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Multiple Sclerosis Overview

Synonym: MS

, MD and , PhD.

Author Information
, MD
Department of Neurology
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas
, PhD
Department of Neurology
University of California, San Francisco
San Francisco, California

Initial Posting: ; Last Update: May 11, 2010.


Clinical characteristics.

Multiple sclerosis (MS) is an inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) of unknown etiology. The peak onset is between age 20 and 40 years; it may develop in children and has also been identified in persons over age 60 years. Women are affected approximately twice as often as men. The most common clinical signs and symptoms, occurring in isolation or in combination, include sensory disturbance of the limbs (~30%), partial or complete visual loss (~15%), acute and subacute motor dysfunction of the limbs (~13%), diplopia (7%), and gait dysfunction (5%). The course may be relapsing-remitting or progressive, severe or mild, and may involve the entire neuroaxis in a widespread fashion or predominantly affect the spinal cord and optic nerves. The four clinical phenotypes of MS are: relapsing-remitting MS (RR-MS) (initially occurring in more than 80% of individuals with MS); primary progressive MS (PP-MS) (occurring in 10%-20% of individuals with MS); progressive relapsing MS (PR-MS) (a rare form); and secondary progressive MS (SP-MS), to which approximately half of all persons diagnosed with RR-MS convert within a decade after the initial diagnosis.


Multiple sclerosis is primarily a clinical diagnosis. The RR-MS phenotype is diagnosed in individuals who have (1) at least two clinical attacks (each lasting ≥24 hours and separated by ≥1 month) or a slow, progressive course for at least six months, and (2) lesions in more than one area or functional system of the brain or spinal cord. Diagnostic criteria for PP-MS include a minimum period of clinical progression of at least 12 months and onset between age 25 and 65 years; three proposed categories include definite PP-MS, probable PP-MS, and possible PP-MS. More recent diagnostic criteria specifically integrate MRI with clinical and paraclinical methods.

Genetic counseling.

Available data suggest that multiple sclerosis is inherited as a complex multifactorial disorder that results from the interaction of genetic and environmental factors. Estimated risk to the sibs of a proband is 3.0%-5.0%, increasing to 29.5% if one or both parents have MS. Risk to the offspring of a person with MS is 2.0%-3.0% and higher if both parents have MS.


Treatment of manifestations: Agents used to treat MS decrease the clinical relapse rate and accompanying inflammation within the CNS. These agents include interferon beta-1b, interferon beta-1a, glatiramer acetate, mitoxantrone, and natalizumab. Various medications are utilized for symptomatic treatment of pain, muscle spasms, fatigue, depression, sexual dysfunction, and bladder and bowel dysfunction. Possible febrile infections require vigilance as they may exacerbate MS. Potential exacerbations during the postpartum period can often be managed by initiating immunomodulatory therapy soon after delivery.

Surveillance: Periodic neurologic examination to track disease progression and periodic brain and spinal cord MRIs to monitor disease activity; additional examination techniques include the ambulation index, the 25-foot timed walk, and the 25-foot walk combined with the nine-hole peg test and the paced serial auditory addition test.

Agents/circumstances to avoid: Pharmacotherapy is typically discontinued in women planning to become pregnant.


Clinical Manifestations of Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) of unknown etiology [Noseworthy et al 2000].

The peak age of onset is between age 20 and 40 years [Kurtzke et al 1992, Liguori et al 2000]. Less commonly, MS may develop in children [Ghezzi et al 1997]. MS has also been identified in older individuals, e.g., age 60 years and older, although it is sometimes difficult to ensure that clinical signs or symptoms were not present previously [Martinelli et al 2004]. It must be noted that age of clinical onset does not coincide, at least in the majority of cases, with age of acquisition.

Earlier studies had suggested that women are affected approximately twice as often as men [Sadovnick & Baird 1982, Wallin et al 2004]. Newer epidemiologic studies indicate an increased incidence, particularly in women, resulting in a higher female to male ratio [Orton et al 2006, Debouverie 2009, Ramagopalan et al 2009]

The most common clinical signs and symptoms at presentation include sensory disturbance of the limbs (~30%), partial or complete visual loss (~16%), acute and subacute motor dysfunction of the limbs (~13%), diplopia (7%), and gait dysfunction (5%).

These signs and symptoms may occur in isolation or in combination, and have to be present for a minimum of 24 hours to be considered a "clinical attack." As any anatomic location of the CNS may be affected, the clinical presentation of individuals with MS is extremely variable.

The course may be relapsing-remitting or progressive, severe or mild, and may involve the entire neuroaxis in a widespread fashion or predominantly affect spinal cord and optic nerves. Very little is known about the underlying cause of disease course variability in MS. Individuals can be stable for many months or years, and suddenly experience a devastating clinical attack. Currently, no biologic markers can assist the clinician in predicting the clinical course and/or the accumulation of disability. Within families, the clinical course of MS among affected relatives can span the entire spectrum of possibilities — the clinical course does not run true to type in families [Dyment et al 2002].

Clinical disease progression is assessed by recording the accumulation of neurologic disability with valid methodologic tools, including the expanded disability status scale (EDSS) [Kurtzke 1983]. One particular cohort of more than 1000 individuals with MS evaluated for over 25 years has been the subject of numerous scientific reports [Weinshenker et al 1989, Weinshenker 1998]. These data have demonstrated that temporal accumulation of disability accelerates with disease duration. Other groups studying other cohorts reported similar results. More recently, other scoring composites, including the Multiple Sclerosis Severity Score (MSSS) [Roxburgh et al 2005] and the Multiple Sclerosis Functional Composite (MSFC) have also been utilized to measure disease progression [Cohen et al 2001].

The Four Clinical Phenotypes of MS

Relapsing-remitting MS (RR-MS). Initially, more than 80% of individuals with MS experience a relapsing-remitting disease course with defined clinical exacerbations of neurologic symptoms, followed by complete or incomplete remission [Lublin & Reingold 1997].

Approximately ten years after disease onset, an estimated 50% of individuals with RR-MS convert to a progressive clinical course called secondary progressive (SP) MS, which is no longer characterized by clinical attacks and remissions, but by insidious progression of clinical symptoms [Confavreux et al 1980, Lublin & Reingold 1997].

Primary progressive MS (PP-MS). Another 10% to 20% of individuals with MS are diagnosed with primary progressive MS, clinically defined as a disease course without any clinical attacks or remission from onset [Lublin & Reingold 1997].

Demographic characteristics of PP-MS are distinct from those of other clinical MS phenotypes:

Progressive relapsing MS (PR-MS). A significantly rarer form is progressive relapsing MS, which initially presents as PP-MS; however, during the course of the disease, these individuals develop true neurologic exacerbations [Tullman et al 2004]. Individuals with SP-MS who have clinical exacerbations followed by incomplete remission are included in this category [Lublin & Reingold 1997].

Secondary progressive MS (SP-MS). While there is no expert consensus on a definition on this particular phenotype, the term describes (1) persons with RR-MS who never fully recover from attacks, and (2) persons with PP-MS who experience acute exacerbations [Lublin & Reingold 1996].

The life expectancy of individuals with MS in developed countries approaches that of the general population [Sadovnick et al 1992]. A nation-wide prognostic study in Denmark assessed in women and men standardized mortality ratios (the proportion of deaths caused by a specific disease compared with those expected in the general population) [Brønnum-Hansen et al 2004]. The reduced life expectancy with respect to that of the general population ranged from ten to 12 years.


Traditionally, the histopathologic correlate of clinical disability was thought to be loss of myelin within the plaque, resulting in exposure to ion channels and impaired propagation of action potentials across the demyelinated region of the axon. However, the early literature on MS already described substantial axonal damage in actively demyelinating lesions. It is not known whether this process is independent or a consequence of demyelination, but renewed interest in MS pathology has focused considerable attention on the neurodegenerative aspects of this disease. Studies confirm that partial or total axonal transection begins early in the disease process and suggest that the cumulative axonal loss may ultimately determine neurologic disability [Ferguson et al 1997, van Waesberghe et al 1999]. Histopathologic studies reveal abundant transected and dystrophic axons in sites of active inflammation and demyelination [Trapp et al 1998]. Axonal loss in MS is perhaps the principal contributor to CNS atrophy and clinical disability, although demyelination may also decrease tissue volume.

One group of investigators described four distinct histologic patterns of demyelination in autopsy and biopsy MS lesions [Lucchinetti et al 1998]. All four patterns were identified in lesions from persons with RR-MS. In contrast, only one pattern was detected in persons with PP-MS. While this study led to speculation regarding the temporal and pathogenic heterogeneity of MS, a more recent histopathologic study suggests that active lesions from persons with established MS are quite homogeneous and characterized by T- and B-cell infiltration [Breij et al 2008]. Further studies will have to determine whether the histopathologic heterogeneity in MS lesions is a true phenomenon or represents lesion evolution.

Establishing the Diagnosis of MS

Multiple sclerosis (MS) is a clinical diagnosis.

Relapsing-remitting MS (RR-MS). The RR-MS phenotype can be diagnosed by commonly used diagnostic criteria if dissemination in time and dissemination in space are present.

  • Dissemination in time. Defined as at least two clinical attacks, each lasting at least 24 hours, separated by at least one month, or a slow, stepwise progressive course for at least six months.
  • Dissemination in space. Defined as lesions in more than one area or functional system of the brain or spinal cord white matter.

Revised diagnostic criteria that specifically integrate MRI with clinical and paraclinical methods facilitate the diagnosis in individuals with monosymptomatic disease, relapsing-remitting disease, and progressive disease [Polman et al 2005].

Primary progressive MS (PP-MS). No diagnostic criteria are universally accepted for PP-MS; however, the following specific diagnostic criteria were formulated by a panel of MS specialists:

  • Definite PP-MS. Reserved for individuals in whom adequate clinical and investigative evidence is present to render the diagnosis definite enough for inclusion in research protocols and clinical trials
  • Probable PP-MS. Strong clinical suspicion of the diagnosis, but insufficient evidence to be definite
  • Possible PP-MS. Limited evidence is required to suggest the diagnosis:
    • Evidence of intrathecal immunoglobulin IgG antibody production
    • One of the following MRI patterns:
      • Nine brain lesions;
      • Two spinal cord lesions; or
      • Four to eight brain lesions and one spinal cord lesion

Differential Diagnosis of Multiple Sclerosis

Because MS is clinically a heterogeneous disorder, the differential diagnosis includes the following [Gasperini 2001]:

Inflammatory and infectious diseases

  • Systemic lupus erythematosus
  • Sjögren syndrome
  • Behget syndrome
  • Sarcoidosis
  • Lyme disease
  • Antiphospholipid antibody syndrome
  • Neurosyphilis
  • Acquired immune deficiency syndrome (AIDS)
  • Whipple disease
  • Human T lymphocyte virus (HTLV)-I-associated myelopathy

Cerebrovascular diseases

  • Recurrent strokes
  • CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)
  • Vascular malformations
  • Moyamoya disease



The worldwide prevalence of MS is estimated at between 1.1 and 2.5 million cases of MS [Pugliatti et al 2002].

The geographic distribution of physician-diagnosed MS is uneven. A greater frequency is observed between 40 and 60 degrees north and south latitude. Thus, areas with a high MS prevalence of 50:100,000-120:100,000 population are:

Zones with a very low disease frequency of 5:100,000 population are:

A reported increase in the prevalence of MS in some of the latter regions over the last decades may represent a real increase or better ascertainment [Callegaro et al 2001, Itoh et al 2003].


Environmental Causes

Epidemiologic and genetic methods have suggested a role of infectious pathogens in MS. At least four lines of evidence support an environmental contribution to MS etiology:

In addition, a concordance rate of only about 30% among monozygotic twin siblings of index cases confirms an etiologic role for non-genomic factors. However, discordance can be related to epigenetics or stochastics.

Despite evolving and ever more sensitive detection techniques, not a single agent (virus, bacteria, toxin) has gained acceptance as the causal agent in MS. The expectation that a single agent would have enough specificity and universality to account for all cases of MS is unrealistic. However, there is now strong evidence to support a pathogenic role for Epstein Barr virus (EBV) [Ascherio & Munger 2007a] and vitamin D in MS [Ascherio & Munger 2007b].

Heritable Causes

Multiple sclerosis clusters with the so-called complex genetic diseases, a group of common disorders characterized by modest disease risk heritability and multifaceted gene-environment interactions.

The genetic component in MS is suggested by familial aggregation of cases and the high incidence in some ethnic populations (particularly those of northern European origin) compared with others (African and Asian groups), irrespective of geographic location. Two genes, HLA-DRB1 and IL7R (CD127), have been unambiguously associated with disease susceptibility following their identification as candidates by function [Oksenberg et al 2004, Gregory et al 2007]. Spearheaded by the remarkable progress in high-throughput genotyping technologies, hypothesis-neutral genome-wide association studies (GWAS) in MS led to the identification of additional true susceptibility genes and loci of interest, demonstrating the power of this approach to identify modest genetic effects that contribute to this complex neurologic trait. The results of four MS-GWAS have been reported [Hafler et al 2007, Wellcome Trust Case Control Consortium 2007, Australia and New Zealand Multiple Sclerosis Genetics Consortium 2009, Baranzini et al 2009].

These GWAS were followed by extensive replications and meta-analysis efforts that provided robust evidence of association for approximately a dozen novel loci affecting disease susceptibility. These include CD6, CD25 (interleukin 2 receptor, alpha, IL2RA), CD40, CD58, CD226, C-type lectin domain family 16, member A (CLEC16a), ectopic viral integration site 5 (EVI5), glypican 5 (GPC5), regulator of G protein signaling 1 (RGS1), tyrosine kinase 2 (TYK2), tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), and interferon regulatory factor 8 (IRF8).

Some of the MS allelic variants were also proposed to be involved in other autoimmune diseases. For example, the IL2RA-mediated susceptibility effect is shared among MS, type 1 diabetes mellitus, Graves’ disease, and rheumatoid arthritis suggesting common mechanisms underlying different autoimmune conditions [Baranzini 2009].

Other strong candidate genes (ribosomal protein L5 (RPL5), kinesin family member 21B (KIF21B), membrane metallo-endopeptidase-like 1 (MMEL1), methyltransferase like 1 (METTL1), and protamine 1 (PRM1) require additional independent replication.

Even with this expanding roster of risk loci, the understanding of MS genetics remains incomplete. HLA-DRB1 explains approximately 7% of the total variance in MS whereas the other genes explain about 3% of the remaining variance. A 10,000-case GWAS with a high-SNP density platform, which is adequately powered to identify common risk alleles with an odds ratio of 1.2 or more, would be a reasonable next step in the genetic analysis of MS [Oksenberg et al 2008].

The role, if any, of copy number variation and epigenetic events remains unknown.

Concordance in families for some early and late clinical features suggests that in addition to susceptibility, genomic variants influence disease severity or other aspects of the phenotype. It has been difficult to discern, however, whether phenotypic diversity reflects true etiologic heterogeneity, modifying roles of specific genes, or some combination of the two. Unfortunately, published reports proposing specific genetic influences on the natural history of MS and response to treatment relied almost exclusively on small series of cases, retrospective clinical assessment, and in some cases, non-validated phenotypic endpoints. Furthermore, the confounding effects of drug treatment and population stratification have not been generally considered. It is also important to recognize that the aggregate contribution of individual germline variants to the disease course may be quite modest. Nevertheless, the demonstration of even a modest genetic effect of a known gene on the course of MS could help elucidate fundamental mechanisms of disease expression and yield a major therapeutic opportunity.

Evaluation Strategy

Once the diagnosis of multiple sclerosis has been established in an individual, it is appropriate to determine if it appears to be heritable. A three-generation family history with attention to other relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or review of their medical records including laboratory test results, neuroimaging studies, and the results of autopsy examinations.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

While evidence implicates a genetic component in the pathogenesis of MS, a simple model of inheritance is unlikely. Available data suggest a complex multifactorial etiology, including interactions of genetic and environmental factors.

  • A nonlinear decrease in disease risk in families with increasing genetic distance from the index case has been observed.
  • Recurrence risk estimates in twin data and multiplex families predict that a genotype predisposing to the development of MS results from multiple independent and/or interacting polymorphic genes, each of which may exert a minor or moderate effect [Dwosh et al 2003a, Dwosh et al 2003b].

Risk to Family Members

Considering a lifetime prevalence of MS in the general population of 0.2%, the age-adjusted recurrence risk estimates (in %) of family members vs the general population are summarized in Table 1.

Table 1.

Risk Estimates for Multiple Sclerosis in First-Degree Relatives of a Proband

Relationship to ProbandAge-Adjusted Risk Estimate vs the General Population 1
If one or both parents have MS, the risk can increase to 29.5% 2
Offspring2.0%-3.0% 3


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Medline Plus
  • Multiple Sclerosis Association of America (MSAA)
    706 Haddonfield Road
    Cherry Hill NJ 08002
    Phone: 800-532-7667 (toll-free); 856-488-4500
    Fax: 856-661-9797
  • Multiple Sclerosis International Federation
    200 Union Street
    3rd Floor Skyline House
    London SE1 0LX
    United Kingdom
    Phone: +44 020 7620 1911
    Fax: +44 020 7620 1922
  • National Multiple Sclerosis Society
    733 Third Avenue
    3rd Floor
    New York NY 10017
    Phone: 800-344-4867 (toll-free)
  • Accelerated Cure Project for Multiple Sclerosis
    300 Fifth Avenue
    Waltham MA 02451
    Phone: 781-487-0008
    Fax: 781-487-0009
  • NARCOMS Registry
    University of Alabama at Birmingham
    1530 3rd Avenue South
    RPHB 507
    Birmingham AL 35294-0022
    Phone: 800-253-7884 (toll-free)


Treatment of Manifestations

Disease-modifying agents. Evidence from controlled randomized clinical trials suggests that all currently approved agents for the treatment of MS decrease the clinical relapse rate and accompanying inflammation within the CNS [IFNB Multiple Sclerosis Study Group 1993, Johnson et al 1995, Jacobs et al 2000, Hartung et al 2002, Polman et al 2006, Rudick et al 2006].

Interferon beta (IFNβ)

  • The first agent to be approved in 1993 for the treatment of RR-MS was IFNβ-1b (Betaseron®). This agent reduced the rate of exacerbations of RR-MS in a multicenter trial [IFNB Multiple Sclerosis Study Group 1993]. In addition, IFNβ-1b reduced the number and frequency of lesions on brain MRI [IFNB Multiple Sclerosis Study Group 1993]
  • In 1996, another multicenter placebo-controlled trial demonstrated that IFNβ-1a (Avonex®) administered intramuscularly once weekly to individuals with RR-MS delayed the time to sustained clinical disability and decreased the exacerbation rate [Jacobs et al 1996].
  • Another IFNβ-1a (Rebif®) preparation reduced the number of clinical attacks, the percentage of MRI T2-weighted lesions, and sustained disease progression. A more recent phase IV clinical trial demonstrated that Rebif®, given at 44 µg subcutaneously three times weekly, was significantly more effective than Avonex®, given at 30 µg intramuscularly once weekly, in reducing relapses and magnetic resonance imaging (MRI) activity in persons with relapsing-remitting multiple sclerosis at 24 and 48 weeks of therapy. This trial led to the approval of Rebif® in the United States [Panitch et al 2002].

The role of interferon beta in clinical phenotypes other than RR-MS is less clear. In 1999, a European double-blinded, placebo-controlled trial demonstrated that IFNβ-1b treatment resulted in a highly significant delay in progression in SP-MS [European Study Group 1998]. These results could not be reproduced in a North American study [unpublished data]. Currently, IFNβ-1b is only approved in Europe for treatment of individuals with SP-MS.

Glatiramer acetate (GA). A multicenter randomized study showed that GA (Copaxone®) decreased the frequency of clinical exacerbations by 29% [Johnson et al 1995]. In a subset of individuals, MRI studies showed that GA treatment significantly decreased the percent annual MRI lesion volume and brain atrophy.

Mitoxantrone. In 2002, Mitoxantrone (Novantrone®) was the first agent to be approved for treatment of SP-MS with worsening relapsing and progressive relapsing disease course [Hartung et al 2002]. In a placebo-controlled randomized trial, mitoxantrone reduced sustained disease progression by 64% and the number of treated relapses by 69% [Hartung et al 2002].

Natalizumab. Based on the results of two phase III clinical trials [Polman et al 2006, Rudick et al 2006], natalizumab was originally approved by the Food and Drug Administration (FDA) for the treatment of relapsing forms of MS in 2004. Subsequently, two patients with MS who had been enrolled in one of the phase III trial were diagnosed with progressive multifocal leukoencephalopathy (PML) [Kleinschmidt-Demasters & Tyler 2005, Langer-Gould et al 2005]. Another patient with Crohn’s disease who had been treated with natalizumab in the context of clinical trials was later also diagnosed with PML [Van Assche et al 2005]. In February 2005, natalizumab was voluntarily withdrawn from the market by its manufacturers and all ongoing clinical trials were discontinued. In June 2006, natalizumab was re-approved as a monotherapy for patients with relapsing forms of MS.

Symptomatic treatment. Various medications are used for symptomatic treatment of pain, muscle spasms, fatigue, depression, sexual dysfunction, and bladder and bowel dysfunction [Krupp & Rizvi 2002].


Assessment with a periodic neurologic examination continues to be the most important means of tracking changes in disease manifestations and hence progression. The interval recommended for follow-up ranges from once a month to every two years, depending on clinical disease activity.

In addition to the clinical neurologic examination, brain and spinal cord MRIs are now routinely obtained in regular intervals to monitor disease activity. Currently no consensus exists regarding the frequency at which imaging studies should be performed nor is there a generally accepted imaging protocol. It is conceivable that with improvement in imaging techniques, new recommendations will emerge regarding the interval for follow-up imaging studies.

Additional examination techniques may be added, including: the ambulation index (AI); EDSS [Kurtzke 1983]; the 25-foot timed walk; and the MS functional composite (MSFC) [Cutter et al 1999], which combines a timed 25-foot walk (T-25), the nine hole peg test (a measure of upper extremity function), and the paced serial auditory addition test (PASAT; a measure of cognitive capabilities) [Hobart et al 2004]. Many of these tests are useful as outcome measures in clinical trials. However, time restraints limit their application in daily clinical practice.

Agents/Circumstances to Avoid

Two circumstances associated with clinical MS exacerbations:

  • Febrile infections [Gilden 2002]. Physicians should be vigilant about possible infections; the threshold for paraclinical diagnostic tests should be low.
  • Postpartum period [Confavreux et al 1998, Vukusic et al 2004]. In women who are planning to become pregnant, pharmacotherapy is typically discontinued because of the potentially teratogenic and abortifacent properties of many experimental and approved agents [Hughes 2004]. In addition, the last two trimesters of pregnancy convey protection from clinical attacks [Confavreux et al 1998, Vukusic et al 2004]. Potential exacerbations during the postpartum period can often be managed by initiating immunomodulatory therapy soon after delivery [Achiron et al 2004, de Seze et al 2004]. Treatment strategies for this period, and their potential implications for mother and child, should be discussed closely with affected individuals and their families.

Evaluation of Relatives at Risk

Early pharmacologic intervention with immunomodulatory agents may be clinically beneficial [Jacobs et al 2000, Comi et al 2001, PRISMS Study Group & University of British Columbia MS/MRI Analysis Group 2001].

Therapies Under Investigation

Currently, numerous experimental therapies and diagnostic procedures are being evaluated in MS. Search for access to information on clinical studies for multiple sclerosis.


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Chapter Notes

Revision History

  • 11 May 2010 (me) Comprehensive update posted live
  • 10 January 2006 (me) Overview posted to live Web site
  • 30 March 2005 (os) Original submission
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