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From: TSS ()
Subject: VV1 CJD, sporadic or variant or new variant another strain ?
Date: October 18, 2005 at 7:46 am PST
##################### Bovine Spongiform Encephalopathy ##################### looking further into this study, some very interesting aspects of VV1 sCJD
cases;
snip...
Discussion
Within the group of sporadic CJD patients, six subtypes have been identified
by genetic
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
literature
and our own cases only three 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 17 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 (8), (1). The median disease duration of
all VV1
cases known to date is 18 months (10 - 49).
It is important to note that two of our VV1 patients also clearly exceed the
duration of
dementia stipulated by the WHO criteria for possible and probable CJD (less
than
two years) and would have to be classified as “no case”, if they had not
undergone
neuropathological 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, three cases) as well as vCJD and genetic cases (1), (17).
Of
interest, some of the patients with MM2 type reported recently may show
similiarities
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).
NEUROLOGY/2005/095190 Meissner 12
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 abnormalities for a long time (median seven months),
compared
to the classic CJD type, in which the cognitive decline is usually
accompanied
by further neurological symptoms after weeks, already.
This prodromal phase is followed by further CJD symptoms such as ataxia
(median
seven months), rigidity (median nine 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, probably 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 behavior (five
cases), a
regression to childish behavior (five cases) and fear (three cases).
The early onset of cognitive decline and personality 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 neuropathological involvement 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 neurological 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 involvement
of the
whole brain.
NEUROLOGY/2005/095190 Meissner 13
The clinical diagnosis of CJD is based on EEG (PSWC, periodic sharp-wave
complexes),
CSF (finding of 14-3-3 protein) and MRI (hyperintense signal of the basal
ganglia) together with a variety of clinical signs. Differences as to the
sensitivity of
diagnostic 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. Consistent with the literature findings (table (E)T-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 seven
months after onset). Focal slowing, however, seems to be a frequent finding
of VV1
patients (displayed by seven out of nine patients), and is consistent with
the more
focal neurological symptoms and main neuropathological 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.
NEUROLOGY/2005/095190 Meissner 14
Basal ganglia signal alterations have been reported 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 abnormality. In one case, these
alterations were
visible on a T2-weighted image four 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 three 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 abnormalities might be that
diffusionweighted
images, the most sensitive technique, were only used in one of our cases
(23).
Hyperintense basal ganglia were reported to correlate with an early onset of
dementia
and shorter survival time in sporadic CJD (all subtypes) (19).
Interestingly, our two
VV1 cases displaying basal ganglia signal alterations were among those with
the
shortest 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 three months after onset. Those patients who were examined after five
months or later, showed a widespread cortical involvement. However, as
stated before
by other authors, 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 comparably 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)T-4). An absence of the 14-3-3 protein in the CSF and signal
increase of the
NEUROLOGY/2005/095190 Meissner 15
pulvinar on MRI (pulvinar sign) may shift the diagnosis towards 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 knowledge, only one case of VV1 sCJD has been
reported
presenting MRI findings according to that definition (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 diagnosis may be the determination
of the
patient’s molecular 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 vCJD patients of
other molecular
types are reported.
NEUROLOGY/2005/095190 Meissner 16
Acknowledgements snip...end..................TSS ----- Original Message -----
From: "Terry S. Singeltary Sr."
To:
Sent: Monday, October 17, 2005 10:14 AM
Subject: sporadic CJD: Clinical and diagnostic characteristics of the rare
VV1 type
##################### Bovine Spongiform Encephalopathy
#####################
From: TSS ()
Subject: sporadic CJD: Clinical and diagnostic characteristics of the rare
VV1 type
Date: October 17, 2005 at 7:59 am PST Published online before print October 12, 2005
(Neurology 2005, doi:10.1212/01.wnl.0000184674.32924.c9) Received February 24, 2005
Accepted August 24, 2005 Sporadic Creutzfeldt-Jakob disease: 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* 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. * To whom correspondence should be addressed. E-mail:
IngaZerr@med.uni-goettingen.de .
Abstract-- Background: Recently, six molecular subtypes of sporadic CJD
(sCJD) have been identified showing differences 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.
http://www.neurology.org/cgi/content/abstract/01.wnl.0000184674.32924.c9v1
TSS
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