The Cross Talk between Underlying Mechanisms of Multiple Sclerosis and Epilepsy May Provide New Insights for More Efficient Therapies

Rayatpour, Atefeh; Farhangi, Sahar; Verdaguer, Ester; Olloquequi, Jordi; Ureña, Jesús; Auladell, Carme; Javan, Mohammad

doi:10.3390/ph14101031

Cited by 16 publications

(5 citation statements)

References 192 publications

(216 reference statements)

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“…Myelin is constantly produced in the adult brain by oligodendrocytes in a plasticity-dependent manner and necessary for memory consolidation (Steadman et al, 2020). Myelination deficiencies have been found in several neurologic disorders in particular in multiple sclerosis (Nave and Werner, 2014) and are often associated with seizure occurrence (Rayatpour et al, 2021). There is increasing awareness that also in epilepsy maladaptive myelination or axon demyelination are of high relevance for seizure generation (De Curtis et al, 2021, Knowles et al, 2022.…”

Section: Discussionmentioning

confidence: 99%

Focal cortical dysplasia type II-dependent maladaptive myelination in the human frontal lobe

Donkels,

Huber,

Demerath

et al. 2024

Preprint

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Focal cortical dysplasias (FCDs) are local malformations of the human neocortex and a leading cause of intractable epilepsy. FCDs are classified into different subtypes including FCD IIa and IIb, characterized by a blurred gray-white matter boundary or a transmantle sign indicating abnormal white matter myelination. Recently, we have shown that myelination is also compromised in the gray matter of FCD IIa of the temporal lobe. Since myelination is key for brain function, we investigated whether deficient myelination is a feature affecting also other FCD subtypes and brain areas. Here, we focused on the gray matter of FCD IIa and IIb from the frontal lobe. We appliedin situhybridization, immunohistochemistry and electron microscopy to quantify oligodendrocytes, to visualize the myelination pattern and to determine ultrastructurally the axon diameter and the myelin sheath thickness. In addition, we analyzed the transcriptional regulation of myelin-associated transcripts by real-time RT-qPCR and chromatin immunoprecipitation (ChIP). We show that densities of myelinating oligodendrocytes and the extension of myelinated fibers up to layer II were unaltered in both FCD types but myelinated fibers appeared fractured mainly in FCD IIa. Interestingly, both FCD types presented with larger axon diameters when compared to controls. A significant correlation of axon diameter and myelin sheath thickness was found for FCD IIb and controls, whereas in FCD IIa large caliber axons were less myelinated. This was mirrored by a down-regulation of myelin-associated mRNAs and by reduced binding-capacities of the transcription factor MYRF to promoters of myelin-associated genes. FCD IIb, however, had significantly elevated transcript levels and MYRF-binding capacities reflecting the need for more myelin due to increased axon diameters. These data show that FCD IIa and IIb are characterized by divergent signs of maladaptive myelination which may contribute to the epileptic phenotype and underline the view of separate disease entities.

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Section: Discussionmentioning

confidence: 99%

Focal cortical dysplasia type II-dependent maladaptive myelination in the human frontal lobe

Donkels,

Huber,

Demerath

et al. 2024

Preprint

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“…Therefore, in the context of MS, seizures may exacerbate demyelination, reflecting the fact that the two diseases share some common pathophysiology. Understanding the pathological processes underlying this relationship will allow us to target common and shared pathological pathways associated with both diseases, which may lead to new approaches to the treatment of these neurological disorders [33].…”

Section: Age and Gender Characteristicsmentioning

confidence: 99%

“…As it was determined in a retrospective study of the Swedish population registry, which included 514, 545 patients with MS, the incidence of epilepsy grew with the increase in the duration and severity of the major disease, with its progressive course, and was dependent on the effect of drug therapy for MS [31]. In addition to MS, several studies have reported seizures in other demyelinating disorders, such as myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and progressive multifocal leukoencephalopathy [32,33].…”

Section: Introductionmentioning

confidence: 99%

Comorbidity of Multiple Sclerosis and Epilepsy: More Questions or Answers?

Maryenko,

Litovchenko,

Nehrych

et al. 2023

Proc Shevchenko Sci Soc Med Sci

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The literature data of the last three decades on the problem of comorbidity of multiple sclerosis (MS) and epilepsy have been analyzed, such as issues of pathogenesis, clinical course, prognosis, and treatment of this dual pathology. Epileptic seizures occur in 2–3% to 5.9% of patients with MS, which is 3–6 times more common than in the general population. The incidence of epilepsy raises with increasing duration and severity of MS, with its progressive course, and also depends on the effect of drugs for the treatment of MS. There is no unanimity in the literature on the age and gender characteristics of the occurrence of epileptic seizures in MS. Probable mechanisms of MS comorbidity and epilepsy are analyzed. Data on certain common pathophysiology of MS and epilepsy and the concept according to which the model of epilepsy in MS is considered as a network disease are presented. Data on clinical manifestations and diagnosis of comorbid MS with epilepsy are presented. Epileptic seizures can occur at any stage of MS: before the clinical manifestations, at the onset of the disease, in the late stages, or can indicate exacerbation of MS. Types of epileptic seizures with a dual diagnosis (MS + epilepsy) are diverse. The majority of patients (up to 87.5%) have focal seizures (aware or unaware) or focal seizures to bilateral tonic-clonic, and a small share of patients have seizures of unknown origin. Most researchers believe that patients with MS and epilepsy have a more severe MS course and a worse long-term prognosis. The main directions of MS treatment and the impact of such treatment on the development of epileptic seizures are highlighted. Data on the effect of some disease-modifying drugs for the treatment of MS on the course of epilepsy and, on the other hand, on the impact of some antiseizure medications on the course of MS are presented. It is concluded that patients with MS have individual profiles and inter-individual variability of epileptogenicity. The principles of treatment of epileptic seizures/epilepsy in patients with MS are proposed.

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“…The distribution of MS lesions may be related to cognitive impairment, recurrent seizures, or status epilepticus (90). Cortical or juxtacortical lesions have been found to be a precipitating factor for epileptic seizures in patients with MS in multiple studies (91,92).…”

Section: The Role Of Imagistic Techniques In Studying the Ms-epilepsy...mentioning

confidence: 99%

Seizures and multiple sclerosis‑more than an epidemiological association (Review)

Antal

Schreiner

Crihan³

et al. 2022

Exp Ther Med

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In order to increase the quality of life of patients with epilepsy, it is essential to develop tools that facilitate early disease diagnosis and encourage the use of individualized therapies. The association between seizures and other neurological pathologies is well known but incompletely explained, with multiple sclerosis (MS)-seizures correlation being a relevant example. In this context, the present review aimed to highlight the most important facts related to the association between the heterogeneous group of epileptic pathology and MS, in order to provide initial directions for establishing a diagnostic and therapeutic protocol. The first part reviewed the most relevant epidemiological and clinical data on seizures; MS association. Subsequently, it highlighted the most common and actually accepted pathophysiological mechanisms that try to explain the association between the two pathologies. Finally, the importance of paraclinical investigations and the optimal choice of antiseizure-based therapies with respect to seizures associated with MS are presented, also revealing several directions that should be explored in the near future. Contents 1. Introduction 2. Methodology and method 3. Epidemiological data revealing a significant association between MS and seizures 4. Relevant aspects of seizures in patients with MS 5. Pathophysiological mechanisms (incompletely) explaining the MS-epilepsy association 6. The role of imagistic techniques in studying the MS-epilepsy association 7. Neurophysiology in patients with MS with epilepsy-in search of specific patterns 8. Individualized ASMs treatment and prognosis in patients with MS with epilepsy 9. Conclusions

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The Cross Talk between Underlying Mechanisms of Multiple Sclerosis and Epilepsy May Provide New Insights for More Efficient Therapies

Cited by 16 publications

References 192 publications

Focal cortical dysplasia type II-dependent maladaptive myelination in the human frontal lobe

Focal cortical dysplasia type II-dependent maladaptive myelination in the human frontal lobe

Comorbidity of Multiple Sclerosis and Epilepsy: More Questions or Answers?

Seizures and multiple sclerosis‑more than an epidemiological association (Review)

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