Heterogeneity in Multiple Sclerosis: Scratching the Surface of a Complex Disease

Multiple Sclerosis (MS) is the most common demyelinating disease of the central nervous system. Although the etiology and the pathogenesis of MS has been extensively investigated, no single pathway, reliable biomarker, diagnostic test, or specific treatment have yet been identified for all MS patients. One of the reasons behind this failure is likely to be the wide heterogeneity observed within the MS population. The clinical course of MS is highly variable and includes several subcategories and variants. Moreover, apart from the well-established association with the HLA-class II DRB1*15:01 allele, other genetic variants have been shown to vary significantly across different populations and individuals. Finally both pathological and immunological studies suggest that different pathways may be active in different MS patients. We conclude that these “MS subtypes” should still be considered as part of the same disease but hypothesize that spatiotemporal effects of genetic and environmental agents differentially influence MS course. These considerations are extremely relevant, as outcome prediction and personalised medicine represent the central aim of modern research.

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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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Absence of Multiple Sclerosis and Demyelinating Diseases among Lacandonians, a Pure Amerindian Ethnic Group in Mexico

Multiple Sclerosis International ◽

10.1155/2012/292631 ◽

2012 ◽

Vol 2012 ◽

pp. 1-4 ◽

Cited By ~ 8

Author(s):

Jose Flores ◽

Silvia González ◽

Ximena Morales ◽

Petra Yescas ◽

Adriana Ochoa ◽

...

Keyword(s):

Multiple Sclerosis ◽

Ethnic Group ◽

Complex Disease ◽

Demyelinating Disease ◽

Family Background ◽

Clinical Signs ◽

Signs And Symptoms ◽

Structured Interview ◽

Demyelinating Diseases ◽

Environmental Agents

Multiple Sclerosis (MS) is a highly polymorphic disease characterized by different neurologic signs and symptoms. In MS, racial and genetic factors may play an important role in the geographic distribution of this disease. Studies have reported the presence of several protective alleles against the development of autoimmune disorders. In the case of MS, however, they help define MS as a complex disease, and confirm the importance of environmental agents as an independent variable not associated with ethnicity. We carried out an on-site epidemiological study to confirm the absence of MS or NMO among Lacandonians, a pure Amerindian ethnic group in Mexico. We administered a structured interview to 5,372 Lacandonians to assess by family background any clinical data consistent with the presence of a prior demyelinating event. Every participating subject underwent a comprehensive neurological examination by a group of three members of the research team with experience in the diagnosis and treatment of demyelinating disorders to detect clinical signs compatible with a demyelinating disease. We did not find any clinical signs compatible with multiple sclerosis among study participants.

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Multiple Sclerosis Biomarker Discoveries by Proteomics and Metabolomics Approaches

Biomarker Insights ◽

10.1177/11772719211013352 ◽

2021 ◽

Vol 16 ◽

pp. 117727192110133

Author(s):

Ameneh Jafari ◽

Amirhesam Babajani ◽

Mostafa Rezaei-Tavirani

Keyword(s):

Multiple Sclerosis ◽

Complex Disease ◽

Biomarker Discovery ◽

Response To Treatment ◽

Inflammatory Disorder ◽

Protein Marker ◽

Complex Disorders ◽

New Information ◽

The Central Nervous System ◽

Monitoring Treatment

Multiple sclerosis (MS) is an autoimmune inflammatory disorder of the central nervous system (CNS) resulting in demyelination and axonal loss in the brain and spinal cord. The precise pathogenesis and etiology of this complex disease are still a mystery. Despite many studies that have been aimed to identify biomarkers, no protein marker has yet been approved for MS. There is urgently needed for biomarkers, which could clarify pathology, monitor disease progression, response to treatment, and prognosis in MS. Proteomics and metabolomics analysis are powerful tools to identify putative and novel candidate biomarkers. Different human compartments analysis using proteomics, metabolomics, and bioinformatics approaches has generated new information for further clarification of MS pathology, elucidating the mechanisms of the disease, finding new targets, and monitoring treatment response. Overall, omics approaches can develop different therapeutic and diagnostic aspects of complex disorders such as multiple sclerosis, from biomarker discovery to personalized medicine.

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

Current Pharmaceutical Design ◽

10.2174/1381612827666210127121829 ◽

2021 ◽

Vol 27 ◽

Author(s):

Jennifer Cadenas-Fernández ◽

Pablo Ahumada-Pascual ◽

Luis Sanz Andreu ◽

Ana Velasco

Keyword(s):

Multiple Sclerosis ◽

Intracellular Signaling ◽

Demyelinating Disease ◽

Lipid Synthesis ◽

Immunosuppressive Drugs ◽

Nerve Fibers ◽

Myelin Sheaths ◽

Demyelinating Lesions ◽

The Central Nervous System ◽

Lipid Structures

: 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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The nervous form of canine distemper

Veterinária e Zootecnia ◽

10.35172/rvz.2006.v13.258 ◽

2018 ◽

Vol 13 (2) ◽

pp. 125-136

Author(s):

Alice Fernandes Alfieri ◽

Alexandre Mendes Amude ◽

Amauri Alcindo Alfier

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Canine Distemper Virus ◽

Demyelinating Disease ◽

Clinical Course ◽

Systemic Infection ◽

Canine Distemper ◽

Systemic Involvement ◽

Clinical Syndromes ◽

The Central Nervous System

Canine distemper is a systemic infection, frequently lethal in dogs. The canine distemper virus(CDV) causes a persistent infection within the central nervous system resulting in aprogressive, multifocal demyelinating disease. In dogs, CDV infection may lead togastrointestinal and/or respiratory signs, frequently with central nervous system involvement.Myoclonus has been a common and characteristic sign observed in dogs with distemperencephalomyelitis. However, the nervous form of distemper may occur in the absence ofmyoclonus and systemic involvement. This review will point the clinical course and theneurological signs of nervous distemper, as well the clinical syndromes of CDV infection,neuropathology of acute and chronic demyelination, and diagnostic aids of CDVencephalomyelitis.

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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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A Review of Various Antioxidant Compounds and their Potential Utility as Complementary Therapy in Multiple Sclerosis

Nutrients ◽

10.3390/nu11071528 ◽

2019 ◽

Vol 11 (7) ◽

pp. 1528 ◽

Cited By ~ 15

Author(s):

Elzbieta Dorota Miller ◽

Angela Dziedzic ◽

Joanna Saluk-Bijak ◽

Michal Bijak

Keyword(s):

Oxidative Stress ◽

Multiple Sclerosis ◽

Complex Disease ◽

Early Stage ◽

Symptomatic Treatment ◽

Complementary Therapy ◽

Antioxidant Compounds ◽

Inflammatory Processes ◽

The Central Nervous System ◽

Stress Mediators

Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS). The etiology of this multifactorial disease has not been clearly defined. Conventional medical treatment of MS has progressed, but is still based on symptomatic treatment. One of the key factors in the pathogenesis of MS is oxidative stress, enhancing inflammation and neurodegeneration. In MS, both reactive oxygen and nitrogen species are formed in the CNS mainly by activated macrophages and microglia structures, which can lead to demyelination and axon disruption. The course of MS is associated with the secretion of many inflammatory and oxidative stress mediators, including cytokines (IL-1b, IL-6, IL-17, TNF-α, INF-γ) and chemokines (MIP-1a, MCP-1, IP10). The early stage of MS (RRMS) lasts about 10 years, and is dominated by inflammatory processes, whereas the chronic stage is associated with neurodegenerative axon and neuron loss. Since oxidative damage has been known to be involved in inflammatory and autoimmune-mediated processes, antioxidant therapy could contribute to the reduction or even prevention of the progression of MS. Further research is needed in order to establish new aims for novel treatment and provide possible benefits to MS patients. The present review examines the roles of oxidative stress and non-pharmacological anti-oxidative therapies in MS.

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