Toward identifying key mechanisms of progression in multiple sclerosis.

A major therapeutic goal in the treatment of multiple sclerosis (MS) is to prevent the accumulation of disability over an often decades-long disease course. Disability progression can result from acute relapses as well as from CNS intrinsic parenchymal disintegration without de novo CNS lesion formation. Research focus has shifted to progression not associated with acute inflammation, as it is not sufficiently controlled by currently available treatments. This review outlines how recent advances in the understanding of the pathogenesis of progressive MS have been facilitated by the development of more precise, less static pathogenetic concepts of progressive MS, as well as by new techniques for the analysis of region-specific proteomic and transcriptomic signatures in the human CNS. We highlight key drivers of MS disease progression and potential targets in its treatment.

B Cells and Antibodies as Targets of Therapeutic Intervention in Neuromyelitis Optica Spectrum Disorders.

The first description of neuromyelitis optica by Eugène Devic and Fernand Gault dates back to the 19th century, but only the discovery of aquaporin-4 autoantibodies in a major subset of affected patients in 2004 led to a fundamentally revised disease concept: Neuromyelits optica spectrum disorders (NMOSD) are now considered autoantibody-mediated autoimmune diseases, bringing the pivotal pathogenetic role of B cells and plasma cells into focus. Not long ago, there was no approved medication for this deleterious disease and off-label therapies were the only treatment options for affected patients. Within the last years, there has been a tremendous development of novel therapies with diverse treatment strategies: immunosuppression, B cell depletion, complement factor antagonism and interleukin-6 receptor blockage were shown to be effective and promising therapeutic interventions. This has led to the long-expected official approval of eculizumab in 2019 and inebilizumab in 2020. In this article, we review current pathogenetic concepts in NMOSD with a focus on the role of B cells and autoantibodies as major contributors to the propagation of these diseases. Lastly, by highlighting promising experimental and future treatment options, we aim to round up the current state of knowledge on the therapeutic arsenal in NMOSD.

Natalizumab promotes activation and pro-inflammatory differentiation of peripheral B cells in multiple sclerosis patients.

BACKGROUND: In the past, multiple sclerosis (MS) medications have been primarily designed to modulate T cell properties. Based on the emerging concept that B cells are equally important for the propagation of MS, we compared the effect of four commonly used, primarily T cell-targeting MS medications on B cells. METHODS: Using flow cytometry, we analyzed peripheral blood mononuclear cells (PBMC) of untreated (n = 19) and dimethyl fumarate (DMF; n = 21)-, fingolimod (FTY; n = 17)-, glatiramer acetate (GA; n = 18)-, and natalizumab (NAT; n = 20)-treated MS patients, focusing on B cell maturation, differentiation, and cytokine production. RESULTS: While GA exerted minor effects on the investigated B cell properties, DMF and FTY robustly inhibited pro-inflammatory B cell function. In contrast, NAT treatment enhanced B cell differentiation, activation, and pro-inflammatory cytokine production when compared to both intraindividual samples collected before NAT treatment initiation as well as untreated MS controls. Our mechanistic in vitro studies confirm this observation. CONCLUSION: Our data indicate that common MS medications have differential, in part opposing effects on B cells. The observed activation of peripheral B cells upon NAT treatment may be instructive to interpret its unfavorable effect in certain B cell-mediated inflammatory conditions and to elucidate the immunological basis of MS relapses after NAT withdrawal. TRIAL REGISTRATION: Protocols were approved by the ethical review committee of the University Medical Center Göttingen (#3/4/14).

An emboligenic pulmonary abscess leading to ischemic stroke and secondary brain abscess.

BACKGROUND: Ischemic stroke by septic embolism occurs primarily in the context of infective endocarditis or in patients with a right-to-left shunt and formation of a secondary cerebral abscess is a rare event. Erosion of pulmonary veins by a pulmonary abscess can lead to transcardiac septic embolism but to our knowledge no case of septic embolic ischemic stroke from a pulmonary abscess with secondary transformation into a brain abscess has been reported to date. CASE PRESENTATION: We report the case of a patient with a pulmonary abscess causing a septic embolic cerebral infarction which then transformed into a cerebral abscess. After antibiotic therapy and drainage of the abscess the patient could be rehabilitated and presented an impressive improvement of symptoms. CONCLUSION: Septic embolism should be considered as cause of ischemic stroke in patients with pulmonary abscess and can be followed by formation of a secondary cerebral abscess. Early antibiotic treatment and repeated cranial CT-scans for detection of a secondary abscess should be performed.

Symptomatic therapy in multiple sclerosis: the role of cannabinoids in treating spasticity.

A large proportion of patients with multiple sclerosis (MS) have spasticity, which has a marked impact on their quality of life. Anecdotal evidence suggests a beneficial effect of cannabis on spasticity as well as pain. Recently, randomized, double-blind, placebo-controlled studies have confirmed the clinical efficacy of cannabinoids for the treatment of spasticity in patients with MS. Based on these data, nabiximols (Sativex), a 1:1 mix of Δ-9-tetrahydrocannabinol and cannabidiol extracted from cloned Cannabis sativa chemovars, received approval for treating MS-related spasticity in various countries around the globe. In this article we review the current understanding of cannabinoid biology and the value of cannabinoids as a symptomatic treatment option addressing spasticity in patients with MS.

Inflammatory demyelinating brain lesions heralding primary CNS lymphoma.

Brain biopsy plays a crucial role in the exploration of suspect white matter lesions in the differential diagnosis of primary central nervous system lymphoma (PCNSL) and inflammatory demyelination. We present the case of a previously healthy, immunocompetent woman, aged fifty-nine, who developed a histologically confirmed demyelinating white matter lesion months prior to the manifestation of a PCNSL. Similar cases of "sentinel lesions" preceding a PCNSL have been reported. In a literature review, we compared the diagnostic features that may be useful to differentiate a PCNSL from inflammatory demyelinating disease in older age. We conclude that the occurrence of large, contrast-enhancing cerebral lesions in older patients with a relapsing-remitting disease course and steroid-resistant vision disorders should lead to the consideration of a PCNSL.

Functional analysis of embryonic stem cell-derived glial cells after integration into hippocampal slice cultures.

Embryonic stem (ES) cell-derived neural progenitor cells (ESNPs) generated in vitro are multipotent progenitors which can differentiate into oligodendrocytes, astrocytes, and neurons. Given the exciting prospects for ES cell-based treatments of neurological disorders, several studies investigated the migration, integration, and differentiation of grafted ESNPs into neurons and glial cells. However, little is known about the functional properties of transplanted ESNPs on the single cell level. In this study, we combined electrophysiology, single cell reverse transcription polymerase chain reaction (RT-PCR) and immunochemistry to determine the developmental time course of molecular and functional properties of ES cell-derived glial precursors (ESGPs) after deposition onto hippocampal slice cultures. Based on functional criteria, donor cells possessed three different phenotypes. During an observation period of 3 weeks after engraftment, the proportion of donor cells with a passive current pattern (type 3) continuously increased. The majority of these cells expressed astroglial markers. Type 3 host cells underwent similar developmental changes. In contrast, donor and host cells expressing time- and voltage-dependent currents (types 1, 2) displayed different developmental profiles. Importantly, type 2 donor and host cells also differed in the expression of inwardly rectifying K(+) channels. This suggests that despite several similarities in overall current phenotypes and timing of maturation, many donor cells integrated into host tissue but did not acquire the full set of ion channels present in their native counterparts. These findings emphasize the need to carefully characterize ES cell-derived progeny aimed for neural repair and cell-mediated gene transfer strategies.

Functional network integration of embryonic stem cell-derived astrocytes in hippocampal slice cultures.

Embryonic stem (ES) cells provide attractive prospects for neural transplantation. So far, grafting strategies in the CNS have focused mainly on neuronal replacement. Employing a slice culture model, we found that ES cell-derived glial precursors (ESGPs) possess a remarkable capacity to integrate into the host glial network. Following deposition on the surface of hippocampal slices, ESGPs actively migrate into the recipient tissue and establish extensive cell-cell contacts with recipient glia. Gap junction-mediated coupling between donor and host astrocytes permits widespread delivery of dye from single donor cells. During maturation, engrafted donor cells display morphological, immunochemical and electrophysiological properties that are characteristic of differentiating native glia. Our findings provide the first evidence of functional integration of grafted astrocytes, and depict glial network integration as a potential route for widespread transcellular delivery of small molecules to the CNS.