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Creutzfeldt-Jakob disease Patterns of worldwide occurrence and the significance of familial and sporadic clustering.

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Creutzfeldt-Jakob Disease: Patterns
of Worldwide Occurrence and the Significance
of Familial and Sporadic Clustering
Colin L. Masters, M D , Jonathan 0.Harris, BA, D. Carleton Gajdusek, M D ,
Clarence J. Gibbs, Jr, PhD, Christoph Bernoulli, M D , and David M. Asher, M D
The worldwide epidemiology of Creutzfeldt-Jakob disease (CJD) is presented from an analysis of 1,435 patients. In
the United States, the average annual mortality rate is at least 0.26 deaths per million. Temporal-spatial clustering
of cases was not found in the United States, but reports from other countries indicate that such clustering does
occur. Fifteen percent of the cases were of the familial type, suggesting a genetic susceptibility to infection.
Iatrogenic transmission by corneal transplantation and neurosurgical operations has occurred, and the possibility
is raised that previous surgery or preexisting neurological disease may be associated with an increased risk of
developing CJD. It remains to be determined whether the virus of CJD is maintained only b y patient-to-patient
transmission, has a zoonotic reservoir such as scrapie, or causes widespread latent infection of man that is occasionally activated.
Masters CL, Harris JO, Gajdusek DC, et al: Creutzfeldt-Jakob disease: patterns of worldwide occurrence and
the significance of familial and sporadic clustering. Ann Neurol 5:177-188, 1979
Creutzfeldt-Jakob disease (CJD) is a slow degeneration of the central nervous system caused by a transmissible virus. Although rare, it is important because
of its uniformly fatal outcome, and because iatrogenic
transmission has occurred [ 5 , 1I]. Creuttfeldt-Jakob
disease, kuru, and two animal disorders, scrapie and
transmissible mink encephalopathy (TME), together
form the subacute spongiform encephalopathies, a
category of diseases caused by filterable agents that
are best called unconventional viruses [ 171. T h e relationships between the animal and human diseases,
and between CJD and kuru, remain unclear. There is
compelling evidence that the virus of kuru was
spread by contamination of skin and eyes associated
with ritual mourning in New Guinea, which included
cannibalism, and it is conjectured that kuru may
have originated from a sporadic case of CJD [17]. A
logical extension of this hypothesis is that CJD might
be the result of human contamination with the
scrapie virus of sheep; this possibility is suggested by
the observation that scrapie virus causes a spongiform encephalopathy that is indistinguishable from
CJD in several species of experimentally infected
nonhuman primates [ 191. Reports of spatial clustering of CJD [25, 32-34, 371 and the familial occurrence of CJD [ 14, 30a] raise the possibility of a com-
mon source of infection, with or without an inherited
susceptibility .
In this paper we report cumulative data o n a series
of 1,435 patients with CJD, examine the patterns of
worldwide occurrence and the significance of familial
and sporadic clustering, and discuss various mechanisms for transmission of the disease.
Materials a n d M e t h o d s
Selection of Cases
The criteria for inclusion of cases in this retrospective survey and the diagnostic classifications used are summarized
in the following outline:
I. Transmissible virus dementia
Cases experimentally transmitted to nonhuman primates and/or other animals, producing an experirnental spongiform encephalopathy (this includes all cases
diagnosed as CJD as well as 2 cases of familial Alzheirner disease and 1 of progressive supranuclear
palsy ).
11. Definite or probable CJD
A . Definite CJD
Neuropathologically confirmed spongiform encephalopathy in a case of progressive dementia
with at least one of the following features:
~
From the Laboratory of Central Nervous System Studies, National
Institute of Neurological and Communicative Disorders and
Stroke, National Insritutes of Health, Bethesda, MD.
Accepted for publication Aug 28, 1978
Address reprint requests
Dr Masters, Building 3h, Room 5B25,
National Institutes of Health, Bcthesda, MD 20014.
0364-5134/79/020177-12$01.25 @ 1978 by Colin L. Masters
177
1. Myoclonus.
2. Pyramidal signs.
3. Characteristic electroencephalogram.
4. Cerebellar signs
5. Extrapyramidal signs.
B. Probable CJD
Neuropathologically unconfirmed cases with the
same clinical features as in IIA.
111. Possible CJD
History, without medical records allowing confirmation, of progressive dementia with:
A. Myoclonus and a course of less than three years; or
B. A member of the family having transmissible definite or probable CJD (Groups I, IIA, IIB); or
C. At least two of the clinical features listed for IIA
together with the appearance of prominent and
early signs of lower motor neuron involvement
(the amyotrophic form of CJD).
The 1,435 CJD patients, whose records were reviewed
for place of residence, history of familial disease, occupation, past medical and surgical histories, and history of previous or concurrent neurological disease, were derived
from two sources:
1. Cases of CJD forwarded to our laboratory. Since
1966, physicians from many countries have sent specimens
from patients with CJD for study in our laboratory. Of the
824 patients brought to our attention, brain tissue from
373 was provided for inoculation. From 111of these cases,
the virus has been successfully transmitted to nonhuman
primates, 97 in our laboratory and 14 in laboratories of
other investigators. Brain tissue from 200 of the remaining
262 patients has already been inoculated into susceptible
nonhuman primates, which have thus far remained well.
Only 4 cases of definite or probable CJD have failed to
transmit to animals after incubation periods of five o r more
years.
2. Cases of CJD retrieved from review of the literature.
A survey of the world literature on CJD from 1910
through 1977, inclusive, yielded 611 cases. The year of
death was reported in 278 cases; for 333 patients the year
of publication was raken as an approximation of the time of
occurrence. The location of residence was not provided in
most of the published cases, and the country of origin of
the report was taken as a guide to the place of occurrence.
Since the nosological unity of CJD continues to be debated, we have adopted a broad classification of CJD, including a large series of cases of proved infectious cause,
definite cases verified neuropathologically, probable cases
with typical clinical features, and cases of CJD in which the
anamnestic data strongly support the diagnosis (see the
outline). Of the 1,435 cases included in the present survey,
111 were transmissible (Group I), 588 were definite o r
probable CJD (Groups IIA and IIB), and 736 were possible CJD (Group 111). Only transmitted cases of CJD have
been used for the analysis of clinical features presented in
the results.
The entity of amyotrophic CJD [36] may be a variant
of amyotrophic lateral sclerosis; it has not y e t been trans-
178
Annals of Neurology
Vol 5
No 2
February 1979
mitted to animals [411. Transmission of spongiform encephalopathy from the brains of 3 patients who had diseases that
were clinically and pathologically distinct from CJD [41]
suggests that the virus of CJD is more widespread than was
previously believed. Therefore, we refer to a category of
transmissible virus dementias (Group I), allowing for the
possibility that diseases other than CJD, with spongiform
change, may be caused by the CJD agent.
Special Studies
Three subsets of CJD were selected for special studies.
1. Familial CJD. A group was identified of familial CJD
patients who had at least one relative die of the disease. A
total of 50 families were identified: 36 families with 148 affected members were referred to our laboratory, and 14 other
families with 70 affected members are reported in the literature ( [ l o , 13, 15, 22, 351, and 9 families referenced in
[ 141). Transmission of CJD to nonhuman primates has
been successful from 11 of the 4 0 familial CJD patients
from whom specimens were received; animals inoculated
with brain tissues from the remaining 29 patients are still
under observation.
2 . Retrospective. survey of cases of CJD occurring in the
urbanized area of Boston. All cases in the Boston area with
a diagnosis of CJD which could be retrieved from the records of the city's major teaching hospitals (Beth Israel
Hospital, Boston City Hospital, Boston University Hospital, Boston Veterans Administration Hospital, Cambridge
Hospital, Children's Hospital Medical Center, Deaconess
Hospital, Faulkner Hospital, Massachusetts General Hospital, Mount Auburn Hospital, Peter Bent Brigham Hospital, St. Elizabeth's Hospital, and Tufts-New England
Medical Center) were included in the file of 824 patients
"referred to our laboratory." Of 43 patients seen in these
Boston area hospitals since 1957, 22 had a usual place of
residence within the urbanized area of Boston [42].These
patients were studied for evidence of temporal-spatial
clustering.
3. Analysis of occupations and past medical ahd surgical
histories. All the cases of CJD were reviewed for the patient's occupation and past medical and surgical histories.
The occupational history was ascertained in only 308 of the
1,435 cases. Medical and surgical histories were available in
337 cases; only illnesses sufficient to warrant physician referral were tabulated.
Results
Worldwide Occurrence of CJD
Examination of the place of occurrence, by country,
of all cases of CJD shows that the disease has a
worldwide distribution (Fig 1, Table 1). Because the
number of cases reported from each country probably reflects the interest and awareness of the country's physicians, it is assumed that i n countries not
represented (especially the larger o n e s such as
China), the disease remains unrecognized or unreported.
Country RepOrtlnQ CJD
Fig 1 . Worldwide distribution of CJD. Forty-one muntrirs reporting CJD are identifed (see Table 1 for absolute number of
ruses iti euih rountr.y:y).Only 10 iuses of CJD were reported from
hloscow, USSR, and therefore the shaditig iit the mup indicates
no ruses i n the eastern provinces in the USSR.
Age and Sex of Patients arid Duration of Disease
Since the cumulative data on all patients with CJD
undoubtedly contain atypical cases and cases that
might be excluded from the category of CJD if more
information were available, we have used the clinical
data o n 74 patients (83 with sporadic and 11 with
familial CJD) whose disease was transmitted to
nonhuman primates in our laboratory to provide the
best estimate of age and sex of patients and duration
of disease. Excluded from these calculations were the
3 transmissions resulting from diseases other than
CJD: 2 cases of clinically and pathologically confirmed Alzheimer disease (women aged 49 and 58
years with durations of illness of 60 and 105 months,
respectively), and 1 case of clinically and pathologically diagnosed progressive supranuclear palsy (a
man aged 50 years with a duration of illness of 9.5
months). These 3 cases are included in the general
demographic data presented later, however.
The 94 transmissible cases included 51 male patients and 43 females. The mean age at death was
57 years (10.2 SD; range, 27 to 78) (Fig 2 ) . The
youngest transmitted case in our data occurred in a
Japanese woman aged 2 7 , and this patient also had
the longest total duration of illness (55 months). The
youngest patient in the overall series was a 17-yearold boy who was infected from contaminated
stereotactic electrodes [5]. There were 6 patients in
the series aged 80 or more; one of these was a man
who developed the disease two years after a bone
homograft.
The clinical course of disease was divided into a
prodromal phase and a dementing/myoclonic phase
[31]. The durations of these phases, together with the
total duration, are shown in Figure 3. In the 94 patients, mean duration of the prodromal phase was 3.5
months (3.9 SD; range, 0.5 to 24.0), the mean duration of the dementing/myoclonic phase was 3.7
months (4.6 SD; range, 0.5 to 36.0), and the mean
total duration of illness was 7.3 months (7.5 SD;
range, 1.5 to 55.0).
Estimation of Average Anizual M0rtalit.y
Since CJD is a comparatively rare disease with an
insidious onset, the true incidence and prevalence are
difficult to ascertain. We therefore present our data
in terms of annual mortality rates, which for practical
purposes are of the same order of magnitude as incidence and prevalence.
The mortality rate could be calculated only in
those areas in which cases have been most reliably
ascertained. Based on cases of CJD made known to
our laboratory and cases published during the fiveyear period 1973 to 1977, the average annual mortality rate for the entire United States population was
0.26 deaths per million (Table 2). With adjustment
for age, the age-specific mortality rate was 0.40
deaths per million. In the urbanized area of Boston,
the average annual mortality rate was 0.43 deaths per
million (Table 3). The secular trend apparent in the
number of cases ascertained each year in the United
Masters et al: Creutzfeldt-Jakob Disease
179
~~
Country
Australia
Austria
Belgium
Brazil
Canada
Chile
Colombia
Czechoslovakia
Egypt
Finland
France
Germany
Greece
Holland
Hungary
India
Indonesia
Iran
Ireland, Northern
Israel
Italy
Japan
New Guinea
Norway
Peru
Poland
Portugal
Romania
Senegal
South Africa
Spain
Sweden
Switzerland
Taiwan
Thailand
Tunisia
United Kingdom
United States
Uruguay
USSR
Yugoslavia
Total
Cases of CJD
Transmitted
in O u r
Laboratory
Cases of CJD
Transmitted
in Other
Laboratories"
Other Cases
of CJD Reported
to O u r
Laboratory
1
1
6
34
32
Cases of CJD
Reported
in the
Literature"
9
23
10
2
8
16
9
1
7
1
11
117
22
1
1
3
2
12
1
2
1
12
25
1
1
2
1
1
2
1
1
2
1
20
1
9
16
1
78
59
207
83
1
7
13
11
6
10
4
1
29
60
3
6 (2)
2
33
360
97'
14 (4)
713
"Numbers in parentheses refer to transmissions also verified in our laboratory.
"Exluding cases also reporred ro our laboratory.
"Includes 3 cases of arypical rransmission (see t e x t ) .
180 Annals of Neurology
Vol 5
No 2
February 1979
6
1
2
1
41
38
52
64
5
6
4
5
9
55
1
2
42
1
5
1
2
6
6
20
99
1
10
2
1
1
2
120
525
1
10
2
61 1
1,435
1
10
12
24
17
3
50
48
8
42
1
5
1
Tocal
No. of
Cases
74
I
Tahlt 2. Estimate fijhiortafitj Ratt f m m CJD
the United Statec. 137-3-1 977
iti
Cases Reported
Cases
Year
I
H m t
Literature
to this
Laboratory
1973
4
31
1974
35
1075
1
2
41
1976
19-77
0
3
70
78
10
255
Total
Duration of Prodromal Stage
in
35
36
43
70
81
265,'
,'Based o n the United States population o f 203.21 1,926 from the
19?0 census [42]. the average number o f cases o f CJD in rhe
five-year interval 1973-1977 was 53; this yielJs an estimatecl average annual mortality rate o f 0.26 per million. When adjustment is
made for rhe age of the population at risk (pcrsons aged 18 ycars
and over). the age-spccific average annual mortality rate I S 0.40 p e r
million
Duration of DementmgIMyoclomc Stage
I
Table 3 Ettrmate ojf\lortdfrt\ Katejroni CJII Otcurrrng 111 the
I:rbun Area of Boston. 1957-1976
Y
m
Year o f Death
z
1957
1958
1059
1
0
1960
1961
1
0
1962
1063
1964
1965
1906
1907
1968
1
1
0
I
101
Toral N o
of Cases
I
I
Total Duration
1909
19-0
States (Table 2 ) almost certainly represents increasing awareness and notification of cases to our laboratory. A similar trend was not observed in the retrospective survey of cases occurring in the urbanized
area of Boston (Table 3 ) .
For comparison there are only a few published estimates of the frequency of occurrence of CJD in
other countries. In France, Brown and Cathala [?, 91
reported that the average mortality rate in thc tcnyear period 1968 t o 1977 was 1.09 deaths per million
in the city of Paris, 0 . 5 5 deaths per million in the
Paris suburbs, and 0.25 deaths per million in the
outlying areas. Matthews 1321 reported an annual incidence of 0.09 p c r million in England and Wales.
Kahana et a1 1251 found annual incidences of between
0.4 and 1.9 cases per million in non-Libyan ethnic
groups in Israel. Farmer et a1 1121 reported an average annual incidence of 0.24 cases p e r million in the
N e w York boroughs of Brooklyn and Staten Island
N o . o f Cases of CJD
7
7
0
0
3
3
19-1
1
0
1972
0
1973
1974
1075
1976
3
Total
2
0
2
22.'
T h e mean popularion o f the urbanizecl area of Boston WAS
2,532,900 for thc ycars 1960-19-0 (based o n 1960 anJ 1970
census figures) [42]. The 22 cases occurring in this twenty-year
interval yield an average annual mortality from CJD o f 0.43 per
million (nor adjusrcJ for age).
in the seventeen-year period 1059 t o 1975; however,
based o n 5 cases seen in 1 0 7 6 and 1977, they estimated a current annual incidence of 1.8 cases per
million.
E aiden re fo r Spu t i d -7'ernporul Clusr e ring
T h e distribution of cases within the United States is
shown in Figure 4. T h e r e is no obvious clustering,
Masters et al: Crcutzfelclt-Jakob D i s e a s e
181
although the average annual mortality rates for each
state vary considerably. In Figure 5 the places of residence of the 22 patients identified in the urbanized
area of Boston are shown. Although there are six
pairs of cases separated in distance by less than 3 km,
only two pairs were separated in time by less than
three years (3.0 and 0.7 km, 12 and 5 months, respectively). This grouping of cases is not statistically
significant using Knox's method for time-space interaction 127, 281.
Five reports of apparent clustering have appeared
in the literature. Matthews 1321 reported two apparent geographic clusters in England. Kahana et a1 1251
described an apparent clustering of cases of CJD
among Israeli Libyan Jews, with an average annual
incidence of 31.3 per million. However, further
studies of this focus have revealed a significant familial clustering 13, 381. Mayer et al [33, 34, 371 reported clustering in a rural community in Czechoslovakia, where 4 cases of CJD were identified within
a four-year interval. Since then, 4 more cases have
been identified (Mayer V: personal communication,
1978), yielding an average annual incidence in excess
of 10 cases per million. The cases reported by Nevin
et a1 1391, discussed in the next section, together with
other episodes of apparent surgical transmission of
CJD involving 2 or more patients, clearly represent a
spatial and temporal clustering. The two reports of
conjugal occurrence of CJD (see the following section) also represent pair association o r clustering.
Other foci of apparent high incidences of CJD
have been reported. Data from Italy show an average
annual mortality in CJD of 1.4 cases per million in
the area of Piacenza/Parma/Reggio/Mantova, where 6
182
Annals of Neurology
Vol 5
No 2 February 1979
F i g 4. Average aiinual viortality rates per million population of
CJD i n the Unitedstates, 1973-2 977. The overallmean rate
was 0.26 deaths per million (see Table 2).The cot/tiiiental
states uith average rates above and below the m a n are indicated. Figures in parentheses indicate the absolute number of
cases orrurriirg iri thefive-.vear ititetvalfroni 1973 t o 1977.
cases were seen in the three-year interval from 1975
to 1977 (Lechi A: personal communication, 1978).
An urban clustering of cases has also been reported
in Italy Ill. The occurrence of 5 cases in the area of
Burlington, VT, within the last five years gives an
incidence of approximately 5 cases per million (Poser
C: personal communication, 1778). Dr S. Galvez of
Santiago, Chile, has observed a high incidence of
CJD in that area [8, 291.
T h e seasonal variation that has been reported for
the clinical onset of symptoms of CJD 16, 351 was not
confirmed in the present series.
Familial Clustering of CJD
The familial occurrence of CJD is well documented. In
addition to data o n 14 families published by other
workers, we now have data on 36 other families
brought to the attention of this laboratory. In the
present series of 1,435 cases of CJD, 218 (15$6) occurred within families with 2 or more affected members. In the 50 families there were 168 CJD-affected
relatives of the 50 propositi. O f these 168 cases, 67
occurred within the same generation and 68 were
in the first generation above the propositus. Eleven
familial cases have been transmitted to experimental
animals.
-
I
\
lOkm
Fig 5 . Di.rtributioii of cases o f CJDqby place of usual resirlrni-e.
withiii the urhanizr7d area of Boston 1421. There as no statiftical evidence of teniporal-.patial clustering. The data pertain to
patient.! d y i n g i n the tu~et~t)~-~~eavperiod
1957 to 1976 (see
TabLe.?).
The maternal line of relationships was not more
affected than the paternal line. T h e mean age at
death for transmitted familial cases was 51 years (N
= 11; range, 35 to 69; SD, 11.7). This figure was
slightly lower than the mean age at death for the
sporadic transmitted cases, which was 58 years (N =
83; range, 27 to 78; SD, 9.7). A detailed analysis of
these families will be published [30al.
Conjugal occurrence of CJD has been recorded
twice 124, 321. In the cases of Jellinger et a1 [24], the
onset of disease and date of death of the husband and
wife were closely related.
The separation of family members in time and
space prior to the onset of symptoms may indicate
minimal incubation periods for the disease. In a Finnish family with CJD (Haltia M: personal communication, 1978), one affected member had resided in
Holland for about thirty years, having little
contact with the other affected members of the family living in Helsinki. In another family [40] the
father migrated from England to the United States at
the age of 24 and died 28 years later of a chronic
neurological disease that was not typical of CJD. A
son died with transmissible CJD thirty-one years
after the death of his father; several relatives living in
England also died from CJD. This family history
would also indicate that if intrafamilial transmission
of CJD virus were occurring, an incubation period of
thirty years might be expected.
Enviro)iniemtul Fuctors Rele?mit t o Cuz4sutiori
The only cases of CJD for which the mechanism of
transmission is definitely known were infected iatrogenically [ 5 , 11, 181. Surgical procedures occurring
within three years of onset of symptoms of CJD can
transmit the disease; this finding prompts a reexamination of possible iatrogenic factors in the medical histories of other patients with CJD.
T h e surgical and medical histories of all patients
with CJD were reviewed using information published
in the literature as well as that pi-vided with cases
referred to this laboratory. Past medical or surgical
histories were recorded in 337 of the 1,435 cases.
These histories are summarized in Tables 4 and 5.
There were 38 cases in which a medical illness or a
surgical procedure was associated with the onset of
symptoms of CJD, and 12 cases in which such events
occurred in the 4-month interval preceding onset
(Table 4). In the 30-month interval from 6 months to
three years before the onset of symptoms, there was
an increased number of recorded surgical procedures
o r medical illness (Table 4), as compared with the
number recorded during later intervals. While this
increase may be only coincidental, reflecting a proportional increase of illnesses in an aging population,
an analysis of the types of surgical procedures suggests otherwise (Table 5 ) .
There were 13 instances of cranial o r ocular surgery, including 9 neurosurgical and 4 ophthalmological operations. The neurosurgical procedures
included 3 craniotomies for removal of meningioma ([16], Case 1 of Nevin et a1 [39], and 1 case
reported to o u r laboratory); 2 stereotactic electroencephalographic depth recordings using CJDcontaminated electrodes 151; 1 instance each of
craniotomy for abscess, prefrontal leukotomy, and
ventriculography ([39], cases 2, 7, and 3, respectively); and 1 operation for trigeminal neuralgia [32].
Of the 4 patients reported by Nevin et a1 [391, 3 were
operated o n by the same neurosurgeon, in the same
neurosurgical unit, within a period of 8 months.
The 4 ophthalmological operations were the CJDcontaminated corneal transplantation of Duffy et a1
[ l l ] and two cataract operations and one photocoagulation that were reported to us (Ghetti B, Sher
J, Porter D: personal communications, 1978).
The past medical history of each patient may be
relevant since a preexisting condition might have subjected the patient to opportunities for iatrogenic
transmission. In this series, the largest proportion of
illnesses occurring in the 6-month to three-year
interval before onset was cardiovascular disease.
Eleven instances of neurological or psychiatric illness
were recorded in this interval. Of the 204 medical
illnesses occurring more than three years before
onset, 56 were neurological or psychiatric. This
Masters et al: Creutzfeldt-Jakob Disease
183
Table 4.Number of Cases in which Surgicul Procedures wid
rMedicd 1tlnesse.c Preceded the Otiset of S,mptoms of CJD"
Interval &fore
Onset of Symptoms
of CJD (yr)
No. of Cases
with Suracal
Procedures
NIL(if Cases
No. of
with Head o r
Other Bodily
Trauma
with Major
0.5
20
21
0.5-1.0
14
4
2
3
4
2)
1
14
0
I
5
0
13
n
6
4
I
7
4
2
0
8
9
1 1-20
21-30
Illnesses
9
30
29
23
8
13
9
5
1
23
23
5
35
II
3
I6
I2
8
I
n
4
41-50
Unknown
I
I2
32
2
'1
Total
193
45
295
31-40
Cases
Mcdical
2
2
2
4
10
Table 6 . Occupatiotts
.'Basecl o n analysis of 337 cases (168 from the Iirerarurc. and I69 reporred
to
our laboratory) in which a pasr medical or s u r g d historv was repimed
Table 5 . Nature of SIirKical Produre.r Ocsurritig betweeti 6
Motith.r
atid 3 Yeur.r before the
O)r.tet
of Sjinptuni.r of CJD
No. o f
Cases
T y p e of Surgery
Cranial and ocular surgery
Neurosurgical procedures (total = 9 )
Removal o f meningionia
Stereoractic EEG recorcling
Craniotomy for abscess
Prefrontal leukotomv
Ventriculogrdphy
Operation for rrigeminal neuralgia
Ophthalmological operations (total = 4 )
Photocoagulation
Corneal transplantation
Cataract removal
O t h e r transplantation
B o n e homograft
O t h e r surgery
Neck
Chest
Abdomen
Extremities
My elogrm
Annals o f Ncurology
1
I
1
I
1
I
1
5
1
53
No 2
No. of
Cases
Occupation
Health professionals
Medical
Physicians
Neurosurgeon
Nurses
Nurse's aide
Dental
Dental surgeon
Dentists
Hospital-associated
Pharrnacisrs
Fool1 aide
AgriculturelMear processing
Vetcrinarian
Butchers, meat packers, and furriers
Farmers and farmers' wives
Food handlers
Housewives
Physicians' wives
Restaurant and food preparation
O t h e r llomestic service
Clerical workers
Professionals, non-health-related
Machine trades an11 factory workers
Building trades
Sales personnel
Civil servants
Transportation workers
Managers and officials
Leather and textile manufacturers
llotel and lollging personnel
Or her.'
2
I
6
1
1
3
3
1
1
7
24
01
3
3
11
2'
25
-74
23
19
18
I5
8
7
5
9
lotal
308
~
~~
.'Barber ( I ) , masseuse ( l ) , prostitute ( I ) , musician ( I ) , photo lab
technician ( 1 ), water treacmenc worker ( 1). beer-tan k cleaner ( 1),
mincr (2).
2
3
20
Vol 5
Patietits w i t h CJD
~
I
Total
184
3
2
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Fcbruary 19-9
finding is emphasized sincc the most likely place for a
patient t o encounter a CJD patient is o n a neurological o r psychiatric scrvice.
T h e patients' occupations were ascertained in 308
of the 1,435 cases (Table 6 ) . T w o classes of occupation are of particular interest: persons in medical and
parameAical fields, w h o might have increased exposure to CJD, and persons in agriculture or meat processing, who could have greater exposure t o the
scrapie virus. Eighteen patients were in the health
professions, including 1 neurosurgeon, 1 dental surgeon, 2 physicians, 3 dentists, 6 nurses, and 1 nurse's
aide. O n e veterinarian, 24 farmers o r farmer's wives,
and 7 raw meat handlers o r butchers were identified
(Table 6). Since most cooks and housewives handle
sheep central nervous system tissue (including the
spinal cord present in lamb chops), it is of interest
that 61 housewives, 3 physicians’ wives, and 3 food
preparers o r restauranteurs were also identified.
T h e travel histories of most patients were not
available. T h e few patients in whom it was possible to
document complete residential histories showed no
unusual features. The report of Grabow et a1 [21] of a
case of CJD with onset of symptoms 10 weeks after
the patient traveled briefly in Papua New Guinea is
of interest; since that patient did not enter the kuru
region or have contact with a kuru patient, and in
view of the brief interval before the onset of CJD,
there is no reason to suspect lateral transmission of
kuru. No lateral transmission has been observed in
the kuru region itself since cannibalism ceased [ 171,
nor has there been any contact transmission in the
rest of New Guinea, where people from the kuru
region have emigrated and lived with others.
Grabow’s patient had clinical CJD, n o t typical kuru,
and his brain tissue induced in chimpanzees a disease
with an incubation period that was typical of CJD and
shorter than any ever seen in a primary transmission
of kuru [ 191.
Discussion
From the results of this descriptive epidemiological
survey, we conclude that the virus of CJD has a
worldwide distribution. There has been a remarkable
increase in awareness of this disease since 1968,
when Kirschbaum [26]was able to survey only 150
cases. Although our estimates of average annual
mortality within the United States show considerable
variation from state to state, it is to be expected that
with even greater awareness and diagnostic acumen, a
uniform mortality rate approaching 1.0 cases per
million will be found.
There are several hypotheses to explain the occurrence of CJD:
Case-to-case transmission, including lateral contact transmission, vertical o r familial transmission,
and transmission resulting from iatrogenic contamination. The possibilities of asymptomatic
subclinical infection and an inherited susceptibility to infection must also be considered in this
category.
Activation of an endogenous (latent) virus infection, through either some environmental trigger
or a genetically determined mechanism.
Zoonotic transmission of the scrapie virus from
sheep, goats, or other animals.
The evaluation of these hypotheses. based on the
epidemiological studies reported in this paper, is
aided by a brief review of human kuru and natural
scrapie and by consideration of the peculiar properties of their unconventional viruses.
lnzplications of the Disappearance of Kuru for the Mode
of Transmission and Maintenance of the Virus of CJD
Kuru is a disease that has progressively disappeared
first among children, and successively thereafter
among adolescents and recently among young adults
[17]. T h e youngest living patient is now over 26 years
of age. No one born in a village since cannibalism
ceased has ever developed kuru, although the disease
continues to affect people born earlier in the same
villages. Each year new patients are one or two years
older than those of the previous year. With some
confidence, we predict that within five years there
will no longer be kuru victims under age 30.
There have been several hundred kuru orphans
under surveillance, children born since 1957 to
mothers who were dying of kuru. N o t one orphan
has yet developed kuru. More than 300 of these children are now over 15 years old; some are over age
20. We conclude that the many children with kuru
who filled the Okapa Hospital in the 1950s were not
infected by their mothers. Twenty years ago, at the
height of kuru incidence in the South Fore region,
where over 90%)of deaths in adult women were from
kuru, almost every woman must have been infected,
indicating that there was no individual variation in
susceptibility to kuru.
Significant conclusions may be drawn from these
phenomena. T h e regular disappearance of kuru is inconsistent with the existence of any natural reservoir
of kuru besides man: with animal o r insect vectors,
with genomic integration of an infectious agent or
other types of i n utero transmission, or with neonatal
infection including transmission by milk. N o n e of
those modes of infection woul~lexplain the regular
pattern with which kuru has actually disappeared.
T h e youngest patient with kuru was 4 years old and
died at age 5; this sets a minimum incubation period
for the disease. Current patients with kuru come
from villages where cannibalism ceased more than
two decades ago, indicating incubations of at least
twenty years. Incubation periods of CJD after infection by peripheral routes might also be expected to
be from four to twenty years or more.
lmplicatiuns of Exprrimental lnfertions with CJD.
K z m ~ and
. Srrapir in Animah for the Epidemiology
of CJD in Man
The failure of all attempts to transmit CJD or kuru
to susceptible nonhuman primates by the oral route,
using huge infectious doses, leads one to question
this as a significant route of natural infection. In
Masters et al: Creutzfeldt-Jakob Disease
185
scrapie, in which oral infections have been documented [ 191, transmission was so irregular that one
wonders whether the true portal of entry was by infection of the gastrointestinal tract itself or from
traumatic mucosal lesions.
In experimentally infected animals, the more peripheral the route of inoculation, the longer and
more variable are the incubation periods. Moreover,
inoculation by the intramuscular and subcutaneous
routes produces “ragged” transmission patterns, with
some animals failing to become ill even after inoculation with high doses of the agent. From these results
we infer that the incubation period and number of
inoculated persons who succumb to CJD might depend on variables such as route of accidental inoculation and dose of virus, and that, as in rabies [4],some
subjects inoculated by peripheral routes might never
develop infection. Thus it may be extremely difficult
to demonstrate the source of infection even if there is
direct contact or iatrogenic infection, as with hepatitis B, except in the rare case in which the virus has
been introduced into the nervous system by surgery.
There is much individual variability in susceptibility to scrapie among sheep; within a given breed,
some individuals fail to succumb even after inoculations with huge doses of the virus rl91. It is not
known whether there is any individual variation of
susceptibility to CJD in man. In intracerebrally inOculated
monkeys and chimpanzees, such
is not usually encountered.
mental studies have also demonstrated that different
strains of CJD, kum, and scrapie virus exist [19, 19al.
Thus one strain of scrapie, when passaged in nonhuman
primates, loses its ability to be passaged back to the
u-
original host. Therefore, the difficulty in transmitting
the human CJD virus to laboratory rodents does not
necessarily rule out its origin from scrapie-infected
material.
Although our attempts to demonstrate viremia
during infection have not been successful, Manuelidis et a1 [30] have shown a persistent viremic state
in guinea pigs. W e have found virus in occasional
specimens of human tissues other than brain (liver,
kidney, lung, lymph node, cerebrospinal fluid), but
not yet in skin or muscle, in external secretions (saliva, semen, tears, sweat), or in urine or feces [19].
These findings indicate that the potential for infection by noninvasive bodily contact (that is, “horizontal transmission” of CJD) must be very low.
lmplicutions of Epidemiology atid Pathogenesis of
Nuturul Scrupie for the Epidemiology of CJD in M a n
There is no evidence that persons living in areas in
which scrapie is endemic are at a greater risk of developing CJD than those living in nonendemic
areas. The worldwide pattern of distribution of
scrapie (Fig 6 ) does not correlate with the distribution of CJD (see Fig 1). For example, in Australia,
where overt scrapie has not been detected in more
than twenty years, the incidence of CJD is probably
F i g 6. Wor/dwide distribution of .tcrapie in sheep (basedon data
supplied b.y Drs J . Hourrigat] aiid A. Klingsporn of the United
States Departrrrrnt of Agriculture). Although scrapie has not
beer? oj$cial(>i reported zit the USSR. an outbreak of nzink encephalopathy occurred ir! Firilarid artd /he in/ictiizg material
was traced t o the USSR (Hourrigaw J : personal comniunication,
1078). Scvapie has noi been reportedin the Middle East.
rn Country Reporting Scrapie
Country W h e r e Scrapie
Has Been Eradicated
186 Annals of Neurology
Vol 5
No 2
February 1979
close to that of the United States and France, where
scrapie is endemic. Similarly, within the United
States, states with the largest number of reported
outbreaks of scrapie (Illinois, Texas, Indiana, Ohio,
and California) d o not have the highest rates of reported CJD. Such a comparison is of limited value,
however, since scrapie-infected material may have
been widely disseminated throughout the country in
meat. Although it has been suggested that the high
incidence of CJD among Libyan-born Israelis might
be related to their habits of eating sheep eyes or brain
[2, 231, natural scrapie has not yet been reported in
the Middle East (see Fig 6).
The spread of natural scrapie by contact infection
is established, but the precise mechanism is unknown. O n e of the largest outbreaks of scrapie
in sheep was the result of “iatrogenic” transmission, when scrapie-contaminated formaldehyde-inactivated louping-ill vaccine was used [20].
General Conszderations on the Natural History
of CJD Virus Infertion
Of the three main hypotheses presented, the zoonotic transmission of sctapie is, at present, the most
difficult to test. In spite of the fact that CJD occurs
where overt scrapie is absent, details concerning subclinical infection of scrapie in animals are unknown.
The possibility that scrapie might cross a large species
barrier to cause CJD in man remains conjectural although five species of monkeys developed a disease
indistinguishable from CJD after inoculation with
scrapie virus [ 191.
Activation of an endogenous (latent) virus infection cannot be excluded. In some cases of CJD there
is a history of head or other bodily trauma immediately preceding the onset of symptoms. T h e unexpected demonstration that an experimental spongiform encephalopathy resulted from inoculation of
brain tissue from 3 patients with diseases other than
CJD [41] could be interpreted as indicative of the
presence of a latent virus instead of isolation of an
etiological agent.
Within the hypothetical category of case-to-case
transmission, most mechanisms now demonstrated
for the spread of hepatitis B virus can be invoked to
explain the spread of the CJD virus [18]. However,
the iatrogenic spread of CJD is the only mechanism
that has been clearly demonstrated; it is a mechanism
consistent with the presumed mode of transmission of
human kuru and one that is most consistent with the
biological behavior of the CJD virus in experimental
studies.
We must conclude that the natural mechanism of
spread and the reservoir of the CJD virus remain
unknown at present. Future case-control studies
should be directed at determining the relative con-
tribution of iatrogenic transmission while at the same
time investigating the other conjectural modes of
transmission.
Addendum
Since this p a p e r was submitted w e a r e n o w aware of cases
of CJD occurring in Argentina, D e n m a r k , Iceland, Mexico,
Morocco, and t h e Philippines (Chamoles N , Platz P,
Palsson P, Wolf S, Cathala F, and Perez M : personal c o m munications, 1978, respectively). T h e total n u m b e r of patients with transmitted CJD in o u r laboratory now exceeds
100, including t h e youngest patient mentioned in t h e text,
w h o was 17 years old at onset. A further clustering of cases
in H u n g a r y has been reported by Majtenyi ([29a] and personal communication, 1978).
We are indebted to the many physicians throughout the world who
have collaborated with us in these studies.
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