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PubMed1998

Genetic studies in the sleep disorder narcolepsy.

Narcolepsy is a chronic neurologic disorder characterized by excessive daytime sleepiness and abnormal manifestations of REM sleep including cataplexy, sleep paralysis, and hypnagogic hallucinations. Narcolepsy is both a significant medical problem and a unique disease model for the study of sleep. Research in human narcolepsy has led to the identification of specific HLA alleles (DQB1*0602 and DQA1*0102) that predispose to the disorder. This has suggested the possibility that narcolepsy may be an autoimmune disorder, a hypothesis that has not been confirmed to date. Genetic factors other than HLA are also likely to be involved. In a canine model of narcolepsy, the disorder is transmitted as a non-MHC single autosomal recessive trait with full penetrance (canarc-1). A tightly linked marker for canarc-1 has been identified, and positional cloning studies are under way to isolate canarc-1 from a newly developed canine genomic BAC library. The molecular cloning of this gene may lead to a better understanding of sleep mechanisms, as has been the case for circadian rhythms following the cloning of frq, per, and Clock.

Alleles↗
PubMed2004

Effects of hypocretin2-saporin and antidopamine-beta-hydroxylase-saporin neurotoxic lesions of the dorsolateral pons on sleep and muscle tone.

The hypocretin neurons have been implicated in regulating sleep-wake states as they are lost in patients with the sleep disorder narcolepsy. Hypocretin (HCRT) neurons are located only in the perifornical region of the posterior hypothalamus and heavily innervate pontine brainstem neurons, such as the locus coeruleus (LC), which have traditionally been implicated in promoting arousal. It is not known how the hypocretin innervation of the pons regulates sleep-wake states as pontine lesions have never been shown to increase sleep. It is likely that in previous studies specific neurons were not lesioned. Therefore, in this study, we applied saporin-based neurotoxins to the dorsolateral pons and monitored sleep in rats. Anti-dopamine-beta-hydroxylase-saporin killed the LC neurons but sleep was affected only during a two hour light-dark transition period. Application of hypocretin2-saporin killed fewer LC neurons relative to other adjacent neurons. This occurred because the LC neurons possess the hypocretin receptor 1 but the ligand hypocretin 2 binds to this receptor with less affinity relative to the hypocretin receptor 2. The hypocretin2-saporin lesioned rats compared to controls had increased sleep during the dark period and displayed increased limb movements during REM sleep. None of the lesioned rats had sleep onset REM sleep periods or cataplexy. We conclude that the hypocretin innervation to the pons functions to awaken the animal when the lights turn off (via its innervation of the LC), sustains arousal and represses sleep during the rest of the night (via a wider innervation of other pontine neurons), and modulates muscle tone.

Animals↗
PubMed1988

Narcolepsy: a review of a common, life-long sleep disorder.

Narcolepsy is a severe debilitating chronic life-long sleep disorder that can be ameliorated but not cured. In the United States, its prevalence is at least 1 in 1000 making it more common than multiple sclerosis or Parkinson's disease. Its symptoms lead to severe lifestyle consequences, with profound impact on the affected persons, their interpersonal relationships, job, school experiences, and family life. Despite this, little has appeared in the nursing literature about the disorder. The most characteristic symptoms include uncontrollable excess daytime sleepiness, cataplexy (bilateral voluntary muscle weakness), sleep paralysis, hypnagogic hallucinations and disturbed night-time sleep. Characteristics of normal sleep are reviewed and compared with disturbances seen in narcolepsy. The aetiology, assessment, diagnosis, pharmacologic therapy, non-pharmacologic therapy and psychosocial issues are discussed along with needed research directions.

Achievement↗
PubMed1993

The origin of excessive daytime sleepiness in the Prader-Willi syndrome.

The polygraphically recorded sleep-wake continuum of 21 Prader-Willi syndrome (PWS) patients was compared with that of 19 normal people. In the Prader-Willi group, excessive daytime sleepiness (EDS) is found in 95% of subjects, and rapid eye movement (REM) sleep disorders occur in 52%. These two features were significantly different from the normal group of subjects. No indications were found for the presence of the apnoea syndrome. The REM sleep disorders are: sleep onset rapid eye movements (SOREM), REM sleep in naps, many arousals during REM sleep, and a significant decrease in total REM sleep. These disturbances in the Prader-Willi group, combined with the presence of EDS and sometimes of cataplexy, are likely to be expressions of a narcoleptic syndrome although this was not sustained by the HLA-DR2 expression above normal. The quality of life of PWS subjects can be improved in some cases by treating them as narcoleptic patients.

Adolescent↗
PubMed1992

Sleep onset rapid-eye-movement episodes in narcolepsy: REM sleep pressure or nonREM-REM sleep dysregulation?

Thirty-two narcoleptic subjects with excessive daytime sleepiness and cataplexy were recorded for 33 continuous hours. The continuous polysomnographic recording (CPSG) was followed by a standard MSLT at 2-h intervals. There were 64 sleep onset REM episodes (SOREMs) vs 64 sleep onset nonREM episodes (SONREMs) during the CPSG, and 102 SOREMs vs 50 SONREMS during the MSLT. Both sleep onset types peaked at 13-15 h during the CPSG while sleep onsets were evenly distributed during the MSLT. In the latter procedure, the mean sleep latency was significantly shorter with SOREMs occurrence than with SONREMs occurrence. Two factors were extracted in each procedure by means of a Varimax Rotated Factor Analysis. During the CPSG, SOREMs were related to the preceding nocturnal sleep parameters in the first factor, and to the daytime total sleep time and the total number of sleep onsets in the second factor. During the MSLT, SOREMs were related only to the mean sleep latency and the total number of sleep onsets. It was concluded that the occurrence of SOREMs is primarily due to the residual somnolence in narcoleptic subjects. However, their occurrence during the MSLT is largely independent of the prior history of sleep and waking. Thus, we propose a nonREM-REM sleep dysregulation hypothesis to account for the appearance of SOREMs in narcolepsy.

Journal Article↗
PubMed1994

The Ullanlinna Narcolepsy Scale: validation of a measure of symptoms in the narcoleptic syndrome.

The Ullanlinna Narcolepsy Scale (UNS) is a simple questionnaire-based method used to measure the symptoms of the narcoleptic syndrome. The 11-item scale (range 0-44) assesses the two main features of the narcoleptic syndrome, the abnormal sleeping tendency and cataplexy. The UNS sum score reliably distinguishes patients with the narcoleptic syndrome from patients with sleep apnoea, multiple sclerosis, and epilepsy. The mean score in patients with the narcoleptic syndrome was 27.3 (95% confidence limits 24.4-33.1); the sleep apnoea group with a mean score of 9.6 (95% confidence limits 7.2-12.0) came closest to this. Validation data were also selected from a large survey of non-institutionalized adults in Finland including groups with insomnia, excessive daytime sleepiness, sleep deprivation, sciatica, alcohol abuse, and high scores on a depression scale and on a scale of neurovegetative symptoms. With the lowest UNS score in the narcoleptic syndrome group (= 14) as the cutpoint, the sensitivity is 100% and the specificity is 98.8% in the subjects studied. The accurate assessment of the symptoms of the narcoleptic syndrome in a format suitable for questionnaire studies is essential.

Journal Article↗
PubMed1987

Diagnostic criteria for narcolepsy and HLA-DR2 frequencies.

HLA-DR2 frequencies were investigated in Japanese patients with narcolepsy as defined by various diagnostic criteria. The DR2 frequency was 100% when our criteria for narcolepsy were employed. The use of other criteria that lacked cataplexy as an obligatory symptom, however, reduced the DR2 frequency and led to an apparent "discovery" of DR2-negative cases with "narcolepsy". This observation indicates the necessity of precise diagnostic criteria in research on the HLA-narcolepsy association.

Gene Frequency↗
PubMed1998

HLA-DQB1*0602 homozygosity increases relative risk for narcolepsy but not disease severity in two ethnic groups. US Modafinil in Narcolepsy Multicenter Study Group.

Narcolepsy is a neurological disorder known to be tightly associated with HLA-DQA1*0102 and DQB1*0602. In this study, we have examined if homozygosity for DQB1*0602 increases disease susceptibility and/or severity. Patients diagnosed at Stanford University (n=160) or enrolled in a multicenter clinical trial (n=509) were included in this analysis. In both African-Americans and Caucasian-Americans with or without cataplexy, a significantly higher than expected number of subjects were DQB1*0602 homozygotes. Relative risks were 2-4 times higher in DQB1*0602 homozygotes vs heterozygotes across all patient groups. In contrast, symptom severity did not differ between DQB1*0602 homozygous and heterozygous subjects. These results indicate that HLA-DQB1*0602 homozygosity increases susceptibility to narcolepsy but does not appear to influence disease severity.

Adult↗
PubMed1987

Clinical study on idiopathic CNS hypersomnolence.

Although idiopathic CNS hypersomnolence is the third most frequent hypersomnia diagnosis, the syndrome is still unfamiliar to physicians, especially in Japan. In the Sleep Disorders Clinic of Kurume University Hospital, seven patients were diagnosed as idiopathic CNS hypersomnolence. All the patients complained of persistent daytime sleepiness, difficulty in morning awakening and lengthening of nocturnal sleep. Their daytime sleepiness had not been reduced even when they have taken sufficient nocturnal sleep. Various autonomic symptoms were observed, but what has noticeably been absent were cataplexy, sleep paralysis, sleep attack, sleep apnea or any other identifiable neurological disorders. The onset of the syndrome in four of the seven patients occurred in their teens. No therapeutic effects had been found after undergoing medical treatments.

Adult↗
PubMed2006

REM sleep changes in rats induced by siRNA-mediated orexin knockdown.

Short interfering RNAs (siRNA) targeting prepro-orexin mRNA were microinjected into the rat perifornical hypothalamus. Prepro-orexin siRNA-treated rats had a significant (59%) reduction in prepro-orexin mRNA compared to scrambled siRNA-treated rats 2 days postinjection, whereas prodynorphin mRNA was unaffected. The number of orexin-A-positive neurons on the siRNA-treated side decreased significantly (23%) as compared to the contralateral control (scrambled siRNA-treated) side. Neither the colocalized dynorphin nor the neighbouring melanin-concentrating hormone neurons were affected. The number of orexin-A-positive neurons on the siRNA-treated side did not differ from the number on the control side 4 or 6 days postinjection. Behaviourally, there was a persistent (approximately 60%) increase in the amount of time spent in rapid eye movement (REM) sleep during the dark (active) period for 4 nights postinjection, in rats treated with prepro-orexin siRNA bilaterally. This increase occurred mainly because of an increased number of REM episodes and decrease in REM-to-REM interval. Cataplexy-like episodes were also observed in some of these animals. Wakefulness and NREM sleep were unaffected. The siRNA-induced increase in REM sleep during the dark cycle reverted to control values on the 5th day postinjection. In contrast, the scrambled siRNA-treated animals only had a transient increase in REM sleep for the first postinjection night. Our results indicate that siRNA can be usefully employed in behavioural studies to complement other loss-of-function approaches. Moreover, these data suggest that the orexin system plays a role in the diurnal gating of REM sleep.

Animals↗
PubMed2005

Hypocretin deficiency in Prader-Willi syndrome.

Four patients with clinically and genetically confirmed Prader-Willi syndrome (PWS) underwent nocturnal polysomnograpy (PSG), multiple sleep latency test (MSLT), human leukocyte antigens (HLA) typing and estimation of cerebrospinal fluid (CSF) hypocretin-1 (Hcrt-1) level to investigate if a role of hypothalamic dysfunction and sleep disturbance might be functionally connected through the hypocretin (orexin) system. In all four patients physical examination confirmed extreme obesity (increasing with age) with dysmorphogenetic features. Excessive daytime sleepiness (EDS) was manifested in only two subjects without any imperative feature. None of the patients under study suffered from cataplexy. Nocturnal PSG revealed fragmented sleep with low efficiency, the hypopnea and apnea indexes increasing from borderline up to very high values in direct proportion to the patients' age. MSLT latency was shortened in two patients with clinically expressed EDS, only one sleep onset rapid eye movements (REM) period (SOREM) was found. HLA typing showed DQB1*0602 positivity in two patients; the further two were negative. Mean value of CSF Hcrt-1 in the patients group was down to 164 +/- 46.8 pg/ml (in comparison with 265.8 +/- 48.8 pg/ml in 10 young healthy subjects, P=0.02). The deficiency of CSF Hcrt-1 level correlated in PWS patients with their EDS severity.

Adolescent↗
PubMed2004

Is motor inhibition during laughter due to emotional or respiratory influences?

We compared the effects of laughter and several respiratory movements on spinal motor excitability to unravel their respective influences. We measured H-reflexes in 13 healthy volunteers during 10 different tasks (including laughter, simulated laughter, and various respiratory movements). We compared the percentage that remained of the initial H-reflex during each task with that during a neutral task. H-reflex percentage differed between the neutral task (79.4 +/- 16.1%), true laughter (43.7 +/- 17.9%), and simulated laughter (66.6 +/- 24.3%), and between the two latter tasks. Coughing also resulted in H-reflex suppression, but not as deeply as true laughter. During the other respiratory maneuvers, the H-reflex increased compared to the neutral task. Our finding that true laughter evoked more H-reflex depression than simulated laughter suggests that mirth on its own depresses the H-reflex. This mechanism may also be involved in the pathophysiology of cataplexy, the main symptom of narcolepsy.

Adolescent↗
PubMed1980

Sleep disturbances in a series of elderly patients: polysomnographic findings.

A group of 27 elderly patients with complaints of either chronic insomnia or excessive daytime sleepiness were studied in the Sleep Evaluation Center of Western Psychiatric Institute and Clinic during the period January 1977-June 1979. On the basis of anamnestic data from patients and bedroom partners, together with polysomnographic findings, sleep disturbances were classified according to the nosology of the Association of Sleep Disorders Centers. Of the 27 patients, 19 had disorders of initiating or maintaining sleep (DIMS), 7 had disorders of excessive somnolence (DOES), and 1 had parasomnia (episodic nocturnal wandering). Of the 19 DIMS patients, two-thirds had either a primary affective disorder (depression) or a persistent psychophysiologic disturbance. Of the 7 DOES patients, 6 had a primary sleep disorder such as a sleep apnea syndrome or narcolepsy-cataplexy. Additional electroencephalographic sleep data are presented on elderly patients with primary nonpsychotic depression. The latency of rapid eye movements (REM) in the depressed patients was shorter (p less than 0.05) than in patients with a persistent psychophysiologic disturbance. The percentage of REM sleep was significantly elevated (p less than 0.05) in the depressed group, and intermittent wakefulness was decreased (p less than 0.01). The causes of sleep disturbance in the elderly are both heterogeneous and complex. The need for accurate differential diagnosis and a multiaxial approach is stressed.

Aged↗
PubMed1979

Mazindol in the treatment of narcolepsy.

Thirty-four subjects with the narcoleptic syndrome were treated with mazindol 3--8 mg daily for 1 year. Treatment cuased a sustained improvement in narcolepsy, but had no effect on cataplexy or sleep paralysis. The response to mazindol was excellent in six subjects, good in 14, moderate in 12 and poor in two. No cardiovascular effects, haematological toxicity, tolerance or dependence occurred. Mazindol 6 mg had the same effect on narcolepsy as d-amphetamine 50 mg, but caused less side effects.

Adolescent↗
PubMed1991

Familial narcolepsy in Finland.

Five patients with narcolepsy-cataplexy (aged 31-69, mean age at onset 15 years) and their 47 relatives were examined. They were interviewed in detail, all patients and 16 relatives (including all symptomatic cases) were examined neurologically and a multiple sleep latency test and HLA-typing were done. One case of narcolepsy and two cases of idiopathic hypersomnia were identified. All the other 45 relatives were symptom-free. The observed rate of familial cases (1/5 for narcolepsy and 2/5 for idiopathic hypersomnia) corresponds the results of other recent studies.

Adult↗
PubMed1994

Dopamine D2-receptors in human narcolepsy: a SPECT study with 123I-IBZM.

Increased dopamine D2 receptor binding in basal ganglia has been reported in human narcolepsy. These studies have been based on post-mortem material of 8 patients, most of them also medicated for narcolepsy. We studied six narcoleptics without stimulant or anticataplectic medication. The patients had an unambiguous history of cataplexy, and they were also studied polygraphically. Single photon emission computed tomography (SPECT) imaging was performed. The D2 receptor density was determined by using 123I-iodobenzamide (IBZM). The control subjects were 8 unmedicated Parkinson patients with one-sided (hemiparkinsonian) clinical symptoms. The D2 receptor density in them is known to be normal or somewhat increased compared to healthy normals. The striatum/frontal D2 activity ratio was 1.331 +/- 0.084 (with phantom study correction 2.101 +/- 0.300) in the narcoleptic patients, and in the parkinsonian controls 1.321 +/- 0.052 (2.067 +/- 0.185) for the asymptomatic side and 1.335 +/- 0.025 (2.117 +/- 0.090) for the symptomatic side (i.e. contralateral to the side with the clinical extrapyramidal signs). There was no statistical difference between the groups or between the symptomatic and asymptomatic side in the Parkinson patients. Thus, our results differ from the earlier post-mortem studies.

Adult↗
PubMed2006

Health-related quality of life in narcolepsy.

OBJECTIVES: To describe health-related quality of life in Norwegian patients with narcolepsy compared with data from the general population. PATIENTS AND METHODS: Seventy-seven patients with narcolepsy with cataplexy were included in the final analysis. Health-related quality of life was assessed by SF-36 questionnaire. RESULTS: Men and women with narcolepsy had lower scores in all SF-36 domains, except vitality. Most profoundly affected were bodily pain (men: p = 0.0001, women: p = 0.0001), social function (men: p = 0.0001, women: p = 0.0001) and general health (men p = 0.04, women: p = 0.0001). CONCLUSIONS: Narcolepsy has a clear negative effect on quality of life which is not sufficiently counteracted by medical treatment. We suggest that earlier diagnosis and treatment after onset of symptoms may be important in reducing the negative effects on quality of life. Special attention should be paid to the patients social functioning and general well-being.

Adolescent↗
PubMed2002

Sleep-waking discharge patterns of neurons recorded in the rat perifornical lateral hypothalamic area.

The perifornical lateral hypothalamic area (PF-LHA) has been implicated in the control of several waking behaviours, including feeding, motor activity and arousal. Several cell types are located in the PF-LHA, including projection neurons that contain the hypocretin peptides (also known as orexins). Recent findings suggest that hypocretin neurons are involved in sleep-wake regulation. Loss of hypocretin neurons in the human disorder narcolepsy is associated with excessive somnolence, cataplexy and increased propensity for rapid eye movement (REM) sleep. However, the relationship of PF-LHA neuronal activity to different arousal states is unknown. We recorded neuronal activity in the PF-LHA of rats during natural sleep and waking. Neuronal discharge rates were calculated during active waking (waking accompanied by movement), quiet waking, non-REM sleep and REM sleep. Fifty-six of 106 neurons (53 %) were classified as wake/REM-related. These neurons exhibited peak discharge rates during waking and REM sleep and reduced discharge rates during non-REM sleep. Wake-related neurons (38 %) exhibited reduced discharge rates during both non-REM and REM sleep when compared to that during waking. Wake-related neurons exhibited significantly higher discharge rates during active waking than during quiet waking. The discharge of wake-related neurons was positively correlated with muscle activity across all sleep-waking states. Recording sites were located within the hypocretin-immunoreactive neuronal field of the PF-LHA. Although the neurotransmitter phenotype of recorded cells was not determined, the prevalence of neurons with wake-related discharge patterns is consistent with the hypothesis that the PF-LHA participates in the regulation of arousal, muscle activity and sleep-waking states.

Action Potentials↗