In this study, we aimed to assess sleep function in patients with recent‐onset familial Creutzfeldt–Jakob disease (fCJD). The largest cluster of fCJD patients is found in Jews of Libyan origin, linked to the prion protein gene ( PRNP ) E200K mutation. The high index of suspicion in these patients often leads to early diagnosis, with complaints of insomnia being a very common presenting symptom of the disease. The study included 10 fCJD patients diagnosed by clinical manifestations, magnetic resonance imaging (MRI) scan of the brain, elevated tau protein in the cerebrospinal fluid (CSF) and positive PRNP E200K mutation. Standard polysomnography was performed after a brief interview confirming the presence of sleep disturbances. All patients showed a pathological sleep pattern according to all scoring evaluation settings. The sleep stages were characterized by (i) disappearance of sleep spindles; (ii) outbursts of periodic sharp waves and shallowing of sleep consisting in increased Stage 2 and wake periods during the night, as well as decrease of slow‐wave sleep and rapid eye movement (REM) sleep. Recordings of respiratory functions reported irregular breathing with central and obstructive apnea and hypopnea. The typical hypotonia occurring during the night and atonia during REM sleep were replaced by hyperactive sleep consisting of multiple jerks, movements and parasomnia (mainly talking) throughout the night. In conclusion, we report unique pathological sleep patterns in early fCJD associated with the E200K mutation. Specific respiratory disturbances and lack of atonia could possibly serve as new, early diagnostic tools in the disease.

Introduction Prion disorders consist of a group of rapidly progressive neurodegenerative diseases caused by an infectious protein, with Creutzfeld–Jacob disease (CJD) being the most common in humans (Gambetti et al., 2003) Currently, no effective treatments are available for such conditions, thus patients deteriorate rapidly. Creutzfeld–Jacob disease is mainly a sporadic disease; however, clusters of genetic cases occur in defined populations. Familial CJD (fCJD) is a genetic autosomic dominant disease resulting from mutations in the open reading frame of the prion protein gene (PRNP). The PRNP E200K mutation occurs among Israeli Jews of Libyan and Tunisian origin (Goldfarb et al., 1990), who represent the largest cluster (~2000 carriers) for this mutation. This genetic signature may allow for an early diagnosis of CJD in this population and is currently under investigation in normal carriers of the mutation (Cohen et al., 2010; Fulbright et al., 2008). The clinical presentation of CJD includes a variety of symptoms. In a meta‐analysis performed by Appleby et al. (2007) including 3083 patients, the most common presenting symptoms were cerebellar/gait symptoms, visual/oculomotor disturbances, dementia/memory impairments and behaviour/personality changes. Sleep disorders are frequent in prion diseases, especially in fatal familiar insomnia (FFI), where they constitute the hallmark of the disease (Lugaresi et al., 1986). FFI is associated with a PRNP 178N mutation associated with methionine at codon 129, while a similar mutation associated with valine at codon 129 results in CJD. Interestingly, clinical and pathological similarities have been reported between FFI and the Israeli CJD cluster bearing the PRNP E200K mutation (Chapman et al., 1996). Although sleep–wake disturbances in CJD have been considered traditionally to be less common than in FFI, insomnia has been reported in CJD patients (Chapman et al., 1996). Among sporadic cases of CJD, sleep disorders seem to be more common: they have been reported in 1.9% of patients at disease onset, while in 7.8% of individuals they appear during the course of the illness. In one study (Landolt et al., 2006), sporadic CJD patients had severe sleep EEG abnormalities with loss of sleep spindles, very low sleep efficiency and virtual absence of REM sleep. In an additional report, intractable insomnia was found in a PRNP E200K fCJD patient with severe thalamic involvement (Taratuto et al., 2002). These findings, together with our clinical insights derived from complaints of early insomnia and decreased total sleep time from many PRNP E200K patients, prompted us to conduct sleep studies and investigate whether sleep disorders can occur in these fCJD patients.

Materials and methods Patients The study included 10 patients (six women and four men) aged 48–71 years (mean 64 years). One patient conducted the sleep study 4 weeks prior to the diagnosis of fCJD, while the remaining patients conducted it 1–6 weeks after diagnosis. The neurological status of the patients was divided into two main categories: (i) cognitive status, mild–moderate decline in six patients; severe decline in four patients; and (ii) mobility, walking without assistance in four patients, walking with aids in five patients and severe walking disability in one patient. The patients recruited to the study were all fCJD patients of Lybian Jewish origin fulfilling World Health Organization (WHO) criteria for probable CJD and were followed until death to confirm the diagnosis. All patients had a magnetic resonance imaging (MRI) scan compatible with the diagnosis of CJD, including symmetrically increased signal intensity in the putamen and caudate nucleus on diffusion tensor weighted imaging (Fulbright et al., 2008), had elevated tau protein levels in the cerebrospinal fluid (CSF) and were heterozygous for the PRNP E200K mutation. The study was approved by the Institutional Review Board (IRB) of the Chaim Sheba Medical Center and the Israel Ministry of Health. All subjects were informed that the sleep study was for research purposes and signed an informed consent form. At the time of entry into the study, all patients were in the early stages of disease and were evaluated to be competent to understand and sign the consent form. Polysomnography (PSG) recordings The sleep studies were performed at the Chaim Sheba Sleep Center. Following an interview concerning their symptoms and a neurological examination, the patients performed a standard polysomnography study (Embla® Systems, Thornton, CA, USA), including the following channels: electroencephalogram (EEG) was obtained through two circular gold‐plated, hat‐shaped, disk‐recording electrodes (0.9 mm diameter). Electrodes were located at positions C3 and C4 according to the 10–20 system, and were referenced to electrodes on the opposite right and left mastoids (A2 and A1, respectively). Electro‐oculogram (EOG) was obtained through two circular Ag/AgCl conductive adhesive electrodes (0.9 cm diameter), placed 1 cm above and laterally to each eye and referenced to electrodes on the opposite right and left mastoids (A2 and A1), respectively. Electromyogram (EMG) was obtained through two circular Ag/AgCl conductive adhesive electrodes (0.9 cm diameter). The electrodes were located bilaterally adjacent to the submentalis muscles. Electrocardiogram (ECG) was obtained through three circular Ag/AgCl conductive adhesive electrodes (0.9 cm diameter). Electrodes were placed on both the left and right sides of the abdomen (just under the thoracic cage), and a ground electrode was placed on the left foot. Blood oxygenation (SpO 2 ) was measured with an oxymeter embedded within a finger clip placed on the index finger. Overall respiration was computed as a reflection of changes in thoracic (TR) and abdominal (AR) circumference measured using two respiratory belt transducers containing a piezo‐electric device, one at abdomen level and the other at chest level. Nasal respiration was measured using an airflow pressure cannula placed below the nostrils. Video monitoring was obtained in order to record movements during the night. Records were obtained with an input range of ±350 mV, sampling rate 100–200 Hz, input impedance >20 mOhm, calibration/test signal CMRR > 90 db at 60 Hz and a 1–35 Hz low cutoff filter. PSG scoring The studies were scored manually offline by a sleep physician according to the criteria outlined by Rechtschaffen and Kales (1968). Due to the difficulty of scoring these pathological studies according to clear criteria, shallow sleep was scored as Stage 2 even without the appearance of sleep spindles. An abrupt change in EEG frequency and/or brief increase in EMG amplitude for more than 3 s or more than 15 s were classified as arousal or awake, respectively, as defined by the EEG arousal atlas (Task Force of the American Sleep Disorders Association, 1992).

Results Index case report The observation of a patient with a pathological sleep study without any additional neurological symptoms led to the current study. The patient was a 56‐year‐old male who was referred to a sleep centre by his family physician upon complaints of acute and severe insomnia that had started 4 weeks earlier. His cognition and neurological examination were reported as completely normal. The PSG demonstrated fragmented sleep lacking the normal sleep stages together with irregular breathing. The sleep physician was not able to interpret the study due to its uniqueness. Four weeks later the patient developed myoclonic movements and was admitted to the neurology department. An MRI scan and the presence of the genetic mutation confirmed the diagnosis of fCJD with the PRNP E200K mutation. Sleep complaints at the time of the study All the participants in this study complained of new‐onset insomnia (disturbances at the onset of sleep in 10 patients; in addition, four patients complained of disturbances in sleep maintenance while non‐refreshing sleep occurred in nine patients). Furthermore, parasomnic events, including talking with or without stereotypical movements during sleep, were reported by the family members of six patients. Daytime somnolence occurred in eight patients while respiratory complaints, including snoring and witnessed apnea, occurred in five patients. Sleep studies results—structure and sleep stages Sleep abnormalities were evident in all patients and consisted of an elevation of wake periods during the night and changes of sleep stages. A typical hypnogram of the patients revealed shallow sleep without solid periods of slow wave sleep (SWS) and REM sleep, known to be crucial for normal and refreshing sleep (Fig. 1). Four patients presented with prolonged wakefulness during the night (Table 1). Figure 1 Open in figure viewer PowerPoint Representative hypnogram of a patient with Creutzfeldt–Jakob disease (CJD). The sleep is fragmented with frequent arousals and multiple wake periods during the night. The percentage of deep sleep (Stages 3 and 4) is very low, similar to the rapid eye movement (REM) periods. Table 1. Summary of sleep stages in percentage of total sleep time and sleep fragmentation of the study subjects, including arousals and awakening. All the subjects had fragmented sleep with multiple arousals and awakenings. The sleep was very shallow, with decrease in slow‐wave sleep (SWS) and rapid eye movement (REM) sleep. The sleep efficiency ranged between 61.9 and 95 Patient Sleep efficiency % Wake % Stage 1% Stage 2% SWS % REM % Arousal Awakenings 1 78 26 3 64 0 7 75 16 2 95 5 0 68 0.9 25 41 15 3 98 1.8 2.2 85 1 9.7 99 10 4 94 7.9 0 87 5 0 29 3 5 65 34.2 1.5 62.4 1.8 0 109 11 6 61.9 38.1 0 57.9 0 5 31 27 7 75 24.8 1.2 71.5 2 0.5 43 17 8 68.2 31.8 0.2 64 3.6 0.3 61 16 9 87.3 12.7 13 60 6.3 7.9 71 15 10 67 32 4 55 3 6 47 22 Sleep studies results—EEG and EMG patterns Five patients showed periodic sharp waves mainly in Stage 2 sleep and SWS. In Stage 2 sleep, all patients demonstrated an almost complete disappearance of sleep spindles. Stage 2 sleep scoring consisted of sleep periods lacking slow waves or REM characteristics. A decrease, and even the complete disappearance, of SWS was noted in every patient, and the degree of decrease correlated with disease severity. All patients with severe cognitive impairment were lacking SWS, unlike the mild–moderate cognitive decline group, which experienced SWS during the night. The REM periods, characterized by REM and a variable EEG background, also decreased in all patients (Table 2). Table 2. Respiratory scoring of all the patients. All patients experienced more respiratory events than the normal subjects. The obstructive events were more frequent; however, central apnea, which is considered to be a rare entity in the normal population, was observed in all Creutzfeldt–Jakob disease (CJD) patients AHI total AHI Obstructive apnea and hypopnea total Central total Desaturations 1 188 25.3 163 25 98 2 59 8.3 40 9 47 3 34 11 21 13 17 4 227 30 107 120 148 5 123 23 107 16 93 6 86 26 70 16 24 7 106 16 17 87 53 8 115 37 74 41 48 9 90 16 56 34 24 10 457 66 176 271 382 Electromyogram analysis revealed increased tone in all sleep stages instead of the typical hypotonia characteristic of sleep. Furthermore, even the typical atonia, which occurs normally during REM sleep was lacking, and continuous movements were observed (Fig. 2). Typical myoclonus events, that are observed during wake periods, also appeared in the sleep studies. Figure 2 Open in figure viewer PowerPoint Thirty‐s epoch of electroencephalography (EEG) channels of polysomnographic study in a Creutzfeldt–Jakob disease (CJD) patient. This epoch represents a rapid eye movement (REM) period. At this stage, the electromyography (EMG) channel should show atonia; however, in the CJD patients jerk movements could be noticed every 10 s. Sleep studies result—respiratory Respiratory scoring revealed multiple breathing disorders, including events of central and obstructive apnea. In addition, irregular breathing consisting of a variation of breathing volume without an apneic pattern was demonstrated in all patients throughout the night (Fig. 3). Figure 3 Open in figure viewer PowerPoint Two‐min epoch of respiratory channels of polysomnographic study in a Creutzfeldt–Jakob disease (CJD) patient. An irregular breathing pattern without an apneic episode or hypopnea. The saturation is preserved.

Discussion The current study demonstrates damaged sleep architecture and unique pathological respiratory patterns during the night in fCJD patients. Unlike FFI, where a characteristic sleep pathological pattern has been reported, sleep pathology is not always considered to be a main feature of fCJD (Capellari et al., 2011). Our present study demonstrates that sleep disturbances are insidious in fCJD, occurring relatively early in the course of the disease. The hypnogram of all patients revealed a decrease in SWS and REM sleep, which contributed most probably to their non‐refreshing sleep. The lack of hypotonia and the atonia in REM sleep might contribute to a missed scoring of wake periods during sleep, which may lead to the diagnosis of excessive insomnia and to the increased parasomnia observed. The respiratory pathology in the sleep studies included central apneas, obstructive apnea and irregular breathing. Central apnea, a typical event including complete cessation of breathing without respiratory effort, is found in various conditions linked to a progressive neurodegenerative state and is believed to be due to lack of central breathing stimuli (Housley, 2011). Obstructive apnea is caused by the collapse of upper airways despite respiratory effort and leads to blood oxygen desaturation and arousal. The obstructive apneas in the fCJD patients are probably secondary to airway collapse or desynchronization of respiratory muscles. Our subjects had a history of sleep disturbances, mainly insomnia and parasomnias, which occurred 2–4 months prior to the diagnosis of CJD. The results of this study, including the early symptoms and PSG findings, point to the inclusion of sleep disturbance questionnaires and the use of PSG as an important component of CJD diagnosis. We are currently conducting a prospective study to examine this point in both early fCJD patients and in healthy controls carrying the PRNP E200K mutation. We hope that these and future investigations will help to reinforce the involvement of sleep pathology in fCJD and the value of detecting changes in sleep patterns as a possible diagnostic tool in early stages of the disease. Our study has several limitations. This work has been scored according to Rechtschaffen and Kales’ (1968) manual, while the new scoring rules from the American Academy of Sleep Medicine (AASM) have been not implemented. In this respect, it should be mentioned that we began the data collection in 2006, before the AASM Visual Scoring Task Force was published in 2007. Therefore, in order to maintain standard measurements among patients, we continued to score the rest of the study according to the old set of rules. As this study was run for many years (fCJD is still a rare disorder, although more common in Lybian Jews compared to the normal population), the team of caregivers among the different patients was not consistent in keeping standard clinical records. Thus, we have not been able to provide a clear statistical analysis of the relationship between clinical symptoms and sleep features. We are implementing this feature in the protocol for novel studies addressing sleep behaviour in fCJD patients. Overall, we provide novel, interesting insights for a unique sleep behavioural pattern in fCJD patients.

Conclusions Familial CJD, associated with the E200K mutation, causes typical sleep disturbances early in the course of the disease that can be demonstrated in PSG study. The sleep disturbances include disruption of the normal sleep pattern with decreased SWS and REM sleep, lack of hypotonia during sleep and parasomnia events. fCJD and FFI may share more common characteristics than thought previously. These early and specific respiratory findings could possibly serve as new diagnostic tools in prion disease.

Acknowledgement This study was supported by a NIH grant (NS043488).