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Clinical course in young patients with sporadic CreutzfeldtЦJakob disease.

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Clinical Course in Young Patients with
Sporadic Creutzfeldt–Jakob Disease
Constanze Boesenberg,1 Walter J. Schulz-Schaeffer, MD,2 Bettina Meissner, MD,1 Kai Kallenberg, MD,3
Mario Bartl,1 Uta Heinemann,1 Anna Krasnianski, MD,1 Katharina Stoeck, MD,1 Daniela Varges,1
Otto Windl, MD,4 Hans A. Kretzschmar, MD, FRCPath,5 and Inga Zerr, MD1
Sporadic Creutzfeldt–Jakob disease (sCJD) is a rare neurodegenerative disease with the greatest incidence occurring in
patients between 60 and 70 years old. Younger patients may also be affected. In this study, we used all case material
available from 52 patients with sCJD aged 50 years or younger at disease onset, who were identified between 1993 and
2003 in Germany. The objective of this study was to describe the psychiatric and neurological features of these young
patients with emphasis on the different codon 129 genotypes and PrP types, and to compare them with elder patients
with sCJD and patients with variant CJD. We also gave particular attention to electroencephalogram, magnetic resonance
imaging, and 14-3-3 results, as well as to the neuropathological lesion profile. The clinical syndrome in young patients
differs from elder patients with CJD with respect to clinical signs, disease duration, technical investigations, and neuropathological lesion profile. The psychiatric symptoms in young patients with sCJD are similar to the psychiatric
symptoms expressed by patients with variant CJD; however, in contrast with the variant cases, young patients with sCJD
experience development of prominent dementia early in the disease course.
Ann Neurol 2005;58:533–543
Sporadic Creutzfeldt–Jakob disease (sCJD) is a rapidly
progressive disorder of the brain that is characterized
by neuronal cell loss, astrocytic gliosis, spongiform
changes of the neuropil, and accumulations of an abnormal form of the prion protein (PrPSc [Sc for
scrapie]). This disease form typically affects people aged
60 to 70 years. Rapidly progressive dementia is accompanied by various focal neurological signs. The typical
clinical syndrome, together with the detection of abnormal periodic sharp and slow wave complexes
(PSWCs) in the electroencephalogram (EEG), 14-3-3
proteins in the cerebrospinal fluid (CSF), and high signals in the basal ganglia in the magnetic resonance images (MRIs), allows the clinical diagnosis of sCJD during the patient’s lifetime in the majority of cases.1–3
The molecular classification of different subtypes of
sCJD is based on the genotype at polymorphic codon
129 of the prion protein gene (PRNP) and the physicochemical properties of the protease-resistant core of
the pathological PrPSc (either as type 1 or 2A).4 – 6
Data from the literature, as well as those collected
within the framework of various CJD surveillance studies, indicate that sCJD also affects young individu-
als.7–9 The clinical syndrome in these patients might
differ from older patients. In addition, a variant of
CJD (vCJD) was first described in 1996.10 Patients
with vCJD are reported to be young at disease onset
(average onset is 27 years), and the clinical syndrome
differs considerably from the disease course in sCJD,
especially regarding the early prominent psychiatric
symptoms.11,12
Because the differential diagnosis of vCJD and sCJD
is important in young patients with rapidly progressive
dementia, we performed a systematic study on young
sCJD.
The main questions posed in this investigation are:
(1) Is there a difference in the symptoms, clinical signs,
and clinical and diagnostic tests between younger and
elder patients with sCJD? (2) Which differences can be
observed in the neuropathological lesion profiles between both groups? (3) Is there a difference in the genetic background with respect to codon 129 genotype
in younger and elder sCJD patients. If so, did it influence the clinical syndrome, disease duration, or neuropathological lesion profile? (4) Are the symptoms and
From the 1Neurologische Klinik und Poliklinik; 2Institut für Neuropathologie; 3Abteilung für Neuroradiologie der Georg-AugustUniversität Göttingen, Göttingen, Germany; 4Veterinary Laboratories Agency-Weybridge, Woodham Lane, New Haw, Addlestone,
United Kingdom; 5Institut für Neuropathologie, LMU München,
München, Germany.
Published online Jul 21, 2005, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20568
Received Oct 19, 2004, and in revised form Apr 15 and Jun 1,
2005. Accepted for publication Jun 1, 2005.
Address correspondence to Dr Zerr, Georg-August-Universität,
Neurologische Klinik und Poliklinik, Robert-Koch-Strasse 40,
37075 Göttingen, Germany. E-mail: ingazerr@med.unigoettingen.de
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
533
clinical signs of the young sCJD patients similar to
those of vCJD patients?
Materials and Methods
Study Design
In 1993, systematic CJD surveillance was established in Göttingen, Germany. After notification, patients are examined
by a study physician at the notifying hospital. Copies of
medical charts, EEG, and MRI are made, and blood and
CSF samples are taken for further investigations. Patients’
relatives or caregivers are interviewed using a standard questionnaire.
Based on the clinical signs and relevant diagnostic findings, as well as autopsy results, the patients are classified as
“definite CJD,” “probable CJD,” “possible CJD,” and “other
cases” by diagnostic criteria according to the World Health
Organization (WHO) and European Collaborative Surveillance’s study on CJD.13,14
Patients
The study population comprised 52 definite and probable
sCJD patients who were registered at the Surveillance Unit
from June 1993 to August 2003.3,15 Patients had to be 50
years or younger when the first symptoms occurred. Iatrogenic and genetic cases were excluded. For comparison, data
on patients who were older than 50 years at disease onset
from the same time period and acquired by the same methodology were included.
Data Collection
A standard questionnaire, which covered a wide spectrum of
psychiatric and neurological signs and symptoms, was developed for all patients. The exact time of disease onset was
defined as the time point when symptoms and signs indicative for a neurological or psychiatric disorder first occurred.
Early disease stages were defined before motor signs occurred; late disease stages were defined after occurrence of an
akinetic mutism.
Genetic analysis, neuropathology, and Western blot analysis of brain tissue were performed at the CJD Surveillance
Unit at the Institute of Neuropathology in Munich and in
Göttingen, according to the procedures described previously.3,16
Genetic Analysis
Analysis of the PRNP was performed after isolation of
genomic DNA from blood according to standard methods.17
The entire coding region of the PRNP was sequenced in each
case, and only sporadic cases were included in the analysis
(52 patients aged 50 or younger at disease onset and 767
patients older than 50 years).
Neuropathology
In this study, 28 of 52 patients were confirmed by neuropathological examination. Twenty-four patients were classified as probable.14
In 14 patients with CJD aged 50 or younger at disease
onset (6 MM1 patients, 5 VV1 patients, and 3 VV2 patients), complete brain material was available to characterize
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the neuropathological lesion profiles. Then, the results were
compared with autopsy material from CJD cases, who were
older than 50 years at disease onset. The cases used for comparison were always the next recorded definite CJD case at
that time for which autopsy material was available: 14 MM1
patients and 3 VV2 patients. There was no difference in the
sex ratio between the younger and older patients. The neuropathological investigation was performed according to the
protocol.16,18 –20
Nine brain regions (medial frontal gyrus, anterior cingulate gyrus, inferior parietal gyrus, area striata, inferior temporal gyrus, caudate, putamen, mediodorsal thalamus, and subiculum) were investigated for the degree of spongiform
changes, gliosis, and nerve cell loss. An investigator blinded
for diagnosis classified the pathological changes semiquantitatively for each section (0 – 4 points: 0 ⫽ no change; 1 ⫽
mild; 2 ⫽ moderate; 3 ⫽ severe; or 4 ⫽ maximal changes
[status spongiosus, excessive gliosis, or almost complete nerve
cell loss]).6
The results of various cortical regions and the basal ganglia were averaged. Thus, the following four regions were
used for comparative analysis: cerebrum (frontal region, anterior cingulate gyrus, parietal region, occipital region, and
temporal region), basal ganglia (anterior caudate and putamen), thalamus, and subiculum.
Electroencephalogram, 14-3-3, and Magnetic
Resonance Imaging
Each EEG was analyzed for the presence of PSWCs according to standard criteria.1,21 Each MRI available for this study
was analyzed by a radiologist (K.K.) for detection of abnormally high signals in the basal ganglia, thalamus, or cortical
structures. Because the basal ganglia changes represent the
most consistent finding in sCJD, MRI scans that displayed
abnormal hyperintense signals in caudate nucleus, putamen,
or both were considered as typical.22–24
The CSF was analyzed with respect to routine diagnostic
tests (cell count, protein, albumin, immunoglobulin) and 143-3 proteins in the laboratory of the Surveillance Unit
(I.Z.).3,25
Young Sporadic Creutzfeldt–Jakob Disease Patients
from the Literature
We screened the medical literature for the last 25 years and
searched for case reports on patients with sCJD aged 50 or
younger at disease onset, paying particular attention to differences and similarities between the young patients described in literature and young patients with sCJD and
vCJD.
Statistical Analyses
The statistic software package we used for our calculations
was SigmaStat 3.1 and SigmaPlot 9.0 (Systat Software, Inc.,
Point Richmond, CA). The following tests were used when
applicable: Mann–Whitney rank-sum, z, analysis of variance
on ranks, and log-rank tests.
Results
Study Population
The study population comprised 52 patients with
sCJD. During the first years of the study, there were
only three definite or probable young patients with
sCJD registered per year. The incidence increased during the subsequent years. The greatest incidences were
during 1996, 1997, and 2001, with seven patients registered each year.
We analyzed which specialist the patients first contacted after disease onset. General practitioners were
excluded. Twenty-eight patients (54%) initially contacted a neurologist, 11 patients (21%) first contacted
a psychiatrist, 6 patients (12%) contacted an ophthalmologist, 4 patients (8%) contacted a specialist in otolaryngology, and 1 patient each contacted an orthopedic surgeon, dentist, and neurologist/psychiatrist.
Table 1 shows results of technical investigations, the
codon 129 distribution, and disease duration in young
patients with sCJD compared with the whole sCJD
group and patients with vCJD. The youngest patient
in our study was 19 years old at disease onset. Tables 1
and 2 present the distribution of codon 129 genotypes
and PrPSc types. The difference between codon 129 ge-
notype distribution in “young” and “old” patients with
CJD was statistically significant for valine homozygous
patients ( p ⫽ 0.025; see Table 1). The median disease
duration was 16 months (range, 2–76 months for all
patients; see Table 1 and Fig 1). Young patients with
CJD had significantly longer disease duration than
older patients with CJD (log-rank test, p ⬍ 0.0001).
In “young” patients, the median disease duration
ranged between 13.5 and 17.5 months. Within the
group of “young” patients with CJD, disease duration
did not differ among genotypes. In the older group,
differences in the disease duration were significant
among all genotypes ( p ⬍ 0.001 for MM/MV, MV/
VV, and MM/VV). In a subsequent analysis, disease
duration between “young” and “old” homozygous patients differed significantly ( p ⬍ 0.001).
Clinical Syndrome at Onset
Reviewing the symptoms at disease onset (Table 3),
more than half of the patients presented with demen-
Table 1. Synopsis of Clinical Data of sCJD Patients ⱕ50 and ⬎50 Years and Patients with vCJD
Variant CJD12,34
Sporadic CJD
ⱕ50
⬎50
Test results, % (n)
24 (12/51)
66 (212/354)
0 (0)
92 (45/49)
94 (281/294)
57 (13/23)
63 (75/157)
70 (22/31)
40 (18/45)
(pulvinar sign)
(basal ganglia
hyperintensities)
Duration of illness, months (median [range]) Mean (standard deviation)
16 (2–76)
6 (1–39)
16.125 (⫾13.506)
8.503 (⫾7.218)
13.5 (2–76)
5 (1–39)
14 (8–38)
15.038 (⫾15.038)
7.645 (⫾6.950)
17.5 (4–44)
12 (2–35)
16.5 (⫾14.775)
12.48 (⫾7.534)
14.5 (6–49)
8 (2–40)
17.750 (⫾10.686)
8.344 (⫾6.741)
EEG (PSWC)
14-3-3 in CSF
MRI
Total
MM
MV
VV
Variant CJD12,34
Sporadic CJD
ⱕ50
MM
MV
VV
PrP-type
1
2A
a
⬎50
All
Men
Women
52
15
33
50
11
39
54
21
25
All
Men
Women
Codon 129 genotype, %
68
66
16
20
16
14
70 (16/23)
30 (7/23)
69
14
17
77 (142/185)
23 (43/185)
100b
Statistical
Analysis
ⱕ50 vs
⬎50 (P )
0.001a
0.829
0.01a
⬍0.001a
⬍0.001a
0.23
⬍0.001a
Statistical
Analysis
ⱕ50 vs
⬎50 (P )
0.074
0.945
0.025a
0.628
0.628
Significant.
vCJD patients diagnosed so far are homozygous for methionine.
b
SCJD ⫽ sporadic Creutzfeldt–Jakob Disease; vCJD ⫽ variant CJD; EEG ⫽ electroencephalogram; PSWC ⫽ periodic sharp and slow wave
complex; MRI ⫽ magnetic resonance imaging; CSF ⫽ cerebrospinal fluid; PrP ⫽ prion protein.
Boesenberg et al: Clinical Course in Young sCJD Patients
535
Table 2. Technical Investigations in Young sCJD Patients
EEG
Patient
Type
14-3-3
No
PSWCs n.d.
n.d.
1 22 (88%)
3 (12%)
2
7 (32%)
15 (68%)
5
0
0 (0%)
0
5 (71%)
2 (29%)
17 (100%) 0 15 (94%)
1 (6%)
1
6 (38%)
10 (62%)
MM ⬎50, 347 (71%) 143 (29%) 47 480 (96%)
n ⫽ 537
MV ⬎50,
32 (39%) 50 (61%) 38 91 (89%)
n ⫽ 120
VV ⬎50,
12 (16%) 61 (84%) 37 99 (98%)
n ⫽ 110
19 (4%)
MM ⱕ50,
n ⫽ 27
MV ⱕ50,
n⫽8
VV ⱕ50,
n ⫽ 17
MM ⱕ50
vs MM
⬎50b (P)
MV ⱕ50
vs MV
⬎50b (P)
VV ⱕ50 vs
VV ⬎50b
(P)
10 (39%) 16 (61%)
2 (25%)
0 (0%)
6 (75%)
8 (100%)
⫺
n.d.
1
2
n.d.
8 (80%)
2 (20%)
17
1
0 (0%)
1 (100%)
7
1
8 (67%)
4 (33%)
5
38 130 (47%) 146 (53%) 261 132 (96%)
11 (11%) 18
2 (2%)
⫹a
PrP Type
⫺
PSWCs
⫹
MRI
9
6 (4%)
399
54 (70%)
23 (30%) 43
9 (39%) 14 (61%)
97
40 (60%)
27 (40%) 43
1 (4%)
86
23 (96%)
⬍0.001c
0.134
0.184
0.139
0.679
0.696
0.735
0.790
0.162
0.883
0.149
⬍0.001c
a
Hyperintense basal ganglia.
Statistical comparison within genotypes stratified by age.
c
Significant.
b
sCJD ⫽ Sporadic Creutzfeldt–Jakob disease; PSWC ⫽ periodic sharp and slow wave complex; n.d. ⫽ not done; EEG ⫽ electroencephalogram;
MRI ⫽ magnetic resonance imaging.
Fig 1. Kaplan–Meier cumulative survival plot for time.
CJD ⫽ Creutzfeldt–Jakob disease.
tia. Affective disorders were frequent (35%); depression, aggression, and personality change were noted in
15 to 17% of the patients. Visual disturbances, fatigue/
autonomic disturbances, dizziness, sleep disturbances,
and unsteadiness in standing and walking also belong
to the presenting symptoms in young patients with
sCJD.
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Clinical Syndrome during Disease Course
We analyzed the symptoms that occurred during the
course of the disease and the median time when these
symptoms appeared. The “main clinical signs” (defined
as dementia, visual, cerebellar, pyramidal/extrapyramidal, myoclonus, and akinetic mutism; see Table 3)
were expressed by at least 65% of all patients, and dementia was expressed in 94%. Dementia could not be
verified in the remaining three patients. However,
there were differences in the median time when these
symptoms were first reported (Fig 2). Dementia occurred in an early stage of the disease (median, 1
month), followed by cerebellar disorders, pyramidal/
motor disorders, extrapyramidal disorders, and myoclonic jerks and akinetic mutism.
Psychiatric symptoms were common (see Table 3),
and 81% of patients showed affective changes, depression, and aggression; paranoia, hallucinations, and personality changes were often seen mainly in an early
stage of the disease. At least half of the patients also
expressed fatigue/autonomic disorders, unsteadiness, visual disorders, dizziness, speech disturbances, and sleep
disturbances during the disease course.
Table 3. Symptoms at Disease Onset and during Course in
Young sCJD Patients
Symptoms
Main symptoms
Visual disorders
Dementia
Cerebellar
disorders
Pyramidal/
motoric
disorders
Extrapyramidal
disorders
Myoclonic jerks
Akinetic mutism
Psychiatric
symptoms
Affective
changesa
Personality
change
Depression
Aggression
Paranoia
Hallucinations
Disturbances of
higher
cognitive
functions
Speech
disturbances
Apraxia
Frontal lobe
syndrome
Other
Fatigue/
autonomic
disturbances
Headache
Dizziness
Sleep
disturbances
Sensory
disturbances
Dysarthria
Hyperhidrosis
Gait
disturbances
Polyneuropathy
Vigilance
disorders
Tremor
Epileptic
seizures
At
Onset,
% (n)
During
Course,
% (n)
Median Time
(months) of
Occurrence
29 (15)
56 (29)
17 (9)
58 (30)
94 (49)
85 (44)
0.5
1
2.5
6 (3)
73 (38)
3
8 (4)
79 (41)
4
15 (8)
0 (0)
90 (47)
65 (34)
4
5
35 (18)
81 (42)
0
17 (9)
27 (14)
0
15 (8)
17 (9)
2 (1)
4 (2)
46 (24)
39 (20)
23 (12)
35 (18)
1
2
3
4
6 (3)
52 (27)
2
6 (3)
6 (3)
37 (19)
23 (12)
3
3
42 (22)
79 (41)
0
17 (9)
31 (16)
19 (10)
23 (12)
54 (28)
60 (31)
0
0
1
12 (6)
35 (18)
1
8 (4)
6 (3)
19 (10)
40 (21)
29 (15)
64 (33)
2
2
3
0 (0)
0 (0)
12 (6)
27 (14)
3.5
3.5
4 (2)
0 (0)
33 (17)
12 (6)
4
7.5
a
Affective changes: at onset, many patients were reported to have
affective changes. At this stage, no further specification was possible.
Therefore, a general term is used.
sCJD ⫽ sporadic Creutzfeldt–Jakob disease.
Fig 2. Most important clinical signs in young sporadic
Creutzfeldt–Jakob disease patients and time of occurrence (median).
Clinical Syndrome in Different Genotypes
There were differences among the genotypes concerning the frequency of the symptoms at disease onset
(Table 4). The most frequent symptoms at disease onset were visual disorders in the MM group (significance
was set at p ⫽ 0.001), and dementia in the MV and
the VV groups. Differences among the three different
genotypes were also found for other neurological signs,
but without significance.
Comparing the three different genotypes, we also
observed differences in the disease course. Sensory disturbances, visual disorders, hallucinations, and paranoia
were found more frequently in the MM group. Headache was reported more frequently in the MV group,
and aggressive behavior was reported more frequently
in valine homozygous patients (data not shown).
Technical Investigations
Table 2 lists the results of the technical investigations.
Of the 51 patients with EEG, 12 patients showed typical PSWC with striking differences among the genotypes: positive rates in 39% of the MM group, but for
only 2 patients (25%) in the MV group and none in
the VV group.
Forty-five of 49 patients tested had a positive 14-3-3
immunoassay (92% sensitivity), without significant differences between genotypes.
MRI scans were available for 45 patients. Among
these, 35 T2-weighted, 25 fluid-attenuated inversion
recovery, and 6 diffusion-weighted images were analyzed. MRI scans showed hyperintensities in the basal
Boesenberg et al: Clinical Course in Young sCJD Patients
537
Table 4. Clinical Syndrome in the Different Genotypes at Disease Onset
Symptoms at Onseta
MM (n ⫽ 27), % (n)
MV (n ⫽ 8),
% (n)
VV (n ⫽ 17),
% (n)
Total (n ⫽ 52),
% (n)
Statistical
Analysis (P)
44 (12)
19 (5)
11 (3)
11 (3)
19 (5)
52 (14)
50 (4)
38 (3)
0 (0)
13 (1)
25 (2)
13 (1)
77 (13)
6 (1)
0 (0)
0 (0)
6 (1)
0 (0)
56 (29)
17 (9)
6 (3)
8 (4)
15 (8)
29 (15)
n.s.
n.s.
n.s.
n.s.
n.s.
0.001b
11 (3)
22 (6)
52 (14)
19 (5)
33 (9)
13 (1)
25 (2)
12 (2)
0 (0)
0 (0)
24 (4)
12 (2)
0 (0)
6 (1)
6 (1)
15 (8)
19 (10)
31 (16)
12 (6)
19 (10)
n.s.
n.s.
0.001b
n.s.
n.s.
Main symptoms
Dementia
Cerebellar disorders
Pyramidal/motor disorders
Extrapyramidal disorders
Myoclonic jerks
Visual disorders
Other
Depression
Sleep disturbances
Vertigo
Sensory disturbances
Gait disturbance
a
Only symptoms with differences between the genotypes in the frequency of occurrence were included.
significant for MM and VV
b
n.s. ⫽ not significant.
ganglia (caudate nucleus and putamen) in 40%, and
the sensitivity was greatest in heterozygous patients
(71%).
The differences in the sensitivities of diagnostic tests
were influenced by the age of patients (see Table 2).
The frequency of detection of PSWCs in the EEG was
significantly less in younger MM patients than in the
older group ( p ⬍ 0.001). A trend for lower sensitivity
of 14-3-3 test and MRI was seen for MM and VV
patients, without significance.
The distribution of PrPSc (either as type 1 or 2A)
did not differ among “young” and “old” patients (see
Table 1). After stratification of the data by codon 129
genotype, no differences were seen for those who were
homozygous for methionine or heterozygous (see Table
2). In valine homozygous, a significantly greater proportion of patients with PrPSc type 1 was seen, and
only one VV1 patient was observed in the older group.
Lesion Profile
We analyzed the data on lesion score by codon 129
genotype and PrPSc type; these data were available in
14 patients of the young group (6 MM1, 5 VV1, and
3 VV2 patients) and 17 patients older than 50 years
(14 MM1 and 3 VV2 patients).
The different lesion profiles of spongiform change in
young MM1 and those patients older than 50 years are
shown in Figures 3A–C. The younger MM1 patients
demonstrated more severe spongiform changes, nerve
cell loss, and gliosis than the older patients in all examined regions. However, because of the small number
of cases analyzed, the differences did not reach a significance level.
The VV patients aged 50 and younger and those
older than 50 years also showed differences concerning
their lesion profiles (see Figs 3D–F). We compared the
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lesion score profiles for VV2 patients and stratified the
data by age. Spongiform changes were more severe in
the basal ganglia and thalamus of young VV2 patients
than the older ones. Nerve cell loss and gliosis were less
severe in young patients than in elder sCJD patients in
all regions examined.
The lesion profiles in young VV1 and VV2 patients
also differed markedly. Spongiform changes were more
severe in VV1 patients in the cortex without marked
differences in other brain regions. Neuronal loss and
gliosis were more severe in cortex and thalamus of VV1
patients.
Comparison with Literature
We identified 18 case reports on young patients with
sCJD (Table 5).26,27 Twelve patients were women and
six were men; their median age at disease onset was
27.5 years (range, 14 – 49 years). The median disease
duration was 10 months (range, 3–73 months). Codon
129 analysis was performed in seven patients, and
PrPSc typing in six patients (see Table 5). The 14-3-3
protein was determined in seven patients, and four of
these seven patients had a 14-3-3–positive immunoassay. Only 5 of the 18 patients had PSWCs in their
EEGs (27%).
Of the clinical signs at disease onset, dementia was
frequent (13/18 patients): 4 presented with gait disturbances/cerebellar disorders, 3 presented with headaches, and 2 demonstrated visual disorders. Psychiatric
symptoms such as depression, paranoia, personality
change, and affective disorders were reported in eight
patients at onset.
Discussion
In our study, we analyzed the clinical syndrome in
young patients with sCJD. Previously described cases
Fig 3. Neuropathological lesion profiles in MM and VV patients in young age groups and controls. Neuropathological lesion profiles
in MM1 patients: (A) degree of spongiform changes; (B) degree of nerve cell loss; and (C) degree of gliosis. Neuropathological lesion
profiles in VV patients: (D) degree of spongiform change; (E) degree of nerve cell loss; (F) degree of gliosis. MM1 ⱕ 50 (black
bars) and MM1 ⬎50 (gray bars) in A, B and C. VV1 ⱕ 50 (dashed bars), VV2 ⱕ 50 (gray bars) and VV2 ⬎ 50 (black bars)
in D, E and F.
of sCJD patients younger than 50 years are usually isolated case reports, and in systematic surveys, the identification of CJD in patients younger than 30 years is
extremely uncommon.7,28,29 The 52 cases of young patients with sCJD included in this report exhibit clinical
and pathological features different from those in older
patients with CJD.9,30 This is supported by the analysis of the data on young sCJD patients from the literature, which indicated a similar clinical presentation as
reported in our study. Remarkably longer disease duration and lower sensitivity of PSWCs in EEGs and of
typical MRI scans raise the possibility that these cases
do not have the typical classical disease course.
Clinical Syndrome
The median disease duration in our patients aged 50 or
younger at disease onset is prolonged compared with
all CJD patients and with those older than 50 years at
onset.3,29,31,32 A recent article has shown that young
age at disease onset is one of the major factors influencing survival in CJD.9 The longer disease duration
may be attributed to the age at onset rather than genetic background because the disease duration was
longer in all genotypes in our CJD patients aged 50 or
younger at onset. Surprisingly, the disease duration of
the young patients with sCJD patients was similar to
those with vCJD.11,33,34
The results of this study led us to conclude that not
only do the different types of CJD have a major influence on the disease duration, but also the age of the
patient does.6 A trend to a shorter disease duration in
older patients was observed not only in sCJD, but in
vCJD, too; in the 74-year-old patient with vCJD, the
disease duration was 7 months, about half of the average disease duration in vCJD patients, which supports
our hypothesis.35
Clinical Syndrome at Onset and during
Disease Course
Presenting symptoms of young patients with sCJD are
similar to those described in previous studies on the
total sCJD group, and dementia at onset is frequent in
young patients, but cerebellar signs were less frequent
in our young patients with CJD compared with 33 to
55% reported previously.29,36 However, the differences
in the clinical syndrome were more striking at disease
onset than during disease course.
Notably, psychiatric symptoms such as affective
changes, depression, aggression, and personality change
were common at disease onset in young patients with
Boesenberg et al: Clinical Course in Young sCJD Patients
539
Table 5. Case Reports on Young sCJD Patients from the Literature (n ⫽ 18)
Sex
Age (yr)
Duration (mo)
Codon
129
PrP
Type
14-3-3
EEG
PSWCs
Symptoms at
Onset
Kozubski26
F
21
4
n.d.
n.d.
n.d.
⫺
Yamashita44
Belay45
F
F
30
28
73
4
MM
MM
2
n.d.
n.d.
n.d.
⫹
⫺
M
M
29
27
10
15
VV
MV
1
1
⫺
⫹
⫺
⫺
Berman46
F
14
24
n.d.
n.d.
n.d.
⫺
Monreal47
Packer48
M
F
16
20
28
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
⫺
⫺
⫺
Brown49
F
19
4
n.d.
n.d.
n.d.
⫹
Head50
F
42
18
VV
1
⫹
⫺
Kulczycki51
Snowden52
F
F
M
F
27
19
23
34
3.5
10
3
9
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
⫺
⫺
⫺
⫹
Dunn53
M
49
n.d.
n.d.
n.d.
⫹
⫹
Colebatch27
Martindale54
M
F
31
36
n.d.
n.d.
n.d.
MV
n.d.
2
n.d.
⫺
⫺
⫹
Rossetti55
F
46
18
VV
1
⫹
⫺
Vertigo, visual and
gait disturbances
Blurred vision
Dementia, gait
disturbances,
ataxia, dysarthria
Dementia
Dementia,
disorientation
Dementia, gait
disturbances,
affective
disorders
Dementia
Affective disorders,
dementia,
headache,
cerebellar
Personality change,
affective
disorders,
headache
Dementia,
depressions,
headache
Dementia
Dementia
Dementia
Dementia, affective
disorders
Dementia,
hallucinations,
paranoia
Dementia
Behavioral changes,
mild depression
Unaccustomed
irritability
F: 12
M: 6
Median
age: 27.5
Median
duration: 10
4/7
PSWC:5/18
Author
All
sCJD ⫽ sporadic Creutzfeldt–Jakob disease; EEG ⫽ electroencephalogram; PSWC ⫽ periodic sharp and slow wave complex; n.d. ⫽ not done.
CJD, and in 21%, the first specialist contacted was a
psychiatrist. Interestingly, patients with vCJD first contacted a psychiatrist in 42% and during the disease
course in 63%.12,37 We assume that psychiatric disorders in young patients with CJD may be more striking,
but also that a more rapid progressive disease in older
patients will probably not allow the detection of some
psychiatric symptoms and signs at a stage when other
prominent neurological deficits dominate the clinical
syndrome. Consequently, there may be a possible bias
in our results.
The median onset of symptoms during the disease
course in young patients is important for the comparison between the clinical syndrome of young patients
with sCJD and the young patients with vCJD. Present-
540
Annals of Neurology
Vol 58
No 4
October 2005
ing symptoms in young patients with sCJD are often
affective disorders and personality change, and after a
median of 2 weeks, the first neurological symptoms
(eg, visual disorders) occur. Patients with vCJD present
with psychiatric and sensory symptoms, and first neurological signs, mainly cerebellar ataxia and pyramidal/
motor disorders, develop after a median period of 6 to
6.25 months compared with 2.5 months in the young
sCJD group.33,37 Myoclonic jerks appear in vCJD after
a median of 8 to 9 months, which is much later than
in the young patients with sCJD.36,37 Accordingly, the
period of psychiatric changes without neurological
symptoms is much longer in vCJD than in sCJD.33,37
In vCJD, neuropsychological results indicate a moderate to severe intellectual decline at a mean of 12.4
months from onset, at a stage when there were also
overt neurological signs; in contrast, in young patients
with sCJD, severe dementia occurs at much earlier
stages. Unfortunately, because of the design of our
study, we cannot comment on neuropsychological tests
results as a potential discriminating test between young
sCJD and vCJD patients.38
Overall, there is a striking similarity of psychiatric
symptoms at disease onset between patients with vCJD
and the young patients with sCJD in our study; but
during the disease course, there are marked differences
in the evolution of the clinical syndrome between both
groups.
Technical Investigations
The EEG was significantly less sensitive in young patients with CJD compared with the older group and
with the literature.13,21,29,31 Stratifying the data by genotypes, only patients with at least one methionine allele had positive EEG results. According to previous
studies, PSWCs develop in 78% of patients with sCJD
with an MM genotype and in 33% of patients with an
MV genotype.3,5,39 Why young patients with sCJD
display such a low sensitivity of the EEG is unclear. It
could be related to the long disease duration or to their
neuropathological lesion profile (see later). It has been
observed previously that the sensitivity of PSWCs is
significantly less in patients with disease duration
longer than 9 months.3 In former studies, it was assumed that PSWCs result from a greatly impaired
subcortical-cortical circuit of neuronal excitability. Patients with typical EEG changes and myoclonus were
found to have a predominant loss of parvalbuminimmunoreactive neurons in the reticular thalamic nucleus.40 In our study, young patients with sCJD had
more severe neuronal loss in the thalamus than the
older group, which might be related to a lower sensitivity of PSWC detection in the EEG.
The characteristic finding in the MRI in sCJD is the
detection of hyperintense basal ganglia in 67 to 79% of
all patients with CJD; but in our study, the sensitivity
in all young patients was much less.2,22 Sensitivity of
the MRI differs among genotypes.2,3 In our study, this
was observed for both age groups: Although young patients with sCJD had a lower positivity rate of the
MRI in general, the sensitivity in heterozygous patients
was as high as in the older group.3
Genetics
The codon 129 genotype distribution differed significantly in young patients with sCJD, the older group,
and studies published previously.3,41– 43 We observed a
significantly greater frequency for VV patients, which
was also because of a high proportion of VV1 patients
among the young sCJD group.
The most frequent molecular subtype in a previous
study was the MM1/MV1 subtype followed by the
VV2 subtype.5 The results in young patients with CJD
differ from the whole group: the MM1 subtype was as
frequent as VV1. Concerning the age at onset, we observed that the youngest patients with CJD were homozygous for valine.
Neuropathology
Differences concerning the neuropathological lesion
profiles were seen between young and old patients with
sCJD. We stratified our data by codon 129 genotypes,
PrP types, and age at disease onset. Our main findings
were a greater degree of spongiform change, neuronal
loss, and gliosis in examined regions in younger MM1
patients than in older ones. Because of a limited number of patients, the differences did not reach the significance levels. Spongiform change was more severe in
younger VV2 than in the older patients in the basal
ganglia and thalamus; but in the cortex, there was no
difference between old and young VV2 patients. In
contrast, nerve cell loss and gliosis were more severe in
the older than in the younger VV2 patients. We assume that the prolonged disease duration might lead to
more severe brain pathology, which we observed in
young MM1 patients. However, this cannot be applied
to VV2 patients as a reason for more severe neuronal
loss and gliosis in the older group.
Comparison with the Literature
Eighteen case reports on young sCJD patients in the
literature show similar clinical features as the patients
in our study with respect to clinical symptoms, sensitivity of technical investigations, and disease duration.
Unfortunately, in 11 of these cases, no PRNP analysis
was performed, thus a genetic CJD cannot be completely excluded. Although this cannot be proved in
retrospect, we assume that in absence of a family history of dementia, many of them are likely to be sporadic. At disease onset, dementia was often reported
and was even more frequent than in our group (72 vs
56%). It is of major importance that psychiatric symptoms such as depression, paranoia, personality changes,
and affective changes were frequently found in patients
at disease onset, which supports our findings that psychiatric symptoms often occur in young patients with
sCJD.
In summary, this study showed differences in the
clinical syndrome and neuropathological lesion profile
between young and old patients with sCJD. The development of the clinical syndrome is prolonged, and
the neuropathological changes are more severe. Young
patients with CJD less frequently show PSWCs in the
EEG and hyperintense basal ganglia in the MRI. The
high frequency of psychiatric symptoms and prolonged
disease duration might cause difficulties in the differential diagnosis of sCJD and vCJD. However, in
Boesenberg et al: Clinical Course in Young sCJD Patients
541
young patients with sCJD, focal neurological signs appear earlier during disease course, the 14-3-3 test is
mostly positive, and MRI, in the 40% that may show
positive findings, will show typical hyperintense basal
ganglia in contrast with the pulvinar sign in vCJD.
This work was supported by grants from the Bundesministerium für
Gesundheit und Soziales (BMGS, I.Z.; Az325-4471-02/15 H.A.K.)
Bundesministerium für Bildung und Forschung (BMBF,
D1GI0301, I.Z.) and the European Commission (QLG3-CT-200281606, I.Z.).
We thank all physicians who notified the German CJD Surveillance
Unit for providing clinical, neuroradiological, and biochemical data,
as well as their help in obtaining CSF specimens. We also thank Dr
B. Steinhoff for reviewing the EEGs. We are especially obliged to J.
Zellner for her help in editing the manuscript. We dedicate this
work to Dr S. Poser, who always supported our work in a friendly
and collegial way.
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Boesenberg et al: Clinical Course in Young sCJD Patients
543
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