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CHaPter 66 Multiple Sclerosis 893

TABLE 66.1 McDonald 2010 Criteria for (ii) at least two T2 spinal cord lesions; and (iii) positive CSF
the Diagnosis of Multiple Sclerosis findings, defined as the presence of oligoclonal bands or elevated
IgG index.
additional Data needed for an
Clinical Presentation MS Diagnosis RISK FACTORS
≥ 2 attacks; objective clinical None
evidence of ≥ 2 lesions or Genetic Risk Factors
objective clinical evidence A monozygotic twin whose cotwin has MS has a 20–30% risk
of 1 lesion with of developing the disease, whereas the corresponding risk for a
reasonable historical dizygotic twin is 2–5%. In contrast, the incidence of MS in the
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evidence of a prior attack
≥ 2 attacks; objective clinical Dissemination in space demonstrated general population is approximately 0.1%. Hence, the risk of
evidence of 1 lesion by ≥ 1 T2 lesion in at least 2 or 4 MS drops with increasing genetic distance, suggesting that genes
MS-typical regions (periventricular, play a significant role in determining MS susceptibility. The
juxtacortical, infratentorial, or spinal human leukocyte antigen (HLA) region represents the strongest
cord) MS susceptibility locus, genome wide, and has been implicated
1 attack; objective clinical Simultaneous presence of in all ethnic populations thus far studied. It accounts for up to
evidence of ≥ 2 lesions asymptomatic gadolinium-enhancing 10.5% of genetic variance underlying risk. The primary signal
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and nonenhancing lesions at any
time; or a new T2 and/or gadolinium- maps to the HLA-DRB1 gene in the class II segment of the locus,
enhancing lesion(s) on follow-up MRI, implicating a role of CD4 T-cell responses in MS pathogenesis.
irrespective of its timing with Genome-wide association studies (GWAS) have revealed over
reference to a baseline scan; or 100 non-HLA susceptibility loci, each of which contributes a
Await a second clinical attack small amount to MS risk. Strikingly, most of these map to regions
1 attack; objective clinical Dissemination in space and time, containing genes implicated in immunological, rather than
evidence of 1 lesion demonstrated by:
(clinically isolated For DIS: neuronal or glial, pathways. Genes involved in T-helper (Th)–cell
syndrome) ≥ 1 T2 lesion in at least 2 of 4 differentiation are overrepresented, including the interleukin-2
MS-typical regions of the CNS (IL-2) receptor α chain and the IL-7 α chain, which modulate
(periventricular, juxtacortical, T-cell proliferation and survival. Over one-third of the MS
infratentorial, or spinal cord); or Await susceptibility loci overlap with regions previously identified in
a second clinical attack implicating a GWAS of other autoimmune diseases, including celiac disease,
different CNS site; and For DIT: type 1 diabetes, rheumatoid arthritis, and/or inflammatory bowel
Simultaneous presence of
asymptomatic gadolinium-enhancing disease. Together these data provide support for a primary
and nonenhancing lesions at any immunological, as opposed to neurodegenerative, etiology of
time; or A new T2 and/or gadolinium- MS. An unresolved question is whether genetic variants affect
enhancing lesion(s) on follow-up MRI, the clinical course of RRMS, including such features as relapse
irrespective of its timing with rate or severity and time to conversion to the SP stage. Genetic
reference to a baseline scan; or variants that are predictive of responsiveness to DMAs have yet
Await a second clinical attack
Insidious neurological 1 year of disease progression to be identified. A growing area of interest that warrants further
progression suggestive of (retrospectively or prospectively investigation is the potential impact of epigenetic modifications
MS (PPMS) determined) plus 2 of 3 of the in different cell types on MS susceptibility, clinical course, and/
following criteria: or therapeutic responsiveness.
1. Evidence for DIS in the brain
based on ≥ 1 T2 lesions in the Environmental Risk Factors
MS-characteristic (periventricular,
juxtacortical, or infratentorial) As mentioned above, twin concordance rates in MS have been
regions used to highlight the importance of heredity in MS susceptibility.
2. Evidence for DIS in the spinal Paradoxically, the same data can be used to argue for the impor-
cord based on ≥ 2 T2 lesions in tance of environmental influences. Hence, over 70% of mono-
the cord zygotic twins of individuals with MS do not develop the disease.
3. Positive CSF (isoelectric focusing Despite arduous attempts, no convincing evidence has been
evidence of oligoclonal bands produced for genetic, epigenetic, or transcriptome differences
and/or elevated IgGindex) 13
that explain MS discordance among monozygotic twin pairs.
From Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple The risk of MS appears to be predicated on a complex interplay
sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69(2): 292–302. between genetic and environmental factors.

Geographic Prevalence Patterns
primary antibody production in the CNS, supports a diagnosis One of the most convincing illustrations of the impact of the
of MS, but those findings are observed in a wide range of environment on the development of MS is its geographical
neuroinflammatory conditions, including subacute sclerosing distribution. The prevalence of MS is highest in the Scandinavian
panencephalitis, neurosarcoidosis, Lyme disease, and systemic countries, Canada, and Scotland and lowest in the equatorial
lupus erythematosus (SLE) with CNS involvement. A diagnosis regions. Kurtzke et al. were the first to notice a latitudinal gradient
of PPMS requires 1 year of disease progression plus two of the in the prevalence of MS across the United States, with the disease
three following criteria: (i) at least one T2 lesion in the peri- being most common in the Northern states and gradually declin-
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ventricular, juxtacortical, or infratentorial cerebral white matter; ing toward the South. Similar latitudinal gradients have been