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Mode of InfectIon of patients perrod, range presentation
into brain
Stereotactic EEG 2 Intracerebral 18 mo (16, 20) Dem/cerebh
Neurosurgery 4 Intracerebral 20 mo (1 S-28) Vlsldemlcereb
Cornea1 transplant 2 Optic nerve 17 mo (16, 18) Dem/cereb
Dura mater graft 25 Cerebral surface 5 5 yr (1 5-12) Cereb (vls/dem)
Gonadotrophm 4 Hematogenous 13 yP (12-16) Cerebellar
12 yP (5-30) Cerebellar
Growth hormone 76 Hematogenous
%alculated from the mldpomt of hormone therapy to the onset of CJD symptoms
hDem, dementlal, Cereb, cerebellar, see text

toto (to demonstrate the complete absence of the mfectlous agent) (29), and,
when this more rigorous type of vahdatlon protocol was finally carried out
several years later (199 l), scraple-infected pltultarles did in fact transmit dls-
ease to a few of several hundred maculated hamsters (30).
The risk of dying from CJD among the treated populations of the United
States, United Kingdom, and France show some interesting differences (Table 1).
In the Umted States and United Kingdom, crosscheck analysis of patients and
hormone lots revealed that occasional random lots produced during the 1960s
and 1970s must have been contaminated in both countries. In contrast, all of
the patients m France, where the risk was greatest, had overlapping treatments
during 1984 and 1985, suggesting a rather more important degree of contaml-
nation confined to lots that were distributed during this period.
Cases of CJD have also occurred m four women treated wtth cadaver-derived
pltultary gonadotrophm, among a total of 1450 treated mdivlduals m Australia
(.31,32) (and unpublished data). Most other pituitary hormones have little or no
use m clinical practice, or if used are derived from animal or synthetic sources.
The only exception 1s pituitary-derived prolactm, which was about to be
released for clmlcal trials, then quickly abandoned when the growth hormone
story unfolded.
The average mcubatlon period for these 78 cases of CJD from contammated
pituitary hormones (calculated from the mldpomt of hormone therapy to the
onset of symptomatic CJD), was approx 12 yr, minimum incubation periods
(calculated from the end of therapy to the onset of symptoms) ranged from
5-25 yr (Table 2). These latencles are m excellent accord with estimated mcu-
batlon periods for km-u, which also ranged from approx 4-30 yr, and support
the presumption that both diseases resulted from peripheral (as opposed to
CNS) body entry routes by small amounts of the infectious agent. Data from
Causes of Human Spongiform Encephalopathy 143

Table 2
Comparison of Risks of Contracting Creutzfeldt-Jakob Disease
and Mean Incubation Periods After Treatment with Native Human
Growth Hormone in the United States, United Kingdom, and France
Number of Treated Risk of Mean mcubatlon
Country of orlgin patients population CJD, % period, yf
Umted Statesb 17 8300 02 18 (+6)
United Kmgdom 17 12(+3)
1750 10
France 41 1700 2.4 8 (+3)
Talculated from the mldpomt of hGH therapy to the onset of CJD symptoms
˜Tncludes two patlents from New Zealand and one from Brazil who received hormone pre-
pared m the Umted States


experimental prlmate transmission studies also had shown that small amounts
of the agent inoculated peripherally (e.g., intradermal or subcutaneous mjec-
tion) may be followed by prolonged incubation times, or even failure to trans-
mit disease altogether (33).
Although our attention was riveted on the increasing number of latrogenlc
pituitary hormone cases, bad news came from yet another direction. surgical
operations employing cadaverlc dura mater graft patches In the United States
m 1987, a case of CJD was identified m a young woman who 19 mo earlier had
a surgical procedure that included placement of a cadaveric dural homograft
(34). Additional caseshave since been identified in the United States (3.5), the
United Kingdom (36,37) (and unpublished), Canada (unpubhshed), Italy
(38,39), Spain (40), Germany @I), Australia (unpublished), New Zealand (42),
and Japan (43,44). The total number of cases currently stands at 25, and like
growth hormone cases,IS slowly increasing every year.
Unlike the hormone sttuatlon, however, in which multiple random lots inde-
pendently produced m several different countries were contaminated over a
period of many years, all but two of the dura mater caseshad received grafts
distributed between the years 1982 and 1986 by a single producer (“Lyodura”
from B. Braun Melsungen AG). The commercial processing protocol, which
includes exposure to H202, acetone, and ionizing radiation (25 kGy), later was
found to have very little effect on mfectlvlty present in dura mater from scrapie-
infected hamsters; but exposure to 1NNaOH (a procedural step that was added
to commercial protocols m 1987) resulted in almost total inactivation of the
infectious agent (45).
The average incubation period for these dura mater cases IS approx 5 yr,
ranging from 16 mo to 12 yr after implantation of the graft, and thus mtermedi-
ate m latency between cases in which the infectious agent was introduced
directly into the brain by contaminated instruments, and cases in which the
144 Brown

agent was mtroduced from peripheral moculattons of contaminated pttuttary
hormone (Table 2). The clmtcal syndromes typically shown by each of these
groups of pattents also differed. After mtracerebral or ocular nerve mfectton
(surgtcal instrument, EEG electrode, and cornea1 graft cases), clmtcal presen-
tations and evolutrons mimicked those seen m sporadic CJD, with many
patients showing an Important early dementia1 component. After cerebral sur-
face contact mfectton (dura mater cases),most patients presented wtth cerebel-
lar abnormaltttes, alone or m combmatton with visual signs or mental
detertoration; and after peripheral infection (pituitary hormone cases), the dis-
ease took on an almost stereotyped evolutton of progressive cerebellar signs,
with little or no mental detertoratton until late m the course of illness.
The first four casesof surgically transmitted CJD that occurred during the 1950s
and 1960s were not recognized for the samplereason that the diseasehad not yet
been shown to be mfecttous, let alone have an mcubatton penod that could extend
over a period of years or even decades. The cornea1 graft and stereotacttc EEG
casesthat occurred m the 1970s were recognized because by that time the mfec-
tious character and long mcubatton period of CJD had been expertmentally docu-
mented, and just as important, the knowledge had been widely disseminated to
the medical communtty; because the donors as well as the recipients were
neuropathologtcally confirmed casesof CJD; and because the interval between
donor and recipient deaths was not so long as to have obscured then relationshtp.
This was also true for the dura mater cases,among which the first case had (provt-
denttally) the shortest incubation period (19 mo), and thus was more readtly
evaluated with respect to antecedent neurosurgery. In contrast, the first growth
hormone-related case was suspected by only one of the many physicians who
saw him, and more than anything else reflects a remarkable exercise of mtumon.
Although the root cause of tatrogemc disease 1sthe awesome resistance of
the infectious agent to procedures designed to inactivate conventtonal patho-
gens, mcludmg exposure to ethanol, H,O*, permanganate, iodine, ethylene
oxide vapor, detergents, organic solvents, formaldehyde, UV or gamma trra-
dtation, and even standard autoclavmg (46-52), genetics has been found to
play an important subsidiary role, A gene on chromosome 20 encoding the
protein that in patients with spongtfotm encephalopathy 1stransformed mto an
amylotdogemc tsoform contains a polymorphism at codon 129 that normally
can specify either of two ammo acids (methtonme or valme). In the general
populatton, heterozygotes and homozygotes occur at about the same frequency,
however, m the tatrogenic CJD populatton, whatever the origin or route of
Infection, this equtltbrium 1s heavtly tilted toward homozygostty (in about a
10: 1 proportion) (Table 3). Thus, codon 129 heterozygotes are, for reasons that
are not yet understood, significantly less vulnerable to tatrogemc mfectton than
are homozygotes (52-M) It 1s also interesting that of the four pattents who
Causes of Human Sponglform Encephalopathy 145
Table 3
Codon 129 Genotypes in Patients
with latrogenic Creutzfeldt-Jakob Disease
Codon 129 genotype
Tested groupsa Met/Met Met/Val Val/Val Homozygous
CNS route of infectton
Stereotactic-EEG electrode 0
1 1 l/2
Neurosurgery 1 0
1 l/2
Cornea1 transplant 0
1 1 212
Dura mater graft 0
13 1 14/14
CNS subtotal 16 (80%) 2 (10%) 2 (10%) 18/20 (90%)b
Peripheral route of mfection
Human gonadotrophin 1
2 1 314
Human growth hormone 20 4 15 35139
Peripheral subtotal 22 (51%) 5 (12%) 16 (37%) 38/43 (88%)”
All iatrogemc cases 38 (60%) 7 (11%) 18 (29%) 56163 (89%)b
Normal controls 97 (37%) 135 (52%) 29(11%) 126126 1 (48%)
“Pooled mformation from the United Kingdom (52), Umted States (53), France (54), and
unpublished data
“P < 0 00I compared normalcontrols(Chl-square
to test)

were “maculated” mtracerebrally (by neurosurgtcal instruments and stereotac-
ttc EEG electrodes), two were heterozygous and two were homozygous, sug-
gesting that heterotypic reststance can be overcome by direct mtroduction of
the Infectious agent into the brain.
To date, all known cases of tatrogemc CJD have resulted from exposure to
mfecttous brain, pituitary, or ocular tissue, almost certamly owing to the high
levels of infectious agent m the central nervous system (CNS) (and organs to
whtch tt is directly connected). However, from tissue dtstrtbutton studies m
both humans and experimental animals (Table 4), it has been well established
that the mfecttous agent is widespread in the body, albeit m much lower con-
centration than m the brain, and with an n-regular and unpredictable occur-
rence; thus, there is reason to suppose that at some point m the future we ˜111
learn of a case for which a peripheral tissue is tmplrcated as the source of con-
tamination. We already are aware of a few cases of CJD m patients who 2-5 yr
earlier had a pertcardtal homograft for tympamc membrane closure (5.5), or
bone, kidney, or liver transplants (unpublished data). In none of these instances,
however, was the donor identified as having had CJD, so then latrogemc ori-
gm still must be considered comectural.
The question of CJD associated with the admmistration of blood or blood
products merits special consideration because blood repeatedly has been shown
146 Brown
Table 4
Distribution of Comparative Frequency of Infectivity in Organs
of Humans or Animals with Spongiform Encephalopathya
Host tissue Human CJDlkurub Sheep/goat scrapte Cattle BSS
+++ +++
+++
Brain
++ +++ (++)
Spmal cord
++ +++ (0)
Cerebrospmal flutd
+++
Eyeball +++ (0)
+++
Pertpheral nerve (0) (0)
Pmutary gland +++
NTC NT
Spleen + +++ (0)
+ +++
Lymph nodes (0)
Leukocytes NT (0)
Serum 0
(k (0)
Whole or clotted blood 0 * (0)
Bone marrow 0
(0) (0)
+
Lung * (0)
+ +
Liver (0)
+
Ktdney 0 (0)
Pancreas NT 0 (0)
Thymus NT + NT
+++
Intestine (0) (0)
Heart 0 0 (0)
Skeletal muscle 0
Fat NT
(0”) A
Testis 0
(0) (0)
Semen 0 0
(0)
+
Ovary NT (0)
+
Uterus NT (0)
Placenta (+I c++>
Amniotic flutd (0) t*> (“0,
Cord blood NT
c+> (0)
Colostrum NT
(+I
Mtlk 0
(0)
OBasedon rsolatrons of the mfecttous agent from the natural hosts of each dtsease
“Infectlvlty +++ almost always present, ++ frequent, + Irregular, k rare, 0 undetectable
Parentheses mdtcate very few tested specrmens
˜NT not tested


to be tnfectious during the incubation period and clmtcal phase of experimen-
tally tnfected animals, and occasionally has been found mfecttous in humans
wtth CJD @G-.59), and because tatrogentc disease from this source would dwarf
147
Causes of Human Spong/form Encephalopathy

m importance all other sources by virtue of the sheer number of people who
theoretically have been or could be at risk. Although a small proportion of
mdivtduals among the CJD patient population is known either to have donated
or received blood, epidemiologic case control studies covermg the years 1980-
1984 and 1990-l 992 in the United Kingdom found no increase in the inci-
dence of CJD m areas where blood from CJD donors had been distributed, nor
any difference between CJD patients and the general population in the fre-
quency of havmg received blood (60).
This report generated two echoes.The first reverberated from Australia under
the alarming title “Transmtssion of Creutzfeldt-Jakob disease by blood trans-
fusion” (32). Four patients dying of CJD were found to have received transfu-
sions 5 yr before the onset of nondementtal cerebellar clmical presentattons.
However, unlike the Brtttsh studies, no information was provided about the
comparable frequency of transfusions in a non-CJD control populatton, nor
was an effort made to identify CJD patients among the blood donors. The um-
formly cerebellar presentation of the four pattents 1stroublmg, because cer-
ebellar onsets are the hallmark of iatrogenic disease from peripheral routes of
mfectton, but because nearly one-third of sporadic cases of CJD may also
present with cerebellar signs, this fact alone cannot be relied on to prove
iatrogenic causality.
The second report echoed from Germany, where an effort was made to trace
all recipients of blood from a regular donor who later died of CJD (61) Nearly
70% (35/55) of the recipients were identified, of whom 2 1 had dted from non-
CJD illnesses up to 22 yr after having received transfusions, and 14 were still
alive without evidence of neurologic disease from 2-21 yr later (mean sur-
vival, 12 yr). Similar efforts are presently being pursued for several more such

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