Diagnostic value of the 2017 McDonald criteria in patients with a first demyelinating event suggestive of relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: For the diagnosis of relapsing-remitting multiple sclerosis (RRMS), the revised 2017 McDonald criteria include cerebrospinal fluid specific oligoclonal bands as a new criterion for dissemination in time. Amongst other things, one expectation of the new criteria is to marginalize the diagnosis of clinically isolated syndrome (CIS), thus allowing for a faster and at the same time still reliable diagnosis of RRMS. METHODS: In this study, data from an unselected patient cohort with a typical CIS and dissemination in space at a large German Multiple Sclerosis Center from 2013 to 2016 were re-analysed to compare differences in diagnosing RRMS with the 2017 versus 2010 McDonald criteria in everyday practice. RESULTS: Out of a cohort of 290 patients presenting with a typical first demyelinating event, 52% (152 patients) with the diagnosis of RRMS and 48% (138 patients) with the diagnosis of CIS according to the 2010 McDonald criteria were identified. The application of the 2017 McDonald criteria in the same patients increased the number of definite RRMS to 94% (273), thus leaving only 6% of patients with the diagnosis of CIS. The reason for this shift was the presence of cerebrospinal fluid specific oligoclonal bands which was found in 92.7% of the total population and in all patients with 2017 McDonald RRMS. Over a mean follow-up of 1.5 years, 50% of patients formerly diagnosed with CIS who are now RRMS also fulfilled the 2010 McDonald criteria. CONCLUSIONS: Our data support the use of the 2017 McDonald criteria for a more sensitive, but not that specific, diagnosis of RRMS in everyday practice.

[Nutrition, microbiome and multiple sclerosis : Current knowledge from basic research and clinical practice]. / Ernährung, Mikrobiom und Multiple Sklerose : Aktuelle Erkenntnisse aus der Grundlagenforschung und der Klinik.

Epidemiological data indicate a disproportional increase in the incidence of multiple sclerosis (MS) over the last decades, particularly in industrialized countries. Although this increase is also associated with altered diagnostic criteria and improved sensitivity of imaging procedures, current data suggest that particularly alterations in our way of life play an important role. In recent years the importance of the gut and intestinal microbiome for some neurological diseases and in particular for MS was recognized. Because nutritional habits have a substantial influence on the composition of the microbiome and our nutrition has changed considerably in the last decades, nutritional components can play an important role in the pathogenesis of MS. In this further education article we summarize the currently available evidence on the role of the gut and on the effects of dietary components on the microbiome in the pathogenesis of MS.

[Monitoring of blood parameters under course-modified MS therapy : Substance-specific relevance and current recommendations for action]. / Monitoring von Blutparametern unter verlaufsmodifizierender MS-Therapie : Substanzspezifische Relevanz und aktuelle Handlungsempfehlungen.

With the approval of various substances for the immunotherapy of multiple sclerosis (MS), treatment possibilities have improved significantly over the last few years. Indeed, the choice of individually tailored preparations and treatment monitoring for the treating doctor is becoming increasingly more complex. This is particularly applicable for monitoring for a treatment-induced compromise of the immune system. The following article by members of the German Multiple Sclerosis Skills Network (KKNMS) and the task force "Provision Structures and Therapeutics" summarizes the practical recommendations for approved immunotherapy for mild to moderate and for (highly) active courses of MS. The focus is on elucidating the substance-specific relevance of particular laboratory parameters with regard to the mechanism of action and the side effects profile. To enable appropriate action to be taken in clinical practice, any blood work changes that can be expected, in addition to any undesirable laboratory findings and their causes and relevance, should be elucidated.

Optical coherence tomography in patients with a history of juvenile multiple sclerosis reveals early retinal damage.

BACKGROUND AND PURPOSE: Some 3%-10% of patients with multiple sclerosis (MS) experience disease onset before the age of 18 years ('early' onset MS, EOMS). Optical coherence tomography is a non-invasive method to measure retinal nerve fibre layer thickness (RNFLT) and total macular volume (TMV) and may be useful to differentiate axonal and neuronal damage in the retina of patients with a history of EOMS. Here RNFLT and TMV in EOMS patients after a mean disease duration of 11.6 years were compared with patients with age- or disease-duration-matched later onset MS (LOMS) and healthy controls (HCs). METHODS: In this observational cross-sectional study at two German academic MS centres, RNFLT and TMV were measured by spectral-domain optical coherence tomography in 32 HCs, 36 EOMS (mean age at onset 15.5 ± 2.0 years) and 58 LOMS patients. RESULTS: In comparison with HCs, EOMS patients displayed a significant reduction of RNFLT and TMV independently of a history of optic neuritis. In particular, RNFLT loss in EOMS was similar to that in LOMS and TMV loss was slightly higher compared with disease-duration-matched LOMS. In a generalized estimating model, the EOMS group also displayed a similar correlation between disease duration and RNFLT or TMV loss to LOMS patients. CONCLUSIONS: These data argue for a significant amount of axonal and neuronal damage in the retina of EOMS patients and may provide a structural basis for the observation that EOMS patients reach states of irreversible disability at a younger age than patients with LOMS.

Analysis of CD4+ CD8+ double-positive T cells in blood, cerebrospinal fluid and multiple sclerosis lesions.

T cells with a CD4(+) CD8(+) double-positive (DP) phenotype are present in small numbers in the peripheral blood of healthy humans and may have anti-viral capacities. Here we investigate numbers and function of DP T cells in patients with relapsing-remitting multiple sclerosis (MS), either treatment-naive or under therapy with natalizumab. Flow cytometry analysis revealed that frequencies of circulating DP T cells in treatment-naive and natalizumab-treated MS patients are comparable to healthy controls. These cells have a memory phenotype with cytotoxic potential, express high levels of CD49d and are similarly functional in treatment-naive as well as natalizumab-treated MS patients. DP T cells were enriched in the cerebrospinal fluid, but do not invade acutely inflamed MS lesions. In conclusion, DP T cells are functional in MS and may play a role in the immune surveillance of the central nervous system, but do not display functional impairment under natalizumab therapy.

Fumaric acid and its esters: an emerging treatment for multiple sclerosis with antioxidative mechanism of action.

Fumaric acid was originally therapeutically used in psoriasis. Several lines of evidence have demonstrated immunomodulatory but also neuroprotective effects for FAE. Clinical studies in psoriasis showed a reduction of peripheral CD4+ and CD8+ T-lymphocytes due to the ability of FAE to induce apoptosis. In vitro studies with the ester dimethylfumarate (DMF) described an inhibitory effect on nuclear factor kappa B (NF-κB)-dependent transcription of tumor necrosis factor-alpha (TNF-α) induced genes in human endothelial cells. Animal experiments in the mouse model of central nervous system demyelination, MOG-induced experimental autoimmune encephalomyelitis, revealed a clear preservation of myelin and axonal density in the plaque. Molecular studies showed that this is based on the antioxidative mechanism of action via induction of the transcription factor Nrf-2. A phase II clinical trial in relapsing-remitting multiple sclerosis (RRMS) patients with dimethylfumarate showed a significant reduction in the number of gadolinium enhancing lesions after 24weeks.

[Fingolimod compassionate use program: case study on the concept of a therapy option for multiple sclerosis prior to marketing approval]. / Fingolimod-Compassionate-use-Programm : Fallstudie zum Konzept einer Therapieoption bei Multipler Sklerose vor Zulassung und Markteinführung.

BACKGROUND: In order to meet the needs of therapy of multiple sclerosis (MS) new immune therapies with a user-friendly application and better effectiveness together with good tolerability are necessary. COMPASSIONATE USE: With respect to its potential to improve MS therapy, patients with a high medical need were given access to Fingolimod even before marketing approval. Therefore, a compassionate use program unique in the field of MS was initiated. In total 137 centers participated (75 % outpatient neurologists and 25 % hospitals). Within 19 weeks 135 patients were enrolled to receive Fingolimod. The patients in the compassionate use program can be representatively described as showing hardly controllable disease activity and progression with currently available, often poorly tolerated therapy. The compassionate use program for these patients offered better control of the disease with Fingolimod. The adverse events were as expected. CONCLUSIONS: The Fingolimod compassionate use program demonstrated the need for this new therapeutic option. Patients who were not yet sufficiently treated were provided with an effective therapy with a good safety profile and a user-friendly administration form.

Fumaric Acid and its esters: an emerging treatment for multiple sclerosis.

Fumaric acid is an intermediate product of the citric acid cycle that is a source of intracellular energy in the form of adenosine triphosphate (ATP). It is generated by oxidation of adenylsuccinate by the enzyme succinate dehydrogenase and is then converted to maleate by the enzyme fumarase. At present, fumaric acid esters (FAE) are licensed for the treatment of psoriasis. Several lines of evidence have demonstrated immunomodulatory effects for FAE. Clinical studies in psoriasis showed a reduction of peripheral CD4(+)- and CD8(+)-T-lymphocytes due to the ability of FAE to induce apoptosis. In vitro studies with the ester dimethyl fumarate (DMF) described an inhibitory effect on nuclear factor kappa B (NF-kappaB)-dependent transcription of tumor necrosis factor-alpha (TNF-alpha) induced genes in human endothelial cells. Animal studies using a model of central nervous system demyelination, MOG-induced experimental autoimmune encephalomyelitis (EAE), revealed a reduction of microglia and macrophages in inflamed lesions. A phase II clinical study in relapsing-remitting multiple sclerosis (RRMS) patients with a modified fumaric acid ester, BG-12, showed as "proof of principle" a significant reduction in the number of gadolinium enhancing lesions after 24 weeks of treatment as compared to placebo. Further phase III studies have now started to explore the long-term efficacy of FAE.

[Rituximab in treatment for neuroimmunological diseases]. / Einsatz von Rituximab in der Behandlung neuroimmunologischer Erkrankungen.

Rituximab, a human-mouse chimeric CD20 monoclonal antibody that depletes CD20-positive B cells, has already demonstrated efficacy in hematologic and rheumatologic diseases. Treatment with rituximab results in depletion of CD20-positive cells via multiple mechanisms, including complement-mediated or antibody-dependent cytotoxicity and apoptosis. Recent histopathologic and immunologic studies reveal an influence of B cells on the development and perpetuation of many chronic inflammatory diseases of the nervous system. Promising results with rituximab were already reported in the therapy of myasthenia gravis, immunoneuropathies, neuromyelitis optica, and multiple sclerosis, in which first controlled studies have been recently published. In this review we summarize available data from these reports and also discuss possible underlying molecular mechanisms.

FLAIRfusion Processing with Contrast Inversion : Improving Detection and Reading Time of New Cerebral MS Lesions.

PURPOSE: To evaluate the performance of an innovative image processing approach for detection of T2-weighted hyperintense multiple sclerosis (MS) lesions. METHODS: In this study 20 consecutive patients with inflammatory demyelinating lesions were retrospectively evaluated of whom 10 patients featured progressive disease and 10 a stable lesion load. 3 mm transversal FLAIRfusion imaging was processed and archived. Image processing was performed through landmark-based 3D co-registration of the previous and current isotropic FLAIR examination followed by inversion of image contrast. Thereby, the hyperintense signals of the unchanged MS plaques extinguish each other, while newly developed lesions appear bright on FLAIRfusion. Diagnostic performance was evaluated by 4 experienced readers. Consensus reading supplied the reference standard. Sensitivity, specificity, NPV (negative predictive value), PPV (positive predictive value), interreader agreement and reading time were the outcome measures analyzed. RESULTS: Combined sensitivity was 100% at a specificity of 88.2%, with PPV ranging from 83.3% to 90.1% and NPV at 100%. Reading time was nearly 5­fold faster than conventional side by side comparison (35.6 s vs. 163.7 s, p < 0.001). Cohen's kappa was excellent (>0.75; p < 0.001) and Cronbach's alpha was 0.994. CONCLUSION: FLAIRfusion provides reliable detection of newly developed MS lesions along with strong interreader agreement across all levels of expertise in 35 s of reading time.

Termination of inflammation in the nervous system.

T cell apoptosis has been studied in animal models for human autoimmune disorders of the nervous system and in other tissues devoid of specialized immune-defense mechanisms. Our data suggest that the central nervous system has a high potential to eliminate T cell inflammation, whereas this mechanism is less effective in the peripheral nervous system, and even more in muscle and skin. In-vitro experiments indicate different scenarios how specific cellular and humoral elements in the nervous system may synergize and sensitize T cells for apoptosis in-vivo. Probably release of TNF-alpha in the nervous system is a central mechanism to limit inflammation in the brain. This is further substantiated since neutralization of TNF-alpha in MS patients increased cellular inflammation and relapses. Therapeutically several conventional and novel approaches like glucocorticosteroids and high-dose antigen therapy induce T cell apoptosis in-situ. We also discuss regulatory, proapoptotic mechanisms such as the Fas/FasL system and counterregulatory mechanisms that have been utilized to limit tissue damage.

Iron particle-enhanced visualization of inflammatory central nervous system lesions by high resolution: preliminary data in an animal model.

BACKGROUND AND PURPOSE: The detection of cell infiltration is critical for the diagnosis and monitoring of inflammatory disorders, especially in the central nervous system (CNS). Superparamagnetic iron oxide (SPIO) particles have recently been introduced as a contrast agent to detect macrophage migration in vivo by MR imaging. We tested the hypothesis that focal hyperechogenicity due to SPIO-laden macrophages can also be visualized on high-resolution sonography. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced by myelin-oligodendrocyte glycoprotein (MOG) in congenic Lewis rats, an animal model mimicking many aspects of human multiple sclerosis. At the height of disease, rats underwent MR imaging with a 1.5T unit. Animals were injected with SPIO particles 24 hours before imaging. Control rats either received no contrast agent or were injected with SPIO particles without prior induction of EAE. Immediately after MR imaging, the rats were sacrificed, and the brains were removed and placed in saline. Sonography was performed directly after brain removal. Brains were embedded in paraffin, and sections were stained for iron with Perls stain and for macrophages with ED1 immunohistochemistry. RESULTS: SPIO-enhanced sonography of rat brains during a relapse of EAE specifically showed marked focal echogenicity in EAE-typical areas of the brain, including the periventricular region, the cerebellum, and the brain stem. The sonographic results corresponded to in vivo MR imaging findings of the respective animals as well to the clinical symptoms of EAE and to histology showing iron-laden macrophages in demyelinated lesions. CONCLUSION: SPIO particles allow the detection and demarcation of inflammatory CNS lesions on sonograms by specific macrophage imaging.

Cloning of the murine relA (p65 NF-kappa B) gene and comparison to the human gene reveals a distinct first intron.

A murine genomic clone encoding the relA (p65 NF-kappa B) locus was isolated and characterized. The clone spanned about 20 kb and included at least 10 exons and the relA promoter. Sequencing of the promoter region revealed the presence of a murine-specific intron of 546 bp intervening the homologue of human exon 1. The species-specific organisation of relA genes and promoter elements is compared and discussed. Despite the presence of potential binding sites for transcription factors NF-kappa B and AP-1 in the murine relA promoter, the constitutive relA transcript level was not affected by treatment of cells with phorbol ester or pyrrolidinedithiocarbamate, compounds which strongly affect NF-kappa B and AP-1 activities. This provides pharmacological evidence that the relA gene is not inducibly controlled by NF-kappa B or AP-1.

Aquaporin-4 antibody negative recurrent isolated optic neuritis: clinical evidence for disease heterogeneity.

Recurrent optic neuritis is frequently observed in multiple sclerosis (MS) and is a typical finding in neuromyelitis optica (NMO). Patients that lack further evidence of demyelinating disease are diagnosed with RION (recurrent isolated optic neuritis) or CRION (chronic relapsing inflammatory neuropathy) if they require immunosuppressive therapy to prevent further relapses. The etiology and disease course of this rare condition are not well defined. We studied a series of 10 patients who presented with recurrent episodes of isolated optic neuritis (ON, n=57) and were followed over a median of 3.5 years. Visual acuity was severely reduced at the nadir of the disease (20/200 to 20/800). All patients had MRI non-diagnostic for MS/NMO and were aquaporin-4 antibody negative. Six patients fulfilled the CRION criteria. In two of these a single ON followed by a long disease-free interval preceded development of CRION for years, suggesting the conversion of an initially "benign" isolated ON into the chronic relapsing course. Cerebrospinal fluid (CSF) analysis revealed mild pleocytosis in 5 patients, identical oligoclonal bands in serum and CSF were observed in 2 patients, while the others remained negative. In conclusion, recurrent ON is a disease entity that requires aggressive glucocorticoid and eventually long-term immunosuppressive therapy to prevent substantial visual impairment.

Small but powerful: short peptide hormones and their role in autoimmune inflammation.

In the recent years, it has become increasingly clear that the immune response is also influenced by mediators which were first discovered as regulators in the nervous or also cardiovascular system. Here, small peptide hormones may play an important role. Kinins like bradykinins act on the endothelium and play a role for trafficking of lymphocytes over the blood-brain barrier. Neuropeptides like vasoactive intestinal peptide or neuropeptide Y also directly act on T cells and favour the differentiation of Th2 cells or regulatory T cell populations. Recently, the renin-angiotensin system (RAS) came into the focus of interest. Inhibition of the RAS at different levels may influence autoimmune responses and involve T cells as well as antigen-presenting cells, probably via different signalling pathways. Inhibitors of angiotensin converting enzyme and antagonists of the angiotensin 1 receptors are used in the treatment of hypertension, kidney disease or stroke by millions of people worldwide. These inexpensive and safe pharmaceuticals may also represent an interesting and innovative approach for the (combination) treatment of autoimmune diseases like multiple sclerosis.