VOL 14, NO 2,1988 231

Schizophrenia andMultiple Sclerosis

by Janice R. Stevens Abstract

Similarities in clinical course, ageof onset, geographical distribution,and immunological responses ofpatients with schizophrenia andmultiple sclerosis (MS) suggestthat these two common illnessesof young adults may belong to asimilar class of disorders. Thisreview examines some of the sim-ilarities and differences betweenthese two disorders and suggeststhat epidemiological, immunologi-cal, and viral studies considereduseful in the investigation ofcausal factors in multiple sclerosismay also be pertinent to thesearch for causes of schizophrenia.

The past several years have seen aresurgence of interest in schizo-phrenia as a disorder of the brain.Computerized tomographic (CT)studies have shown relative en-largement of the third and lateralventricles of 15-20 percent ofpatients with a diagnosis of schizo-phrenia compared with controls(Johnstone et al. 1976; Weinbergeret al. 1979; Boronow et al. 1985).Post-mortem measurements ofsubcortical nuclei show diminishedsize of hippocampus, amygdala,parahippocampal gyrus, globuspallidus, or periventricular nuclei ina significant percentage of studiedcases compared with controls(Lesch and Bogerts 1984; Bogertset al. 1985). Gliosis and nerve cellloss in diencephalon, limbic system,and basal ganglia have beendescribed (Nieto and Escobar 1972;Stevens 1982). These data support-ing morphological pathology inschizophrenia have stimulated thesearch for biological causes of thiscommon and disabling psychosis.

There are a number of similari-ties between schizophrenia andmultiple sclerosis (MS) that suggestthat schizophrenia as well as MS

may have an infectious or immuno-logical etiology. Both disorders arecharacterized by onset in earlyadult life, and by progressive orremitting-exacerbating course withgradual increase in disability inmany cases and spontaneous re-mission in others. Although schizo-phrenia and MS are pathologicallyand clinically very distinct dis-orders, some formal similarities ofclinical course, epidemiology, andimmune response suggest thatboth disorders may belong to aclass of disturbances characterizedby initial or persistent viral infec-tion that can be followed byaltered response of the immunesystem.

Onset and Course

Like MS, although 10-100 timesmore prevalent, schizophrenia is adisorder of young adults with apeak age of onset in the early tomiddle twenties (range 15-45 years,figure 1). Schizophrenia, like MS,has a unimodal age distributionwhich, as Johnson (1975) noted, istypical of, although not unique toinfection acquired or activated inearly adulthood. As in MS, theonset of schizophrenia may beeither acute or subacute and ischaracterized by a steadily progres-sive course or by remissions andexacerbations resulting in increas-ing disability. In both disorders, thevariable clinical picture and courseare usually unaccompanied by signsor symptoms of systemic illness,although a history of chronic low-grade headache and of frequentsomatic complaints is not unusualin early schizophrenia and easy

Reprint requests should be sent toDr. J.R. Stevens, Department of Psy-chiatry, Oregon Health Sciences Uni-versity, Portland, OR 97201.

SCHIZOPHRENIA BULLETIN

Figure 1. Age of onset for males and females with schizophrenia(Mayer-Gross et al. 1960) and multiple sclerosis (McAipine et al.1972)

60

50

Schizophrenia/100,000

Itmaltt

30

20 1

I .01

MultipleSclerosis /100.000

5

4

3

2

1

Mol«i

-- F«mole

10 20 25 35 45 55 65 75 and ov.r

age group

fatigability is common in early MS.In both disorders, formes frustesoccur, characterized by complete re-mission without residual

Geographic Distribution

As is well known, MS is muchmore common in northern andtemperate regions of the worldthan in the tropics, where it isquite rare. There is also a distinctnorth to south gradient of preva-lence within Europe and NorthAmerica (Acheson 1972). Differ-ences in diagnostic requirementsfor schizophrenia in different partsof the world have gravely handi-capped epidemiological studiesSchizophrenia incidence datareported from many developingcountries, particularly in Africa, arenearly all based on hospital andclinic incidence rates rather than

community- or country-wide sur-veys, and are inaccurately low dueto shortages of medical facilitiesand to greater tolerance for someforms of schizophrenia in thecommunity. However, even theserelatively low numbers are errone-ously high in many areas of thedeveloping world due to wide-spread misdiagnosis of the "briefreactive psychoses," which are verycommon in these regions, as schizo-phrenia (German 1972)

In a recent study undertaken inHarare, capital and largest city inZimbabwe, 40-50 percent of alladmissions to the mental wards oftwo university-affiliated hospitalswere diagnosed as schizophrenia in1983-84. However, when ResearchDiagnostic Criteria (Spitzer andEndicott 1978), requiring at least 2weeks of illness for a diagnosis ofschizophrenia, were applied, more

than half of these patients failed tomeet this duration criterion andwere accordingly diagnosed as briefreactive psychosis. When the 6months of illness specified byDSM-II1 (American PsychiatricAssociation 1980) were required,only 10-15 percent of admissionsmet criteria for schizophrenia(Stevens 1987).

Thus, although it is often statedthat prevalence of schizophrenia issimilar throughout the world (e g ,Sartonus et al. 1986), available datado not permit this conclusion.Indeed, the few population-basedsurveys that do exist indicate anapproximately tenfold variationwith much lower rates in Africaand parts of southwest Asia thanin western Europe or the UnitedStates (Eaton 1985) As is the casewith MS, reported cases of schizo-phrenia also appear to have theirhighest distribution in northernand eastern Europe, but arecomparatively less common insouthern Europe and in Africa,even in areas where schizophreniahas been looked for systematicallyby trained European personnel (seeTorrey, this issue) This trendremains true for schizophrenia asfor MS when prevalence data arepresented only for the populationat risk—i e., over age 15. Just asthe British Isles and northernEurope have the highest prevalenceof MS in the world, westernIreland, Sweden, and westernCroatia reportedly have the highestprevalence of schizophrenia, withIreland alone showing a rate 44times that of Guyana (Walsh andWalsh 1970) There are alsoconsiderable differences in hospitaladmissions for schizophrenia in theUnited States that cannot bewholly accounted for by "drift"hypothesis but could reflect admis-sion policies or genuine geo-

VOL 14. NO. 2,1988 233

Figure 2. Number of admissions for schizophrenia to State andcounty hospitals In United States in 19811

SCHIZOPHRENIA RATES PER 100.000 FOR ADMISSION TOSTATE AND COUNTY HOSPITALS USA 1981 (DSM III)

Data from Survey and Reports Branch, NIMH (1981).

graphical differences as in MS (fig-ure 2).

Sartorius et al. (1986) did not setminimum duration criteria for thediagnosis of schizophrenia. Theinclusion of brief psychoses maythus have contributed to their con-clusion that schizophrenia occurswith equal incidence throughoutthe world. For want of adequatepopulation data, this importantarticle also omitted three of thefour developing countries studiedfrom their incidence statistics.Finally, their conclusion that thereis a similar incidence of schizophre-nia in all the countries studied andhence world-wide, relied on inci-dence data derived with the Present

State Examination and CATEGO's"narrow" definition of schizophre-nia (S+). The narrow definition,which only requires one ofSchneider's first-rank symptoms fordiagnosis, is highly reliable (repro-ducible among observers) but doesnot distinguish schizophrenia frommany acute psychoses, and givesessentially zero heritability andvery poor final diagnosis predict-ability for the "nuclear" schizo-phrenia so diagnosed (Brockingtonet al. 1978; McGuffin et al. 1984).Hence, the validity of the diagnosismay be questioned.

These facts are stressed herebecause accurate epidemiology is soimportant to any hypothesis

attempting to explain schizophre-nia. An unequal geographical dis-tribution with pockets of very highincidence is compatible with thehypothesis that, as in MS, anenvironmental event in addition toa generic predisposition bestexplains the known epidemiologyof the illness. Although epi-demiological data for schizophreniaare less than adequate, the avail-able information indicates that thedictum that schizophrenia is moreor less equally distributed through-out the world is a prematureextension of the observation thatschizophrenia-like illnesses exist inall parts of the world.

In contrast to MS, which has apoorer prognosis in the tropics(Liebowitz and Alter 1973), theprognosis of schizophrenia is saidto be significantly better in thedeveloping world than in the devel-oped (largely temperate) lands(World Health Organization 1973;Sartorius et al. 1986). The betterprognosis in developing countriesmay, like the prevalence, be erro-neously exaggerated by inclusion ofthe brief schizophreniform psy-choses that contribute significantlyto all admissions to psychiatrichospitals in these countries. Thebetter prognosis in these areascould also signal greater immunityto a schizophrenia-inducing agentor agents. Alternatively, betteroutcome could be related to themuch wider use of electroconvulsivetherapies, to the less prolongedand smaller doses of neuroleptics,to much less psychotherapy, or asis usually assumed, to local culturalfactors of care and aftercare.

Migration and Risk of MS andSchizophrenia

Adults who emigrate from coun-tries of high risk for MS (e.g.,

234 SCHIZOPHRENIA BULLETIN

northern Europe, northern UnitedStates, and Canada) to areas oflow risk have the same chance ofdisease as those who remainbehind. In contrast, it has untilrecently been understood on thebasis of data available that childrenwho live in low-risk areas untilaround age 15 have a risk of MSno greater than those in the low-risk region in which they spenttheir childhood even if theymigrate after this age to the high-risk higher latitudes. These datahave been interpreted to mean thatexposure to the responsible agentin childhood or around puberty isa crucial factor. Recent evidencefrom Israel and from Scandinavianimmigrants to North America,however, indicates that native-bornresidents carry the risk of theirparents (Biton and Abramsky 1986;Waksman 1986).

The data for schizophrenia, al-though less precisely gathered withrespect to age of migration, alsoindicate that adult immigrantsfrom countries and regions at highrisk for this disorder bring theirhigh risk with them (Malzberg1936). More recent data indicatethat immigrants to England fromIndia, the Caribbean, and severalAfrican countries are at increasedrisk for hospitalization with adiagnosis of schizophrenia (Shelley1976)

Epidemics

For both schizophrenia and MS,there are reports of clusters ofincreased prevalence in space andtime. Kurtzke and Hyllested (1986)documented the abrupt appearanceof MS in the previously MS-freeFaeroe Islands following the Britishoccupation in World War II. Arecent survey in Micronesia pre-sented similar findings for schizo-

phrenia (Dale 1981). Fortes andMayer (1969) studied a group ofvillages in Ghana in the 1950's andfound only one case of schizophre-nia in a population of 5,000 On hisreturn 26 years later to resurveythe area, Mayer found 13 cases per5,000. Between his first and secondvisits, the population had for thefirst time experienced considerableexposure to Western civilization.

Genetic Factors

Heredity has long been consideredof primary importance in schizo-phrenia and of much less signifi-cance in MS. However, concordancefigures for twins and siblings aresurprisingly similar for both dis-orders- 40-80 percent (MS) and50-60 percent (schizophrenia) formonozygotic twins, 5-10 percent forsiblings and DZ twins, and negli-gible risk for spouses in both dis-orders. Parents and children have arisk almost equal to sibs in bothdisorders (Gottesman and Carey1983; Bundey 1985). Since thepopulation risk for schizophrenia isat least 20 times higher than forMS, hentability of MS may be atleast equal to that of schizophreniaIn both disorders the heritabilityfactor is, however, considerably lessthan required for a purely geneticdisorder unless one introduces theincomplete penetrance explanation.Differences in geographical distribu-tions and migration patterns of thedisease are thus critical evidence ofenvironmental factors in thesedisorders.

There is considerable evidence foran association between several HLAfactors and MS in certain but notall populations studied (Stewart andKirk 1983). Although, in general,HLA studies have not supportedpredominance of one or more HLAfactors in unclassified schizophrenia

(McGuffin et al. 1983), in all sixcenters where a paranoid subgroupwas delineated, HLA A9 was in-creased; HLA Al was significantlyincreased in hebephreruc patientscompared with controls in three offour centers (McGuffin et al. 1981).Miyanaga et al. (1984) also reportedelevated incidence of DRW8 in agroup of Japanese patients withschizophrenia.

Season of Onset

The principal interest in season-of-onset differences for diseases ofunknown etiology is to relate suchdisorders to known fluctuations inincidence of recognized infections ortoxic syndromes. Analysis of ad-missions to mental hospitals in Eng-land and Wales during the 1970'sdemonstrated a 4.7 percent rise inadmission rate of schizophrenicpatients in July and August and a9 5 percent excess of admissions formania during the same period (Hare1983). From Japan, Abe (1963)reported a 9 percent excess ofschizophrenic admissions in Julyamong 90,000 patients admitted tohospitals between 1955 and 1961.

Although seasonal correlationswith onset or relapse of MS areless well demonstrated, Bamford etal (1983) reported a slight predomi-nance of attacks in the summermonths in Arizona and a differencein time of onset in several otherparts of the world Sibley et al(1985) reported that more than 25percent of clinical exacerbations ofMS are associated with upper respi-ratory infections.

Season of Birth

There has been great interest inthe unequal yearly distribution ofbirths in a number of disordersbecause this may indicate exposure

VOL 14. NO. 2,1388 235

of the fetus or infant to specialrisks at time of conception, birth,or during a critical intrauterineperiod. An approximately 8 percentexcess of births of future schizo-phrenic patients was shown duringwinter months and a 4 percentexcess in early spring months inthe large English-Wales populationstudied by Hare (1983). A relativeexcess of winter-early spring birthshas also been reported for Scan-dinavian countries, the UnitedStates, Japan, and Australia (Dalen1975; Parker and Baize 1977). In arecent study from Finland, Med-nick et al. (1987) found that theincidence of schizophrenia wasnearly doubled in a cohort ofschizophrenic patients who were intheir second trimester of gestationduring the widespread influenza Aepidemic of 1957. The data con-cerning preferred season of birthfor future MS victims are contro-versial. Dalen (1975) cites a singlereport from the Netherlands indi-cating an elevated optic neuritisincidence in individuals born inFebruary and March.

Immunological Factors

The strongest evidence that MS isan infectious or immunological dis-order stems from the reports ofintrathecal IgG synthesis, oligoclo-nal bands in cerebrospinal fluid(CSF), and decrease in T-cells dur-ing exacerbations of disease (Antelet al. 1978; Rostrom et al. 1981;Kastrukoff and Paty 1984). Thesefactors have been searched for in arelatively small number of schizo-phrenic patients. Ahokas et al.(1985) reported increased CSF IgGand oligoclonal bands in 36 percentof diagnosed schizophrenics, a find-ing only partially supported byKirch et al. (1985). Coffey et al.(1983) reported a reduction in T-

lymphocytes ' n patients with acute,including never-treated, schizophre-nia and a rise to normal ratiofollowing treatment with neurolep-tics. DeLisi et al. (1982, 1983) didnot find a reduction in total T-cellsin chronically hospitalized schizo-phrenia patients, most of whomwere taking neuroleptics, but didobserve a decrease in natural killer(NK) cells, a finding also reportedfor MS (Merrill et al. 1982).Decreased lymphocyte migration tomeasles or other antigens has beeninconsistently reported in MS (VanMeulen and Stephenson 1977) andin schizophrenia (Vartanian et al.1978).

Hirata Hibi et al. (1982) reportedabnormal lymphocytes resemblingthose of infectious mononucleosisin the peripheral blood of schizo-phrenic patients, a finding not con-firmed or attributed to pheno-thiazine effects by others (DeLisiet al. 1982). Again, studies of arelatively acute population by onegroup and chronic or drug-treatedpatients by another could explainthe discrepancy. Ultrastructuralabnormalities in lymphocyte nuclei(Bonartsev 1971) and other peri-pheral lymphocyte and serologicabnormalities including increasedantibrain antibodies (Kuritzky et al.1976; Kolyaskina 1983), abnormalprotein in the CSF (Harrington etal. 1985), and an inhibitory effectof schizophrenic serum onphytohemagglutinin-stimulatedlymphocytes (Vartanian et al. 1978)have been reported. Heath andKrupp (1967) described an IgGcomponent in schizophrenic serumdirected against the septal regionof the brain that induced be-havioral and electroencephalo-graphic changes in systemicallyinjected monkeys. Although a sim-ilar protein cross-reacting withbrain was identified from schizo-

phrenic serum in several otherlaboratories (Baron et al. 1977;Bergen et al. 1980), in most hands,autoantibodies against brain havebeen found with equal frequencyin schizophrenic and control sub-jects (Whittingham et al. 1968;Boehme et al. 1974; DeLisi et al.1985). Using immunocytochemicalmethods, we have not succeeded inour laboratory in demonstratingantibrain antibodies in serum orCSF of chronic schizophrenicpatients against normal or schizo-phrenic brain specimens from sep-tal regions, hypothalamus, orhippocampus (unpublished observa-tions). The effects of medicationand the great differences in thestage of illness in which patientsare studied are likely to be veryimportant barriers to achievingcoherent results.

Search for VirusInvestigation of serum and CSFantibodies to a number of commonviruses have been carried out inboth MS and schizophrenia. Ele-vated titers against measles aremost commonly specified for MS,but antibodies to herpes simplex(HSV), influenza A, mumps,Epstein Barr, rubella, and vacciniahave also been reported (Norrby1978; Cook and Dowling 1980;Cremer et al. 1980). Increasedserum and/or CSF titers againstHSV, influenza A, measles, andcytomegalovirus (CMV) have alsobeen reported in schizophreniafrom some laboratories (Halonen etal. 1974; Albrecht et al. 1980;Torrey et al. 1982; Libikova 1983)but unfortunately have not stoodup to replications (Lycke et al.1974; Gotlieb-Stematsky et al.1981; King et al. 1985; Rim6n etal. 1986). Tests for HTLV-III anti-body in schizophrenic serum and

236 SCHIZOPHRENIA BULLETIN

reverse transcriptase in CSF havethus far yielded negative results(Robert-Guroff et al. 1985; DeLisiand Saran 1986). Serum interferonelevation was found by Preble andTorrey (1985) but not by Rimon etal. (1983).

Following the publications ofAlbrecht et al (1980) and Torrey etal (1982) of increased CMV anti-body in CSF of patients withschizophrenia, we began a searchfor CMV and HSV antigen in thebrains of schizophrenic patients,many of whom had died at a rela-tively early age during both acuteand chronic stages of theirillnesses. Although our earlyimmunohistochemical studies withcrude CMV antisera yielded posi-tive results in a series of patients,with later use of affinity purifiedCMV antisera, we could not repli-cate our own initial positiveresults. Only 1 patient out of the22 we have studied demonstratedimmunoreactivity against CMV (inseveral large neurons of the vesti-bular nucleus) (Stevens et al. 1984).In other studies, high titer antiserato CMV, HSV-1 and HSV-2,mumps, measles, rubella, andrubeola were incubated with frozenspecimens of 10 schizophrenic and13 control brains. In one case, a21-year-old woman, ill for less than5 years before her death by sui-cide, there were scattered largeneurons in amygdala and hippo-campus that showed a distinct dif-fuse granular staining of the cyto-plasm but sparing of nucleusfollowing incubation with HSV-1antibody.

Although a number of differentviruses have reportedly been iso-lated from MS tissue, attempts toculture, cocultivate, or transmitvirus from MS plaques or nervoustissue have had generally disap-pointing results. A few similar

investigations have been carriedout with schizophrenic material.Libikova (1983) reported growth ofa herpes virus in cell cultures froma schizophrenic brain specimen.Tyrrell et al. (1979) described acytopathic effect on human embry-onic fibroblasts of CSF fromschizophrenic patients and fromindividuals with a number ofneurodegenerative disorders, butwere unable to passage the agentor inhibit its effect with metabolicor DNA and RNA antagonistsIntracerebral inoculation of mar-mosets with the cytotoxic CSFreportedly caused behavioralchanges (Baker et al 1983). Cyto-pathic effects of schizophrenic CSFwere also reported by Libikova(1983). No cytopathic effects wereobserved by Mered et al. (1983),who attempted to replicate theTyrrell et al. experiments with CSFfrom a new group of patients.

In 1979, a group of workers atthe National Institutes of Healthinjected material from 20 brainspecimens of patients diagnosed(mostly chronic) schizophrenia andfrom 19 controls with other neuro-logical disorders, including MS, intoguinea pigs {n = 22) and subhumanprimates (n - 37). Animals weresacrificed or died 2-4 years later.With the exception of one guineapig that developed a paralysis ofthe hindlimbs 18 months afterinoculation with material from apatient who committed suicide dur-ing the first year of his schizo-phrenia, no illness ensued in theother animals. Examination of cen-tral nervous system (CNS) tissuefrom these animals with light andelectron microscopy generally failedto reveal significant pathology(Kaufmann et al. 1983)

During the past 2 years, we haveinoculated fresh and frozen brainand CSF from 24 schizophrenic

patients and 10 controls on culturesof human dorsal root ganglia,human neuroblastoma, and medullo-blastoma cells. Although no cyto-toxic changes have been observed,one line of neuroblastoma cellsinoculated with fresh CSF fromschizophrenic patients has shownchanges in growth characteristicsand increased cyclic adenosinemonophosphate (AMP) productioncompared with controls. Theresponsible agent has been pas-saged in subcultures and cell-freemedia CSF from additionalpatients and controls is underinvestigation (J.P Schwartz andJ.R. Stevens, unpublished).

Electron Microscopy andGenome Hybridization

Electron microscopic studies of MShave yielded controversial results.Although several workers havedescribed viral-like particles, thesefindings have generally not beenconfirmed (DuBois-Dalq et al 1973;Melnick et al. 1982; Lampert andLampert 1975). Most recently,Koprowski et al. (1985) reportedfinding both serum antibodies toHTLV and genomic material of aretrovirus related to HTLV-1 inCSF T-cells of patients with MS.This work awaits replicationAlthough much less extensivelyinvestigated than in MS, virus-likeparticles resembling herpes simplexhave also been described in schizo-phrenic brain specimens by Mesaand Cabrera (1979). As in MS,there are no convincing replicationsand further studies are required Insitu hybridization for CMV viralgenome has been negative in MSand in schizophrenic brain speci-mens in our hands and others(Aulakh et al. 1980, 1982, Taylorand Crow 1986). Reported HSVgenome in schizophrenic brains

VOL 14, NO. 2,1988 237

(Sequiera et al. 1979) may be dueto specious hybridization withhuman DNA (Jones and Hyman1983).

Discussion

Similarities between the course ofillness and of several epidemiologi-cal features of MS and schizo-phrenia suggest that both disordersmay be of infectious or immuno-logical origin. This concept haslong received wide acceptanceamong neurologists for MS, but isgenerally viewed with some incre-dulity for schizophrenia.

There are also, of course, veryimportant differences between MSand schizophrenia. MS is associatedwith characteristic neuropathologi-cal changes in the brain and spinalcord that generally correspond toand account for the clinical signsand symptoms of the disease. Themore modest and variable neuro-pathological and radiologicalabnormalities of schizophrenia arestill subjects of argument amonginvestigators. Thus, Roberts et al.(1986), using an optical densi-tometry method to measure glialfibrillary acid protein in schizophre-nic and control material, concludedthere is no evidence for the gliosisof schizophrenic brains reported byothers. Inspection of their data,however, reveals that althoughtheir method is very insensitive togliosis (even the intensely gliosedcaudate nucleus of Huntington'schorea showed only a 4.1 percentincrease compared with control), 17out of 20 areas of schizophrenicbrain measured showed more glio-sis than controls (p < .0001)(Casanova et al. 1987).

Clinical-pathological correlationsare difficult and imprecise in a dis-order characterized by symptomsand signs that have no agreed-

upon anatomical substrates.Moreover, it is not known whetherthe changes that have been foundin a percentage of patients (e.g.,increased ventricular size, atrophicor dystrophic nuclear masses, glio-sis, and increased dopamine recep-tors in striatum) antedate, coincidewith, or follow the onset and pro-gression of the illness and itstreatment.

There are other important differ-ences between these disorders. MSis more common in females by aratio of 1.5:1, while age of onset isslightly lower and prognosis lessfavorable in females than males. Incontrast, the incidence of schizo-phrenia is approximately equal formales and females, the age ofonset is 5 to 10 years later inwomen (Mayer Gross et al. 1960;Eaton 1985), and the prognosis forfull or partial recovery in womenis considerably better (Watt et al.1983). The earlier the onset ofschizophrenia, the worse the prog-nosis, while for MS, the oppositeis the case. Schizophrenia isreportedly more common in blacksthan whites in the United Statesand in the city than in rural areas.The opposite is the case for MS.For both MS and schizophrenia,the search for an infectious agenthas turned up evidence for in-creased antibody production to anumber of common viruses, butreplications of these data forschizophrenia are few.

It is not difficult to associate aviral etiology with MS, as theacute disease is associated with dis-tinct inflammatory lesions in theCNS that later become glioticplaques. However, it is now evi-dent that viral infection need notcause either cell destruction orreactive inflammation, but may beassociated with only altered cell me-tabolism or membrane properties

(Knight 1982; Oldstone et al. 1984;Manuelides et al. 1987).

There is solid evidence for de-creased T-suppressor cells in periph-eral blood, coincident with exacer-bations of MS, and for thepresence of oligoclonal bands inCSF in 85-90 percent of MSpatients. There is a single reportof decreased T-suppressor cells inperipheral blood in schizophrenia(Coffey et al. 1983) and a singleinstance of oligoclonal bands foundin CSF (Kirch et al. 1985). Thisarea needs further investigation inuntreated patients early in the dis-ease process. In both schizophreniaand MS, there are inconsistentreports of an autoimmune processdirected against the brain. Recentadvances in molecular and immuno-logical techniques offer new oppor-tunities to resolve the earlier con-troversial data. The viralhypothesis of schizophrenia (orMS) does not require that the dis-order itself be contagious. Indeed,there is no evidence of this foreither schizophrenia or MS.Spouses of patients with eitherdisease have no greater incidenceof the illness than the generalpopulation. The strong evidencefor genetic predisposition in bothillnesses suggests that if a virusinitiates the illness, this complica-tion is related to the uniquegenetic characteristics of the indi-vidual response.

This essay does not suppose orsuggest that schizophrenia and MShave similar etiologies, but onlyproposes that as for MS there aregood reasons to seek infectious orimmunological factors as causalagents in schizophrenia. Nor doesthis hypothesis propose a singlecause for all cases of schizophrenia.Comprehensive epidemiologicalstudies, especially in the developingcountries, evaluation of immunolog-

238 SCHIZOPHRENIA BULLETIN

ical and potential infectious factors,especially during the acute diseaseprocess, and ultrastructural andmolecular investigations of braintissue are areas needing furtherinvestigation.

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The AuthorJanice R. Stevens, M.D., is Profes-sor of Neurology and Psychiatry,Oregon Health Sciences University,Portland, OR, and Senior StaffPhysician, Intramural ResearchProgram, NIMH, NeuropsychiatricResearch Hospital at St. Elizabeths,Washington, DC.