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Creutzfeldt-Jakob disease of long duration Clinicopathological characteristics transmissibility and differential diagnosis.

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Creutzfeldt-Jakob Disease of Long
Duration: Clinicopathological Characte;istics,
Transmissibility, -md Daerentid Diagnosis
'
Paul Brown, MD,* Pamela Rodgers-Johnson, MD," Franqoise Cathala, MD,? Clarence J. Gibbs, Jr, PhD,"
and D. Carleton Gajdusek, MD"
Five to 10% of patients with Creutzfeldt-Jakob disease have a clinical course that extends for 2 years or more. In the
present series 33 (9%)of 357 histopathologically verified cases, including 15 (7%) of 225 transmitted cases, fell into this
long-duration category, the longest transmitted case having had a 13-year duration. As a group these cases were
characterized by a higher familial representation (30%),a younger age at onset (average, 48 years), and lower frequencies of myoclonus (79%) and periodic electroencephalographic activity (45%) than occur in series of unselected cases.
The clinical course most often showed a long, very slowly progressive first stage, with symptoms limited to intellectual
deterioration or behavioral abnormalities, followed by a shorter, rapidly progressive terminal stage with both mental
and physical deterioration. Although transmission of disease by primate inoculation was less successful in this group of
long-duration cases (64%) than in cases of shorter duration (88%), incubation periods and durations of illness in the
inoculated animals bore no relation to the duration of illness in the patients. Clinical differentiation from other chronic
dementing processes, particularly Alzheimer's disease, can prove impossible; however, the correct pathological diagnosis was readily evident by light microscopic examination, and spongiosis was at least as prominent as gliosis in all but
4 (15%) of the 27 patients studied postmortem, the same frequency fouhd in case series not selected for length of illness.
Brown P, Rodgers-Johnson P, Cathala F, Gibbs CJ Jr, Gajdusek DC. Creuttfeldt-Jakob disease
of long duration: clinicopathological characteristics, transmissibility, and differential diagnosis.
Ann Neurol 16:295-304, 1984
Most patients with Creutzfeldt-Jakob disease (CJD)
have a comparatively rapid clinical course that terminates in death within a few months of onset. However,
a proportion of cases are known to evolve over much
longer periods of time, often with a clinical picture that
is difficult if not impossible to distinguish from those of
more chronic progressive dementia syndromes, particularly Alzheimer's disease 12, 31. In this report we review our 20 years of experience with CJD of long
duration and compare three groups of patients for
whom clinical, neuropathological, and experimental
transmission results were available: those with transmitted CJD, those with untransmitted CJD, and those
referred to us with clinically suspected CJD later disproved by neuropatholagical examination.
mation was retrieved by follow-up letters and telephone calls
before a final diagnostic assignment was made.
ClinicaI Studies
Criteria for the diagnosis of CJD were a clinical illness of
progressive dementia and physical neurological deficits (usually but not necessarily including myoclonus or other
abnormal movements), and histopathological findings in
either biopsy or postmortem specimens of neuronal degeneration, gliosis, and characteristic spongiosis evident on
light microscopic examination of brain tissue. Uncharacreristic or equivocal spongiosis evident on light microscopy, or
vacuolation seen only by electron microscopy, even in the
presence of neuronal loss and gliosis, was not considered
sufficient for neuropathological confirmation.
Transmission Studies
Materials and Methods
During the past 20 years, tissue specimens from nearly 500
patients referred to this laboratory with a suspected diagnosis
of CJD have been inoculated into primates. For the present
study, files for each patient were reviewed, clinical information and neuropathological descriptions (and, in many cases,
representative slides) were evaluated, and any missing inforFrom the *Laboratory of Central Nervous System Studies, National
Institute of Neurological
and Communicative Disorders and Stroke,
National Institutes of Health, Bethesda, MD 20205, and the
thboratoire de Neurovirologie, HBpital de la SalpetriPre, 75013Paris. France.
All transmissions of CJD to primates were confirmed by histological examinationof brain tissue from inoculated animals.
Transmission attempts were not recorded as failures until
inoculated primates had remained asymptomatic for a period
exceeding the longest verified incubation period in the
species used for the experiment-from 3 years in squirrel
monkeys to 6 years in capuchin and rhesus monkeys. ExperiRecelved Nov 18, 1983,and m revised form Jan 25, 1984. Accepted
for publication Jan 26, 1984.
Address reprint requests to D~ firown
295
Table I . Case Summaries of 15 Patients with Transmitted Creutzfedtt-JakobDisease of 2 or More Years’ Clinical Duration
Totai
Patient
Age at
Onset
No.
(yr)
1
46
Disease
Duration
Sex
Terminal Phase
13
Anorexia nervosa syndrome;
very slowly progressive
3 mo; rapid progression of
mental deterioration, ataxia,
rigidity, visual signs
Periodic ( 1 cis)
triphasic slow
waves
Postmortem:
spongiosis.
gliosis.
neuronal loss
Depression, memory loss,
“schizophrenic” behavior, incoordination, unsteady gait;
slowly progressive, then hallucinations and higher cortical
function deficits
3 mo; rapid progression of
mental deterioration, rruncal
ataxia, tremors, rigidity, myo-
Diffuse high-amplitude slowwavc bursts
Postmortem
sp<,ilgioSiS,
Memory loss, depression, nearly
stable for 8 yr, then increasing insomnia and irrationality
2 mo, rapid progression of
Personality change, with lewdness, foul language, drinking,
and anorexia; slowly progressive
4 mo; rapid progression of
Neurasthenia; later, argumentativeness, slowly progressive
memory loss, insomnia, indifference
2 mo; rapid progression of
Forgetfulness and suspiciousness; slowly progressive
Memory loss and sleep disturbance, very slowly progressive
(L.S.)
3
(J. A.)
41
ss
4
(M. Bo
M
M
10
4
)
5
53
(J K.)
7
(E. S.1
8
51
27
(Y. M . )
9
53
(T. S . )
11
tM H )
13
(T. K.)
43
44
M
Histopat tiokigicdk
Findings
Initial Symptoms and Evolution
II
?I
EEG
(yr)
(M. Ba.)
2
Clinical Features
4 ’/i
Comments
Famlllal case
ghosls,
neuronal loss
clonus
Periodic ( 1 cis)
triphasic slow
waves
Postmrtrtem:
spongiosis,
gliosis,
neurondl luss
Diffuse sk)w-wdve
activity
Postmortem:
spongiosis,
gliosis,
neurondl loss
Periodic ( 1 c i s )
triphasic slow
waves
Postmortem.
spongiosis,
gliosis.
ncuroiial loss
8 mo, progression of mental
deterioration, abnormal hehavior, seizures, rigidity,
myoclonus
Diffuse SkiW-WdVe
activity
Postmortem
spongiosis,
gll(,sls,
neuronal loss
’mo; progrewon of increas-
Periitdic ( 1 cis)
triphasic SIOR,
WdVeS
Posrrnorrtm
Ataxia; then incrementally progressive evolution including iiysar.
thria. finger tremor, emotional instability, alexia. auditory hallucinations, rnutism, dysphagia, nystagmus, Babinski’s signs,
muscular atrophy, rigidity, stupor, myoclonus
Periodic t 1 ci\)
triphasic slow
waves
Postmortem.
spongiosis, gliosis, neurondl
Ioss, plaques in
cerebral cortex
;md cerelxllum
Published
CdSr [ 8 ]
Failing memory; inability to hold job, then gradually progressive
deterioration including speech difficulties, dyscalculia, disorientation, tremors, ataxia, mutism, rigidity, pyramidal and extrapyramidal signs, nystagmus, inyoclonus
Diffuse slow-wavc
activity
Postmortem
spongiosis,
Familial case,
published
case [7 1
mental deterioration. hallucinations then cortical bhndness, rigidity, cerebellar and
pyrmidal SigllS, myoclOllUS
mental deterioration, ataxia,
dysarthria, right-sided Vlth
and Vllth nerve palsy with
nystagmus, right spastic hemiparesis, tremor, occasional
fasciculation, myoclonus
mental deterioration. focal
motor deficits, grand ma1 seizure, myoclonus
ingly bizarre hehavior, hallucinations, ataxia. Icft hemiparesis with Babinski’s signs,
right-sided rigidity, seizures,
cortical blindness, myoclonus
gllosls,
Diffuse slowwave
activiry
At hiopsy (18
rno hetore
death): spon-
Failing memory, confusion, depression; slow progression, with sequential appearance of ataxia, right hand tremors, disorientation, parkinsonian syndrome, myoclonus, grand mal seizures,
mutism
Diffuse slow-wavc
activity
Postmortem:
spongiosis, severe gliosis,
neurmal loss
Diffuse slow-wave
activity
Postmortem:
spongiosis, severc‘ gliosis,
neuronal loss
296 Annals of Neurology Vol 16 No 3 September 1084
[I61
ncuronal loss
Behavioral abnormalities, depression; then gradually progressive
deterioration with ataua, emotional lability, tremors, rigidity,
paraparesis, Parindud’s syndrome, pyramidal and exrrapyrmidal
signs, cortical blindness, myoclonus
condition with increasing
rigidity
idSc
sp~~rlqctsrs.
Postmortem.
spongiosis,
44 mo; nearly stable clinical
Familial case;
published
gliosis,
neuronal lws
Headaches, drowsiness, poor business decisions; after 1 yr. episode Periodic ( 1 c i s )
of ataxia and dysphasia with right leg clonus, then gradually
triphasic slow
progressive mental deterioration, apraxia, tremor, rigidity,
waves
mutism. increasingly severe myoclonus
Failing memory; then rapid progression over 4-mo period of
behavioral abnormalities, insomnia, hypersexuahty, tremhling, mental deterioration,
ataxla, rnutism, m y d o n u s
Familial case,
published
case [ 2 ]
gllosls,
neuronal loss
gl05iS, ~ ~ I O S l S
Must severe
dbnormaIiry
in white
matte r,
puhlirhec
case 3
1
Table 1 . (Continued)
~
Patient
No.
Age at
Onset
(yr)
Sex
14
52
M
54
M
Total
Disease
Duration
(yr)
Clinical Features
Initial Symptoms and Evolution Terminal Phase
EEG
4
Paresthesias of feet and ataxia; 37 mo; nearly stable clinical
then rapid progression over
condition with disappearance
9-mo period of mental deteriof myoclonus. appearance of
oration, incoordination, dysoptic atrophy
graphia, apraxia, rigidity, mutism, myoclonus
Diffuse slow-wave
activity
2%
Headaches, memory loss; then
rapid progression over 4-mo
period of visual troubles, irritability, violent temper,
blindness, disorientation,
mental deterioration, higher
cortical function deficits
Periodic (1 ds)
triphasic slow
waves
Histopdrho1ogical
Findings
Comments
~
(K.F.)
I5
(H. M.)
EEG
=
electroencephalogram; F
=
27 mo; very slow progression
to stuporous state, increasing
rigidity, myoclonus
~~~~~~~~~~
Postmortem.
Most severe
abnormality
spongiosis. severe gliosis,
in whitc
matter,
neuronal loss,
published
plaques in cerebral cortex.
case (201
midbrain, cerebellum
At biopsy ( 2 yr
before death):
spongiosis,
gliosis
female; M = male.
ments in which animals died during these periods without
symptoms or typical histopathological findings were considered to be inconclusive; animals still alive and well were considered to be on test. Both groups were excluded from transmission rate calculations, as were cases for which optimal
inocula (1 to 20% saline suspensions of frozen brain tissue)
were unavailable for the transmission attempt, i.e., cases inoculated using frozen brain suspensions in dilutions greater
than lo-*, tissue culture preparations, formol-fixed specimens. and nonbrain tissues.
Results
Clinical Characteristics
Among the patients referred to our laboratory for attempted disease transmission, 33 (996) of 357 with
histopathologically verified CJD, including 15 (7%) of
225 with transmitted cases, had illnesses that extended
over a period of 2 years or more. In Table 1 brief
summaries of these 15 transmitted long-duration cases
are arranged (in order of decreasing length of illness)
into three groups with different types of clinical evolution.
Seven of the 15 patients had illnesses characterized
by the onset of some form of intellectual deterioration
or behavioral abnormality that remained nearly stable
or very gradually progressive until late in the clinical
course, when the patients experienced a sharp downward inflection with rapidly progressive mental deterioration coupled with neurological deficits that led to
death within a few weeks to months. The 3 patients
with disease of longest duration (10, 11, and 13 years)
all fell into this category.
Five patients showed a fairly steadily progressive
type of clinical course, with gradual or incremental
worsening of symptoms following initial appearance
and a stepwise addition of other, increasingly serious
neurological abnormalities.
Three of the 15 patients deteriorated rapidly over a
period of several months following the onset of disease
and then progressed to a nearly stable or very slowly
progressive terminal stage of mute stupor and complete physical disability for periods of 2 to 4 years before death.
In Table 2 the frequencies of signs and symptoms
occurring during the clinical course in all 33 patients
with long-duration disease are compared with those in
two unselected series of patients with CJD. In the longduration group, behavioral abnormalities were more
frequent, and myoclonus and periodic electroencephalographic (EEG) activity less frequent, than in either of
the unselected case series. As shown in Table 3, however, this comparatively low occurrence of myoclonus
and periodic EEG activity was largely due to the
findings in the untransmitted subgroup of longduration cases: myoclonus in only 38% of the subgroup (compared with 100% in the transmitted group)
and periodic EEG activity in only 14% (compared with
53% in the transmitted group).
The percentage of familial cases in the long-duration
series was three to four times as high as in the unselected series and was similar in both transmitted and
untransmitted subgroups. Each of the 10 familial cases
originated from a different pedigree, so disease characteristics in a given family did not bias analysis of the
entire series. It is also noteworthy that illness began at a
comparatively early age in many long-duration cases:
the average age at onset was 48 years and did not differ
significantly between transmitted and untransmitted
subgroups. Younger patients tended to have longer
illnesses than did older patients: the average duration
was 6 years in patients under 40 years of age but only 4
years in those over the age of 5 5 . Also, the 6 patients
with illnesses lasting 10 years or more had a mean age
Brown et al: Creutzfeldt-Jakob Disease
297
Table 2. Comparison of Patients with Long-Duration Creutzfeldt-Jakob Disease with Two Series
of Affected Patients Unselectedfor Duration of Illness
Characteristic
No. of cases
Sex (M/F)
Familial cases (96)
Average age at onset (yr)
Average disease duration (mo)
Clinical picture (%)
Mental deterioration
Dementia
Behavioral abnormalities
Higher cortical function deficits
Movement disorder
Myoclonus
Other
Extrapyramidal signs
Cerebellar signs
Periodic EEG activity
Visual disturbances
Pyramidal signs
Seizures
Lower motor neuron signs
Sensory signs
Headache
Cranial nerve signs
Vertigo
Histopathological findings: gliosis > spongiosis
(no. of patients)"
LongDuration
Series
NIH
1967-1 976
Series"
French
1978- 1082
Seriesh
33
17116
30
48
63
54
28126
105
47158
7
62
8.6
100
100
73
45
88
79
33
79
67
5 5'
52
49
24
12
100
100
52
56
. . .
100
94
54
43
92
89
. . .
54
66
70
44
78
21
92
23
72
70
73
55
42
10
10
9
6
6
3
4127 (15%)
9
57
8.0
. . .
. . .
. . .
. . .
. . .
7/51 (1457)
11
12
3
8
. . .
-
"Consecutive transmitted cases referred to this laboratory between 1967 and 1976. Recalculated from series of cases o f transmissible virus
dementia presented in Table VI of Traub and colleagues {22] after elimination of unverified transmissions from 2 patients with Alzheimer's
disease.
bConsecutive histologically verified cases from French survey between 1978 and 1982 (P. Brown, unpublished data). Includes transmitted and
untransmitted cases.
'EEG not recorded in 2 cases.
dIncludes only patients studied postmortem.
M = male; F
=
female; EEG
=
electroencephalogram
at onset of 40 years, compared with 48 years for the
group as a whole.
In other respects, differences in the clinical characteristics varied as much between the two unselected
series as between either unselected series and the longduration cases.
Neuropatbological Findings
At postmortem examination most patients were noted
to have moderate to severe cortical atrophy, with brain
weights between 900 and 1,000 gm. Histopathological
findings by light microscopy were in all cases characteristic of CJD, with widespread spongiosis, gliosis, and
neuronal loss. In 2 cases involvement of white matter
was more pronounced than gray matter involvement,
and senile plaques were noted in 4 cases. Both biopsy
298
Annals of Neurology
Vol 16
No 3
and postmortem specimens were available in 6 cases: in
4 the typical features of CJD were seen in both specimens; in 1 the biopsy showed only nonspecific abnormalities, whereas postmortem study showed typical
CJD abnormalities; and in 1 the biopsy showed only
spongiosis, whereas the postmortem examination revealed spongiosis and an even more intense gliosis. In
only 4 (15%) of the 27 long-duration cases that were
studied postmortem, however, was gliosis noted to be
the predominant pathological feature at postmortem
examination, a figure nearly identical to the 7 (14%) of
5 1 autopsies in our earlier series of patients unselected
for duration of illness (see Table 2). Representative
cortical sections are shown in the Figure for the 3 patients with transmitted disease of longest duration13, 11, and 10 years, respectively-illustrating the
September 1984
Table 3 . Comparison of Patients with Long-Duration CreutzfedtJakob Disease
in Transmitted, Inconclusive, and Untransmitted Subgroups
Characteristic
No. of cases
Sex (MIF)
Familial cases (%)
Average age at onset (yr)
Average disease duration (mo)
Clinical picture (%)
Mental deterioration
Dementia
Behavioral abnormalities
Higher cortical function deficits
Movement disorder
Myoclonus
Other
Extrapyramidal signs
Cerebellar signs
Periodic EEG activity
Visual disturbances
Pyramidal signs
Seizures
Lower motor neuron signs
Sensory signs
Headache
Cranial nerve signs
Vertigo
Histopathological findings: gliosis > spongiosis
Transmitted
Subgroup
Inconclusive
Subgroup
15
8/ 7
27
48
60
10"
6i4
40
100
100
80
47
100
100
40
73
13
53
53
47
27
13
7
13
13
100
8
315
25
49
52
47
77
100
70
50
70
80
30
80
60
67h
50
70
20
20
10
0
0
0
0
3/12 (25%)
Untransmitted
Subgroup
1/10 (10%)
100
100
63
38
63
38
25
50
63
14b
50
38
25
0
13
0
0
13
Oi5 (0%)
(no. of patients)'
"Includes S cases still o n test, 4 cases in which suboptimal inocula were used, and 1 case in which all 4 inoculated animals died prematurely from
other diseases.
bEEG not recorded in 1 case.
'Includes only patients studied postmortem.
Abbreviations as in Table 2.
continued presence of intense spongiosis that was described in each case by the examining neuropathologis t.
Transmission Studies
Of the 357 cases of histopathologically verified CJD
inoculated into primates in this laboratory, experimental results for 50 were either inconclusive (early animal
death) or are pending (animals still alive), leaving 307
cases for which data are complete. Exclusion of a further 64 cases for which transmission was attempted
using suboptimal inocula yielded a final figure of 208
transmissions in a total of 243 cases, for an overall
transmission rate of 86%.
When analyzed according to long- and shorter-duration groups (Table 4 ) , the transmission rate for the
long-duration group (64%) was found to be significantly lower than that for the shorter-duration group
(88%). No relationship was observed between the du-
ration of a patient's illness and the duration of either
the incubation period or the clinical illness in the primates used for transmission; indeed, the average
lengths of the incubation period and duration of illness
in the inoculated animals were virtually identical for
both long- and shorter-duration patient groups.
Whereas 10 of the 15 transmitted long-duration
cases were inoculated into several animals (and in each
case at least one of the inoculated animals remained
unaffected), only 3 of the 8 untransmitted cases were
inoculated into more than one animal.
Differential Diagnosis
In addition to our series of 33 patients with histologically verified long-duration CJD, 4 1 patients with comparably long histories of chronic progressive dementia
and associated neurological signs have been referred to
us with suspected CJD. Subsequent postmortem examinations in these 4 1 patients, however, did not confirm
Brown et
al:
Creutzfeldt-Jakob Disease 299
A
B
the diagnosis. In more than half of these cases, histopathological examination was unable to account for the
clinical picture, revealing only the nonspecific changes
of mild neuronal loss or gliosis, sometimes with occasional senile plaques. In a few cases histopathological
findings were essentially normal. Several of these cases
were thought to include electron microscopic features
of CJD in spite of nonspecific light microscopic abnormalities and atypical signs and symptoms; all failed to
transmit disease. The remaining diagnoses were partitioned, in decreasing order of frequency, among Alzheimer’s disease, amyotrophic lateral sclerosis with dementia, cerebrovascular disease (including a case of
chronic bilateral subdural hematomas), cerebellar or
multisystem degeneration syndromes, GerstmannStraussler syndrome, and individual cases of chronic
encephalitis of unknown cause, striatonigral degeneration, and Schilder’s disease.
A review of the clinical histories of these patients
indicated that CJD was in most instances not the primary consideration and would pose no special problem
of differential diagnosis; unusual presenting symptoms,
episodic courses, the absence of either myoclonus or
periodic EEG activity, or the early appearance of progressive lower motor neuron signs in many cases made
Photomicrographs of representative histological sections from the
cerebral cortex of each of the 3 patients with transmitted Creutzfeldt-Jakobdisease of longest duration: (A) patient 1 , duration
13 years; (B)patient 2, duration I I years; and (C) patient 3,
duration 10 years. Clinical histories ure summarized in Table 1.
((A) x 340; (B) x 340; (Ci x 220; all befure 33% reduction.)
the diagnosis of CJD a very distant possibility. A few
cases, however, were remarkably similar to the cases of
transmitted long-duration CJD described in Table 1.
Case summaries of these patients, together with a few
additional reports culled from among the patients referred to us during a surveillance of CJD in France, are
presented in Table 5 to underscore the difficulty of
correct antemortem diagnosis in some patients with
chronic dementing illnesses.
Discussion
As the clinical and pathological characteristics of typical
transmissible CJD have become increasingly well defined, interest has turned to the identification of less
typical cases in an effort to establish the outer limits of
the disease entity. Recent publications from this laboratory have explored the fringes of CJD by analysis of the
extent to which syndromes of amyotrophic lateral scle-
300 Annals of Neurology Vol 16 No 3 September 1984
rosis and dementia C 191 and Gerstmann-Straussler syndrome E12) overlap with transmissible CJD. The present study approaches these same fringes by analyzing a
group of patients with proved transmissible CJD with
unusually prolonged illnesses, searching for characteristics that might distinguish them from patients with
untransmitted long-duration CJD, from unselected
series of patients with CJD with mostly typical subacute clinical courses, and from patients with other
chronic dementia.
Earlier c a e series have reported figures of 6 to 10%
for the proportion of patients with CJD with illness
of more than 2 years' duration C2, 10, IS}. Our series
confirms this range of frequency: in 9% of histologically verified cases and 7% of transmitted cases, the
illnesses lasted 2 years or more. The longest illnesses in
transmitted cases of CJD that have been described to
date are those of a 37-year-old woman whose illness
lasted 9 years 121) and a 43-year-old man whose illness
lasted 10 years C21. These durations for transmissible
CJD are now eclipsed by the 46- and 31-year-old
women (patients 1 and 2 in Table 1) whose illnesses
lasted 13 and 1I years, respectively.
Because the infective event in sporadic cases of CJD
is unrecognizable, the length of the incubation period
before clinical illness supervenes is unknown. In the
four cases of iatrogenically acquired infection reported
in the literature C1, 4, 51, incubation periods of 16, 18,
20, and 28 months were followed by illnesses of 8, 8,
23, and 6 months, respectively. Thus, if there were any
parallel between the lengths of incubation periods and
the duration of symptomatic disease, the incubation
periods in patients with a more prolonged clinical
C
Table 4. Comparison of Transmission Characteristics in Cases of Long- and Shorter-Duration Creutzfeldt-Jakob Disease
No. of Cases
~
Population
CJD 2 2 yr
Transmitted
Untransmitted
Total
Crude
Case
Total
Inconclusive
or Pending
Resultsd
15
. . .
18
6
6
33
~
Suboptimal
Inoculab
1
4
5
Final
Case
Total
14
8
22
Transmission
Rate (F)
64
Average'
Incubation
Period (mo)
23.4
5
3.5
(range, 20-32)
CJD < 2 years
Transmitted
Untransmitted
Total
210
114
324
44
44
16
43
59
194
27
22 1
88
24.5
2
4.7
(range, 11-37)
Average'
Duration of
Illness (mo)
1.0
* 0.8
(range, 0-2)
1.2 t- 1.4
(range, 0-1 1 )
"Animals remamed alive and well, or died from other diseases (without histopathological evidence of CJD) within a time interval equal to the
longest recorded incubation period of CJD in the species inoculated.
hlnocula other than 1 to 20% saline suspensions of frozen brain tissue employed.
'In squirrel monkeys, the most reliable and frequently used species for inoculation.
CJD
=
Creutzfeldt-Jakob disease.
Brown et al: Creutzfeldt-Jakob Disease
301
Table 5 . Case Summaries of 15 Patients with Clinical(y Suspected Creutzfldt-JaRob Disease
of 2 or More Years' Duration Found Postmortem t o Haue Other Diseases
Patient
No
1
(A. F )
Age at
Onset
(yr)
Sex
Total
Disease
Duration
(yrl
60
M
17
Clinical Features
~
~
_
_
Initial Symptoms and Evolutii~n Terminal Phase
Memory loss; extremely slowly
progressive
24 mo; grand mal seizure, mutism, pyramidal and extrapyramidal signs, myoclonus
EEG
Diffuse highamplitude
slow-wave
Histopathological
Findings
Diagnosis/
Comments
Postmortem: N F
tangle$, senile
plaques
Alzheimer's
disease
Postmortem NF
tangles, senile
plaques, neur o d loss,
gliosis
Alzheimer's
dlSedSe;
in(x-ulateil
bursts
2
( S C.)
0I
M
10
Visual deterioration; very
gradually progressive
24 mo; mental deterioration,
spasticity, primitive reflexes,
seizures, cortical blindness,
myoclonus
Periodic
paroxgsmal
slowwave
bursts
bur not
WMS-
ntitred
z
03
F
7
(C. B.)
4
38
M
6
(E. F.)
Memory loss, mood change,
difficulty in speaking;
gradually progressive
Mental deterioration; very
slowly progressive. later associated with depressim,
agnosia, and apraxia
23 mo; increasingly severe
mental deterioration, tremors, rigidity, seizures, myoclonus
1 I mo; grand ma1 seizure,
ataxia, rigidity, accelerating
mental deterioration, Babinski's signs, myoclonus
Diffuse high
amplitude
slov:-wave
bursts
A t biopsy 1 2 0
mu betore
death) N F
Periodic (1 c / s )
triphasic slow
waves
Postmortem: NF
tangles, sen&
plaques, ~ I O S L S ,
vacuolation by
electron microscopy
Alzheimer's
disease
tangles. senile
plaques
Alzheimer's
disease
tfamllld),
inoculated
h u t n(it
trans-
mtte<l.
published
case [(I]
5
07
M
5
( C . M.1
Memciry loss, aphasia, gradually progressive, later associared with occasional
mycwlonus
S mo; rapidly progressive
mental deterioration, tremors, rigidity, fasciculationc,
and increasing myoclonus
Periodic ( 1 cls)
triphasic slow
waves
Postmortem. N F
tangles, senile
plaques, spongiosis i n basal
ganglia. neuronal loss,
Alzheimer's
disease
(farmid);
inoculated
h u t ncit
transmitted
glllJSlS
6
52
M
5
(M. S.)
'0
F
5
(G G.)
X
60
M
3
(M. E.)
Memory loss, depression; sk)w
progression. with subsequent
appearance of higher cortical
function tielicits
I
Memory loss, gradual worsetiing for 2 yr, then acceleration t o global mental ileterioration
I 2 mo; parkinsoniaii-type
tremor and rigidicy, increasing demtvtia to mutism and
Parkinsonian-type tremur and
rigidity; stable
10 mil. rapid deterioration of
higher cortical function; then
dytdrthria, aggravation of
tremor, rigidity, myoclonus
rapid progression of
mental dcterioratiim, visiial
hallucinations, grand mal seizures. mvoclonus
mi,
COmd
Diffuce slowwave activity;
<KCZ5i<Xld
I'ostmortrin NF
rmgles, senile
plaque?
Alzheimer's
'llSc.ase
(fmiilial)
spikes
Periodic
paroxysmal
slow-wave
bursts
Postm(irtem.
rieuronal loss
arid ~ I l ( 1 S i S(Jf
striatonigral
nuclei
Diffuse hwh
amplitude
Postniorrem
Lewy hoilics.
substantla
SIC JW-U'AVC!
bursts
Striatoriigral
degcilerati011
nigra c k p l g -
mentation,
NF tsnglcs,
senile plaques
9
5
F
2'14
Llncharacteristic ineptitude in
keeping house: progressive
appearance of agitation and
higher cortical function
deficits
3 mo; rapidly progressive
mental deterioration, trcmors. rigidity, myoclonus
Perioilic (Icis)
triphasic SIOW
waves
Postmortem N F
tangles. senile
plaques, n e u
rr~nalloss
Alzheimer's
illseaw
62
M
?
Intellectual deterioratim, very
sl(iwly progressive for I yr.
then tiearly stable
1 mo; rapidly progressive men
tal deterioration to coma,
Periodic
paroxysmal
Postm(irtem iliffuse subcortical ~ 1 l " S i S
Diffuse suhcortical
gliosis
Postmortem NF
tangles, Senile
plaques, ghosis,
Lcwy hodies,
substanria
nigra &pigmentation
Alzheimer's
disease +
Parkinson's
disease
(M. G.)
10
(M T.J
with rigidity and myoclonus
SIC J W - W l V C
bursts
61
F
2
( H . B.)
Withdrawal, memory loss, disorientation; slow,ly progressive
302 Annals of Neurology
Vol 16 No 3
11
3 mo; difficulty in walking, extrapyrmidal signs, mental
deterioration, myoclonus,
coma
September 1984
Periodic ( 1 cis,
triphasic slow
Waves
Table 5 . (Continued)
Total
Disease
Duration
(yr)
Age at
Onset
(yr)
Sex
12
(L. M.)
54
M
3
Headaches, pviality, discrete mental deterioration; slowly progressive for 1% yr, then more rapi4 progression to confusjon
and total dementia, with hyperactive reflexes, rigidity, myoclonus
13
(H. D )
51
M
3
14
61
M
3
56
M
2
Patient
No.
(J. Q-)
15
(K. A,)
NF
=
Clinical Features
Histoparhologicdl
Findings
Diagiiosid
Comments
Diffuse highamplitude
Sk)W-WdVe
bursts
At biopsy i1 mo
before death)
NF tdngles,
senile plaques,
neurmal loss,
g11osis
Alzheimer’s
dlSYdSe
Irritability, mild memory and language loss; aggravation after several mo, with anxiety, dyspraxia, hypertonus, myoclonus; progressive deterioration over next 2 yr, visual, cerebellar, and extrapyramidal signs, higher cortical function deficits progressing
to dementia, continuing myoclonus
Diffuse slowwave activirv
At biopsy ( 5 mu
before death)
NF tangles,
senile plaques
Alzheimer’s
dlSCdSe
Memory loss, inattention, aphasia; gradual progression with
euphoria, sleep disturbances, apraxia, dysesthesia, increasing
mental deterioration, confusion, and myoclonus after 2 yr; comatose during last 6 mo of illness, with increasing rigidity and
continued myoclonus
Diffuse hghdmplitude
slow-wave
bursts
At biopsy ( 2 mo
before death):
N F tangles,
senile plaques
Alzheimer’s
disease,
inoculated
but not
transmitted
Periodic ( 1 cis)
triphasic slow
waves
Postmortem: NF
tangles, senile
plaques
Alzheimer’s
dlSl2dSe
Initial Symptoms and Evolution
Terminal Phase
EEG
Confusional episode with ideas of persecution; improved, then
became permanently confused, with higher cortical function
deficits, clumsiness, and myoclonus; gradual progression to
mutism, with hypertonus, continuing myoclonus, coma
neurofibrilldry; other abbreviations as in Table 1
course could extend to several decades, as has been
shown to occur in kuru [ll].
The categories of transmissible and untransmissible
CJD have been applied to the general population of
patients with CJD in earlier publications from our laboratory [Is, 227 and merit reconsideration here.
Specifically, were there any clinical, pathological, or
experimental features in the 8 untransmitted cases that,
when compared with the 15 transmitted cases, might
explain the transmission failures?
Clinically, the untransmitted case group was unusual
in the absence in most patients of myoclonus and periodic EEG activity. In patients with an atypically long
illness, the further absence of these two diagnostic hallmarks would make the diagnosis of CJD most unlikely
were it not for characteristic histopathological findings
that were indistinguishable from those seen in transmitted cases. Also, experimental transmission in 5 of
these 8 cases was attempted using only one animal per
case, and it is possible that inoculation of additional
animals would have been successful. The remaining 3
cases, however, which were inoculated into several animals, must be considered to have represented either a
truly untransmissible form of CJD or some other disorder with a similar histopathological picture.
In the entire group of patients with long-duration
CJD, the only major difference from the usual subacute variety of CJD, apart from the lower frequency
of myoclonus and periodic EEG activity, was the overrepresentation of familial cases and younger patients.
The high familial occurrence may have been a chance
phenomenon, because the average duration of illness is
not significantly different in familial and sporadic CJD
[l 31. A similar tendency toward longer clinical illnesses
in younger patients has already been observed in a
tabulation of 8 published cases of CJD in which death
occurred before the age of 30, and in an age-duration
analysis of several hundred consecutive cases of CJD in
France [ 177. It is possible that the prolonged and subtle
nature of early symptoms caused them to be recognized more easily in many of these younger patients
than in older patients, whose failing memories or behavioral changes could have been overlooked or attributed to normal aging.
The paucity of neurological signs until late in the
clinical course can result in a diagnostic quandary that is
not resolved until the terminal stage of illness. The
appearance of myoclonus or periodic EEG activity is
particularly important in long-duration cases, and although both features are not invariably present, their
combined absence is strong evidence against the diagnosis. Some atypical forms of other chronic dementias,
however, especially Alzheimer’s disease, may masquerade as long-duration CJD. If all the case histories tabulated in this report were combined into a single table
without the inclusion of pathological data, identification of those patients with CJD would be impossible.
Thus, in the final analysis it is the neuropathologist
who must validate (and sometimes discover) the correct diagnosis, and our findings indicate that he or she
would be well advised to trust to the presence of characteristic spongiosis, as seen by conventional light mi-
Brown et al: Creutzfeldt-Jakob Disease
303
croscopy, as the linchpin of diagnostic interpretation.
We have found unequivocal spongiosis evident on light
microscopy to be present in all transmitted longduration cases, whereas no transmission occurred in
any case in which spongiosis on light microscopy was
arguable, even in the presence of gliosis and neurond
degeneration, or vacuolar-membranous abnormalities
detected on electron microscopy.
It has been proposed, based on a semiquantitative
histopathological evaluation of 2 1 patients, that when
CJD lasts for more than 5 months (4 of the 2 1 patients
fell into this category), gliosis and neuronal loss become more important than spongiform change 1141. A
more recent study of 11 patients with clinical durations
of 3 months to 9 years showed a similar trend 121).
Results of the present study, based on neuropathological examinations conducted by various university hospital services, indicate that although the degree of
spongiosis may in some cases decrease because of progressive gliotic atrophy during the course of disease,
the proportion of patients with long-duration CJD
showing predominant gliosis postmortem is no greater
than the proportion in case series unselected for length
of illness.
Supported in part by INSERM, section Sante Mentale et Cerveau,
Convention no. 120053: "Etude Diagnostique et Therapeutique des
Affections DGgGnCratives du Systeme Nerveux de I'Homme er de
1'Animal."
The authors are grateful to Dr H. H. Itabashi, Department of Parhology, University of California at San Diego, CA, for slides of patient 1
(Fig IA); to Dr M. 2. Jones, Department of Pathology, Michigan
State University, East Lansing, MI, for slides of patient 2 (Fig 1B);
and to Dr C. Marty-Double, Department of Neuropathology, University of Montpellier, Monrpellier, France, for slides and phoromicrographs of patient 3 (Fig 1C).
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