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.

Direct Estimation of Local pH Change at Infection Sites of Fungi in Potato Tubers.

Fungi can modify the pH in or around the infected site via alkalization or acidification, and pH monitoring may provide valuable information on host-fungus interactions. The objective of the present study was to examine the ability of two fungi, Colletotrichum coccodes and Helminthosporium solani, to modify the pH of potato tubers during artificial inoculation in situ. Both fungi cause blemishes on potato tubers, which downgrades tuber quality and yield. Direct visualization and estimation of pH changes near the inoculation area were achieved using pH indicators and image analysis. The results showed that the pH of the area infected by either fungus increased from potato native pH of approximately 6.0 to 7.4 to 8.0. By performing simple analysis of the images, it was also possible to derive the growth curve of each fungus and estimate the lag phase of the radial growth: 10 days for C. coccodes and 17 days H. solani. In addition, a distinctive halo (an edge area with increased pH) was observed only during the lag phase of H. solani infection. pH modulation is a major factor in pathogen-host interaction and the proposed method offers a simple and rapid way to monitor these changes.

[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.

["Time is brain" in relapsing remitting multiple sclerosis. Current treatment concepts in immunotherapy]. / "Time is brain" bei der schubförmigen Multiplen Sklerose. Aktuelle Behandlungskonzepte in der Immuntherapie.

BACKGROUND: Despite highly divergent time scales of disease evolution in multiple sclerosis (MS) and ischemic stroke, clear analogies are apparent that may point the way to optimization of MS treatment. Inflammatory disease activity and neurodegeneration may induce potentially irreversible damage to central nervous system structures and thus lead to permanent disability. For the treatment of MS early detection of disease activity and early immunotherapy or treatment optimization are pivotal determinants of long-term outcomes. Such therapeutic concepts may be described with the catchy phrase "time is brain" as coined for the acute thrombolytic treatment of ischemic stroke. RESULTS AND DISCUSSION: For MS a "time is brain" concept would comprise an early initiation of first line therapy as well as sensitive and structured monitoring of disease activity under therapy in conjunction with a low threshold for timely treatment optimization to achieve sustained freedom from measurable disease activity. This approach may substantially improve the long-term outcome in patients who show insufficient response to platform therapies. The intersectorial collaboration in regional MS care networks involving office-based neurologists and specialized MS centers may facilitate the timely use of highly active therapies with their specific benefit-risk profiles thus supporting sustained stabilization of patient quality of life.

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 as therapeutic agent for multiple sclerosis]. / Fumarsäure in der Therapie der Multiplen Sklerose.

After the approval of fumaric acid in February 2014 another first line agent is now available for the treatment of multiple sclerosis (MS). Along with the various beta interferon preparations, glatiramer acetate, teriflunomide and fumaric acid add to the repertoire of oral therapeutics for the initial treatment of relapsing remitting MS in daily practice. In order to employ these drugs in an individualized and precise medical manner and considering their efficacy and side effects, it seems worthwhile to learn the so far known mode of action and background history. Fumaric acid, as one of the newest drugs approved for MS, reveals the longest history as it was in use for decades as a treatment in psoriasis patients. Furthermore, fumaric acid is a good example for so far not extensively exploited option of drug reposition in medicine in general. The current review summarizes the outcomes of the clinical approval studies of fumaric acid in MS and discusses the dual mode of action, the immunomodulatory and tissue protective effect, as well as the reported adverse events under fumaric acid treatment. This review aims to serve an aid in the daily decision-making practice when choosing the baseline therapy for MS patients.

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.

Heterogeneous oxidation of the insecticide cypermethrin as thin film and airborne particles by hydroxyl radicals and ozone.

Evaluation of pesticides' fate in the atmosphere is important in terms of environmental effects on non-target areas and risk assessments analysis. This evaluation is usually done in the laboratory using analytical grade materials and is then extrapolated to more realistic conditions. To assess the effect of the pesticide purity level (i.e. analytical vs. technical) and state (i.e. sorbed film vs. airborne particles), we have investigated the oxidation rates and products of technical grade cypermethrin as thin film and in its airborne form, and compared it with our former results for analytical grade material. Technical grade thin film kinetics for both ozone and OH radicals revealed reaction rates similar to the analytical material, implying that for these processes, the analytical grade can be used as a good proxy. Oxidation products, however, were slightly different with two additional condensed phase products: formanilide, N-phenyl and 2-biphenyl carboxylic acid, which were seen with the technical grade material only. OH experiments revealed spectral changes that suggest the immediate formation of surface products containing OH functionalities. For the ozonolysis studies of airborne material, a novel set-up was used, which included a long-path FTIR cell in conjugation with a Scanning Mobility Particle Sizer (SMPS) system. This set-up allowed monitoring of real-time reaction kinetics and product formation (gas and condensed phases) together with aerosol size distribution measurements. Similar condensed phase products were observed for airborne and thin film technical grade cypermethrin after ozonolysis. Additionally, CO, CO(2) and possibly acetaldehyde were identified as gaseous oxidation products in the aerosols experiments only. A kinetic model fitted to our experimental system enabled the identification of both primary and secondary products as well as extraction of a formation rate constant. Kinetic calculations (based on gaseous products formation rate) have revealed values similar to that of the thin film experiments. Interestingly, heterogeneous oxidation of cypermethrin was also found to generate ultra fine secondary organic aerosols. Again, no significant difference was observed between analytical and technical grade materials. However, particle size distribution was much broader when films were exposed to OH and ozone than to ozone alone.

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.

The German trial on Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE): a multicenter, randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Comprehensive treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major clinical challenge. The current therapy gold standard is aciclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains around 20% and a majority of survivors suffer from severe disability. Experimental research and recent retrospective clinical observations suggest a favourable therapy response to adjuvant dexamethasone. Currently there is no randomized clinical trial evidence, however, to support the routine use of adjuvant corticosteroid treatment in HSVE. METHODS: The German trial of Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE) studied the effect of adjuvant dexamethasone versus placebo on top of standard aciclovir treatment in adult patients aged 18 up to 85 years with proven HSVE in German academic centers of Neurology in a randomized and double blind fashion. The trial was open from November 2007 to December 2012. The initially planned sample size was 372 patients with the option to increase to up to 450 patients after the second interim analysis. The primary endpoint was a binary functional outcome after 6 months assessed using the modified Rankin scale (mRS 0-2 vs. 3-6). Secondary endpoints included mortality after 6 and 12 months, functional outcome after 6 months measured with the Glasgow outcome scale (GOS), functional outcome after 12 months measured with mRS and GOS, quality of life as measured with the EuroQol 5D instrument after 6 and 12 months, neuropsychological testing after 6 months, cranial magnetic resonance imaging findings after 6 months, seizures up to day of discharge or at the latest at day 30, and after 6 and 12 months. RESULTS: The trial was stopped prematurely for slow recruitment after 41 patients had been randomized, 21 of them treated with dexamethasone and 20 with placebo. No difference was observed in the primary endpoint. In the full analysis set (n = 19 in each group), 12 patients in each treatment arm achieved a mRS of 0-2. Similarly, we did not observe significant differences in the secondary endpoints (GOS, mRS, quality of life, neuropsychological testing). CONCLUSION: GACHE being prematurely terminated demonstrated challenges encountered performing randomized, placebo-controlled trials in rare life threatening neurological diseases. Based upon our trial results the use of adjuvant steroids in addition to antiviral treatment remains experimental and is at the decision of the individual treating physician. Unfortunately, the small number of study participants does not allow firm conclusions. TRIAL REGISTRATION: EudraCT-Nr. 2005-003201-81.

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.

Determination of soil nitrate and water content using attenuated total reflectance spectroscopy.

Direct determination of nitrate and soil moisture can significantly improve N-application management and thus reduce N-derived environmental pollution related to agriculture. Several studies have shown that Fourier transform infrared attenuated total reflectance (FT-IR/ATR) spectroscopy could be used to estimate the nitrate content of standardized soil pastes. Paste standardization appeared to be the main obstacle to in situ application of this approach, and the present study shows how FT-IR/ATR can be used to estimate both water content and nitrate concentration of field soil samples. Water content and nitrate concentration are determined sequentially using two subsamples of the initial soil sample. An a priori determined amount of highly concentrated nitrate solution is added to the first subsample and the ATR spectrum of this paste is used to estimate the sample water content. It is then possible to calculate the amount of water that should be added to the second subsample so that the resulting paste is very close to the ideal standard paste. Nitrate concentration, mg [N]/kg [dry soil], is estimated using the FT-IR/ATR spectrum of this second paste. Results are presented for a laboratory experiment with four agricultural soils, as well as for a field trial with a calcareous soil. For water content, the determination errors range from 0.01 to 0.02 g [water]/g [dry soil]. For nitrate concentration, the errors for three of the soils range from 5.9 to 8.4 mg [N]/kg [dry soil], while for the fourth, calcareous clay soil, the determination error is 13.6 mg [N]/kg [dry soil]. The determination errors obtained for the field trial are similar to the ones obtained for a similar soil under laboratory conditions, which shows the potential usefulness of the approach for improving N-application management and reducing environmental pollution.