One of the major clues to MS etiology comes from analysis of the remarkable worldwide pattern of MS. This shows a crude but inconsistent north-south gradient in North America and Europe; a lower prevalence in most of Asia, Africa, and South America (although many of these studies are less than definitive because of uncertainty about the completeness of case ascertainment); and a reverse south-north gradient in Australia and New Zealand (Chapters 1 and 2). This nonrandom pattern is different from that seen with many other acute or chronic "autoimmune" diseases of the central and peripheral nervous systems (PNS), such as acute disseminated encephalomyelitis (ADEM), the Guillain-Barre syndrome (GBS), and chronic inflammatory demyelinating polyneuropathy (CIDP); however, a similar worldwide pattern can be seen for type 1 diabetes in Europe and other allergic or "autoimmune" disorders such as Crohn's disease are not randomly distributed (15).

When unusual worldwide patterns of the disease are seen, interest heightens the potential for identifying causative mechanisms. Some diseases with characteristic geographical features are genetic in origin. This would include Tay-Sachs disease, affecting primarily Ashkenazi Jews; thalassemia, occurring in populations originating in southern Italy, other Mediterranean countries, Africa, and Asia; and sickle cell disease in individuals with African ancestry. Other diseases caused by specific infectious agents may have a unique distribution because of environmental factors, including cultural characteristics of the population and degree of exposure to the vectors involved in transmission. Rabies and some parasitic diseases can be considered in this category. Yet other diseases—such as tuberculosis, paralytic poliomyelitis, and rheumatic heart disease—may have a restricted global pattern owing to a combination of environmental factors, including poor hygiene or crowded conditions, and genetic predisposition. Which of these possibilities best fits MS is debatable, but on the basis of available evidence, the latter two seem more likely than the former.

There is also a consistent but not invariable effect of migration in altering MS risk in migrants or their offspring, depending on age at migration and whether the movement is from high- to low-risk regions or the converse (Chapters 1 and 2). The effect of migration on disease risk has not been associated clearly with other chronic (immune-mediated) diseases with some exceptions, i.e., type 1 diabetes and asthma (15). For example, the development of both MS and type 1 diabetes in the offspring of immigrants from the Indian subcontinent who migrate to the United Kingdom is the same as the endogenous British population (15,16).

Further evidence for an infectious agent comes from controversial reports of changes in MS incidence, up or down, or even frank clustering in some locales, suggesting that MS is not always a stable endemic disease as would be predicted for a purely genetic disorder. In addition, MS patients often have measles, EBV, or other childhood infections at a later age than controls (17-23). Whether this indicates that late exposure to multiple, a few, or a single pathogen is a critical factor in triggering MS remains to be determined. Others have not confirmed or criticized these studies as the retrospective determination of date of childhood infections may be inaccurate due to the long time which has elapsed or because of recall bias (24).

Twin Studies

Although genetic factors also seem important in determining MS susceptibility (see Chapter 2), the Canadian MS twin study showed a concordance rate of only 31% in monozygotic pairs when compared with less than 5% in dizygotes, even with magnetic resonance imaging (MRI) brain scans to detect subclinical disease, and long-term follow-up evaluations (25). This means that in over two-thirds of identical twins, both twins do not develop MS, even when one of the pair does. It seems safe to conclude from this evidence that in most instances genetic factors alone are insufficient to cause MS. It is also of interest that the concordance rate for type 1 diabetes, which shares a similar geographic distribution to MS, is 33% in monozygotic twins. A remarkably similar concordance rate in monozygotic as compared to dizygotic twins is also seen in paralytic poliomyelitis (26). Although genetic factors may have determined who develops paralysis following a polio virus infection, the key to preventing the disease was identifying the viruses responsible and developing an effective vaccine. The same may yet prove to be true for MS.

Identical twins share not only genetic sameness but many common environmental exposures including diet, exposure to sunlight, vaccination schedules, and communicable diseases during the first 15 to 18 years of life. Assuming that an infectious agent is important in causing MS, one can speculate that either the agent is not readily spread from twin to twin (i.e., low infectivity, sexual spread, animal vector) or that host factors other than exposure are important (i.e., dose of infectious agent, route of infection, status of the individual's immune system). The relatively low concordance rate in identical twins, narrow age range for onset of MS, restricted geography, and migration effects appear to the author to be more suggestive of one or a few agents causing MS rather than a large number, as many experts believe.

CNS and CSF Studies

CNS inflammatory lesions, abnormal profiles of chemokines and cytokines, and other effector molecules in brain, blood, and CSF; alterations in T- and B-cell subset concentrations (Chapters 4 and 8) as well as CSF changes in immunoglobulin G (IgG) and free light chains levels, including the presence of electrophoretically restricted oligoclonal bands (OCBs) in MS (Chapters 4 and 8) are all compatible with the effect of either an infectious agent or an autoimmune process. Similar pathological changes can be seen with viral and nonviral encephalitides as well as in the animal model experimental allergic encephalomyelitis (EAE). Likewise, the CSF IgG abnormalities seen in MS are mirrored in many infectious disorders including subacute sclerosing panencephalitis (SSPE), neurosyphilis, Lyme disease, and viral encephalitis as well as in autoimmune disorders such as EAE (24-30). Whereas in most viral infections OCBs react with or can be adsorbed by disease-specific viral antigens (28,31,32), attempts at removing MS oligoclonal bands after exposure to candidate agents have generally been unsuccessful (25,28) or, if positive (33), remain unconfirmed. It is currently unclear whether the OCBs in MS CSF react to as yet undefined specific infectious agents or to host antigens.

Infectious Agents Causing Demyelination

Clues to the etiology of MS might come from viruses and other infectious agents capable of causing spontaneous demyelination in humans or animals (Table 2). Several DNA and RNA viruses can produce inflammatory myelin loss in the CNS or PNS. In humans, infection with measles, EBV, varicella, and other pathogens can result in ADEM or postinfectious encephalomyelitis (1), whereas infections with Campylobacter jejuni, EBV, Mycoplasma pneumoniae, and cytomegalovirus (CMV) are often associated with GBS (34). However, acute infection with these agents does not usually produce recurrent or chronic demyelination, suggesting that a persistent infection, host factors, or as yet unidentified agents are responsible for causing MS and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Persistent infection with other viruses—including papovavirus (progressive multifocal leu-koencephalopathy), human T-cell leukaemia/lymphoma virus type 1 (HTLV-1; tropical spastic paraparesis), and human immunodeficiency virus (HlV)—result in chronic demyelination, although there are distinct pathological differences between these chronic encephalitides and MS. In contrast, canine distemper virus (CDV) infection in dogs, Theiler's murine encephalomyelitis virus, and coronavirus infections in mice, and other animal viruses can cause demyelination in their hosts, similar to MS, with an acute, exacerbating, or progressive course.

Serological Studies

Serological studies of MS serum and CSF show increased antibody titers to EBV, measles, and CDV as well as to other infectious agents when compared with controls (Table 3). Using a variety of techniques, serum antibodies from MS sera are elevated to multiple EBV, measles, and CDV peptides. The viral antibody titer increases are usually modest (up to a fivefold increase for EBV vs. a twofold increase for measles). Increases in viral antibody titers have been reported to numerous other agents, including vaccinia, herpes zoster, rubella, mumps, herpes simplex, adenovirus, parainfluenza 2, and influenza viruses. Although any agent inducing a consistent increase

Table 2 Spontaneous Human and Animal Viral Models of Inflammatory Central Nervous System Demyelinating Disease



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