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    Key Clinical Features of MS

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    Key Clinical Features of MS

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    36 views5 pages

    Key Clinical Features of MS

    Uploaded by

    dimitris698
    ms

    Copyright:

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    Download as PDF, TXT or read online from Scribd
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    of 5

    Chapter 1

    Introduction
    Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that produces demyelination and axonal/neuronal damage, resulting in characteristic multifocal lesions on magnetic resonance imaging (MRI) and a variety of neurologic manifestations (Figure 1). The clinical manifestations typically first develop in young adults as acute relapses, and then evolve into a gradually progressive course with permanent disability after 1015 years. It is important to make the diagnosis of MS accurately and expeditiously, to relieve uncertainty and allow institution of disease-modifying therapy. The purpose of therapy is to decrease relapses and MRI activity, with the ultimate goal of reducing the long-term risk of permanent disability. Furthermore, because
    Key clinical features of MS
    Typical onset is in the age range 2040 years Female predominance ~3:2 Neurologic manifestations reflect multifocal involvement of the CNS (brain, spinal cord, optic nerves) Non-focal manifestations (eg, cognitive impairment, mood disorders, pain, and fatigue) also significantly contribute to disability Relapsingremitting course at onset in 7080% of patients, usually evolving into a secondary progressive phase Progressive course from onset in ~20% of patients Most patients develop disability over 1015 years The range and severity of clinical manifestations have marked heterogeneity, both in individual patients over time and between patients Diagnosis is straightforward in typical patients, but differential diagnosis is extensive when there are atypical features Effective therapies are available and should be considered early to lessen the risk of permanent disability Treatment of symptoms and addressing psychosocial sequelae are important aspects of management Figure 1 Key clinical features of MS.

    J. A. Cohen et al., Handbook of Multiple Sclerosis Springer Healthcare, a part of Springer Science+Business Media 2010

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    of the myriad of potential manifestations that interfere with function and negatively impact quality of life, symptom management also is an important aspect of management.

    Pathology and pathogenesis


    The pathology of MS is characterized by multifocal lesions within the CNS, both in the white matter and gray matter (Figure 2), with perivenular inflammatory cell infiltrates, demyelination, axonal transection, neuronal degeneration, and gliosis (Figure 3) [1]. The pathogenesis of MS is complex and multifactorial [2]. Recently emerging concepts concerning MS pathogenesis are summarized in Figure 4. Traditional theory postulates that myelin-specific CD4+ T cells play a central role MS pathogenesis. Other T cell subsets, natural killer cells, monocytes/macrophages, B cells (both as producers of antibody and antigen-presenting cells), and humoral factors have been implicated. In addition, studies of a large number of biopsy and autopsy specimens suggested that the mechanisms leading to tissue damage differ from patient to patient [3]. Ongoing studies are investigating the relationship between pathogenic patterns, clinical and imaging characteristics, and response to therapy. Finally, it appears that inflammatory mechanisms predominate early in the disease (reflected most directly in clinical relapses and MRI lesion activity), but the gradual worsening in primary progressive MS and late in the disease in secondary progressive MS are due to neurodegeneration [4]. Intrinsic repair mechanisms function in MS and are effective early but, in most patients, over
    Pathology of MS
    A CSO cortex B

    CC white matter lesion LV CSO

    cortical lesion

    Figure 2 Pathology of MS. A, Demyelinated lesion in periventricular white matter; B, Demyelinated lesion in cortex. CSO, centrum semiovale; CC, corpus callosum; LV, lateral ventricle.

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    High power view of a white matter lesion in MS

    Figure 3 High power view of a white matter lesion in MS. This confocal micrograph shows demyelination (arrowheads) and axonal transection (arrow).

    time they become insufficient to compensate for ongoing damage, resulting in accrual of permanent disability. For example, oligodendrocyte precursors can be demonstrated in chronic lesions but appear unable to remyelinate dystrophic axons [5]. An important implication of these observations is that therapeutic strategies need to address multiple pathogenic mechanisms.

    Genetics
    Relatives of patients with MS are at increased risk for the disease (Figure 5), and several lines of evidence (Figure 6) indicate that MS has a genetic component [6]. However, the genetic basis of MS is complex (ie, multiple genes contribute cumulatively to the risk of MS and disease behavior) and is heterogeneous (ie, the genes and alleles involved probably differ from patient-to-patient). Genetic studies have most consistently implicated genes encoded in the class II region of the major histocompatibility complex (MHC) on chromosome 6,

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    Emerging concepts in pathogenesis of MS


    MRI studies demonstrate ongoing subclinical disease activity Pathology includes both demyelination and axonal damage, in both white and gray matter Pathogenesis is complex, including both T and B cell mechanisms Pathogenesis is heterogeneous, varying from patient to patient Pathogenesis is inflammatory early, and degenerative late and in purely progressive MS Compensatory mechanisms, repair and plasticity, are active early but fail late The underlying etiology remains unknown Figure 4 Emerging concepts in pathogenesis of MS.

    Population-based prevalence of MS in relatives of patients with MS


    Cohort General population Adopted siblings First cousin Sibling Child Offspring of conjugal MS pair Monozygotic twin Prevalence (per 1000) 1 1 7 35 197 200 270

    Figure 5 Population-based prevalence of MS in relatives of patients with MS. Adapted from Ebers [9].

    specifically the HLA-DR2 haplotype DRB1*1501-DQB1*0602. It is postulated that the MHCdisease association results from effects on antigen-presenting cells, altering immune reactivity to auto-antigens (possibly myelin-related auto-antigens). Recent studies also implicated a number of non-MHC genes, including those encoding components of the interleukin-2 and interleukin-7 receptors [7]. These molecules also would be expected to affect immune function or the tissue response to injury. It is likely that separate (though possibly overlapping) sets of genes determine the risk for developing MS and disease behavior [8]. Genes implicated in modifying MS disease behavior include alleles of HLA-DR2, APOE-4, neurotrophic factors, and chemokine receptors.

    Epidemiology
    The prevalence of MS is approximately 1/1000, affecting approximately 400,000 people in the US and 2 million worldwide [10]. It is the most common non-traumatic cause of neurologic disability in young adults. Onset typically is

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    Evidence that MS has genetic aspects


    MS is relatively common in people of Northern European descent and rare in Asians, Native Americans, and Gypsies The risk of MS is increased 20- to 30-fold in first-degree relatives and up to 500-fold in monozygotic twins Dizygotic twins have the same risk as siblings Adoptees and spouses have the same risk as unrelated individuals Genetic studies have implicated several loci, particularly the HLA-DR2 haplotype DRB1*1501DQB1*0602 Figure 6 Evidence that MS has genetic aspects. Adapted from Ebers [9].

    between the ages of 20 and 40 years, and women are affected more frequently than men (approximately 3:2). Approximately 70% of monozygotic twins are discordant for MS; ie, more than half of the monozygotic twins of patients with MS do not develop MS. This observation implies there is an interaction between the genetic propensity for MS and environmental factors. Epidemiologic studies demonstrated unequal geographic distribution of MS. There is a distinct latitude gradient: MS is relatively rare in the tropics and increases in prevalence with increasing latitude in both the northern and southern hemispheres. Migration studies suggest that the risk of acquiring MS is determined at the time of puberty or before. Postulated factors include infectious agents, diet, environmental toxins, and sunlight [9], but none has been definitively implicated.

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