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Creutzfeldt-Jakob disease in France II. Clinical characteristics of 124 consecutive verified cases during the decade 1968Ц1977

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Creutzfeldt-Jakob Disease
in France: 11. Clinical Characteristics
of 124 Consecutive Verified Cases
during the Decade 1968-1977
Paul Brown, MD, Francoise Cathala, M D , Doris Sadowsky, and D. C. Gajdusek, M D
One hundred twenty-four consecutive cases of Creutzfeldt-Jakob disease (CJD) in France, verified by biopsy or
autopsy between 1968 and 1977, were analyzed with respect to their clinical characteristics. The series comprised
equal numbers of men and women, with the most frequent age at onset being 60 to 64 years and the most frequent
duration, two to three months. A prodromal illness was observed in more than one-third of the patients. Clinical
presentations and symptom frequencies are tabulated, and a multifactor analysis has been performed to obtain those
combinations of symptoms and signs which occurred at least as often as the triad of dementia, myoclonus, and a
positive electroencephalogram. Two groups of atypical cases are also emphasized: one with sudden, strokelike
presentation and rapidly evolving illness of less than 2 months’ duration, and the other with a long clinical course of
between 2 and 10 years.
Brown P, Cathala F, Sadowsky D , e t al: Creutzfeldt-Jakob disease in France: 11. Clinical characteristics of 124
consecutive verified cases during the decade 1968-1977. Ann Neurol 6:430-437, 1979
In an earlier paper we reported on the clinical and
epidemiological features of 56 cases of CreutzfeldtJakob disease (CJD) found in the region of Paris
during the 10-year period 1968 through 1977 [ 3 ] .
Our search for CJD has now been expanded to include the whole of continental France, and in this
paper we present an analysis of the clinical characteristics of all histopathologically verified cases found in
France during the decade 1968-1977. These 124
cases represent the largest unselected consecutive series y e t published, the clinical analysis of which is of
interest both in its own right and as a basis for
evaluating the diagnostic probabilities of additional,
unverified cases included in our epidemiological
study [4].
Materials a n d M e t h o d s
Fifty-seven cases were located in the eight neuropathology
services available to Paris and its surrounding departments,
which constitute the Paris region. Sixty-seven cases were
drawn from neuropathology services in eight regional hospital centers to which specimens were referred from provincial departments. T h e Paris region, containing approximately one-fifth the population of France, thus supplied
nearly half the verified CJD cases in the country. This disproportion may be d u e not only to a higher frequency of
From rhe Laboratory of Central Nervous System Studies and the
Office of Biomerr), -and
NINcns, NIH, and the
Laboratoire de Neurovirologie, H6pital de la SalpGtriere, Paris,
France.
430
CJD in Paris, but also to the higher rate of autopsies and
greater number of neuropathologists in Paris than in the
provinces.
All cases were diagnosed as CJD on the basis of light
microscopy findings of unequivocal spongiosis and gliosis
and in autopsy specimens, neuron loss as well. Ninety-four
patients were autopsied (35 of whom had also been biopsied), and 30 patients were diagnosed from biopsy only. Of
the patients for whom both biopsy and autopsy material
was available, 4 were not diagnosed from examination of
the biopsy specimen alone.
All neuropathology reports and, in many cases, histological sections, were reviewed with the pathologist, and
clinical histories were then obtained from the full hospital
records. In certain cases in which complete clinical data
were lacking, family members and attending physicians
were interviewed for additional information.
Seven patients in this series have been the subjects of
reports appearing in the French literature 12, 6, 8 , 12, 131;
2 of these and 10 others have also been included in reviews
of transmissible virus dementia originating from our laboratory at the National Institutes of Health [7, 14, 161.
Transmission of the disease into primates has been accomplished in 12 cases in the series.
Statistical Methods
Since the signs or symptoms present themselves as either a
positive response (displaying a symptom) o r a negative reAccepted for publication Apr 15, 1979
Address
requesrs c b Dr Brown, Bldg 36, Room 5B25,
N,NCDS, NIH, Berhesda, MD 2o014,
sponse (not displaying a symptom), nonparametric statistics
were used for analyzing 13 symptoms. Nonparametric
statistics allow for making comparisons between distributions (without specifying their underlying forms) and not
between parameters; for setting hypotheses which relate to
the nature of the distribution as a whole; and for use with
measurements which consist of ordered categories (positive or negative responses) and their frequencies of occurrence [15]. Among the nonparametric statistics used to
analyze the 13 symptoms were Cochran’s Q test, chi-square
tests, and composite tests.
Independence (in an overall sense) between the 13symptom sets of response frequencies was demonstrated
using Cochran’s Q test (p < 0.001). Chi-square tests (for
testing double dichotomies, testing for independence, or
testing real differences between sets of responses) were
used to single out the symptom responses which indicated
the largest significant differences, each from the others;
they showed significant response differences (p < 0.01 orp
< 0.001). Composite tests (a single test of the significance
of the aggregate of chi-square tests of each symptom versus
the other symptoms, itself a chi-square test) made possible
the selection of the 7 most important symptoms: dementia;
myoclonus; pyramidal, extrapyramidal, cerebellar, or visual
abnormalities; and a positive electroencephalogram.
To select combinations of symptoms for diagnostic
value, these symptom responses were formed empirically
into combinations and the combinations were tested
F i g 1 . Age at onset of illness in 124 consecutive uerijied cases of
CJD.
against the other symptom responses (individually) by chisquare tests. Further selections of the most comprehensive
combinations were made by use of composite tests ( p <
0.01 or p < 0.001).
Results
A g e , Sex, and Duration of Illness
The series comprises 62 men and 62 women. The
distribution of age at onset of illness is shown in Figure 1, in which it can be seen that the majority of
patients (77%) were between 55 and 75 years old
and that the peak frequency occurred in the 60- to
64-year age group. The average age at onset was 60
(k 9) years.
The mean illness duration of 8.5 mohths was heavily influenced by the few cases which lasted from 2 to
10 years; the median duration of illness was only 4
months. The distribution histogram presented in
Figure 2 gives a more accurate picture of the typically
rapid course of illness, which in 88% of the patients
lasted no more than twelve months and in 69% no
more than 6 months, with the most frequent duration
being 2 to 3 months.
It must be noted that the duration of illness was
probably shortened in some cases by the practice of a
cerebral biopsy, since of the 65 patients on whom a
biopsy was performed, 5 died within 24 hours of the
procedure and 8 others within the next 4 days. However, the mean duration of illness in the entire group
3025 -
20 -
15 -
l
am--I
65-69 70 74 75 79 80 84 85 89
AGE AT ONSET
Brown et al: Clinical Characteristics of CJD in France
431
DURATION OF ILLNESS (MONTHS)
of biopsied patients was not significantly different
from that in the nonbiopsied group ( p < 0.01).
These figures for age at onset and duration of illness are based o n the earliest signs and symptoms
clearly referable to disease of the nervous system,
including simple memory loss or behavioral abnormalities; they d o not include prodromal syndromes,
however, because in the absence of detailed personal
inquiry, these nonspecific symptoms were only imperfectly recalled and were very difficult to date.
Clizical Pre.rentatzon
Prodromal symptoms, which in retrospect could be
considered t o have heralded the onset of neurological illness, occurred in 39% of the 124 patients in
this series. In most patients these consisted of a moderate to severe asthenia (23$6), which occasionally
progressed to a frankly depressive state; weight loss
(159$),usually without a concomitant loss of appetite; or a disorder of sleeping habits (149%),about
equally divided between insomnia and somnolence.
In 2 patients sleep was agitated, and nocturnal myoclonic jerks of the lower limbs were considered possible, if unproved. Combinations of these symptoms
occurred frequently.
The onset of neurological disease is classified in
Table 1 according to whether it was manifested by
mental deterioration or physical signs, by single or
multiple symptoms, and by the rapidity of symptom
progression. I t can be seen that in approximately half
the patients, the onset was manifested exclusively by
mental deterioration, whereas in another third the
onset was limited to physical signs. T h e remaining
14% presented with a combination of both mental
deterioration and physical signs.
Onset with a single symptom or sign was more
frequent than multiple-symptom presentations, and a
432
F i g 2. Distribution of duration of illness i n 124 consecutive
verified cases of CJD.
Table 1. Types of Clinical Onset in 124
Consecutive Verified Cases of CJD
No. of
Patients
Mental deterioration only
Physical signs only
Mixed mental and physical
61
46
17
Single symptom or sign
Mental
Physical
Multiple symptoms or signs
76
Gradual progression
Sudden onset
Mental
Physical
Mixed
Sudden single symptom or sign
Percentage
49
37
14
61
43
33
35
27
48
39
100
81
24
19
9
8
7
6
6
7
13
10
gradual evolution was much more common than a
suddenly appearing abnormality in which physical
signs predominated. Abrupt onset of a single symptom or sign nevertheless occurred in 10% of the patients; for example, the sudden appearance of vertigo, transient episodes of cortical blindness, o r a
rapidly evolving aphasia.
T h e distribution of presenting symptoms and signs
in all 124 patients is shown in Table 2 . Some type of
mental deterioration was noticeable at the outset in
approximately two-thirds of the patients. Mental deterioration has been subdivided into the categories of
Annals of Neurology Vol 6 No 5 November 1977
Table 3. Frequency Distribution of Symptoms during the
Clinical Course of 124 Consecutive Verified Cases of CJD
Table 2. Frequency Distribution of Presenting Symptoms
in 124 Consecutive Verified Cases of CJD
Symptom Category
Mental deterioration
Dementia
Behavioral abnormalities
Higher cortical function
Cere bellar/visual
Cerebellar
Visual
Vertigo
Headache
Pyramidal
Extrapyramidal
Sensory
Abnormal movements
No. of
Patients
Percentagea
Symptom Category
78
63
Mental deterioration
Dementia
Behavioral abnormalities
Higher cortical function
Movement disorder
Myoclonus
Other
Evocative EEG
“Characteristic”
Extrapyramidal
Cerebellar
Pyramidal
Visual
Headache
Lower motor neuron
Vertigo
Seizures
Sensory
Vegetative
Cranial nerve
36
37
22
27
30
18
44
54
36
21
10
12
4
4
3
1
27
17
8
10
3
3
2
1
“Total exceeds 100% because of the 48 patients with multiple
symptom onsets (cf. Table 1).
dementia, behavioral abnormalities, and disorders of
higher cortical function. The term dementia is meant
to include a broad range of deficits affecting intellectual competence, from simple memory loss
through disordered faculties of reason and judgment
to frank confusional states. Although the line between confusion and irrational behavior can be
blurred, behavioral abnormalities were usually distinct enough to warrant separation as an individual
category. Disorders of higher cortical function comprise the various types of aphasias, apraxia, and agnosia.
Dementia and behavioral abnormalities, alone or
in combination, accounted for most of the observed
mental symptoms, with disorders of higher cortical
function being much less common. Symptoms and
signs referable to the cerebellar and visual systems
were the preponderant physical neurological manifestations, occurring in 44% of the patients. Headaches, usually in combination with other symptoms,
arose at the outset in 10% of the patients. Pyramidal,
extrapyramidal, and movement disorders were very
uncommon components of the presenting clinical
picture. One of the 3 individuals with a sensory disturbance (paresthesias of the right arm and leg) and
the single individual with a movement abnormality
(choreoathetosis) had the coincident onset of Parkinson syndrome.
Clinical Course
The frequency of different symptoms appearing during the course of the illness is presented in Table
3. Mental deterioration, almost always including dementia, occurred in all patients (8 cases progressed to
No. of
Patients
Percentage
124
100
116
56
48
111
74
45
37
70
104
40
75
84
32
77
47
75
70
54
47
17
15
14
11
7
4
2
40
60
56
44
40
15
12
11
7
7
3
2
a state of mutism before signs of dementia could be
appreciated). Movement disorders were seen in 90%
of the patients, in nearly all of whom myoclonus was
a prominent feature late in the illness. Occasionally
myoclonic movements were subtle and transient, and
rarely they did not occur spontaneously but had to be
elicited by means of startling or tapping maneuvers.
Most other types of abnormal movements were of
a trembling or choreoathetoid character, but unclassified, complex types of movements also occurred. Such movements were noted in the absence
of myoclonus in only 6% of the patients.
An EEG suggesting CJD was observed in threequarters of the patients at some point during their
illness, usually after the disease had become well advanced but before the terminal stage. Two types of
EEG patterns were considered evocative and could
sometimes be correlated with myoclonic activity.
One type consisted of diffuse, irregular bursts of
high-amplitude, spiking slow waves, which can also
be seen in many other encephalopathic conditions,
and so, while suggestive, is not specific. The second
EEG pattern consisted of diffuse and nearly regular
single or multiple slow-wave spikes at a frequency of
approximately 1 cycle per second. Such a tracing is
rarely seen in nonacute diseases other than CJD, and
this “characteristic” pattern was observed in 40% of
the patients in the series. All patients had at least one
abnormal EEG, even if not suggestive of CJD.
Brown et al: Clinical Characteristics of CJD in France
433
Table 4.Symptom Combinations Occurring at Least as Frequently as the Triad of Dementia,
Myoclonus, and a Positive EEG in 124 Consecutive Verified Cases of CJD
Any Form
of Mental
Deterio-
Other Neurological Signs
Dementia ration"
Myoclonus
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Positive
EEG
Pyramidal
Extrapyramidal
Cerebellar
Visual
X
X
X
X
X
X
X
X
X
X
x
or
or
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Frequency Probof Occurability
rence (96) Levelb
61.5
77.8
69.7
68.0
85.2
76.2
75.4
75.4
66.4
68.0
82.0
82.8
89.3
...
0.01
M.05
>0.05
0.001
0.05
0.05
0.05
>0.05
>0.05
0.001
0.001
0.001
"Dementia, behavioral abnormalities, or disorders of higher cortical function.
"Probability level of difference between symptom combinations and the triad of dementia, myoclonus, and a positive EEG.
Extrapyramidal symptoms-especially a profound,
generalized oppositional rigidity-and
cerebellar,
pyramidal, and visual abnormalities (including hallucinations) were also frequently encountered during
the course of illness in our series of patients. Lower
motor neuron signs, including fasciculations and
amyotrophy in a typically distal distribution, were
relatively common, but in only 1 case were they observed before an advanced stage of the disease.
Headache, o n the other hand, was invariably an early
symptom in those patients in whom it occurred. Seizures, which were observed in 995 of the patients,
were nearly all of the grand ma1 type (1 patient had
jacksonian seizures, and 1 other patient developed
partial continuous epilepsy). Vegetative symptoms
consisted of otherwise unexplained disorders of
sweating, temperature regulation, appetite, or menstrual periodicity.
pendently of each other in an overall sense. Individual symptoms were also found to be independent
in all possible pairings by the chi-square test, with the
single exception of myoclonus and a positive EEG ( p
Familial Cases
Cases of Long Duration
T h e 8 patients in Figure 2 whose illness evolved over
an unusually extended period-between
2 and 10
years-merit special attention. Very brief case summaries of these patients follow, in order of increasing
duration of illness.
Six patients in this series had a family history of
proved CJD ( 2 were members of the same family),
and 6 others had a family history of possible CJD.
The disease occurred at a comparatively early age in
this group of patients, particularly in the 6 proved
familial cases (46 6 years), and in several patients it
lasted more than a year, including a duration of 40
months in 1 and of 120 months in another. T h e
spectrum of clinical manifestations was not otherwise
distinctive from the series as a whole.
*
Muhifactor Anuhsis
As mentioned in the section o n statistical methods,
signs and symptoms were shown to occur inde-
> 0.7).
Table 4 presents all combinations of signs and
symptoms that occurred at least as frequently as the
triad of dementia, myoclonus, and a positive EEG.
We have in fact included this triad, together with its
incomplete variants, mainly for purposes of comparison with the other combinations in which dementia
has been replaced by the less restrictive (and more
realistic) category of mental deterioration.
In con junction with the duration of illness, these
symptom combinations have formed the basis for our
diagnostic judgment o n cases of dementia without
neuropathological verification included in our companion study on the epidemiology of CJD [41.
PATIENT 1 (R.Le.). Male, onset at age 67 years with instability of gait. After 12 months appearance of behavioral
abnormalities with progressive dementia and syndrome of
amyotrophic lateral sclerosis (ALS). EEG abnormal but not
characteristic. Death 27 months after onset.
PATIENT 2 (M.Ro.). Female, onset at age 66 with behavioral abnormalities, weight loss, and depressive state.
After 2 years appearance of progressive dementia, higher
434 Annals of Neurology Vol 6 No 5 November 1979
function deficits, rigidity, trembling, choreoathetosis, and
myoclonus. EEG abnormal but not characteristic. Death 30
months after onset.
PATIENT 3 (C.Pa.). Male, onset at age 6 1 with depression and progressive dementia following wife’s death. After
2 years sequential appearance of paresthesias, cerebellar
signs, myoclonus and other unclassified abnormal movements, and muscular fasciculations. EEG abnormal but not
characteristic. Death 30 months after onset.
PATIENT 4 (A.Ja.). Female, rapid onset at age 5 5 of dementia and hemiparesis. After 2 years appearance of Parkinson syndrome. EEG abnormal but not characteristic.
Death 40 months after onset. Familial case.
5 (E.Fo.). Male, onset at age 38 with paranoid
depressive syndrome. After 4 years appearance of dementia, rigidity, pyramidal signs, myoclonus and other complex
movements, seizures, and amyotrophy. EEG characteristic.
Death 5 years after onset. Family history of Alzheimer disease. Autopsy showed Alzheimer disease as well as CJD.
PATIENT
6 (A.Py.). Male, onset at age 61 with paresthesias of the right arm and Parkinson syndrome. After 1
year appearance of progressive dementia, cerebellar signs,
hemianopia, myoclonus, and choreiform movements. EEG
characteristic. Death 6 years after onset.
PATIENT
PATIENT 7 (M.Ve.). Female, onset at age 60 with Parkinson syndrome and dementia. After 1 year appearance of
behavioral abnormalities, pyramidal and cerebellar signs,
myoclonus, and amyotrophy. EEG abnormal but not characteristic. Death 6 years after onset.
PATIENT 8 U.Ar.). Male, onset at age 43 with gradually
progressive memory loss. After 8 years, rapid worsening of
mental deterioration with episodes of delirium. One year
later appearance of pyramidal, extrapyramidal, cerebellar,
and visual signs and myoclonus. EEG characteristic. Death
10 years after onset. Familial case.
Discussion
The “typical” patient with CJD in France is in his
sixties when the first neurological symptoms appear,
often following a prodromal illness of weeks to
months of asthenia, altered sleeping habits, and loss
of weight. The onset is most commonly characterized
by gradual mental deterioration rather thafi by physical signs, which, if they do occur, are likely to be of a
cerebellar or visual nature. A progressive dementia
almost invariably appears at some time during the
course of the disease, together with one or more
symptoms referable to the pyramidal, extrapyramidal, cerebellar, or visual systems. At an advanced
stage of illness, myoclonus, alone or in combination
with other types of abnormal movements, and a suggestively abnormal EEG are observed. Death occurs
2 to 5 months after the onset of illness as a result of
cachexia, intercurrent infection, and cardiopulmonary collapse.
Although this description represents the most
common course of CJD, the illness is far from stereotyped, and it is probably safe to say that almost
every neurological sign or combination of signs has
been described in individual reports of patients with
the disease. Multifactor analysis of the clinical characteristics of our own series has yielded several
symptom combinations which occurred at least as
often as the triad of dementia, myoclonus, and a
positive EEG, but the diagnostic value of such combinations will depend upon comparison with similarly
analyzed series of other types of presenile dementia,
especially Alzheimer disease. Such a study is currently in progress.
Kirschbaum [9], May [ll], and Van Rossum [17]
each reviewed the world literature on CJD to 1966.
Their series varied from 120 to 150 cases according
to the inclusion of cases observed personally as well
as individual judgment about the diagnosis of certain
other cases; the material in these three series therefore overlaps to a major degree. Matthews [lo] in
1975 reported upon an ongoing study of CJD in England, numbering at that time 49 cases and occurring
for the most part since 1966. Traub et a1 [16] summarized the clinical characteristics of 126 transmitted
and untransmitted case of CJD referred to our N I H
laboratory between 1966 and 197 5, incorporating
the series of 47 patients reported earlier by Roos et a1
[ 141. A few cases in Matthews’ and the present series
were also included in that review.
The most comprehensive of these earlier case series are compared to our own series in Table 5.
Among our patients, the average age at onset was
somewhat later and the average duration of illness
somewhat shorter than in the earlier series. However, the same group of symptoms-mental, myoclonic, pyramidal, extrapyramidal, cerebellar, and
visual-are
predominant in each series, although
varying somewhat in frequency.
Most of these differences are probably due to
biases inherent in collections of published or referred
cases as opposed to an unselected consecutive case
series. Some of the differences, particularly in the
eatliest reviews [9, 11, 171, may also be due to
evolving diagnostic critera and to the inclusion in
other series of a proportion of histopathologically
unverified (and therefore only probable) cases of
CJD. Nevertheless, the similarity between the clinical characteristics of our patients and those in the
earlier series indicates that case collection biases and
some variability in diagnostic criteria are not of major
consequence, and that CJD in France is representative of CJD generally.
The excellent detailed analysis by Bernoulli et al
[ l ] of the early stage of illness in the first 100 trans-
Brown et al: Clinical Characteristics of CJD in France
435
Table 5 . Clinical Characteristics of the Present Series Compared to Other Large Published Series of Creutzfeldt-Jakob Disease
Data
No. of cases
Average age at onset (yr)
Percentage of cases with average
duration of:
1-6 mo
7-12 mo
13-24 mo
>24 mo
Clinical picture (9;)
Mental deterioration
Dementia
Behavioral abnormality
Higher cortical function
Abnormal movement5
Myoclonus
Other
EEG
Extrapyramidal
Cerebellar
Pyramidal
Visual
Lower motor neuron
Vertigo
Seizures
Sensory
Familial cases (9;)
Brown et a1
(this report)
Traub et a1
[I61
124
60
8.5
126
56
10.3
Matthews
Kirschbaum
[lo1
[71
49
150
52"
...
...
...
...
...
...
100
100
74
46
39
90
100
...
...
98''
...
83
...
...
71
...
61''
84
...
84
32
77
57
54
64
76
42
38
60
56
44
40
12
11
17
9
7
25
5-10
9
5
100
100
47
58
...
80
27
"Frequent"
27
12
...
14
4
6
...
...
...
...
87
53
77
25
21
...
...
...
"<10"
"Age at death
'Dementia and/or behavioral abnormalities
' Myoclonus and/or seizures
mitted cases of CJD referred to our NIH laboratory
merits additional comment. Although some differences exist, the data from their study and our own
are, on the whole, remarkably similar, so that these
two independent studies tend to confirm each other.
As in the present study, a significant proportion of
their patients (25 to 30%))was found to have experienced prodromal symptoms of fatigue, disorders of
sleep or appetite, and similar abnormalities. Early
neurological signs and symptoms were also found to
be predominantly those of mental deterioration and
abnormalities of the visual and cerebellar systems,
alone or in combination. Headache was relatively uncommon, and involuntary movements, pyramidal
signs, and extrapyramidal signs were rare. A small but
important group of patients (12%) experienced sudden onset of disease.
W e especially wish to emphasize the exceptions to
the norm at both the short and long ends of the time
scale. Sudden onset of disease occurred in nearly
one-fifth of our patients, often with a single symptom, and could easily have been mistaken for a cerebrovascular accident. In many such patients the sub-
436 Annals of Neurology
Vol 6
No 5
sequent course of the illness was among the most
rapid recorded in the series, with death occurring 1
to 2 months after onset.
At the other end of the spectrum fall the 8 patients
whose illness lasted from 2 to 10 years. Although no
particular clinical subtype, such as the amyotrophic
form of CJD, was prominent in this group of patients,
one feature common to all of them was the relative
stability of the initial clinical syndrome over a comparatively long period before additional neurological
abnormalities appeared. Thus, in the patient with the
shortest illness, of 27 months' duration, the only
symptom during the first 12 months was disequilibrium; and in the patient with the longest illness, lasting 1 0 years, the only symptom during the first 8
years was a slowly progressive memory loss.
A question arises whether the long duration of illness in some of these patients was attributable to
CJD alone or if it resulted from a combination of
CJD and another, distinct neurological disease. Parkinson syndrome occurred in 3 patients, ALS syndrome in a fourth, and a fifth had autopsy findings of
both CJD and Alzheimer disease. However, 2 of the
November 1979
5 patients (Nos. 1 and 4 ) had already had symptoms
for 1 to 2 years before the onset of ALS or Parkinson
syndrome, and 2 others (Patients 6 and 7), who presented with Parkinson syndrome lasting a year, subsequently developed typical symptoms of CJD which
evolved over the next 5 years. Only in the patient
whose autopsy showed the changes of Alzheimer disease as well as CJD (Patient 5 ) can it be supposed that
the first 4 years of his 5-year illness might have been
due to Alzheimer disease rather than CJD. Moreover, apart from the atypically long evolution of disease, an illness fully characteristic of CJD occurred in
6 of the 8 patients. In only 2 patients (Nos. 1 and 4 )
would the clinical diagnosis of CJD not have been
possible, even with a rapidly evolving illness. It thus
appears that coincident neurological disease cannot
explain the long duration of illness in most of these
patients, and that, however “atypical,” they must be
accepted as validating the concept of CJD as a sometimes very slowly evolving disease process.
A final note of caution may be sounded with respect to the clinical criteria for diagnosis of CJD.
Although in its most typical form CJD is not difficult
to identify, we have nevertheless been repeatedly
surprised in our search in France by “typical” cases
that later proved to be due to other diseases, some of
which are reported elsewhere in detail [ 5 ] . Early in
the course of illness we have seen CJD exactly imitated by metabolic, vitamin deficiency, toxic, and
carcinomatous encephalopathies. Later in the course
the most important diagnostic alternative was Alzheimer disease, but Pick disease, parkinsonian dementia, and ALS with dementia were also confused
with CJD.
While the true incidence of CJD lasting more than
a year is certainly higher than is currently appreciated, it is important in such cases to be wary of
the diagnosis on clinical grounds alone. Neuropathology and transmission studies remain the final
arbiters.
Supported in part by INSERM ATP No. 507782.
Iris apleasure to thank the many neuropathologists and neurologists
throughout France whose collaboration made this study possible.
References
1. Bernoulli C, Masters C, Gajdusek DC, et al: The early clinical
features of Creutzfeldt-Jakob disease (subacute spongiform
encephalopathy), in Hadlow WJ, Prusiner SB (eds): Slow
Transmissible Diseases of the Nervous System. New York,
Academic, 1979, vol 1, pp 229-252
2. Bonduelle M, Escourolle R, Bouyques P, et al: Maladie de
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