Typical EEG Pattern Research Articles

EEG Patterns in Hypoxic Encephalopathies (Post–Cardiac Arrest Syndrome)

In patients with coma resulting from hypoxic encephalopathy (e.g., after cardiac arrest), the EEG may reflect the severity of brain dysfunction, although the exact relationship among the EEG changes, the extent of neuronal damage, and consequent prognosis is still under study. Many prognostications are based on particular EEG patterns at a time point, such as burst suppression or generalized periodic discharges, but with sequential, repeated, or with prolonged or continuous EEG monitoring, it has become increasingly clear that more information might be gleaned from EEG pattern changes over time. Short-term fluctuations (as opposed to permanent transitions), or preserved reactions to exogenous stimuli, have to be differentiated. This review presents many of the typical postanoxic EEG patterns, along with their evolution over time. This preliminary report illustrates the temporal dynamic changes of EEG over time. It is hoped that it will act as a starting point for prospective and systematic investigation to test whether EEG evolution and transitions add diagnostic and prognostic value.

Screening of UBE3A gene in patients referred for Angelman Syndrome

Angelman Syndrome (AS) is a neurodevelopmental disorder characterized by severe developmental delay, speech impairment and unique behaviors including inappropriate laughter and happy disposition. AS is related to deficient maternal UBE3A gene expression caused either by chromosomal deletions, uniparental disomy, molecular defects of the imprinted 15q11-q13 critical region or by loss of function mutations in the maternally inherited UBE3A. In the present study, screening UBE3A was performed in 43 patients who were referred for AS but whom previous molecular diagnostic tests failed to provide a diagnosis. Two causative mutations – one of them novel – and four polymorphic variants one of which is also novel were revealed. Further investigation of 7 patients disclosed defects in other genes involved in clinical phenotypes mimicking AS. A typical EEG pattern and microcephaly in patients with developmental delay prompt for AS investigation while wide genetic screening should be applied to help resolution of the complex phenotypes characterized by developmental delay.

Electroclinical pattern in MECP2 duplication syndrome: Eight new reported cases and review of literature

Duplications encompassing the MECP2 gene on the Xq28 region have been described in male patients with moderate to severe mental retardation, absent speech, neonatal hypotonia, progressive spasticity and/or ataxia, recurrent severe respiratory infections, gastrointestinal problems, mild facial dysmorphisms (midface hypoplasia, depressed nasal bridge, large ears) and epilepsy. Epilepsy can occur in >50% of cases, but the types of seizures and the electroclinical findings in affected male individuals have been poorly investigated up to the present. Herein we describe eight patients with MECP2 duplication syndrome and a specific clinical and electroencephalographic pattern. Array CGH of genomic DNA from the probands was performed, and an Xq28 duplication ranging from 209 kb to 6.36 Mb was found in each patient. Electroencephalography studies and clinical and seizure features of all the patients were analyzed. We found that epilepsy tended to occur between late childhood and adolescence. Episodes of loss of tone of the head and/or the trunk were the most represented seizure types. Generalized tonic-clonic seizures were rarely observed. The typical interictal EEG pattern showed abnormal background activity, with generalized slow spike and wave asynchronous discharge with frontotemporal predominance. Sleep electroencephalography studies also demonstrated abnormal background activity; spindles and K complex were often abnormal in morphology and amplitude. Response to therapy was generally poor and drug resistance was a significant feature. Although these cases and a review of the literature indicate that epilepsy associated with MECP2 duplication syndrome cannot be considered a useful marker for early diagnosis, epilepsy is present in >90% of adolescent patients and shows a peculiar electroclinical pattern. Consequently, it should be considered a significant sign of the syndrome, and an EEG follow-up of these patients should be encouraged from early childhood. Moreover, the definition of a more specific epileptic phenotype could be useful in order to suspect MECP2 duplication syndrome in older undiagnosed patients.

Therapy of encephalopathy with status epilepticus during sleep (ESES/CSWS syndrome): an update

Electrical status epilepticus in sleep (ESES)/continuous spikes and waves during slow sleep (CSWS) is an age-related, self-limiting disorder characterised by epilepsy with different seizure types, global or selective neuropsychological regression, motor impairment, and a typical EEG pattern of continuous epileptiform activity for more than 85% of non-rapid eye movement (NREM) sleep. Although the first description of ESES/CSWS dates back to 1971, an agreement about the optimal treatment for this condition is still lacking. ESES/CSWS is rare (incidence is 0.2-0.5% of all childhood epilepsies) and no controlled clinical trials have been conducted to establish the efficacy of different antiepileptic drugs; only uncontrolled studies and case reports are reported in the literature. Treatment options for ESES/CSWS include some antiepileptic drugs (valproic acid, ethosuximide, levetiracetam, and benzodiazepines), steroids, immunoglobulins, the ketogenic diet, and surgery (multiple subpial transections). In this study, the comparative value of each of these treatments is reviewed and a personal therapeutic approach is proposed.

West syndrome: early remission is not assurance of normal final outcome

West syndrome (WS), an age-specific epilepsy of infancy and early childhood, considered of poor prognosis, may have remission. With the objective of describing the clinical features, treatment and outcome of the children with WS followed in a Latin American country, we devised a retrospective study. Infants with recurrent spasms, and typical or atypical hypsarrhythmia on electroencephalography (EEG) were included, and their medical report reviewed with particular interest on therapy (anti-epileptic drug, steroids) and outcome. Short-term (remission of spasms up to 6 months after the beginning) and long-term outcome (development and seizure status over the age of 2 years) were focused. Of the 37 selected infants, most (29/37, 78.3%) were classified as symptomatic, and neonatal history of hypoxia (10/29) was the most frequent etiology. The majority had a typical hypsarrhythmia EEG pattern. Most used a combination of anti-epileptic drugs and steroids. A favourable short-term outcome occurred in 20 infants, but only three had normal development and were seizure free after the age of 2 years. Early seizure remission is not assurance of normal final outcome in WS.

Lennox-Gastauts syndrom - forløp og behandling

Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy, which starts in childhood with various seizure types. The children develop cognitive impairment and a typical EEG pattern. The aim of this article is to describe the clinical presentation of LGS, with particular emphasis on the course in adulthood. The article is based on literature (up to November 2009) identified through a non-systematic search in PubMed and our own clinical experience. There are cases with unknown etiology and symptomatic cases with a wide spectrum of etiologies. While children with LGS have a high frequency of generalized seizures, seizure activity tends to decrease somewhat in adulthood and the seizures may become more focal. The prognosis is usually poor. The adult patient with LGS is clearly affected by global encephalopathy and is typically characterized by bluntness, apathy, progressive cognitive failure and motoric deficits. Valproate has been the first-line treatment for many years, but newer antiepileptic drugs; such as lamotrigine, topiramate and rufinamide, have shown efficacy as add-on therapy. Overtreatment with antiepileptic drugs is common. For optimal treatment, a specialist should follow LGS patients at all ages. New treatment options with milder side effects may improve the quality of life for these patients.

Complex Segmental Duplications Mediate a Recurrent dup(X)(p11.22-p11.23) Associated with Mental Retardation, Speech Delay, and EEG Anomalies in Males and Females

Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.

Eyelid fluttering, typical EEG pattern, and impaired intellectual function: A homogeneous epileptic condition among the patients presenting with eyelid myoclonia

This retrospective study aims to review the electroclinical features of patients presenting with eyelid myoclonia (EM) with and without absences. The Italian chapter of the International League Against Epilepsy (ILAE) has been conducting an electroclinical study of patients with EM. Among these, we searched for and selected the patients presenting with both impairment of intellectual functions and a peculiar ictal electroencephalography (EEG) pattern, that is, a discharge of fast generalized polyspikes/polyspikes and waves. We found 18 patients matching this electroclinical picture. All the patients were photosensitive. All of them had associated generalized, mostly nocturnal, tonic-clonic seizures. During the evolution, 13 patients presented episodes of EM status. Despite adequate antiepileptic treatment, the patients remained drug resistant for many years or throughout the evolution. The degree of impairment of intellectual functions varied from borderline level to moderate mental retardation. The patients we described herein can be considered a homogeneous group in the more heterogeneous group of patients presenting with EM. Further clinical and, more probably, genetic studies will clarify whether this condition could be considered a specific and homogeneous condition in the more heterogeneous group of patients presenting with EM.

Electroencephalographic evolution of hypsarrhythmia: Toward an early treatment option

A retrospective study for a classification of prehypsarrhythmic elecroencephalographies (EEGs) was carried out to enable an early treatment option for West syndrome. Out of 39 infants with symptomatic West syndrome, 18 infants (age 3-14 months) with 61 serial non-REM sleep EEG records of the prehypsarrhythmic phase were identified. The prehypsarrhythmic phase encompassed 2 to 13 months (mean 4.5 months) after an initial insult. A classification system of three EEG types corresponding to the clinical states prior to West syndrome occurrence was developed. In addition, follow-up of all patients presenting with type 2 EEGs (n = 22) was evaluated. Three clinical states and corresponding EEG types were classified. Clinical state 1 (weeks to months, silent phase) presented with (multi-)focal epileptic discharges <50% of the non-REM EEG recording time (type 1 EEG). Clinical state 2 (several weeks, beginning mental deterioration) was accompanied by type 2 EEG with bihemispheric epileptic discharges >50% of the non-REM EEG recording time within abnormal background activity (imminent hypsarrhythmia). Clinical state 3 (mental deterioration) was characterized by hypsarryhthmia. Interrater reliability of seven blinded raters was good (median weighted kappa 0.67). Out of 22 patients presenting with type 2 EEGs, two were lost for follow-up, and 16 developed West syndrome, whereas four were treated early with anti-epileptic drugs and remained stable. Infants with West syndrome could be reliably identified several weeks before the occurrence of hypsarrhythmia by a typical EEG pattern (type 2), thereby opening the way for early intervention studies.

Combined Transcranial Doppler and EEG Recording in Vasovagal Syncope

Background: In neurally mediated syncope a ‘typical’ EEG pattern during hyperventilation (HV) may be observed. This study aimed to investigate transcranial Doppler (TCD) and EEG variations in response to hyper- and hypocapnia using simultaneous recording. Methods: Syncope patients with a typical EEG pattern during HV (SEEG+, n = 15) and those without abnormalities (SEEG–, n = 16) were compared with healthy controls (n = 20). Simultaneous TCD and EEG recordings were performed at rest (baseline), during 2 apnea tests and during HV. Cerebrovascular vasoreactivity, index for hypocapnia, total vasomotor reserve and time to flow velocity normalization after HV (t-norm) were recorded. Results: With TCD, a reduction in Vasomotor reserve was observed in SEEG+ compared with the other 2 groups (control: 67 ± 8%; SEEG–: 67 ± 10%; SEEG+: 57 ± 8%; p < 0.0001). t-norm was longer in all syncopal patients and in particular in SEEG+ (control: 20.2 ± 3 s; SEEG–: 40 ± 7 s; SEEG+: 123 ± 45s; p < 0.0001). Quantitative EEG showed an increase in slow bands in all subjects during HV, small and nonsignificant in controls and SEEG–, higher and significant in SEEG+, related with flow reduction. Conclusions: Changes in the sympathetic modulation of cerebral vasoconstriction may explain both the pathophysiology of vasovagal syncope and the typical paroxysmal EEG findings.

Animal Models of Infantile Spasms: Is the Holy Grail Finally in Sight?

A New Animal Model of Infantile Spasms with Unprovoked Persistent Seizures. Lee CL, Frost JD Jr, Swann JW, Hrachovy RA. Epilepsia 2008;49(2):298–307. PURPOSE: Infantile spasms is one of the most severe epileptic syndromes of infancy and early childhood. Progress toward understanding the pathophysiology of this disorder and the development of effective therapies has been hindered by the lack of a relevant animal model. We report here the creation of such a model. METHODS: The sodium channel blocker, tetrodotoxin (TTX), was chronically infused into the developing neocortex or hippocampus of infant rats by way of an osmotic minipump starting on postnatal day 10–12. RESULTS: After a minimum of 10 days of infusion, approximately one-third of these rats began to display very brief (1–2 s) spasms, which consisted of symmetric or asymmetric flexion or extension of the trunk and sometimes involvement of one or both forelimbs. The typical ictal EEG pattern associated with the behavioral spasms consisted of an initial generalized, high amplitude, slow wave followed by an electrodecrement with superimposed fast activity. The interictal EEG revealed multifocal spikes and sharp waves, and in most animals that had spasms a hypsarrhythmic pattern was seen, at least intermittently, during NREM sleep. Like in humans, the spasms in the rat often occurred in clusters especially during sleep–wake transitions. Comparison of the ictal and interictal EEGs recorded in this model and those from humans with infantile spasms revealed that the patterns and the frequency components of both the ictal events and hypsarrhythmia were very similar. DISCUSSION: The TTX model of infantile spasms should be of value in furthering an understanding of the pathophysiology of this seizure disorder.

Atypical presentation of Creutzfeldt–Jakob disease: The first Italian case associated with E196K mutation in the PRNP gene

Genetic Creutzfeldt–Jakob disease (gCJD) is caused by a range of mutations in the prion protein gene (PRNP). We describe the first Italian case of gCJD associated with the rare PRNP E196K mutation. The disease showed an atypical presentation featuring dementia without motor signs in a 75-year-old woman. The case lacked both a known family history of a similar neurological disease and the typical EEG pattern; it was misdiagnosed as frontotemporal dementia. The present case emphasizes that vigilance must be kept high to avoid missing gCJD cases falling outside a typical phenotypical presentation and a known family history, especially in the elderly, in whom an alternative, more common, but incorrect diagnosis may be made.

A new animal model of infantile spasms with unprovoked persistent seizures

Infantile spasms is one of the most severe epileptic syndromes of infancy and early childhood. Progress toward understanding the pathophysiology of this disorder and the development of effective therapies has been hindered by the lack of a relevant animal model. We report here the creation of such a model. The sodium channel blocker, tetrodotoxin (TTX), was chronically infused into the developing neocortex or hippocampus of infant rats by way of an osmotic minipump starting on postnatal day 10-12. After a minimum of 10 days of infusion, approximately one-third of these rats began to display very brief (1-2 s) spasms, which consisted of symmetric or asymmetric flexion or extension of the trunk and sometimes involvement of one or both forelimbs. The typical ictal EEG pattern associated with the behavioral spasms consisted of an initial generalized, high amplitude, slow wave followed by an electrodecrement with superimposed fast activity. The interictal EEG revealed multifocal spikes and sharp waves, and in most animals that had spasms a hypsarrhythmic pattern was seen, at least intermittently, during NREM sleep. Like in humans, the spasms in the rat often occurred in clusters especially during sleep-wake transitions. Comparison of the ictal and interictal EEGs recorded in this model and those from humans with infantile spasms revealed that the patterns and the frequency components of both the ictal events and hypsarrhythmia were very similar. The TTX model of infantile spasms should be of value in furthering an understanding of the pathophysiology of this seizure disorder.

EEG Features in Idiopathic Generalized Epilepsy: Clues to Diagnosis

To investigate the EEG profile and its contribution for diagnosis and management in a group of patients with a clinical diagnosis of idiopathic generalized epilepsy (IGE) who were referred to a tertiary hospital. We retrospectively studied clinical and EEG features of 180 consecutive patients with IGE. Eighty patients were diagnosed with juvenile myoclonic epilepsy (JME), 35 had absence epilepsy (AE), 13 had generalized tonic-clonic seizures on awakening (GTCS-A), 28 had generalized tonic-clonic seizures only (TCS), and 24 had adult-onset idiopathic generalized epilepsy (AIGE). The EEGs were classified in typical (synchronous generalized spike or polyspikes-and-wave discharges with normal background), atypical (with clear focalities or asymmetries), and normal. The 493 EEG exams were analyzed. The first EEG was normal in 45% of the 180 patients, and only 33% had typical abnormalities. AE had a higher proportion of typical examinations and needed fewer sequential examinations to register a typical abnormality compared with the other groups. By contrast, the serial EEG profile of TCS and AIGE showed a higher proportion of normal and atypical EEG findings. These findings support previous recommendations that IGE patients should be treated with appropriate therapy based on clinical history. Waiting for a typical abnormal EEG pattern can generate an unacceptable delay in the correct diagnosis and treatment of these patients. In patients with long-term epilepsy, the diagnosis may be difficult. Furthermore, serial EEGs can help to elucidate the syndromic diagnosis, especially in patients with TCS and AIGE.

Time-dependent variation in cerebral and autonomic activity during periodic leg movements in sleep: implications for arousal mechanisms.

A hierarchy in arousal response has been proposed for spontaneous arousal by analyzing the temporal changes in heart rate (HR) and electroencephalographic (EEG) activity. To address the question as to whether the same continuum may be proposed in sleep disorders, we performed temporal spectral EEG and HR analyses during periodic leg movements (PLM) associated or not with microarousal (MA). Data were obtained in 12 patients with restless leg syndrome and/or PLM syndrome. PLMs were classified into 3 types including PLM associated with MA, PLM without MA, and PLM associated with delta or K-complex bursts. HR and EEG spectral analyses were done for 10s before and 10s after the PLM onset. Each type of PLM was associated with a typical EEG and autonomic pattern consisting of an increase in HR and delta band activity before the PLM, regardless of the presence or absence of MA. Thereafter, a rise in delta, alpha and beta(2) activity was noted associated with tachycardia. This was greater when MA or bursts of slow wave activity were present. In the period following the PLM, HR, delta and alpha power showed a long-lasting decrease with values significantly below the baseline. From these data, we can conclude that: (1) cardiac and cerebral changes occur in association with PLM even when MA cannot be detected; (2) the combined increase in delta activity and HR before the onset of PLM suggests that these changes are part of the arousal response during PLM; (3) the graded arousal response during PLM confirms that the human arousal response involves a progression of central nervous system activation from brainstem to cortical level.

Encephalopathy with electrical status epilepticus during slow sleep or ESES syndrome including the acquired aphasia

Encephalopathy with electrical status epilepticus during sleep or ESES is an age-dependent and self-limited syndrome whose distinctive features include a characteristic age of onset (with a peak around 4–5 years), heterogeneous seizures types (mostly partial motor or unilateral seizures during sleep and absences or falls while awake), a typical EEG pattern (with continuous and diffuse paroxysms occupying at least 85% of slow wave sleep) and a variable neuropsychological regression consisting of IQ decrease, reduction of language (as in acquired aphasia or Landau–Kleffner syndrome), disturbance of behaviour (psychotic states) and motor impairment (in the form of ataxia, dyspraxia, dystonia or unilateral deficit). Despite the long-term favourable outcome of epilepsy and status epilepticus during sleep (SES), the prognosis is guarded because of the persistence of severe neuropsychological and/or motor deficits in approximately half of the patients. No specific treatment has been advocated for this syndrome, but valproate sodium, benzodiazepines and ACTH have been shown to control the seizures and the SES pattern in many cases, although often only temporarily. Subpial transection is proposed in some instances as in non-regressive acquired aphasia. Recent data support the concept that ESES syndrome may include a large subset of developmental or acquired regressive conditions of infancy.

Topographical characteristics of slow wave activities during the transition from wakefulness to sleep

Objectives: This study examined the topographical characteristics of slow wave(delta and theta) activities during the transition from wakefulness to sleep, using topographic mapping of EEG power and coherence.Methods: Sonography of nocturnal sleep was recorded on 10 male subjects. Each recording, from ‘lights-off’ to 5 min after the appearance of the first sleep spindles, was analyzed. Typical EEG patterns during the transition from wakefulness to sleep were classified into 9 stages (EEG stages).Results and conclusions: Topographic maps of coherence in delta-and theta-band activities demonstrated that the synchronous component at the anterior-central areas of the scalp appeared corresponding with increasing power. The populations of high coherence pairs among total pairs were computed for each band and each EEG stage to examine the regional differences of EEG. The populations of the delta-band activity increased clearly from EEG stage 6 in the anterior-central areas. The populations of the theta-band activity increased clearly from EEG stage 7 in the anterior-central areas. These results suggest that the dominant synchronous component of slow wave activities during the transition from wakefulness to sleep increased as a function of EEG stages in the anterior-central areas and increased clearly after the appearance of vertex sharp waves.

Seizure detection using a self-organizing neural network: validation and comparison with other detection strategies

Objective: A previously described seizure detection algorithm (CNET) (Gabor, A.J., Leach, R.R. and Dowla, F.U. Automated seizure detection using a self-organizing neural network. Electroenceph. clin. Neurophysiol., 1996, 99: 257–266) was validated with 200 records from 65 patients (4553.8 h of recording) containing 181 seizures. Design and methods: Performance of the algorithm was manifest by its sensitivity ((seizures detected/total seizures)×100) and selectivity (false-positive errors/Hr-FPH). Comparisons with the Monitor detection algorithm (Version 8.0c, Stellate Systems) and audio-transformation (Oxford Medilog) were performed. Results: CNET detected 92.8% of the seizures and had a mean FPH of 1.35±1.35. Monitor detected 74.4% of the seizures and had a mean FPH of 3.02±2.78. Audiotransformation detected all but 3 (98.3%) of the seizures. Selectivity for this detection strategy was not defined. Conclusions: This study not only validates the CNET algorithm, but also the notion that seizures have frequency-amplitude features that are localized in signal space and can be selectively identified as being distinct from other types of EEG patterns. The ear is a specialized frequency-amplitude detector and when the signal is transformed into audio frequency range (audio-transformation), seizures can be detected with better sensitivity as compared to the other strategies examined.

Topographical characteristics and principal component structure of the hypnagogic EEG.

The purpose of the present study was to identify the dominant topographic components of electroencephalographs (EEG) and their behavior during the waking-sleeping transition period. Somnography of nocturnal sleep was recorded on 10 male subjects. Each recording, from "lights-off" to 5 minutes after the appearance of the first sleep spindle, was analyzed. The typical EEG patterns during hypnagogic period were classified into nine EEG stages. Topographic maps demonstrated that the dominant areas of alpha-band activity moved from the posterior areas to anterior areas along the midline of the scalp. In delta-, theta-, and sigma-band activities, the differences of EEG amplitude between the focus areas (the dominant areas) and the surrounding areas increased as a function of EEG stage. To identify the dominant topographic components, a principal component analysis was carried out on a 12-channel EEG data set for each of six frequency bands. The dominant areas of alpha 2- (9.6-11.4 Hz) and alpha 3- (11.6-13.4 Hz) band activities moved from the posterior to anterior areas, respectively. The distribution of alpha 2-band activity on the scalp clearly changed just after EEG stage 3 (alpha intermittent, < 50%). On the other hand, alpha 3-band activity became dominant in anterior areas after the appearance of vertex sharp-wave bursts (EEG stage 7). For the sigma band, the amplitude of extensive areas from the frontal pole to the parietal showed a rapid rise after the onset of stage 7 (the appearance of vertex sharp-wave bursts). Based on the results, sleep onset process probably started before the onset of sleep stage 1 in standard criteria. On the other hand, the basic sleep process may start before the onset of sleep stage 2 or the manually scored spindles.

Putative neurosurgical transmission of Creutzfeldt-Jakob disease with analysis of donor and recipient: agent strains

A woman, aged 59 years, underwent a cortical biopsy that led to the diagnosis of Creutzfeldt-Jakob disease (CJD). A man, aged 46 years, underwent cranial surgery in the same department 3 days later for brain contusion, with an uneventful recovery. Twenty six months later, he developed clinical signs of CJD with a typical EEG pattern. Both cases exhibited features of the ‘atoxic’ form of the disease with depletion of cerebellar granule cells, without kuru plaques or PrP deposits. PrP deposits were immunohistochemically observed in the cerebrum, spinal cord and peripheral nerve. Molecular genetic analysis performed on brain tissue revealed the codon 129 polymorphism to be Met129Met in the donor and Met129Val in the recipient. The shared ‘cerebellar’ phenotype and the genotypic discrepancy between the two patients lead us to postulate that the ‘cerebellar’ agent strain plays a major role in CJD phenotype and transmission.