Recent advances on immunosuppressive drugs and remyelination enhancers for the treatment of multiple sclerosis

: Mammalian nervous systems depend crucially on myelin sheaths covering the axons. In the central nervous system, myelin sheaths consist of lipid structures which are generated from the membrane of oligodendrocytes (OL). These sheaths allow fast nerve transmission, protect axons and provide them metabolic support. In response to specific traumas or pathologies, these lipid structures can be destabilized and generate demyelinating lesions. Multiple sclerosis (MS) is an example of a demyelinating disease in which the myelin sheaths surrounding the nerve fibers of the brain and spinal cord are damaged. MS is the leading cause of neurological disability in young adults in many countries, and its incidence has been increasing in recent decades. Related to its etiology, it is known that MS is an autoimmune and inflammatory CNS disease. However, there are no effective treatments for this disease and the immunomodulatory therapies that currently exist have proven limited success since they only delay the progress of the disease. Nowadays, one of the main goals in the MS research is to find treatments which allows the recovery of neurological disabilities due to demyelination. To this end, different approaches, such as modulating intracellular signaling or regulating the lipid metabolism of OLs, are being considered. Here, in addition to immunosuppressive or immunomodulatory drugs that reduce the immune response against myelin sheaths, we review a diverse group of drugs that promotes endogenous remyelination in MS patients and whose use may be interesting as potential therapeutic agents in MS disease. To this end, we compile specific treatments against MS that are currently in the market with remyelination strategies which have entered into human clinical trials for future reparative MS therapies. The method used in this study is a systematic literature review on PubMed, Web of Science and Science Direct databases up to May 31, 2020. To narrow down the search results in databases, more specific keywords, such as, “myelin sheath”, “remyelination”, “demyelination”, “oligodendrocyte” and “lipid synthesis” were used to focus the search. We favoured papers published after January, 2015, but did not exclude earlier seminal papers.

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Tumor-Like Multiple Sclerosis: Report of Four Cases and Literature Review

Tumori Journal ◽

10.1177/030089160609200619 ◽

2006 ◽

Vol 92 (6) ◽

pp. 559-562 ◽

Cited By ~ 5

Author(s):

Emanuela Caroli ◽

Maurizio Salvati ◽

Luigi Ferrante

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Nervous System ◽

Demyelinating Disease ◽

Brain Lesion ◽

Mri Scan ◽

Cerebral Tumor ◽

Demyelinating Lesions ◽

The Central Nervous System ◽

Demyelinating Process

Aims and background Classical multiple sclerosis plaques usually have typical features on gadolinium-enhanced MRI scan. This non-neoplastic demyelinating process of the central nervous system generally does not produce focal space-occupying lesions associated with ring enhancement. However, atypical appearance of demyelinating lesions simulating a brain tumor is a possible well-known phenomenon. Methods We present our experience with 4 cases of multiple sclerosis indistinguishable clinically and neuroradiologically from a cerebral tumor. All patients underwent surgery. Results Histological examinations of all cases were positive for multiple sclerosis plaques. Conclusions The presented cases demonstrate the importance of considering a demyelinating disease in the differential diagnosis of a tumor-like brain lesion.

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Biology of the repair of central nervous system demyelinated lesions: an appraisal

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x1996000200026 ◽

1996 ◽

Vol 54 (2) ◽

pp. 331-334 ◽

Cited By ~ 3

Author(s):

L. A. V Peireira ◽

M. A. Cruz-Höfling ◽

M. S. J. Dertkigil ◽

D. L. Graça

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Schwann Cells ◽

Demyelinating Disease ◽

Experimental Models ◽

Primitive Cell ◽

Marked Influence ◽

Myelin Sheaths ◽

Human Material ◽

The Central Nervous System

The integrity of myelin sheaths is maintained by oligodendrocytes and Schwann cells respectively in the central nervous system (CNS) and in the peripheral nervous system. The process of demyelination consisting of the withdrawal of myelin sheaths from their axons is a characteristic feature of multiple sclerosis, the most common human demyelinating disease. Many experimental models have been designed to study the biology of demyelination and remyelination (repair of the lost myelin) in the CNS, due to the difficulties in studying human material. In the ethidium bromide (an intercalating gliotoxic drug) model of demyelination, CNS remyelination may be carried out by surviving oligodendrocytes and/or by cells differentiated from the primitive cell lines or either by Schwann cells that invade the CNS. However, some factors such as the age of the experimental animals, intensity and time of exposure to the intercalating chemical and the topography of the lesions have marked influence on the repair of the tissue.

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HIV infection and multiple sclerosis: a case with unexpected “no evidence of disease activity” status

Journal of International Medical Research ◽

10.1177/0300060521999577 ◽

2021 ◽

Vol 49 (3) ◽

pp. 030006052199957

Author(s):

Fernando Labella ◽

Fernando Acebrón ◽

María del Carmen Blanco-Valero ◽

Alba Rodrígez-Martín ◽

Ángela Monterde Ortega ◽

...

Keyword(s):

Multiple Sclerosis ◽

Hiv Infection ◽

Disease Activity ◽

Demyelinating Disease ◽

Clinical Course ◽

Disease Modifying Drugs ◽

Immunodeficiency Virus ◽

Relapsing Remitting ◽

The Central Nervous System ◽

Disease Modifying

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system whose etiology remains unclear. It has been suggested that MS can be triggered by certain viruses; however, human immunodeficiency virus (HIV) infection is associated with reduced incidence of MS. We present the case of a young patient diagnosed with active relapsing-remitting MS whose clinical course substantially improved following HIV infection and treatment. The patient achieved no evidence of disease activity status without any disease-modifying drugs. Both HIV-induced immunosuppression and antiretroviral therapy may have attenuated the clinical course in this patient.

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PECULIARITIES OF THE CLINICAL COURSE OF POSTMEASLES ENCEPHALITIS IN IMMUNOSUPRESSED PEOPLE

Proceedings of the Shevchenko Scientific Society. Medical Sciences ◽

10.25040/ntsh2021.01.06 ◽

2021 ◽

Vol 64 (1) ◽

Author(s):

Tetiana Nehrych ◽

◽

Maria Shorobura ◽

Irina Hritsyna ◽

Liliia Yukhimiv ◽

...

Keyword(s):

Multiple Sclerosis ◽

Monoclonal Antibodies ◽

Inclusion Body ◽

Bacterial Pneumonia ◽

Clinical Course ◽

Risk Group ◽

Neurological Complications ◽

Immunosuppressive Drugs ◽

The Central Nervous System ◽

The Brain

Primary acute measles encephalitis and acute postmeasles encephalitis are the most common neurological complications of measles. It is important to detect encephalitis, which develops a month or more after the manifestations of measles infection. These encephalitis are rare and occur mainly in people with immunodefi ciency. Multiple sclerosis is a chronic disease of the central nervous system for the treatment of which diseasemodifying therapy is used, namely monoclonal antibodies, that can lead to immunosuppression and immunodefi ciency. Nowadays, there is insuffi cient information about the course of postcortical encephalitis in patients with multiple sclerosis who are taking immunosuppressive drugs. The article presents data on the clinical classifi cation, diagnosis and treatment of measles encephalitis. A clinical case of measles inclusion body encephalitis in a thirty-threeyear-old patient with multiple sclerosis on the background of annual intake of monoclonal antibodies is presented. She also had viral-bacterial pneumonia and developed disseminated intravascular coagulation in the brain and lungs. These complications of measles infection led to the death of the person after a month and a half of intensive care. Thus, patients with multiple sclerosis who are taking drugs with immunosuppressive eff ects are among the risk group for measles inclusion body encephalitis. Measles inclusion body encephalitis in such patients can be severe, which complicates timely diagnosis, proper treatment and leads to death.

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Relapsing Tumefactive Demyelination: A Case Report

Acta Medica Academica ◽

10.5644/ama2006-124.231 ◽

2018 ◽

Vol 47 (2) ◽

pp. 193

Author(s):

Ibrahim Omerhodžić ◽

Almir Džurlić ◽

Dino Lisica ◽

Nevena Mahmutbegović ◽

Maida Nikšić ◽

...

Keyword(s):

Multiple Sclerosis ◽

Case Report ◽

Female Patient ◽

Demyelinating Disease ◽

Diagnostic Procedures ◽

Young Female ◽

Diagnostic Challenge ◽

Fresh Frozen ◽

The Central Nervous System ◽

Tumorlike Lesion

Objective. We present a case of relapsing tumefactive demyelination in a young female patient, that posed a real diagnostic challenge, with a heterogeneous clinical picture, atypical for multiple sclerosis (MS) presentation, and neuroradiological manifestations with a high suspicion of neoplastic diseases.Case Report. An 18-year old female patient presented to our Neurosurgical Out-patients’ Clinic with symptoms atypical for multiple sclerosis, unremarkable neurological deficit, one tumefactive lesion on MRI, followed by relapse and another two lesions within a period of six months. We decided to perform biopsy of the tumefactive lesion with compressive effect. Serological and clinical data were negative for MS, and the patient did not respond well to corticosteroid therapy. Fresh frozen tumor tissue aroused a strong suspicion of gemistocytic astrocytoma, so total resection was done, but the definitive pathohistological examination confirmed tumefactive demyelination.Conclusion. For clinicians, it is important to consider demyelinating disease in the differential diagnosis of a tumorlike lesion of the central nervous system, in order to avoid invasive and potentially harmful diagnostic procedures, especially in younger patients.

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Multiple Sclerosis

Neuropathic Pain ◽

10.1093/med/9780190298357.003.0024 ◽

2018 ◽

pp. 209-216

Author(s):

Samuel W. Samuel ◽

Jianguo Cheng

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Neuropathic Pain ◽

Demyelinating Disease ◽

Spontaneous Pain ◽

Disease Course ◽

The Central Nervous System ◽

Disease Modifying ◽

Multiple Treatments ◽

Surgical Treatments

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS). The diagnosis is based on evidence of at lease two different lesions in the CNS, at least two different episodes in the disease course, and chronic inflammation of the CNS as determined by analysis of the cerebrospinal fluid. Central neuropathic pain is the most common form of pain in patients with MS, with an estimated prevalence of about 50%. Along with the classical neuropathic pain features, such as spontaneous pain (dysesthesia and burning) and evoked pain (allodynia and hyperalgesia), patients with MS may also suffer from intermittent neuropathic pain, such as trigeminal neuralgia, Lhermitte sign, and glossopharyngeal neuralgia. In addition to disease-modifying therapies of MS, multiple treatments are available to manage neuropathic pain secondary to MS, including medical, interventional, and surgical treatments with varying levels of evidence.

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Exome-Sequence Analyses of Four Multi-Incident Multiple Sclerosis Families

Genes ◽

10.3390/genes11090988 ◽

2020 ◽

Vol 11 (9) ◽

pp. 988

Author(s):

Tobias Zrzavy ◽

Fritz Leutmezer ◽

Wolfgang Kristoferitsch ◽

Barbara Kornek ◽

Christine Schneider ◽

...

Keyword(s):

Multiple Sclerosis ◽

Genome Wide Association Study ◽

Rare Variants ◽

Demyelinating Disease ◽

Phenotypic Variability ◽

Convincing Evidence ◽

Risk Variants ◽

Unbiased Manner ◽

The Central Nervous System ◽

Reduced Penetrance

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the Central Nervous System (CNS). Currently, it is estimated that 30–40% of the phenotypic variability of MS can be explained by genetic factors. However, low susceptibility variants identified through Genome Wide Association Study (GWAS) were calculated to explain about 50% of the heritability. Whether familial high-risk variants also contribute to heritability is a subject of controversy. In the last few years, several familial variants have been nominated, but none of them have been unequivocally confirmed. One reason for this may be that genetic heterogeneity and reduced penetrance are hindering detection. Sequencing a large number of MS families is needed to answer this question. In this study, we performed whole exome sequencing in four multi-case families, of which at least three affected individuals per family were analyzed. We identified a total of 138 rare variants segregating with disease in each of the families. Although no single variant showed convincing evidence for disease causation, some genes seemed particularly interesting based on their biological function. The main aim of this study was to provide a complete list of all rare segregating variants to provide the possibility for other researchers to cross-check familial candidate genes in an unbiased manner.

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Impact of Exercise on Immunometabolism in Multiple Sclerosis

Journal of Clinical Medicine ◽

10.3390/jcm9093038 ◽

2020 ◽

Vol 9 (9) ◽

pp. 3038 ◽

Cited By ~ 1

Author(s):

Remsha Afzal ◽

Jennifer K Dowling ◽

Claire E McCoy

Keyword(s):

Multiple Sclerosis ◽

Cell Function ◽

Immune Cell ◽

Therapeutic Benefits ◽

Demyelinating Lesions ◽

Inflammatory State ◽

Autoimmune Condition ◽

The Central Nervous System ◽

Axonal Degradation

Multiple Sclerosis (MS) is a chronic, autoimmune condition characterized by demyelinating lesions and axonal degradation. Even though the cause of MS is heterogeneous, it is known that peripheral immune invasion in the central nervous system (CNS) drives pathology at least in the most common form of MS, relapse-remitting MS (RRMS). The more progressive forms’ mechanisms of action remain more elusive yet an innate immune dysfunction combined with neurodegeneration are likely drivers. Recently, increasing studies have focused on the influence of metabolism in regulating immune cell function. In this regard, exercise has long been known to regulate metabolism, and has emerged as a promising therapy for management of autoimmune disorders. Hence, in this review, we inspect the role of key immunometabolic pathways specifically dysregulated in MS and highlight potential therapeutic benefits of exercise in modulating those pathways to harness an anti-inflammatory state. Finally, we touch upon current challenges and future directions for the field of exercise and immunometabolism in MS.

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Hypoperfusion of the Cerebral White Matter in Multiple Sclerosis: Possible Mechanisms and Pathophysiological Significance

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2008.72 ◽

2008 ◽

Vol 28 (10) ◽

pp. 1645-1651 ◽

Cited By ~ 66

Author(s):

Jacques De Keyser ◽

Christel Steen ◽

Jop P Mostert ◽

Marcus W Koch

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Adrenergic Receptors ◽

Perfusion Magnetic Resonance Imaging ◽

Cerebral White Matter ◽

Perivascular Spaces ◽

Axonal Loss ◽

Normal Appearing White Matter ◽

Demyelinating Lesions ◽

The Central Nervous System

Multiple sclerosis (MS) is a disease of the central nervous system characterized by patchy areas of demyelination, inflammation, axonal loss and gliosis, and a diffuse axonal degeneration throughout the so-called normal-appearing white matter (NAWM). A number of recent studies using perfusion magnetic resonance imaging in both relapsing and progressive forms of MS have shown a decreased perfusion of the NAWM, which does not appear to be secondary to axonal loss. The reduced perfusion of the NAWM in MS might be caused by a widespread astrocyte dysfunction, possibly related to a deficiency in astrocytic β2-adrenergic receptors and a reduced formation of cAMP, resulting in a reduced uptake of K+ at the nodes of Ranvier and a reduced release of K+ in the perivascular spaces. Pathologic and imaging studies suggest that ischemic changes might be involved in the development of a subtype of focal demyelinating lesions (type III lesions), and there appears to exist a relationship between decreased white matter perfusion and cognitive dysfunction in patients with MS.

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Multiple sclerosis attacks are associated with picornavirus infections

Multiple Sclerosis Journal ◽

10.1191/1352458504ms1005oa ◽

2004 ◽

Vol 10 (2) ◽

pp. 145-148 ◽

Cited By ~ 21

Author(s):

John D Kriesel ◽

Andrea White ◽

Frederick G Hayden ◽

S L Spruance ◽

Jack Petajan

Keyword(s):

Multiple Sclerosis ◽

At Risk ◽

Demyelinating Disease ◽

Respiratory Infections ◽

Risk Period ◽

Relapsing Remitting ◽

The Central Nervous System ◽

Upper Respiratory ◽

Polymerase Chain

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system, which often follows a relapsing-remitting (RR) course with discrete attacks. MS attacks have been associated with upper respiratory infections (URIs), but the specific viruses responsible have not been identified. We studied a cohort of 16 RRMS patients experiencing URI and followed them for clinically identifiable attacks. The viral causes of 21 separate URIs were investigated using culture and polymerase chain reactio n (PCR) of nasal swab specimens, and by serology. Sibley’s ‘at-risk’ period for MS attacks, beginning two weeks before and continuing for five weeks after a URI, was used for the analysis. Seven of the nine (78%) URIs due to picornaviruses were associated with an MS attack during the at-risk period. By contrast, only two of 12 (17%) picornavirus-negative URIs were associated with an MS attack (P =0.01). The possible role of picornaviruses in the patho genesis of MS deserves further study.

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