory infiltration into the central nervous system (CNS). When treatment was started after disease onset, atorvastatin reduced the incidence of relapses and protected from the development of further disability. Both the reduced autoreactive T cell response measured by proliferation toward the encephalitogenic peptide PLP139–151 and the cytokine profile indicate a potent blockade of T helper cell type 1 immune response. In in vitro assays atorvastatin not only inhibited antigen-specific responses, but also decreased T cell proliferation mediated by direct TCR engagement independently of MHC class II and LFA-1. Inhibition of proliferation was not due to apoptosis induction, but linked to a negative regulation on cell cycle progression. However, early T cell activation was unaffected, as reflected by unaltered calcium fluxes. Thus, our results provide evidence for a beneficial role of statins in the treatment of autoimmune attack on the CNS.

Distinct lesion morphology at 7-T MRI differentiates neuromyelitis optica from multiple sclerosis

Objective: To investigate distinct white matter and cortical gray matter pathology in neuromyelitis optica spectrum disorders (NMOSDs) and multiple sclerosis (MS) at 7-T MRI in a cross-sectional study. Methods: We included 10 patients with NMOSDs and 18 patients with MS in our 7-T MRI study. The imaging protocol comprised T2*-weighted fast low angle shot and turbo inversion recovery magnitude sequences. White matter and cortical gray matter lesions were assessed with special regard to their (perivascular) localization as well as the expression of a hypointense rim. Results: In total, we detected 140 white matter lesions in 7 of 10 patients with NMOSDs. In contrast to MS plaques, which were nearly exclusively centered by a small vein (92%) and showed a characteristic hypointense rim (23%), white matter changes in patients with NMOSDs were nonspecific in appearance and were only infrequently neighbored by a blood vessel (49 lesions [35%], p = 0.003). Hypointense rims were very rarely detectable (3 lesions [2%], p < 0.001). Cortical pathology was absent in NMOSDs. In our MS cohort, we detected 36 leukocortical, 8 intracortical, and 8 subpial cortical lesions in 7 of 18 patients. Conclusion: The MRI features of white matter and the absence of cortical gray matter findings substantially differentiate NMOSDs from MS and can be used as a potential marker to distinguish these 2 entities. The fact that cortical pathology is common in MS but is not present in patients with NMOSDs may reflect the difference in the underlying pathogenesis.

Lower motor neuron loss in multiple sclerosis and experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is considered a chronic inflammatory and demyelinating disease of the central nervous system. Evidence that axonal and neuronal pathology contributes to the disease is accumulating, however, the distribution of neuronal injury as well as the underlying mechanisms have not yet been fully clarified. Here, we investigated the role of neuronal cell loss in MS and its animal model, experimental autoimmune encephalomyelitis (EAE).

Oral high-dose atorvastatin treatment in relapsing-remitting multiple sclerosis.

Background Recent data from animal models of multiple sclerosis (MS) and from a pilot study indicated a possible beneficial impact of statins on MS. Methodology/Principal Findings Safety, tolerability and effects on disease activity of atorvastatin given alone or in combination with interferon-beta (IFN-β) were assessed in a phase II open-label baseline-to-treatment trial in relapsing-remitting MS (RRMS). Patients with at least one gadolinium-enhancing lesion (CEL) at screening by magnetic resonance imaging (MRI) were eligible for the study. After a baseline period of 3 monthly MRI scans (months −2 to 0), patients followed a 9-month treatment period on 80 mg atorvastatin daily. The number of CEL in treatment months 6 to 9 compared to baseline served as the primary endpoint. Other MRI-based parameters as well as changes in clinical scores and immune responses served as secondary endpoints. Of 80 RRMS patients screened, 41 were included, among them 16 with IFN-β comedication. The high dose of 80 mg atorvastatin was well tolerated in the majority of patients, regardless of IFN-β comedication. Atorvastatin treatment led to a substantial reduction in the number and volume of CEL in two-sided multivariate analysis (p = 0.003 and p = 0.008). A trend towards a significant decrease in number and volume of CEL was also detected in patients with IFN-β comedication (p = 0.060 and p = 0.062), in contrast to patients without IFN-β comedication (p = 0.170 and p = 0.140). Immunological investigations showed no suppression in T cell response but a significant increase in IL-10 production. Conclusions/Significance Our data suggest that high-dose atorvastatin treatment in RRMS is safe and well tolerated. Moreover, MRI analysis indicates a possible beneficial effect of atorvastatin, alone or in combination with IFN-β, on the development of new CEL. Thus, our findings provide a rationale for phase II/III trials, including combination of atorvastatin with already approved immunomodulatory therapy regimens. Trial Registration ClinicalTrials.gov NCT00616187

Characteristics of Susac syndrome: a review of all reported cases

In Susac syndrome, occlusions of microvessels—presumed to be mediated by an autoimmune response to an as yet unknown antigen—lead to a characteristic clinical triad of CNS dysfunction, branch retinal artery occlusions, and sensorineural hearing impairment. Susac syndrome is considered a rare but important differential diagnosis in numerous neurological, psychiatric, ophthalmological, and ear, nose and throat disorders. Improved understanding of this disorder is crucial, therefore, to ensure that patients receive appropriate treatment and care. Current knowledge on Susac syndrome is largely based on reports of single patients, small case series, and nonsystematic reviews. The aim of this Review is to extend these previous, primarily anecdotal findings by compiling data from all 304 cases of Susac syndrome that have been published worldwide, which were identified following a literature search with predefined search, inclusion and exclusion criteria. From this data, we present an overview of demographic, clinical and diagnostic data on Susac syndrome, providing a reliable basis for our current understanding of this rare disease. Where possible, we make recommendations for clinical diagnosis, differential diagnosis, and management of patients with suspected Susac syndrome.

Optic neuritis interferes with optical coherence tomography and magnetic resonance imaging correlations

Background: Retinal nerve fibre layer (RNFL) thinning is associated with brain atrophy in multiple sclerosis (MS). An influence of optic neuritis is well documented but sparsely investigated. Recently, the retinal ganglion cell layer (GCL) has been shown to provide superior information regarding visual function and retinal neurodegeneration as compared with RNFL. Objective: To investigate the association of white and grey matter brain volume with peripapillary RNFL and macular GCL in MS patients with and without a history of optic neuritis. Methods: 63 patients with relapsing–remitting MS were included in a two-centre cross-sectional prospective study. All patients underwent retinal examination with spectral domain optical coherence tomography and 1.5 T MRI for determination of normalized brain volume (NBV), white matter volume (NWMV) and grey matter volume (NGMV). Results: Both RNFL and GCL were associated with NBV, NWMV and NGMV in eyes without previous optic neuritis. This association is disrupted in the case of NGMV following optic neuritis. Conclusions: Both RNFL and GCL as parameters of neuro-axonal damage are comparably linked to whole brain as well as white and grey matter atrophy. An event of optic neuritis interferes with this relation, adding further damage to the optic nerve and disrupting especially an association with grey matter.

Lesion morphology at 7 Tesla MRI differentiates Susac syndrome from multiple sclerosis

Background: Although an orphan disease with still obscure aetiopathogenesis, Susac syndrome has to be considered as differential diagnosis in multiple sclerosis (MS), since its clinical presentation and paraclinical features including routine magnetic resonance imaging (MRI) findings partially overlap. Objective: We aimed to study a potential benefit of 7T MRI for (i) the differentiation between Susac syndrome and MS and (ii) the clarification of pathogenesis of Susac syndrome. Methods: Five patients suffering from Susac syndrome, 10 sex- and age-matched patients with relapsing–remitting MS (median Expanded Disability Status Scale (EDSS) score 1.5) and 15 matching healthy controls were investigated at 7 Tesla MRI. The protocol included T1-weighted MPRAGE, T2*-weighted FLASH, and TIRM sequences. Results: Almost all T2* FLASH lesions in patients with MS were centred by a small central vein (325 lesions; 92%) and often showed a small hypointense rim (145 lesions; 41%). In contrast, white matter lesions in Susac syndrome exhibited a perivascular setting significantly less frequently (148 lesions; 54%, p=0.002), and very rarely exhibited a hypointense rim (12 lesions; 4%, p=0.004). Furthermore, in addition to callosal atrophy, Susac patients showed cerebrospinal fluid-isointense lesions within the central part of corpus callosum that are not commonly seen in MS. Conclusion: At 7T MRI, plaques in MS patients and patients with Susac syndrome differed substantially with respect to morphology and pattern. Thus, lesion morphology at 7T (i) may serve as a marker to distinguish Susac syndrome from MS and (ii) reflects a different pathophysiological mechanism underlying Susac syndrome, for example microinfarction rather than demyelination.

Efficacy of Vitamin D Supplementation in Multiple Sclerosis (EVIDIMS Trial): study protocol for a randomized controlled trial

BackgroundMultiple sclerosis is the most common chronic inflammatory disease of the central nervous system in young adults. Despite the fact that numerous lines of evidence link both the risk of disease development and the disease course to the serum level of 25-hydroxyvitamin D it still remains elusive whether multiple sclerosis patients benefit from boosting the serum level of 25-hydroxyvitamin D, mainly because interventional clinical trials that directly address the therapeutic effects of vitamin D in multiple sclerosis are sparse. We here present the protocol of an interventional clinical phase II study to test the hypothesis, that high-dose vitamin D supplementation of multiple sclerosis patients is safe and superior to low-dose supplementation with respect to beneficial therapeutic effects.Methods/DesignThe EVIDIMS trial is a German multi-center, stratified, randomized, controlled and double-blind clinical phase II pilot study. Eighty patients with the diagnosis of definite multiple sclerosis or clinically isolated syndrome who are on a stable immunomodulatory treatment with interferon-β1b will be randomized to additionally receive either high-dose (average daily dose 10.200 IU) or low-dose (average daily dose 200 IU) cholecalciferol for a total period of 18 months. The primary outcome measure is the number of new lesions detected on T2-weighted cranial MRI at 3 tesla. Secondary endpoints include additional magnetic resonance imaging and optical coherence tomography parameters for neuroinflammation and -degeneration, clinical parameters for disease activity, as well as cognition, fatigue, depression, and quality of life. Safety and tolerability of high-dose vitamin D supplementation are further outcome parameters.DiscussionIn light of the discrepancy between existing epidemiological and preclinical data on the one hand and available clinical data on the other the EVIDIMS trial will substantially contribute to the evaluation of the efficacy of high-dose vitamin D supplementation in MS patients. The study design presented here fulfills the criteria of a high-quality clinical phase II trial in MS.Trial RegistrationClinicalTrials.gov Identifier: NCT01440062

Patterns of retinal nerve fiber layer loss in multiple sclerosis patients with or without optic neuritis and glaucoma patients

OBJECTIVE Optical coherence tomography (OCT) has gained increasing attention in multiple sclerosis (MS) research and has been suggested as outcome measure for neuroprotective therapies. However, to date it is not clear whether patterns of retinal nerve fiber layer thickness (RNFLT) loss are different in MS compared to other diseases such as glaucoma and data on RNFLT loss in MS patients with or without optic neuritis (ON/NON) have remained inconsistent or even contradictory. METHODS In this large cross-sectional study we analyzed the patterns of axonal loss of retinal ganglion cells in MS eyes (n=262) with and without history of ON (MS/ON: 73 eyes; MS/NON: 189 eyes) and patients eyes with glaucomatous optic disc atrophy (GA: n=22; 39 eyes) in comparison to healthy control eyes (HC: n=406 eyes). RESULTS We found that significant average and quadrant RNFLT loss is detectable by OCT in both MS and GA patients compared to healthy controls (p<0.01). The age- and gender adjusted average and quadrant RNFLT did not differ significantly between MS and GA patients (p>0.05). Average (p<0.0001) and quadrant (p<0.05) RNFL thinning is significantly more severe in MS/ON versus MS/NON eyes, and the extent of RNFL thinning varies across quadrants in MS/ON eyes with the highest degree of RNFLT loss in the temporal quadrant (p<0.001). CONCLUSION RNFLT reduction across all four quadrants in MS patients as a whole as well as in MS/NON eyes argues for a diffuse neurodegenerative process. Superimposed inflammatory attacks to the optic nerve may cause additional axonal damage with a temporal preponderance. Future studies are necessary to further evaluate the capacity of OCT to depict disease specific damage patterns.

Correlation of self-assessed fatigue and alertness in multiple sclerosis

Background: Fatigue is the most common symptom in multiple sclerosis patients, but is difficult to measure; quantification thus relies on self-assessed questionnaires. Objective: To evaluate a battery of neuropsychological tests regarding their capacity to objectify self-reported fatigue. Methods: We assessed the correlation between age, gender, education, Kurtzke’s Expanded Disability Status Scale, depression, fatigue and neuropsychological testing using a cross-sectional approach in 110 multiple sclerosis patients. Fatigue was measured with the Fatigue Severity Scale. Cognition was measured using a series of neuropsychological tests including three subtests of the Test of Attentional Performance, the Brief Repeatable Battery of Neuropsychological Tests and the Faces Symbol Test. Results: According to the Fatigue Severity Scale 51.4% of the cohort were fatigued (scores ≥4). Age, education and depression showed a significant correlation with the Fatigue Severity Scale. Only 5.5% of the cohort exhibited cognitive impairment in the Brief Repeatable Battery of Neuropsychological Tests scores. After correction for age, education, Expanded Disability Status Scale and depression, Fatigue Severity Scale scores were an independent predictor of performance in the alertness subtest of the Test of Attentional Performance (standardized coefficient beta = 0.298, p = 0.014). Conclusion: The alertness subtest of the Test of Attentional Performance may offer an objective method of evaluating self-reported fatigue, and may therefore — in addition to the Fatigue Severity Scale — be a suitable tool for the assessment of multiple sclerosis patients complaining of fatigue.