Journal of

J Neurol (1989) 236 : 456-460

Neurology

© Springer-Verlag 1989

Temporal evolution of electroencephalographic abnormalities in Creutzfeldt-Jakob disease G. K. Schlenska 1 and G. F. Waiteß

1Department of Neurology, Niedersächsisches Landeskrankenhaus Hildesheim, Goslarsche Landstrasse 60, D-3200 Hitdesheim, Federal Republic of Germany 2Department of Neuropathology, Medizinische Hochschule Hannover, Konstanty-Gutschow-Strasse 8, D-3000 Hannover, Federal Republic of Germany

Summary. Frequent serial E E G investigations of three patients with neuropathologically confirmed Creutzfeldt-Jakob disease lasting 13, 24 and 68 weeks revealed typical periodic activity of short duration with stereotyped bilateral sharp waves at the 7th, 8th, and 12th week, respectively, after the onset of symptoms. During the later stages, there were several deviations from this typical pattern. However, periodic activity was preceded between the 3rd and 9th week by intermittent localized or lateralized delta rhythms, which gradually changed into periodic activity. This early temporal evolution of E E G abnormalities may be helpful in the early diagnosis of Creutzfeldt-Jakob disease when accompanied by other investigations to exclude other causes of intermittent delta rhythms.

Key words: Creutzfeldt-Jakob disease - Electroencephalography - Periodic activity - Delta rhythms

Introduction

In patients with Creutzfeldt-Jakob disease, which is believed to be caused by an infectious pathogen or prion [6, 18, 20], an electroencephalographic pattern consisting of bilateral, symmetrical, synchronous, stereotyped, periodic discharges has been frequently reported since its original description by Jones and Nevin [23]. This pattern, which is the only helpful laboratory test [28], is thought to be so typical that brain biopsy, which is the only other method of intra vitam diagnosis of this transmissible disease [3, 19, 30], should be unnecessary [28]; but this pattern may not appear in the early stages of the disease [28]. Transmission from man to man [5, 13, 30] of this infectious (although minimally contagious [9]) disease may also be iatrogenic [13, 30, 31, 34] and special precautions are required [7, 8, 18, 20] if an early diagnosis is to be obtained by biopsy. We therefore report the results of frequent E E G investigations, especially in the early phase, in three patients with neuropathologically confirmed Creutzfeldt-Jakob disease. Offprint requests to." G. K. Schlenska

Patients and methods Case 1. At admission, a 56-year-old female with no remarkable past history, who first noticed vertigo, gait disturbances, and difficulty in calculation 3 weeks previously, was orientated, but anxious, suspicious, and irritable. She showed rapid succession of unmotivated amusement and aggressive agitation, and marked cerebellar ataxia. Deep tendon reflexes were pronounced on the right side. In the following days generalized epileptic seizures occurred. After becoming increasingly somnolent, she then showed akinetic mutism and frequent generalized, lateralized or segmental myoclonus, and finally became comatose. Myoclonus persisted until the patient died on the 69th day after admission. Case 2. A 62-year-old male suffered from generalized seizures from the l l t h to 14th year of his life. Seizures appeared again when he was 50, provoked by alcohol ingestion. Four weeks before admission he noticed exhaustion, tiredness, difficulty in writing and speaking, and gait disturbance. He then became forgetful with poor concentration, noticed difficulty in calculating, and finally needed help in carrying out movements. On admission there was marked dysarthria, cerebellar ataxia and a rigor-like increase of muscle tone. He was disorientated, restless, apathetic and sometimes irritable. Later generalized seizures and then numerous tateralized or segmental myoclonic movements appeared. He became more somnolent and by the 138th day after admission he was comatose. Myoclonus persisted until the 156th day after admission, when he died. Case 3. A 65-year-old female who lived in the same village as case 1 was in good health until she complained of difficulty in recognizing shapes 2 months before admission. She then developed vertigo, gait disturbance, forgetfulness and a decrease in power of concentration. On admission there was cerebellar ataxia and horizontal nystagmus; she complained and was irritable but was fully orientated except for an impairment of short memory. Later she developed cortical blindness and had optic hallucinations and sense of being in danger; she was aggressive and unable to perform simple physical actions. Later-

457 alized and segmental myoclonus appeared. From the 23rd day after admission she became more somnolent and developed a right hemiparesis with Babinski's sign. After the l l 9 t h day there was a marked increase of muscle tone; she became comatose and died on the 419th day after admission. Laboratory tests, including microbiological studies, were all normal except for slight elevation of cerebrospinal fluid protein in cases 1 and 2. Cranial computed tomography showed a slight (case 1), moderate (case 2) or advanced (case 3) brain atrophy later to be confirmed at autopsy. In case 3 a bilateral, later unilateral subdural hygroma was seen.

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Histologically at autopsy the cerebral cortex in all three cases showed at different sites spongiform changes of various degree (most prominent in case 3) with vacuolation, shrunken neurons, neuronal loss, and astrocytic proliferation as weil as rarefaetion in the cerebellar granular layer. A total of 52 electroencephalograms (EEGs) were evaluated; 37 were during illness, 35 of these after the patients were hospitalized (13 in case 1; 7 in case 2; 15 in case 3); 23 were during the first 40 days. EEGs were recorded on a 12-channel machine (Picker-Schwarzer ES 12000, time constant 0.3s, high-frequency filter 70Hz, paper speed 30mm/s, sensitivity 7 gV/mm) with simultaneous recording of electrocardiogram (ECG) and respiration. In all recordings unipolar, longitudinal and transverse bipolar, and toposelective montages were used according to the international 10/20 system. The time when the majority of EEGs were recorded is shown in Fig. 1. The terms repetitive transient (RT), interval, and recurring period (RP) used in this report are defined as follows. RT is the recurrent wave or complex; interval is the time between two consecutive RTs from the end of the first to the beginning of the following RT;RP means the time from the beginning of the first to the beginning of the following RT.RPs were estimated by manual measuring; overprojeetion of RTs as shown in Fig. 2 was done by manual superimposition.

Results Clinical signs and symptoms as well as neuropathological findings with neuronal loss, spongiform change and astrocytic proliferation in all three cases correspond weil with the diagnosis of Creutzfeld-Jakob disease. Serial EEGs of all three patients besides a much slowed background activity showed a characteristic pattern, with continuous periodic activity consisting of stereotyped (Fig. 2, last row), bilateral, generalized, synchronous (Fig. 4d-f) sharp waves lasting about 200ms with amplitudes up to 200pV, which first appeared on the 31th (cases 1 and 2) and 36th (case 3) day after admission, 7, 8,

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and 12 weeks aßer onset of first symptoms. Repetition at this time was characterized by a strict periodicity with recurring periods between 0.75 and 1.05s with a small variation (Figs. 1, 3), clearly distinguishable from ECG artefacts by simultaneous ECG recording. Nevertheless, during the early and late stages there were distinct deviations from this typical pattern. In the early phase of the disease the RT itself was of longer duration in all patients, mainly of the late component, creating a "pulse-like" pattern (Figs. 2, 4a-c) as observed in the 3rd (cases 1 and 2) and the 9th week (case 3) of illness, and appeared lateralized (Fig. 4a, b) or localized (Fig. 4b, c). Howerer, RTs were already stereotyped (Fig. 2) and periodicity was intermittent (Fig. 4b), as observed in all three cases. In case 2 an E E G recorded 3 months previously was normal. In contrast to the typical pattern described above in the early stage, in all cases periodic activity was blocked when eyes were open (Fig. 5a). Alteration of shape and duration of RTs, which was apparent in all three cases, occurred in a gradual,

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progressive manner (Fig. 2a-c). Not only the shape and duration of the RTs varied with the stage of disease, but also the periodicity. The measurement of 200 consecutive RPs in each recording revealed a significant (P < 0.05) increase within 1 month in all three cases (Fig. 1), which could not be reduced by drugs given during that time. Variation of RPs within one E E G in the early stage was smaller than in later stages (Fig. 3). After that a slight, not significant decrease occurred; later very long periods with a wide variation were observed in the terminal stage. For example, it was 3.28, SD 0.85 s on the 164th day, 2.0,SD 0.8s on the 193rd day, and 1.1,SD 0.6s on the 227th day in case 3; in case 2 it was 1.2, SD 0.5 s on the 126th day (not shown in Fig. 1). During the late stage when intervals were very long, a bigeminus-like pattern sometimes appeared (Fig. 5b), or repetitive discharges of more than two grouped complexes (Fig. 5c). Otherwise long periods without any periodic activity were orten seen, especially during the last weeks before death (Fig. 5h). Several times there appeared a shift of frequency with an increase or decrease (Fig. 5d). After loss of periodic activity, a repeated occurrence was often preceded by a sudden decrease of amplitude of the slow background activity (Fig. 5e). In cäse 3 EEGs for the last 4 months before death showed no further periodic activity. Apart from

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suppression of periodic activity in the early stages when the eyes were open, we found no reaction to acoustic or painful stimuli in the EEG. Chlonazepam ( l i n g ) given intravenously in two cases led to an incomplete disappearance of periodic activity after 45 s (Fig. 5f, g). In contrast, up to 6mg clonazepma/die given orally did not influence the E E G , but myoclonus appeared to be less frequent and less marked.

Discussion

The E E G pattern in Creutzfeldt-Jakob disease, which is characteristic in the fully developed stage, is a periodic activity of short duration [17, 32, 37], probably generated in the upper brain stem [36] and appearing after neuronal loss [28] and membrane coupling [38] and even found in deep electrode recordings when missed by scalp E E G s [12]. This periodic activity consists of an RT and an interval with lower amplitude [37]. Numerous terms have been used to describe the stereotyped, synchronous, and bilateral RT; these include bi- or triphasic sharp wave [15, 16, 39], bi- or triphasie sharp wave complex [14, 15, 27, 28, 35, 36, 38], or triphasic complex [14, 15, 17, 23]. Whereas this pattern, which was also observed in our cases, is well described in numerous reports [1, 4, 10-12, 14-17, 21-24, 26-28, 33, 35-37, 39] with all the irregularities demonstrated in Fig. 5, only some have dealt with early E E G abnormalities [10, 1i, 16, 21, 27, 28, 35]. As shown in our cases and also in a previous report [10], stereotypy of RTs is demonstrable even in early E E G recordings when RTs are of long duration with no interval, a pattern what should be described as rhythmic, not periodic [37]. RTs in these recordings are higher voltage delta waves with consistent amplitude asymmetries [28, 35]. Thereafter RTs will gradually become shorter, then becoming sharp waves. Simultaneously a gradually increasing interval appears, creating the typical periodic activity. During this temporal evolution between the 3rd and 9th week of illness there is a significant increase of RPs. This increase of RPs, as shown in Fig. 1, has recently been reported in one case [16], but in this report it was not thought to be significant, probably because only 20 periods were measured.

Reviewing the literature, initial rhythmic delta waves preceding periodic activity have been demonstrated or mentioned [1, 2, 4, 10, 11, 14, 15, 17, 21, 22, 24, 26, 33, 35], but temporal evolution as shown here is apparent only in single cases [21, 28, 35, 39] when E E G recordings were done in an early stage. During the following weeks there is a decline but in the terminal stage there is a well-known increase again [10, 27, 28], reaching a duration of up to several seconds. Early repetitive activity appears intermittently; later periodic activity in most E E G recordings tends to appear nearly but not quite permanently. Beyond that, we could not confirm a progressive increase in percentage of periodic activity with increasing duration of illness, as has been reported [16]. In many E E G s our patients showed numerous runs lasting more than 10s free of periodic activity without any correlation with the course of the disease. Whereas there is almost no alternative diagnosis when the typical pattern of rapid progressive dementia, different neurological signs and symptoms, and myoclonus [28] are observed, the diagnosis within the first weeks is a challenge especially because myoclonus is absent. Early E E G abnormalities with their temporal evolution as described here are only found by frequent recordings and may provide the first clue for the diagnosis of Creutzfeldt-Jakob disease. But these early E E G abnormalities should be considered carefully, because they are not specific, and therefore should be accompanied by other investigations to exclude other causes, e.g. metabolic or inflammatory encephalopathies [32]. However, CreutzfeldtJakob disease is not excluded when periodic activity is not found even in the terminal stage, because there have been some reports of absent periodic activity during the whole course [25, 29]; nevertheless the true number of these cases may be small, because the intervals between E E G recordings were too long.

References

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Received April 10, 1989 / Received in revised form July 5, 1989 / Accepted July 18, 1989