Low intensity repetitive transcranial magnetic stimulation enhances remyelination by newborn and surviving oligodendrocytes in the cuprizone model of toxic demyelination.

In people with multiple sclerosis (MS), newborn and surviving oligodendrocytes (OLs) can contribute to remyelination, however, current therapies are unable to enhance or sustain endogenous repair. Low intensity repetitive transcranial magnetic stimulation (LI-rTMS), delivered as an intermittent theta burst stimulation (iTBS), increases the survival and maturation of newborn OLs in the healthy adult mouse cortex, but it is unclear whether LI-rTMS can promote remyelination. To examine this possibility, we fluorescently labelled oligodendrocyte progenitor cells (OPCs; Pdgfrα-CreER transgenic mice) or mature OLs (Plp-CreER transgenic mice) in the adult mouse brain and traced the fate of each cell population over time. Daily sessions of iTBS (600 pulses; 120 mT), delivered during cuprizone (CPZ) feeding, did not alter new or pre-existing OL survival but increased the number of myelin internodes elaborated by new OLs in the primary motor cortex (M1). This resulted in each new M1 OL producing ~ 471 µm more myelin. When LI-rTMS was delivered after CPZ withdrawal (during remyelination), it significantly increased the length of the internodes elaborated by new M1 and callosal OLs, increased the number of surviving OLs that supported internodes in the corpus callosum (CC), and increased the proportion of axons that were myelinated. The ability of LI-rTMS to modify cortical neuronal activity and the behaviour of new and surviving OLs, suggests that it may be a suitable adjunct intervention to enhance remyelination in people with MS.

[Tumefactive Demyelinating Lesions].

Tumefactive demyelinating lesions (TDL), defined as inflammatory demyelinating lesions, may develop either during treatment for multiple sclerosis and related disorders or as the first demyelinating episode without any past medical history suggesting demyelination. If the latter, it would be so delicate to diagnose as demyelination. Especially in such situations, biopsy is often necessary in addition to neuroimaging for distinction TDL with tumorous or infectious diseases. In this article, we will review about concept, epidemiology, diagnosis, and treatment of TDL.

Multisensory gamma stimulation mitigates the effects of demyelination induced by cuprizone in male mice.

Demyelination is a common pathological feature in a wide range of diseases, characterized by the loss of myelin sheath and myelin-supporting oligodendrocytes. These losses lead to impaired axonal function, increased vulnerability of axons to damage, and result in significant brain atrophy and neuro-axonal degeneration. Multiple pathomolecular processes contribute to neuroinflammation, oligodendrocyte cell death, and progressive neuronal dysfunction. In this study, we use the cuprizone mouse model of demyelination to investigate long-term non-invasive gamma entrainment using sensory stimulation as a potential therapeutic intervention for promoting myelination and reducing neuroinflammation in male mice. Here, we show that multisensory gamma stimulation mitigates demyelination, promotes oligodendrogenesis, preserves functional integrity and synaptic plasticity, attenuates oligodendrocyte ferroptosis-induced cell death, and reduces brain inflammation. Thus, the protective effects of multisensory gamma stimulation on myelin and anti-neuroinflammatory properties support its potential as a therapeutic approach for demyelinating disorders.

Emergent Management of Central Nervous System Demyelinating Disorders.

OBJECTIVE: This article reviews the various conditions that can present with acute and severe central nervous system demyelination, the broad differential diagnosis of these conditions, the most appropriate diagnostic workup, and the acute treatment regimens to be administered to help achieve the best possible patient outcomes. LATEST DEVELOPMENTS: The discovery of anti-aquaporin 4 (AQP4) antibodies and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in the past two decades has revolutionized our understanding of acute demyelinating disorders, their evaluation, and their management. ESSENTIAL POINTS: Demyelinating disorders comprise a large category of neurologic disorders seen by practicing neurologists. In the majority of cases, patients with these conditions do not require care in an intensive care unit. However, certain disorders may cause severe demyelination that necessitates intensive care unit admission because of numerous simultaneous multifocal lesions, tumefactive lesions, or lesions in certain brain locations that lead to acute severe neurologic dysfunction. Intensive care may be necessary for the management and prevention of complications for patients who have severely altered mental status, rapidly progressive neurologic worsening, elevated intracranial pressure, severe cerebral edema, status epilepticus, or respiratory failure.

Extracellular vesicles containing miR-181a-5p as a novel therapy for experimental autoimmune encephalomyelitis-induced demyelination.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system. Recent research has revealed that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), containing specific miRNAs, possess immunomodulatory properties and have demonstrated therapeutic potential in the treatment of MS. This study aimed to investigate the role MSC-EVs, containing microRNA-181a-5p (miR-181a-5p) in both experimental autoimmune encephalomyelitis (EAE), an established animal model of MS, and lipopolysaccharide-stimulated BV2 microglia. We evaluated clinical symptoms and inflammatory responses in EAE mice following intrathecal injections of MSC-EVs. MSC-EVs containing miR-181a-5p were co-cultured with microglia to explore their impact on inflammation and cell pyroptosis. We validated the interaction between miR-181a-5p and its downstream regulators and conducted in vivo verification by injecting manipulated EVs containing miR-181a-5p into EAE mice. Our results demonstrated that MSC-EVs, containing miR-181a-5p reduced the clinical symptoms of EAE mice. Furthermore, we observed downregulation of miR-181a-5p in EAE model mice, and its expression was restored after treatment with MSC-EVs, which corresponded to suppressed microglial inflammation and pyroptosis. Additionally, EVs containing miR-181a-5p mitigated spinal cord injury and demyelination in EAE mice. Mechanistically, ubiquitin-specific protease 15 (USP15) exhibited high expression in EAE mice, and miR-181a-5p was specifically targeted and bound to USP15, thereby regulating the RelA/NEK7 axis. In conclusion, MSC-EVs containing miR-181a-5p inhibit microglial inflammation and pyroptosis through the USP15-mediated RelA/NEK7 axis, thus alleviating the clinical symptoms of EAE. These findings present a potential therapeutic approach for the treatment of MS.

Vagus nerve stimulation enhances remyelination and decreases innate neuroinflammation in lysolecithin-induced demyelination.

BACKGROUND: Current treatments for Multiple Sclerosis (MS) poorly address chronic innate neuroinflammation nor do they offer effective remyelination. The vagus nerve has a strong regulatory role in inflammation and Vagus Nerve Stimulation (VNS) has potential to affect both neuroinflammation and remyelination in MS. OBJECTIVE: This study investigated the effects of VNS on demyelination and innate neuroinflammation in a validated MS rodent model. METHODS: Lysolecithin (LPC) was injected in the corpus callosum (CC) of 46 Lewis rats, inducing a demyelinated lesion. 33/46 rats received continuously-cycled VNS (cVNS) or one-minute per day VNS (1minVNS) or sham VNS from 2 days before LPC-injection until perfusion at 3 days post-injection (dpi) (corresponding with a demyelinated lesion with peak inflammation). 13/46 rats received cVNS or sham from 2 days before LPC-injection until perfusion at 11 dpi (corresponding with a partial remyelinated lesion). Immunohistochemistry and proteomics analyses were performed to investigate the extend of demyelination and inflammation. RESULTS: Immunohistochemistry showed that cVNS significantly reduced microglial and astrocytic activation in the lesion and lesion border, and significantly reduced the Olig2+ cell count at 3 dpi. Furthermore, cVNS significantly improved remyelination with 57.4 % versus sham at 11 dpi. Proteomic gene set enrichment analyses showed increased activation of (glutamatergic) synapse pathways in cVNS versus sham, most pronounced at 3 dpi. CONCLUSION: cVNS improved remyelination of an LPC-induced lesion. Possible mechanisms might include modulation of microglia and astrocyte activity, increased (glutamatergic) synapses and enhanced oligodendrocyte clearance after initial injury.

Progressive demyelinating polyneuropathy after hematopoietic cell transplantation in metachromatic leukodystrophy: a case series.

Metachromatic leukodystrophy (MLD) is a neuro-metabolic disorder due to arylsulfatase A deficiency, causing demyelination of the central and peripheral nervous system. Hematopoietic cell transplantation (HCT) can provide a symptomatic and survival benefit for pre-symptomatic and early symptomatic patients by stabilizing CNS disease. This case series, however, illustrates the occurrence of severely progressive polyneuropathy shortly after HCT in two patients with late-infantile, one with late-juvenile, and one with adult MLD, leading to the inability to walk or sit without support. The patients had demyelinating polyneuropathy before HCT, performed at the ages of 2 years in the first two patients and at 14 and 23 years in the other two patients. The myeloablative conditioning regimen consisted of busulfan, fludarabine and, in one case, rituximab, with anti-thymocyte globulin, cyclosporine, steroids, and/or mycophenolate mofetil for GvHD prophylaxis. Polyneuropathy after HCT progressed parallel with tapering immunosuppression and paralleled bouts of infection and graft-versus-host disease (GvHD). Differential diagnoses included MLD progression, neurological GvHD or another (auto)inflammatory cause. Laboratory, electroneurography and pathology investigations were inconclusive. In two patients, treatment with immunomodulatory drugs led to temporary improvement, but not sustained stabilization of polyneuropathy. One patient showed recovery to pre-HCT functioning, except for a Holmes-like tremor, for which a peripheral origin cannot be excluded. One patient showed marginal response to immunosuppressive treatment and died ten months after HCT due to respiratory failure. The extensive diagnostic and therapeutic attempts highlight the challenge of characterizing and treating progressive polyneuropathy in patients with MLD shortly after HCT. We advise to consider repeat electro-neurography and possibly peripheral nerve biopsy in such patients. Nerve conduction blocks, evidence of the presence of T lymphocytes and macrophages in the neuronal and surrounding nerve tissue, and beneficial effects of immunomodulatory drugs may indicate a partially (auto)immune-mediated pathology. Polyneuropathy may cause major residual disease burden after HCT. MLD patients with progressive polyneuropathy could potentially benefit from a more intensified immunomodulatory drug regime following HCT, especially at times of immune activation.

Efficacy and comparison of corticosteroids only and corticosteroids with plasmapheresis or intravenous immunoglobulin for the treatment of optic neuritis in demyelinating disease: A systematic review and network meta-analysis.

PURPOSE: To compare the efficacy of treatment of optic neuritis (ON) with corticosteroids (CTC) alone, CTC+plasmapheresis (PLP), and CTC+intravenous immunoglobulin (IVIG). DESIGN: After an episode of ON, although visual recovery is usually good, some patients may have significant visual sequelae. While the efficacy of first-line CTC is now indisputable, there is no consensus on the nature of second-line treatment. To date, no systematic review has compared the efficacy of treatment of ON with CTC alone, CTC+plasmapheresis (PLP), and CTC+intravenous immunoglobulin (IVIG). A meta-analysis is needed to compare the efficacy of PLP and IVIG in steroid-resistant ON. METHODS: This systematic review included all studies comparing at least two of the three treatments for steroid-resistant ON (CTC alone, CTC+PLP, and CTC+IVIG). From all articles published on PubMed between January 2000 and June 2022, two independent ophthalmologists selected studies of interest using the PRISMA method. Methodology, patient characteristics, and outcomes were identified. A network metaanalysis was then performed to compare the efficacy of the three treatments. RESULTS: Six comparative studies were included, representing 209 patients. The percentage of significant visual recovery after CTC alone, CTC+PLP, and CTC+IVIG in the acute treatment of steroid-resistant ON was 30 %, 45 %, and 77 %, respectively. Comparison of CTC+IVIG vs CTC alone, CTC+PLP vs CTC only, and CTC+PLP vs CTC+IVIG yielded odds ratios of 12.81, 2.47, and 0.19 respectively. CONCLUSION: Treatment of steroid-resistant ON with CTC+PLP or CTC+IVIG is more effective than treatment with CTC alone. Although no study has directly compared the two treatments, IVIG may be more effective than PLP.

Engineered PDGFA-ligand-modified exosomes delivery T3 for demyelinating disease targeted therapy.

Demyelination is a proper syndrome in plenty of central nervous system (CNS) diseases, which is the main obstacle to recovery and still lacks an effective treatment. To overcome the limitations of the brain-blood barrier on drug permeability, we modified an exosome secreted by neural stem cells (NSCs), which had transfected with lentivirus armed with platelet-derived growth factors A (PDGFA)-ligand. Through the in vivo and in vitro exosomes targeting test, the migration ability to the lesion areas and OPCs significantly improved after ligand modification. Furthermore, the targeted exosomes loaded with 3,5, 30-L-triiodothyronine (T3) have a critical myelination ability in CNS development, administrated to the cuprizone animal model treatment. The data shows that the novel drug vector loaded with T3 significantly promotes remyelination compared with T3 alone. At the same time, it improved the CNS microenvironment by reducing astrogliosis, inhibiting pro-inflammatory microglia, and alleviating axon damage. This investigation provides a straightforward strategy to produce a targeting exosome and indicates a possible therapeutic manner for demyelinating disease.

Clinical and radiological characteristics and outcomes of patients with recurrent or relapsing tumefactive demyelination.

BACKGROUND: Relapsing or recurrent tumefactive demyelination is rare and has not been studied beyond individual case reports. OBJECTIVE: We examined the clinical course, neuroimaging, cerebrospinal fluid (CSF), treatment and outcomes of patients with recurrent tumefactive demyelinating lesions (TDLs). METHODS: We used PubMed to identify reports of recurrent TDLs and included the details of an additional, unpublished patient. RESULTS: We identified 18 cases (11F, 7 M). The median age at onset of the index TDL was 37 years (range 12-72) and most were solitary lesions 72 % (13/18). CSF-restricted oligoclonal bands (OCBs) were detected in 25 % (4/16). Only one of those tested (n = 13) was positive for AQP4-IgG. A moderate-to-marked treatment response (high dose corticosteroid with or without additional plasmapheresis, IVIg or disease modifying therapies) was evident in 89 % of treated patients. Median EDSS at the median follow-up of 36 months (range 6-144) was 2 (range 1-10). Most remained ambulatory (EDSS < 4 in 13/18), but 1 patient died. CONCLUSION: The median age of patients with relapsing TDLs is similar to that of typical MS, but differences include a lower female:male sex ratio, larger lesions, and a comparative lack of CSF-restricted OCBs. Outcomes vary among this group of patients ranging from minimal disability through to death.

Impacto de la pandemia COVID-19 en pacientes con enfermedades desmielinizantes / IMPACT OF THE COVID-19 PANDEMIC ON PATIENTS WITH DEMYELINIZING DISEASES

Introducción: A más de un año del inicio de la pandemia, el seguimiento y la atención presencial de pacientes con enfermedades desmielinizantes se ha visto modificado. Según la evidencia, pacientes con diagnóstico de esclerosis múltiple (EM), síndrome desmielinizante aislado (SDA), Síndrome Radiológico Aislado (SRA) o enfermedades del espectro de neuromielitis óptica (NMO) no parecen ser un grupo de riesgo para COVID19 por el hecho de tener la enfermedad. La presencia de ciertas condiciones puede hacerlos susceptibles de cursar infección severa. Se ha descripto una asociación de curso grave con drogas anti CD20, faltan datos sobre la respuesta a vacunas COVID19 en esta población. Objetivos: Establecer características clínico-epidemiológicas de pacientes con enfermedades desmielinizantes que han padecido COVID-19 y describir su evolución. Caracterizar población vacunada, evaluar acceso al seguimiento médico/ terapéutico durante la pandemia. Materiales y métodos: Estudio observacional descriptivo. Se revisaron las historias clínicas de 168 pacientes con EM, SDA y SRA y 33 pacientes con NMO correspondientes al Hospital de Clínicas José de San Martin. Mediante encuesta telefónica se evaluó adherencia al tratamiento, evolución clínica, infección COVID-19, vacunación y acceso durante la pandemia. Resultados: Se encontraron 49 pacientes que desarrollaron COVID-19 en el grupo de pacientes con EM, y 7 en el grupo de NMO. Del primer grupo ninguno requirió internación, mientras que en el segundo, 2 fueron hospitalizados y uno de ellos falleció. La complicación post-COVID más frecuente fue: astenia prolongada y 3 pacientes presentaron un brote de la enfermedad de base en los 3 meses posteriores. Cerca del 90% de nuestra población ya contaba con al menos 1 dosis de vacuna para SARS-CoV2. Se interrogó sobre el acceso a la consulta neurológica y casi el 70% de los pacientes otorgó máximo puntaje al acceso a consultas virtuales. Conclusión: Los pacientes con enfermedades desmielinizantes que cursaron COVID-19 no tuvieron complicaciones severas por la infección, con solamente 2 pacientes cursando un brote en los 3 meses posteriores. No observamos reacciones adversas severas post vaccinales, ni infección posterior, sólo 2 pacientes presentaron un brote en el período post aplicación. Gran cantidad de pacientes percibieron acceso fluido a sus neurólogos de manera virtual, lo que podría relacionarse con alta tasa de adherencia a sus tratamientos a pesar de la limitación a la consulta presencial.

Introduction: More than a year after the start of the pandemic, the follow-up and face-to-face care of patients with demyelinating diseases has been modified. According to the evidence, patients with a diagnosis of multiple sclerosis (MS), isolated demyelinating syndrome (ADS), Isolated Radiological Syndrome (RAS) or neuromyelitis optica (NMO) spectrum diseases do not seem to be a risk group for COVID19 due to the fact that they have the disease. The presence of certain conditions can make them susceptible to severe infection. A severe course association with anti-CD20 drugs has been described, data on the response to COVID19 vaccines in this population are lacking. Objectives: To establish clinical-epidemiological characteristics of patients with demyelinating diseases who have suffered from COVID-19 and describe their evolution. Characterize the vaccinated population, evaluate access to medical/therapeutic follow-up during the pandemic. Materials and methods: Descriptive observational study. The medical records of 168 patients with MS, ADS and ARS and 33 patients with NMO corresponding to the Hospital de Clínicas José de San Martin were reviewed. Through a telephone survey, adherence to treatment, clinical evolution, COVID-19 infection, vaccination, and access during the pandemic were evaluated. Results: 49 patients who developed COVID-19 were found in the MS patient group, and 7 in the NMO group. Of the first group, none required hospitalization, unlike in the second, 2 were hospitalized and one of them died. The most frequent post-COVID complication was: prolonged asthenia and 3 patients presented an outbreak of the underlying disease in the following 3 months. Close to 90% of our population already had at least 1 dose of SARS-CoV2 vaccine. Access to the neurological consultation was questioned and almost 70% of the patients gave the highest score to access to virtual consultations. Conclusion: Patients with demyelinating diseases who had COVID-19 did not have severe complications from the infection, with only 2 patients having an outbreak in the subsequent 3 months. We did not observe severe post-vaccinal adverse reactions, nor subsequent infection, only 2 patients presented an outbreak in the post-application period. A large number of patients perceived fluid access to their neurologists virtually, which could be related to a high rate of adherence to their treatments despite the limitation to face-to-face consultation

A case of tumor-like inflammatory demyelinating disease with progressive brain and spinal cord involvement / Um caso de doença desmielinizante inflamatória semelhante a tumor com envolvimento progressivo de cérebro e medula espinhal

CONTEXT: Tumor-like inflammatory demyelinating disease (TIDD) usually occurs in the brain and rarely occurs in the spinal cord. TIDD appears to be very similar to tumors such as gliomas on imaging, which may lead to incorrect or delayed diagnosis and treatment. CASE REPORT: Because of headache and incoherent speech, a 24-year-old Chinese male presented to our hospital with a two-week history of respiratory infections. After dexamethasone treatment, his symptoms still got worse and surgery was performed for diagnostic purposes. Histological examination revealed that the lesion was inflammatory. Further lesions appeared in the spine (T3 and T4 levels) after two months and in the right occipital lobe after three months. After intravenous immunoglobulin (IVIG) and methylprednisolone treatment, his symptoms improved. CONCLUSION: Progressive lesions may damage the brain and spinal cord, and long-term prednisolone and IVIG therapy are beneficial in TIDD patients.

CONTEXTO: A doença desmielinizante inflamatória tumoral (DDIT) geralmente ocorre no cérebro e raramente na medula espinhal. A DDIT é muito semelhante a tumores tais como gliomas em exames de imagem, o que pode conduzir a diagnóstico e tratamento tardios e incorretos. RELATO DO CASO: Por causa de dor de cabeça e discurso incoerente, um homem chinês de 24 anos de idade foi ao hospital com história de duas semanas de infecções respiratórias. Após o tratamento com dexametasona, seus sintomas ficaram ainda piores e a cirurgia foi realizada para fins de diagnóstico. O exame histológico revelou que a lesão era inflamatória. Mais lesões apareceram na coluna vertebral (níveis T3 e T4) após dois meses, e no lobo occipital direito depois de três meses. Depois de tratamento com imunoglobulina intravenosa (IGIV) e metilprednisolona, seus sintomas melhoraram. CONCLUSÃO: Lesões progressivas podem danificar o cérebro e a medula espinhal, e prednisolona a longo prazo e terapia de IGIV são benéficas em pacientes DDIT.

Síndrome de Miller Fisher: presentación de un caso clínico / Miller Fisher syndrome: review of a clinic case

Presentamos el caso una paciente con síndrome de Miller Fisher, una entidad neurológica infrecuente considerada como una variante del síndrome de Guillain-Barre. El pronóstico aún sin terapéutica parece ser favorable. Se realiza una revisión bibliográfica haciendo particular énfasis en la ubicación de la lesión, métodos paraclínicos y tratamiento actual

Insuficiencia supra-renal na infancia associada a severas alteracoes do sistema nervoso central: relato de um caso de adrenoleucodistrofia / Supra-renal failure in infancy associated with severe alterations of central nervous system: a adrenoleukodystrophy case report

E apresentado um caso de adrenoleucodistrofia (ALD), doenca metabolica hereditaria ligada ao sexo e caracterizada por alteracoes no metabolismo de acidos graxos de cadeia muito longa (Very Long-Chain Fatty Acids - VLCFA), manifestando-se clinicamente por insuficiencia adrenal e anormalidades neurologicas progressivas. Sao discutidas a forma de apresentacao da doenca e o seu diagnostico, sendo enfatizada a importancia de ter-se presente a possibilidade de ALD em criancas portadoras de doenca de Addison, porque trata-se de molestia sujeita a intervencao terapeutica, com prevencao e ate regressao dos disturbios neurologicos