Clinical Neurophysiology 117 (2006) 935–951

www.elsevier.com/locate/clinph

Invited review
EEG in Creutzfeldt–Jakob disease
Heinz Gregor Wieser a,*, Kaspar Schindler a, Dominik Zumsteg b
a
Department of Neurology, University Hospital Zürich, Zürich, Switzerland
b
Toronto Western Hospital, University of Toronto, Toronto, Ont., Canada
Accepted 5 December 2005
Available online 25 January 2006

Abstract

Electroecenphalography (EEG) is an integral part of the diagnostic process in patients with Creutzfeldt–Jakob disease (CJD). The EEG has
therefore been included in the World Health Organisation diagnostic classification criteria of CJD. In sporadic CJD (sCJD), the EEG exhibits
characteristic changes depending on the stage of the disease, ranging from nonspecific findings such as diffuse slowing and frontal rhythmic
delta activity (FIRDA) in early stages to disease-typical periodic sharp wave complexes (PSWC) in middle and late stages to areactive coma
traces or even alpha coma in preterminal EEG recordings. PSWC, either lateralized (in earlier stages) or generalized, occur in about two-
thirds of patients with sCJD, with a positive predictive value of 95%. PSWC occur in patients with methionine homozygosity and
methionine/valine heterozygosity but only rarely in patients with valine homozygosity at codon 129 of the prion protein gene. PSWC tend to
disappear during sleep and may be attenuated by sedative medication and external stimulation. Seizures are an uncommon finding, occurring
in less than 15% of patients with sCJD. In patients with iatrogenic CJD, PSWC usually present with more regional EEG findings
corresponding to the site of inoculation of the transmissible agent. In genetic CJD, PSWC in its typical form are uncommon, occurring in
about 10%. No PSWC occur in EEG recordings of patients with variant CJD.
q 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Keywords: Creutzfeldt–Jakob disease; Prion disease; Prion protein; EEG; Periodic patterns; PSWC

1. Introduction

Abbreviations: Asp, aspartic acid; Asn, asparagine; AV, anteroventral Creutzfeldt–Jakob disease (CJD) is a rapidly progressive,
nucleus of the thalamus; BSE, bovine spongiform encephalopathy; CJD, uniformly fatal, transmissible spongiform encephalopathy
Creutzfeldt–Jakob disease; CM, centromedian nucleus of the thalamus;
CSF, cerebrospinal fluid; fCJD, familial Creutzfeldt–Jakob disease; FFI,
(TSE) characterized by the accumulation of an abnormal
fatal familial insomnia; FIRDA, frontal intermittent rhythmic delta activity; isoform (PrPSc) of the host encoded cellular prion protein
gTSE, genetic transmissible spongiform encephalopathy; GSS, Gerstmann- (PrPC) in the brain (Kretzschmar et al., 1996; Masters et al.,
Sträussler-Scheinker syndrome; iCJD, iatrogenic Creutzfeldt–Jakob 1979). Human prion diseases occur in diverse phenotypes or
disease; LD, laterodorsal nucleus of the thalamus; ORF, open reading
subtypes and can be familial, sporadic, or acquired.
frame; Met, methionine; MM, methionine homozygote; MV, methionine/-
valine heterozygote; PLED, periodic lateralized epileptiform discharges; Sporadic CJD (sCJD) is the most common subtype of
PRNP, prion protein gene; PrP, prion protein; PrPC, cellular prion protein; CJD, occurring worldwide in 84% of cases with an annual
PrPSc, disease associated protease resistant prion protein; PSWC, periodic mortality rate of 1.39 per million (range 0.8–1.61; Ladogana
sharp wave complexes; PV, parvalbumine; R, reticular nucleus of the et al., 2005; nZ4441; sCJDZ3720). Genetic subtypes,
thalamus; sCJD, sporadic Creutzfeldt–Jakob disease; TSE, transmissible
spongiform encephalopathy; vCJD, variant Creutzfeldt–Jakob disease; Val, including Gerstmann-Sträussler-Scheinker syndrome (GSS)
valine; VLa, ventrolateral anterior nucleus; VLp, ventrolateral posterior and fatal familial insomnia (FFI), are less common and
nucleus; VV, valine homozygote. occur in about 10%. Iatrogenic CJD (iCJD) caused by the
* Corresponding author. Abteilung für Epileptologie & Elektroencepha- transmission of infection in the course of medical treatment
lographie, Neurologische Klinik, Universitätsspital Zürich, Frauenklinik-
strasse 26, 8091 Zürich, Switzerland. Tel.: C41 1 255 5530/31; fax: C41 1
occurs in 3–4%. Variant CJD (vCJD), which has been linked
255 4429. to transmission of the causative agent of bovine spongiform
E-mail address: hgwepi@neurol.unizh.ch (H.G. Wieser). encephalopathy (BSE) to the human population, occurs
1388-2457/$30.00 q 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.clinph.2005.12.007
936 H.G. Wieser et al. / Clinical Neurophysiology 117 (2006) 935–951

in 3% (mainly in the UK). Kuru, finally, reached epidemic [nZ4]; Collie, 2001 [review]; Shiga et al., 2004 [nZ36];
proportions in the mid-1950s in New Guinea, but apparently Urbach et al., 2001 [nZ14]), showing an overall sensitivity
disappeared within a generation after the practice of of about 60–70% and a specificity of about 80–90%
cannibalism has been eliminated (Goldfarb et al., 2004). (Tschampa et al., 2005 [nZ193]; Zeidler et al., 2001 [nZ
Early and reliable diagnosis of CJD is crucial in 52]; Zerr et al., 2000b [nZ354]). MRI may be particularly
excluding other, potentially treatable, causes of rapidly reliable and helpful in the clinical diagnosis of patients
progressive encephalopathies and in counseling relatives of with certain PrP genotypes (e.g. MV2; Zerr et al., 2000b)
patients suffering from this fatal disease. However, early and in patients with vCJD (Zeidler et al., 2000 [nZ56]).
diagnosis of CJD is complicated by the marked heterogeneity In this article, we review the characteristics and
of clinical presentation of the disease. For decades, diagnostic value of EEG findings in patients with sporadic,
electroencephalography has been the method of choice to acquired and familial CJD. Special emphasis was placed on
substantiate the clinical diagnosis of CJD. Periodic sharp the discussion of the neurophysiological concepts under-
wave complexes (PSWC) were reported to occur in EEG lying the typical EEG findings of patients with sCJD.
recordings of about two-thirds of patients with sCJD (Levy
et al., 1986 [nZ28]; Steinhoff et al., 1996 [nZ29, 68
EEGs]; Steinhoff et al., 2004 [nZ150]) and the occurrence 2. Sporadic Creutzfeldt–Jakob disease (sCJD)
of PSWC was, therefore, included in the World Health
Organisation (1998) diagnostic classification criteria of 2.1. Clinical presentation, classification and staging
sCJD. The current WHO diagnostic criteria allow diagnostic
classification as definite, probable or possible sCJD (World Sporadic CJD commonly develops in the fifth to 7th
Health Organisation, 1998). The definite diagnosis of decade of life, with a mean age of onset of 62 years (median
sporadic CJD still requires neuropathological examination 65). Mean survival times of about 8.2 months (range 1.5–58
or detection of scrapie prion protein (PrPSc) by Western blot months; Roos et al., 1973 [nZ1435]) or 5.2 months (range
analysis of brain bioptic or autoptic specimens 1–15 months; Geiger et al., 2002 [nZ22]) have been
(Kretzschmar et al., 1996; World Health Organisation, reported. About 5–10% of patients with sCJD, however,
1998). The diagnostic criteria for probable sCJD are: (1) have a clinical course that extends for 2 years or more
rapidly evolving dementia (!2 years), (2) typical PSWC (Brown et al., 1984 [nZ357]). The clinical presentation of
with triphasic morphology in EEG recordings and/or sCJD is heterogeneous. As a consequence, the differential
presence of 14-3-3 protein in cerebrospinal fluid (CSF) diagnosis of sCJD primarily depends on the predominant
examination, and (3) at least two of the following 4 clinical signs and symptoms present at early stages of the disease
signs: (a) myocloni, (b) ataxia and/or visual signs and and may include Alzheimer’s disease, Pick’s disease,
symptoms, (c) extrapyramidal and/or pyramidal signs and normal pressure hydrocephalus, Parkinson’s disease, cer-
symptoms, and (d) akinetic mutism. Patients with the ebrovascular disease, Huntington’s disease, Hashimoto’s
clinical signs of sCJD but without the EEG and CSF encephalitis, metabolic and toxic encephalopathies, and
abnormalities (either not present or investigation not many others. Two rare but well-recognized clinical
available) are classified as possible sCJD. presentations of sCJD are the so-called Heidenhain variant
In recent years, several markers of neuronal injury in the (beginning with progressive visual disturbances and
CSF have been monitored in patients with human prion eventually blindness; Heidenhain (1929) [nZ11, 3 own
disease. The most promising of these surrogate markers is cases, 8 from the literature including cases of Creutzfeldt
the 14-3-3 protein, for which a specificity of 84% and a (1920); Jakob (1921); Kirschbaum (1924)]) and the
sensitivity of 94% have been reported (Zerr et al., 1998 [nZ Brownell-Oppenheimer variant (beginning with progressive
484]; Zerr et al., 2000a [nZ805]). Consequently, the 14-3-3 cerebellar disturbances with unsteadiness and incoordina-
protein has also been included in the diagnostic criteria of tion; Brownell and Oppenheimer, 1965 [nZ10, 4 own
the WHO. Other surrogate markers such as the Tau protein, cases, 6 from the literature]). Other variants are myoclonic
neuron-specific enolase (NSE) and the astrocytic protein or diffuse cerebral, dyskinetic with or without muscular
S-100-B may also be elevated in the CSF of patients with atrophy, thalamic, and panencephalopathic forms (Mas-
CJD (Kropp et al., 1999 [nZ16]; Otto et al., 1997a [nZ53]; trianni and Roos, 2000 [review]).
Otto et al., 1997b [nZ135]), but these markers are not (yet) The clinical evolution of sCJD has been arbitrarily
included in the diagnostic criteria of the WHO. Neuroima- subdivided into 3 sequential stages (Roos et al., 1973). In
ging studies may show characteristic findings in patients Stage 1 (mean duration of 9 weeks, range 1–52), 25% of
with CJD. Recent studies revealed increased signal intensity patients experienced neurologic or psychiatric symptoms
in caudate nucleus, putamen and parietal or occipital such as dizziness or vertigo (21%), headache (17%),
cortical areas in fluid-attenuated inversion recovery depression or anxiety (10%), ‘nervousness’ (7%) and
(FLAIR) and diffusion-weighted (DW) MRI sequences autonomic disturbances including fatigue, disturbances
(Finkenstaedt et al., 1996 [nZ29]; Hirose et al., 1998 of sleep–wakefulness, and loss of appetite or nausea.
[nZ1]; Schröter et al., 2000 [nZ162]; Urbach et al., 1998 Myoclonus occurred in 6% of patients, but otherwise there
 H.G. Wieser et al. / Clinical Neurophysiology 117 (2006) 935–951 937

were only minor or ‘subtle’ neurological signs, and patients 1999 [nZ300]). Parchi et al. (1999) found that 70% of
were usually not impaired in their day-to-day activities. individuals showed the classic CJD phenotype (PrPSc type
Stage 2 (mean duration of 10 weeks, range 1–104) was 1) and at least one methionine allele at codon 129, whereas
defined by the occurrence of a distinct neurological 25% of cases displayed the ataxic and kuru-plaque variants
syndrome with a prominent involvement of higher cortical and were associated with PrPSc type 2 and valine
functions (but no dementia) and sensorimotor integration homozygosity or heterozygosity at codon 129. Valine
leading to visual disturbances (blurred vision, diplopia, homozygotes accounted for approximately 10%. Two
metamorphopsis or hallucinations) in about 25%, impair- variants, including a thalamic form of CJD and a phenotype
ment of balance in about 20% and disturbances of stance characterized by prominent dementia and cortical pathol-
and gait in about 33%. More than half of the patients showed ogy, were linked to PrPSc type 2 and methionine
clinical features that could be attributed to involvement of homozygosity. Finally, a rare phenotype characterized by
cerebellar, brain-stem or occipital cortical structures, but progressive dementia was linked to PrPSc type 1 and valine
myoclonus was still an uncommon finding during this stage. homozygosity.
The patients were clearly impaired in daily activities. In
stage 3 (mean duration of 14 weeks, range 1–116), moderate 2.3. Typical EEG findings in sCJD
to severe myoclonus and dementia were typical findings.
There was a significant positive correlation between the Periodic sharp wave complexes (PSWC) are the
duration of stage 1 and the duration of stages 2 and 3 hallmark EEG finding in patients with sCJD (Furlan
combined. Bernoulli found a significant negative correlation et al., 1981 [nZ1]; Hess et al., 2002 [text book article];
between the duration of stage 1 and the age of the individual Jones and Nevin, 1954 [nZ2]; Levy et al., 1986 [nZ28];
(Bernoulli et al., unpublished data). More recently, the Steinhoff et al., 1996 [nZ29, 68 EEGs]). Morphologically,
Japanese Slow Virus Infection Research Committee (1999; typical PSWC consist of either simple sharp waves
see also Shiga et al., 2001) suggested a subdivision into 5 (including biphasic and triphasic waves) or complexes
clinical stages, with stage 4 representing late stage with mixed spikes, polyspikes and slower waves with a
disease characterized by reduced movement, and stage 5 typical duration of 100–600 ms, recurring every 0.5–2 s
representing terminal stage characterized by complete (Gloor, 1980). The intervening background usually consists
akinetic mutism. of generalized low voltage slowing. Fig. 1 shows an
example of typical PSWC in an EEG recording of a patient
with advanced sCJD (stage 3).
2.2. Molecular classification There is no satisfactory model to explain the periodicity
of the pattern. It is important to note that PSWC are
Recent understanding of molecular mechanisms of sCJD generally not related to myoclonic jerks. Traub and Pedley
has led to a more rational classification. Most importantly, (1981) suggested that bihemispherically synchronized
the PrP genotype underlying sCJD may have a major discharges such as PSWC do not necessarily imply pacing
influence on the course of the disease. In the Caucasian from deep midline structures but might be synchronized by
population, codon 129 of the prion protein gene (PRNP; way of the corpus callosum. They further speculated that
located on the short arm of chromosome 20) has been shown fusion of dendritic membranes of affected neurons could
to be the site of a common methionine (M)/ valine (V) result in increased electrotonic coupling and pathologically
polymorphism: 52% of individuals are M homozygous synchronized bursting activity.
(MM), 36% are heterozygous (MV) and 12% are V Topographically, PSWC commonly reveal a bilateral
homozygous (VV) (Palmer et al., 1991 [nZ22, plus nZ voltage distribution with a fronto-precentral midline
23 with suspected sCJD]). Considering that 74% of patients maximum. A regional voltage maximum over occipital
with sCJD in Europe are methionine homozygotes at codon areas has been shown in a patient with the Heidenhain
129, this genotype has been denoted as a predisposing factor variant of sCJD (Furlan et al., 1981 [nZ1]), but this is a rare
for sCJD in the Caucasian population. In Japanese finding. More commonly, PSWC may occur lateralized or
populations, a site of a common polymorphism has been even reveal a strictly unilateral voltage distribution (Au
located at codons 219 (Shibuya et al., 1998 [nZ85, 20 with et al., 1980 [nZ3]; Heye and Cervos-Navarro, 1992
definite, 65 with probable sCJD]) and 232 (substitution from [nZ13]; Heye et al., 1990 [nZ1]; Neufeld and Korczyn,
methionine to arginine; Hoque et al., 1996 [nZ3]). In 1992 [nZ4]). Hence, lateralized PSWC may resemble
addition to the PrP genotype, the clinical presentation of periodic lateralized epileptiform discharges (PLED). Fig. 2
sCJD may also be associated with PrPSc types, which are shows an example of PLED-like PSWC in an EEG
responsible for encoding prion strain diversity (Gambetti et al., recording of a patient with early stage of sCJD (stage 2).
2003 [review]; Tschampa et al., 2002 [nZ21]). Based on the It has been suggested that the occurrence of lateralized
genotype at codon 129, the size of protease resistant PrPSc PSWC (or PLED) in sCJD may reflect an early state of
fragments and disease phenotype, sCJD has been subdivided disease, when the commissural progress has not yet led to
into several subtypes (Hill et al., 2003 [nZ119]; Parchi et al., diffuse cortical disease (Heye and Cervos-Navarro, 1992
938 H.G. Wieser et al. / Clinical Neurophysiology 117 (2006) 935–951

Fig. 1. (A) EEG recording of a 83-year-old woman with stage 3 sCJD 2 weeks before death showing typical generalized periodic triphasic sharp wave (PSWC)
complexes occurring at a rate of approximately 1/s. The PSWC were unreactive to acoustical stimulation. (B) Serial surface voltage mapping of a typical sharp
wave (yellow line) showing a dipole configuration with a frontal–precentral negativity during the large upward deflection of the sharp wave complex evolving
to a shallower bifrontal–precentral slightly asymmetrical positivity during the third phase of the complex.

[nZ13]; Primavera et al., 1984 [nZ12]; Steinhoff et al., of various etiologies do not necessarily imply a common
2004 [nZ150]). Chiofalo et al. (1980) found asymmetric neurophysiological basis of these two periodic EEG
EEG abnormalities in 23 of 27 patients with sCJD, mainly in patterns. In fact, there are some fundamental differences
the prodromal stage of the disease, and stated that “some between sCJD-associated lateralized PSWC and classical
cases showed asymmetric records throughout the entire PLED. Unlike sCJD-associated PSWC, PLED usually
course of the disease” (but did neither mention of whether denote a transient EEG phenomenon, which typically
these asymmetries referred to PSWC or to background EEG decrease in amplitude and repetition rate during the course
abnormalities nor did they specify the time of the last of the disease and usually disappear within 2 weeks of the
EEG recording). However, most studies reporting on serial acute lesion (Westmoreland et al., 1986 [nZ6]). Further-
EEG recordings in patients with sCJD have shown that more, PLED but not sCJD-associated PSWC are frequently
lateralized PSWC consistently evolve into sCJD-typical associated with epileptic seizures (Snodgrass et al., 1989
bilateral PSWC during the course of the disease (Au et al., [nZ147]). Finally, PLED are usually not influenced by
1980 [nZ3]; Steinhoff et al., 2004 [nZ150]; Wieser et al., manipulation and sleep, whereas PSWC in sCJD may
2004 [nZ6]). Moreover, the morphological similarities of commonly be influenced by external stimulation. PSWC
lateralized or regional PSWC in sCJD and classical PLED may also be attenuated by sedative medication, in particular
associated with acute unilateral cerebral processes with benzodiazepines including midazolam and diazepam

Fig. 2. (A) Lateralized PSWC in a 73-year-old man with stage 2 sCJD. (B) Surface voltage mapping showing a dipole configuration with maximal negativity
over the left fronto-temporal region.
 H.G. Wieser et al. / Clinical Neurophysiology 117 (2006) 935–951 939

Fig. 3. EEG recording of a 67-year-old patient with early stage CJD presenting with intermittent unresponsiveness. These absence-like attacks of
unresponsiveness lasted for 1–2 min and occurred with a frequency of about 5 per hour. An intermittent nonconvulsive status epilepticus was clinically
suspected. The epileptiform EEG activity, characterized by rhythmical bifronto-temporal and right fronto-central sharp and slow waves, promptly resolved
following intravenously applied benzodiazepines (arrow) and the patient regained consciousness.

(Elliott et al., 1974 [nZ3, 1 with methylphenidate and The disappearance of PSWC during sleep is of particular
diazepam]; Rossini et al., 1979 [nZ1]; Wieser et al., 2004 interest in light of the very similar scalp voltage
[nZ6, 1 with diazepam]; Fig. 3). topographies of PSWC and physiological sleep potentials
PSWC in patients with sCJD, on the other hand, are most including vertex-waves, sleep spindles and K complexes.
prominent during wakefulness and tend to disappear during The generation of both PSWC and physiologic sleep
sleep. Terzano et al. (1995) demonstrated three types of patterns have been related to thalamo-cortical loops,
EEG findings in serial polygraphic night sleep studies although, with respect to PSWC in sCJD, convincing
performed during the last 3 months of life in a 68-year-old studies on the role of thalamic nuclei in the generation of
sCJD patient: (a) sustained sequences of PSWC, (b) runs of these complexes are lacking.
pseudoperiodic discharges cyclically replaced at about Previous studies investigating PSWC in patients with
1-min intervals with semi-rhythmic theta-delta activity sCJD with the use of simultaneous depth and scalp EEG
and (c) less rhythmic NREM sleep-like patterns with recordings have demonstrated PSWC recorded from basal
0.5–4-Hz activity. PSWC were associated with a high ganglia structures that were only inconsistently detected on
level of vigilance or a state of alert-appearing silent simultaneous scalp EEG recordings (Chiofalo et al., 1980
immobility. Mamdani et al. (1983) reported a patient with [nZ27, 1 with depth EEG]; Rayport, 1963 [nZ2]). Rayport
CJD in whom periods of apnea during sleep were associated (1963) recorded PSWC from the pial surface of the right
with abrupt cessation of PSWC and replaced by 7–9 Hz frontal lobe and from the globus pallidus. The former were
waves persisting throughout the apnoic episode. Teszner markedly attenuated in their amplitude after neuronal
and Foucher (1978 [nZ1]) described similar findings and isolation. Depth electrode recordings from the white matter
suggested a common triggering mechanisms for the close revealed PSWC of ‘simpler’ configuration and lower
temporal correlation between variations in vigilance, amplitude. Chiofalo et al. (1980) reported on serial
respiration, periodic EEG activity and myoclonic activity. simultaneous scalp EEG and depth electrode recordings
Donnet et al. (1992) reported disorganized sleep patterns in from the right caudate nucleus and the ‘external hypothala-
a polysomnographical study of 3 patients suffering from mus’ in a patient with late stage sCJD. Twenty-one days
early stages of sCJD. The sleep patterns were characterized before death, they found ‘no difference between deep and
by sudden transitions from one sleep stage to the next, very superficial activity’, with similar periodic complexes
few sleep spindles and K complexes in stage 2, absence of appearing in both tracings during myoclonus. One week
stage 4 sleep and a lower percentage of REM sleep with before death, there was a diffuse flattening of the scalp EEG
fewer rapid eye movements. The awake EEG of these traces, despite persistence of periodic activity in depth
patients showed characteristic PSWC or a slow electrogenesis recordings, in particular during intense acoustic stimulation.
of low amplitude suggesting diffuse cerebral pathology. Four days before death, the flattening of the scalp EEG was
940 H.G. Wieser et al. / Clinical Neurophysiology 117 (2006) 935–951

complete, but occasional periodic complexes could still be 2.4. Nonspecific EEG findings in sCJD
seen in deeper structures, both occurring spontaneously and
during painful stimulation. It is important to recall that typical periodic EEG
These findings are in good accordance with a recent activity may be lacking in patients with sCJD, in particular
study reporting on the correlation between PSWC and in early stages, and less common also in terminal stages of
immunoreactivity for the calcium-binding protein parval- the disease. In early stages of sCJD, EEG recordings may
bumine in thalamic nuclei of patients with sCJD (Tschampa be characterized by nonspecific EEG patterns such as
et al., 2002 [nZ21, 5 controls]). The authors found a loss of diffuse slowing of background activity, intermingled focal
parvalbumine positive (PVC) cells in most thalamic nuclei, slow activity (in the theta or delta range) or FIRDA-like
including the reticular (R), ventrolateral (VLa and VLp), EEG patterns (Hansen et al., 1998 [nZ7]; Wieser et al.,
laterodorsal (LD) and anteroventral (AV) nucleus. Interest- 2004 [nZ6]). FIRDA may be of particular interest
ingly, the centromedian nucleus (CM) was the only thalamic (Fig. 4). The term FIRDA denotes bursts of generalized
region with an increase of PVC cells. With respect to monomorphic delta activity with a mean frequency of
PSWC, the most marked differences were found for the AV, about 2.5 Hz, having a notched or sinusoidal appearance.
the R and the CM, with a significant increase of PVC cells Occasionally, FIRDA may be asymmetric and the bursts
may be nonrhythmic or may include theta activity (Schaul
in the former and nonsignificant decreases in the latter two
et al., 1981). The ascending phase of the delta waves is
nuclei for patients with PSWC (the decrease in the R was
typically more rapid than the descending phase (Hess,
only significant for patients who had both PSWC and
1975; Van der Drift and Magnus, 1961). Whereas FIRDA
myoclonus). Based on the generally accepted concept that
is a clearly abnormal finding indicating primary cerebral
the R plays a key role in the generation and maintenance of
dysfunction, it is definitely not specific for any single
thalamic, cortical or thalamocortical spindle rhythms or
etiology and may occur in response to a variety of diffuse
synchrony (Avanzini et al., 1993; Fuentealba and Steriade, or focal intracranial diseases, such as neoplasms, epilepsy,
2005; Huntsman et al., 1999; Steriade et al., 1993), the toxic or metabolic encephalopathy, and cerebrovascular
authors hypothesized that the predominant reduction of disease. Such nonspecific EEG findings in patients with
PVC cells in the R may determine the generation of PSWC sCJD, in particular the occurrence of FIRDA and
(associated with myoclonus) in patients with sCJD. The intermittent localized and lateralized delta rhythms in
authors further suggest that the functional integrity (at least early stages of the disease, should always be regarded as
in parts) of the subcortico-cortical or thalamo-cortical compatible with the diagnosis of sCJD and encourage
network is a prerequisite for the generation of PSWC. further EEG studies for the demonstration of PSWC in a
Ferrer et al. (1993 [nZ3]) also found massive parvalbumin more advanced stage of the disease (Schlenska and Walter,
immunoreactivity abnormalities in cortical neurons. 1989 [nZ3]).

Fig. 4. EEG recording of a 73-year-old man with histologically proven sCJD (14-3-3 positive; methionine homozygote at codon 129, no mutation) showing
FIRDA-like activity 23 days before death. PSWC were documented 30–16 days before death.
 H.G. Wieser et al. / Clinical Neurophysiology 117 (2006) 935–951 941

In later stages of sCJD, the intensity of the periodic EEG (Elliott et al., 1974 [nZ3]; Hansen et al., 1998 [nZ7];
patterns may gradually decrease. In a longitudinal EEG Wieser et al., 2004 [nZ6]). Therefore, EEG response to
study comprising 34 EEG recordings during a 14 months AEDs alone, in particular to administration of benzo-
period in a patient with autopsy confirmed sCJD, Schäffler diazepines, is definitely not sufficient to conclude that the
et al. (1983) found maximal PSWC occurring at about week periodic discharges represent the electroencephalographic
15 after onset of the prodromal stage of the disease. From correlate of seizures. The effects of drugs such as
the 5th month onwards, the intensity of the periodic EEG benzodiazepines on the EEG should always be correlated
pattern gradually decreased. In the time-span from the 10th to the consequences for mental status: the EEG changes
to the 13th month, they found considerable fluctuations of should be accompanied by a significant clinical improve-
periodic activity, ranging from pronounced typical PSWC to ment (Fountain and Waldman, 2001 [nZ10]). Furthermore,
complete disappearance of periodic activity. Morphologi- epileptic discharges are usually time-locked with clinical
cally, the PSWC showed a progressive ‘simplification’ of motor signs whereas typical sCJD related myocloni are not
the complexes during this time, characterized by a broad- and may occur before, during and after the PSWC (Burger
ening of the sharp wave complexes and a slight increase of et al., 1972 [nZ8]; Lee and Blair, 1973 [nZ3]).
the interval duration. The authors discussed a variable
driving by the hypothetical subcortical pacemaker as well as 2.6. Diagnostic yield of EEG findings in sCJD
a decreased capability of cerebral cortex to react to
subcortical stimuli as possible causes for these fluctuations. The diagnostic value of early EEG findings including
Clinically, these EEG changes were associated with a slowing of background activity, focal or diffuse slow
disappearance of perioral reflexes, deep tendon reflexes, activity and FIRDA is limited. As mentioned above, such
oral automatisms and myoclonus. No PSWC were found EEG findings are compatible, or at best suggestible, but by
after month 14, and the last EEG recording performed no means specific for sCJD. The diagnostic usefulness of
3 days before death revealed isoelectric periods, which PSWC, on the other hand, is generally accepted and has
alternated with episodes of delta waves or sharp slow wave been demonstrated in numerous studies. Steinhoff et al.
complexes. Areactive coma tracings with predominantly (2004 [nZ150, 56 controls]) found positive criteria
slow waves, low-voltage activity or, rarely, an alpha coma (Table 1) in the EEG recordings of 96 of 150 (64%)
pattern are a common finding in preterminal EEG patients with autopsy confirmed CJD, and falsely positive
recordings (Lee and Blair, 1973 [nZ3]; Aguglia et al., criteria in only 5 of 56 (9%) of patients with dementia of
1997 [nZ2]; Asai et al., 2001 [nZ1]). other etiology (4 with Alzheimer’s disease and one with
vascular dementia). These figures correspond to a high
2.5. Epileptiform and seizure activity in sCJD specificity of 91% and a high positive predictive value
(PPV) of 95%, and improved the PPV of clinical symptoms
Focal motor or generalized seizures have been reported by no less than 19% to a value of 99%.
to occur in 15% of patients with sCJD, typically occurring Zerr et al. (2000a) reported on a specificity of 74% and a
late in the disease (Johnson and Gibbs, 1998 [review]; Roos PPV of 93% for PSWC in a study including 805 patients
et al., 1973 [nZ1435]) to 21% (Cokgor et al., 1999 with probable or possible CJD (the PPV for detection of the
[nZ21]). Seizures as the presenting symptom of sCJD, 14-3-3 protein in CSF was 97%, and 99% for the
however, are an uncommon finding, occurring in only about combination of both tests). Hence, PSWC only rarely
3% of cases (Aronyk et al., 1984 [nZ1]). Rarely, EEG and occur in patients with rapidly progressive dementia of other
clinical findings may suggest partial status epilepticus (SE) etiology (e.g. Alzheimer’s disease, vascular dementia and
including epilepsia partialis continua (Lee et al., 2000 Lewy body disease; Tschampa et al., 2001 [nZ25 with
[nZ1]; Parry et al., 2001 [nZ1]), complex partial SE (Rees definite CJD, nZ56 with probable sCJD; nZ19 with
et al., 1999 [nZ2]), nonconvulsive SE (Schwinn et al., 2001 Alzheimer’s disease, and nZ12 with dementia with Lewy
[nZ1]; Cohen et al., 2004 [nZ1]; Fernandez-Torre et al., bodies]; Steinhoff et al., 2004 [nZ150, 56 controls]).
2004 [nZ1]; Shapiro et al., 2004 [nZ1]) or generalized SE Although these studies unequivocally indicate the high
(Cokgor et al., 1999 [nZ21]). Fig. 5 shows the EEG diagnostic value of PSWC in patients with suspected CJD, it
recordings in a patient with sCJD referred to our hospital has to be mentioned that these studies usually included
with the diagnosis of nonconvulsive frontal SE. patients with CJD typical presentation only. Triphasic
Seizure-like EEG activity in patients with sCJD, in waves resembling PSWC, however, may frequently occur
particular EEG findings suggesting nonconvulsive SE, must in other neurological or systemic diseases including
be carefully distinguished from PSWC. At least some cases metabolic (mostly hepatic) encephalopathy (Karnaze and
of the above-mentioned studies might indeed have revealed Bickford, 1984 [nZ50]), anoxic encephalopathy (usually
typical PSWC rather than the EEG correlate of clinical associated with fatal outcome; Kuroiwa et al., 1982 [nZ1];
seizures (as noted in the study of Fernandez-Torre et al., Scollo-Lavizzari and Bassetti, 1987 [nZ26]) and toxic
2004 [nZ1]). PSWC of sCJD are well known to be encephalopathy (in particular baclofen, lithium and the
attenuated or even abolished by antiepileptic drugs (AEDs) antidepressant mianserin; Hormes et al., 1988 [nZ1]; Smith
942 H.G. Wieser et al. / Clinical Neurophysiology 117 (2006) 935–951

Fig. 5. Serial scalp EEG recordings of a 54-year-old woman with histologically proven CJD (14-3-3 positive; methionine homozygote at codon 129, no
mutation; history of a resection of a pituitary adenoma via right frontal craniotomy and lyodural graft at age 32) in relation to treatment and clinical state
showing marked asymmetrical EEG findings and dynamic changes of the EEG pattern (K33 to K15 days before death). Presentation at day K33 with
headache, ataxia, neuropsychological deficits and hallucinations; treatment with various drugs including clobazam 15 mg/d, Levothyroxin (Eltroxinw),
Cortison, Estradiol-Norethisteron (Kliogestw), Felodipin (Plendilw), Omeprazolum (Antraw), Aciclovirum (Zoviraxw) and Ceftriaxon (Rocephinw). At day
K27 the somnolent patient was referred to ICU, showing a slowing of PSWC to 0.8–1/s with right frontal predominance under treatment with carbamazepin
800 mg/d, valproic acid 2000 mg/d and midazolam 3 mg/h i.v. After increasing midazolam to 7–15 mg/h i.v. (days K24 and K23), the patient became
comatose and the EEG exhibited predominant subdelta activity with a slow periodicity of 0.5/s and additional sharp transients. A flattening of the EEG trace
with slow periodicity of about 0.4/s was seen after midazolam has been reduced to 6 mg/h i.v. (days K22 to K20). Prototypical PSWC of about 1/s reappeared
after cessation of midazolam (days K17 to K15; patient comatose; carbamazepin 800 mg and valproic acid 2000 mg).

and Kocen, 1988 [nZ2]; Koponen et al., 1990–91 [nZ2]). that disease processes leading to vast destruction of the
Lateralized or unilateral PSWC (PLED per definition) are white matter rather than the cortex might be predominantly
often seen in acute unilateral cerebral lesions such as associated with periodic EEG patterns with longer intervals
infarction (embolic more so than thrombotic), encephalitis (Cobb and Hill, 1950; Markand and Panszi, 1975;
(in particular herpes simplex encephalitis), and neoplasm Radermecker and Poser, 1960). Long-interval PSWC may
(more often in malignant ones) or abscess (Westmoreland also occur in patients with phencyclidine (angel dust) or
et al., 1986 [nZ6]). PSWC with longer interval duration (up ketamine intoxication (Fariello and Black, 1978 [nZ1]).
to 30 s), which were initially described in children with Furthermore, nonconvulsive generalized status epilepticus
subacute sclerosing panencephalitis (SSPE; Radermecker, and burst-suppression patterns due to anoxia or barbiturate
1949 [nZ3]), are far less common. It has been suggested, intoxication can result in a similar, PSWC-like EEG pattern
 H.G. Wieser et al. / Clinical Neurophysiology 117 (2006) 935–951 943

Table 1 of PSWC in a study investigating 7 CJD patients with serial

Objective Diagnostic Criteria of PSWC typical for sCJD (Steinhoff et al., EEG recordings during the course of the disease. At the
1996)
onset of PSWC in the EEG recordings (mean 8.7 weeks
Strictly periodic cerebral potentials, the majority with a duration between after onset of disease), 5 of 7 patients (71%) had already
100 and 600 ms and an intercomplex interval between 500 and 2000 ms progressed to stage 3, showing akinetic mutism and CJD-
Generalized and lateralized complexes accepted
typical-movement disorder such as myoclonia, exaggerated
At least 5 repetitive intervals with a duration difference of less than 500 ms
to rule out semiperiodic activity startle reaction or focal dyskinesia. Less commonly, PSWC
may also be missed if the EEG recording is performed too
late in the course of the disease, when PSWC are no longer
(Kuroiwa and Celesia, 1980 [nZ62]; see Fig. 5). Such present and replaced by prefinal EEG findings in at least
conditions, however, usually present with other symptoms some of the patients with sCJD. In the study of Steinhoff
and history than sCJD, and may thus be easily distinguished et al. (2004 [nZ150]), the latest typical EEG was recorded
on clinical grounds. 2.3 months (mean, range day of death to 17.1 months).
The sensitivity and negative predictive value (NPV) of
PSWC in sCJD, in contrast, may be substantially lower.
Steinhoff et al. (2004 [nZ150, 56 controls]) found a 3. Iatrogenic Creutzfeldt–Jakob disease (iCJD)
sensitivity of 64% and a NPV of 49% in their cohort. Zerr
et al. (2000b [nZ354]) established a sensitivity of 66%. 3.1. Clinical presentation and incubation period
Several factors may account for these moderate values.
Most importantly, it has been shown that not all patients Human-to-human transmission of CJD was reported for
with sCJD develop PSWC during the course of the disease. the first time in 1974 in a 55-year-old woman who
With respect to the PrP genotype at codon 129, Zerr et al. developed iCJD 18 months after a corneal transplantation
(2000b [nZ354]) found PSWC predominantly in the EEG (Duffy et al., 1974). Bernoulli et al. (1977) subsequently
recordings of patients with MM1 and MV1 genotypes, but reported on transmission of CJD by EEG depth electrodes in
not in those of valine-homozygous patients. The lack of two young patients (the contaminated electrodes were
PSWC in the EEG recordings of 12 patients with a codon reused after sterilization in formaldehyde and alcohol after
129-valine homozygote genotype was also reported by the cortical recordings in the sCJD patient). Iatrogenic
National CJD Surveillance Unit in Edinburgh (Kovacs et al., transmission of CJD by neurosurgical instruments insuffi-
2000). Hill et al. (2003) reported on PSWC in the EEG ciently decontaminated by routine sterilization methods was
recordings of 5 of 8 MM1 patients, 14 of 18 MM2, 2 of 4 identified in 6 cases by Will and Matthews (1982 [nZ3,
MV2, 1 of 5 MV3, but in none of 4 patients with the VV2 plus 1 of Jones and Nevin (1954) and 2 of Nevin et al.
subtype. Hence, PSWC seem to be limited to M (1960)]). Hundred and fourteen cases of putative CJD
homozygous (MM1 or MM2) and MV heterozygous transmission caused by cadaveric lyophilized dura trans-
(MV1, MV2, and MV3) patients, whereas valine homo- plants from CJD patients were reported by Brown et al.
zygous patients typically do not show PSWC (Table 3). The (2000). Treatment with cadaveric pituitary-derived growth
reason for this finding is not known. Interestingly, Kovacs hormone has resulted in transmission to at least 139 young
et al. (2000) also reported on the involvement of people (Brown et al., 2000). Overall, at least 267 cases of
hippocampal structures in their PSWC-negative valine iCJD have been reported up to the end of year 2000 (Brown
homozygote subgroup. Taking into consideration that the et al., 2000).
hippocampal structures are only rarely involved in patients The incubation period of iCJD may depend on the mode
with sCJD, this finding might be helpful in distinguishing of transmission. The shortest incubation periods were found
valine homozygous patients from patients with other in iCJD caused by contaminated EEG depth electrodes or
genotypes with the help of MR imaging. neurosurgical instruments, ranging from 16.6 to 28 months
Another explanation for the moderate sensitivity of (Bernoulli et al., 1977 [nZ2]; Will and Matthews, 1982
PSWC in sCJD might be the timing of the EEG recording in [nZ6]). In iCJD associated with dural grafts and growth
relation to the disease stage. As mentioned above, the hormone therapy, incubation periods up to 20 years (mean
occurrence of PSWC corresponds to the amount of neuronal 6–9 years, rarely up to 30 years) have been reported (Brown
cell loss (Bortone et al., 1994 [nZ15]), the ‘classical’ et al., 2000 [nZ267]; Croes et al., 2001 [nZ2]; Fushimi et
bilateral diffuse PSWC usually marking the middle and late al., 2002 [nZ1]; Kretzschmar et al., 2003 [nZ1]).
stage of sCJD. Hence, the characteristic PSWC may be Interestingly, iCJD often presents with cerebellar signs,
missed if the EEG is performed too early in the course of the whereas sCJD more commonly begins with mental
disease. Steinhoff et al. (2004) assessed a total number of deterioration. Moreover, the PrP genotype may also
443 EEG recordings in 150 patients with CJD and found influence the occurrence of iCJD: homozygosity for Met
typical PSWC after a mean latency of 3.7 months (range or Val at the polymorphic codon 129 of the PRNP has been
0.2–19.2) after onset of disease. Hansen et al. (1998) found to represent a risk factor for iCJD, as for sCJD
reported on a mean survival time of 8 weeks after onset (Blättler, 2002 [review]). In hormone cases, homozygosity
944 H.G. Wieser et al. / Clinical Neurophysiology 117 (2006) 935–951

may also promote shorter incubation periods (Huillard localized infection and with serial EEG recordings during
d’Aignaux et al., 1999 [nZ55 out of 1361]). the incubation period (from the time of infection to death)
offered a unique opportunity to correlate the EEG changes
with the clinical signs and symptoms. The first clinical
3.2. Typical EEG findings
symptoms were observed after 16.6 (patient 1) and 19.8
The EEG findings in patients with iCJD are similar to months (patient 2), and the patients died 23.7 and 41.7
those in patients with sCJD. PSWC with a lateralized or months after infection. Concerning the question of
bilateral voltage distribution as well as nonspecific EEG ‘infectiosity’ of the contaminated depth electrode it is
patterns such as localized or generalized slowing and interesting to note that patient 1 had received the prion-
FIRDA have been reported. However, the localized contaminated depth electrode prior to patient 2. The serial
inoculation of the transmissible agent of CJD (the PrPSc) EEG recordings revealed a progressive alteration of the
may lead to more restricted EEG findings, at least in early EEG evolving from (1) focal progressive slowing at the
stages. Fushimi et al. (2002) reported on lateralized PSWC location of the infected electrode (11 and 18 months), to (2)
corresponding with the location of the dural graft, which to FIRDA-like trains of periodic frontal delta (17 and 19
later evolved into CJD-typical symmetrical PSWC in a months; still with a regional predominance at the site of the
patient who developed iCJD 14 years after surgery. We implantation of the contaminated electrode) to marked
observed typical PSWC in a patient who received a lyodura FIRDA (17.5 and 20 months), to (3) intermingled sharper
graft of unknown brand 22 years before disease onset (see slow theta activity (18 and 20.5 months), to (4) PSWC, first
Fig. 5; this patient, however, may also have suffered from intermingled, then stereotyped (patient 2: 22.4 months), and
sCJD rather than iCJD). Kretzschmar et al. (2003) described finally leading into (5) dispersion of PSWC with progressive
generalized slowing but no PSWC in a patient with a dura decrement of the EEG amplitude. Hence, EEG findings in
mater graft following surgery for angioblastoma of the iCJD might exist along a continuum of EEG changes,
cerebellum 20 years prior to death. ranging from localized slowing at the site of infection to the
We have previously reported on the two patients with most typical PSWC. This unfortunate transmission of CJD
iCJD due to the contaminated depth electrode (Bernoulli in two patients also gave us the opportunity to explore the
et al., 1977; Wieser et al., 2004). These patients with role of thalamo-cortical interaction in the index patient

Fig. 6. Depth electrode recording of a 69-year-old woman with histologically proven CJD (index patient for the two iCJD patients who received the prion
contaminated depth electrodes). The recording was performed during cortical biopsy and stereotactic electrocoagulation in the ventrolateral thalamus for
treatment of violent myoclonus. Depth electrode recordings from the electrodes 1 and 2 (contact 1 denotes the deepest contact) showing typical generalized
PSWC (A), also depicted with a better time resolution in (B) and (C). Note the phase reversal of the thalamic deflection (C, upper traces) and its delay with
respect to the cortical discharge (C, lower traces). Intraoperative radiography showing the position of the depth electrodes (D). Modified from Wieser et al.
(2004).
 H.G. Wieser et al. / Clinical Neurophysiology 117 (2006) 935–951 945

(Wieser et al., 2004; see Fig. 6). Local-fields attributable to and dementia is seen in terminal stages only. FFI is
the PSWC were recorded both from the frontal cortex and characterized by progressive and autonomic dysfunction,
the ventrolateral thalamus, with the discharges recorded ataxia, dementia, and myoclonus. Lugaresi et al. (1998
from the frontal cortex generally showing higher amplitudes [review]) have reported on a relationship between selective
and preceding the thalamic complexes by about 4 ms (note atrophy of the anteroventral and mediodorsal limbic
that the thalamic complexes did not show the initial spike; thalamic nuclei and hypovigilance, attention deficit,
unfortunately, phase- and coherence analysis was not inability to generate EEG sleep patterns, sympathetic
carried out at the time of examination, and the available hyperactivity and attenuation of vegetative and hormonal
paper recordings do not allow for such analysis post-hoc circadian oscillations. Taratuto et al. (2002 [nZ1]) reported
either). In the case of Fushimi et al. (2002), a 61-year-old on insomnia associated with thalamic involvement in
man who received a cadaveric dura mater graft and E200K 129M haplotype CJD.
developed CJD 14 years later, right lateralized PSWC
coinciding with the location of the dural graft were observed 4.2. EEG findings
(lateralized PSWC were seen 14 days after admission and
generalized PSWC 1.5 months later). ‘Classical’ periodic sharp wave complexes, with or
without triphasic morphology, occur in about 10% of
patients with genetic CJD (Kovacs et al., 2002 [nZ365,
4. Genetic Creutzfeldt–Jakob disease review]; Kovacs et al., 2005 [nZ455, with genetic
transmissible spongiform encephalopathies (gTSE), EEG
4.1. Molecular findings and clinical presentation available in 82%]. Moreover, a ‘CJD-typical EEG’ was
more frequent in fCJD than in FFI and GSS (only 2 of 26
Genetic CJD cases are associated with point mutations or patients with GGS revealed PSWC in the study of Kovacs
insertions (rarely deletions and silent or influential et al., 2005). No PSWC were found in fCJD patients
polymorphisms) within the open reading frame (ORF) of bearing codon 178, 200 or 210 mutations and in 4 members
the PRNP (the entire ORF resides within a single exon of a kindred with CJD in whom myclonus did not develop
which encodes for a sequence of 253 amino acids; Basler (Tietjen and Drury, 1990). Neufeld et al. (2003) reported
et al., 1986). More than 20 mutations have currently been on a patient with a codon E200K mutation in the PRNP
described, the most common being an amino acid gene presenting with status epilepticus (focal motor
substitution at codon 200. By definition, familial CJD seizures with frequent generalization). Seizures are
(fCJD) is diagnosed when a progressive neuropsychiatric reported in a few cases of P102L (Hainfellner et al.,
disorder is encountered in combination with a pathogenic 1995 [nZ221 (9 generations)]), A117V (Nochlin et al.,
PRNP mutation (Budka et al., 1995). Mutations within ORF 1989 [nZ24 (5 generations), 2 with seizures]), D178N-
are also responsible for two rare autosomal inherited 129M (McLean et al., 1997 [nZ6, 2 with seizures]; Julien
diseases, the Gerstmann-Sträussler-Scheinker syndrome et al., 1998 [nZ4, 2 families]), E200K (Seno et al., 2000
(GSS, several point mutations) and fatal familiar insomnia [nZ4, 1 with seizures]), 120 BPI (Cochran et al., 1996
(FFI; single point mutation at codon 178, Asp to Asn). It is [nZ10]), 144 BPI (Collinge et al., 1992 [nZ174]; Poulter
the codon 129 genotype that determines whether the patient et al., 1992 [same pedigree as in Collinge et al., 1992;
segregates with FFI (patients with M at the same allele at the nZ16 with the 144 base pair insertion within the PRNP
polymorphic codon 129) or familial CJD (fCJD, patients ORF]; Oda et al., 1995 [nZ6, one with attacks of
with V at the same allele). unconsciousness after ‘apoplectic episode’, one with
Phenotypically, genetic CJD cases are usually classified generalized seizures; and review]; Capellari et al., 1997
on neuropathological grounds: fCJD are characterized by [nZ3]), and 192 BPI (Goldfarb et al., 1991 [nZ9, 1 with
the classical neuropathological triad of spongiform change, seizures]).
neuronal loss and gliosis, GSS reveal multicentric amyloid
plaques in the brain, and FFI show predominant thalamic
pathology (Kovacs et al., 2002 [nZ365, review]; Lugaresi 5. Variant Creutzfeldt–Jakob disease (vCJD)
et al., 1998 [review]). The clinical presentation of fCJD
overlaps between mutations and may resemble patients with 5.1. Clinical presentation, classification and staging
sCJD. Nevertheless, some genotypes of fCJD may reveal
characteristic clinical and neuropathological features. In 1996, Will et al. published the first 10 cases with
Patient with base pair insertion mutations, for example, vCJD. These patients had no family history of CJD, were
have been shown to exhibit a significant earlier disease unusually young and presented with atypical clinical
onset and longer disease duration than other fCJD cases features comprising psychiatric symptoms and dysesthesia
(Kovacs et al., 2002 [nZ365, review]; Vital et al., 1998 at disease onset and ataxia and dementia at later stages.
[nZ3, review]). GSS usually presents with predominant These patients died within 7.5–22.5 months after onset of
cerebellar dysfunction, whereas myoclonus is very rare disease. From October 1996 to November 2002, 129 cases
946 H.G. Wieser et al. / Clinical Neurophysiology 117 (2006) 935–951

of vCJD have been reported in the UK, 6 in France and one in approximately 75% of vCJD patients (Zeidler et al.,
each in Canada, Ireland, Italy and the United States of 2000 [nZ36, 57 controls]; Zerr and Poser, 2002 [review]).
America. vCJD is strongly linked to exposure to BSE of the
cattle (Bruce et al., 1997 [nZ9, 6 with sCJD and 3 with 5.2. EEG findings
vCJD]; Scott et al., 1997 [experimental study (mice)]; Will
et al., 1996). Experimental studies have shown that the prion Periodic sharp wave complexes do not occur in patients
protein in BSE-infected cows (and other ruminants and with vCJD (in fact, the lack of PSWC is one of the
domestic cats) has an identical glycosylation pattern as the diagnostic criteria for vCJD, see Table 2, criteria class IIIA).
prion protein of vCJD cases (the PrPvCJD) but not of sCJD Will et al. (2000) found nonspecific slow wave activity in
patients (Collinge, 2005; Collinge et al., 1996). By most patients of a cohort of 33 patients with vCJD: 5
definition, mutations of PRNP are not found in patients patients revealed normal EEG tracings despite neurological
with vCJD. The incubation time in vCJD may range signs at the time of the recording. Only two recordings were
between 5 years and more than 40 years, and the mean reported as suggestive of CJD, but none of the recordings
disease duration is longer than in patients with sCJD showed the PSWC typical of sCJD.
(median of 14 months as opposed to 4.5 months; Spencer
et al., 2002 [nZ100]). The diagnostic criteria of the World
Health Organisation for vCJD are shown in Table 2. 6. Summary
Magnetic resonance imaging typically reveals bilateral
signal alterations in the pulvinar. This so-called ‘pulvinar Periodic sharp wave complexes are the hallmark EEG
sign’ is relatively specific for vCJD and is present finding in patients with CJD and are thus very helpful to
substantiate the clinical diagnosis of suspected CJD. In
Table 2 patients with sCJD, PSWC are fairly common (occuring in
Case definition for vCJD (adapted from the revision of the WHO
about two-thirds of patients) and quite disease specific
surveillance case definition for variant CJD, 2001)
(occuring in only about 5–7% of patients presenting with a
Class I rapidly progressive cognitive decline of other cause
A, Progressive neuropsychiatric disorder
including Alzheimer’s disease, vascular dementia and
B, Duration of illness longer than 6 months
C, Routine investigations not suggestive of alternative diagnosis Lewy body disease). Other neurological or systemic
D, No history of iatrogenic exposure diseases associated with PSWC (including metabolic,
E, No history of familial form of transmissible spongiform encephalopathy toxic, anoxic encephalopathies) usually present with other
Class II
A, Early psychiatric symptoms (i.e. depression, anxiety, apathy, with-
drawal, delusions)
Table 3
B, Persistent painful sensory symptoms (i.e. including frank pain and/or
Age of onset, duration of disease, and prototypical EEG findings (PSWC)
dysesthesia)
according to codon 129 status and PrPSc type in sCJD
C, Ataxia
D, Myoclonus or chorea or dystonia Codon 129 Age of onset Disease EEG with PSWC Studya
E, Dementia genotype and (years) duration
Class III PrPSc type (months)
A, EEG without typical appearance of sporadic CJD (i.e. generalized MM 52.3% (185/354) (1)
triphasic periodic complexes at approximately one per second) or no EEG MV 5.4% (19/354) (1)
B, Brain MRI showing bilateral symmetrical pulvinar high signal intensity VV 2.3% (8/354) (1)
(relative to the signal intensity of the other deep gray matter nuclei and
PrPSc type1 78% (62/80) (1)
cortical gray matter; modification of the case definition of the characteristic
PrPSc type2 4% (1/28) (1)
MRI features [IIIb] to brain MRI shows bilateral symmetrical pulvinar
MM1 56–79 1–5 62.5% (5/8) (2)
hyperintensity relative to the signal intensity of the anterior putamen is
66.5G7.8 7.4G6.9 80% (56/70) (1)
recommended to improve the accuracy of the pulvinar sign in variant CJD)
MM2 52–78 1–17 77.8% (14/18) (2)
Class IV 64.6G7.8 16.9G6.7 33% (1/3) (1)
A, Positive findings on tonsil biopsy (biopsy not routinely recommended MV1 61.8G7.5 4.0G2.7 75% (6/8) (1)
and not recommended in cases with EEG appearance typical of sporadic MV2 54–79 2–9 50% (2/4) (2)
CJD but may be helpful in suspected cases in which the clinical features are 61.4G7.0 17.6G5.7 0% (0/10) (1)
compatible with variant CJD without MRI findings of bilateral pulvinar MV3 61–77 7–21 25% (1/4) (2)
high signal intensity) VV1 27.0G5.7 20 and 31b 0% (0/2) (1)
The possible diagnoses are VV2 41–79 5–11 0% (0/4) (2)
Definite, Class Ia and neuropathologic confirmation of variant CJD (i.e. 60.9G10.5 7.9G3.3 0% (0/15) (1)
spongiform change and extensive prion protein deposition with florid VV3 46–62 2–11 0% (0/5) (2)
plaques throughout the cerebrum and cerebellum) MM4 21–48 9–29 0% (0/10) (2)
Probable, Class I and 4 of 5 of class II and classes IIIa and IIIb or class I and MM6 69 100% (1/1) (2)
class IVa
a
Possible, Class I and 4 of 5 of class II and class IIIa Modified from (1) Zerr et al. (2000b) and (2) Hill et al. (2003) .
b
Two patients with disease duration of 20 and 31 months.
 H.G. Wieser et al. / Clinical Neurophysiology 117 (2006) 935–951 947

Table 4
Human Prion Diseases: Clinical and EEG features (modified from Glatzel et al., 2005)

Human prion Age of onset Disease duration Leading clinical signs and symptoms EEG
disease (range) (range)
sCJD 60–70 years 6 months (1–35) Progressive dementia and neurological signs PSWC in 60–70% (PPV of 96%); Nonspecific
(myoclonus, cerebellar ataxia, extrapyrami- alterations (slowing, FIRDA) in early stages
dal symptoms, visual disturbances)
fCJD 50–60 years 6 months (2–41) Similar to sCJD PSWC in w10%
GSS 50–60 years 5–6 years (3 Cerebellar dysfunction (ataxia, nystagmus, Nonspecific alterations, PSWC in !10%
months–13 years) dysarthria)
FFI 50 years (20–63) 14 months (6–42) Insomnia, autonomic dysfunctions Nonspecific alterations, PSWC uncommon
iCJD 1–30 years Similar to sCJD Similar to sCJD Similar to sCJD, PSWC often lateralized in early
(incubation) stages
vCJD 26 years (12–74) 14 months (6–24) Early psychiatric symptoms (depression, Nonspecific alterations, no PSWC
anxiety, social withdrawal) and dysesthesia,
later neurological and cognitive deficits

symptoms and other clinical history than sCJD, and may mater grafts, fCJD or unexplained neurodegenerative
thus be distinguished on clinical grounds. Several reasons disease) and ‘at virtual risk’ (including treatment which
may account for the lack of PSWC in patients with CJD. involves contact with lymph nodes, blood, intestines, lung,
First, the EEG exhibits characteristic changes during the liver, kidney and placenta). Established decontamination
course of the sCJD, ranging from nonspecific EEG findings methods of possibly prion-contaminated materials are: (1)
such as diffuse slowing and FIRDA in early stages to sodium hypochlorite solution containing 20,000 ppm
disease-typical PSWC in middle and late stages to a reactive available chlorine for 1 h; (2) porous-load autoclaving at
coma traces or even alpha coma in preterminal EEG 134–138 8C for 18 min; (3) exposure to 1 M sodium
recordings. Hence, PSWC may be missed if the EEG is hydroxide for 1 h; and (4) gravity displacement autoclaving
performed too early or, less commonly, too late in the at 132 8C for 1 h (Blättler, 2002).
course of the disease. Nonspecific EEG changes (in
particular the appearance of FIRDA) may help to support
the diagnosis of sCJD and repeated EEG recordings may be Acknowledgements
helpful in such situations. Second, EEG findings obviously
depend on the codon 129 status of the PRNP of sCJD DZ has been supported by the Swiss National Science
patients. PSWC are likely to occur in patients with Foundation (grant PA00A-101502).
methionine homozygosity and methionine/valine hetero-
zygosity but are only rarely seen in patients with valine
homozygosity at codon 129 of the prion protein gene. References
Moreoever, PSWC are more likely to occur in patients with
the PrPSc type 1 than in patients with PrPSc type 2 or 3 Aguglia U, Gambardella A, Le Piane E, Messina D, Farnarie G, Oliveri RL,
(Table 3). Third, PSWC may also occur lateralized or even Zappia M, Quattrone A. Disappearance of periodic sharp wave
complexes in Creutzfeldt–Jakob disease. Neurophysiol Clin 1997;27:
reveal a strictly unilateral voltage distribution (in particular 277–82.
in patients with iCJD) and may thus resemble PLED. Such Aronyk K, Petito F, Solomon GE. Partial elementary motor seizures as the
lateralized PSWC may reflect an early state of disease and first symptom of Creutzfeldt–Jakob disease. Ann Neurol 1984;15:
the pattern usually evolves into sCJD-typical bilateral 210–1.
PSWC during the course of the disease. Fourth, PSWC are Asai Y, Shimoda M, Sasaki K, Nakayasu H, Takeshima T, Miyata H,
Ohama E, Nakashima K. Alpha-like activity in terminal stage of
an uncommon finding in patients with genetic CJD, Creutzfeldt–Jakob disease. Acta Neurol Scand 2001;104:118–22.
occurring in only about 10% of patients with fCJD, even Au WJ, Gabor AJ, Vijayan N, Markand ON. Periodic lateralized
less often in patients with GSS and rarely in patients with epileptiform complexes (PLEDs) in Creutzfeldt–Jakob disease. Neu-
FFI. No PSWC occur in EEG recordings of patients with rology 1980;30:611–7.
vCJD (Table 4). Avanzini G, Vergnes M, Spreafico R, Marescaux C. Calcium-dependent
regulation of genetically determined spike and waves by the reticular
Finally, it is pertinent to note that prion diseases and in thalamic nucleus of rats. Epilepsia 1993;34:1–7.
particular CJD are characterized by their transmissibility Basler K, Oesch B, Scott M, Westaway D, Walchli M, Groth DF,
and the unusual resistance of the infectious agent to McKinley MP, Prusiner SB, Weissmann C. Scrapie and cellular PrP
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