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incidents by the American Red Cross and the European BioMed-1 CJD sur-
veillance study.
Finally, it is worth recalling that no case of CJD has been identified among
patients whose diseases require (or required before recombinant technology)
repeated administration of whole blood, blood components (e.g., plasma or
leukocytes), or blood derivatives (e.g., albumin, nnmune globulm, interferon,
a-l antitrypsm, clotting factors VIII and IX). Such potentially htgh risk groups
include patients with congenital anemias and clotting deficiencies (e.g., sickle
cell disease, thalassemia maJor, hemophtha), immune deficiency/suppression
syndromes, multiple scleroses,a-l antitrypsm deficiency, bone marrow trans-
plants, and multiple surgical procedures.
None of these epidemiologtc observations should be considered definmve,
because population-based studies can never prove or disprove the possibility
that one or two cases do indeed result from contaminated blood products but
are insufficient to break through the barrier of statistical sigrnficance, and single
Brown
148

incident studtes, even tf all rectptents are traced (whtch is almost never pos-
sible), may be criticized because a proportion of recipients will have died from
other illnesses before CJD has had a chance to declare itself On balance, the
available evidence favors the concluston that blood-borne mfectton IS not a
cause of CJD; however, rather than come down hard with either a guilty or not
guilty verdict, for the present we might be better advised to render the Scottish
Judgment of “not proven ”
Biologrcals derived from tissues other than blood are also candidates for
evaluatton as potential sources of tatrogemc infection Certain products, such
as CNS ganghostdes (of either human or bovine origin) have an obvious poten-
tial to be contaminated, whereas other products that derive from animal spe-
cies not known to be susceptible to spongtform diseases, or even from
nonammal sources, nevertheless may be exposed to culture media and protein
broths containmg small amounts of tissue extracts from a variety of animals,
and stabtltzed wtth human albumin m the course of processmg protocols Each
such product must be evaluated on an mdtvidual basis, and although an
mformedJudgment usually can be made about the potential risk inherent m its
components, no amount of reasoning can take the place of “validatton” experi-
ments to determine whether m fact mfectrous starting material retains any
mfectivtty m the final product.
Such studtes have been performed only for human growth hormone and
bovine gangliosides, and have shown that residual infectivity is indeed present
m the final products. However, it was found that growth hormone remamed
biologrcally active after exposure to 6Murea and ultrafiltratton steps that effec-
tively decontammated the purified hormone (30), and that gangliosides could
withstand exposure to NaOH and steam autoclavmg that totally inactivated the
infectivity present m the starting brain material (62). Similar validation studies
will be required to determine if the harsh physicochemtcal treatments and
ultrafiltration steps that are required to disinfect the agent of CJD are compat-
ible with btologtcal activity of the final products.
Two other potential but as yet unproven envrronmental sources of disease
relate to workplace mfecttons m healthcare professionals, and zoonotic mfec-
tions from animals with analogous spongrform diseases, such as scrapie or bovine
spongiform encephalopathy (BSE). During the last 15 yr, several instances of
CJD m health professionals have been recorded, either m systematic epidemio-
logtc CJD surveillance studies (63--65), or as mdrvidual case reports (66-71),
and include physicians, nurses, nurses aides, dentists, and pathology technicians.
In surverllance studres, comparrsons of the observed and expected mcidence
of CJD m these professions usually has not differed significantly from that of
the general population, and even when they have differed must be viewed with
cautton because stattstrcs tend to lose their power of persuasion when dealing
Causes of Human Spongiform Encephalopathy

with small differences m the incidence of a rare disease, and because equally
“significant” differences have been observed among nuns and vicars, for whom
no evident risk factors can be Imagined (64,72).
Nevertheless, the occurrence of disease in an mdtvidual with a recognized
high-risk potential never can be dismissed out of hand, and thus the reports of
CJD in a neurosurgeon (66), a pathologtst (69), and two neuropathology techm-
clans (67,68), even if no defimte infecting event was tdenttfiable, are cause for
concern. Another recent report described a caseof CJD tn an orthopedtc surgeon
who 20 yr earlier had worked with both sheep and human dura mater (the latter
material having been sent to the same firm that inadvertently distributed CJD-
contaminated human dura mater) (70). Eventually, tt may happen that the accu-
mulated weight of such anecdotal reports will become great enough to be
persuasive even without the buttress of statistical significance. Fortunately (for
the author), no case of CJD has yet occurred m a research laboratory worker.
As concerns zoonotic mfectton, scientists and the general public have been
much exercised over the posstbihty that the current UK epidemic of BSE could
pose a sertous risk to human health, from eating beef or other tissues, or drmk-
mg milk from animals mcubatmg the disease that might find thetr way to the
marketplace. The question at the moment is unanswerable, because mforma-
tton about the tissue dtstrtbution of mfecttvity and Its ability to transmit dts-
ease by ingestion (a very inefficient route of infection) will take some years to
acquire To date (and we are now approx 10 yr down the road from the onset of
the epidemic) the accumulated epidemiologtcal evidence indicates that BSE
(like scrapte, whrch has been prevalent m the United Kingdom for at least 250 yr)
does not pose a significant risk to human health. Although CJD has occurred m
four farmers with BSE-infected herds (72 and unpubhshed data), more con-
vincing data come from the ongoing active surveillance of CJD m several
European countrtes, m which the annual mortality rates of CJD do not differ
between countries that have BSE and those that do not (73).
In conclusion, we know enough today to suspect a wide variety of sources
and modes of exposure as potential risks of envn-onmentally acquired CJD; to
evaluate m a logical manner the hkelihood of these sources to contam the
mfecttous agent and transmit disease by routes of infectton with differing efti-
ctenctes, to know that we may never encounter mcrtmmating case “clusters”
because of the very small amounts of infectious agent to which the victtms
may have been exposed, and the consequent length and variability of mcuba-
tton periods that can extend up to 30 yr; and to be alert to the fact that the
predominant disease symptoms may be cerebellar rather than mental. In
pattents that come to autopsy, we also may be able to dtstmgutsh envnonmen-
tally acquired from sporadic cases of CJD by different regional patterns of
amyloid protein distribution in the CNS (59,74).
150 Brown

All of thts knowledge, gamed both from planned experiments and natural
mtsfortunes, should provide us enough information to reason, predict, and, tf
possible, prevent future occurrences But surprises may still he ahead, perhaps
m the form of an isolated case of CJD years or even decades after a marrow
transplant for leukemia, dura mater grafting for perrcardtal repair, or leukocyte
interferon treatment for multiple scleroses. For these unforeseen events, we
shall need the mtutttve gemus that, although informed both by knowledge and
reason, only comes to us unbidden and alone m magical moments, a gift from
the gods.

References
1 GaJdusek, D C and Zrgas, V (1957) Degenerattve disease of the central nervous
system m New Gumea. epidemrc occurrence of “kuru” m the native population
N Engl J Med 257,97&978
2 Hadlow, W. J (1959) Scrapie and kuru. Lancet 2,289,290
3 GaJdusek,D C , Gibbs, C J J , and Alpers, M (1966) Experimental transmission
of a kuru-like syndrome m chimpanzees Nature 209,794-796
4 Klatzo, I , GaJdusek,D , and Zigas, V (1959) Pathology of kuru Lab Invest 8,
799-847
5 Gibbs, C J , Jr, GaJdusek,D C , Asher, D M., Alpers, M P., Beck, E , Daniel, P
M , et al (1968) Creutzfeldt-Jakob disease(sponglform encephalopathy) trans-
mission to the chimpanzee Sczence161, 388,389
Duffy, P , Wolf, J , Collms, G , DeVoe, A G., Streeten, B , and Cowen, D (1974)
6
Possible person-to-persontransmissionof Creutzfeldt-Jakob disease N Engl J
Med 290,692,693
Bernoulli, C , Siegfried, J , Baumgartner, G , Regh, F , Rabmowrcs,T , GaJdusek,
7
D C , et al (1977) Danger of accidental person-to-person transmission of
Creutzfeldt-Jakob disease surgery Lancet i, 478,479
by
Brown, P (1994) Transmissiblehuman spongiform encephalopathy (infectious
8
cerebral amylotdosts)*Creutzfeldt-Jakob disease, Gerstmann-Straussler-Schemker
syndrome, and kuru, m NeurodegeneratzveDzseases (Calne, D B , ed ), Philadel-
phia, pp 839-876
Foncm, J , Gaches,J., Cathala, F , El Sherif, E , and Le Beau, J (1980) Transmis-
9
sion iatrogbne mterhumame possible de maladle de Creutzfeldt-Jakob avec
atteinte desgrams du cervelet Rev New-01 (Pans) 136,280
10 Will, R. G and Matthews, W B (1982) Evidence for case-to-casetransmission
of Creutzfeldt-Jakob disease J Neurol. Neurosurg Psychzat 45,235-238
11 Nevm, S., McMenemey, W H , Behrman, S , and Jones, D P (1960) Subacute
spongiform encephalopathy-a subacute form of encephalopathy attributable to
vascular dysfunction (spongtform cerebral atrophy) Brazn 83, 5 19-564
Koch, T. K , Berg, B O., De Armond, S J , and Gravma, R F. (1985) Creutzfeldt-
12
Jakob diseasem a young adult with idiopathic hypopmntarism N Engl J A4ed
313.73 l-733
151
Causes of Human Spongiform Encephalopathy
13. Gibbs, C. J , Jr , Joy, A., Heffner, R., Franko, M., Miyazakt, M , Asher, D M , et
al. (1985) Clmical and pathologrcal features and laboratory confirmatton of
Creutzfeldt-Jakob disease m a recipient of pttuitary-derived human growth hor-
mone. N. Engl J Med 313,734-738
14 Tmtner, R , Brown, P , Hedley-Whyte, E. T , Rappaport, E B , Plccardo, C P ,
and Gajdusek, D. C (1986) Neuropathologic vertficatton of Creutzfeldt-Jakob
disease in the exhumed Amertcan recipient of human pttuttary growth hormone
epidemtologrc and pathogenettc tmplications. Neurology 36, 932-936
15. Brown, P., GaJdusek, D C , Gibbs, C J., Jr., and Asher, D M. (1985) Potential
eptdemlc of Creutzfeldt-Jakob disease from human growth hormone therapy N
Engl J Med 313,728-73 I
16 Marzewskt, D. J , Towfight, J , Harrmgton, M G., Merrtl, C R., and Brown, P
(1988) Creutzfeldt-Jakob disease followmg pmntary-dertved growth hormone
therapy a new American case Neurology 38, 113 l-l 133
17. New, M I , Brown, P , Temeck, J. W , Owens, C , Hedley-Whyte, E. T., and
Richardson, E P. (1988) Preclmtcal Creutzfeldt-Jakob dtsease discovered at
autopsy in a human growth hormone reciprent. Neurology 38, 1133,1134.
18 Fradkm, J. E , Schonberger, L B., Mills, J L , Gunn, W J , Piper, J M ,
Wysowskt, D. K., et al. (1991) Creutzfeldt-Jakob disease m pttuttary growth hor-
mone recrprents m the Umted States. JAMA 265, 880-884.
19. Anderson, J. R , Allen, C M C., and Weller, R. 0 (1990) Creutzfeldt-Jakob
disease following human prtuttary-derived growth hormone admnnstratton
Neuropathol Appl Neuroblol 16, 543
20. Buchanan, C R , Preece, M A., and Milner, R. D G (199 1) Mortality, neoplasta,
and Creutzfeldt-Jakob disease m patients treated wtth human pttuttary growth
hormone in the United Kingdom Br. Med J 302,824-828
21 Markus, H S., Duchen, L W., Parkm, E. M., Kurtz, A B , Jacobs, H. S , Costa,
D C., et al. (1992) Creutzfeldt-Jakob disease m recrptents of human growth hormone
m the United Kingdom* a clmtcal and radtographtc study Q. J Med 297,43 -5 1.
22. Powell-Jackson, J , Weller, R. O., Kennedy, P., Preece, M. A , Whttcombe, E M.,
and Newsom-Davies, J. (1985) Creutzfeldt-Jakob disease after administratron of
human growth hormone Lancet ii, 244-246
23. Brllette de Vtllemeur, T., Beauvais, P., Gourmelon, M , and Rrchardet, J. M
(1991) Creutzfeldt-Jakob disease m chrldren treated wrth growth hormone Lan-
cet 337, 864,865.
24 Job, J. C , Matllard, F., and Goqard, J (1992) Eptdemtologic survey of patients
treated with growth hormone m France m the period 1959-199˜prehmmary
results Horh Res 38, 35-43.
25. Macario, M. E., Varsman, M , Buescu, A, Neto, V. M., Araujo, H M M., and
Chagas, C. (1991) Prturtary growth hormone and Creutzfeldt-Jakob disease Br
Med. J 302, 1149.
26. Croxson, M , Brown, P , Synek, B., Harrington, M. G , Frith, R., Clover, G , et al
(1988) A new case of Creutzfeldt-Jakob disease associated with human growth
hormone therapy in New Zealand. Neurology 38, 1128-l 130.
Brown
152

27 Gtbbs, C. J., Jr, Asher, D M , Brown, P W , Fradkm, J. E , and GaJdusek, D C
(1993) Creutzfeldt-Jakob dtsease mfecttvtty of growth hormone dertved from
human pmntary glands N Engl J Med 328, 358,359
28 Taylor, D M , Dtckmson, A G , Fraser, H., Robertson, P A., Salacmskt, P R ,
and Lowry, P J (1985) Preparation of growth hormone free from contammatton
wtth unconventtonal slow viruses Lancet ii, 260-262
29. Brown, P (1985) Vtrus sterthty for human growth hormone Lancet ii, 729,730
30. Pocchtart, M , Peano, S , Conz, A., Eshkol, A, Matllard, F., Brown, P , et al
(199 1) Combmatton ultrafiltratton and 6 M urea treatment of human growth hor-
mone effectively mmimtzes rusk from potenttal Creutzfeldt-Jakob disease vtrus
contammatton Horm Res 35, 161-166.
3 1 Cochms, J I., Burns, R J , Blumbergs, P. C , Mack, K., and Alderman, D P
(1991) Creutzfeldt-Jakob disease m a recipient of human pituitary-derived gona-
dotrophin Aust NZ J Med 20,592,593
32 Klein, R and Dumble, L J (1993) Transmisston of Creutzfeldt-Jakob disease by
blood transfusion Lancet 341,768
33 Brown, P , Gibbs, C J , Jr., Rodgers-Johnson, P , Asher, D M , Suhma, M P ,
Bacote, A , et al (1994) Human spongiform encephalopathy the National Instt-
tutes of Health series of 300 cases of expertmentally transmitted disease Ann
Neural 35,5 13-529
34 Thadam, V , Penar, P L., Partmgton, J , Kalb, R , Jansson, R , Schonberger, L B ,
et al (I 988) Creutzfeldt-Jakob disease probably acquired from a cadaveric dura
mater graft. J Neurosurg 69, 766-769.
35. Lane, K. L., Brown, P., Howell, D N., Cram, B. J., Hulette, C M., Burger, P. C.,
et al (1994) Creutzfeldt-Jakob dtsease m a pregnant woman wtth an implanted
dura mater graft. Neurosurgery 34,737-740.
36 Esmonde, T., Lueck, C J , Symon, L , Duchen, L W , and Will, R G (1993)
Creutzfeldt-Jakob disease and lyophthsed dura mater grafts: report of two cases
J New-01 Neurosurg Psychzat 56,999,1000.
37 Wtlhson, H J , Gale, A N , and Mclaughlm, J E (1991) Creutzfeldt-Jakob dts-
ease followmg cadavertc dura mater graft. J Neurol Neurosurg Psychrat 54,940
38 Masullo, C , Pocchtart, M., Macche, G., Alema, G., Piazza, G , and Panzera, M.
A (1989) Transmission of Creutzfeldt-Jakob dtsease by dural cadavertc graft J
Neurosurg 71,954,955
39. Pocchtart, M , Masullo, C , Salvatore, M , Genuardt, M , and Galgam, S. (1992)
Creutzfeldt-Jakob disease after non-commerctal dura mater graft Lancet 340,
614,615
40 Martinez-Lage, J F., Poza, M., Sola, J , Totosa, J. G., Brown, P., Cervenakova,
L , et al (1994) Accidental transmission of Creutzfeldt-Jakob disease by dural
cadavertc grafts J Neurol Neurosurg Psychzat 57, 1091
4 1 Lang, C J G , Schuler, P., Engelhardt, A., Spring, A , and Brown, P (1995) Prob-
able Creutzfeldt-Jakob disease after a cadavenc dural graft. Eur J Epldemtol 11, 1
42 Ntsbet, T J., MacDonaldson, I., and Bishara, S. N. (1989) Creutzfeldt-Jakob dts-
ease m a second patient who received a cadavenc dura mater graft. JAMA 261, 1118
Causes of Human Spongiform Encephalopathy 153

43 Mlyashita, K , Inuzuka, T , Kondo, H , Salto, Y , FUJita,N., Matsubara, N , et al
(1991) Creutzfeldt-Jakob disease a patient with a cadaverlc dural graft Neurol-
m
ogy 41,940,941
44 Yamada, S , Alba, T., Endo, Y , Hara, M , Kltamoto, T , and Tatelshl, J. (1994)
Creutzfeldt-Jakob diseasetransmitted by a cadaverlc dura mater graft Neuro-
surgery 34,740-744
45 Dnmger, H and Bralg, H R. (1989) Infectivity of unconventional viruses m dura
mater Lancet i, 439,440
46 Dickinson, A G. and Taylor, D M (1978) Resistanceof scraple agent to decon-
tamination N Engl J Med 299, 1413,1414
47 Gibbs, C J , Jr, GaJdusek,D C., and LatarJet, R (1978) Unusual resistanceto
ionizing radiation of the viruses of km-u, Creutzfeldt-Jakob disease,and scraple
(unconventional viruses) Proc Natl Acad Scl USA 75,6268+270
48 Brown, P., Rohwer, R. G., Green, E. M , and GaJdusek,D C. (1982) Effect of
chemicals, heat, and hlstopathologlc processing on high infectivity hamster-
adapted scraple virus J Infect Dis 145, 683-687.
49 Brown, P , Gibbs, C J , Jr, Amyx, H L., Kingsbury, D T., Rohwer, R G , Suhma,
M. P., et al (1982) Chemical dlsinfectlon of Creutzfeldt-Jakob diseasevirus N
Engl J Med 306, 1279-1282
50 Brown, P , Rohwer, R. G , and GaJdusek,D C (1986) Newer data on the mactl-
vatton of scraplevirus or Creutzfeldt-Jakob disease virus m brain tissue.J Infect

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