The geographical gradient of MS (Figure 1), which sharply declines at the 37° latitude 1215, entirely spares the tropical belt where human treponematoses caused by T. carateum, T. pertenue, and endemic T. pallidum prevail 27. This negative correlation between areas of endemic treponematoses on the one hand and MS as well as schizophrenic birth excesses on the other is striking. With the notable exception of Florida, Australia and Tunisia (see Figure 1), subtropical areas exhibit neither a significant schizophrenic birth excess nor a prevalence rate (PR) of MS higher than 5/100'000 15.

In central Europe, the highest relative risks for MS can be found along the breeding sites of migratory birds. These hot spots are located along the north-south axis of the Upper Rhine plain and its tributaries, the Bas Rhin, Haut Rhin, Moselle regions 31, around Basel 32, in the Swabian Alps 33, Sardinia, as well as the Aosta Valley 15, the only place in Italy where the white stork (Ciconia ciconia) still nests (see insert in Figure 1). Tunisia, which is reached by passerine European birds carrying Ixodes ticks and B. garinii 34, scores the highest rate of MS in Africa 15. Malta, by contrast (see Figure 1), which compared to Sicily is relatively free of MS 1115, hosts a number of endemic lizards, and ticks lose their infectious potential for humans when feeding on these reptiles. This so-called zooprophylactic effect also applies to the low-risk areas of MS and sporadic schizophrenia 9 in the United States, where south of the 37° latitude infections by B. burgdorferi are poorly maintained in lizards 35.

Although of low prevalence, MS exists in South East Asia: in Japan and Taiwan 1536 down to the Philippines 12, where the Wallace Line (see Figure 1) limits the southward spread of B. burgdorferi harbouring Ixodid ticks into Austronesia 37. In Irian Jaya (I.J.) and P.N.G. (see Figure 1), from where neither the presence of Lyme disease nor MS has been reported, schizophrenia is non-existent apart from the south-west coast which is sporadically reached by migratory birds and ticks 16. In the southern hemisphere, MS 15and schizophrenic birth excesses 38 are, compared to the northern hemisphere, less significant. From the area of Singapore, which is non-endemic for Ixodes ticks and B. burgdorferi but endemic for treponematoses (see Figure 1), a schizophrenic birth excess is significantly absent. This trend parallels the scarcity of MS and relatively recent upsurge of schizophrenic birth excesses in Japan, where B. garinii harbouring ticks have been sporadically introduced by migratory birds from North East Asia (for discussion see 16). Southern Australia and New Zealand, by contrast, which can be reached by polar seabirds carrying Ixodes uriae and B. garinii via the Antarctic 39, score relatively high rates of schizophrenia 40 and MS 15.

The infection rates of B. garinii in I. uriae ticks 29 reflect not only the global distribution of MS, but also its worldwide gradient. The highest number of spirochaetes detected by microscopy were collected from seabirds in Iceland, Alaska and the Faroes (see Figure 1) all areas from where epidemics as well as very high rates of MS have been published 1241. Ticks from Sweden yielded lower spirochaetal counts and on an island south of New Zealand, where MS is reportedly less prevalent compared to the northern hemisphere 15, the number of detected spirochaetes was the lowest 29. Ticks from Cape Sizun (France) yielded negative results, and, unfortunately, the ticks collected on the Falklands and the Crozet Islands (South Africa) were dead and thus not examined by microscopy. Regardless of the geographical origin, B. garinii DNA was isolated and detected by PCR in all ticks and cultured spirochaetes, with two notable exceptions. The samples from the Atlantic coast of France and those from the Falklands - which do not appear as particularly hot spots for MS 3142 - were all negative 29.

If the stochastic annual fluctuations of schizophrenic births 43 and Lyme disease 44 are taken into account, the birth excesses of MS in Denmark 8 and those of schizophrenia in Finland 45 are exactly nine months apart. In northern Europe, the seasonal patterns thereby reflect the activity of endemic Ixodes ricinus 4446 at the time of conception and parturition respectively. Likewise, there exists a nine months' shift between MS birth excesses in Canada near Vancouver 3047 and schizophrenic births in the USA 48. The respective seasonal distribution exactly mirrors the periodicity of the adult and juvenile stages of B. burgdorferi transmitting I. pacificus ticks along the West Coast 49 and that of I. scapularis ticks along the East Coast (see 37). Amongst all other neuropsychiatric disorders, only amyotrophic lateral sclerosis (ALS) 50 shows a similar seasonal trend 3051 with respect to Ixodes tick activity in Europe 37 (see Figure 2).

Since current opinion favours a genetic/immune process for MS, as well as ALS, the possibility of spirochaetal infection has not been considered in depth. The similar global distribution of seabird-borne ticks and Scandinavians and their descendants, who appear to be at high genetic risk for MS 55, is not entirely coincidental. One Viking legend claims that the Faroes were discovered by following marine birds 56. While seabirds themselves often follow ships and eat fish offal floating on the water suface 57, the scandinavians were apparently led by such birds to new fishing grounds 56.

Little more than 300 of the approximately 9000 known bird species are seabirds. Yet, these birds occur throughout the world and are the only group of birds to have successfully colonised Antarctica, the most inhospitable continent. Although some seabirds breed and winter within comparatively small areas, many are champions in long distance migration, travelling thousands of kilometres on journeys from the far north of the northern hemisphere to the limits of the Antarctic pack ice in the southern hemisphere 5758.

The seabirds, which spend most of their lives far out to sea, must procreate on land. To avoid predators, they often breed on isolated islands and peninsulas leading to the aggregation of hundreds of thousands, and sometimes millions of pairs during the breeding season. The presence of such huge numbers not only depends on the abundance of food in the surrounding seas, the crowding habit also makes the birds and their offspring vulnerable to the seabird associated Ixodes uriae tick. No wonder, infestation by I. uriae has been reported from more than 50 species of seabirds in both hemispheres (see 29).

Because seabirds take their food from shallow waters, many coastlines and islands are prime sites for breeding colonies 5758, Borrelia transmitting I. uriae 29, and MS 56. On the Faroe Islands (see Figure 1), where Ixodes uriae reportedly transmits Borrelia from seabirds to human bird catchers 59, the MS scenario apparently unfolded after an annulled ban on fowling seabirds during a food shortage in World War II 56. Whatever speculation be more plausible - transmission by ticks 56 or soldiers 1214 - the prevalence of MS subsequently rose from apparently zero to 21 cases heralding the first of four successive epidemics 12.

On Iceland and elsewhere such epidemics have been attributed to increased awareness, changes in ascertainment or better diagnosis of MS, particularly of more benign cases in the post-war era 11. However, a common setting for MS 'epidemics' is proximity to coastal areas or islands where seabirds nest 56. From western Alaska both the presence of Ixodes uriae and B. garinii have been reported 29, and in Sitka being surrounded by three major seabird colonies in south-eastern Alaska (see Figure 1) MS was unknown until its first outbreak occurred in 1965 41.

Genetic 6061 as well as epidemiological studies, in which biological plausibility had been ignored 11, often provided contradictory information. One of the significant risk factors mentioned in a study from Key West (Florida), for instance 62, were visits to a local military base, a finding that the authors noted as a point of similarity to the military occupation and its reported effect on the Faroe Islanders 12. In Malta, however, which was occupied by British troops from 1802 to 1978, the low PR of MS doubled from 1978 to 1988 (from 4.2 to 8.4), after the British left 11. In contrast to Sicily with a relatively high MS PR of 61, however, the population of Malta (see Figure 1) still enjoys significant protection from MS that cannot be convincingly explained by geneticists either. It is noteworthy that since the Arabs were driven out by a band of Scandinavian adventurers, who had established a kingdom in southern Italy, Malta became a Norman appendage of Sicily for almost half a millennium. Yet, in addition to Scandinavian genes 55, Malta also hosts four endemic races of lizards (Podarcis filfolensis), and ticks lose their infectious potential for human beings when feeding on these reptiles. This so-called zooprophylactic effect also applies to the USA 35, where south of the 37° latitude (see Figure 1) the PR of MS is significantly lower 1215. The only notable exception is Florida 62, where migratory seabirds stop over for nesting 56. Otherwise, infections by B. burgdorferi are poorly maintained by lizards in the south of the United States 35. While seabirds are not common in states such as North Dakota, Montana, Idaho and Colorado where MS is high, the inland spread of Ixodes ticks and Lyme disease by land birds is well documented in the United States 63.

At the expense of a persistent vulnerability to lizards, the tick-borne pathogen has proven successful in spreading neuroborreliosis including MS via sub-polar routes 29 across the globe (see Figure 1). European strains of B. garinii infections have been documented in human cases from the USA 64 and Australia 39. The case of Lyme borreliosis in the southern hemisphere has been confirmed by culture and serotyping 39. Being of European origin, this type of B. burgdorferi s.l. was most probably introduced into Australia by a migratory seabird. Not surprisingly after all, southern Australia and New Zealand, which polar seabirds carrying Ixodes uriae 29 reach via the Antarctic, score relatively high risks of MS. Even the highest PR in these communities, largely originating from the United Kingdom, is not much more than half the rate in most parts of the British Isles 15. This difference in relative risk is hard to understand from a purely genetic point of view. But there isn't much room for 'pure' environmentalists either, as Waikato in New Zealand, where the main step in MS morbidity occurs across the North Island, scores a lower rate than places in Australia on a comparable southerly latitude 215. For migratory seabirds introducing Ixodes uriae from the northern hemisphere 29 reach New Zealand later than Australia (see Figure 1).

In the northern and southern hemispheres, several species are responsible for this transhemispheric exchange. Great puffins or Manx shearwaters (Puffini puffini), for example, move around the world in giant loops. They are abundant off the European continental shelf in July and August, when they are heading southeast. Between September and December, the puffins spend their time mainly along the American coast form Rio de Janeiro in the north to the Rio de la Plata in the south. Along these coasts, the nutrient-rich water advances during this period with the Falkland Current producing upwellings on the water surface rich in fish. By March and April the birds leave their breeding colonies on the Falklands and other islands in the South Atlantic heading northwest across the equator to the rich fishing waters off Newfoundland. Then they gradually move back across the North Atlantic, where they are often seen around Scotland, Ireland and the Faroes, where the traditional puffin-hunting season starts in the end of July 575859.

In the southern oceans, where the winds blow almost continuously eastwards in the roaring forties and furious fifties, a ringed great puffin has even been found in south Australia. The distribution of short-tailed puffins, or short tailed shearwaters (Puffini tenuirostri), is limited to this part of southern hemisphere, where the birds breed on islands off the coast of New Zealand and Australia. In Tasmania, as in the Faroes, their so-called mutton-bird chicks are regularly fowled 58.

Among the most successful and widespread marine birds are the seagulls. There are some 45 species, which occur in both hemispheres. Colonies may be tens of thousands strong, particularly if there is a major source of food thereby. Outside the breeding season most gulls, such as the black headed gull (Larus ridibundus), undertake migratory movements, sometimes wintering well out to sea. They move parallel to latitude to avoid cold weather, or they simply disperse over comparatively short distances along rivers 5865 (see Figure 1). Along the tributaries of the upper Rhine 65 they thus reach the foot of the Swiss Alps where B. garinii has become highly endemic among other terrestrial passarine birds. These, in turn, may spread borreliosis to other hosts 66 by regularly migrating to northern 67 and southern Europe either along the valley of the upper Rhone or directly via Alpine passes (personal communication 2002, Christian Marti, Swiss Ornithological Institute, Sempach).

Extending a previous report from the United States, Templer and colleagues found a high geographical correlation between MS and schizophrenia in Italy 7. As a correct temporal relation between cause and effect is essential in epidemiology 6, correlated birth patterns of MS and schizophrenia were then studied. In Denmark, a significant birth excess of MS was disclosed in spring-early summer, but the data on schizophrenia were insignificant compared to the general population 8. This negative finding, which can be explained by stochastic fluctuations (for discussion see 43), was unfortunate since accumulating evidence from most other studies 28 did yield significant schizophrenic birth excesses in winter and spring.

In Sicily, interestingly enough, MS birth excesses being shifted towards the end of the year 68 show a seasonal trend reminiscent of the seasonal Ixodes tick activity in neighbouring North Africa 37. And in Tunisia, where Ixodes ticks harbour B. garinii and B. lusitaniae 34 - species known to be scattered geographically by birds from Europe - MS scores the highest rates in Africa 15.

MS has never been reported in ethnically pure Eskimos, Inuit, Lapps, Amerindians, Australian aborigines, New Zealand Maoris or Pacific Islanders 11. Yet, most of these natives either live near the polar circle, where tick activity abates due to low ambient temperature, or they live in tropical climates where Treponema 27 but not Borrelia spirochaetes prevail (see Figure 1).

The most convincing evidence for the importance of genetic or acquired resistance is the extreme rarity of MS in native Africans. In the Cape Province of South Africa, the disease is recognised among the so-called coloured, but neurologists in Johannesburg are extremely reluctant to make the diagnosis in a black person 11. Hawkes 14 maintains that in developing countries a general immunity is acquired against infection, which might also spread "in utero or during parturition" and possibly increases the resistance against MS and sexually transmitted disease. Until the early nineties, I was working as a medical delegate in southern Africa and cannot share Hawkes's opinion on the isolation of 'black' Africans from 'white' sexual permissiveness. Venereal diseases including syphilis were highly prevalent among natives of South Africa, Angola and Mozambique, and in that part of the world it is the incidence of AIDS, but not MS, which has substantially risen. The "infrequency of MS and AIDS in the same patient" 14 rather favours the hypothesis of a hyperergic immune process 23 which is suppressed in a state of immunodeficiency such as AIDS.

Whilst it is always more prudent to await the discovery of new facts 69, long-held 25 hypotheses 14 often raise testable questions if taken together and dissected with Occam's razor. The MS gradient, which sharply declines at the 37° latitude, suggests a temperature-related environmental factor that cannot be ignored (see Figure 1). The geographical distribution of endemic treponematoses, by contrast, as well as blood group 0 antigens which appear to convey resistance against Treponema pallidum 70, are restricted to exactly those parts of the tropics that are free of MS. This contrast is of evolutionary importance with regard to the adaptation of intracellular pathogenic spirochaetes. Like the AB0 blood group system 71, the evolutionary conserved heat shock proteins (HSPs) do not only induce heat resistance, but also activate host immune defences that are detrimental for pathogens (see for example 72737475767778).

Molecular evidence reveals that Treponema pallidum - the agent of syphilis being an exclusively human pathogen and B. burgdorferi s. l. - the human and animal pathogens of Lyme borreliosis - have circumvented this immunological impasse differently. Whilst in the course of evolution Treponema pallidum, being directly transmissible from human to human, lost its capacity to induce HSPs 79, heat resistance 80 and thus vector-borne transmission, B. garinii has adapted to a broad temperature range 81. To survive heat shocks during vector-borne transmission, the gram-negative Borrelia pathogen therefore expresses HSP-60 and HSP-70 82, which are members of the evolutionary conserved HSP family. This form of vector adaptation is essential during rapid changes in temperature, in particular when transmitted from ticks to their warm-blooded hosts 83 including birds.

In the absence of other vertebrate hosts on certain islands, the presence of Borrelia in I. uriae ticks suggests seabirds to be competent reservoirs and amplifying hosts. In contrast to B. burgdorferi sensu stricto being cleared from the respective Ixodes vectors at 37°C 84, a temperature of 38°C is permissive for the transmission of B. garinii 81. The relatively low body temperature of 38°C in marine birds, compared to the body temperature of terrestrial birds of 40°C, explains why these B. burgdorferi s.l. spirochaetes are particularly adapted to seabirds 29.

But the pathogen's success of transmission also depends on its ability to replicate and survive within a host for long periods. One option is to remain latent inside the long-lived cells of the CNS whose temperature is about 38° in humans. This coincidence elucidates the characteristic spread and neurotropism of B. garinii, which is frequently associated with neurological manifestations 85. In vitro evidence suggests early invasion of the CNS by B. burgdorferi sensu lato by adherence of this organism to sphingolipids 86. Functionally linked to a flagellar protein, HSP-60 is thereby involved in binding to the neural cell surface for intrusion into the CNS 8788. As HSP-60 is a major immunodominant antigen of B. burgdorferi 89, it comes as no surprise that antibodies to HSP-60 were also detected in the synovial fluid of Lyme arthritis patients 90. Although still a controversial issue 919293, molecular mimicry of flagellar epitopes, which are highly antigenic 94, may misdirect antibodies against host tissues as well 9596. For pathogens must avoid being destroyed by the immune response while maintaining access to a new host, and protracted antigenic exposure destabilises the immune system.

Epidemiology cannot replace molecular, experimental and pathological investigation including case reports, despite the fact that these are often dismissed as 'anecdotal'.

Is it possible that the Borrelia flagellar basal rod protein (fbrp), implicated in the pathogenesis of sporadic schizophrenia at conception 169798, also plays a pathogenic role in MS following transmission at birth? As fbrp shares an epitope with the human interleukin-1 receptor antagonist IL-1ra (see Table 1 an 99), it is plausible to assume that such amino acid homology between B. burgdorferi and its human host potentially induces and misdirects anti-IL-1ra antibodies. Might re-exposure to the same 100 or similar antigens 101102 subsequently trigger MS later in life? Conversely, may cross-reacting antibodies acquired against Treponema spirochaetes protect migrants from tropical countries against infection by Borrelia spirochaetes and thus antigenic exposure to fbrp?

Not only tropical spastic paraplegia 14 mimics the clinical pattern of MS. In several respects, MS is more reminiscent of neuroborreliosis 102103104105, which in its chronic form is supposed to be an autoimmune disease triggered by these spirochaetes 95105. MS plaque-derived DNA 106 shows an abundance of transcripts for several heat shock proteins (HSPs), including HSP-70 and anti-HSP-70 antibodies, but apparently not for interleukin-1 (IL-1β), the underlying pro-inflammatory cytokine (see also 107108109110). This contrasts with other common gram-negative infection, in which HSP-70 induction correlates with elevated levels of IL-1β transcripts 111. A putative anti-IL-1ra immune response against IL-1 receptor antagonists (IL-1ra) might therefore explain this specific post-transcriptional dysbalance at the level of the IL-1 receptor unleashing a cascade of ruinous inflammatory cytokines. There are three arguments in support of such a role: reduced genetic expression of IL-1ra versus IL-1β has been associated with disease severity in MS 112. IL-1ra can be increased by interferon beta 113, the first neuromodulatory drug approved for the treatment of MS 4. Conversely, lower IL-1ra versus higher IL-1 activity enhances inflammation, whereas a dysbalance in favour of IL-1ra versus IL-1 reportedly mitigates this reaction in MS, experimental allergic encephalomyelitis (EAE) and B. burgdorferi induced Lyme disease 114115.

When in 1925 Adams et al. 116 inoculated rhesus monkeys with material from MS plaques, spirochaetes emerged in their ventricular fluid after several months. More recently, cystic structures originating from B. burgdorferi were found in eight of ten MS patients by immunofluorescence and in all the MS patients by use of transmission electron microscopy and staining after culture 21. The patients originated from a well-defined coastal area of southern Norway, where Lyme borreliosis 117118 as well as MS 1215 is highly endemic. No such cysts could be observed in the five controls with either method, but the investigators noted a similarity between those found in the MS patients and the cystic forms characteristic of spirochaetes and chronic B. burgdorferi infection. More importantly, the cysts of the MS patients exhibited positive reactions to antispirochaetal antiserum 21.

In analogy to the induction of heptocellular carcinomas upon chronic hepatitis B infection acquired during delivery 24 and in analogy to lymphomas of the skin induced by chronic B. burgdorferi s.l. infection 117118, we would expect an association of MS and ALS with neoplastic transformations of the lymphatic system. A significant correlation between non-Hodgkin's lymphomas and MS appears to exist 119, and in a review of neurolymphomatosis a case was documented with schizophrenia and anterior horn involvement, a hallmark of ALS 120. As the cause could not be identified, a virally mediated autoimmune pathogenesis was proposed.

Whatever the pathogenic link between schizophrenia and MS - an infection followed by an altered immunologic response 5 or a continuum of chronic inflammatory CNS disorders including neuroborreliosis, syphilis, or viral encephalitis 121 - we would expect an analogous link between schizophrenia and ALS in terms of latitude 5354, season (see Figure 2) and causality 122.

Among relatives of Ashkenazi immigrants to metropolitan New York suffering from schizophrenia 123, the prevalence of ALS compared to the expected population rate in the USA, where B. garinii is non-endemic, was more than a hundred times higher. Not surprisingly after all, the countries of ancestral origin included eastern Europe and Russia 123 areas where B. garinii is endemic 117118.

Up to ten percent of patients initially diagnosed as having ALS are re-diagnosed as having a disease other than ALS 124. Although it seems unlikely that infection by B. burgdorferi is a frequent cause of ALS 117, a discrete subset of patients living in hyperendemic areas appears to be significantly more likely to have immunologic evidence of exposure to B. burgdorferi than do controls, and some of these patients do appear to improve if treated with antibiotics 125.

Although the nosological criteria for MS and schizophrenia have high diagnostic reliability, affected individuals may differ substantially in the specific profile of signs and symptoms, as well as in the severity and course of their illness. What we recognise clinically as 'schizophrenia' or 'MS', is likely to encompass a complex set of disorders. A major task of future studies will thus be to resolve the question of heterogeneity in MS 2 as well as its aetiologic overlap with other disease processes.

Seroepidemiological studies relating B. burgdorferi to MS 126127128 and ALS 125129130 have produced conflicting results. However, when entering the CNS, microorganisms can undergo antigenic 131 and extensive metabolic changes, which prevent them from being recognised by the current serologic test methods. These changes protect B. burgdorferi from the host's immune system and reduce the effect of antibiotics 21132. Although infections all induce specific antibodies and cell-mediated immunity, microbial virulence factors have not often been individually defined or even identified 133. There are hundreds or thousands of antigens, and immune responses develop to many of these. Resistance to infection, however, depends on the reaction against a few antigens on the surface of the microorganism 133. The flagellar basal rod protein of B. burgdorferi (fbrp) responsible for locomotion, adherence and host cell penetration is part of such a virulence factor. Influencing parasite-host interaction, gram-negative bacteria use this type of basal ring assembly to secrete and translocate flagellar and virulence proteins directly into the cytoplasm of their host cell 134. While temperature is a key environmental cue for the switch between motility and plasmid-encoded gene expression of virulence, stress-related degradation of the secreted substrates is accordingly prevented by the chaperonising function of HSPs 135. The coincidence of both genetic and antigenic exposure to Borrelia fbrp is therefore not casual, but a highly specific pathogenic event. Mutations by homologous recombination affecting the implanting blastocyst at conception 16 and chronic infection afflicting the immunologically immature newborn upon delivery 24, it is conjectured, will subsequently trigger sporadic congenital schizophrenia and MS respectively.