ORIGINAL RESEARCH
Electroencephalographic Changes in Sporadic Creutzfeldt–Jakob Disease and Correlation With Clinical Stages: A Retrospective Analysis Sujith Ayyappan* and Udaya Seneviratne*†
Purpose: To analyze clinical features and EEG changes in patients with sporadic Creutzfeldt–Jakob disease and study the association between different EEG patterns and clinical stages. Methods: We retrospectively analyzed the clinical features and EEG patterns of 3 patients with clinical stage II and 10 patients with stage III sporadic Creutzfeldt–Jakob disease (EEG n ¼ 17). Chi-square test was used to study the association between EEG features and disease stages. Results: Diffuse slowing of the background was the dominant EEG pattern in stage II disease. All stage III patients showed additional abnormalities, such as frontal intermittent rhythmic delta activity, periodic discharges, and nonperiodic triphasic waves. Periodic discharges had significant association with stage III disease, present in 64% of EEGs in this group. Sixty-seven percentage of periodic discharges had a peculiar pattern labeled by us as posterior–anterior–posterior lag. Conclusions: The EEG of stage II sporadic Creutzfeldt–Jakob disease is characterized by background slowing while the presence of periodic discharge has a significant association with stage III of the disease. The posterior–anterior–posterior lag of periodic discharge is a new observation. Key Words: Creutzfeldt–Jakob disease, Electroencephalography, Periodic discharges, Triphasic waves, Dementia. (J Clin Neurophysiol 2014;31: 586–593)
and immune encephalopathies, as well as infective processes (Murray, 2011). Biopsy or postmortem pathologic examination of brain tissue is necessary for a definitive diagnosis of prion diseases. However, the clinical features in combination with MRI findings, EEG changes, and the presence of protein 14-3-3 in the cerebrospinal fluid (CSF) allow an early and reliable clinical diagnosis of sCJD. EEG remains an integral part in substantiating the diagnosis and assessment of clinical severity of the disease. In the early stages, the EEG shows only nonspecific patterns. Periodic discharges (PDs), the hallmark EEG changes of sCJD, emerge in 64% to 97% of patients later in the disease and tend to disappear in the terminal stages (Asai et al., 2001). They are less frequently observed in other types of CJD. About 10% of patients with familial CJD demonstrate PD, but those are rarely seen in fatal familial insomnia and Gerstmann–Straussler–Scheinker syndrome (Kovacs et al., 2005). Periodic discharges are typically absent in variant CJD and included as an exclusion criterion for the diagnosis (Heath et al., 2010). Iatrogenic CJD may show EEG changes similar to sCJD, including PD. Patients with iatrogenic CJD because of direct brain inoculation from neurosurgical procedures often show EEG changes restricted to the site of inoculation until late in the disease course (Wieser et al., 2004). There are insufficient data regarding the association between the EEG changes and the clinical stages of sCJD.
C
reutzfeldt–Jakob disease (CJD) is a relentlessly progressive and uniformly fatal transmissible spongiform encephalopathy, characterized by the accumulation of an abnormal prion protein in the brain. Sporadic Creutzfeldt–Jakob disease (sCJD) is the most common subtype of CJD, constituting about 84% of the total CJD cases (Ladogana et al., 2005). Sporadic CJD commonly develops in the fifth to seventh decades of life, with a mean age of onset of 62 years. The mean survival time ranges from 5.2 to 8.2 months (Roos et al., 1973); however, about 5% to 10% of patients have a clinical course extending more than 2 years (Brown et al., 1984). The clinical presentation of sCJD is heterogeneous and dominated by rapidly progressive dementia, accompanied by focal neurologic features. In the early stages, the differential diagnosis may include Alzheimer disease and other dementias, extrapyramidal diseases including Parkinson disease, cerebrovascular diseases, toxic, metabolic, paraneoplastic,
From the *Department of Neuroscience, Monash Medical Centre, Clayton, Victoria, Australia; and †Department of Medicine, Monash University, Melbourne, Victoria, Australia. Address correspondence and reprint requests to Udaya Seneviratne, FRACP, Department of Neuroscience, Monash Medical Centre, Clayton, Victoria 3168, Australia; Department of Medicine, Monash University, Melbourne, Victoria 3800, Australia; e-mail: [email protected]. Copyright Ó 2014 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/14/3106-0586
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AIM We sought to analyze the EEG changes of patients with sCJD and study the association between the EEG patterns and clinical stages of the disease.
MATERIALS AND METHODS Patients treated at Monash Medical Centre of Melbourne, Australia, with a diagnosis of probable, possible, or definite sCJD, who had at least 1 available EEG recording during the period from January 2005 to November 2012, were included in the study. Cases were identified from the hospital medical records database by running a search using the International Classification of Diseases code and from the EEG database of the neurophysiology laboratory. The study was approved by the Human Research Ethics Committee of the hospital.
Diagnosis and Classification of Sporadic Creutzfeldt–Jakob Disease We followed the World Health Organization consensus criteria (Asher et al., 1999) for the diagnosis and classification of
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sCJD into definite, probable, and possible groups. Neuropathological confirmation of sCJD from the brain tissue obtained from postmortem examination or brain biopsy is mandatory for the diagnosis of definite sCJD. When this is unavailable, a diagnosis of probable and possible sCJD may be reached based on the clinical, laboratory, and EEG features. The clinical diagnostic criteria are rapidly evolving dementia of less than 2-year duration, plus at least 2 of the following 4 clinical signs: (1) myoclonus, (2) ataxia and/or visual signs and symptoms, (3) extrapyramidal and/or pyramidal signs and symptoms, and (4) akinetic mutism. Diagnosis of probable sCJD requires the clinical criteria and presence of typical PD with triphasic morphology in EEG recordings and/or protein 14-3-3 in CSF examination. Patients with positive clinical criteria but without the characteristic EEG abnormalities and CSF protein 14-3-3 are classified as possible sCJD.
Determination of Stages The collection of clinical and epidemiological data as well as classification and staging of the disease was done by an author (S.A.) masked to the EEG data. We used the staging criteria described by Roos et al. (1973) and determined the stage of the disease based on clinical symptoms and signs documented in the medical records. The stage I sCJD was characterized by neurologic or psychiatric symptoms, but only with minor neurologic signs. These patients usually did not have impairment in their day-to-day activities. Myoclonus, typically seen in stages II and III, was rare in the first stage. The stage II sCJD was a distinct neurologic syndrome with marked impairment of higher cortical functions, sensorimotor integration, and variable cerebellar, brain stem, pyramidal and extrapyramidal involvement. Patients were clearly impaired in daily activities, but dementia per se was not evident. The stage III was defined by moderate-to-severe myoclonus and dementia, progressing to marked akinetic mutism and death (Roos et al., 1973).
EEG Recording and Analysis The EEGs were recorded with gold-plated electrodes placed over the scalp in accordance with the 10-20 international electrode system, using Compumedics digital EEG system (Compumedics Ltd, Melbourne, Australia) with low- and high-pass filters set at 70 and 0.5 Hz, respectively. A 50-Hz notch filter was also used to reduce electrical interference. All EEGs were reviewed, analyzed, and classified by an author (U.S.) masked to the clinical data. We followed the latest American Clinical Neurophysiology Society’s critical care EEG terminology in classifying the EEGs (Hirsch et al., 2013). According to this classification, PDs are defined as recurring, monomorphic waveforms at nearly regular intervals with #3 phases or duration of #0.5 seconds. The morphology of the waveform (of PD) could be sharp wave or triphasic wave. The anterior–posterior lag (AP lag) of PD was defined as $100 milliseconds delay between the most anterior and the most posterior EEG channels. The posterior– anterior lag implied a similar definition in the opposite direction. When triphasic waves occurred in isolation without periodicity, those were classified as nonperiodic triphasic waves.
intermittent or continuous) and disease stages. P , 0.05 was considered statistically significant.
RESULTS The study population comprised 12 patients with sCJD with a total of 17 EEGs available for analysis. The mean age was 67.3 6 6.7 years (range, 57–79 years) and 11 patients were females. Definite sCJD was diagnosed in two patients with autopsy confirmation. The other 10 patients had probable disease. Eight patients had data on protein 14-3-3 test that was positive in 6 and negative in 2. There were three patients in stage II and nine in stage III, but none in stage I of the disease. One patient who initially presented with stage II disease had clinical and EEG data available after progressing to stage III and was included also in stage III group for EEG analysis, increasing the total number of stage III patients to 10. The main clinical, laboratory, and EEG features of the study patients are presented in Table 1. Shortterm memory impairment without dementia and visual, cerebellar, and motor symptoms were common in the clinical presentation of stage II patients. All patients in stage III had dementia. In addition, half of stage III patients had myoclonus, whereas this was seen in only a third in stage II disease. Delirium and extrapyramidal features were seen only in stage III patients. Generalized tonic–clonic seizures were observed in three patients with stage III disease. Theta and/or delta range slowing of the background was a universal feature irrespective of the clinical stage (Table 2). Slowing was continuous in two thirds of the EEGs. In stage II patients, the background slowing was the only EEG abnormality, except for one patient who also had nonperiodic triphasic waves. In contrast, all stage III patients had additional EEG abnormalities. Frontal intermittent rhythmic delta activity was seen in one patient in stage III. A third of stage III EEGs showed triphasic waves (Fig. 1) randomly without periodicity and were distinguished from the PD and classified as nonperiodic triphasic waves. Only 20- to 30-minute routine EEGs were performed and none of the patients had sleep recordings to assess changes in PD with arousal state. Periodic discharges were noted in 9 EEGs (64.3%) in stage III disease. Detailed analysis of the PD is presented in Table 2. Periodic discharges occurred at a frequency of 1 to 1.5 Hz and showed generalized distribution in 89% of EEGs (Fig. 2) and lateralized distribution in 1 EEG. All of them had characteristic triphasic morphology. Only 22% of PD demonstrated AP lag pattern (Fig. 3). A peculiar pattern (Fig. 3) labeled by us as posterior–anterior–posterior lag (PAP lag) was seen in the majority of the PD in our patients (66.7%). We defined PAP lag of PD as initial posterior–anterior lag of $ 100 milliseconds in the anterior head region followed by AP lag in the posterior head region ( $ 100 milliseconds) with the directions resembling an asymmetric arrowhead shape in the longitudinal bipolar montage (Fig. 3). Both AP lag and PAP lag coexisted in the same EEG in 2 patients (22%). The x2 test was used to find out which EEG features were associated with advanced disease. The presence of PD was significantly associated with stage III of the illness (p ¼ 0.04; relative risk ¼ 1.6; 95% confidence interval of relative risk ¼ 0.94–2.74). There was no difference in the presence of background slowing among stages II and III (p ¼ 0.87).
Statistical Analysis Statistical analysis was performed with the IBM SPSS (Version 21) software package from IBM Corporation, New York, NY. Chi-square test was used to study the association between EEG features (background slowing, presence of PD, generalized slowing Copyright Ó 2014 by the American Clinical Neurophysiology Society
DISCUSSION In this retrospective case series, we have described the demographic and clinical data and patterns of EEG abnormalities 587
Patient
Summary of Clinical, Laboratory, and EEG Data of the Study Patients Age/Sex
Main Clinical Features
Protein 14-3-3 in CSF
1
66/M
Myoclonus, visual symptoms
2
2
67/F
Visual symptoms, short-term memory loss
1
3*
64/F
Disorientation, ataxia
1
64/F
Dementia, akinetic mutism Dementia, myoclonus, visual symptoms
1
58/F
NA
5
74/F
Dementia, seizures
6
69/F
Dementia, visual symptoms
7
57/F
Dementia, myoclonus
8
72/F
Dementia, ataxia
9
62/F
Dementia, myoclonus, visual symptoms
NA
10
75/F
Dementia, visual symptoms, seizures
2
11
65/F
Dementia, myoclonus, akinetic mutism
1
12
79/F
Dementia, myoclonus, seizures
1
NA
1
NA
1
Confluent cortical diffusion restriction involving the occipital, parietal, posterior temporal, and frontal lobes Widespread cortical diffusion restriction in the frontal, parietal, and temporal lobes; basal ganglia hyperintensities Bilateral deep subcortical white matter hyperintensities Bilateral deep subcortical white matter hyperintensities Diffusion restriction in bilateral frontal and temporal cortex; hyperintensity in basal ganglia and thalamus Mild diffuse cortical atrophy and white matter hyperintensity without diffusion restriction Diffusion restriction in bilateral frontal and temporal cortex; hyperintensity in caudate and thalamus Bilateral cortical diffusion restriction in the occipital, posterior frontal, parietal, and temporal lobes Widespread cortical diffusion restriction in the frontal, parietal, and temporal lobes and basal ganglia hyperintensities Diffusion restriction in bilateral frontal cortex and parasagittal region Cortical diffusion restriction involving the frontal, parietal, and temporal lobes; basal ganglia hyperintensities Widespread cortical diffusion restriction in the frontal, occipital, parietal, and temporal lobes Mild diffuse cortical atrophy
Histopathology
sCJD Diagnosis
Clinical Stage
Generalized slowing
1
Definite
II
Generalized slowing
1
Definite
II
Generalized slowing, nonperiodic triphasic waves Generalized slowing, PD with triphasic morphology and PAP lag Generalized slowing, nonperiodic triphasic waves, FIRDA
NA
Probable
II
NA
Probable
III
NA
Probable
III
Generalized slowing, PD with triphasic morphology and AP lag
NA
Probable
III
Generalized slowing, nonperiodic triphasic waves
NA
Probable
III
Generalized slowing, PD with triphasic morphology, and AP and PAP lag Generalized slowing, PD with triphasic morphology, and PAP lag
NA
Probable
III
NA
Probable
III
Generalized slowing, PD with triphasic morphology, and PAP lag
NA
Probable
III
Generalized slowing, nonperiodic triphasic waves, PD with triphasic morphology, and PAP lag
NA
Probable
III
Generalized slowing, PD with triphasic morphology and AP lag
NA
Probable
III
Generalized slowing, PD with triphasic and sharp morphology, and AP and PAP lag
NA
Probable
III
Main EEG Findings
*This patient had clinical and EEG data after progressing to stage III and was therefore analyzed in both stage II and stage III. AP lag, anterior–posterior lag; FIRDA, frontal intermittent rhythmic delta activity; NA, not available; PAP lag, posterior–anterior–posterior lag; PD, periodic discharge; sCJD, sporadic Creutzfeldt–Jakob disease.
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4
MRI Features
S. Ayyappan and U. Seneviratne
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TABLE 1.
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TABLE 2. Age/Sex
EEG Features of the Study Patients Stage
Background
FIRDA
66/M 67/F 64/F 64/F
II II II III
Continuous theta slowing Intermittent theta/delta slowing Continuous theta/delta slowing Continuous theta/delta slowing
2 2 2 2
58/F 74/F
III III
Continuous theta/delta slowing Continuous theta/delta slowing
1 2
69/F 57/F
III III
Intermittent theta/delta slowing Continuous theta/delta slowing
2 2
72/F
III
Continuous theta/delta slowing
2
62/F
III
Continuous theta/delta slowing
2
75/F
III
Continuous theta/delta slowing
2
65/F
III
Continuous theta/delta slowing
2
79/F
III
Continuous theta/delta slowing
2
Periodic Discharges (Distribution, Morphology, Lag, Frequency) d d d Generalized, triphasic morphology, PAP lag, 1.5 Hz d Generalized, triphasic morphology, AP lag, 1 Hz d Generalized, triphasic morphology, PAP and AP lag, 1.5 Hz Lateralized, triphasic morphology, PAP lag, 1 Hz Generalized, triphasic morphology, PAP lag, 1.5 Hz Generalized, triphasic morphology, PAP lag, 1.5 Hz Generalized, triphasic morphology, AP lag, 1 Hz Generalized, triphasic and sharp morphology, AP and PAP lag, 1 Hz
Nonperiodic Triphasic Waves 2 2 1 2 1 2 1 2 2 2 1 2 2
AP lag, anterior–posterior lag; FIRDA, frontal intermittent rhythmic delta activity; PAP lag, posterior–anterior–posterior lag.
of patients with stages II and III of sCJD. Table 3 compares our data with the previous literature.
Clinical Features and Stages Sporadic CJD typically affects patients in the middle and old age, usually in the seventh decade of life, and is slightly more
FIG. 1.
common in women (Will et al., 1998). The clinical presentation is often nonspecific at the onset of the disease, but key clinical features, such as rapidly progressive dementia, visual symptoms, cerebellar involvement, psychiatric and behavioral dysfunction, and myoclonus, emerge as the disease advances. The demographic characteristics and clinical picture of our group of patients are comparable with the current literature. Protein 14-3-3 in CSF has 90% to 97%
EEG showing nonperiodic triphasic waves in a patient with stage II disease.
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589
S. Ayyappan and U. Seneviratne
FIG. 2.
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EEG of a stage III patient with generalized periodic discharges.
sensitivity and 87% to 100% specificity for diagnosis of sCJD (Collins et al., 2000) in patients with suspected sCJD. Two patients in the study group were negative for CSF protein 14-3-3, and one of these patients had histopathologically proven definite sCJD. The other patient was diagnosed with probable sCJD according to the WHO criteria by fulfillment of clinical criteria with characteristic PD in the EEG. Only 3% of sCJD patients present with seizures as an initial symptom; however, 15% to 20% of patients develop focal motor or generalized seizures more in the later stages (Johnson and Gibbs,
1998). In our series, 30% of patients present with stage III disease had generalized tonic–clonic seizures.
EEG Changes in Early Disease In the earlier stages of the disease, EEG often shows nonspecific changes, such as a decrease of normal background activity and emergence of slow wave abnormalities, which are usually generalized, but at times focal (Hansen et al., 1998;
FIG. 3. EEG showing periodic discharges. Anterior–posterior lag of the triphasic waves is shown in the EEG on the left half and marked with arrow. Posterior–anterior–posterior lag is shown with arrows in the EEG on the right half. 590
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67% NA NA NA NA NA NA NA
Periodic Discharges and Progressive EEG Abnormalities
AP lag, anterior–posterior lag; F, fully developed stage; NA, data not available; P, prodromal stage; PAP lag, posterior–anterior–posterior lag; PD, periodic discharge; T, terminal stage.
100% 100% NA NA NA NA NA 100% 64% P 33%, F 94%, T 78% 78% 67% 86% 66% 64% 75% Current study Chiofalo et al. (1980) Levy et al. (1986) Steinhoff et al. (1996) Hansen et al. (1998) Zerr et al. (2000) Steinhoff et al. (2004) Wieser et al. (2004)
12 27 36 15 7 219 150 4
1, 11 14, 13 14, 22 6, 9 3, 4 NA 58, 92 2, 2
57–79 (67.3) 23–67 (52.9) 35–77 (61) 50–82 (68.7) 45–72 (60.7) NA 24–85 (66) 67–73 (71)
17 76 NA 68 50 NA 443 9
PDs
11% P 22%, F 82%, T 56% 100% 100% 100% 100% NA 100%
44% NA NA NA NA NA NA NA
100% NA 100% NA 100% NA NA NA 35% NA NA NA NA NA NA NA
Levy et al., 1986). All patients in our series had generalized slowing of the background, and this was the sole EEG abnormality in the majority of patients in stage II disease. In addition, one patient in stage II disease had nonperiodic triphasic waves. Frontal intermittent rhythmic delta activity is a common EEG pattern reported in up to 86% of patients along with progressive slow wave abnormalities (Hansen et al., 1998; Wieser et al., 2004). One patient in stage III disease in our series demonstrated this pattern.
PD With Triphasic Morphology Total EEG (n) Age Range (Mean) Total Male, Patients (n) Female Study
TABLE 3.
Comparison of Current Study With Previous Literature
PD With Sharp Wave Morphology
Nonperiodic Triphasic Background Slowing AP Lag PAP Lag Discharges
Journal of Clinical Neurophysiology Volume 31, Number 6, December 2014 EEG Changes in Sporadic Creutzfeldt–Jakob Disease
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Periodic discharges, the hallmark EEG changes of sCJD, have been reported in 64% to 97% of patients with sCJD in previous literature (Hansen et al., 1998; Levy et al., 1986; Steinhoff et al., 1996, 2004; Wieser et al., 2004; Zerr and Poser, 2002). They emerge by 12 to 15 weeks from the onset of disease in the majority of patients (Schlenska and Walter, 1989) and become less frequent in the terminal stages (Chiofalo et al., 1980). Levy et al. (1986) reported significant association of early appearance of PD with shorter duration of illness (p , 0.05). Periodic discharges were seen in 64% of our sCJD patients, all in stage III of the disease (Table 2). We also identified a significant association of the presence of PD with stage III of the disease. As the disease progresses, PD become smaller in amplitude with longer interburst intervals. In the terminal stages, the EEG becomes almost isoelectric, with infrequent bursts of sharp or slow waveforms that finally disappear (Asai et al., 2001; Nevin et al., 1960). Serial EEG change in individual patients was not addressed in our study because of the lack of prospective data in some patients.
Morphology of Periodic Discharges The morphology of a typical PD consists of monomorphic waveforms with #3 phases or any monomorphic waveform with duration of #0.5 seconds irrespective of the phases (Hirsch et al., 2013). Periodic discharges recur at intervals of 0.5 to 2 seconds and can show variable periodicity in the same patient. Initially, these discharges may occur sporadically or intermittently and may be unilateral or asymmetric in distribution, resembling periodic lateralized epileptiform discharges (Burger et al., 1972). With progression of the disease, they eventually evolve into the characteristic pattern of generalized and bisynchronous continuous PD. Myoclonic jerks often occur in association with PD but there is no constant relationship between them (Burger et al., 1972). Classical PDs are reported to have a fronto-precentral midline maximum and an AP lag. However, 67% of PD in our series showed a unique pattern of PAP lag. Posterior–anterior– posterior lag coexisted with AP lag in 22% but was seen in isolation in 44%. To the best of our knowledge, this particular pattern has not been previously reported in the literature. The generator of PD in sCJD is not clearly defined. However, several lines of evidence indicate involvement of both cortical and subcortical structures. A depth EEG study captured PD from frontal cortex and globus pallidus (Rayport, 1963). Another study demonstrated PD simultaneously with myoclonus on scalp EEG and depth electrodes implanted in caudate nucleus. In the terminal stage, the scalp EEG was “diffusely flat” while the depth electrode continued to show PD accentuated by auditory and pain stimuli (Chiofalo et al., 1980). Source localization of PD with independent component analysis found involvement of basal ganglia, thalami, and frontal cortex in the generation of activity 591
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(Jung et al., 2007). Significant reduction in parvalbumin-positive inhibitory neurones in the thalamus, in particular reticular thalamic nucleus, was demonstrated on immune histochemical analysis of brains from sCJD patients who had PD and myoclonus (Tschampa et al., 2002). The authors postulated that loss of inhibition would lead to generation and synchronization of PD with thalamus acting as a pacemaker. Another study found similar changes in frontal lobe biopsies, indicating the possible role played by cerebral cortex (Ferrer et al., 1993). Computerized topographic analysis found that seemingly generalized PD in sCJD in fact had multifocal cortical onset (Neufeld and Korczyn, 1992). Overall, these studies indicate generation of PD in sCJD involves both cortical and subcortical structures possibly with oscillations in thalamocortical networks. Furthermore, methionine homozygosity and methionine/valine heterozygosity as opposed to valine homozygosity at codon 129 of the prion protein gene have been shown to be associated with typical PD, suggesting genetic influence on this phenomenon (Parchi et al., 1999). The explanation for PAP lag of PD in our patients is unclear. Most patients in our series had extensive signal changes in the cortex and subcortical structures on MRI (Table 1). In the light of theories behind the genesis of PD, PAP lag is probably a reflection of complex interactions between cortical and subcortical structures in the generation and propagation of PD.
Utility of Periodic Discharges as Biomarker for Diagnosis and Staging of sCJD Periodic discharges have sensitivity of 64% to 67% in the diagnosis of sCJD (Steinhoff et al., 1996; Zerr and Poser, 2002) and high specificity (up to 91%) in the high clinical probability group (Steinhoff et al., 2004). The positive predictive value of a combination of PD and CSF protein 14-3-3 in patients with probable or possible CJD is as high as 99% (Zerr and Poser, 2002). Periodic discharges are typically seen in advanced disease and our demonstration of a significant association of PD with stage III sCJD further signifies its utility as a biomarker of this stage. Periodic discharges are rare in progressive dementia of other etiology like Alzheimer disease, vascular dementia, and Lewy body disease. Triphasic waves mimicking PD may occur in other neurologic or systemic diseases, including severe hypoxic, metabolic, or toxic encephalopathy, but clinical features enable the differentiation from sCJD.
Distinction From Epileptiform Activity Periodic discharges in sCJD should be carefully distinguished from epileptic activity. Epileptic discharges are usually time-locked with the motor clinical manifestations, whereas the myocloni associated with sCJD may occur before, during, or after the PD (Burger et al., 1972). Nonconvulsive status epilepticus with similar EEG features might pose a diagnostic dilemma. Periodic discharges are most prominent during wakefulness, tend to disappear in sleep, and are usually responsive to external stimulation, whereas the periodic epileptiform discharges are not usually influenced by sleep or external stimuli (Wieser et al., 2006). Administration of benzodiazepines is known to attenuate or abolish the PD of sCJD but without an accompanying clinical improvement. In nonconvulsive status epilepticus, abolition of periodic epileptiform discharges with benzodiazepine is usually associated with a significant improvement in the mental status (Wieser et al., 2006). In our series, three had generalized tonic–clonic seizures, but none had evidence of complex partial seizures or nonconvulsive status epilepticus. Yet, we would like to emphasize the value of sleep EEG in patients with sCJD to 592
make the distinction between typical PD of CJD and nonconvulsive status epilepticus.
LIMITATIONS We acknowledge some limitations of this study. The study was retrospective and the sample size was relatively small, mainly because of low incidence of the disease. Being a retrospective study, clinical features had to be collected from the medical records. Clinical or EEG data of patients in stage I sCJD is not available in our series, which reflects the observed delay in clinical recognition and initiation of diagnostic work-up in early disease. Definitive diagnosis of sCJD based on neuropathological confirmation was available only for two patients. However, this is unlikely to have affected the quality of the study as the rest of our patients had probable sCJD. The time course of emergence of PD and its association with mean survival were not addressed in our study because of the lack of clear information regarding the onset of disease in some patients.
CONCLUSIONS EEG remains an integral part in the diagnosis and evaluation of clinical severity of sCJD. Our study demonstrates that certain EEG patterns are helpful in recognizing the disease stage. Background slowing seems to be the main EEG feature in early stages. Triphasic waves may occur in nonperiodic manner in both stages II and III. Periodic discharges, the hallmark EEG changes of sCJD, typically occur in stage III of disease and our data demonstrate a statistically significant association of PD with stage III of the disease. We also identified a peculiar pattern of PAP lag of PD, which has not been previously reported in the literature to the best of our knowledge. Further studies are needed to delineate the specificity and sensitivity of this finding in sCJD. REFERENCES Asai Y, Shimoda M, Sasaki K, et al. Alpha-like activity in terminal stage of Creutzfeldt-Jakob disease. Acta Neurol Scand 2001;104:118–122. Asher DM, Padilla AM, Pocchiari M. WHO consultation on diagnostic procedures for transmissible spongiform encephalopathies: need for reference reagents and reference panels, Geneva, Switzerland, 22–23 March 1999. Biologicals 1999;27:265–272. Brown P, Rodgers-Johnson P, Cathala F, et al. Creutzfeldt-Jakob disease of long duration: clinicopathological characteristics, transmissibility, and differential diagnosis. Ann Neurol 1984;16:295–304. Burger LJ, Rowan AJ, Goldensohn ES. Creutzfeldt-Jakob disease: an electroencephalographic study. Arch Neurol 1972;26:428–433. Chiofalo N, Fuentes A, Galvez S. Serial EEG findings in 27 cases of CreutzfeldtJakob disease. Arch Neurol 1980;37:143–145. Collins S, Boyd A, Fletcher A, et al. Creutzfeldt–Jakob disease: diagnostic utility of 14-3-3 protein immunodetection in cerebrospinal fluid. J Clin Neurosci 2000;7:203–208. Ferrer I, Casas R, Rivera R. Parvalbumin-immunoreactive cortical neurons in Creutzfeldt–Jakob disease. Ann Neurol 1993;34:864–866. Hansen HC, Zschocke S, Sturenburg HJ, Kunze K. Clinical changes and EEG patterns preceding the onset of periodic sharp wave complexes in CreutzfeldtJakob disease. Acta Neurol Scand 1998;97:99–106. Heath C, Cooper S, Murray K, et al. Validation of diagnostic criteria for variant Creutzfeldt-Jakob disease. Ann Neurol 2010;67:761–770. Hirsch LJ, LaRoche SM, Gaspard N, et al. American Clinical Neurophysiology Society’s Standardized Critical Care EEG Terminology: 2012 version. J Clin Neurophysiol 2013;30:1–27. Johnson RT, Gibbs CJ. Creutzfeldt-Jakob disease and related transmissible spongiform encephalopathies. N Engl J Med 1998;339:1994–2004. Jung KY, Seo DW, Na DL, et al. Source localization of periodic sharp wave complexes using independent component analysis in sporadic CreutzfeldtJakob disease. Brain Res 2007;1143:228–237. Kovacs GG, Puopolo M, Ladogana A, et al. Genetic prion disease: the EUROCJD experience. Hum Genet 2005;118:166–174.
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Ladogana A, Puopolo M, Croes EA, et al. Mortality from Creutzfeldt–Jakob disease and related disorders in Europe, Australia, and Canada. Neurology 2005;64:1586–1591. Levy SR, Chiappa KH, Burke CJ, Young RR. Early evolution of incidence of electroencephalographic abnormalities in Creutzfeldt-Jakob disease. J Clin Neurophysiol 1986;3:1–21. Murray K. Creutzfeldt-Jacob disease mimics or how to sort out the subacute encephalopathy patient. Pract Neurol 2011;11:19–28. Neufeld MY, Korczyn AD. Topographic distribution of the periodic discharges in Creutzfeldt-Jakob disease. Brain Topogr 1992;4:201–206. Nevin S, McMenemey WH, Behrman S, et al. Subacute spongiform encephalopathyda subacute form of encephalopathy attributable to vascular dysfunction (spongiform cerebral atrophy). Brain 1960;83:519–564. Parchi P, Giese A, Capellari S, et al. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999;46:224–233. Rayport M. Electroencephalographic, corticographic and intracerebral potentials in two anatomically verified cases of Creutzfeldt-Jakob disease. Electroencephalogr Clin Neurophysiol 1963;15:922–931. Roos R, Gajdusek DC, Gibbs CJ Jr. The clinical characteristics of transmissible Creutzfeldt-Jakob disease. Brain 1973;96:1–20.
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Schlenska GK, Walter GF. Temporal evolution of electroencephalographic abnormalities in Creutzfeldt-Jakob disease. J Neurol 1989;236:456–460. Steinhoff BJ, Racker S, Herrendorf G, et al. Accuracy and reliability of periodic sharp wave complexes (PSWC) in Creutzfeldt–Jakob disease. Arch Neurol 1996;53:162–166. Steinhoff BJ, Zerr I, Glatting M, et al. Diagnostic value of periodic complexes in Creutzfeldt-Jakob disease. Ann Neurol 2004;56:702–708. Tschampa HJ, Herms JW, Schulz-Schaeffer WJ, et al. Clinical findings in sporadic Creutzfeldt–Jakob disease correlate with thalamic pathology. Brain 2002;125:2558–2566. Wieser HG, Schwarz U, Blättler T, et al. Serial EEG findings in sporadic and iatrogenic Creutzfeldt-Jakob disease. Clin Neurophysiol 2004;115:2467–2478. Wieser HG, Schindler K, Zumsteg D. EEG in Creutzfeldt-Jakob disease. Clin Neurophysiol 2006;117:935–951. Will RG, Alpérovitch A, Poser S, et al. Descriptive epidemiology of CreutzfeldtJakob disease in six European countries, 1993–1995. EU Collaborative Study Group for CJD. Ann Neurol 1998;43:763–767. Zerr I, Pocchiari M, Collins S, et al. Analysis of EEG and CSF 14-3-3 proteins as aids to the diagnosis of Creutzfeldt–Jakob disease. Neurology 2000;55:811–815. Zerr I, Poser S. Clinical diagnosis and differential diagnosis of CJD and vCJD with special emphasis on laboratory tests. APMIS 2002;110:88–98.
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Electroencephalographic Changes in Sporadic Creutzfeldt–Jakob Disease and Correlation With Clinical Stages: A Retrospective Analysis Sujith Ayyappan* and Udaya Seneviratne*†
Purpose: To analyze clinical features and EEG changes in patients with sporadic Creutzfeldt–Jakob disease and study the association between different EEG patterns and clinical stages. Methods: We retrospectively analyzed the clinical features and EEG patterns of 3 patients with clinical stage II and 10 patients with stage III sporadic Creutzfeldt–Jakob disease (EEG n ¼ 17). Chi-square test was used to study the association between EEG features and disease stages. Results: Diffuse slowing of the background was the dominant EEG pattern in stage II disease. All stage III patients showed additional abnormalities, such as frontal intermittent rhythmic delta activity, periodic discharges, and nonperiodic triphasic waves. Periodic discharges had significant association with stage III disease, present in 64% of EEGs in this group. Sixty-seven percentage of periodic discharges had a peculiar pattern labeled by us as posterior–anterior–posterior lag. Conclusions: The EEG of stage II sporadic Creutzfeldt–Jakob disease is characterized by background slowing while the presence of periodic discharge has a significant association with stage III of the disease. The posterior–anterior–posterior lag of periodic discharge is a new observation. Key Words: Creutzfeldt–Jakob disease, Electroencephalography, Periodic discharges, Triphasic waves, Dementia. (J Clin Neurophysiol 2014;31: 586–593)
and immune encephalopathies, as well as infective processes (Murray, 2011). Biopsy or postmortem pathologic examination of brain tissue is necessary for a definitive diagnosis of prion diseases. However, the clinical features in combination with MRI findings, EEG changes, and the presence of protein 14-3-3 in the cerebrospinal fluid (CSF) allow an early and reliable clinical diagnosis of sCJD. EEG remains an integral part in substantiating the diagnosis and assessment of clinical severity of the disease. In the early stages, the EEG shows only nonspecific patterns. Periodic discharges (PDs), the hallmark EEG changes of sCJD, emerge in 64% to 97% of patients later in the disease and tend to disappear in the terminal stages (Asai et al., 2001). They are less frequently observed in other types of CJD. About 10% of patients with familial CJD demonstrate PD, but those are rarely seen in fatal familial insomnia and Gerstmann–Straussler–Scheinker syndrome (Kovacs et al., 2005). Periodic discharges are typically absent in variant CJD and included as an exclusion criterion for the diagnosis (Heath et al., 2010). Iatrogenic CJD may show EEG changes similar to sCJD, including PD. Patients with iatrogenic CJD because of direct brain inoculation from neurosurgical procedures often show EEG changes restricted to the site of inoculation until late in the disease course (Wieser et al., 2004). There are insufficient data regarding the association between the EEG changes and the clinical stages of sCJD.
C
reutzfeldt–Jakob disease (CJD) is a relentlessly progressive and uniformly fatal transmissible spongiform encephalopathy, characterized by the accumulation of an abnormal prion protein in the brain. Sporadic Creutzfeldt–Jakob disease (sCJD) is the most common subtype of CJD, constituting about 84% of the total CJD cases (Ladogana et al., 2005). Sporadic CJD commonly develops in the fifth to seventh decades of life, with a mean age of onset of 62 years. The mean survival time ranges from 5.2 to 8.2 months (Roos et al., 1973); however, about 5% to 10% of patients have a clinical course extending more than 2 years (Brown et al., 1984). The clinical presentation of sCJD is heterogeneous and dominated by rapidly progressive dementia, accompanied by focal neurologic features. In the early stages, the differential diagnosis may include Alzheimer disease and other dementias, extrapyramidal diseases including Parkinson disease, cerebrovascular diseases, toxic, metabolic, paraneoplastic,
From the *Department of Neuroscience, Monash Medical Centre, Clayton, Victoria, Australia; and †Department of Medicine, Monash University, Melbourne, Victoria, Australia. Address correspondence and reprint requests to Udaya Seneviratne, FRACP, Department of Neuroscience, Monash Medical Centre, Clayton, Victoria 3168, Australia; Department of Medicine, Monash University, Melbourne, Victoria 3800, Australia; e-mail: [email protected]. Copyright Ó 2014 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/14/3106-0586
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AIM We sought to analyze the EEG changes of patients with sCJD and study the association between the EEG patterns and clinical stages of the disease.
MATERIALS AND METHODS Patients treated at Monash Medical Centre of Melbourne, Australia, with a diagnosis of probable, possible, or definite sCJD, who had at least 1 available EEG recording during the period from January 2005 to November 2012, were included in the study. Cases were identified from the hospital medical records database by running a search using the International Classification of Diseases code and from the EEG database of the neurophysiology laboratory. The study was approved by the Human Research Ethics Committee of the hospital.
Diagnosis and Classification of Sporadic Creutzfeldt–Jakob Disease We followed the World Health Organization consensus criteria (Asher et al., 1999) for the diagnosis and classification of
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sCJD into definite, probable, and possible groups. Neuropathological confirmation of sCJD from the brain tissue obtained from postmortem examination or brain biopsy is mandatory for the diagnosis of definite sCJD. When this is unavailable, a diagnosis of probable and possible sCJD may be reached based on the clinical, laboratory, and EEG features. The clinical diagnostic criteria are rapidly evolving dementia of less than 2-year duration, plus at least 2 of the following 4 clinical signs: (1) myoclonus, (2) ataxia and/or visual signs and symptoms, (3) extrapyramidal and/or pyramidal signs and symptoms, and (4) akinetic mutism. Diagnosis of probable sCJD requires the clinical criteria and presence of typical PD with triphasic morphology in EEG recordings and/or protein 14-3-3 in CSF examination. Patients with positive clinical criteria but without the characteristic EEG abnormalities and CSF protein 14-3-3 are classified as possible sCJD.
Determination of Stages The collection of clinical and epidemiological data as well as classification and staging of the disease was done by an author (S.A.) masked to the EEG data. We used the staging criteria described by Roos et al. (1973) and determined the stage of the disease based on clinical symptoms and signs documented in the medical records. The stage I sCJD was characterized by neurologic or psychiatric symptoms, but only with minor neurologic signs. These patients usually did not have impairment in their day-to-day activities. Myoclonus, typically seen in stages II and III, was rare in the first stage. The stage II sCJD was a distinct neurologic syndrome with marked impairment of higher cortical functions, sensorimotor integration, and variable cerebellar, brain stem, pyramidal and extrapyramidal involvement. Patients were clearly impaired in daily activities, but dementia per se was not evident. The stage III was defined by moderate-to-severe myoclonus and dementia, progressing to marked akinetic mutism and death (Roos et al., 1973).
EEG Recording and Analysis The EEGs were recorded with gold-plated electrodes placed over the scalp in accordance with the 10-20 international electrode system, using Compumedics digital EEG system (Compumedics Ltd, Melbourne, Australia) with low- and high-pass filters set at 70 and 0.5 Hz, respectively. A 50-Hz notch filter was also used to reduce electrical interference. All EEGs were reviewed, analyzed, and classified by an author (U.S.) masked to the clinical data. We followed the latest American Clinical Neurophysiology Society’s critical care EEG terminology in classifying the EEGs (Hirsch et al., 2013). According to this classification, PDs are defined as recurring, monomorphic waveforms at nearly regular intervals with #3 phases or duration of #0.5 seconds. The morphology of the waveform (of PD) could be sharp wave or triphasic wave. The anterior–posterior lag (AP lag) of PD was defined as $100 milliseconds delay between the most anterior and the most posterior EEG channels. The posterior– anterior lag implied a similar definition in the opposite direction. When triphasic waves occurred in isolation without periodicity, those were classified as nonperiodic triphasic waves.
intermittent or continuous) and disease stages. P , 0.05 was considered statistically significant.
RESULTS The study population comprised 12 patients with sCJD with a total of 17 EEGs available for analysis. The mean age was 67.3 6 6.7 years (range, 57–79 years) and 11 patients were females. Definite sCJD was diagnosed in two patients with autopsy confirmation. The other 10 patients had probable disease. Eight patients had data on protein 14-3-3 test that was positive in 6 and negative in 2. There were three patients in stage II and nine in stage III, but none in stage I of the disease. One patient who initially presented with stage II disease had clinical and EEG data available after progressing to stage III and was included also in stage III group for EEG analysis, increasing the total number of stage III patients to 10. The main clinical, laboratory, and EEG features of the study patients are presented in Table 1. Shortterm memory impairment without dementia and visual, cerebellar, and motor symptoms were common in the clinical presentation of stage II patients. All patients in stage III had dementia. In addition, half of stage III patients had myoclonus, whereas this was seen in only a third in stage II disease. Delirium and extrapyramidal features were seen only in stage III patients. Generalized tonic–clonic seizures were observed in three patients with stage III disease. Theta and/or delta range slowing of the background was a universal feature irrespective of the clinical stage (Table 2). Slowing was continuous in two thirds of the EEGs. In stage II patients, the background slowing was the only EEG abnormality, except for one patient who also had nonperiodic triphasic waves. In contrast, all stage III patients had additional EEG abnormalities. Frontal intermittent rhythmic delta activity was seen in one patient in stage III. A third of stage III EEGs showed triphasic waves (Fig. 1) randomly without periodicity and were distinguished from the PD and classified as nonperiodic triphasic waves. Only 20- to 30-minute routine EEGs were performed and none of the patients had sleep recordings to assess changes in PD with arousal state. Periodic discharges were noted in 9 EEGs (64.3%) in stage III disease. Detailed analysis of the PD is presented in Table 2. Periodic discharges occurred at a frequency of 1 to 1.5 Hz and showed generalized distribution in 89% of EEGs (Fig. 2) and lateralized distribution in 1 EEG. All of them had characteristic triphasic morphology. Only 22% of PD demonstrated AP lag pattern (Fig. 3). A peculiar pattern (Fig. 3) labeled by us as posterior–anterior–posterior lag (PAP lag) was seen in the majority of the PD in our patients (66.7%). We defined PAP lag of PD as initial posterior–anterior lag of $ 100 milliseconds in the anterior head region followed by AP lag in the posterior head region ( $ 100 milliseconds) with the directions resembling an asymmetric arrowhead shape in the longitudinal bipolar montage (Fig. 3). Both AP lag and PAP lag coexisted in the same EEG in 2 patients (22%). The x2 test was used to find out which EEG features were associated with advanced disease. The presence of PD was significantly associated with stage III of the illness (p ¼ 0.04; relative risk ¼ 1.6; 95% confidence interval of relative risk ¼ 0.94–2.74). There was no difference in the presence of background slowing among stages II and III (p ¼ 0.87).
Statistical Analysis Statistical analysis was performed with the IBM SPSS (Version 21) software package from IBM Corporation, New York, NY. Chi-square test was used to study the association between EEG features (background slowing, presence of PD, generalized slowing Copyright Ó 2014 by the American Clinical Neurophysiology Society
DISCUSSION In this retrospective case series, we have described the demographic and clinical data and patterns of EEG abnormalities 587
Patient
Summary of Clinical, Laboratory, and EEG Data of the Study Patients Age/Sex
Main Clinical Features
Protein 14-3-3 in CSF
1
66/M
Myoclonus, visual symptoms
2
2
67/F
Visual symptoms, short-term memory loss
1
3*
64/F
Disorientation, ataxia
1
64/F
Dementia, akinetic mutism Dementia, myoclonus, visual symptoms
1
58/F
NA
5
74/F
Dementia, seizures
6
69/F
Dementia, visual symptoms
7
57/F
Dementia, myoclonus
8
72/F
Dementia, ataxia
9
62/F
Dementia, myoclonus, visual symptoms
NA
10
75/F
Dementia, visual symptoms, seizures
2
11
65/F
Dementia, myoclonus, akinetic mutism
1
12
79/F
Dementia, myoclonus, seizures
1
NA
1
NA
1
Confluent cortical diffusion restriction involving the occipital, parietal, posterior temporal, and frontal lobes Widespread cortical diffusion restriction in the frontal, parietal, and temporal lobes; basal ganglia hyperintensities Bilateral deep subcortical white matter hyperintensities Bilateral deep subcortical white matter hyperintensities Diffusion restriction in bilateral frontal and temporal cortex; hyperintensity in basal ganglia and thalamus Mild diffuse cortical atrophy and white matter hyperintensity without diffusion restriction Diffusion restriction in bilateral frontal and temporal cortex; hyperintensity in caudate and thalamus Bilateral cortical diffusion restriction in the occipital, posterior frontal, parietal, and temporal lobes Widespread cortical diffusion restriction in the frontal, parietal, and temporal lobes and basal ganglia hyperintensities Diffusion restriction in bilateral frontal cortex and parasagittal region Cortical diffusion restriction involving the frontal, parietal, and temporal lobes; basal ganglia hyperintensities Widespread cortical diffusion restriction in the frontal, occipital, parietal, and temporal lobes Mild diffuse cortical atrophy
Histopathology
sCJD Diagnosis
Clinical Stage
Generalized slowing
1
Definite
II
Generalized slowing
1
Definite
II
Generalized slowing, nonperiodic triphasic waves Generalized slowing, PD with triphasic morphology and PAP lag Generalized slowing, nonperiodic triphasic waves, FIRDA
NA
Probable
II
NA
Probable
III
NA
Probable
III
Generalized slowing, PD with triphasic morphology and AP lag
NA
Probable
III
Generalized slowing, nonperiodic triphasic waves
NA
Probable
III
Generalized slowing, PD with triphasic morphology, and AP and PAP lag Generalized slowing, PD with triphasic morphology, and PAP lag
NA
Probable
III
NA
Probable
III
Generalized slowing, PD with triphasic morphology, and PAP lag
NA
Probable
III
Generalized slowing, nonperiodic triphasic waves, PD with triphasic morphology, and PAP lag
NA
Probable
III
Generalized slowing, PD with triphasic morphology and AP lag
NA
Probable
III
Generalized slowing, PD with triphasic and sharp morphology, and AP and PAP lag
NA
Probable
III
Main EEG Findings
*This patient had clinical and EEG data after progressing to stage III and was therefore analyzed in both stage II and stage III. AP lag, anterior–posterior lag; FIRDA, frontal intermittent rhythmic delta activity; NA, not available; PAP lag, posterior–anterior–posterior lag; PD, periodic discharge; sCJD, sporadic Creutzfeldt–Jakob disease.
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4
MRI Features
S. Ayyappan and U. Seneviratne
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TABLE 1.
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TABLE 2. Age/Sex
EEG Features of the Study Patients Stage
Background
FIRDA
66/M 67/F 64/F 64/F
II II II III
Continuous theta slowing Intermittent theta/delta slowing Continuous theta/delta slowing Continuous theta/delta slowing
2 2 2 2
58/F 74/F
III III
Continuous theta/delta slowing Continuous theta/delta slowing
1 2
69/F 57/F
III III
Intermittent theta/delta slowing Continuous theta/delta slowing
2 2
72/F
III
Continuous theta/delta slowing
2
62/F
III
Continuous theta/delta slowing
2
75/F
III
Continuous theta/delta slowing
2
65/F
III
Continuous theta/delta slowing
2
79/F
III
Continuous theta/delta slowing
2
Periodic Discharges (Distribution, Morphology, Lag, Frequency) d d d Generalized, triphasic morphology, PAP lag, 1.5 Hz d Generalized, triphasic morphology, AP lag, 1 Hz d Generalized, triphasic morphology, PAP and AP lag, 1.5 Hz Lateralized, triphasic morphology, PAP lag, 1 Hz Generalized, triphasic morphology, PAP lag, 1.5 Hz Generalized, triphasic morphology, PAP lag, 1.5 Hz Generalized, triphasic morphology, AP lag, 1 Hz Generalized, triphasic and sharp morphology, AP and PAP lag, 1 Hz
Nonperiodic Triphasic Waves 2 2 1 2 1 2 1 2 2 2 1 2 2
AP lag, anterior–posterior lag; FIRDA, frontal intermittent rhythmic delta activity; PAP lag, posterior–anterior–posterior lag.
of patients with stages II and III of sCJD. Table 3 compares our data with the previous literature.
Clinical Features and Stages Sporadic CJD typically affects patients in the middle and old age, usually in the seventh decade of life, and is slightly more
FIG. 1.
common in women (Will et al., 1998). The clinical presentation is often nonspecific at the onset of the disease, but key clinical features, such as rapidly progressive dementia, visual symptoms, cerebellar involvement, psychiatric and behavioral dysfunction, and myoclonus, emerge as the disease advances. The demographic characteristics and clinical picture of our group of patients are comparable with the current literature. Protein 14-3-3 in CSF has 90% to 97%
EEG showing nonperiodic triphasic waves in a patient with stage II disease.
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S. Ayyappan and U. Seneviratne
FIG. 2.
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EEG of a stage III patient with generalized periodic discharges.
sensitivity and 87% to 100% specificity for diagnosis of sCJD (Collins et al., 2000) in patients with suspected sCJD. Two patients in the study group were negative for CSF protein 14-3-3, and one of these patients had histopathologically proven definite sCJD. The other patient was diagnosed with probable sCJD according to the WHO criteria by fulfillment of clinical criteria with characteristic PD in the EEG. Only 3% of sCJD patients present with seizures as an initial symptom; however, 15% to 20% of patients develop focal motor or generalized seizures more in the later stages (Johnson and Gibbs,
1998). In our series, 30% of patients present with stage III disease had generalized tonic–clonic seizures.
EEG Changes in Early Disease In the earlier stages of the disease, EEG often shows nonspecific changes, such as a decrease of normal background activity and emergence of slow wave abnormalities, which are usually generalized, but at times focal (Hansen et al., 1998;
FIG. 3. EEG showing periodic discharges. Anterior–posterior lag of the triphasic waves is shown in the EEG on the left half and marked with arrow. Posterior–anterior–posterior lag is shown with arrows in the EEG on the right half. 590
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67% NA NA NA NA NA NA NA
Periodic Discharges and Progressive EEG Abnormalities
AP lag, anterior–posterior lag; F, fully developed stage; NA, data not available; P, prodromal stage; PAP lag, posterior–anterior–posterior lag; PD, periodic discharge; T, terminal stage.
100% 100% NA NA NA NA NA 100% 64% P 33%, F 94%, T 78% 78% 67% 86% 66% 64% 75% Current study Chiofalo et al. (1980) Levy et al. (1986) Steinhoff et al. (1996) Hansen et al. (1998) Zerr et al. (2000) Steinhoff et al. (2004) Wieser et al. (2004)
12 27 36 15 7 219 150 4
1, 11 14, 13 14, 22 6, 9 3, 4 NA 58, 92 2, 2
57–79 (67.3) 23–67 (52.9) 35–77 (61) 50–82 (68.7) 45–72 (60.7) NA 24–85 (66) 67–73 (71)
17 76 NA 68 50 NA 443 9
PDs
11% P 22%, F 82%, T 56% 100% 100% 100% 100% NA 100%
44% NA NA NA NA NA NA NA
100% NA 100% NA 100% NA NA NA 35% NA NA NA NA NA NA NA
Levy et al., 1986). All patients in our series had generalized slowing of the background, and this was the sole EEG abnormality in the majority of patients in stage II disease. In addition, one patient in stage II disease had nonperiodic triphasic waves. Frontal intermittent rhythmic delta activity is a common EEG pattern reported in up to 86% of patients along with progressive slow wave abnormalities (Hansen et al., 1998; Wieser et al., 2004). One patient in stage III disease in our series demonstrated this pattern.
PD With Triphasic Morphology Total EEG (n) Age Range (Mean) Total Male, Patients (n) Female Study
TABLE 3.
Comparison of Current Study With Previous Literature
PD With Sharp Wave Morphology
Nonperiodic Triphasic Background Slowing AP Lag PAP Lag Discharges
Journal of Clinical Neurophysiology Volume 31, Number 6, December 2014 EEG Changes in Sporadic Creutzfeldt–Jakob Disease
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Periodic discharges, the hallmark EEG changes of sCJD, have been reported in 64% to 97% of patients with sCJD in previous literature (Hansen et al., 1998; Levy et al., 1986; Steinhoff et al., 1996, 2004; Wieser et al., 2004; Zerr and Poser, 2002). They emerge by 12 to 15 weeks from the onset of disease in the majority of patients (Schlenska and Walter, 1989) and become less frequent in the terminal stages (Chiofalo et al., 1980). Levy et al. (1986) reported significant association of early appearance of PD with shorter duration of illness (p , 0.05). Periodic discharges were seen in 64% of our sCJD patients, all in stage III of the disease (Table 2). We also identified a significant association of the presence of PD with stage III of the disease. As the disease progresses, PD become smaller in amplitude with longer interburst intervals. In the terminal stages, the EEG becomes almost isoelectric, with infrequent bursts of sharp or slow waveforms that finally disappear (Asai et al., 2001; Nevin et al., 1960). Serial EEG change in individual patients was not addressed in our study because of the lack of prospective data in some patients.
Morphology of Periodic Discharges The morphology of a typical PD consists of monomorphic waveforms with #3 phases or any monomorphic waveform with duration of #0.5 seconds irrespective of the phases (Hirsch et al., 2013). Periodic discharges recur at intervals of 0.5 to 2 seconds and can show variable periodicity in the same patient. Initially, these discharges may occur sporadically or intermittently and may be unilateral or asymmetric in distribution, resembling periodic lateralized epileptiform discharges (Burger et al., 1972). With progression of the disease, they eventually evolve into the characteristic pattern of generalized and bisynchronous continuous PD. Myoclonic jerks often occur in association with PD but there is no constant relationship between them (Burger et al., 1972). Classical PDs are reported to have a fronto-precentral midline maximum and an AP lag. However, 67% of PD in our series showed a unique pattern of PAP lag. Posterior–anterior– posterior lag coexisted with AP lag in 22% but was seen in isolation in 44%. To the best of our knowledge, this particular pattern has not been previously reported in the literature. The generator of PD in sCJD is not clearly defined. However, several lines of evidence indicate involvement of both cortical and subcortical structures. A depth EEG study captured PD from frontal cortex and globus pallidus (Rayport, 1963). Another study demonstrated PD simultaneously with myoclonus on scalp EEG and depth electrodes implanted in caudate nucleus. In the terminal stage, the scalp EEG was “diffusely flat” while the depth electrode continued to show PD accentuated by auditory and pain stimuli (Chiofalo et al., 1980). Source localization of PD with independent component analysis found involvement of basal ganglia, thalami, and frontal cortex in the generation of activity 591
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(Jung et al., 2007). Significant reduction in parvalbumin-positive inhibitory neurones in the thalamus, in particular reticular thalamic nucleus, was demonstrated on immune histochemical analysis of brains from sCJD patients who had PD and myoclonus (Tschampa et al., 2002). The authors postulated that loss of inhibition would lead to generation and synchronization of PD with thalamus acting as a pacemaker. Another study found similar changes in frontal lobe biopsies, indicating the possible role played by cerebral cortex (Ferrer et al., 1993). Computerized topographic analysis found that seemingly generalized PD in sCJD in fact had multifocal cortical onset (Neufeld and Korczyn, 1992). Overall, these studies indicate generation of PD in sCJD involves both cortical and subcortical structures possibly with oscillations in thalamocortical networks. Furthermore, methionine homozygosity and methionine/valine heterozygosity as opposed to valine homozygosity at codon 129 of the prion protein gene have been shown to be associated with typical PD, suggesting genetic influence on this phenomenon (Parchi et al., 1999). The explanation for PAP lag of PD in our patients is unclear. Most patients in our series had extensive signal changes in the cortex and subcortical structures on MRI (Table 1). In the light of theories behind the genesis of PD, PAP lag is probably a reflection of complex interactions between cortical and subcortical structures in the generation and propagation of PD.
Utility of Periodic Discharges as Biomarker for Diagnosis and Staging of sCJD Periodic discharges have sensitivity of 64% to 67% in the diagnosis of sCJD (Steinhoff et al., 1996; Zerr and Poser, 2002) and high specificity (up to 91%) in the high clinical probability group (Steinhoff et al., 2004). The positive predictive value of a combination of PD and CSF protein 14-3-3 in patients with probable or possible CJD is as high as 99% (Zerr and Poser, 2002). Periodic discharges are typically seen in advanced disease and our demonstration of a significant association of PD with stage III sCJD further signifies its utility as a biomarker of this stage. Periodic discharges are rare in progressive dementia of other etiology like Alzheimer disease, vascular dementia, and Lewy body disease. Triphasic waves mimicking PD may occur in other neurologic or systemic diseases, including severe hypoxic, metabolic, or toxic encephalopathy, but clinical features enable the differentiation from sCJD.
Distinction From Epileptiform Activity Periodic discharges in sCJD should be carefully distinguished from epileptic activity. Epileptic discharges are usually time-locked with the motor clinical manifestations, whereas the myocloni associated with sCJD may occur before, during, or after the PD (Burger et al., 1972). Nonconvulsive status epilepticus with similar EEG features might pose a diagnostic dilemma. Periodic discharges are most prominent during wakefulness, tend to disappear in sleep, and are usually responsive to external stimulation, whereas the periodic epileptiform discharges are not usually influenced by sleep or external stimuli (Wieser et al., 2006). Administration of benzodiazepines is known to attenuate or abolish the PD of sCJD but without an accompanying clinical improvement. In nonconvulsive status epilepticus, abolition of periodic epileptiform discharges with benzodiazepine is usually associated with a significant improvement in the mental status (Wieser et al., 2006). In our series, three had generalized tonic–clonic seizures, but none had evidence of complex partial seizures or nonconvulsive status epilepticus. Yet, we would like to emphasize the value of sleep EEG in patients with sCJD to 592
make the distinction between typical PD of CJD and nonconvulsive status epilepticus.
LIMITATIONS We acknowledge some limitations of this study. The study was retrospective and the sample size was relatively small, mainly because of low incidence of the disease. Being a retrospective study, clinical features had to be collected from the medical records. Clinical or EEG data of patients in stage I sCJD is not available in our series, which reflects the observed delay in clinical recognition and initiation of diagnostic work-up in early disease. Definitive diagnosis of sCJD based on neuropathological confirmation was available only for two patients. However, this is unlikely to have affected the quality of the study as the rest of our patients had probable sCJD. The time course of emergence of PD and its association with mean survival were not addressed in our study because of the lack of clear information regarding the onset of disease in some patients.
CONCLUSIONS EEG remains an integral part in the diagnosis and evaluation of clinical severity of sCJD. Our study demonstrates that certain EEG patterns are helpful in recognizing the disease stage. Background slowing seems to be the main EEG feature in early stages. Triphasic waves may occur in nonperiodic manner in both stages II and III. Periodic discharges, the hallmark EEG changes of sCJD, typically occur in stage III of disease and our data demonstrate a statistically significant association of PD with stage III of the disease. We also identified a peculiar pattern of PAP lag of PD, which has not been previously reported in the literature to the best of our knowledge. Further studies are needed to delineate the specificity and sensitivity of this finding in sCJD. REFERENCES Asai Y, Shimoda M, Sasaki K, et al. Alpha-like activity in terminal stage of Creutzfeldt-Jakob disease. Acta Neurol Scand 2001;104:118–122. Asher DM, Padilla AM, Pocchiari M. WHO consultation on diagnostic procedures for transmissible spongiform encephalopathies: need for reference reagents and reference panels, Geneva, Switzerland, 22–23 March 1999. Biologicals 1999;27:265–272. Brown P, Rodgers-Johnson P, Cathala F, et al. Creutzfeldt-Jakob disease of long duration: clinicopathological characteristics, transmissibility, and differential diagnosis. Ann Neurol 1984;16:295–304. Burger LJ, Rowan AJ, Goldensohn ES. Creutzfeldt-Jakob disease: an electroencephalographic study. Arch Neurol 1972;26:428–433. Chiofalo N, Fuentes A, Galvez S. Serial EEG findings in 27 cases of CreutzfeldtJakob disease. Arch Neurol 1980;37:143–145. Collins S, Boyd A, Fletcher A, et al. Creutzfeldt–Jakob disease: diagnostic utility of 14-3-3 protein immunodetection in cerebrospinal fluid. J Clin Neurosci 2000;7:203–208. Ferrer I, Casas R, Rivera R. Parvalbumin-immunoreactive cortical neurons in Creutzfeldt–Jakob disease. Ann Neurol 1993;34:864–866. Hansen HC, Zschocke S, Sturenburg HJ, Kunze K. Clinical changes and EEG patterns preceding the onset of periodic sharp wave complexes in CreutzfeldtJakob disease. Acta Neurol Scand 1998;97:99–106. Heath C, Cooper S, Murray K, et al. Validation of diagnostic criteria for variant Creutzfeldt-Jakob disease. Ann Neurol 2010;67:761–770. Hirsch LJ, LaRoche SM, Gaspard N, et al. American Clinical Neurophysiology Society’s Standardized Critical Care EEG Terminology: 2012 version. J Clin Neurophysiol 2013;30:1–27. Johnson RT, Gibbs CJ. Creutzfeldt-Jakob disease and related transmissible spongiform encephalopathies. N Engl J Med 1998;339:1994–2004. Jung KY, Seo DW, Na DL, et al. Source localization of periodic sharp wave complexes using independent component analysis in sporadic CreutzfeldtJakob disease. Brain Res 2007;1143:228–237. Kovacs GG, Puopolo M, Ladogana A, et al. Genetic prion disease: the EUROCJD experience. Hum Genet 2005;118:166–174.
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Journal of Clinical Neurophysiology Volume 31, Number 6, December 2014 EEG Changes in Sporadic Creutzfeldt–Jakob Disease
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