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adolescents have been identified in countries free of BSE However, m any
mdtvtdual case, a putative lmk with BSE can only be determined through other
methods, for example, laboratory transmission studies.
The evident dlfficulttes m studying a rare disease with a prolonged mcuba-
tlon pet-rod would be resolved tf there were an in VIVO diagnostic marker for
mfectlon. There have already been remarkable advances in the understanding
of basic pathogenic mechanisms m prton dtseases and It may be that the cause
of sporadic CJD will be ldentlfied from further basic sctenttfic research rather
than through eptdemlology.

References
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cerebral amyloidoses caused by unconventional viruses, m Fuzld™s Vzrology
(Fields, B. N. and Knipe, D. M., eds), Raven, New York, pp. 2289-2324
2 Hstao, K., Baker, H F , Crow, T J., Poulter, M , Owen, F., Terwtlhger, J D ,
Westaway, D., Ott, J., and Prusmer, S B (1989) Lmkage of a prion protein mis-
sense variant to Gerstmann Strausslersyndrome Nature 338,342-345
3 Hstao, K , Memer, Z , Kahana, E , Cass,C , Kahana, I., Avrahami, D., Scarlatto,
G., Abramsky, O., Prusmer, S. B , and Gabtzon, R (1991) Mutation of the prton
Prion Disease Surveillance 135
protem m Libyan Jews wtth Creutzfeldt-Jakob drsease. New Engl J Med 324,
1091-1097
4 Medori, R , Tritschler, H J , LeBlanc, A., Vdlare, F , Manetto, V , Ymg Chen, H ,
Xuf, R , Leal, S., Montagna, P , Cortelli, P., Tmuper, P , Avon], P , Mocha, M ,
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P (I 992) Fatal famihal msomma, a prron drsease wrth a mutation at codon 178 of
the prron protem gene New Engl J Med. 326,444-449
5. Cousens, S. N., Harries-Jones, R., Knight, R., Wrll, R G , Smith, P G , and
Matthews, W B (1990) Geographical distribution of cases of Creutzfeldt-Jakob
dtsease m England and Wales 197U-84. J Neural Neurosurg Psychzat. 53,45+465
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in the Umted Kingdom-Thud Annual Report
7 Brown, P and Cathala, F (1979) Creutzfeldt-Jakob disease m France, m Slow
Transmzsszble Dzseases ofthe Nervous System, vol. 1 (Prusmer, S B. and Hadlow,
W J , eds.), Academic, New York, pp 213-227.
8 Rudge, P (1989) Clmtcal neurology: a review. J Roy Co/f Phys. Land 23,
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9 Davampour, Z , Smoak, C , Bohr, I , Sobel, E , Llwmcz, B , and Chang, S (1995)
Death certificates. an efficient source for ascertainment of Creutzfeldt-Jakob drs-
ease cases Neuroepzdemiology 14, l-6
10 Holman, R C., Khan, A S , Kent, J , Strme, T W., and Schonberger, L B. (1995)
Eprdemiology of Creutzfeldt-Jakob disease m the United States, 1979-l 990,
analysrs of nattonal mortahty data Neuroepzdemzology 14, 174-l 8 1
11 Will, R G , Matthews, W B., Smith, P. G , and Hudson, C (1986) A retrospec-
tive study of Creutzfeldt-Jakob drsease m England and Wales 1970-l 979 II: epr-
demrology. J. Neural Neurosurg. Psychzat. 49,749-755
12 Jones, D P and Nevm, S. (1954) Rapidly progressive cerebral degeneration (sub-
acute vascular encephalopathy) with mental drsorder, focal disturbance, and
myoclonlc epilepsy. J Neurol Neurosurg Psychzat 17, 148-159.
13. Masters, C. L , Harris, J. 0 , GaJdusek, D C , Gibbs, C J , Jr , Bernoulli, C ,
and Asher, D M. (1979) Creutzfeldt-Jakob drsease* patterns of worldwide
occurrence and the significance of famrlral and sporadic clustering. Ann Neural
5, 177-188
14 Will, R. G. and Matthews, W B (1984) A retrospectrve study of Creutzfeldt-
Jakob disease m England and Wales 1970-79 I: clmtcal features. J Neural
Neurosurg Psychzat 47, 134-140
15. Miyanaga, K , Takahashi, S., and Fukuda, M. (1982) An autopsy case of
Alzheimer™s disease accompanied with periodic synchronous discharge and
myoclonus. Clzn. New-01 22, 128-134.
16 Will, R. G. and Matthews, W. B. (1992) Creutzfeldt-Jakob disease epidemrology,
in Przon Diseases of Humans and Anrmals (Prusmer, S. B., Collmge, J., Powell,
J., and Anderton, B., eds.), Ellis Horwood, Chichester, pp. 188-199
17. Bell, J. E and Ironside, J W (1993) How to tackle a possible Creutzfeldt-Jakob
disease necropsy J Clzn Path01 46, 193-197
136 Will

18 Salazar, A M , Masters, C L , Gajdusek, D C , and Gibbs, C J , Jr (I 983) Syn-
dromes of amyotrophic lateral scleroses and dementia* relation to transmtsstble
Creutzfeldt-Jakob disease Ann Neurol 14, 17-26
19. Brown, P , Kaur, P , Sulima, M P., Goldfarb, L , Gibbs, C J., Jr., and GaJdusek,
D C (1993) Real and imagined clmicopathologtcal hmtts of “prton dementta”
Lancet 341,127-129
20 Collmge, J , Poulter, M , Davts, M B , Barattser, M , Owen, F , Crow, T J , and
Harding, A E (1991) Presymptomatic detection or exclusion of prton protem
gene defects m famthes wtth Inherited prton diseases Am J Hum Genet 49,
1351-1354.
21 Brown, P., Cervenakova, L , Goldfarb, L G., GaJdusek, D C., Haverkamp, A ,
Haverkamp, C , Horwttz, J , Creacy, S D , Bever, R A, Wexler, P , SuJansky, E ,
and Bjork, R. J. (1994) Molecular genetic testing of a fetus at rusk of Gerstmann-
Straussler-Schemker syndrome Lancet 343, 18 l-l 82
22 Brown, P., Preece, M. A., and W111, R. G (1992) ˜Friendly fire™ m medicine
hormones, homografts, and Creutzfeldt-Jakob disease Lancet 340, 2627
23 W111, R G (1992) BSE and the spongtform encephalopathies, m Recent Advances
m Clzmcal Neurology (Kennard, C , ed ), Churchtll Ltvmgstone, London, pp 115-127
24 Collmge, J , Brown, J., Hardy, J , Mullan, M., Rossor, M. N , Baker, H , Crow, T
J , Lofthouse, R., Poulter, M , Rtdley, R M , Owen, F., Bennett, C , Dunn, G ,
Harding, A. E., Qumn, N , Dosht, B , Roberts, G W , Honavar, M., Janota, I., and
Lantos, P L (1992) Inhertted priori disease wtth 144 base patr gene msertton 2
Clinical and pathologtcal features Brazn 115, 687-7 10.
25 Brown, P , Rodgers-Johnson, P , Cathala, F , Gibbs, C. J , Jr., and GaJdusek, D C
(1984) Creutzfeldt-Jakob dtsease of long duration clmtcopathologtcal character-
istics, transmtsstbthty, and differential diagnosis Ann Neurol l&295-304
26 Brown, P , Goldfarb, L , Gtbbs, C J , and GaJdusek, D C (1991) The phenotyptc
expression of different mutations m transmtsstble familial Creutzfeldt-Jakob dts-
ease. Eur J Epldemlol 7,469-476.
27. Gambettt, P , Parch1 P , Petersen, R B , Chen, S G , and Lugarest, E (1995) Fatal
familial insomnia and famtltal Creutzfeldt-Jakob disease* clinical, pathological
and molecular features, Brain Path01 5,43-5 1.
28 Schellenberg, G. D., Anderson, L , O™Dahl, S., Wiqman, E M , Sadovnick, A
D , Ball, M. J , Larson, E. B., Kukull, W. A, Martin, G. M , Roses, A. D , and
Btrd, T D (1991) APP-7 17 APP-693 and PRIP gene mutations are rare m
Alzhetmer™s disease. Am J Hum Genet. 49, 5 1 l-5 17
29 Collmge, J , Palmer, M , Sidle, K C L., Mahal, S P., Campbell, T., Brown, J.,
Hardy, J , Brun, A. E , Gustafson, L , Bakker, E., Roes, R., and Groen, J J (1994)
Famtltal Pick™s disease and dementia m frontal lobe degeneration of non-
Alzhetmer type are not vartants of prton disease J Neurol Neurosurg Psychlat
57,762-768.
30 Jendroska, K , Hoffmann, 0 , Schelosky, L , Lees, A J , Poewe, W , and Daniel, S E
(1994) Absence of disease related pnon protem in neurodegenerattve dtsorders pre-
senting with Parkmson™s syndrome J Neurol Neurosurg Psychlat 57, 1249-125 1
Prion Disease Surveillance 137

3 1 Revesz, T., Daniel, S E , Lees, A. J., and W111,R G. (1995) A case of progresstve
subcortical glrosis assoctated with deposrtron of abnormal prton protem (PrP). J
Neural. Neurosurg Psychzat 58,759-760
32 Petersen, R. I3 , Tabaton, M., Chen, S. G., Monari, L., Rtchardson, S L , Lynches,
T., Manetto, V., Lanska, D J , Markesbery, W. R , Currier, R. D , Autrlto-
Gambetti, L , Wilhelmsen, K C , and Gambetti, G. (1995) Famtltal progresstve
subcorttcal ghosis* presence of prtons and linkage to chromosome 17. Neurology
45,1062-1067
33 Masters, C. L , GaJdusek, D C., and Grbbs, C. J , Jr. (1981) The famtltal occur-
rence of Creutzfeldt-Jakob disease and Alzheimer™s dtsease Brazn 104,535-558.
34 Edttortal (1990) Prton disease spongrform encephalopathres unveiled Lancer
336,21-22
35. Edrtortal (1993) Do eptdemtologtsts cause epidemics? Lancet 341,993-994
36 Bobowtck, A. R , Brody, J A., Matthews, M. R., Roos, R., and GaJdusek, D C.
(1973) Creutzfeldt-Jakob drsease.a case-control study. Am J Epldemlol. 98,38 l-394.
37. Kondo, K. and Kurotwa, Y. (1982) A case-control study of Creutzfeldt-Jakob
disease: association with physical mjuries. Ann Neural 11,377-38 1
38. Kondo, K (1985) Epidemiology of Creutzfeldt-Jakob disease in Japan, in
Disease (Mizutani, T. and Shirakt, H , eds ), Elsevteri
Creutzfeldt-Jakob
Nishimura, Amsterda/Nugate, pp. 17-30
39 Davanipour, Z., Alter, M , Sobel, E , Asher, D., and Gajdusek, D C (1985)
Creutzfeldt-Jakob disease* possible medical risk factors Neurology 35, 1483-1486
40. Davanipour, Z., Alter, M., Sobel, E., Asher, D. M , and Gajdusek, D. C (1985) A
case-control study of Creutzfeldt-Jakob dtsease dtetary rusk factors. Am J
Eptdemlol 122,443-45 1
41. Davampour, Z , Alter, M , Sobel, E., Asher, D M , and GaJdusek, D C. (1986)
Transmtsstble vrrus dementia evaluation of a zoonottc hypothesis Neuruepr-
demiology 5, 194-206.
42. Harrtes-Jones, R., Knight, R , Wtll, R G., Cousens, S., Smtth, P G., and
Matthews, W. B. (1988) Creutzfeldt-Jakob disease m England and Wales, l980-
1984: a case-control study of potential risk factors. J. Neural. Neurosurg Psychlat.
51,1113-1119
Environmental Causes
of Human Spongiform Encephalopathy
Paul Brown


This chapter reviews all proven or highly probable casesof envn-onmentally
acquired human spongiform encephalopathy (cannibalism, neurosurgical pro-
cedures, cornea1 and dura mater homografts, and natrve pituitary hormone
therapy), and evaluates potential but as yet unverified environmental sources
of disease, such as peripheral tissue homografts, organ transplants, admtmstra-
non of blood, blood products, and other biologicals, occupattonal exposures,
and zoonotic infections. Implicit in this breviary of known and putative origins
of envtronmentally acquired disease are laboratory and epidemiologic meth-
ods for recogmzmg and tf possible preventing subsequent cases both from
present and future sources of infection.
Like so much else m the field of human spongtform encephalopathy, it all
began with km-u. Long before Carleton Gajdusek introduced this exotic New
Guinea Highlands neurologic disease to the medical community m 1957 (I),
local missionaries, district officers, bush pilots, and bartenders were already
speculating that kuru was being “caught” as a result of ritual cannibalism.
Indeed, despite the absence of any clinical or neuropathological signs of an
mflammatory process, Gajdusek™s first priority was to explore its contagtous
(and presumably viral) character, for which he mitrated an extensive program
of inoculation studies mvolving countless rodent species and tissue culture cell
lines. All failed to reveal an mfecttous agent, because no precedent existed rn
human vtrology for experiments to be contmued beyond the l-2 mo periods
when most of these studies were terminated.
Genetic, endocrine, and toxic causes of kuru were also being explored, but
they too failed to yield the answer, and attention turned to the possibility of a
noninflammatory parasitic or fungal infection, with a new set of inoculated
From Methods m Molecular Medrone Pnon Diseases
Edlied by H Baker and R M Rdley Humana Press Inc , Totowa, NJ

139
animals (mcludmg monkeys) held for longer-term observation. After the patho-
logic similarity of kuru to scrapie was appreciated (2), it was decided to add
chimpanzees to the list of experimental animals, and to extend even further the
period of surveillance By the time the first animals showed signs of disease, 2 yr
after their inoculation m 1963 (3), kuru was well on its way to becoming extinct
as a result of the rapid decline of canmbahsm m the late 1950s. The obvious
best explanation for the epidemic of kuru, so quickly evident to medical and
nonmedical observers alike, and later authenticated by formal epidemiologic
study and expertmental transmission, turned out to be correct, but required
almost 10 yr to prove. Its burden of mortalny still far outnumbers deaths from
all other sources of disease.
Creutzfeldt-Jakob disease (CJD) had m the meantime been languishmg m
the backwaters of neurology since the early 1920s as a rare, progressive
neurodegenerative process of unknown ettology, but its neuropathologic
resemblance to kuru caught the eye of Igor Klatzo (4). Experimental primate
maculation studies demonstrated its transmissibihty m 1968 (.5), and epide-
miologic mvestigations characterized both its rarity and sporadic character,
although a small number of familial cases had also been described. Apart from
these few families, m which mfection could theoretically pass from affected to
unaffected members, it dtd not seem possible that a randomly occurring disease
at an annual frequency of cl case/million people could be transmitted horizon-
tally, surely not by case-to-case contact, unless a cluucally silent carrier state were
postulated, and unlikely by any other environmental mode, such as exposure to
analogous animal diseases (e.g., scrapie), or to some ubtquitous pathogen that
infected only the rare (and presumably genetically susceptible) Individual.
It was not until 1974 that a case of CJD was suspected to have resulted from
an environmental source. The donor of a cornea1 graft was found at autopsy to
have died from CJD, and, after a latency of 18 mo, the graft recipient also
developed CJD (6). This remained the only recognized instance of horizontally
transmitted disease until 1977, when a second report described the occurrence
of two cases of CJD 16 and 20 mo after stereotactic electroencephalography
procedures employmg the same (conventionally sterihzed) needles that earlier
had been used on a patient with CJD (7). To this day, these two cases represent
the only fully proven instances of iatrogemc CJD, because the brains of both
cases as well as the electrodes used for the EEG procedures later were shown
to transmtt disease experimental primates (8).
to
Given the fact that surgically induced CJD could occur, retrospective stud-
ies revealed a high probability that at least three earlier episodes of iatrogemc
C JD had occurred as a consequence of neurosurgical procedures (9, IO). Among
cases of CJD reported by Nevm et al. m 1960 (1 I) were two patients (cases 1
and 3) whose illnesses began 15 and 19 mo after operations m 1952 m which
Causes of Human Spongiform Encephalopathy 141

the same mstruments had been used 2 wk before on a patient with CJD; another
patient (case 7) became 111 mo after an operation m 1956 m which the same
18
instruments had been used several hours earlier on a patient with CJD. The
third episode occurred in 1965 m France, where a patient developed CJD 28 mo
after an operation m which the same instruments probably had been used 3 d
before on a patient with CJD (9)
Nothing more was heard about ratrogemc disease for the next several years,
but the sanguine outlook encouraged by this lull was to change dramatically m
1985, when the pediatric endocrinologist Raymond Hmtz notified the US
National Institutes of Health of a case of CJD m a young hypopituitary patient
who many years earlier had been treated with native human growth hormone
(12), and suggested that pituitary glands from CJD patients inadvertently might
have found then way mto cadaver pituitary pools from which the growth hor-
mone had been extracted.
With a speed that is almost never encountered m government reactions to
potential problems, Mortimer Lipsett, Director of the NIH Institute responsible
for overseeing the pituitary treatment program, held advisory meetmgs and
within 2 wk notified pediatric endocrinologists around the country to be on the
lookout for unexplained neurologic deaths m their patient population. When, 2 mo
later, two more casessurfaced m quick succession (13,14), native growth hor-
mone was withdrawn from circulation and replaced by recombinant hormone,
but only time would tell whether we would witness a mere handful of further
cases or a full-blown epidemic of iatrogenic CJD (IS). As it turned out, the
damage was somewhere between the two extremes: The current total stands at
76 cases,with new casesoccurrmg at the rate of about two to three each year,
prmcipally in the United States (1648; and unpublished data), the United
Kmgdom (29-22; and unpublished data), and France (23,24; and unpublished
data) (each using their own sources of pituitary glands), although cases also
have been identified in Brazil (25) and New Zealand (26) in patients given
hormone processed m the United States, and m Australia from locally pro-
duced hormone (unpublished data). Causality was unequivocally established
when a sample of one US lot that was inoculated into experimental primates
transmitted disease after an mcubation period of 5 yr (27).
The potential for human pituitary gland infectivity had actually been appre-
ciated several years earlier, and a study was carried out m 1979 m which a
normal human pituitary gland was mixed with scrapie-infected mouse bram
tissue, processedfor growth hormone (Lowry method), and the residual mfectiv-
ity measured at several successive steps (28). Because infectivity was unde-
tectable in the final product, the identically purified hormone distributed for
human use was thought to be without risk, Unfortunately, the final sample was
only sampled for infectivity (the customary method) rather than inoculated m
142 Brown
Table 1
Summary of All Proven
or Highly Probable Cases of latrogenic Creutzfeldt-Jakob Disease
Number Agent entry Mean mcubatlon Clmical

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