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The former and current multiple sclerosis (MS) classifications are essential for describing different phenotypes and disease dynamics. To establish personalized treatment regimes, further clinical and paraclinical parameters have to be considered such as imaging, cerebrospinal fluid (CSF) findings, past disease-modifying therapies (DMTs), and disease activity under these therapies. In clinical practice, this information is often difficult to overview. Especially, patients with a long course of disease offer an extensive medical history so that comprehending all of the necessary information can be very time consuming.
Anticoagulation with warfarin and rivaroxaban ameliorates experimental autoimmune encephalomyelitis
(2017)
Background: In multiple sclerosis, coagulation factors have been shown to modulate inflammation. In this translational study, we investigated whether long-term anticoagulation with warfarin or rivaroxaban has beneficial effects on the course of autoimmune experimental encephalomyelitis (EAE).
Methods: Female SJL/J mice treated with anticoagulants namely warfarin or rivaroxaban were immunized with PLP139–151. Stable anticoagulation was maintained throughout the entire experiment. Mice without anticoagulation treated with the vehicle only were used as controls. The neurological deficit was recorded during the course of EAE, and histopathological analyses of inflammatory lesions were performed.
Results: In preventive settings, both treatment with warfarin and rivaroxaban reduced the maximum EAE score as compared to the control group and led to a reduction of inflammatory lesions in the spinal cord. In contrast, therapeutic treatment with warfarin had no beneficial effects on the clinical course of EAE. Signs of intraparenchymal hemorrhage at the site of the inflammatory lesions were not observed.
Conclusion: We developed long-term anticoagulation models that allowed exploring the course of EAE under warfarin and rivaroxaban treatment. We found a mild preventive effect of both warfarin and rivaroxaban on neurological deficits and local inflammation, indicating a modulation of the disease induction by anticoagulation.
Background: Inflammation is essential for the pathogenesis of multiple sclerosis (MS). While the immune system contribution to the development of neurological symptoms has been intensively studied, inflammatory biomarkers for mental symptoms such as depression are poorly understood in the context of MS. Here, we test if depression correlates with peripheral and central inflammation markers in MS patients as soon as the diagnosis is established. Methods: Forty-four patients were newly diagnosed with relapsing-remitting MS, primary progressive MS or clinically isolated syndrome. Age, gender, EDSS, C-reactive protein (CRP), albumin, white blood cells count in cerebrospinal fluid (CSF WBC), presence of gadolinium enhanced lesions (GE) on T1-weighted images and total number of typical MS lesion locations were included in linear regression models to predict Beck Depression Inventory (BDI) score and the depression dimension of the Symptoms Checklist 90-Revised (SCL90RD). Results: CRP elevation and GE predicted significantly BDI (CRP: p = 0.007; GE: p = 0.019) and SCL90RD (CRP: p = 0.004; GE: p = 0.049). The combination of both factors resulted in more pronounced depressive symptoms (p = 0.04). CSF WBC and EDSS as well as the other variables were not correlated with depressive symptoms. Conclusions: CRP elevation and GE are associated with depressive symptoms in newly diagnosed MS patients. These markers can be used to identify MS patients exhibiting a high risk for the development of depressive symptoms in early phases of the disease.
Objective: To determine whether the performance of multiple sclerosis (MS) patients in the sound-induced flash illusion (SiFi), a multisensory perceptual illusion, would reflect their cognitive impairment.
Methods: We performed the SiFi task as well as an extensive neuropsychological testing in 95 subjects [39 patients with relapse-remitting MS (RRMS), 16 subjects with progressive multiple sclerosis (PMS) and 40 healthy control subjects (HC)].
Results: MS patients reported more frequently the multisensory SiFi than HC. In contrast, there were no group differences in the control conditions. Essentially, patients with progressive type of MS continued to perceive the illusion at stimulus onset asynchronies (SOA) that were more than three times longer than the SOA at which the illusion was already disrupted for healthy controls. Furthermore, MS patients' degree of cognitive impairment measured with a broad neuropsychological battery encompassing tests for memory, attention, executive functions, and fluency was predicted by their performance in the SiFi task for the longest SOA of 500 ms.
Conclusions: These findings support the notion that MS patients exhibit an altered multisensory perception in the SiFi task and that their susceptibility to the perceptual illusion is negatively correlated with their neuropsychological test performance. Since MS lesions affect white matter tracts and cortical regions which seem to be involved in the transfer and processing of both crossmodal and cognitive information, this might be one possible explanation for our findings. SiFi might be considered as a brief, non-expensive, language- and education-independent screening test for cognitive deficits in MS patients.
Evoked potentials (EPs) are well established in clinical practice for diagnosis and prognosis in multiple sclerosis (MS). However, their value is limited to the assessment of their respective functional systems. Here, we used transcranial magnetic stimulation (TMS) coupled with electroencephalography (TMS-EEG) to investigate cortical excitability and spatiotemporal dynamics of TMS-evoked neural activity in MS patients. Thirteen patients with early relapsing–remitting MS (RRMS) with a median Expanded Disability Status Scale (EDSS) of 1.0 (range 0–2.5) and 16 age- and gender-matched healthy controls received single-pulse TMS of left and right primary motor cortex (L-M1 and R-M1), respectively. Resting motor threshold for L-M1 and R-M1 was increased in MS patients. Latencies and amplitudes of N45, P70, N100, P180, and N280 TMS-evoked EEG potentials (TEPs) were not different between groups, except a significantly increased amplitude of the N280 TEP in the MS group, both for L-M1 and R-M1 stimulation. Interhemispheric signal propagation (ISP), estimated from the area under the curve of TEPs in the non-stimulated vs. stimulated M1, also did not differ between groups. In summary, findings show that ISP and TEPs were preserved in early-stage RRMS, except for an exaggerated N280 amplitude. Our findings indicate that TMS-EEG is feasible in testing excitability and connectivity in cortical neural networks in MS patients, complementary to conventional EPs. However, relevance and pathophysiological correlates of the enhanced N280 will need further study.
Die Multiple-Sklerose (MS)-Mortalität 1975-1993 im Bundesland Nordrhein-Westfalen wurde kreisweise (n=54) ausgewertet und hinsichtlich geographischer Verteilung und Beziehung zu geoklimatischen und soziokulturellen Faktoren, vorwiegend aus den 1950er und 1970er Jahren, hin untersucht. Die jährliche MS-Rohmortalität betrug für das gesamte Bundesland 1,27 / 100000 und war damit vergleichbar der Rate in Baden-Württemberg (1,30 / 100000), jedoch niedriger als in Hessen (1,50 / 100000) und Rheinland-Pfalz (1,47 / 100000). Das Verhältnis Frauen / Männer betrug 1,17. Während sich für die vier zeitlichen Untereinheiten (1975-79; 1980-84; 1985-89; 1990-93) ein signifikant abnehmender Trend für die MS-Mortalität ergab, ließ die geographische Verteilung einen klassischen Nord-Süd-Gradienten vermissen. In der bivariaten Analyse nach Spearman ergab sich für alle Stadt- und Landkreise (n=54) eine signifikante (p <= 0,05) Korrelation für folgende Variable: „Fortzüge / Bevölkerung“ (negativ), „tatsächlich betriebene Betten in Sonderkrankenhäusern / Bevölkerung“, „Standardisierte Mortalitätsrate (SMR) 1976-80 des Kolonkarzinoms der Frauen“, „Ozon in µg / m³ Luft 1992“ und „Nickelverbindungen im Schwebstaub in µg /m³ 1989“. Öffentliche und private Realschulen, papiererzeugende und –verarbeitende Industrie, SMR des Blasenkarzinoms der Männer, Kraftfahrzeugdichte (negativ), Benzol- und Trichlorethan-Immission waren grenzwertig mit der MS-Mortalität assoziiert. In der nach Kreisgrößenklassen stratifizierten Analyse waren in den Stadtkreisen (n=23) „öffentliche und private Realschulen“, „Schülerzahlen an Realschulen“, „Beschäftigte in der Gesamtindustrie 1954 und 1976“, „Beschäftigte in der Metallindustrie 1954 und 1976“, Beschäftigte in der Textilindustrie 1976“, „Beschäftigte in der papiererzeugenden Industrie 1976“ (alle pro Bevölkerung), „Haus- und Kleingärten / Gesamtwirtschaftsfläche“, „SMR des Rektumkarzinoms 1976-80 der Männer“ (negativ) und „SMR des Hodgkin-Lymphoms 1976-80 der Männer“ mit der MS-Mortalität signifikant korreliert. In den Landkreise (n=31) zeigte sich für „Ärzte“, „tatsächlich betriebene Betten in Allgemeinkrankenhäusern“ und „tatsächlich betriebene Betten in Sonderkrankenhäusern“ (alle pro Bevölkerung), „SMR 1976-80 des Kolonkarzinoms der Frauen“, „Nickelverbindungen im Schwebstaub in µg / m³ 1989“ und „Arsenverbindungen im Schwebstaub in µg / m³ 1989“ eine signifikante Assoziation, während alle Klimadaten nicht signifikant waren. In der schrittweisen multivariaten Analyse für alle Kreise (n=54) schieden mit der „Backward elimination“- Methode alle Variablen aus dem Modell aus. Von den zahlreichen bivariat korrelierten Variablen waren die papierzeugende Industrie und das Kolonkarzinom bemerkenswert, da sie auch in einem Teil anderer untersuchter Regionen mit der MS-Rate verknüpft waren. Die Umweltparameter bedürfen zunächst der Bestätigung in weiteren Arealen.
Background and purpose: The transition from relapsing–remitting to secondary progressive multiple sclerosis (SPMS) is not well defined. Different definitions and tools to identify SPMS have been proposed. Meanwhile, early diagnosis of “active” SPMS is getting progressively more important as pharmaceutical treatment options are developed. In this study, we compared different classification methods regarding their accuracy to reliably identify “active SPMS.”
Methods: Independent from previous diagnostic classification, we descriptively analyzed the disease course (regarding relapses, progression, and magnetic resonance imaging activity) in 208 consecutive multiple sclerosis (MS) patients treated in our MS outpatient clinic in 2018. Patients were reclassified according to different SPMS criteria and tools. Diagnostic accuracy in identifying patients with “active SPMS” was determined.
Results: Comparing the tools to each other, significant variability in the number of patients identified as having SPMS as well as in the proportion of these patients having “active SPMS” was noted. Applying both diagnostic criteria “SPMS” and “active disease” reduced the sensitivity in identifying patients with active progressive disease in all approaches.
Conclusions: We propose lessening the emphasis on the label “SPMS” in favor of the more open term “active progressive disease” to simplify the process of identifying patients who may benefit from immune therapy.
Purpose: Diffuse cortical damage in relapsing–remitting multiple sclerosis (RRMS) is clinically relevant but cannot be directly assessed with conventional MRI. In this study, it was aimed to use diffusion tensor imaging (DTI) techniques with optimized intrinsic eddy current compensation to quantify and characterize cortical mean diffusivity (MD) and fractional anisotropy (FA) changes in RRMS and to analyze the distribution of these changes across the cortex.
Materials and Methods: Three-Tesla MRI acquisition, mapping of the MD providing information about the integrity of microstructural barriers and of the FA reflecting axonal density and surface-based analysis with Freesurfer were performed for 24 RRMS patients and 25 control subjects.
Results: Across the whole cortex, MD was increased in patients (p < 0.001), while surface-based analysis revealed focal cortical FA decreases. MD and FA changes were distributed inhomogeneously across the cortex, the MD increase being more widespread than the FA decrease. Cortical MD correlated with the Expanded Disability Status Scale (EDSS, r = 0.38, p = 0.03).
Conclusion: Damage of microstructural barriers occurs inhomogeneously across the cortex in RRMS and might be spatially more widespread than axonal degeneration. The results and, in particular, the correlation with the clinical status indicate that DTI might be a promising technique for the monitoring of cortical damage under treatment in larger clinical studies.
Dysregulation of lysophosphatidic acids in multiple sclerosis and autoimmune encephalomyelitis
(2017)
Bioactive lipids contribute to the pathophysiology of multiple sclerosis. Here, we show that lysophosphatidic acids (LPAs) are dysregulated in multiple sclerosis (MS) and are functionally relevant in this disease. LPAs and autotaxin, the major enzyme producing extracellular LPAs, were analyzed in serum and cerebrospinal fluid in a cross-sectional population of MS patients and were compared with respective data from mice in the experimental autoimmune encephalomyelitis (EAE) model, spontaneous EAE in TCR1640 mice, and EAE in Lpar2 -/- mice. Serum LPAs were reduced in MS and EAE whereas spinal cord LPAs in TCR1640 mice increased during the ‘symptom-free’ intervals, i.e. on resolution of inflammation during recovery hence possibly pointing to positive effects of brain LPAs during remyelination as suggested in previous studies. Peripheral LPAs mildly re-raised during relapses but further dropped in refractory relapses. The peripheral loss led to a redistribution of immune cells from the spleen to the spinal cord, suggesting defects of lymphocyte homing. In support, LPAR2 positive T-cells were reduced in EAE and the disease was intensified in Lpar2 deficient mice. Further, treatment with an LPAR2 agonist reduced clinical signs of relapsing-remitting EAE suggesting that the LPAR2 agonist partially compensated the endogenous loss of LPAs and implicating LPA signaling as a novel treatment approach.
Background: Network science provides powerful access to essential organizational principles of the brain. The aim of this study was to investigate longitudinal evolution of gray matter networks in early relapsing–remitting MS (RRMS) compared with healthy controls (HCs) and contrast network dynamics with conventional atrophy measurements.
Methods: For our longitudinal study, we investigated structural cortical networks over 1 year derived from 3T MRI in 203 individuals (92 early RRMS patients with mean disease duration of 12.1 ± 14.5 months and 101 HCs). Brain networks were computed based on cortical thickness inter-regional correlations and fed into graph theoretical analysis. Network connectivity measures (modularity, clustering coefficient, local efficiency, and transitivity) were compared between patients and HCs, and between patients with and without disease activity. Moreover, we calculated longitudinal brain volume changes and cortical atrophy patterns.
Results: Our analyses revealed strengthening of local network properties shown by increased modularity, clustering coefficient, local efficiency, and transitivity over time. These network dynamics were not detectable in the cortex of HCs over the same period and occurred independently of patients’ disease activity. Most notably, the described network reorganization was evident beyond detectable atrophy as characterized by conventional morphometric methods.
Conclusion: In conclusion, our findings provide evidence for gray matter network reorganization subsequent to clinical disease manifestation in patients with early RRMS. An adaptive cortical response with increased local network characteristics favoring network segregation could play a primordial role for maintaining brain function in response to neuroinflammation.