Clues To Etiology

Prevalence data imply that racial and ethnic differences are important in influencing the worldwide distribution of MS and that its geography must be interpreted in terms of the probable discontinuous distribution of genetic susceptibility alleles, which can, however, be modified by environment (1). But the story does not end there, because variability in the populations studied, the use of different diagnostic criteria, and variable levels of ascertainment must all reduce our confidence in the meaningfulness of the data currently available. Nevertheless, it seems indisputable that MS is a degenerative disease of the CNS resulting from an externally derived attack, occurring only in a proportion of those people who are genetically susceptible. As this chapter has shown, complete understanding of the etiopathogenesis of the disease is still elusive. Many hypotheses regarding potential exogenous provo-kers of MS have been suggested, as discussed above and in Table 3, but almost all remain controversial. The defined but complex genetic interrelationships have defied interpretation and the conclusion can be drawn that a genetic predisposition appears to be a necessary (but not a sufficient) factor to confer susceptibility to MS. Further complicating the interpretation of the data, it is by no means certain that MS is a single disease entity (102); MS may represent a spectrum of disease.

The following genetic, epidemiological, and environmental clues have been repeatedly verified, but it is tantalizing that they are still insufficient to rationalize a theory of etiopathogenesis.

Incidence and Prevalence Rates Have Increased. Updated epidemiologic data in the context of new diagnostic criteria have more accurately characterized the spatial, if not the temporal, distribution of the disease. Our figures from Newfoundland show a near-doubling of the prevalence rate over 20 years, but we cannot incriminate any specific familial or infectious factors for this. Rather, the better availability of neurologists, heightened awareness of the disorder, and an improvement in available diagnostic techniques seem to be most likely responsible in this Canadian province, and probably elsewhere.

There Is an Important Genetic Component. This is witnessed by family history studies, demonstrating concordance rates for monozygotic twins that affirm a genetic influence in the disease; by documented racial susceptibilities; and by the variation of the proportion of disease subtypes between races (the opticospinal variant, NMO, occurs more frequently in east Asians than in other races). Racial variations in susceptibility can be explained using isolation of genomes in combination with distant founder effects, especially in races where extra-racial intermarriage has been rare. Although races with isolated genomes show differences in recessive and multi-factorial diseases due to differences in allele frequencies when compared with other races, not all racial variations can be explained strictly by genetics—some may be attributed to culture and environment, as evidenced by the frequency of Kuru in certain Papua New Guinean populations.

An increased familial risk has been repeatedly demonstrated. It tends to decrease the further one, which is related from the proband, implying a strong genetic role. Thus, monozygotes have an increased risk over dizygotes, who have the same risk as other siblings, and have a higher risk than first-degree cousins. There is no difference between maternally versus paternally transmitted risk, although children of two affected parents have a 10 times risk over children with only one affected parent. Adoptees and spouses have the same risk as the local population, arguing against an isolated environmental risk in families with MS.

There is no evidence for any specific Mendelian inheritance pattern. The sib risk is not the 25% or 50% that one would expect with a pure recessive or dominant disease and the twin concordance rate is far from 100%. (Curiously, the risk of parents with affected children is higher than with recessive disease while the risk

Table 3 External Influences Examined for Their Effect in Producing Multiple Sclerosis

External influence

Conclusion

References

Comment

School teaching

Ionizing radiation

Inhaled radon gas

Smoking and certain infectious diseases Welding Oral contraceptive use Exposure to mercury Dental caries, mercury, and lead exposure Inhaled particu-

late matter Exposure to organic solvents

Environmental pollution Inhalable airborne particu-late matter; ambient air pollutants

Organic solvents De-worming

Excess mortality among schoolteachers from autoimmune diseases Excess MS in subjects exposed to ionizing radiation Considered to be a risk factor Causative effect

No effect

No lasting protective effect

No effect

21% increase in MS with caries only

Increases trigger MS relapses

Double rate of MS disability pensions awarded to painters when compared with those not exposed

4x risk of MS relapses (4.143, P < 0.001) when the concentration of inhalable particulate matter was at the highest quartile

Walsh and DeChello (208)

Axelson et al. (209)

Bolviken et al. (210)

Casetta et al. (214)

Presumed to be due to early occupational exposures

Prospective study

McGrother et al. (215) Suggests geographical association

Spirin (217)

Oikonen et al. (124) SW Finnish study

16 ys follow-up study from Norway

Weatherby (161) Weinstock et al. (218)

Abbreviation: MS, multiple sclerosis.

of parents with affected children is lower than with dominant disease.) The risk is always greater for females and female relatives, so neither is this X-linked inheritance. Moreover, full scale genomic searches in sib pairs have suggested that no specific region of the genome plays a major role in susceptibility. One might speculate as to whether there is a susceptibility factor on the X chromosome or a protective one on the Y.

There Are Age and Gender Differences in Disease Presentation and Prognosis.

Females are at least twice as often affected as males; in women the disease presents at a relatively fixed time following menarche; the prognosis for disease development is worse in males and in those with older age of onset or with polysymptomatic signs (especially pyramidal and cerebellar); and it is better in younger females with mono-symptomatic sensory or optic involvement. The operation of an undefined hormonal factor may account for the gender-related findings. Paradoxically, the younger the age of onset, the better the prognosis.

There Is Repetitive Evidence of Increasing Equatorofugal Prevalence Rates. Such data incriminate some factor related to the geographical environment. In this context it is noted that there is a fair correlation between sunlight and/or other sources of vitamin D and prevalence rates worldwide, but the mechanism of this remains elusive.

Clinically Defined Variants Exist. These variants include relapsing-remitting/ secondary progressive MS (which are surely the same condition at different stages of development); a form that appears to be benign for years; and yet another that remains subclinical; a primary progressive type; the opticospinal variant; and acute lethal MS (the Marburg variant). Genetic predispositions are likely to be responsible for such phenotypic variability, but the nature of the inciting external agents provoking the specific clinical variants is unknown and the boundaries of immunopatholo-gical classification may not fully correlate with the classification of accepted clinical variants. In sum, the clinical variability of MS indicates that at least PPMS and that form heralded by ON have different natural histories and may represent separate etiopathologic entities.

Thyroid Disease Is Unusually Frequent in Populations of MS Patients. Whether this is evidence of a shared tendency to autoimmune disease or whether both the CNS and the thyroid are susceptible to attack by the same inciting agent remains undetermined.

Intercurrent Challenges to the Immune System Such As Vaccination, Infections, and Poor Air Quality Can Precipitate MS or Its Relapses. Recent evidence that an unusual form of HHV (type A) is detectable in the brains of MS patients, its viral load in the blood correlates with relapses of MS, and that this neurotropic virus is almost universally present and can be reactivated by stressful events (99) tie together these observations, but await confirmatory proof. Most vaccinations and infective agents have been shown not to correlate with disease initiation or course.

In the Northern Hemisphere There Is a Significant Excess of Births in May Compared with Those in November. Some external influence appears to operate upon the fetal environment during the northern hemispheric winter months.

There seem to be two questions that one can try to answer on the basis of the data discussed above.

Is MS a Polygenetic Disease with Reduced Penetrance?

Observations from twin, family, and racial studies leave little doubt that there is a genetic component to the etiology of MS (Fig. 1), the risk increasing with genetic similarity; but the mode of inheritance is neither purely recessive, nor dominant or X-linked. That MS is a genetic disease with multiple genes that contribute variably to both phenotype and susceptibility may be close to the truth, but it cannot be the whole truth, since 100% concordance between twins is not observed, thus ruling out any pure Mendelian mechanism.

MS might be a late-onset polygenetic disease with reduced penetrance, but one must search for the cause of the reduced penetrance in the context of the absence of a cost-effective screening method. In order to study penetrance in a family, a reliable means of diagnosis is necessary to make conclusions about the penetrance rate. Usually this is a known gene. However, (new paraclinical contributions to diagnosis notwithstanding) MS is a clinical diagnosis and the nature of any responsible gene or set of genes remains unknown. Therefore, familial studies are biased in two ways at present: subclinical disease is not adequately accounted for, and verifiable genetic markers of disease susceptibility are unavailable.

Even though reduced penetrance is a possible contributing factor, it is difficult to quantify a penetrance rate because of this bias. A molecular/genetic basis for reduced penetrance can arise from variation in the action of gene transcription modifiers which can be strictly genetic (e.g., trinucleotide repeats of varying length of local gene transcription modifiers) but might also include factors that are remotely influenced by action through cell and nuclear membrane receptors. The latter (receptor-influenced) factors suggest a mechanism for external influence, so that environmental factors may indeed influence disease initiation and induction.

In conjunction with observations based on both hormonal and gender influences, a further observation relevant to the effects of environment stands out. Hormones (including vitamin D) are derived from steroids, are lipid soluble molecules, and may act on nuclear membrane receptors. The separate discussions on menarche, vitamin D and related hormone studies above, and variation of MS with birth month, coupled with observed gender differences in both disease course and susceptibility suggest a likely role for hormones in either the induction of the disease or susceptibility to it.

Is MS a Virally-lnduced Autoimmune Disease?

Not mutually exclusive to the polygenetic hypothesis presented above, a viral cause for MS (either as a primary mechanism of neuronal attack or secondary to an induced immune/inflammatory process) has had continued attention for years. While no specific virus nor other infectious agent nor any specific vaccine has been definitively incriminated as a causative factor in MS occurrence or deterioration, an association between infections or other stresses and the unmasking or deterioration of MS has been shown repeatedly. The range of putative causative agents is wide. For disease induction, it is perhaps necessary that repeated exposures to causative agents occur in a certain contextual environment. (Fig. 1). Molecular mimicry via shared epitopes from an unknown viral influence has been suggested as a mechanism for disease induction in purported autoimmune diseases (such as type I diabetes, Hashimoto disease, and MS). Although the classification of MS as an autoimmune disease remains controversial, immune dysregulation has been repeatedly observed and genetics may play a role in susceptibility to immune dysfunction. The simplest explanation might be that such clinical deteriorations represent a nonspecific reaction to an immune or hormonal challenge.

While this summarizing statement is hardly original, it seems that MS is the end result of a re-awakening by stressors of a latent neurotropic virus, or some other pathogen capable of causing axonal and (perhaps indirectly) oligodendroglial damage within the CNS. The precise mode of operation of such stressors still awaits discovery. This may be as far as the evidence takes us today, but although in the last five years we have moved forward only slowly in the hunt for the etiology of MS, the data reviewed here perhaps orient us more reliably to the pathways of future research that are most likely to be fruitful.

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