Copyright 1996 Lancet Ltd. The Lancet
April 6, 1996
SECTION: Vol. 347 ; No. 9006 ; Pg. 921; ISSN: 0099-5355
LENGTH: 4505 words
HEADLINE: A new variant of Creutzfeldt-Jacob disease in the UK.
BYLINE: Will, R.G. ; Ironside, J.W. ; Zeidler, M. ; Cousens, S.N. ;
Estibeiro, K. ; Alperovitch, A. ; Poser, S. ; Pocchiari, M. ; Hofman, A. ;
Smith, P.G.
BODY: A Alperovitch, S Poser, M Pocchiari, A Hofman, P G Smith
Summary
Background
Epidemiological surveillance of Creutzfeldt-Jakob disease (CJD) was
reinstituted in the UK in 1990 to identify any changes in the occurrence
of this disease after the epidemic of bovine spongiform encephalopathy
(BSE) in cattle.
Methods
Case ascertainment of CJD was mostly by direct referral from
neurologists and neuropathologists. Death certificates on which CJD was
mentioned were also obtained. Clinical details were obtained for all
referred cases, and information on potential risk factors for CJD was
obtained by a standard questionnaire administered to patients' relatives.
Neuropathological examination was carried out on approximately 70% of
suspect cases. Epidemiological studies of CJD using similar methodology to
the UK study have been carried out in France, Germany, Italy, and the
Netherlands between 1993 and 1995.
Findings
Ten cases of CJD have been identified in the UK in recent months with a
new neuropathological profile. Other consistent features that are unusual
include the young age of the cases, clinical findings, and the absence of
the electroencephalogram features typical for CJD. Similar cases have not
been identified in other countries in the European surveillance system.
Interpretation
These cases appear to represent a new variant of CJD, which may be
unique to the UK. This raises the possibility that they are causally
linked to BSE. Although this may be the most plausible explanation for
this cluster of cases, a link with BSE cannot be confirmed on the basis
of this evidence alone. It is essential to obtain further information on
the current and past clinical and neuropathological profiles of CJD in the
UK and elsewhere.
Lancet 1996; 347: 921-25
Introduction
Because of the epidemic of bovine spongiform encephalopathy (BSE) in
cattle, surveillance of Creutzfeldt-Jakob disease (CJD) in the UK was
reinstituted in May, 1990. The purpose of the surveillance is to identify
changes in the pattern of CJD which might indicate an association with
BSE. We report ten cases of CJD in the UK with clinical onset of disease
in 1994 and 1995. These cases all have neuropathological changes which, to
our knowledge, have not been previously reported. They are also unusual in
that they occurred in relatively young people, and the clinical course was
not typical of cases of sporadic CJD in the UK.
Methods
Since May, 1990, cases of CJD have been identified to the CJD
Surveillance Unit, usually by direct referral from professional groups,
which include neurologists and neuropathologists. All death certificates
in the UK on which CJD is mentioned are obtained and some cases are
identified retrospectively in this way; some are identified from other
sources. Clinical details are obtained for all cases, and information on
potential risk factors for CJD is obtained with a standard questionnaire,
usually administered to a close relative of the case. After obtaining
informed consent from the relatives or patients, blood is obtained for DNA
analysis in most patients. Information on all known cases of CJD in
England and Wales since 1970 and in Scotland and Northern Ireland since
1985 is also available from previous surveys of CJD.1 Parallel studies of
CJD have been carried out in France, Italy, Germany, and the Netherlands
between 1993 and 1995 with similar methods.2
Whenever possible, neuropathological examination is carried out on
cases and suspect cases notified to the CJD Surveillance Unit. Such
examinations have been done on about 70% of cases notified since May,
1990, either by referral for necropsy in Edinburgh or in cooperation with
neuropathologists in other centres who refer cases after diagnosis. Blocks
from the frontal, temporal, parietal, and occipital cortex; basal ganglia;
thalamus; hypothalamus; cerebellum midbrain; pons; and medulla are fixed
in formalin. Blocks are immersed in 96% formic acid for 1 hour before
routine processing into paraffin wax. Sections are cut at 5m and stained
by conventional histological techniques and immunocytochemistry for prion
protein (PrP). Pretreatments for immunocy tochemistry with two monoclonal
PrP antibodies (KG9 and 3F4)3 include incubation in 96% formic acid for 5
min, then 4 mol/L guanidine thiocyanate for 2 hours, and hydrated
autoclaving at 121C for 10 min.
Results
Patients
Of the 207 cases of CJD examined neuropathologically since May, 1990,
ten have neuropathological findings that clearly distinguish them from
other cases examined by the CJD Surveillance Unit (two have been reported
previously4,5).
These ten cases (four male) had disease onset from February, 1994, to
October, 1995. One came to the attention of the CJD Surveillance Unit in
March, 1995, and the other nine between October, 1995, and January, 1996.
The ages at death of the eight patients who have died range from 19 to 41
years (median 29). Two patients remain alive at ages 18 and 31 years.
Intervals between disease onsets and death range from 7a5 to 22a5 months
(median 12). Surviving patients in March, 1996, have disease durations of
6 and 22 months. These patients are relatively young compared with most
patients with CJD and their disease duration is relatively long. Among 185
cases of sporadic CJD identified since May, 1990, average age at onset was
65 years and median duration of disease four months; for half of these
patients, duration was 2!s to 6!s months. Since May, 1990, only two other
sporadic cases of CJD with age less than 45 years have been identified,
both aged 44 years. These cases had disease onsets in 1993 and 1994;
neither showed the neuropathological changes described.
Table 1 shows the cases of CJD dying in England and Wales between 1970
and 1984 and in the UK from 1985 to 1996 at age less than 45 years. Six
cases of CJD aged less than 30 years and three aged 30 to 34 years have
been identified since 1990--all these cases were identified within the
last 10 months. In comparison only one case of CJD aged less than 30 years
and three aged 30 to 34 years were identified between 1970 and 1989. We
have been able to examine pathological material from one of these earlier
cases which did not show the neuropathological pattern described in this
report and in the three other caes review of neuropathological reports did
not suggest this pattern.
Table 1: Known cases of sporadic CJD* in the UK, 1970-96, dying aged
less than 45 years
<30 30-34 35-39 40-44
1970-79 0 2 3 2
1980-84 1 1 3 1
1985-89 0 0 3 3
1990-94 0 0 1n 2
1995-96 alpha 5 (1) 2 (1) 0 1
*Excludes known iatrogenic and inherited cases. aEngland and Wales
only for the period 1970-84.
alpha Numbers in brackets indicate patients alive.
nDied before May 1990.
Clinical course
The clinical course of disease in the ten patients was distinct from that
usually seen in sporadic CJD (table 2). Nine had behavioural changes as an
early clinical feature and were referred to a psychiatrist. In four
patients, an early symptom was dysaesthesiae and in another, pain in the
feet persisted throughout the illness. Nine patients developed ataxia
early in the course of the disease. While all patients developed
progressive dementia, in only two was memory impairment part of initial
clinical presentation. Seven of the patients developed myoclonus, often
late in the course of the disease, and three had choreoathetosis. None of
the cases had the electroencephalographic (EEG) features usually
associated with CJD.
With established diagnostic criteria for CJD,6 none of these cases
would have been classified as "probable" cases of CJD on clinical grounds.
At the time of initial referral to the CJD Surveillance Unit, two patients
were classified as definite cases (after brain biopsy) and another as a
possible case, while the remaining seven did not fulfil the criteria for
even "possible" CJD.
Information on PrP genotype is available for eight cases. All were
methionine homozygotes at codon 129 of the PrP gene and none of the known
mutations associated with the inherited forms of CJD was identified. In a
study of codon 129 genotypes in sporadic CJD in the UK, 1990-93, 83% of
cases (n=111) were methionine homozygotes.
Neuropathological features
Neuropathological examination in all ten cases showed spongiform change
and PrP plaques confirming the diagnosis of CJD.6 In two cases
investigated by cerebral biopsy and in the eight necropsy cases,
neuropathological features were uniform, with spongiform change in a
relatively sparse distribution throughout the cerebral cortex (although
all areas were involved to a variable extent in each case who came to
necropsy). Spongiform change, neuronal loss, and astrocytosis were most
evident in the basal ganglia and thalamus, and were present focally in
the cerebrum and cerebellum, most evidently in areas with confluent
spongiform change.
The most striking and consistent neuropathological abnormality in all
cases was PrP plaques. In the eight necropsy cases, plaques were
extensively distributed throughout the cerebrum and cerebellum, with
smaller numbers in the basal ganglia, thalamus, and hypothalamus. Many of
these plaques resembled kuru-type plaques with a dense eosinophilic centre
and pale periphery and, unusually for this type of lesion, were surrounded
by a zone of spongiform change (figures 1 and 2). This unusual feature was
not seen in any of the other 175 sporadic CJD cases investigated. Similar
lesions have, however, been described in scrapie, where they have been
referred to as "florid" plaques.7 Immunocyto-chemistry for PrP showed
strong staining of these plaque-like lesions, but also showed many other
smaller plaques, which appeared both as single and multicentric deposits.
PrP deposition was also seen in a pericellular distribution in the
cerebral cortex and in the molecular layer of the cerebellum, the pattern
of which suggested deposition around small neurons (figure 3). Plaque and
pericellular PrP deposits occurred throughout the cerebrum and cerebellum,
and were clearly visible in the absence of confluent spongiform change in
the surrounding neuropil. In the basal ganglia and thalamus, a
perivacuolar pattern of PrP staining was also seen, with linear tract-like
deposits within the grey matter. PrP plaques were also noted in these
regions although there were fewer than in the cerebrum and cerebellum
(figure 4).
These qualitative differences in the nature of the neuropathological
lesions and morphology of PrP deposits were matched by an apparent
increase in the amount of PrP deposited in all grey-matter regions
compared with sporadic cases, 12 iatrogenic cases, six cases of inherited
CJD, and in four cases of Gerstmann-Straussler-Scheinker syndrome.
Age at Sex Year of Year of death Duration of
onset onset illness (months)
16* F 1994 Alive >22
18* M 1994 1995 >11
19 M 1995 1996 >13
26 F 1994 1996 >22-5
28* F 1995 1996 >10
28 F 1995 1995 >11
29 F 1994 1996 >17
29 M 1995 1995 >7.5
31 M 1995 Alive >6
39 F 1994 1996 >21
Age at Sex Presenting Psychiatric onset
symptom symptoms
16* F Dysaesthesiae +
18* M Behavioural change +
19 M Personality change +
26 F Dysaesthesiae +
28* F Memory impairment +
28 F Behavioural change +
29 F Depression +
29 M Foot pain +
31 M Memory impairment +
39 F Dysaesthesiae +
Age at Sex Ataxia Dementia Myoclonus onset
16* F + + +
18* M + + +
19 M + +
26 F + + +
28* F + + +
28 F + + +
29 F + +
29 M + + +
31 M + +
39 F + + +
Risk factors
Information on potential risk factors for CJD is available for nine
cases. None had a history of potential iatrogenic exposure to CJD through
neurosurgery or human-pituitary-derived hormones, and none had had a blood
transfusion. Four cases had no history of any operation, four had
undergone minor surgery (two tonsillectomy in 1975 and 1991, one a foot
operation in 1984, one a dilatation and curetage in 1989), and one had had
a caesarean section (1974), colonoscopy (1992, 1994), and laparoscopy
(1986). One patient had worked as a butcher from 1985 to 1987 and another
had visited an abattoir for two days in 1987. None had ever worked on
farms with livestock, although one patient had spent 1 week's holiday a
year on a dairy farm between 1976 and 1986.
There was no record of BSE in this herd. All nine cases were reported to
have eaten beef or beef products in the last 10 years, but none was
reported to have eaten brain. One of the cases had been a strict
vegetarian since 1991.
Discussion
The ten cases of CJD in this report are remarkable in that they have a
specific neuropathological profile which, to our knowledge, has not been
described previously6,8 and which is so consistent that neuropathological
samples from the cases are virtually indistinguishable. The cases are
further characterised by having remarkably low ages at onset for CJD and
other atypical features, including a generally protracted and unusual
clinical course and absence of EEG changes typical of CJD. These findings
raise the possibility that the cases represent a new clinicopathological
variant of CJD.
Effect of age
It is possible that the unusual neuropathological profile of these
cases is due to their young age. Review of published reports on previous
young patients worldwide did not reveal any descriptions of neuropathology
similar to these UK cases. In 14 cas es of CJD aged less than 30 years
previously reported outside the UK, plaques are described in only one, and
in this report the possible diagnosis of Gerstmann-Straussler-Scheinker
syndrome was raised. In four of these cases,9-12 pathological reports
have been reviewed and there was no evidence of PrP plaques (Paul Brown,
personal communication). We did immunocytochemical staining on another of
these cases of CJD aged 27 years from Poland (courtesy of Professor
Kulczycki) and on a 16-year-old patient from the UK dying of CJD in 1980,
and there was no evidence of plaque formation in either case. We also did
immunocytochemical staining on 11 cases of CJD developing after
administration of human growth hormone (mean age 27a5 years) and although
PrP plaques were present predominantly in the cerebellum, the
neuropathological features in these cases13 were otherwise quite distinct
from the young patients in this report. We emphasise that plaque
distribution and spongiform change in these ten young cases were clearly
apparent on routine light microscopy. Current evidence suggests,
therefore, that the pathological profile in these cases is unlikely to be
simply an age-related feature.
CJD has been described previously in young patients, but these are
usually isolated case reports9-12 and in systematic surveys the
identification of CJD in patients aged less than 30 years old is
exceptional. In the UK, only one such case was identified between 1970
and 1989. In France, between 1968 and 1982,14 only two patients aged less
than 30 years old were identified; only one was identified in Japan
between 1975 and 1977; and none at all in Israel between 1963 and 1987.
Additional cases aged less than 40 years have been identified through the
European surveillance project on CJD (1993-95); two cases aged 22 and 34
years old were found in the Netherlands; two aged 31 and 33 years old in
Germany; two aged 26 and 37 years old in France; and one aged 37 years
old in Italy. Six of these cases are judged on clinical evidence not to be
similar to the cases described in this report. Neuropathological
information is available on two of these six cases, neither of which
showed the characteristic changes. In the remaining case, full
neuropathological information will be available shortly.
Case ascertainment
The overall incidence of CJD has risen in the UK in the 1990s,15
although this is due mainly to an increase in the incidence of CJD in
those aged over 75 years (these cases have a typical clinicopathological
profile). The most likely explanation for this is improved ascertainment
of CJD in the elderly, with the possible implication that the
identification of young cases of CJD may be due to similar improved case
ascertainment due in part to the publicity surrounding the BSE epidemic.
It is noteworthy that three of the ten cases in this report were notified
to the CJD Surveillance Unit as suspect cases of CJD only after biopsy
samples had been examined. In the absence of neuropathological
examination, these cases might not have come to the attention of the CJD
Surveillance Unit. It seems likely, however, that patients of this age
dying of a progressive neurological condition would have undergone
necropsy in the past. Two cases came to the attention of the CJD
Surveillance Unit through unconventional means (through a newspaper report
and after a clinical presentation of other cases) which led to their
notification earlier than would otherwise have been the case. All of the
ten cases were identified over 10 months and although there was extensive
publi city surrounding two young cases in late 1995, there has been
considerable publicity regarding CJD and BSE since 1990. Other European
countries have undertaken systematic surveillance of CJD over a similar
period and there has been no obvious increase in the incidence of CJD in
young patients despite detailed investigation.
There is a possibility that the diagnosis of such atypical cases may
previously have been previously missed. Three of the 14 cases discussed
above were from Poland, aged 19, 23, and 27 years, and were identified in
the course of a study of subacute sclerosing panencephalitis (SSPE).16 A
recent review of the clinical details of suspect but unconfirmed cases of
SSPE held by the SSPE register in the UK has provided no evidence that
cases of CJD were misdiagnosed as SSPE in the UK. Although improved
ascertainment remains a potential explanation for the identification of the
young patients we report, such information as is available does not
support this interpretation.
Possible link with BSE
The first aim of the CJD Surveillance Unit has been to identify any
changes in CJD that might be attributable to the transmission of BSE to
the human population. Although the small number of cases in this report
cannot be regarded as proof, the observation of a potentially new form of
CJD in the UK is consistent with such a link. The common neuropathological
picture may indicate infection by a common strain of the causative agent,
as in sheep scrapie in which strains of the disease have been identified
which can be distinguished on the basis of disease-incubation period and
distinctive neuropathological profile in mouse models.17 Exposure of the
human population to the BSE agent is likely to have been greatest in the
1980s, and especially towards the end of that decade, before the ban on
the use of specified bovine offal was introduced. This would be consistent
with an incubation period of between 5 and 10 years for these cases.
If the present cases are due to exposure to the BSE agent and this
accounts for the distinctive neuropathological appearance, it is not clear
why this previously unrecognised variant of the disease has been found
only in persons under the age of 45 years. The absence of this variant in
older persons could be due to age-related exposure to the agent; to
reduced susceptibility among older persons; or to misdiagnosis of this
variant of the disease in older age-groups, especially in those in which
dementia is more common.
We were alerted earlier to a possible link between CJD and BSE by our
finding of an apparent excess of CJD among cattle farmers.15 Our
interpretation of this was tempered by observations of high rates among
cattle farmers in other European countries in which BSE was either very
rare or had not been reported. None of the four farmers showed the
neuropathological features described here, and all were consistent with
previous experience of sporadic cases of CJD.
Conclusions
We believe that our observation of a previously unrecognised variant of
CJD occurring, to date, only in persons under the age of 45 years is a
cause for great concern. That it is due to exposure to the BSE agent is
perhaps the most plausible interpretation of our findings. However, we
emphasise that we do not have direct evidence of such a link and other
explanations are possible. That these cases have been observed now because
of improved ascertainment cannot be completely dismissed. It seems
unlikely, however, that such a distinctive neuropathological pattern
would have been missed previously, especially among persons dying at a
young age. It is essential to obtain information on the clinical and
neuropathological characteristics of young patients with CJD in Europe
and elsewhere, and historically in the UK, but proof of an association
between BSE and CJD may depend on animal transmission studies and
continued epidemiological vigilance. If there is a causal link then, given
the potentially long and widespread exposure to the BSE agent, further
cases of this new variant of CJD are likely to arise.
We thank J Mackenzie for data management, P Brown for reviewing an early
version of the manuscript, J Collinge for assistance with the molecular
analysis, and W B Matthews who initiated CJD surveillance in the UK in the
1980 for advice. The CJD Surveillance Unit is funded by the Department of
Health and the Scottish Home and Health Department and suported by BBSRC
(grant no 15/BS204814). The Concerted Action on CJD Surveillance in Europe
was funded through the EC Biomed I Programme. The epidemiological
surveillance of CJD would not be possible without the collaboration of
neurologists and neuropathologists throughout the UK and Europe.
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