Elsevier

Clinical Neurophysiology

Volume 115, Issue 11, November 2004, Pages 2467-2478
Clinical Neurophysiology

Serial EEG findings in sporadic and iatrogenic Creutzfeldt–Jakob disease

https://doi.org/10.1016/j.clinph.2004.05.032Get rights and content

Abstract

Objective: To study temporal and spatial development of EEG patterns in sporadic and iatrogenic Creutzfeldt–Jakob disease patients.

Methods: Temporal and spatial development of EEG patterns in 4 patients with sporadic Creutzfeldt–Jakob disease and 2 patients with iatrogenic Creutzfeldt–Jakob disease due to implantation of contaminated brain depth electrodes were investigated. A total of 56 EEGs were analyzed, over time spans ranging from 1272 to 3 days prior to death.

Results: Frontal intermittent rhythmical delta activity (FIRDA) was seen at early timepoints in 4/6 patients and might represent an early EEG pattern that is associated, with human prion diseases. EEG patterns associated with CJD are sensitive to midazolam. Initial EEG changes were seen at the site of prion exposure in iatrogenic Creutzfeldt–Jakob disease patients, before they could be observed at distant sites, suggesting that prion disease was initiated at the site of prion exposure.

Conclusions: Serial EEG recordings are a valuable tool not only in the early diagnosis of sporadic CJD, but also in the determination of prion exposure in iatrogenic Creutzfeldt–Jakob disease.

Significance: FIRDA occur at an early stage of CJD and are progressively replaced by the classical PSWC. The EEG patterns of CJD are sensitive to midazolam. The initial EEG changes in iatrogenic CJD are seen at the site of prion exposure.

Introduction

Transmissible spongiform encephalopathies or prion diseases are a group of diseases occurring both in humans and a wide variety of animals. Although the true nature of the agent causing transmissible spongiform encephalopathies has yet to be determined, a wealth of evidence indicates that an essential component of the infectious agent, termed prion, is composed of an abnormal isoform of the host encoded prion protein (PrPC), designated PrPSc (Glatzel et al., 2003).

Human prion diseases are categorized into sporadically occurring diseases (sporadic Creutzfeldt–Jakob disease, sCJD) or inherited forms (genetic Creutzfeldt–Jakob disease, fCJD). Alternatively these diseases may be caused by accidental transmission of prion-contaminated material, be it in the framework of neurosurgical interventions, or be it through injection of prion-contaminated hormones (iatrogenic Creutzfeldt–Jakob disease, iCJD). Variant Creutzfeldt–Jakob disease (vCJD), a new member of the family of acquired human prion diseases, is probably caused by uptake of material contaminated with bovine spongiform encephalopathy prions (Ironside et al., 2002, Ironside, 2003, Ironside et al., 2002).

Definite diagnosis of most human prion diseases is only possible by neuropathological examination of cerebral tissue originating from a brain biopsy or post-mortem examination. The diagnosis of a probable human prion disease, however, is based on clinical findings in combination with auxiliary examinations such as magnetic resonance tomography, cerebrospinal fluid (CSF) analysis and EEG findings.

The EEG still constitutes one of the most important investigations in the diagnosis of human prion diseases or in the judgment of the clinical course of this disease entity.

Surprisingly little is known on the temporal or spatial development of EEG patterns both in sCJD or iCJD. In this study we investigated the development of EEG patterns in a group of sCJD patients and iCJD patients with serial EEG recordings (minimum 4, maximum 29, mean 9.3), documented prior to prion exposure (iCJD) or during various disease phases (iCJD and sCJD). Iatrogenic CJD patients had been exposed to intracerebrally implantated, prion contaminated stereo EEG electrodes.

By examining 56 EEG patterns in 4 patients with sCJD and two patients with iCJD, we were able to substantiate the observation that frontal intermittent rhythmical delta activity (FIRDA) might represent an EEG pattern associated with the initial phase of clinical CJD, whereas typical periodic sharp wave complexes (PSWC) can only be observed at late stages of the disease, usually occurring with or shortly after the onset of myoclonus and akinetic mutism (Sun et al., 2003). EEG analyses in two patients with iCJD demonstrate that pathological EEG findings spread from the site of infection to other parts of the central nervous system suggesting a centrifugal spread of the agent causing human prion diseases.

Section snippets

Diagnosis of sporadic and iatrogenic CJD

Sporadic and iatrogenic CJD were diagnosed according to the classification criteria established by the WHO (Asher et al., 1999). For sCJD, definite sCJD can only be diagnosed via neuropathological examination. Probable sCJD encompasses rapid progressive dementia in less then 2 years and at least 2 out of 4 of the following clinical signs: myoclonus, cerebellar and/or visual symptoms, extrapyramidal and/or pyramidal signs and akinetic mutism. Additional investigations such as CJD-typical EEG

Patients characteristics for sporadic CJD

Patient 1. This patient, a 73 year old woman, with a disease duration of around 3 months, developed typical clinical signs of sporadic CJD with rapid progressive dementia followed by severe ataxia and myoclonic jerks (Table 1). She was tested positive for 14-3-3 in CSF and serial EEG analysis demonstrated CJD typical PSWC; documented 53–3 days before death (Fig. 1). Neuropathological, biochemical and genetic examination gave evidence of sCJD, MM1 (Parchi et al., 1999).

Patient 2. This patient, a

Discussion

The diagnosis of human prion diseases is based on the appraisal of clinical signs and symptoms and a number of auxiliary examinations. Over the last decades electroencephalography has been the method of choice in order to substantiate the diagnosis of a human prion disease. In the last years additional methods such as the elevation of markers of neuronal injury in the CSF have facilitated clinical diagnosis of human prion diseases and the combination of EEG and CSF analysis carries a positive

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