EEG in Creutzfeldt–Jakob disease

Invited review

EEG in Creutzfeldt–Jakob disease

Heinz Gregor Wieser a,*, Kaspar Schindler a, Dominik Zumsteg b

a Department of Neurology, University Hospital Zurich, Zurich, Switzerlandb 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

1388-2457/$30.00 q 2006 International Federation of Clinical Neurophysiology.

doi:10.1016/j.clinph.2005.12.007

Abbreviations: Asp, aspartic acid; Asn, asparagine; AV, anteroventral

nucleus of the thalamus; BSE, bovine spongiform encephalopathy; CJD,

Creutzfeldt–Jakob disease; CM, centromedian nucleus of the thalamus;

CSF, cerebrospinal fluid; fCJD, familial Creutzfeldt–Jakob disease; FFI,

fatal familial insomnia; FIRDA, frontal intermittent rhythmic delta activity;

gTSE, genetic transmissible spongiform encephalopathy; GSS, Gerstmann-

Straussler-Scheinker syndrome; iCJD, iatrogenic Creutzfeldt–Jakob

disease; LD, laterodorsal nucleus of the thalamus; ORF, open reading

frame; Met, methionine; MM, methionine homozygote; MV, methionine/-

valine heterozygote; PLED, periodic lateralized epileptiform discharges;

PRNP, prion protein gene; PrP, prion protein; PrPC, cellular prion protein;

PrPSc, disease associated protease resistant prion protein; PSWC, periodic

sharp wave complexes; PV, parvalbumine; R, reticular nucleus of the

thalamus; sCJD, sporadic Creutzfeldt–Jakob disease; TSE, transmissible

spongiform encephalopathy; vCJD, variant Creutzfeldt–Jakob disease; Val,

valine; VLa, ventrolateral anterior nucleus; VLp, ventrolateral posterior

nucleus; VV, valine homozygote.* Corresponding author. Abteilung fur Epileptologie & Elektroencepha-

lographie, Neurologische Klinik, Universitatsspital Zurich, Frauenklinik-

strasse 26, 8091 Zurich, Switzerland. Tel.: C41 1 255 5530/31; fax: C41 1

255 4429.

E-mail address: [email protected] (H.G. Wieser).

1. Introduction

Creutzfeldt–Jakob disease (CJD) is a rapidly progressive,

uniformly fatal, transmissible spongiform encephalopathy

(TSE) characterized by the accumulation of an abnormal

isoform (PrPSc) of the host encoded cellular prion protein

(PrPC) in the brain (Kretzschmar et al., 1996; Masters et al.,

1979). Human prion diseases occur in diverse phenotypes or

subtypes and can be familial, sporadic, or acquired.

Sporadic CJD (sCJD) is the most common subtype of

CJD, occurring worldwide in 84% of cases with an annual

mortality rate of 1.39 per million (range 0.8–1.61; Ladogana

et al., 2005; nZ4441; sCJDZ3720). Genetic subtypes,

including Gerstmann-Straussler-Scheinker syndrome (GSS)

and fatal familial insomnia (FFI), are less common and

occur in about 10%. Iatrogenic CJD (iCJD) caused by the

transmission of infection in the course of medical treatment

occurs in 3–4%. Variant CJD (vCJD), which has been linked

to transmission of the causative agent of bovine spongiform

encephalopathy (BSE) to the human population, occurs

Clinical Neurophysiology 117 (2006) 935–951

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H.G. Wieser et al. / Clinical Neurophysiology 117 (2006) 935–951936

in 3% (mainly in the UK). Kuru, finally, reached epidemic

proportions in the mid-1950s in New Guinea, but apparently

disappeared within a generation after the practice of

cannibalism has been eliminated (Goldfarb et al., 2004).

Early and reliable diagnosis of CJD is crucial in

excluding other, potentially treatable, causes of rapidly

progressive encephalopathies and in counseling relatives of

patients suffering from this fatal disease. However, early

diagnosis of CJD is complicated by the marked heterogeneity

of clinical presentation of the disease. For decades,

electroencephalography has been the method of choice to

substantiate the clinical diagnosis of CJD. Periodic sharp

wave complexes (PSWC) were reported to occur in EEG

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

of PSWC was, therefore, included in the World Health

Organisation (1998) diagnostic classification criteria of

sCJD. The current WHO diagnostic criteria allow diagnostic

classification as definite, probable or possible sCJD (World

Health Organisation, 1998). The definite diagnosis of

sporadic CJD still requires neuropathological examination

or detection of scrapie prion protein (PrPSc) by Western blot

analysis of brain bioptic or autoptic specimens

(Kretzschmar et al., 1996; World Health Organisation,

1998). The diagnostic criteria for probable sCJD are: (1)

rapidly evolving dementia (!2 years), (2) typical PSWC

with triphasic morphology in EEG recordings and/or

presence of 14-3-3 protein in cerebrospinal fluid (CSF)

examination, and (3) at least two of the following 4 clinical

signs: (a) myocloni, (b) ataxia and/or visual signs and

symptoms, (c) extrapyramidal and/or pyramidal signs and

symptoms, and (d) akinetic mutism. Patients with the

clinical signs of sCJD but without the EEG and CSF

abnormalities (either not present or investigation not

available) are classified as possible sCJD.

In recent years, several markers of neuronal injury in the

CSF have been monitored in patients with human prion

disease. The most promising of these surrogate markers is

the 14-3-3 protein, for which a specificity of 84% and a

sensitivity of 94% have been reported (Zerr et al., 1998 [nZ484]; Zerr et al., 2000a [nZ805]). Consequently, the 14-3-3

protein has also been included in the diagnostic criteria of

the WHO. Other surrogate markers such as the Tau protein,

neuron-specific enolase (NSE) and the astrocytic protein

S-100-B may also be elevated in the CSF of patients with

CJD (Kropp et al., 1999 [nZ16]; Otto et al., 1997a [nZ53];

Otto et al., 1997b [nZ135]), but these markers are not (yet)

included in the diagnostic criteria of the WHO. Neuroima-

ging studies may show characteristic findings in patients

with CJD. Recent studies revealed increased signal intensity

in caudate nucleus, putamen and parietal or occipital

cortical areas in fluid-attenuated inversion recovery

(FLAIR) and diffusion-weighted (DW) MRI sequences

(Finkenstaedt et al., 1996 [nZ29]; Hirose et al., 1998

[nZ1]; Schroter et al., 2000 [nZ162]; Urbach et al., 1998

[nZ4]; Collie, 2001 [review]; Shiga et al., 2004 [nZ36];

Urbach et al., 2001 [nZ14]), showing an overall sensitivity

of about 60–70% and a specificity of about 80–90%

(Tschampa et al., 2005 [nZ193]; Zeidler et al., 2001 [nZ52]; Zerr et al., 2000b [nZ354]). MRI may be particularly

reliable and helpful in the clinical diagnosis of patients

with certain PrP genotypes (e.g. MV2; Zerr et al., 2000b)

and in patients with vCJD (Zeidler et al., 2000 [nZ56]).

In this article, we review the characteristics and

diagnostic value of EEG findings in patients with sporadic,

acquired and familial CJD. Special emphasis was placed on

the discussion of the neurophysiological concepts under-

lying the typical EEG findings of patients with sCJD.

2. Sporadic Creutzfeldt–Jakob disease (sCJD)

2.1. Clinical presentation, classification and staging

Sporadic CJD commonly develops in the fifth to 7th

decade of life, with a mean age of onset of 62 years (median

65). Mean survival times of about 8.2 months (range 1.5–58

months; Roos et al., 1973 [nZ1435]) or 5.2 months (range

1–15 months; Geiger et al., 2002 [nZ22]) have been

reported. About 5–10% of patients with sCJD, however,

have a clinical course that extends for 2 years or more

(Brown et al., 1984 [nZ357]). The clinical presentation of

sCJD is heterogeneous. As a consequence, the differential

diagnosis of sCJD primarily depends on the predominant

signs and symptoms present at early stages of the disease

and may include Alzheimer’s disease, Pick’s disease,

normal pressure hydrocephalus, Parkinson’s disease, cer-

ebrovascular disease, Huntington’s disease, Hashimoto’s

encephalitis, metabolic and toxic encephalopathies, and

many others. Two rare but well-recognized clinical

presentations of sCJD are the so-called Heidenhain variant

(beginning with progressive visual disturbances and

eventually blindness; Heidenhain (1929) [nZ11, 3 own

cases, 8 from the literature including cases of Creutzfeldt

(1920); Jakob (1921); Kirschbaum (1924)]) and the

Brownell-Oppenheimer variant (beginning with progressive

cerebellar disturbances with unsteadiness and incoordina-

tion; Brownell and Oppenheimer, 1965 [nZ10, 4 own

cases, 6 from the literature]). Other variants are myoclonic

or diffuse cerebral, dyskinetic with or without muscular

atrophy, thalamic, and panencephalopathic forms (Mas-

trianni and Roos, 2000 [review]).

The clinical evolution of sCJD has been arbitrarily

subdivided into 3 sequential stages (Roos et al., 1973). In

Stage 1 (mean duration of 9 weeks, range 1–52), 25% of

patients experienced neurologic or psychiatric symptoms

such as dizziness or vertigo (21%), headache (17%),

depression or anxiety (10%), ‘nervousness’ (7%) and

autonomic disturbances including fatigue, disturbances

of sleep–wakefulness, and loss of appetite or nausea.

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

were usually not impaired in their day-to-day activities.

Stage 2 (mean duration of 10 weeks, range 1–104) was

defined by the occurrence of a distinct neurological

syndrome with a prominent involvement of higher cortical

functions (but no dementia) and sensorimotor integration

leading to visual disturbances (blurred vision, diplopia,

metamorphopsis or hallucinations) in about 25%, impair-

ment of balance in about 20% and disturbances of stance

and gait in about 33%. More than half of the patients showed

clinical features that could be attributed to involvement of

cerebellar, brain-stem or occipital cortical structures, but

myoclonus was still an uncommon finding during this stage.

The patients were clearly impaired in daily activities. In

stage 3 (mean duration of 14 weeks, range 1–116), moderate

to severe myoclonus and dementia were typical findings.

There was a significant positive correlation between the

duration of stage 1 and the duration of stages 2 and 3

combined. Bernoulli found a significant negative correlation

between the duration of stage 1 and the age of the individual

(Bernoulli et al., unpublished data). More recently, the

Japanese Slow Virus Infection Research Committee (1999;

see also Shiga et al., 2001) suggested a subdivision into 5

clinical stages, with stage 4 representing late stage

disease characterized by reduced movement, and stage 5

representing terminal stage characterized by complete

akinetic mutism.

2.2. Molecular classification

Recent understanding of molecular mechanisms of sCJD

has led to a more rational classification. Most importantly,

the PrP genotype underlying sCJD may have a major

influence on the course of the disease. In the Caucasian

population, codon 129 of the prion protein gene (PRNP;

located on the short arm of chromosome 20) has been shown

to be the site of a common methionine (M)/ valine (V)

polymorphism: 52% of individuals are M homozygous

(MM), 36% are heterozygous (MV) and 12% are V

homozygous (VV) (Palmer et al., 1991 [nZ22, plus nZ23 with suspected sCJD]). Considering that 74% of patients

with sCJD in Europe are methionine homozygotes at codon

129, this genotype has been denoted as a predisposing factor

for sCJD in the Caucasian population. In Japanese

populations, a site of a common polymorphism has been

located at codons 219 (Shibuya et al., 1998 [nZ85, 20 with

definite, 65 with probable sCJD]) and 232 (substitution from

methionine to arginine; Hoque et al., 1996 [nZ3]). In

addition to the PrP genotype, the clinical presentation of

sCJD may also be associated with PrPSc types, which are

responsible for encoding prion strain diversity (Gambetti et al.,

2003 [review]; Tschampa et al., 2002 [nZ21]). Based on the

genotype at codon 129, the size of protease resistant PrPSc

fragments and disease phenotype, sCJD has been subdivided

into several subtypes (Hill et al., 2003 [nZ119]; Parchi et al.,

1999 [nZ300]). Parchi et al. (1999) found that 70% of

individuals showed the classic CJD phenotype (PrPSc type

1) and at least one methionine allele at codon 129, whereas

25% of cases displayed the ataxic and kuru-plaque variants

and were associated with PrPSc type 2 and valine

homozygosity or heterozygosity at codon 129. Valine

homozygotes accounted for approximately 10%. Two

variants, including a thalamic form of CJD and a phenotype

characterized by prominent dementia and cortical pathol-

ogy, were linked to PrPSc type 2 and methionine

homozygosity. Finally, a rare phenotype characterized by

progressive dementia was linked to PrPSc type 1 and valine

homozygosity.

2.3. Typical EEG findings in sCJD

Periodic sharp wave complexes (PSWC) are the

hallmark EEG finding in patients with sCJD (Furlan

et al., 1981 [nZ1]; Hess et al., 2002 [text book article];

Jones and Nevin, 1954 [nZ2]; Levy et al., 1986 [nZ28];

Steinhoff et al., 1996 [nZ29, 68 EEGs]). Morphologically,

typical PSWC consist of either simple sharp waves

(including biphasic and triphasic waves) or complexes

with mixed spikes, polyspikes and slower waves with a

typical duration of 100–600 ms, recurring every 0.5–2 s

(Gloor, 1980). The intervening background usually consists

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).

There is no satisfactory model to explain the periodicity

of the pattern. It is important to note that PSWC are

generally not related to myoclonic jerks. Traub and Pedley

(1981) suggested that bihemispherically synchronized

discharges such as PSWC do not necessarily imply pacing

from deep midline structures but might be synchronized by

way of the corpus callosum. They further speculated that

fusion of dendritic membranes of affected neurons could

result in increased electrotonic coupling and pathologically

synchronized bursting activity.

Topographically, PSWC commonly reveal a bilateral

voltage distribution with a fronto-precentral midline

maximum. A regional voltage maximum over occipital

areas has been shown in a patient with the Heidenhain

variant of sCJD (Furlan et al., 1981 [nZ1]), but this is a rare

finding. More commonly, PSWC may occur lateralized or

even reveal a strictly unilateral voltage distribution (Au

et al., 1980 [nZ3]; Heye and Cervos-Navarro, 1992

[nZ13]; Heye et al., 1990 [nZ1]; Neufeld and Korczyn,

1992 [nZ4]). Hence, lateralized PSWC may resemble

periodic lateralized epileptiform discharges (PLED). Fig. 2

shows an example of PLED-like PSWC in an EEG

recording of a patient with early stage of sCJD (stage 2).

It has been suggested that the occurrence of lateralized

PSWC (or PLED) in sCJD may reflect an early state of

disease, when the commissural progress has not yet led to

diffuse cortical disease (Heye and Cervos-Navarro, 1992

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.,

2004 [nZ150]). Chiofalo et al. (1980) found asymmetric

EEG abnormalities in 23 of 27 patients with sCJD, mainly in

the prodromal stage of the disease, and stated that “some

cases showed asymmetric records throughout the entire

course of the disease” (but did neither mention of whether

these asymmetries referred to PSWC or to background EEG

abnormalities nor did they specify the time of the last

EEG recording). However, most studies reporting on serial

EEG recordings in patients with sCJD have shown that

lateralized PSWC consistently evolve into sCJD-typical

bilateral PSWC during the course of the disease (Au et al.,

1980 [nZ3]; Steinhoff et al., 2004 [nZ150]; Wieser et al.,

2004 [nZ6]). Moreover, the morphological similarities of

lateralized or regional PSWC in sCJD and classical PLED

associated with acute unilateral cerebral processes

Fig. 2. (A) Lateralized PSWC in a 73-year-old man with stage 2 sCJD. (B) Surfac

over the left fronto-temporal region.

of various etiologies do not necessarily imply a common

neurophysiological basis of these two periodic EEG

patterns. In fact, there are some fundamental differences

between sCJD-associated lateralized PSWC and classical

PLED. Unlike sCJD-associated PSWC, PLED usually

denote a transient EEG phenomenon, which typically

decrease in amplitude and repetition rate during the course

of the disease and usually disappear within 2 weeks of the

acute lesion (Westmoreland et al., 1986 [nZ6]). Further-

more, PLED but not sCJD-associated PSWC are frequently

associated with epileptic seizures (Snodgrass et al., 1989

[nZ147]). Finally, PLED are usually not influenced by

manipulation and sleep, whereas PSWC in sCJD may

commonly be influenced by external stimulation. PSWC

may also be attenuated by sedative medication, in particular

with benzodiazepines including midazolam and diazepam

e voltage mapping showing a dipole configuration with maximal negativity

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

diazepam]; Rossini et al., 1979 [nZ1]; Wieser et al., 2004

[nZ6, 1 with diazepam]; Fig. 3).

PSWC in patients with sCJD, on the other hand, are most

prominent during wakefulness and tend to disappear during

sleep. Terzano et al. (1995) demonstrated three types of

EEG findings in serial polygraphic night sleep studies

performed during the last 3 months of life in a 68-year-old

sCJD patient: (a) sustained sequences of PSWC, (b) runs of

pseudoperiodic discharges cyclically replaced at about

1-min intervals with semi-rhythmic theta-delta activity

and (c) less rhythmic NREM sleep-like patterns with

0.5–4-Hz activity. PSWC were associated with a high

level of vigilance or a state of alert-appearing silent

immobility. Mamdani et al. (1983) reported a patient with

CJD in whom periods of apnea during sleep were associated

with abrupt cessation of PSWC and replaced by 7–9 Hz

waves persisting throughout the apnoic episode. Teszner

and Foucher (1978 [nZ1]) described similar findings and

suggested a common triggering mechanisms for the close

temporal correlation between variations in vigilance,

respiration, periodic EEG activity and myoclonic activity.

Donnet et al. (1992) reported disorganized sleep patterns in

a polysomnographical study of 3 patients suffering from

early stages of sCJD. The sleep patterns were characterized

by sudden transitions from one sleep stage to the next, very

few sleep spindles and K complexes in stage 2, absence of

stage 4 sleep and a lower percentage of REM sleep with

fewer rapid eye movements. The awake EEG of these

patients showed characteristic PSWC or a slow electrogenesis

of low amplitude suggesting diffuse cerebral pathology.

The disappearance of PSWC during sleep is of particular

interest in light of the very similar scalp voltage

topographies of PSWC and physiological sleep potentials

including vertex-waves, sleep spindles and K complexes.

The generation of both PSWC and physiologic sleep

patterns have been related to thalamo-cortical loops,

although, with respect to PSWC in sCJD, convincing

studies on the role of thalamic nuclei in the generation of

these complexes are lacking.

Previous studies investigating PSWC in patients with

sCJD with the use of simultaneous depth and scalp EEG

recordings have demonstrated PSWC recorded from basal

ganglia structures that were only inconsistently detected on

simultaneous scalp EEG recordings (Chiofalo et al., 1980

[nZ27, 1 with depth EEG]; Rayport, 1963 [nZ2]). Rayport

(1963) recorded PSWC from the pial surface of the right

frontal lobe and from the globus pallidus. The former were

markedly attenuated in their amplitude after neuronal

isolation. Depth electrode recordings from the white matter

revealed PSWC of ‘simpler’ configuration and lower

amplitude. Chiofalo et al. (1980) reported on serial

simultaneous scalp EEG and depth electrode recordings

from the right caudate nucleus and the ‘external hypothala-

mus’ in a patient with late stage sCJD. Twenty-one days

before death, they found ‘no difference between deep and

superficial activity’, with similar periodic complexes

appearing in both tracings during myoclonus. One week

before death, there was a diffuse flattening of the scalp EEG

traces, despite persistence of periodic activity in depth

recordings, in particular during intense acoustic stimulation.

Four days before death, the flattening of the scalp EEG was


complete, but occasional periodic complexes could still be

seen in deeper structures, both occurring spontaneously and

during painful stimulation.

These findings are in good accordance with a recent

study reporting on the correlation between PSWC and

immunoreactivity for the calcium-binding protein parval-

bumine in thalamic nuclei of patients with sCJD (Tschampa

et al., 2002 [nZ21, 5 controls]). The authors found a loss of

parvalbumine positive (PVC) cells in most thalamic nuclei,

including the reticular (R), ventrolateral (VLa and VLp),

laterodorsal (LD) and anteroventral (AV) nucleus. Interest-

ingly, the centromedian nucleus (CM) was the only thalamic

region with an increase of PVC cells. With respect to

PSWC, the most marked differences were found for the AV,

the R and the CM, with a significant increase of PVC cells

in the former and nonsignificant decreases in the latter two

nuclei for patients with PSWC (the decrease in the R was

only significant for patients who had both PSWC and

myoclonus). Based on the generally accepted concept that

the R plays a key role in the generation and maintenance of

thalamic, cortical or thalamocortical spindle rhythms or

synchrony (Avanzini et al., 1993; Fuentealba and Steriade,

2005; Huntsman et al., 1999; Steriade et al., 1993), the

authors hypothesized that the predominant reduction of

PVC cells in the R may determine the generation of PSWC

(associated with myoclonus) in patients with sCJD. The

authors further suggest that the functional integrity (at least

in parts) of the subcortico-cortical or thalamo-cortical

network is a prerequisite for the generation of PSWC.

Ferrer et al. (1993 [nZ3]) also found massive parvalbumin

immunoreactivity abnormalities in cortical neurons.

Fig. 4. EEG recording of a 73-year-old man with histologically proven sCJD (14

FIRDA-like activity 23 days before death. PSWC were documented 30–16 days

2.4. Nonspecific EEG findings in sCJD

It is important to recall that typical periodic EEG

activity may be lacking in patients with sCJD, in particular

in early stages, and less common also in terminal stages of

the disease. In early stages of sCJD, EEG recordings may

be characterized by nonspecific EEG patterns such as

diffuse slowing of background activity, intermingled focal

slow activity (in the theta or delta range) or FIRDA-like

EEG patterns (Hansen et al., 1998 [nZ7]; Wieser et al.,

2004 [nZ6]). FIRDA may be of particular interest

(Fig. 4). The term FIRDA denotes bursts of generalized

monomorphic delta activity with a mean frequency of

about 2.5 Hz, having a notched or sinusoidal appearance.

Occasionally, FIRDA may be asymmetric and the bursts

may be nonrhythmic or may include theta activity (Schaul

et al., 1981). The ascending phase of the delta waves is

typically more rapid than the descending phase (Hess,

1975; Van der Drift and Magnus, 1961). Whereas FIRDA

is a clearly abnormal finding indicating primary cerebral

dysfunction, it is definitely not specific for any single

etiology and may occur in response to a variety of diffuse

or focal intracranial diseases, such as neoplasms, epilepsy,

toxic or metabolic encephalopathy, and cerebrovascular

disease. Such nonspecific EEG findings in patients with

sCJD, in particular the occurrence of FIRDA and

intermittent localized and lateralized delta rhythms in

early stages of the disease, should always be regarded as

compatible with the diagnosis of sCJD and encourage

further EEG studies for the demonstration of PSWC in a

more advanced stage of the disease (Schlenska and Walter,

1989 [nZ3]).

-3-3 positive; methionine homozygote at codon 129, no mutation) showing

before death.


In later stages of sCJD, the intensity of the periodic EEG

patterns may gradually decrease. In a longitudinal EEG

study comprising 34 EEG recordings during a 14 months

period in a patient with autopsy confirmed sCJD, Schaffler

et al. (1983) found maximal PSWC occurring at about week

15 after onset of the prodromal stage of the disease. From

the 5th month onwards, the intensity of the periodic EEG

pattern gradually decreased. In the time-span from the 10th

to the 13th month, they found considerable fluctuations of

periodic activity, ranging from pronounced typical PSWC to

complete disappearance of periodic activity. Morphologi-

cally, the PSWC showed a progressive ‘simplification’ of

the complexes during this time, characterized by a broad-

ening of the sharp wave complexes and a slight increase of

the interval duration. The authors discussed a variable

driving by the hypothetical subcortical pacemaker as well as

a decreased capability of cerebral cortex to react to

subcortical stimuli as possible causes for these fluctuations.

Clinically, these EEG changes were associated with a

disappearance of perioral reflexes, deep tendon reflexes,

oral automatisms and myoclonus. No PSWC were found

after month 14, and the last EEG recording performed

3 days before death revealed isoelectric periods, which

alternated with episodes of delta waves or sharp slow wave

complexes. Areactive coma tracings with predominantly

slow waves, low-voltage activity or, rarely, an alpha coma

pattern are a common finding in preterminal EEG

recordings (Lee and Blair, 1973 [nZ3]; Aguglia et al.,

1997 [nZ2]; Asai et al., 2001 [nZ1]).

2.5. Epileptiform and seizure activity in sCJD

Focal motor or generalized seizures have been reported

to occur in 15% of patients with sCJD, typically occurring

late in the disease (Johnson and Gibbs, 1998 [review]; Roos

et al., 1973 [nZ1435]) to 21% (Cokgor et al., 1999

[nZ21]). Seizures as the presenting symptom of sCJD,

however, are an uncommon finding, occurring in only about

3% of cases (Aronyk et al., 1984 [nZ1]). Rarely, EEG and

clinical findings may suggest partial status epilepticus (SE)

including epilepsia partialis continua (Lee et al., 2000

[nZ1]; Parry et al., 2001 [nZ1]), complex partial SE (Rees

et al., 1999 [nZ2]), nonconvulsive SE (Schwinn et al., 2001

[nZ1]; Cohen et al., 2004 [nZ1]; Fernandez-Torre et al.,

2004 [nZ1]; Shapiro et al., 2004 [nZ1]) or generalized SE

(Cokgor et al., 1999 [nZ21]). Fig. 5 shows the EEG

recordings in a patient with sCJD referred to our hospital

with the diagnosis of nonconvulsive frontal SE.

Seizure-like EEG activity in patients with sCJD, in

particular EEG findings suggesting nonconvulsive SE, must

be carefully distinguished from PSWC. At least some cases

of the above-mentioned studies might indeed have revealed

typical PSWC rather than the EEG correlate of clinical

seizures (as noted in the study of Fernandez-Torre et al.,

2004 [nZ1]). PSWC of sCJD are well known to be

attenuated or even abolished by antiepileptic drugs (AEDs)

(Elliott et al., 1974 [nZ3]; Hansen et al., 1998 [nZ7];

Wieser et al., 2004 [nZ6]). Therefore, EEG response to

AEDs alone, in particular to administration of benzo-

diazepines, is definitely not sufficient to conclude that the

periodic discharges represent the electroencephalographic

correlate of seizures. The effects of drugs such as

benzodiazepines on the EEG should always be correlated

to the consequences for mental status: the EEG changes

should be accompanied by a significant clinical improve-

ment (Fountain and Waldman, 2001 [nZ10]). Furthermore,

epileptic discharges are usually time-locked with clinical

motor signs whereas typical sCJD related myocloni are not

and may occur before, during and after the PSWC (Burger

et al., 1972 [nZ8]; Lee and Blair, 1973 [nZ3]).

2.6. Diagnostic yield of EEG findings in sCJD

The diagnostic value of early EEG findings including

slowing of background activity, focal or diffuse slow

activity and FIRDA is limited. As mentioned above, such

EEG findings are compatible, or at best suggestible, but by

no means specific for sCJD. The diagnostic usefulness of

PSWC, on the other hand, is generally accepted and has

been demonstrated in numerous studies. Steinhoff et al.

(2004 [nZ150, 56 controls]) found positive criteria

(Table 1) in the EEG recordings of 96 of 150 (64%)

patients with autopsy confirmed CJD, and falsely positive

criteria in only 5 of 56 (9%) of patients with dementia of

other etiology (4 with Alzheimer’s disease and one with

vascular dementia). These figures correspond to a high

specificity of 91% and a high positive predictive value

(PPV) of 95%, and improved the PPV of clinical symptoms

by no less than 19% to a value of 99%.

Zerr et al. (2000a) reported on a specificity of 74% and a

PPV of 93% for PSWC in a study including 805 patients

with probable or possible CJD (the PPV for detection of the

14-3-3 protein in CSF was 97%, and 99% for the

combination of both tests). Hence, PSWC only rarely

occur in patients with rapidly progressive dementia of other

etiology (e.g. Alzheimer’s disease, vascular dementia and

Lewy body disease; Tschampa et al., 2001 [nZ25 with

definite CJD, nZ56 with probable sCJD; nZ19 with

Alzheimer’s disease, and nZ12 with dementia with Lewy

bodies]; Steinhoff et al., 2004 [nZ150, 56 controls]).

Although these studies unequivocally indicate the high

diagnostic value of PSWC in patients with suspected CJD, it

has to be mentioned that these studies usually included

patients with CJD typical presentation only. Triphasic

waves resembling PSWC, however, may frequently occur

in other neurological or systemic diseases including

metabolic (mostly hepatic) encephalopathy (Karnaze and

Bickford, 1984 [nZ50]), anoxic encephalopathy (usually

associated with fatal outcome; Kuroiwa et al., 1982 [nZ1];

Scollo-Lavizzari and Bassetti, 1987 [nZ26]) and toxic

encephalopathy (in particular baclofen, lithium and the

antidepressant mianserin; Hormes et al., 1988 [nZ1]; Smith

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]).

Lateralized or unilateral PSWC (PLED per definition) are

often seen in acute unilateral cerebral lesions such as

infarction (embolic more so than thrombotic), encephalitis

(in particular herpes simplex encephalitis), and neoplasm

(more often in malignant ones) or abscess (Westmoreland

et al., 1986 [nZ6]). PSWC with longer interval duration (up

to 30 s), which were initially described in children with

subacute sclerosing panencephalitis (SSPE; Radermecker,

1949 [nZ3]), are far less common. It has been suggested,

that disease processes leading to vast destruction of the

white matter rather than the cortex might be predominantly

associated with periodic EEG patterns with longer intervals

(Cobb and Hill, 1950; Markand and Panszi, 1975;

Radermecker and Poser, 1960). Long-interval PSWC may

also occur in patients with phencyclidine (angel dust) or

ketamine intoxication (Fariello and Black, 1978 [nZ1]).

Furthermore, nonconvulsive generalized status epilepticus

and burst-suppression patterns due to anoxia or barbiturate

intoxication can result in a similar, PSWC-like EEG pattern

Table 1

Objective Diagnostic Criteria of PSWC typical for sCJD (Steinhoff et al.,

1996)

Strictly periodic cerebral potentials, the majority with a duration between

100 and 600 ms and an intercomplex interval between 500 and 2000 ms

Generalized and lateralized complexes accepted

At least 5 repetitive intervals with a duration difference of less than 500 ms

to rule out semiperiodic activity


(Kuroiwa and Celesia, 1980 [nZ62]; see Fig. 5). Such

conditions, however, usually present with other symptoms

and history than sCJD, and may thus be easily distinguished

on clinical grounds.

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

sensitivity of 64% and a NPV of 49% in their cohort. Zerr

et al. (2000b [nZ354]) established a sensitivity of 66%.

Several factors may account for these moderate values.

Most importantly, it has been shown that not all patients

with sCJD develop PSWC during the course of the disease.

With respect to the PrP genotype at codon 129, Zerr et al.

(2000b [nZ354]) found PSWC predominantly in the EEG

recordings of patients with MM1 and MV1 genotypes, but

not in those of valine-homozygous patients. The lack of

PSWC in the EEG recordings of 12 patients with a codon

129-valine homozygote genotype was also reported by the

National CJD Surveillance Unit in Edinburgh (Kovacs et al.,

2000). Hill et al. (2003) reported on PSWC in the EEG

recordings of 5 of 8 MM1 patients, 14 of 18 MM2, 2 of 4

MV2, 1 of 5 MV3, but in none of 4 patients with the VV2

subtype. Hence, PSWC seem to be limited to M

homozygous (MM1 or MM2) and MV heterozygous

(MV1, MV2, and MV3) patients, whereas valine homo-

zygous patients typically do not show PSWC (Table 3). The

reason for this finding is not known. Interestingly, Kovacs

et al. (2000) also reported on the involvement of

hippocampal structures in their PSWC-negative valine

homozygote subgroup. Taking into consideration that the

hippocampal structures are only rarely involved in patients

with sCJD, this finding might be helpful in distinguishing

valine homozygous patients from patients with other

genotypes with the help of MR imaging.

Another explanation for the moderate sensitivity of

PSWC in sCJD might be the timing of the EEG recording in

relation to the disease stage. As mentioned above, the

occurrence of PSWC corresponds to the amount of neuronal

cell loss (Bortone et al., 1994 [nZ15]), the ‘classical’

bilateral diffuse PSWC usually marking the middle and late

stage of sCJD. Hence, the characteristic PSWC may be

missed if the EEG is performed too early in the course of the

disease. Steinhoff et al. (2004) assessed a total number of

443 EEG recordings in 150 patients with CJD and found

typical PSWC after a mean latency of 3.7 months (range

0.2–19.2) after onset of disease. Hansen et al. (1998)

reported on a mean survival time of 8 weeks after onset

of PSWC in a study investigating 7 CJD patients with serial

EEG recordings during the course of the disease. At the

onset of PSWC in the EEG recordings (mean 8.7 weeks

after onset of disease), 5 of 7 patients (71%) had already

progressed to stage 3, showing akinetic mutism and CJD-

typical-movement disorder such as myoclonia, exaggerated

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

present and replaced by prefinal EEG findings in at least

some of the patients with sCJD. In the study of Steinhoff

et al. (2004 [nZ150]), the latest typical EEG was recorded

2.3 months (mean, range day of death to 17.1 months).

3. Iatrogenic Creutzfeldt–Jakob disease (iCJD)

3.1. Clinical presentation and incubation period

Human-to-human transmission of CJD was reported for

the first time in 1974 in a 55-year-old woman who

developed iCJD 18 months after a corneal transplantation

(Duffy et al., 1974). Bernoulli et al. (1977) subsequently

reported on transmission of CJD by EEG depth electrodes in

two young patients (the contaminated electrodes were

reused after sterilization in formaldehyde and alcohol after

cortical recordings in the sCJD patient). Iatrogenic

transmission of CJD by neurosurgical instruments insuffi-

ciently decontaminated by routine sterilization methods was

identified in 6 cases by Will and Matthews (1982 [nZ3,

plus 1 of Jones and Nevin (1954) and 2 of Nevin et al.

(1960)]). Hundred and fourteen cases of putative CJD

transmission caused by cadaveric lyophilized dura trans-

plants from CJD patients were reported by Brown et al.

(2000). Treatment with cadaveric pituitary-derived growth

hormone has resulted in transmission to at least 139 young

people (Brown et al., 2000). Overall, at least 267 cases of

iCJD have been reported up to the end of year 2000 (Brown

et al., 2000).

The incubation period of iCJD may depend on the mode

of transmission. The shortest incubation periods were found

in iCJD caused by contaminated EEG depth electrodes or

neurosurgical instruments, ranging from 16.6 to 28 months

(Bernoulli et al., 1977 [nZ2]; Will and Matthews, 1982

[nZ6]). In iCJD associated with dural grafts and growth

hormone therapy, incubation periods up to 20 years (mean

6–9 years, rarely up to 30 years) have been reported (Brown

et al., 2000 [nZ267]; Croes et al., 2001 [nZ2]; Fushimi et

al., 2002 [nZ1]; Kretzschmar et al., 2003 [nZ1]).

Interestingly, iCJD often presents with cerebellar signs,

whereas sCJD more commonly begins with mental

deterioration. Moreover, the PrP genotype may also

influence the occurrence of iCJD: homozygosity for Met

or Val at the polymorphic codon 129 of the PRNP has been

found to represent a risk factor for iCJD, as for sCJD

(Blattler, 2002 [review]). In hormone cases, homozygosity


may also promote shorter incubation periods (Huillard

d’Aignaux et al., 1999 [nZ55 out of 1361]).

3.2. Typical EEG findings

The EEG findings in patients with iCJD are similar to

those in patients with sCJD. PSWC with a lateralized or

bilateral voltage distribution as well as nonspecific EEG

patterns such as localized or generalized slowing and

FIRDA have been reported. However, the localized

inoculation of the transmissible agent of CJD (the PrPSc)

may lead to more restricted EEG findings, at least in early

stages. Fushimi et al. (2002) reported on lateralized PSWC

corresponding with the location of the dural graft, which

later evolved into CJD-typical symmetrical PSWC in a

patient who developed iCJD 14 years after surgery. We

observed typical PSWC in a patient who received a lyodura

graft of unknown brand 22 years before disease onset (see

Fig. 5; this patient, however, may also have suffered from

sCJD rather than iCJD). Kretzschmar et al. (2003) described

generalized slowing but no PSWC in a patient with a dura

mater graft following surgery for angioblastoma of the

cerebellum 20 years prior to death.

We have previously reported on the two patients with

iCJD due to the contaminated depth electrode (Bernoulli

et al., 1977; Wieser et al., 2004). These patients with

Fig. 6. Depth electrode recording of a 69-year-old woman with histologically pr

contaminated depth electrodes). The recording was performed during cortical b

treatment of violent myoclonus. Depth electrode recordings from the electrodes 1

PSWC (A), also depicted with a better time resolution in (B) and (C). Note the p

respect to the cortical discharge (C, lower traces). Intraoperative radiography sho

(2004).

localized infection and with serial EEG recordings during

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

symptoms were observed after 16.6 (patient 1) and 19.8

months (patient 2), and the patients died 23.7 and 41.7

months after infection. Concerning the question of

‘infectiosity’ of the contaminated depth electrode it is

interesting to note that patient 1 had received the prion-

contaminated depth electrode prior to patient 2. The serial

EEG recordings revealed a progressive alteration of the

EEG evolving from (1) focal progressive slowing at the

location of the infected electrode (11 and 18 months), to (2)

to FIRDA-like trains of periodic frontal delta (17 and 19

months; still with a regional predominance at the site of the

implantation of the contaminated electrode) to marked

FIRDA (17.5 and 20 months), to (3) intermingled sharper

slow theta activity (18 and 20.5 months), to (4) PSWC, first

intermingled, then stereotyped (patient 2: 22.4 months), and

finally leading into (5) dispersion of PSWC with progressive

decrement of the EEG amplitude. Hence, EEG findings in

iCJD might exist along a continuum of EEG changes,

ranging from localized slowing at the site of infection to the

most typical PSWC. This unfortunate transmission of CJD

in two patients also gave us the opportunity to explore the

role of thalamo-cortical interaction in the index patient

oven CJD (index patient for the two iCJD patients who received the prion

iopsy and stereotactic electrocoagulation in the ventrolateral thalamus for

and 2 (contact 1 denotes the deepest contact) showing typical generalized

hase reversal of the thalamic deflection (C, upper traces) and its delay with

wing the position of the depth electrodes (D). Modified from Wieser et al.


(Wieser et al., 2004; see Fig. 6). Local-fields attributable to

the PSWC were recorded both from the frontal cortex and

the ventrolateral thalamus, with the discharges recorded

from the frontal cortex generally showing higher amplitudes

and preceding the thalamic complexes by about 4 ms (note

that the thalamic complexes did not show the initial spike;

unfortunately, phase- and coherence analysis was not

carried out at the time of examination, and the available

paper recordings do not allow for such analysis post-hoc

either). In the case of Fushimi et al. (2002), a 61-year-old

man who received a cadaveric dura mater graft and

developed CJD 14 years later, right lateralized PSWC

coinciding with the location of the dural graft were observed

(lateralized PSWC were seen 14 days after admission and

generalized PSWC 1.5 months later).

4. Genetic Creutzfeldt–Jakob disease

4.1. Molecular findings and clinical presentation

Genetic CJD cases are associated with point mutations or

insertions (rarely deletions and silent or influential

polymorphisms) within the open reading frame (ORF) of

the PRNP (the entire ORF resides within a single exon

which encodes for a sequence of 253 amino acids; Basler

et al., 1986). More than 20 mutations have currently been

described, the most common being an amino acid

substitution at codon 200. By definition, familial CJD

(fCJD) is diagnosed when a progressive neuropsychiatric

disorder is encountered in combination with a pathogenic

PRNP mutation (Budka et al., 1995). Mutations within ORF

are also responsible for two rare autosomal inherited

diseases, the Gerstmann-Straussler-Scheinker syndrome

(GSS, several point mutations) and fatal familiar insomnia

(FFI; single point mutation at codon 178, Asp to Asn). It is

the codon 129 genotype that determines whether the patient

segregates with FFI (patients with M at the same allele at the

polymorphic codon 129) or familial CJD (fCJD, patients

with V at the same allele).

Phenotypically, genetic CJD cases are usually classified

on neuropathological grounds: fCJD are characterized by

the classical neuropathological triad of spongiform change,

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

et al., 1998 [review]). The clinical presentation of fCJD

overlaps between mutations and may resemble patients with

sCJD. Nevertheless, some genotypes of fCJD may reveal

characteristic clinical and neuropathological features.

Patient with base pair insertion mutations, for example,

have been shown to exhibit a significant earlier disease

onset and longer disease duration than other fCJD cases

(Kovacs et al., 2002 [nZ365, review]; Vital et al., 1998

[nZ3, review]). GSS usually presents with predominant

cerebellar dysfunction, whereas myoclonus is very rare

and dementia is seen in terminal stages only. FFI is

characterized by progressive and autonomic dysfunction,

ataxia, dementia, and myoclonus. Lugaresi et al. (1998

[review]) have reported on a relationship between selective

atrophy of the anteroventral and mediodorsal limbic

thalamic nuclei and hypovigilance, attention deficit,

inability to generate EEG sleep patterns, sympathetic

hyperactivity and attenuation of vegetative and hormonal

circadian oscillations. Taratuto et al. (2002 [nZ1]) reported

on insomnia associated with thalamic involvement in

E200K 129M haplotype CJD.

4.2. EEG findings

‘Classical’ periodic sharp wave complexes, with or

without triphasic morphology, occur in about 10% of

patients with genetic CJD (Kovacs et al., 2002 [nZ365,

review]; Kovacs et al., 2005 [nZ455, with genetic

transmissible spongiform encephalopathies (gTSE), EEG

available in 82%]. Moreover, a ‘CJD-typical EEG’ was

more frequent in fCJD than in FFI and GSS (only 2 of 26

patients with GGS revealed PSWC in the study of Kovacs

et al., 2005). No PSWC were found in fCJD patients

bearing codon 178, 200 or 210 mutations and in 4 members

of a kindred with CJD in whom myclonus did not develop

(Tietjen and Drury, 1990). Neufeld et al. (2003) reported

on a patient with a codon E200K mutation in the PRNP

gene presenting with status epilepticus (focal motor

seizures with frequent generalization). Seizures are

reported in a few cases of P102L (Hainfellner et al.,

1995 [nZ221 (9 generations)]), A117V (Nochlin et al.,

1989 [nZ24 (5 generations), 2 with seizures]), D178N-

129M (McLean et al., 1997 [nZ6, 2 with seizures]; Julien

et al., 1998 [nZ4, 2 families]), E200K (Seno et al., 2000

[nZ4, 1 with seizures]), 120 BPI (Cochran et al., 1996

[nZ10]), 144 BPI (Collinge et al., 1992 [nZ174]; Poulter

et al., 1992 [same pedigree as in Collinge et al., 1992;

nZ16 with the 144 base pair insertion within the PRNP

ORF]; Oda et al., 1995 [nZ6, one with attacks of

unconsciousness after ‘apoplectic episode’, one with

generalized seizures; and review]; Capellari et al., 1997

[nZ3]), and 192 BPI (Goldfarb et al., 1991 [nZ9, 1 with

seizures]).

5. Variant Creutzfeldt–Jakob disease (vCJD)

5.1. Clinical presentation, classification and staging

In 1996, Will et al. published the first 10 cases with

vCJD. These patients had no family history of CJD, were

unusually young and presented with atypical clinical

features comprising psychiatric symptoms and dysesthesia

at disease onset and ataxia and dementia at later stages.

These patients died within 7.5–22.5 months after onset of

disease. From October 1996 to November 2002, 129 cases


of vCJD have been reported in the UK, 6 in France and one

each in Canada, Ireland, Italy and the United States of

America. vCJD is strongly linked to exposure to BSE of the

cattle (Bruce et al., 1997 [nZ9, 6 with sCJD and 3 with

vCJD]; Scott et al., 1997 [experimental study (mice)]; Will

et al., 1996). Experimental studies have shown that the prion

protein in BSE-infected cows (and other ruminants and

domestic cats) has an identical glycosylation pattern as the

prion protein of vCJD cases (the PrPvCJD) but not of sCJD

patients (Collinge, 2005; Collinge et al., 1996). By

definition, mutations of PRNP are not found in patients

with vCJD. The incubation time in vCJD may range

between 5 years and more than 40 years, and the mean

disease duration is longer than in patients with 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.

Magnetic resonance imaging typically reveals bilateral

signal alterations in the pulvinar. This so-called ‘pulvinar

sign’ is relatively specific for vCJD and is present

Table 2

Case definition for vCJD (adapted from the revision of the WHO

surveillance case definition for variant CJD, 2001)

Class I

A, Progressive neuropsychiatric disorder

B, Duration of illness longer than 6 months

C, Routine investigations not suggestive of alternative diagnosis

D, No history of iatrogenic exposure

E, No history of familial form of transmissible spongiform encephalopathy

Class II

A, Early psychiatric symptoms (i.e. depression, anxiety, apathy, with-

drawal, delusions)

B, Persistent painful sensory symptoms (i.e. including frank pain and/or

dysesthesia)

C, Ataxia

D, Myoclonus or chorea or dystonia

E, Dementia

Class III

A, EEG without typical appearance of sporadic CJD (i.e. generalized

triphasic periodic complexes at approximately one per second) or no EEG

B, Brain MRI showing bilateral symmetrical pulvinar high signal intensity

(relative to the signal intensity of the other deep gray matter nuclei and

cortical gray matter; modification of the case definition of the characteristic

MRI features [IIIb] to brain MRI shows bilateral symmetrical pulvinar

hyperintensity relative to the signal intensity of the anterior putamen is

recommended to improve the accuracy of the pulvinar sign in variant CJD)

Class IV

A, Positive findings on tonsil biopsy (biopsy not routinely recommended

and not recommended in cases with EEG appearance typical of sporadic

CJD but may be helpful in suspected cases in which the clinical features are

compatible with variant CJD without MRI findings of bilateral pulvinar

high signal intensity)

The possible diagnoses are

Definite, Class Ia and neuropathologic confirmation of variant CJD (i.e.

spongiform change and extensive prion protein deposition with florid

plaques throughout the cerebrum and cerebellum)

Probable, Class I and 4 of 5 of class II and classes IIIa and IIIb or class I and

class IVa

Possible, Class I and 4 of 5 of class II and class IIIa

in approximately 75% of vCJD patients (Zeidler et al.,

2000 [nZ36, 57 controls]; Zerr and Poser, 2002 [review]).

5.2. EEG findings

Periodic sharp wave complexes do not occur in patients

with vCJD (in fact, the lack of PSWC is one of the

diagnostic criteria for vCJD, see Table 2, criteria class IIIA).

Will et al. (2000) found nonspecific slow wave activity in

most patients of a cohort of 33 patients with vCJD: 5

patients revealed normal EEG tracings despite neurological

signs at the time of the recording. Only two recordings were

reported as suggestive of CJD, but none of the recordings

showed the PSWC typical of sCJD.

6. Summary

Periodic sharp wave complexes are the hallmark EEG

finding in patients with CJD and are thus very helpful to

substantiate the clinical diagnosis of suspected CJD. In

patients with sCJD, PSWC are fairly common (occuring in

about two-thirds of patients) and quite disease specific

(occuring in only about 5–7% of patients presenting with a

rapidly progressive cognitive decline of other cause

including Alzheimer’s disease, vascular dementia and

Lewy body disease). Other neurological or systemic

diseases associated with PSWC (including metabolic,

toxic, anoxic encephalopathies) usually present with other

Table 3

Age of onset, duration of disease, and prototypical EEG findings (PSWC)

according to codon 129 status and PrPSc type in sCJD

Codon 129

genotype and

PrPSc type

Age of onset

(years)

Disease

duration

(months)

EEG with PSWC Studya

MM 52.3% (185/354) (1)

MV 5.4% (19/354) (1)

VV 2.3% (8/354) (1)

PrPSc type1 78% (62/80) (1)

PrPSc type2 4% (1/28) (1)

MM1 56–79 1–5 62.5% (5/8) (2)

66.5G7.8 7.4G6.9 80% (56/70) (1)

MM2 52–78 1–17 77.8% (14/18) (2)

64.6G7.8 16.9G6.7 33% (1/3) (1)

MV1 61.8G7.5 4.0G2.7 75% (6/8) (1)

MV2 54–79 2–9 50% (2/4) (2)

61.4G7.0 17.6G5.7 0% (0/10) (1)

MV3 61–77 7–21 25% (1/4) (2)

VV1 27.0G5.7 20 and 31b 0% (0/2) (1)

VV2 41–79 5–11 0% (0/4) (2)

60.9G10.5 7.9G3.3 0% (0/15) (1)

VV3 46–62 2–11 0% (0/5) (2)

MM4 21–48 9–29 0% (0/10) (2)

MM6 69 100% (1/1) (2)

a Modified from (1) Zerr et al. (2000b) and (2) Hill et al. (2003) .b Two patients with disease duration of 20 and 31 months.

Table 4

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

Human prion

disease

Age of onset

(range)

Disease duration

(range)

Leading clinical signs and symptoms EEG

sCJD 60–70 years 6 months (1–35) Progressive dementia and neurological signs

(myoclonus, cerebellar ataxia, extrapyrami-

dal symptoms, visual disturbances)

PSWC in 60–70% (PPV of 96%); Nonspecific

alterations (slowing, FIRDA) in early stages

fCJD 50–60 years 6 months (2–41) Similar to sCJD PSWC in w10%

GSS 50–60 years 5–6 years (3

months–13 years)

Cerebellar dysfunction (ataxia, nystagmus,

dysarthria)

Nonspecific alterations, PSWC in !10%

FFI 50 years (20–63) 14 months (6–42) Insomnia, autonomic dysfunctions Nonspecific alterations, PSWC uncommon

iCJD 1–30 years

(incubation)

Similar to sCJD Similar to sCJD Similar to sCJD, PSWC often lateralized in early

stages

vCJD 26 years (12–74) 14 months (6–24) Early psychiatric symptoms (depression,

anxiety, social withdrawal) and dysesthesia,

later neurological and cognitive deficits

Nonspecific alterations, no PSWC


symptoms and other clinical history than sCJD, and may

thus be distinguished on clinical grounds. Several reasons

may account for the lack of PSWC in patients with CJD.

First, the EEG exhibits characteristic changes during the

course of the sCJD, ranging from nonspecific EEG findings

such as diffuse slowing and FIRDA in early stages to

disease-typical PSWC in middle and late stages to a reactive

coma traces or even alpha coma in preterminal EEG

recordings. Hence, PSWC may be missed if the EEG is

performed too early or, less commonly, too late in the

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

helpful in such situations. Second, EEG findings obviously

depend on the codon 129 status of the PRNP of sCJD

patients. PSWC are likely to occur in patients with

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.

Moreoever, PSWC are more likely to occur in patients with

the PrPSc type 1 than in patients with PrPSc type 2 or 3

(Table 3). Third, PSWC may also occur lateralized or even

reveal a strictly unilateral voltage distribution (in particular

in patients with iCJD) and may thus resemble PLED. Such

lateralized PSWC may reflect an early state of disease and

the pattern usually evolves into sCJD-typical bilateral

PSWC during the course of the disease. Fourth, PSWC are

an uncommon finding in patients with genetic CJD,

occurring in only about 10% of patients with fCJD, even

less often in patients with GSS and rarely in patients with

FFI. No PSWC occur in EEG recordings of patients with

vCJD (Table 4).

Finally, it is pertinent to note that prion diseases and in

particular CJD are characterized by their transmissibility

and the unusual resistance of the infectious agent to

conventional inactivation procedures. Recommendations

to prevent CJD spread in the neurological–neurosurgical

milieu usually differentiate between ‘at risk’ (including

treatment of patients with documented or suspected CJD

and those treated with cadaveric pituitary hormones, dura

mater grafts, fCJD or unexplained neurodegenerative

disease) and ‘at virtual risk’ (including treatment which

involves contact with lymph nodes, blood, intestines, lung,

liver, kidney and placenta). Established decontamination

methods of possibly prion-contaminated materials are: (1)

sodium hypochlorite solution containing 20,000 ppm

available chlorine for 1 h; (2) porous-load autoclaving at

134–138 8C for 18 min; (3) exposure to 1 M sodium

hydroxide for 1 h; and (4) gravity displacement autoclaving

at 132 8C for 1 h (Blattler, 2002).

Acknowledgements

DZ has been supported by the Swiss National Science

Foundation (grant PA00A-101502).

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EEG in Creutzfeldt–Jakob disease

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