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Discussion of the cause or causes of the disease that leads to sclerosis, that is, scarring, is being hampered by misleading and inaccurate descriptions which form the basis for the teaching of medical undergraduates and post graduates for fund-raising, and, most importantly, for grant applications.

PROBABLE CAUSE OF MULTIPLE SCLEROSIS
Ashton F. Embry

INTRODUCTION
Ashton Embry's approach to the problem of MS has been to try to find the most probable cause of the disease by using published data on MS epidemiology (who gets and who doesn't), MS pathogenesis (how the damage to the body happens) and MS recovery (who has recovered from MS and how they did it).

This has led to the identification of a single factor, Diet, which satisfies the epidemiological constraints.

CONSTRAINTS ON INTERPRETATIONS OF THE CAUSE OF MULTIPLE SCLEROSIS

GENETICS
There are two different aspects to a possible cause of multiple sclerosis. One is a genetic cause and the other is an environmental cause. The importance of both of these factors can be understood when one considers the research which has been done on identical twins. Current data from Europe and North America, which are both high risk areas for MS, indicate that, for identical twins with MS, about 20-30% of such twins both have MS (Ebers et al., 1986; Mumford et al., 1994). This compares with only 2% of affected fraternal twins both having MS (Ebers et al., 1986).

The fact that MS is more prevalent in women than men (~1.5/1) also demonstrates the role of genes in MS. Thus there is little doubt that there is a genetic factor in MS and it is likely that only genetically susceptible individuals have the possibility of getting the disease.

This interpretation was recently confirmed by Ebers et al. (1995). However, it appears that there is no one dominant gene which determines genetic susceptibility and that many genes, each with a small influence, are involved (Ebers, 1996). Not much more can be said about the genetic factor and the best we can do is accept the fact that it exists.

Importantly the twin data also convincingly show that, in high prevalence areas, only about 50-60% of individuals (5 of 8 identical twins) who are genetically capable of getting MS, actually contract the disease. Thus almost half the people in high prevalence areas who are "genetically programmed" for MS don't get it.

In low prevalence areas it would seem that less than 10% of susceptible individuals have MS. This demonstrates that there is at least one dominant environmental factor which results in a genetically susceptible individual being afflicted with MS. These are very important constraints on interpreting the environmental factor which can be regarded as the "ultimate cause of MS". It must be so common that it occurs over much of the world but it has to be very specific such that only half or less of susceptible people are affected by it. Furthermore this environmental factor must be much more prevalent or effective in certain areas of the world.

Another important facet of MS research has been the investigation into the timing of the action of the environmental factor on the individual. Immigration data have been used to elucidate this question (Alter et al., 1966; Dean and Kurtzke, 1971). It has been determined that adult immigrants retain the risk factor of their country of origin whereas their children tend towards the risk factor of the country they have immigrated to. This has been interpreted to indicate that the environmental factor only affects an individual before puberty (approx. age 15). The more obvious interpretation, that the adults do not experience the same environmental influences as their children do in the new country, was seemingly ignored.

The data on identical twins also provide insight into the question of timing. Twins share essentially the same environment until they leave home (16-21). Thus, the fact that only 25% of identical twins both have MS, is good evidence for the interpretation that the environmental factor comes into play mainly after age 18. Thus we have an apparent paradox. Immigration data apparently indicate the environmental factor acts before age 15 whereas identical twin data indicate that it acts mainly after age 18. Any interpreted cause of MS must explain this paradox.

 RISK AREAS

Another area of research which yields important constraints for interpretation is the global variance in MS prevalence (the number of people having MS which is usually recorded as the number for each 100,000 population) and incidence (the number of people who get MS per year, again recorded as the number for each 100,000 population). As alluded to earlier, the world can be divided into a high prevalence (risk) area which encompasses Europe, Canada, United States, Australia and New Zealand and a low prevalence (risk) area which encompasses the rest of the world (Kurtzke, 1980).

In the high risk area prevalences between 50 and 100 per hundred thousand people are common. In the low risk areas MS prevalences are an order of magnitude less (Kurtzke, 1980). This distribution is in part due to the genetic factor because all the high risk areas are dominantly populated by individuals of European origin (Poser, 1994). However, the environmental factor is also responsible for the occurrence of these two very different risk regions.

One line of evidence for this is the fact that immigrants to London, U.K. from areas of low risk (e.g. West Indies) have a low prevalence but their British-born children have the same high prevalence as British Caucasians (Elian et al., 1990). An interpretation of the environmental factor must take into account these two different risk areas with the factor being much more common or active in the high risk area.

There are also lower order geographic trends in MS prevalence. One of the most oft quoted trends is the occurrence of a north/south gradient within the areas of high prevalence. For Canada and USA, prevalences are lowest in the southern USA, become higher in the northern states and are highest in Canada (Kurtzke, 1980). In western Europe the gradient is not as well expressed but prevalences are higher in the nordic countries and Britain than in the more southerly Mediterranean countries (Rosati, 1994).

The north/south gradient is well expressed in Australia and New Zealand with the highest prevalences in the temperate, southern portions of these countries (Sadovnick and Ebers, 1993). In all these cases genetics cannot explain the north/south gradient and it is clear that the environmental factor is primarily responsible for this general increase in MS in areas of higher latitude. Any interpretation of the environmental factor must be compatible with the north/south gradient of MS prevalences.

MS also shows large differences in prevalence within some individual countries in the high risk area. For example in Norway MS is up to five times more common in the inland farming areas than in the relatively nearby coastal fishing areas (Alter, 1977). Similarly in Canada, MS is at least twice as prevalent in the Prairie provinces (100-225) as it is on the island of Newfoundland (50) (Sadovnick and Ebers, 1993). In these cases genetics has no bearing on this distribution (Newfoundland has a higher percentage of Caucasians) and the environmental factor must be primarily responsible for such drastic differences.

This conclusion has been recently confirmed by Rosati (1994) who states in his review of MS in Europe "variations in both prevalence and incidence rates in ethnically homogeneous populations confirm the importance of environmental factors". These macro and micro differences of MS prevalence in the world must be explained by any interpretation of the environmental factor.

ENVIRONMENTAL

Crucial data for constraining the nature of the environmental factor come from prevalences for both those of Japanese and Caucasian descent in Hawaii. Those of Japanese descent have a prevalence of 6.5 (i.e. 6.5 Japanese with MS per 100,000 Japanese in Hawaii) which is over three times that of Japan (2.1) (Kuroiwa et al., 1983; Alter et al., 1971). Conversely the Caucasians who were born and raised in Hawaii have a prevalence of 10.5 which is only one third that of the Caucasians of California (29.9) (Poser, 1994). Thus we have another paradox concerning the environmental factor. In Hawaii it acts such that it adversely affects those of Japanese descent whereas at the very same time it has a very beneficial effect on Caucasians. This puzzling paradox must be regarded as a critical constraint for an objective interpretation of the environmental factor.

One of the most interesting and widely quoted epidemiological studies of MS is that of the greatly increased prevalence of MS in the Faroe Islands (North Atlantic, west of Norway) following the occupation by 1500-2000 British troops between 1941 and 1944 (Kurtzke, 1977, 1980, 1995). Kurtzke has classified this increase as an epidemic although other authors have challenged this view (Benedikz et al., 1994, Poser et al. 1988).

Regardless, there can be no doubt that MS prevalence substantially increased in the Faroes following the British occupation. Furthermore, the relationship between MS in the Faroe islanders and the presence of British soldiers is strongly supported by the fact the cases of MS all occurred in islanders who lived close to British bases.

This is an extremely important constraint because it demonstrates that the environmental factor is not solely indigenous and can transported from one area to another. Any interpretation of the cause of MS must satisfactorily explain the sudden increased prevalence in the Faroes and the mobility of the environmental factor.

Recently another very important epidemiological study was published by Ebers et al. (1995). These authors were able to demonstrate that children, who were raised in families in which non-blood relatives (step parents, step brothers and sisters, adoptees, etc.) had MS, had no increased risk of MS. This provided good evidence of the genetic factor in MS but more importantly demonstrated that MS is not transmitted by person to person contact. An earlier study which involved spouses of persons with MS also demonstrated this.

Another important piece of evidence for determining MS cause is the fact that there is no recorded case of MS having been transmitted to another person through a blood transfusion (Theofilopoulos, 1995a).

Inhalants
Another possible cause of immune reactions which damage the BBB and possibly activate T-cells are hypersensitivities (type I, III, IV) to inhalants. IgE, immediate sensitivity reactions to inhalants seem relatively rare in persons with MS (Oro et al., 1996) but IgG reactions may be more common and problematic. Once again a blood-allergy ELISA or RAST test which measures IgE and IgG4 production on antigen challenge for a variety of inhalants is a reasonable way of determining if this is a major contributing factor to your MS. If the test is positive for a number of inhalants then once again it is essential to avoid or greatly lower the exposure to these substances. This maybe more difficult than for foods but allergists should be able to advise on various methods of avoidance and reduction. Extreme measures such as moving to another part of the country may be necessary in rare cases.

Viruses and Bacteria
Common viral and bacterial infections undoubtedly can affect the BBB and activate T-cells against the CNS through molecular mimicry. It is very doubtful if common viral and bacterial infections are the main cause of MS onset and progression as revealed by the epidemiological data but, in a few cases, such occurrences may play a major role in progression. Strong antibiotics are useful in cases where bacteria play a significant role in MS. In general, strategies to avoid infections should be adopted and any common bacterial infection should be treated with standard antibiotics as soon as possible.

Heavy Metals
Heavy metals can be very toxic to the CNS and thus, in some cases, may play a significant role in MS onset and progression. One of the most obvious sources of heavy metal toxicity is mercury in dental fillings. Currently there is considerable debate on this point and it is difficult to separate the data from the hype. Current scientific data do not support the concept of mercury amalgams being a major cause of MS. Such data include (1) PwMS do not have abnormal amounts of mercury in the CNS. (2) Many persons with MS have no fillings. (3) Professions which are exposed to abnormal amounts of mercury do not have abnormal rates of MS.

Furthermore, replacement of mercury amalgams is very expensive and may itself cause problems. However there is enough theoretical and anecdotal data available to indicate that mercury fillings may possibly contribute to MS progression. If diet revision does not result in an effective halt of MS progression then it may well be worth the trouble and expense to have the fillings replaced.

An interesting and insightful study of the effect of toxins on the CNS concerns the response of 26 women with failed, silicone breast implants (Shoab and Patten, 1996). "All patients had evidence of disseminated CNS lesions" and 80% had oligoclonal bands (IgG antibodies) in their spinal fluid. All the women had "systemic, inflammatory, autoimmune disease with CNS involvement" which was "triggered by the foreign material (silicone) in their body". This example clearly indicates that foreign, "antigenic" material can cause BBB failure and demyelinating immune reactions.

It is worth having a blood test and perhaps even a hair analysis for levels of heavy metals (see appendix). Chelation therapy can be valuable for detoxifying when anomalously high levels of heavy metals are detected.

Vaccinations
Poser (1986, 1993) has stated that vaccinations may be an important factor in MS onset and progression. Given the fact that vaccinations cause immune reactions it is clear that they may well affect the BBB and cause CNS inflammation (not necessarily an exacerbation). Poser (1986) provides references for a number of incidences where vaccinations resulted in MS. The most reasonable explanation of such occurrences is that the vaccination provided the final stress on an already embattled immune system. Also the hepatitis B virus has similar molecular structures to myelin basin protein and thus could cause molecular mimicry. Overall I would suggest that vaccinations (including the flu shot) be avoided unless they are absolutely necessary.

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