Abstract
Recent studies have better defined the association between the human leukocyte antigen (HLA)-DR, cytotoxic T-lymphocyte antigen-4, interleukin-7 receptor, and interferon-gamma polymorphisms and susceptibility to multiple sclerosis (MS), while many more studies have been added to the controversial pool of likely false-positive and false-negative genetic association and linkage studies. Apolipoprotein E alleles may yet play an important role in disease course and cognitive impairment, although largely refuted as being directly associated with ambulatory measures of disease severity. Natural history studies have started to better define the clinical phenotypic heterogeneity of idiopathic inflammatory diseases of the central nervous system, fueling new hypotheses about immunopathogenesis of MS. Our understanding of phenotype measurement tools is improving. However, despite all the ongoing effort, the cause of MS and the determinants of heterogeneity in the clinical phenotype of MS remain largely unknown. As advances in our understanding of the immunobiology of MS start to bridge the gap between pathological and clinical natural history of the disease, biologically relevant phenotypes of MS will hopefully emerge to allow more specific treatment modalities to be developed and brought to practice.
Introduction
Multiple sclerosis (MS) belongs to a heterogenous spectrum of idiopathic inflammatory demyelinating diseases of the central nervous system (CNS) that vary from each other by pathology, lesion characteristics (extent, location, size, and number), time course of disease evolution, and clinical outcome ( Table 1 , Fig. 1). Pathological differences of individual idiopathic inflammatory demyelinating diseases have recently been reviewed.[1]
The dynamic natural history of idiopathic inflammatory demyelinating diseases of the central nervous system (CNS) in relation to disease severity as defined by the EDSS score. Idiopathic inflammatory demyelinating diseases are defined in two axes of disease severity: (1) as a function of pathological extent ranging from limited-restricted CNS involvement to multifocal or diffuse disease and pathological severity ranging from inflammation to necrosis (Y axis); and (2) as a function of time-dependent balance between predominant demyelination, extent of remyelination, and axonal loss (X axis).
Natural history defines the study of clinical evolution and outcome of individual syndromes in the absence of any disease-modifying treatment modalities. Being able to diagnose these syndromes separately constitutes probably the most important aspect of being able to predict the natural history because there is considerable variation in clinical outcome and response to treatment modalities by syndrome alone. Some of the individual idiopathic inflammatory demyelinating diseases, including acute disseminated encephalomyelitis (ADEM), acute transverse myelitis (ATM), and neuromyelitis optica (NMO), are extensively discussed in subsequent articles in this issue of Seminars of Neurology. Following the initial presentation, these syndromes may evolve (e.g., isolated ATM versus recurrent ATM or progressive myelopathy); however, surrogate markers are not always available to predict such an evolution.[2]
Diagnosis of MS is based on currently accepted consensus clinical and magnetic resonance imaging (MRI) criteria (McDonald criteria) requiring documentation of white matter disease disseminated in time and space ( Table 2 ).[3] However, some of the earlier studies referenced in this review have used the previous consensus criteria (Poser's criteria) for diagnosis of MS.[4] Although diagnostic criteria are essential for clinical trials, they do not necessarily encompass the full biological spectrum of MS. Furthermore, other idiopathic inflammatory demyelinating diseases (e.g., NMO) may fulfill the criteria for MS but represent a different disease process. Additionally, once a MS diagnosis is established, subsequent clinical manifestations and temporal course are heterogenous. This phenotypic heterogeneity likely results from complex interactions of multiple genetic, environmental, physiological, and pathological factors.[5,6]
This review discusses the current state of our understanding of genetic epidemiology of MS susceptibility and outcome, and the natural history of clinically isolated idiopathic inflammatory demyelinating diseases and MS in the context of predictors of disease outcome and disease course.
Recent studies have better defined the association between the human leukocyte antigen (HLA)-DR, cytotoxic T-lymphocyte antigen-4, interleukin-7 receptor, and interferon-gamma polymorphisms and susceptibility to multiple sclerosis (MS), while many more studies have been added to the controversial pool of likely false-positive and false-negative genetic association and linkage studies. Apolipoprotein E alleles may yet play an important role in disease course and cognitive impairment, although largely refuted as being directly associated with ambulatory measures of disease severity. Natural history studies have started to better define the clinical phenotypic heterogeneity of idiopathic inflammatory diseases of the central nervous system, fueling new hypotheses about immunopathogenesis of MS. Our understanding of phenotype measurement tools is improving. However, despite all the ongoing effort, the cause of MS and the determinants of heterogeneity in the clinical phenotype of MS remain largely unknown. As advances in our understanding of the immunobiology of MS start to bridge the gap between pathological and clinical natural history of the disease, biologically relevant phenotypes of MS will hopefully emerge to allow more specific treatment modalities to be developed and brought to practice.
Introduction
Multiple sclerosis (MS) belongs to a heterogenous spectrum of idiopathic inflammatory demyelinating diseases of the central nervous system (CNS) that vary from each other by pathology, lesion characteristics (extent, location, size, and number), time course of disease evolution, and clinical outcome ( Table 1 , Fig. 1). Pathological differences of individual idiopathic inflammatory demyelinating diseases have recently been reviewed.[1]
The dynamic natural history of idiopathic inflammatory demyelinating diseases of the central nervous system (CNS) in relation to disease severity as defined by the EDSS score. Idiopathic inflammatory demyelinating diseases are defined in two axes of disease severity: (1) as a function of pathological extent ranging from limited-restricted CNS involvement to multifocal or diffuse disease and pathological severity ranging from inflammation to necrosis (Y axis); and (2) as a function of time-dependent balance between predominant demyelination, extent of remyelination, and axonal loss (X axis).
Natural history defines the study of clinical evolution and outcome of individual syndromes in the absence of any disease-modifying treatment modalities. Being able to diagnose these syndromes separately constitutes probably the most important aspect of being able to predict the natural history because there is considerable variation in clinical outcome and response to treatment modalities by syndrome alone. Some of the individual idiopathic inflammatory demyelinating diseases, including acute disseminated encephalomyelitis (ADEM), acute transverse myelitis (ATM), and neuromyelitis optica (NMO), are extensively discussed in subsequent articles in this issue of Seminars of Neurology. Following the initial presentation, these syndromes may evolve (e.g., isolated ATM versus recurrent ATM or progressive myelopathy); however, surrogate markers are not always available to predict such an evolution.[2]
Diagnosis of MS is based on currently accepted consensus clinical and magnetic resonance imaging (MRI) criteria (McDonald criteria) requiring documentation of white matter disease disseminated in time and space ( Table 2 ).[3] However, some of the earlier studies referenced in this review have used the previous consensus criteria (Poser's criteria) for diagnosis of MS.[4] Although diagnostic criteria are essential for clinical trials, they do not necessarily encompass the full biological spectrum of MS. Furthermore, other idiopathic inflammatory demyelinating diseases (e.g., NMO) may fulfill the criteria for MS but represent a different disease process. Additionally, once a MS diagnosis is established, subsequent clinical manifestations and temporal course are heterogenous. This phenotypic heterogeneity likely results from complex interactions of multiple genetic, environmental, physiological, and pathological factors.[5,6]
This review discusses the current state of our understanding of genetic epidemiology of MS susceptibility and outcome, and the natural history of clinically isolated idiopathic inflammatory demyelinating diseases and MS in the context of predictors of disease outcome and disease course.
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