Sporadic Creutzfeldt–Jakob disease: Clinical and diagnostic characteristics of the

rare VV1 type

B. Meissner, I. M. Westner, K. Kallenberg, A. Krasnianski, M. Bartl, D. Varges, C.
Bösenberg, H. A. Kretzschmar, M. Knauth, W. J. Schulz-Schaeffer and I. Zerr
Neurology 2005;65;1544-1550; originally published online Oct 12, 2005;
DOI: 10.1212/01.wnl.0000184674.32924.c9

This information is current as of December 29, 2006

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 Sporadic Creutzfeldt–Jakob disease
CME
Clinical and diagnostic characteristics of the
rare VV1 type
B. Meissner, MD; I.M. Westner, MD; K. Kallenberg, MD; A. Krasnianski, MD; M. Bartl, MD;
D. Varges; C. Bösenberg; H.A. Kretzschmar, MD, FRCPath; M. Knauth, MD;
W.J. Schulz-Schaeffer, MD; and I. Zerr, MD

Abstract—Background: Recently, six molecular subtypes of sporadic CJD (sCJD) have been identified showing differ-
ences regarding the disease course, neuropathologic lesion patterns, and sensitivity to diagnostic tools. Only isolated cases
of the rare VV1 type have been reported so far. Objective: To describe the clinical characteristics and neuropathologic
lesion profiles in nine cases. Methods: In the years 1993 until late 2003, 571 definite neuropathologically confirmed cases
of sporadic CJD were identified in Germany. Of these, nine were homozygous for valine and displayed type 1 of the
pathologic PrPSc in the brain (VV1 type). Results: The authors describe eight men and one woman belonging to the VV1
type. All patients were relatively young at disease onset (median 44 years vs 65 years in all sCJD) with prolonged disease
duration (median 21 months vs 6 months in all sCJD). During the initial stages, their main clinical signs were personality
changes and slowly progressive dementia as well as focal neurologic deficits. None of the nine VV1 patients had periodic
sharp-wave complexes (PSWCs) in the EEG. Only two out of seven displayed the typical signal increase of the basal
ganglia on MRI, whereas signal increase of the cortex was seen in all patients. The 14-3-3 protein levels were elevated in
CSF in all cases tested. Conclusions: The clinical diagnosis of the VV1 type of sCJD can be best supported by the 14-3-3
test and cortical signal increase on MRI. Because of the young age at onset vCJD is sometimes suspected as a differential
diagnosis. MRI plays an important role in differentiating these two disease types and should be performed early during
the disease course.
NEUROLOGY 2005;65:1544–1550

The classic type of Creutzfeldt–Jakob disease (CJD)
is characterized by rapidly progressive dementia,
ataxia, abnormal muscle tone, and myoclonus. It
leads to a state of akinetic mutism and death after a
median disease duration of 6 months.1
Recently, six different molecular subtypes (MM1,
MM2, MV1, MV2, VV1, VV2) of the sporadic form of
the disease (sCJD) have been identified, based on the
methionine-valine polymorphism at codon 129 of the
prion protein gene (PRNP) and two different types of
prion protein (PrPSc type 1 and 2).2 The latter ones
show different sizes after proteinase K digestion and
can therefore be distinguished by electrophoresis.
The CJD subtypes differ concerning the disease
Additional material related to this article can be found on the Neurology
Web site. Go to www.neurology.org and scroll down the Table of Con-
tents for the November 22 issue to find the title link for this article.
course, age at onset, and sensitivity to diagnostic
tests.1
The most common disease type (70%, MM1 and
MV1) is characterized by periodic sharp-wave com-
plexes (PSWC) on EEG, signal increase of the basal
ganglia on MRI (on T2-, fluid attenuated inversion
recovery [FLAIR], and diffusion-weighted images
[DWI]), and 14-3-3 protein in the CSF.3-5
In contrast, the second most frequently occurring
type, the VV2 type (25%), has been characterized by
ataxia and dementia as presenting neurologic fea-
tures, a median duration of 7.5 months, and an ab-
sence of typical EEG findings.1,2
The VV1 type represents one of the rarest sub-
types of CJD (only about 1% of all cases).2 In contrast
to the classic sCJD types, these patients are char-
acterized by a young age at onset, a long disease
duration, and only slowly progressive dementia

Editorial, see page 1520

This article was previously published in electronic format as an Expedited E-Pub on October 12, 2005, at www.neurology.org.
From the Departments of Neurology (Drs. Meissner, Krasnianski, Bartl, Zerr, D. Varges and C. Bösenberg), Neuroradiology (Drs. Kallenberg and Knauth),
and Neuropathology (Dr. Schulz-Schaeffer), Georg-August-Universität Göttingen; and Center for Neuropathology and Prion Research (Drs. Westner and
Kretzschmar), Ludwig-Maximilians-Universität München, Germany.
Supported by grants from the Bundesministerium für Bildung und Forschung (BMBF 01GI0301 and KZ: 0312720), the European Commission (EC)
(QLG3-CT-2002-81606), and by the Bundesministerium für Gesundheit (BMG Az325-4471-02/15).
Disclosure: The authors report no conflicts of interest.
Received February 24, 2005. Accepted in final form August 24, 2005.
Address correspondence and reprint requests to Dr. Inga Zerr, Department of Neurology, University of Göttingen, Robert-Koch-Str. 40, D-37073 Göttingen,
Germany; e-mail: IngaZerr@med.uni-goettingen.de

1544 Copyright © 2005 by AAN Enterprises, Inc.

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Table 1 Patients and characteristic tests of patients with VV1 Creutzfeldt–Jakob disease

Clinical signs and symptoms during course†

MRI: signal increase* Muscle tone

Case M/F Age at onset, y Duration, mo Cortical BG Dementia Rigidity Spasticity Ataxia Myoclonus

1 M 33 32 (⫹) (⫺) ⫹ ⫹ ⫹ ⫺ ⫹
2 M 45 49 (⫺) (⫺) ⫹ ⫹ ⫺ ⫹ ⫹
3 M 24 19 ⫹ ⫺ ⫹ ⫹ ⫹ ⫹ ⫺
4 M 44 24 ⫹ ⫺ ⫹ Increased ⫺ ⫹
5 M 27 18 ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫺
6 M 47 22 ⫹ ⫺ ⫹ ⫺ Opisthotonus ⫹ ⫹
7 M 55 21 ⫹ ⫺ ⫹ Increased ⫺ ⫺
8 M 46 10 ⫹ ⫹ ⫹ ⫺ ⫺ ⫺ ⫺
9 F 19 17 ⫹ ⫺ ⫹ ⫹ ⫹ ⫹ ⫹
Median 44 21

* Case 1: assessed as cortical signal increase including ventral brainstem at the referring hospital; Case 2: scan was assessed as nor-
mal 4 months after onset at the referring hospital.
† At onset, focal changes in the EEG were observed in seven patients. Six out of nine patients presented with cognitive decline and de-
mentia and three patients had a psychiatric onset.

BG ⫽ basal ganglia; ( ) ⫽ MRI assessed at the referring hospital.

(non-classic subtype).1,2,6-9 A similarity of clinical
characteristics sometimes raises the suspicion of
variant CJD (vCJD) as a differential diagnosis.10 It
is, therefore, the aim of the present study to further
characterize the clinical and diagnostic features of
the VV1 type based on the current knowledge of the
disease and to identify factors that help to differenti-
ate it from vCJD.
Methods. Patients with suspected CJD are reported to the CJD
Surveillance Unit in Göttingen, which was established in 1993.
After notification, suspected cases are examined by a study physi-
cian at the hospital reporting the patient, and a questionnaire
about the patient’s history (profession, habits, meat consumption)
is filled out together with their relatives. In addition, copies are
made of the medical charts (clinical findings, laboratory tests) as
well as EEG and MRI and a neurologic examination is carried out.
Based on the clinical signs, EEG, and CSF findings, the patients
are classified according to the established criteria.11 Their MRI
scans are assessed by a neuroradiologist (K.K.) who is aware of
the diagnosis of CJD, but unaware of the disease subtype. The
EEGs are reviewed according to the standard criteria.3
Genetic analysis. Analysis of the prion protein gene (PRNP)
was performed after isolation of genomic DNA from blood accord-
ing to standard methods.12
Neuropathology. Histologic examination was performed on
4-␮m-thick sections of formalin-fixed and paraffin-embedded
brain tissue blocks. Hematoxylin and eosin stains, as well as
immunochemistry, were performed using standard techniques.
Monoclonal antibodies Gö 138 and L42 were used for immunohis-
tochemical detection of PrPSc. In all cases a PET blot was
performed.13
Immunoblotting (Western blotting). The immunoblot profile of
PrPSc was classified as type 1 (unglycosylated PrPSc of 20 –21 kD)
or type 2 (unglycosylated PrPSc of 18 –19 kD) based on electro-
phoretic mobility after proteinase K digestion.14
Scoring profiles. The histopathologic changes in Creutzfeldt–
Jakob diseases comprise spongiform changes, gliosis, and neuro-
nal loss. The degree of these changes is scored (absent ⫽ 0, mild ⫽
1, moderate ⫽ 2, severe ⫽ 3, maximal ⫽ 4) for the frontal, cingu-
late, parietal, temporal, and occipital cortex and the cortex of the
lateral cerebral fissure, the putamen, the hippocampal formation
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(CA1), and the vermis cerebelli. The standard regions were not
available in three patients.
Clinical examination. The patients were examined for the
presence of typical CJD symptoms (dementia, ataxia, pyramidal
and extrapyramidal signs, myoclonus, and akinetic mutism).
Spasticity was considered as present if the tonus increase was
typical (clasp-knife phenomenon) or if pyramidal signs and exag-
gerated muscle reflexes were present. Rigidity was considered as
present if the tonus increase was typically waxy or a cogwheel
phenomenon was found. Further symptoms such as apraxia, apha-
sia, dysarthria, visual disturbances, sensory disturbances, halluci-
nations, and paranoia were not always documented by the study
physician or the referring hospital, which might be due to the
restricted communication with the patient and general difficulty
in diagnosing less prominent disturbances.
Results. Study collective. From 1993 to 2003, nine VV1
sCJD cases were diagnosed by molecular analysis of the
prion protein gene (PRNP) and Western blot analysis of
frozen brain tissue. None of the cases carried a mutation of
the PRNP.
The study comprised eight men and one woman (signif-
icant difference in the men to women ratio compared to the
healthy population, p ⫽ 0.039, one-sample test for binomi-
nal distribution). The median age at onset was 44 years
(19 – 55 years). The median duration of the illness was 21
months (17– 49 months) (table 1).
Clinical findings. Major CJD-presenting symptoms in
nine VV1 cases include slowly developing dementia (six
out of nine of our study patients) and personality changes
(three out of nine). Two patients had headache (in addition
to dementia) and one patient showed apraxia of the right
hand as the first sign (see table 1).
During the disease course, all patients developed de-
mentia and personality changes (aggression and childish
behavior in five cases each, fear in three cases, paranoia in
one case), eight out of nine developed tonus abnormalities
(four cases with rigidity and spasticity, one patient with
rigidity only, in two cases the tonus increase was not
November (2 of 2) 2005 NEUROLOGY 65 1545
Table 2 Affected brain regions in the MRI in patients with VV1 Creutzfeldt–Jakob disease

Case Frontal Temporal Insula Parietal Occipital BG GC HC Atrophy MAO Technique

3 ⫺ ⫹ ⫹ ⫺ ⫹ ⫺ ⫺ (⫹) None 10 FLAIR, T2 (normal)

4 ⫹ ⫹ ⫹ ⫺ ⫹ ⫺ ⫹ ⫹ (Vermis of the cerebellum) 7 FLAIR
5 ⫺ ⫹ (⫹) ⫹ ⫺ ⫹ ⫺ ⫺ Parietal and frontal lobe, also 4 FLAIR, T2
caudate in follow-up
6 ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫹ (⫹) None 5 T2, PD
7 ⫹ ⫹ ⫹ ⫹ ⫺ ⫺ ⫹ (⫹) None 1 T2, FLAIR
8* ⫹ ⫹ ⫹ ⫹ ⫹ (⫹) ⫹ ⫹ Cerebellum, (parietal lobe) 3 T2, FLAIR, DWI
9† ⫹ ⫹ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ None 5 T2, FLAIR

No thalamic signal increase was observed in any of the patients.

* Case 8: signal increase of the right caudate head could be seen in relation to the left side.
† Case 9: additional signal increase of the pulvinar had been seen at the hospital referring the case.

BG ⫽ basal ganglia; GC ⫽ gyrus cinguli; HC ⫽ hippocampus; MAO ⫽ months after onset; (⫹) ⫽ only slight signal increase; FLAIR ⫽
fluid-attenuated inversion recovery; PD ⫽ proton-diffusion-weighted image; DWI ⫽ diffusion-weighted image.

clearly defined, one patient showed opisthotonus). Ataxia
and myoclonus were each found in five out of nine
patients.
Dementia and psychiatric disturbances as presenting
symptoms were followed by ataxia (median 7 months), ri-
gidity (median 9 months), myoclonus (median 10 months),
and spastic tonus increase (median 12 months).
In five patients, focal neurologic signs appeared during
the disease course. One patient (Case 7), who had shown
apraxia of the right hand as a first sign, developed hemi-
neglect on the right side, Broca aphasia, and hemiparesis
on the right side 3 months after onset. Another patient
(Case 9) showed vertical gaze palsy 5 months after onset.
Hemiparesis developed in three patients (3, 8, and 9
months after onset). Furthermore, left-sided hypacusis (9
months after onset) and left-sided hemianopsia (11 months
after onset) were observed in two patients. Further symp-
toms reported were apraxia, visual and sensory distur-
bances, hallucination, seizures, and chorea-ballismus.
Diagnostic tests. All nine patients underwent EEG,
MRI, and lumbar puncture during the disease course (see
table 1).
EEG. In eight out of nine patients at least three EEGs
were performed. Seven patients displayed focal slowing
during the disease course. This finding was already visible
in four cases on the first EEG (median 4 months after
onset). Five patients showed focal slowing of the temporal
lobe (mostly unilaterally), in two cases the frontal lobe and
in two cases the occipital lobe was also affected. In one
patient, the EEG was assessed as showing a focus of the
left hemisphere. Typical periodic sharp-wave complexes
(PSWCs) were not seen in any of our patients. EEG exam-
inations were carried out over a median of 7 months after
onset (range 4 to 17 months).
MRI. We evaluated the FLAIR and T2 images in
seven out of nine patients. One DWI and one proton
density-weighted image (PD) were available in addition
(table 2 and figure 1, A through D). All but one patient
(Case 3) were examined after a third of the overall disease
duration. All seven patients showed cortical signal in-
crease, whereas only two out of seven patients displayed
hyperintense basal ganglia. The brain regions most often
affected were the temporal lobes (all patients), insula and
1546 NEUROLOGY 65 November (2 of 2) 2005
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hippocampus (six cases each), followed by the frontal, pari-
etal, and occipital lobes as well as the cingulate gyrus (five
cases each). In patients presenting focal signs, the corre-
sponding brain areas were affected on MRI: the frontal
lobe was affected in patients showing apraxia and aphasia,
the temporal lobe in a patient showing hypacusis, the oc-
cipital lobe in a patient with visual disturbances.
SPECT/PET. Six out of nine patients underwent nu-
clear diagnostic tests such as SPECT (five cases) and PET
(one case) (table E-1, available on the Neurology Web site
at www.neurology.org). As in MRI, the temporal lobes
were most often affected (six cases) followed by the pari-
etal lobes (five cases) as well as the frontal and occipital
lobes (four cases each).
CSF. In all patients tested (eight out of nine) the 14-
3-3 protein was found in the CSF. The examinations were
performed after a median duration of 7 months after onset.
In one patient, the 14-3-3 protein was already detectable
after 3 months. In two other patients the 14-3-3 protein
was still found after 13 and 14 months (Cases 4 and 6).
Serial punctures were performed on three patients. In one
of them, the 14-3-3 protein was no longer detectable in the
second and third puncture (14 and 18 months after onset).
Neuropathology. Mainly generalized cortical atrophy
was found in all investigated patients (five cases) (table
E-2). Characteristically for VV1 patients, the cortex and
basal ganglia were severely affected by spongiform
changes and gliosis. Among the cortex regions, the fronto-
parietal and insula region showed the most prominent
changes, followed by the occipital and temporal lobes. In
one patient (Case 3), severe spongiform changes were re-
stricted to the temporal cortex and insula, whereas the
other cortical regions showed only mild involvement.
PrP deposits were detected immunohistochemically in
three out of six cases in small areas of the cerebellar mo-
lecular layer. Using the PET blot technique, proteinase-
resistant prion protein deposits were detectable in the
cortical areas, basal ganglia, and cerebellum (mainly in the
molecular layer) of all patients.
Risk factors. We analyzed potential CJD risk factors
as discussed in the literature.15,16 Five out of nine patients
had a positive family history for psychiatric disorders. Five
patients had a history of surgery (three cases of tonsillec-

tomy and one each for surgery of paranasal sinuses, ure-
thral stricture, and sterilization, and one case of intestinal
biopsy). With regard to environmental risk factors, two
patients had been working on a farm, one patient had been
working in a hospital, all patients consumed beef at least
several times a month, and four patients were reported to
consume bovine tripe and liver.
The following case reports were chosen to illustrate a typ-
ical MRI showing signal increase of the cortex region in one
case (Case 8) and SPECT abnormalities in another (Case 4).
Case reports. Case 8. A 46-year-old man initially developed
sleep disturbances, fear, and nervousness, which had at first been
attributed to his unemployment. He then developed loss of short-
term memory, severe headaches, and weight loss, and he startled
easily.
He was admitted to hospital 2 months after the onset of symp-
toms. The MRI revealed a signal increase in the frontal lobes and
right-temporal lobe on T2. FLAIR also showed a signal increase in
both parieto-occipital lobes and both hippocampi. Three months
after onset, the patient was sent to a psychiatric hospital because
he developed behavioral abnormalities and became afraid of elec-
tricity. Four months after onset, his neurologic status was still
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Figure 1. (A) Fluid attenuated inver-
sion recovery (FLAIR)-weighted
follow-up MRI of a patient (Case 8) 4
months after onset showing signal in-
crease of the cingulate gyrus, both insu-
lae, both hippocampi, and the basal
ganglia (more marked on the right
side). (B) Diffusion-weighted follow-up
MRI of the same patient (Case 8) 4
months after onset showing signal in-
crease of the cingulate gyri, the right
insula, and both hippocampi. (C)
FLAIR-weighted MRI of a 19-year-old
woman (Case 9) 5 months after onset
showing signal increase of the cortex of
both temporal lobes, the insulae, and
both parieto-occipital lobes. (D) FLAIR-
weighted MRI (coronar) of the same
patient (Case 9) showing bilateral sig-
nal increase of the temporal cortex, hip-
pocampus, and the cortex of the
cingulate gyrus.
normal, except for a disinhibited glabella reflex and mild demen-
tia (21 of 30 points in the Mini-Mental State Examination). The
MRI at that time showed less involvement of the fronto-parieto-
occipital lobes but slight signal alterations of the basal ganglia
(right caudate head in relation to the left side) (see figure 1A).
SPECT revealed hypoperfusion of the left temporal lobe. EEG
showed intermittent theta-delta activity but no PSWCs. The pa-
tient died 10 months after the disease onset.
Case 4. A 44-year-old man initially developed personality
changes. He was nervous and argued a lot with his children.
Three months later he had a nervous breakdown. He started hav-
ing sleeplessness and hyperhidrosis, became depressed, and
showed loss of short-term memory. An MRI 7 months after onset
showed signal increase of both hippocampi on T2. One month later
signal alterations of the left temporo-occipital lobe and cingulate
gyrus were seen on FLAIR.
During the further course of the disease he developed visual
disturbances, vertigo, and numbness of hands and feet. He
achieved 14 of 30 points in the Mini-Mental State Examination.
SPECT revealed hypoperfusion of the left hemisphere (figure 2).
EEG showed a focus in the left frontotemporal lobe. The patient
developed childish behavior and loss of speech. One year after
onset he was in a state of akinetic mutism, showed increased
muscle tone, and myoclonus. He remained in this state for 1 more
year and died after a total disease course of 2 years.
November (2 of 2) 2005 NEUROLOGY 65 1547

Discussion. Within the group of patients with spo-
radic CJD, six subtypes have been identified by ge-
netic and molecular analysis. Among those, the VV1
type represents the rarest one.
In contrast to the classic disease type with rapid
dementia at an old age, VV1 sCJD patients are
young (typically under 50 years of age) and more
frequently men (significant, p ⫽ 0.039, one-sample
test for binominal distribution): regarding the litera-
ture and our own cases only 3 out of 16 VV1 patients
were women, which results in a men to women ratio
of four to one.
The disease duration of the VV1 cases in this
study ranged from 10 to 49 months.
In the literature, the shortest disease duration in
a VV1 patient has been reported as 10 months, the
longest as 31 months.1,8 The median disease duration
of all VV1 cases known to date is 18 months (range
10 to 49).
It is important to note that two of our VV1 pa-
tients also clearly exceed the duration of dementia
stipulated by the WHO criteria for possible and prob-
able CJD (less than 2 years) and would have to be
classified as ⬙no case⬙ if they had not undergone neu-
ropathologic examination.11 Comparably long disease
durations have only been reported for the MV2 type
(median 17 months, 10 cases), the rare MM2 type
(median 14 months, 3 cases), as well as vCJD and
genetic cases.1,17 Of interest, some of the patients
with MM2 type reported recently may show similar-
ities to the VV1 patients with respect to the cortical
pattern of MRI signal increase, no PSWCs in the
EEG, and long duration of the disease.18
As for the clinical disease course, VV1 patients
typically develop slowly progressive dementia and
behavioral disorders at the beginning of the disease.
These symptoms mostly remain the only abnormali-
ties for a long time (median 7 months), compared to
the classic CJD type, in which the cognitive decline
is usually accompanied by further neurologic symp-
toms after weeks.
This prodromal phase is followed by further CJD
symptoms such as ataxia (median 7 months), rigidity
(median 9 months), myoclonus (median 10 months),
and spasticity (median 12 months). The suspicion of
CJD is thus only raised during a later disease stage
(mostly with the onset of myoclonus).
In the literature dementia has been described as
the only leading clinical feature of VV1 types, proba-
1548 NEUROLOGY 65 November (2 of 2) 2005
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Figure 2. HMPAO-SPECT of a 44-year-
old man (Case 4) showing hypoperfu-
sion of the left brain hemisphere.
bly because of the small number of patients known
at the time.1,2 We can now report personality changes
as another characteristic found in all VV1 patients.
The main psychiatric features were aggressive be-
havior (five cases), a regression to childish behavior
(five cases), and fear (three cases).
The early onset of cognitive decline and personal-
ity changes might be due to an early affection of the
neocortex as well as the limbic system, which would
be in line with the prominent neuropathologic in-
volvement of these areas and the frequent signal
increase of the cortex and hippocampus seen on MRI.
Interestingly, only those three patients who already
displayed behavioral abnormalities at onset showed
a strong signal increase of the hippocampus region
on MRI.
As another feature of VV1 patients, focal neuro-
logic deficits were seen in five out of nine patients,
comprising hemiparesis, hemineglect, hemianopsia,
Broca aphasia, as well as one-sided apraxia. Due to
the longer overall disease duration with lesions
slowly affecting various functional systems, focal
signs may be seen more often in VV1 patients than
in MM1 CJD cases who have a relatively rapid in-
volvement of the whole brain.
The clinical diagnosis of CJD is based on EEG
(periodic sharp-wave complexes [PSWC]), CSF (find-
ing of 14-3-3 protein), and MRI (hyperintense signal
of the basal ganglia) together with a variety of clini-
cal signs. Differences as to the sensitivity of diagnos-
tic methods, depending on the underlying subtype of
sCJD, have been reported.1,19
As for VV1 patients, no useful paraclinical test—
apart from the 14-3-3 protein detection in CSF—
could be offered, so far.1 It has been recently shown
that the sensitivity of this test varies among the
sCJD subtypes.20
The eight VV1 cases examined in this study were
all positive for the 14-3-3 protein in the CSF. Consis-
tent with the literature findings (table E-3), the 14-
3-3 protein was detected in the CSF of all tested
patients but no typical EEG findings (PSWC) were
found (although EEGs were performed repeatedly
over a median time of 7 months after onset). Focal
slowing, however, seems to be a frequent finding of
VV1 patients (displayed by seven out of nine pa-
tients), and is consistent with the more focal neuro-
logic symptoms and main neuropathologic affection
of the cortex and basal ganglia.
 Signal increase on MRI was detected in all cortex
areas of our VV1 patients. In the literature, cortical
signal increase has been reported before in single
VV1 case reports. In our cases, the temporal cortex
was affected most often (seven out of seven cases),
followed by the hippocampus and insula (six out of
seven cases, each).
Signal increase of the hippocampus has not been
described as a typical finding in sCJD and has only
been reported twice.21,22 The frequent occurrence of
this abnormality in our VV1 cases suggests that it
might be a specific feature of this rare CJD subtype.
Basal ganglia signal alterations have been re-
ported as a typical MRI finding in 63% of sCJD cases
(only T2-weighted MRIs included).19 However, only
two out of seven VV1 patients displayed this abnor-
mality. In one case, these alterations were visible on
a T2-weighted image 4 months after onset. The other
patient showed only a slight signal increase of the
right caudate (in relation to the left caudate) on a
first scan 3 months after onset (T2, FLAIR) and a
more prominent one in a FLAIR-weighted follow-up
examination 3.5 months after onset. The reason for
the rare occurrence of basal ganglia signal abnormal-
ities might be that diffusion-weighted images, the
most sensitive technique, were only used in one of
our cases.23
Hyperintense basal ganglia were reported to cor-
relate with an early onset of dementia and shorter
survival time in sporadic CJD (all subtypes).19 Inter-
estingly, our two VV1 cases displaying basal ganglia
signal alterations were among those with the short-
est disease duration (10 months and 18 months),
which is in line with this observation.
As on MRI, the temporal lobes were also most
often affected on SPECT and PET.
The earliest SPECT finding in one of our patients
was a hypoperfusion of the temporal lobe 3 months
after onset. Those patients who were examined after
5 months or later showed a widespread cortical in-
volvement. However, as stated before by other au-
thors, no specific lesion pattern has been found for
CJD so far.24,25
A prolonged disease course, young age at disease
onset, frequent psychiatric symptoms, and compara-
bly slowly progressive dementia are characteristics
of both VV1 sCJD and vCJD. Differentiating these
two patient groups may be difficult as the ranges
concerning the disease age as well as the disease
duration largely overlap (table E-4). An absence of
the 14-3-3 protein in the CSF and signal increase of
the pulvinar on MRI (pulvinar sign) may shift the
diagnosis toward vCJD. In contrast, the presence of
the 14-3-3 protein and hippocampal signal increase
on MRI may speak for VV1 sCJD.
The pulvinar sign—the most specific criterion for
the diagnosis of vCJD—is clearly defined as bilateral
hyperintensity of the pulvinar of the thalamus in
relation to the anterior putamen.26 To our knowl-
edge, only one case of VV1 sCJD has been reported
presenting MRI findings according to that defini-
Downloaded from www.neurology.org at HOSPITAL DE GERONA on December 29, 2006
tion.10 Thus, to avoid false diagnoses of vCJD, special
attention should be paid to the relation between the
signal increases in the individual brain regions.
A further and simple method to rule out a diagno-
sis may be the determination of the patient’s molec-
ular type. As until today all cases of vCJD have been
reported to be methionine homozygous at the codon
129 of the prion protein gene, a genetic analysis may
be the fastest way to differentiate vCJD from the
valine homozygous VV1 sCJD.27 This is, however,
only valuable as long as no patients with vCJD of
other molecular types are reported.
Acknowledgment
The authors thank the physicians who notified suspect cases to
the German CJD Surveillance unit for providing pertinent clini-
cal, neuroradiologic, and biochemical data as well as for their help
in obtaining CSF specimens. They also thank Prof. Dr. B. Stein-
hoff for reviewing the EEGs, Monika Bodemer and Barbara
Ciesielczyk for 14-3-3 analyses, Maja Schneider-Dominco and Jol-
anthe Zellner for support in data management and editing the
manuscript, and Karola Koehler, Department of Genetic Epidemi-
ology, for help with statistics.
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Sporadic Creutzfeldt–Jakob disease: Clinical and diagnostic characteristics of the
rare VV1 type
B. Meissner, I. M. Westner, K. Kallenberg, A. Krasnianski, M. Bartl, D. Varges, C.
Bösenberg, H. A. Kretzschmar, M. Knauth, W. J. Schulz-Schaeffer and I. Zerr
Neurology 2005;65;1544-1550; originally published online Oct 12, 2005;
DOI: 10.1212/01.wnl.0000184674.32924.c9
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