Medical Science Publication No. 4, Volume II
NEUROTROPIC VIRAL DISEASES IN THE FAR EASTDURING THE KOREAN WAR*
WILLIAM L. POND, PH.D., AND JOSEPH E. SMADEL,M. D.
Introduction
When one speaks of neurotropic viruses he generally has in mind thearthropod-borne encephalitides, poliomyelitis, and rabies. However, theneurotropic virus group is generally extended to include many other viruseswhich affect the central nervous system, for example, agents of lymphocyticchoriomeningitis, mumps, the Coxsackie group, and the agents from mosquitoesand patients of the equatorial areas of Africa and South America; thislast group has, in our patois, come to be known as the "tropical group"of viruses.
It should be mentioned at once that the two neurotropic virus diseasesof importance in the Korean conflict were Japanese encephalitis and poliomyelitis.The total numbers of cases occurring in American troops in Korea duringthe years 1950-1953 were not great, 402 of encephalitis and 120 of paralyticpoliomyelitis.
At the beginning of World War II the subject of Japanese encephalitiswas one which caused much worry to those concerned with maintaining thehealth of American troops in case they should enter the areas where thisdisease was endemic. One had only to recall the great epidemics in Japanand the complete susceptibility of Americans to this virus which does notexist in the Western Hemisphere to understand the reasons for such worry.The theme of this report is to de-emphasize to some extent the militaryimportance of Japanese encephalitis. However, it should be pointed outat once that the basis for de-emphasis has developed since the end of WorldWar II. Moreover, we should continue to respect the judgment and admirethe work of those who contributed so much to our knowledge and preparednessin this field during World War II.
Incidence of Japanese Encephalitis
The number of cases of encephalitis in civilian populations of Japan,Korea, and Okinawa in certain years since 1924 are indicated in table 1.Epidemic encephalitis has been recognized as a clinical entity in Japanat least since 1924 (1). Subsequently, epidemics were recognizedin
*Presented 28 April 1954, to the Course on Recent Advances in Medicine and Surgery, Army Medical Service Graduate School, Walter Reed Army Medical Center, Washington,
D. C.
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Table 1. Number of Cases of Encephalitis inCivilian Populations of Okinawa, Korea, and Japan from 1924-52
| Number of cases of encephalitis in civilians of- | ||
Japan (population 75,000,000) | Korea (population 20,000,000) | Okinawa (population 500,000) | |
1924 | 6,125 | (*) | ----- |
1935 | 5,370 | ----- | ----- |
1946 | 150 | ----- | 32 |
1947 | 259 | ----- | 196 |
1948 | 7,208 | ----- | 47 |
1949 | 1,294 | 5,548 | 35 |
1950 | 5,182 | ----- | 31 |
1951 | 2,152 | Rare | 45 |
1952 | 711 | ----- | ----- |
*Designates data not known.
this population yearly with incidences ranging from 150 cases up toover 7,000 cases (1-3). The disease was recognized in Korea at leastin 1949 (4); however, the mass movement of civilian residents hasprecluded any reliable data during the years of the Korean conflict exceptthat the incidence of encephalitis in Korea, 1951, was considered rare(2). Encephalitis on Okinawa has been studied extensively by Americanpersonnel, yielding data (2, 5, 6) more reliable than the otherdata presented, since most statistical data are compilations made throughnative public health organizations.
The actual experience of the American troops with encephalitis is epitomizedin table 2 which summarizes the annual incidence of encephalitis in Americanpersonnel in the Far East (5-8) and also
Table 2. Number of Cases of Encephalitis inMilitary Forces, Their Dependents, and Department of the Army Civiliansin Various Areas of the FECOM
| Number of cases of encephalitis | Proved Japanese encephalitis FECOM | |||
Japan | Korea | Okinawa | FECOM | ||
1946 | 0 | 4 | 0 | 4 | 4 |
1947 | 23 | 2 | 2 | 27 | 2 |
1948 | 23 | 0 | 16 | 39 | 31 |
1949 | 17 | 0 | 17 | 34 | 13 |
1950 | 26 | 299 | 17 | 342 | 201 |
1951 | 11 | 21 | 16 | 48 | 7 |
1952 | 65 | 36 | 17 | 118 | 30 |
1953 | 53 | 46 | 29 | 128 | 10 |
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indicates the number of cases which were proved to be caused by Japaneseencephalitis virus. Such proof was obtained at the 406th Medical GeneralLaboratory and consisted of isolation of the virus from autopsy or clinicalmaterials or demonstration of specific antibodies in the sera of convalescentpatients.
The figures for 1950 are of particular importance since they includethe outbreak during the late summer and early fall in our troops who werethen compressed into the Pusan perimeter (6). Colonel Long willreport the details of this episode later in this symposium, hence no morewill be said about it now. It is worth pointing out that, during 1950,when the vast majority of cases of encephalitis in the Far East Commandconsisted of cases from the Korean epidemic, about two-thirds of the patientswere proved to have been infected with the virus of Japanese encephalitis.Since then a progressively smaller proportion of the cases with a clinicaldiagnosis of encephalitis have been caused by Japanese virus. This mattercannot be explained on the basis of inadequate laboratory methods sincethe armamentarium of technics has been constantly improving in recent years.It is suggested that this change is connected with such factors as theincreasing awareness of clinicians regarding the diagnosis of central nervoussystem infections and their tendency at times to include patients withaseptic meningitis in the group of encephalitides. Many of the paired serahave been tested in the usual battery of diagnostic procedures employedat the 406th Medical General Laboratory and the Army Medical Service GraduateSchool (3) without throwing light on the etiology.
Japanese Encephalitis Vaccine
An important decision regarding vaccination against Japanese encephalitiswas made during the Korean conflict. Therefore, it is appropriate to reviewthe background for the decision and to estimate its effects.
Vaccination against Japanese encephalitis had been practiced by theRussians since 1941 (9), and in the United States a formalinizedmouse brain vaccine was developed by Sabin and others for trials in theU. S. Army (10). This mouse brain vaccine was safe and potent asjudged by laboratory tests (10). Inoculation of over 250,000 personson Okinawa with this type of vaccine in 1945 and 1946 (11) did notprovide sufficient data to draw a firm conclusion as to its efficacy inengendering immunity to Japanese encephalitis. Dr. Sabin claimed that nocase of demyelinating encephalitis occurred in these vaccinated troops.However, he noted three cases of polyneuritis (one fatal) in this vaccinatedgroup but also pointed out that patients with the same signs were presentduring this period in non-vaccinated troops.
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In 1945 and 1946, commercially prepared mouse brain vaccine was usedin the Far Eastern Theater (12). The new chick-embryo-type Japaneseencephalitis vaccine was introduced into the Far East in 1946 (12),when, in this year and in 1947, the Army Medical Service Graduate Schoolsupplied over 800,000 ml. of mouse brain vaccine. These vaccines were effectivein protecting mice against challenge with Japanese encephalitis virus andin eliciting neutralizing antibodies in 60 percent of human volunteersinoculated under controlled conditions. Routine immunization of all troopsin the Far East Command with the chick embryo vaccine was adopted in 1948and continued until the fall of 1951.
Of 11,338 persons inoculated with Japanese encephalitis chick embryovaccine, on whom observations were made in the Far East and the recordsforwarded to The Surgeon General's Office, eight developed reactions ofan allergic nature. Three of these were classed as severe and anaphylacticin nature with onset varying from 20 minutes to 24 hours after administrationof vaccine. The other five had moderate reactions characterized by feverand urticaria. There were no fatalities (13).
Trials of the vaccine were also made in civilians and those trials inOkayama, Japan, offered the most complete results (6). In 1946 over14,000 children in Okayama received three inoculations of commerciallyprepared mouse brain vaccine and in 1948 and 1949 almost 40,000 additionalchildren were vaccinated in the same manner with the standard Army chickembryo vaccine. After the initial series of inoculations each child wasrevaccinated yearly until 1950 with one stimulating dose of the chick embryovaccine. Thus, during the period 1946-1949, over 50,000 children between5 and 10 years of age were vaccinated, leaving other children unvaccinated.
This population was observed yearly and the results (quoted from Dr.Sabin's report to the Virus and Rickettsial Commission, Armed Forces EpidemiologicalBoard) (14) were as follows: ". . . the incidence of the diseasein the unvaccinated group turned out to be much less than was anticipated.The evaluation of the results is further less than was anticipated. Theevaluation of the results is further complicated by the fact that onlya varying and sometimes small proportion of the clinically diagnosed caseswere studied serologically. Nevertheless, during the years of 1948 and1949, when chick embryo vaccine was administered and a sufficient numberof clinically diagnosed cases occurred in the group under investigation,the incidence was 7.6 and 9.2 times higher in the unvaccinated than inthe vaccinated group. While the data are not statistically significantfor any one year, they do achieve such significance when the results forthe years 1947 to 1949 are combined. Even in 1950, when no vaccine wasadmin-
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istered but a residual effect from the previous years might still havebeen in operation the incidence was 4.6 times greater in the unvaccinatedgroup. It should be noted that cases, not all confirmed, occurred amongthe vaccinated, but the incidence was at all times greater among the unvaccinated.However, these results cannot be completely transposed to individuals ofArmy age, since it has been found that the same dosage of vaccine givesrise to a higher incidence of neutralizing antibodies in children thanin adults . . . ."
The value of the vaccine in protecting U. S. troops was more difficultto judge. This was due to the lack of control of unvaccinated troops, theirrapid movements, and the lack of complete individual immunization records.Using those data available, however, a reconsideration of the value ofthis vaccine was made by certain members of the Virus and Rickettsial DiseaseCommission, Armed Forces Epidemiological Board, in the fall of 1951. Briefly,the considered opinion (15) was:
There is some evidence that the annual administration of this vaccineto Japanese children has lowered the incidence of clinically reported casesin Okayama prefecture (in Japan).
The evidence so far fails to indicate that vaccination of the U. S.troops in Japan and Korea has been effective as a prophylactic measure.No controlled studies have been made in American troops and the data collectedhave not proved conclusively that the vaccine is worthless. It appears,however, that the vaccine is of dubious value as a prophylactic measurefor the protection of troops.
On the basis of these recommendations, the commercial production ofJapanese encephalitis vaccine was stopped and the Adjutant General orderedthat, "effective with the 1952 season," routine vaccination ofpersonnel in the Far East Command with Japanese encephalitis vaccine cease(16).
The failure of the vaccine has been attributed by some to low potencyand lack of stability. At the present time no vaccine is available forroutine vaccination of military personnel against Japanese encephalitisbut a search is still being carried out at the Army Medical Service GraduateSchool for a safe, potent and stable immunizing material to be used againstthis disease. To achieve this, various procedures have been attempted withoutyielding any preparation with advantages over formalinized mouse brainvaccine, already used in the field. The procedures have included investigationsof various methods of inactivation of Japanese encephalitis virus suchas the use of ethylene oxide, acetone, high-speed cathode rays, ultravioletlight, ultrasonic vibration, and various levels of formaldehyde (17);various methods of purification using protamine sulfate, norite, cellite,or
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attaclay (17); attempts to obtain higher titers of virus to usein a vaccine (17); and attempts to attenuate the infectivity ofthe virus for use as a live virus vaccine (17). At the present timea satisfactory immunizing agent against Japanese encephalitis is consideredhighly desirable.
Recent Research on Japanese Encephalitis
Most of the recent advances concerning Japanese encephalitis have beenin its ecology and this approach has been most fruitfully pursued at the406th Medical General Laboratory in Tokyo (2, 3, 6). It had alreadybeen found by them that Japanese encephalitis epidemics occurred at thesame time as the Culex tritaenorrhynchus mosquito population peak;moreover, without this peak, epidemics did not occur. Even with this informationit was not known how the mosquito became infected and potentiated the virusduring inter-epidemic seasons. Investigations on the ecology of this diseasein Japan revealed that certain migrating fowl also experienced infectionwith Japanese encephalitis virus and the mosquitoes associated with themwere found to contain active virus but at approximately the same time thatepidemics occurred in man. This does not indicate that the fowl is a reservoirof infection but indicates that it may be vitally concerned in the potentiationof the epidemic, once started. It should be mentioned that viral infectionshad previously been diagnosed in animals in Japan (18) when no visibleepidemic was occurring in human beings in the same locality.
The use of hemagglutination-inhibition procedures for demonstrationof antibodies to Japanese encephalitis as well as to certain other arthropod-borneviral diseases has been described in the literature (19, 20) andoffers hope as an additional diagnostic tool. Although much experienceneeds to be obtained with any new diagnostic tool in order for it to beof value and to establish suitable criteria for its use as a routine diagnosticaid, this procedure is being evaluated at the present time in Japan (3).In conjunction with the complement-fixation test and neutralization testit may form part of a widely varied armamentarium of available diagnostictests.
At the time of the Korean conflict, studies on Japanese encephalitiswere proceeding in other geographical locations: in 1951, a U. S. ArmyMedical Research Team, in conjunction with British scientists, isolateda virus from a fatal case of encephalitis in Malaya which was later identifiedas Japanese encephalitis virus (21). Subsequently other isolationsof this same virus were made by British investigators in Malaya (22,23).
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Serological studies carried out by the Japanese in World War II (24)and by the U. S. Army Medical Research Team in 1951 (25) indicatedthat 75 percent of the Malayan indigenous population tested had evidenceof past infection with Japanese encephalitis virus. Also most pigs, bovines,equines, and dogs showed evidence of past infection. This is in no waydifferent from serological studies carried out in Japan (18, 26)but epidemic encephalitis has been reported very rarely in Southeast Asia(25). The lack of outbreaks is thought to be due to the possiblepresence of arthropod vectors throughout the year in this tropical regionbut this does not explain the quantitative lack of clinical cases one wouldexpect in a population where Japanese encephalitis virus is continuallypresent. A semi-permanent U. S. Army laboratory was established in 1953at the Institute for Medical Research, Kuala Lumpur, Malaya, and therefurther studies on the ecology of Japanese encephalitis as well as otherarthropod-borne viral diseases are being carried out.
Using published results in which neutralizing antibodies to Japaneseencephalitis in man and animals have been described, Japanese encephalitisvirus has been isolated and identified, or cases of Japanese encephalitishave been proved, a chart of the probable distribution of Japanese encephalitisin the world has been constructed as figure 1. Although the zones of Japaneseencephalitis incidence appear dispersed, as exemplified by serologicalsurvey results in the cities of Kirin, Tientsin and others, it would seemlogical from the data to consider Japanese encephalitis present, not asfoci, but as a broad endemic band in all of Eastern Asia (4, 7, 9, 21,22, 24, 25, 27, 32), at least as far north as the Maritime Districtof Siberia and extending south well into the East Indies, possibly eveninto New Guinea and Australia. This band would include the islands offthe coast of Asia; of Japan (1, 26), Okinawa (5, 11, 28),Formosa (24, 33), Guam (34), the Philippine Islands (24,35, 36), and Borneo (25). Moreover, it is believed on the basisof serological surveys that the disease extends to the westward in SouthernAsia at least as far as India (37); antibodies to this virus wereeven reported at one time in the sera of African residents (38).However, in certain of these areas, notably Africa, where serological surveysindicate that West Nile virus is present, such data must now be interpretedwith some caution; since an antigenic relationship is known to exist betweenWest Nile and Japanese virus, and may exist between other "tropicalviruses" and the Japanese encephalitis virus (39).
In 1951 an epidemic of encephalitis occurred in Australia and from thisoutbreak an infective agent was isolated (40) and identified asa newly recognized arthropod-borne virus called Murray Valley encephalitisvirus, closely related antigenically to Japanese encepha-
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litis virus (41). Its distribution and importance outside Australiaare not known. However, because of its very close antigenic relationshipto Japanese encephalitis virus it could logically be considered a variantof Japanese encephalitis virus in the same way as influenza A´ isa variant of influenza A. Interesting speculations have been publishedthat this newly discovered virus disease is a recurrence of AustralianX disease last seen in Australia in 1925 (42). Its distributionin Australia, and possibly in New Guinea (43), is indicated alsoin figure 1 in lighter shading. It should be pointed out that the limitsof the endemic Japanese encephalitis areas, as represented on this map,are delineated not by evidence of the lack of disease but by our ignorance.
Russian Spring-Summer Encephalitis
Russian spring-summer encephalitis (RSSE), a tick-borne disease, wasnot observed in any American troops in the Far East nor has
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any report been received of RSSE in our troops in Korea. Louping ill(LI), serologically similar (44) and even indistinguishable (45)from RSSE, is a cause of epizootics in sheep in the British Islands butthe relationship of these epizootics to the epidemics of RSSE is not clearlyunderstood. The probable geographic distribution of RSSE and LI is indicatedin figure 2.
It is unfortunate that we do not have more accurate data on the distributionof this important disease. However, language barriers as well as the lackof published experimental data require us to form only general conclusionsas to the location of those zones in the Soviet Union where RSSE has existedand may now exist. RSSE is predominantly a disease of the U. S. S. R. (1)extending from the steppes of Russia in East Siberia to continental Europewhere the disease has been recognized in West Russia. Outbreaks have beenreported recently from Central Europe; in Czechoslovakia (46), aswell as in Austria and Slovenia. (47). Here it is termed by someworkers as Central European encephalitis. Louping ill exists predominantlyin the British Islands where it has been endemic for over a century andonly a few cases of human infection under natural conditions have beenreported from the area representing the LI distribution (48-50).
Neutralizing antibodies to RSSE virus were found in the sera of a fewinhabitants of India (37) but as yet such antibodies have not beenreported in Southeast Asia, Japan or Korea (24). Its presence inKhabarovsk, in the eastern Maritime Province of Siberia, was dangerouslyclose to the area of combat during the Korean conflict. This severe neurotropicvirus disease, as judged by morbidity, case fatality rate and presenceof residual signs, has not yet been recognized in Korea nor have neutralizingantibodies to this virus been demonstrated in small numbers of sera testedfrom Japanese nationals (17) and Okinawan natives (5).
Russian spring-summer encephalitis mouse brain vaccine used for vaccinatinglaboratory personnel working with this virus has been satisfactory foreliciting neutralizing antibody responses in these individuals and forprotecting mice against subsequent challenge with RSSE viruses. In thehands of the Russians, the vaccine was reported to decrease the rate ofinfection in Siberian residents (1). It appears, however, that thisvaccine cannot be lyophilized without losing large amounts of antigenicity(17). Therefore, it must be left in the wet state under refrigerationand under these conditions it becomes antigenically unsatisfactory within60 to 90 days (17, 27).
Other Arthropod-borne Virus Diseases, Rabies and Poliomyelitis
In the years preceding and during the Korean conflict, St. Louis encephalitis,Western equine encephalomyelitis and Venezuelan equine
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encephalomyelitis were reported only in the Western Hemisphere. However,Eastern equine encephalomyelitis, another disease of the Americas, wasrecognized in the Philippine Islands (51).
Although rabies never became a serious problem in the Far East Commandand only one human case was recorded in U. S. troops (6), nevertheless,laboratory facilities were frequently employed in the Far East on diagnosticwork on specimens submitted from animals suspected of having rabies. Duringthis period, ideas regarding prophylaxis against this disease in exposedhuman beings, guided by the recommendations of investigators in this field(52), swung toward administration of immune serum coupled with fewerdoses of the standard rabies vaccine. As yet, the use of this method inthe Army is reserved for those persons experiencing possible accidentalinfection with rabies in the laboratory. Although there are other worth-whilerecent advances in the prophylaxis against this disease, such as the WorldHealth Organization sponsored field use of the avian adapted Flury vaccinein dogs (53), these had little or no effect on the practice of medicinein Japan and Korea during the period of the Korean conflict.
Table 3. Number of Cases of Paralytic Poliomyelitisin Military Forces, Their Dependents, and Department of the Army Civiliansin Various Areas of the FECOM During the Korean Conflict
| Number of cases of poliomyelitis | |||
Japan | Korea | Okinawa | FECOM | |
1950 | 19 | 10 | 0 | 29 |
1951 | 4 | 21 | 1 | 26 |
1952 | 34 | 25 | 3 | 62 |
1953 | 30 | 64 | 24 | 118 |
Clinically diagnosed paralytic poliomyelitis accounted for about one-fourthas many cases of central nervous system infection (3, 8) duringthis period as did infectious encephalitis (table 3). The technical difficultiesin laboratory diagnosis of poliomyelitis are only now being resolved; hence,little has been done among troops in the Far East regarding laboratoryproof of inapparent infection and non-paralytic disease caused by the threeantigenic types of poliomyelitis virus. Nevertheless, these forms of theinfection undoubtedly are fairly common in such personnel as they are inany group with a high proportion of susceptibles that live in contact withrelatively unsanitary populations in which poliomyelitis virus circulatesfreely. In one group of 18 soldiers in Japan who were diagnosed clinicallyin
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1946 as having aseptic meningitis, 2 were shown by laboratory studiesto have suffered an infection with poliomyelitis virus (54).
No isolation of Coxsackie agents was reported from the military forcesin the Far East Command during the Korean War. However, the members ofthis ubiquitous group have become so numerous and their identificationso cumbersome that routine diagnosis is usually avoided.
Lymphocytic choriomeningitis was not reported as a cause of diseasein the Far East Command during or just preceeding the Korean conflict.Moreover, materials from 47 cases of aseptic meningitis from this theaterwere studied in the laboratory for evidence of infection with the agent,with negative results (3). However, with the wide geographic distributionof lymphocytic choriomeningitis virus in mice, it would be presumptuousto conclude that this disease has never occurred in troops of the Far EastCommand.
We should not close this discussion without mentioning that group ofheterogeneous agents conveniently called the "tropical viruses."These viruses, isolated in Africa or South America, sometimes from manbut usually from mosquitoes, produce a fulminating encephalitis in micewhen inoculated intracerebrally, but the nature of most of the diseasescaused by these viruses under natural conditions is yet unknown. They are,no doubt, arthropod-borne viruses but whether in man most of them are neurotropicin character remains to be determined. Much effort is being expanded currentlyby groups from the Rockefeller Foundation and the Army Medical ServiceGraduate School to determine the distribution of these viruses in the worldand their importance as causes of diseases in man. These agents include:Semliki (55), Uganda S (56), Ntaya (57), AnophelesA (58), Anopheles B (58), Wyeomyia (58), Zika (59),Ilheus (60), West Nile (61), Bunyamwera (62), Mengo(63), and Bwamba, (64).
No discussion of neurotropic viruses in Northeast Asia could neglectto mention at this time (April 1954) the additional available informationon the occurrence of arthropod-borne viral agents in Southeast Asia, particularlyIndochina. Recent, and as yet unpublished, serological surveys undertakenin our laboratory in collaboration with other groups of workers, as wellas other recently published results (65) indicate that infectionswith Zika, Ntaya, Ilheus, and Dengue I and II viruses are almost as frequentin the population of Malaya as is that with Japanese encephalitis virus.Furthermore, Semliki Forest and Uganda S agents have left a few antibodytrails in this area but Anopheles A and B, Bunyamwera, Bwamba and Wyeomyiahave not. Little is known about the occurrence of these agents in the morenortherly parts of Southeast Asia; however, the flora and fauna of muchof this general region are similar and one would anticipate that
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the viruses of Malaya spread beyond its geographic boundaries. Japaneseencephalitis virus, at least, is found in Indochina and Burma; during WorldWar II Japanese investigators found antibodies against this agent in 44percent of the native peoples of Hanoi and in 52 percent of the horsesin Burma (24).
Conclusions
What new things have we learned about the neurotropic viruses as militaryproblems from the Korean experience? The following statements answer thequestion in part at least.
1. Japanese encephalitis has not yet been brought under adequate controlin armies in the field by either immunization or mosquito control measures.Additional work is indicated in preventive measures.
2. Despite this, Japanese encephalitis has not turned out to be theawe-inspiring epidemic disease which the Americans in 1942 thought it mightprove to be, when susceptible populations were brought into endemic areas.Four hundred and two cases of encephalitis occurred in American militaryforces in Korea during the years 1950 to 1953 and about half of these wereproved to be caused by Japanese encephalitis virus.
3. Paralytic poliomyelitis was the second most important neurotropicvirus disease among troops in Korea with 120 cases occurring over the period1950-53. With the increasing numbers of susceptibles (no neutralizing antibodiesagainst one or more of the three types of poliomyelitis virus) among youngAmerican adults, poliomyelitis can be expected to be an increasing problemamong troops maintained under unsanitary conditions or in contact withforeigners with unsuitable habits.
4. Other neurotropic viral diseases were of relatively little importanceduring the Korean conflict. No evidence of infection with Russian spring-summerencephalitis virus has been encountered in our forces in Korea. Fifty toa hundred sporadic cases of central nervous system disease in which a viraletiology was suspected occurred in the Far East annually from 1950 to 1953,but the responsible etiological agents in most instances remained undetermined,a finding also common in other geographic areas.
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