Epilepsy as a predictor of disease progression in multiple sclerosis

Background: Epilepsy development during the course of multiple sclerosis (MS) is considered to be the result of cortical pathology. However, no long-term data exist on whether epilepsy in MS also leads to increasing disability over time. Objective: To examine if epilepsy leads to more rapid disease progression. Methods: We analyzed the data of 31,052 patients on the German Multiple Sclerosis Register in a case–control study. Results: Secondary progressive disease course (odds ratio (OR) = 2.23), age (OR = 1.12 per 10 years), and disability (OR = 1.29 per Expanded Disability Status Scale (EDSS) point) were associated with the 5-year prevalence of epilepsy. Patients who developed epilepsy during the course of the disease had a higher EDSS score at disease onset compared to matched control patients (EDSS 2.0 vs 1.5), progressed faster in each dimension, and consequently showed higher disability (EDSS 4.4 vs 3.4) and lower employment status (40% vs 65%) at final follow-up. After 15 years of MS, 64% of patients without compared to 54% of patients with epilepsy were not severely limited in walking distance. Conclusion: This work highlights the association of epilepsy on disability progression in MS, and the need for additional data to further clarify the underlying mechanisms.

Anti-CD20 treatment effectively attenuates cortical pathology in a rat model of widespread cortical demyelination

Background Cortical demyelination represents a prominent feature of the multiple sclerosis (MS) brain, especially in (late) progressive stages. We recently developed a new rat model that reassembles critical features of cortical pathology characteristic to progressive types of MS. In persons affected by MS, B-cell depleting anti-CD20 therapy proved successful in the relapsing remitting as well as the early progressive course of MS, with respect to reducing the relapse rate and number of newly formed lesions. However, if the development of cortical pathology can be prevented or at least slowed down is still not clear. The main goal of this study was thus to increase our understanding for the mode of action of B-cells and B-cell directed therapy on cortical lesions in our rat model. Methods For this purpose, we set up two separate experiments, with two different induction modes of B-cell depletion. Brain tissues were analyzed thoroughly using histology. Results We observed a marked reduction of cortical demyelination, microglial activation, astrocytic reaction, and apoptotic cell loss in anti-CD20 antibody treated groups. At the same time, we noted increased neuronal preservation compared to control groups, indicating a favorable impact of anti-CD20 therapy. Conclusion These findings might pave the way for further research on the mode of action of B-cells and therefore help to improve therapeutic options for progressive MS.

Subdural haematoma, the great imitator, mimicking acute spinal cord lesion

Acute non-traumatic paraparesis is usually caused by vascular, inflammatory or neoplastic myelopathies; however, it is sometimes caused by non-myelopathic pathologies, including polyradiculoneuropathies, myopathies, psychogenic aetiologies or parasagittal cortical pathologies. A 73-year-old woman reported weakness of the bilateral lower limbs and urinary incontinence. Together with the sensory level at the left T6 dermatome, we initially considered thoracic myelopathy as the most likely diagnosis. However, MRI of the cervicothoracic cord was negative and subsequent cranial CT revealed a bilateral subdural haematoma. A parasagittal cortical pathology should not be excluded from differential diagnoses as a rare cause of paraparesis until its possibility is carefully ruled out.

Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

Meningeal inflammation strongly associates with demyelination and neuronal loss in the underlying cortex of progressive MS patients, thereby contributing significantly to clinical disability. However, the pathological mechanisms of meningeal inflammation-induced cortical pathology are still largely elusive. By extensive analysis of cortical microglia in post-mortem progressive MS tissue, we identified cortical areas with two MS-specific microglial populations, termed MS1 and MS2 cortex. The microglial population in MS1 cortex was characterized by a higher density and increased expression of the activation markers HLA class II and CD68, whereas microglia in MS2 cortex showed increased morphological complexity and loss of P2Y12 and TMEM119 expression. Interestingly, both populations associated with inflammation of the overlying meninges and were time-dependently replicated in an in vivo rat model for progressive MS-like chronic meningeal inflammation. In this recently developed animal model, cortical microglia at 1-month post-induction of experimental meningeal inflammation resembled microglia in MS1 cortex, and microglia at 2 months post-induction acquired a MS2-like phenotype. Furthermore, we observed that MS1 microglia in both MS cortex and the animal model were found closely apposing neuronal cell bodies and to mediate pre-synaptic displacement and phagocytosis, which coincided with a relative sparing of neurons. In contrast, microglia in MS2 cortex were not involved in these synaptic alterations, but instead associated with substantial neuronal loss. Taken together, our results show that in response to meningeal inflammation, microglia acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex. Furthermore, our in vivo data suggests that microglia initially protect neurons from meningeal inflammation-induced cell death by removing pre-synapses from the neuronal soma, but eventually lose these protective properties contributing to neuronal loss.

Anti-CD20 Treatment Effectively Attenuates Cortical Pathology in a Rat Model of Widespread Cortical Demyelination

BackgroundCortical demyelination represents a prominent feature of the multiple sclerosis (MS) brain, especially in (late) progressive stages. We recently developed a new rat model that reassembles critical features of cortical pathology characteristic to progressive types of MS. In persons affected by MS, B-cell depleting anti-CD20 therapy proved successful in the relapsing remitting as well as the early progressive course of MS, with respect to reducing the relapse rate and number of newly formed lesions. However, if the development of cortical pathology can be prevented or at least slowed down is still not clear. The main goal of this study was thus to increase our understanding for the mode of action (MOD) of B-cells and B-cell directed therapy on cortical lesions in our rat model. MethodsFor this purpose, we set up two separate experiments, with two different induction modes of B-cell depletion. Brain tissues were analyzed thoroughly using histology. ResultsWe observed a marked reduction of cortical demyelination, microglial activation, astrocytic reaction and apoptotic cell loss in anti-CD20 antibody treated groups. At the same time, we noted increased neuronal preservation compared to control groups, indicating a favorable impact of anti-CD20 therapy. ConclusionThese findings might pave the way for further research on the MOD of B-cells and therefore help to improve therapeutic options for progressive MS.

Kinematic Analysis of Dance-Based Exergaming: A Cross-Sectional Study

Background: Recent studies demonstrate improvements in both postural stability and mobility among aging populations and those with stroke who are exposed to dance-based exergaming (DBExG). However, age-related deficits and aging with cortical pathology may lead to distinct movement adaptation patterns during DBExG, which could impact therapeutic outcomes.Aim: The aim of this study was to examine the movement kinematics (postural stability and mobility) of healthy older adults, older adults with stroke, and young adults for different paces of dance during DBExG. Method: The study included 33 particpants (11 participant from each group of healthy older adults, older adults with chronic stroke, and healthy young adults) who performed the DBExG using slow- (SP), medium- (MP), and fast-paced (FP) songs with movements in the anteroposterior (AP) and mediolateral (ML) directions. Center of mass (CoM) sway area, excursion (Ex), and peaks as well as hip, knee, and ankle joint excursions were computed. Results: Results of the study revealed that CoM sway areas and Exs were greater for healthy young adults than for older adults with stroke for the SP dance (p < 0.05) and that there were significantly more AP CoM peaks for young adults than for healthy older adults and those with stroke for the FP dance (p < 0.05). Young adults also exhibited greater hip and ankle Exs than older adults with stroke (p < 0.05) for all song paces. Similarly, knee and ankle Exs were greater for healthy older adults than for older adults with stroke for all song paces (p < 0.05). Conclusion: The quantitative evaluation and comparison of the movement patterns presented for the three groups could provide a foundation for both assessing and designing therapeutic DBExG protocols for these populations.

Laminar analysis of the cerebellar cortex shows widespread damage in early MS patients: A pilot study at 7T MRI

Background To date, little is known about the presence and extent of cerebellar cortical pathology in early stages of MS. Objective The aims of this study were to (i) investigate microstructural changes in the normal-appearing cerebellar cortex of early MS patients by using 7 T MRI and (ii) evaluate the influence of those changes on clinical performance. Methods Eighteen RRMS patients and nine healthy controls underwent quantitative T1 and T2* measurement at 7 T MRI using high-resolution MP2RAGE and multi-echo gradient-echo imaging. After subtracting lesion masks, average T1 and T2* maps were computed for three layers in the cerebellar cortex and compared between groups using mixed effects models. Results The volume of the cerebellar cortex and its layers did not differ between patients and controls. In MS patients, significantly longer T1 values were observed in all vermis cortical layers and in the middle and external cortical layer of the cerebellar hemispheres. No between-group differences in T2* values were found. T1 values correlated with EDSS, SDMT and PASAT. Conclusions We found MRI evidence of damage in the normal-appearing cerebellar cortex at early MS stages and before volumetric changes. This microstructural alteration appears to be related to EDSS and cognitive performance.

Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

Meningeal inflammation strongly associates with demyelination and neuronal loss in the underlying cortex of progressive MS patients, contributing to clinical disability. However, the pathological mechanisms of meningeal inflammation-induced cortical pathology are still largely elusive. Using extensive analysis of human post-mortem tissue, we identified two distinct microglial phenotypes, termed MS1 and MS2, in the cortex of progressive MS patients. These phenotypes differed in morphology and protein expression, but both associated with inflammation of the overlying meninges. We could replicate the MS-specific microglial phenotypes in a novel in vivo rat model for progressive MS-like meningeal inflammation, with microglia present at 1 month post-induction resembling MS1 microglia whereas those at 2 months acquired an MS2-like phenotype. Interestingly, MS1 microglia were involved in presynaptic displacement and phagocytosis and associated with a relative sparing of neurons in the MS and animal cortex. In contrast, the presence of MS2 microglia coincided with substantial neuronal loss. Taken together, we uncovered that in response to meningeal inflammation, microglia acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex. Our data suggests that these phenotypes occur sequentially and that microglia may lose their protective properties over time, contributing to neuronal loss.