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PubMed1998

Pharmacokinetics of gammahydroxybutyrate (GHB) in narcoleptic patients.

Sodium gammahydroxybutyrate (GHB) is an endogenous compound that has been under investigation in the management of narcolepsy for about two decades. The data confirm that GHB treatment decreases daytime sleepiness and episodes of cataplexy, sleep paralysis, and hypnagogic hallucinations. The current study evaluated the pharmacokinetics of GHB, given twice in one night to six narcoleptic patients who had been chronically taking GHB nightly on a similar basis. Results confirmed earlier reports and showed nonlinear pharmacokinetics. Maximum concentrations were reached in 40 +/- 6.2 and 35.7 +/- 7 minutes after the first and second dose respectively. Mean AUCinf was 17731.6 +/- 4867 mg/mL/m. Mean GHB T1/2 was 53 +/- 19 minutes. GHB elimination appears to be capacity-limited in some patients when administered at a fixed dose of 3 g twice nightly at a 4-hour interval.

Brain↗
PubMed1999

EEG spectral analysis of the sleep-onset period in narcoleptics and normal sleepers.

The sleep-onset period of 10 drug-free patients with narcolepsy-cataplexy and 10 normals matched for age and gender was investigated using the multiple sleep latency test to elicit episodes of intentional sleep onset. Spectral analyses were calculated for delta, theta, alpha, sigma, and beta frequencies using 5-second epochs beginning at lights-out and continuing until the first 2 minutes of stage 2 or REM sleep were reached, or until 20 minutes had elapsed. The sleep-onset period was divided into quartiles, and mean root mean square (RMS) amplitude within each quartile was calculated. Mean delta amplitude was significantly higher across the sleep-onset period of narcoleptic REM naps and narcoleptic stage 2 naps compared to the sleep-onset period of normal stage 2 naps or normal stage 1 naps. Mean theta amplitude was significantly higher for narcoleptic REM naps compared to normal stage 1 naps, and tended to be higher for narcoleptic stage 2 naps compared to normal stage 1 naps. Mean alpha amplitude was significantly lower for narcoleptic REM naps and narcoleptic stage 2 naps compared to normal naps containing just stage 1. Mean sigma amplitude was significantly lower for narcoleptic REM naps compared to normal stage 1 naps, and tended to be lower for narcoleptic REM naps compared to normal stage 2 naps. Mean beta amplitude did not differ between the narcoleptic and normal sleep-onset process. These findings support the existence of electrophysiologic differences within the microstructure of the process of sleep entry in narcoleptics and normals.

Adult↗
PubMed2002

Diagnoses received by narcolepsy patients in the year prior to diagnosis by a sleep specialist.

STUDY OBJECTIVES: Narcolepsy is a neurological disorder whose clinical features include excessive daytime sleepiness, hypnagogic hallucinations, cataplexy, sleep paralysis, and disrupted nocturnal sleep. It has been shown that there may be quite a long interval between the onset of symptoms, and the correct diagnosis. We tested the hypothesis that given their severe symptomatology, these patients would have been diagnosed more often with a variety of psychiatric and neurologic conditions than controls in the year prior to confirmation of their narcolepsy diagnosis. DESIGN: Using the Province of Manitoba Health database, we compared the diagnoses made in the year prior to initial sleep disorder center evaluation of 77 patients with narcolepsy (33 males, 44 females) and 1,155 matched control subjects from the general population. SETTING: Sleep disorders center in University-based teaching hospital PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Patients were much more likely than controls to be diagnosed with mental disorders (Odds ratio (OR) = 4.0645; 95% confidence limit (CL) = 2.4671-6.6962; p<0.0001) and nervous system disorders (OR= 5.0495; CL = 3.0606 -8.3309; p<0.0001) and there was a trend towards more injuries in these patients (OR =1.6316; CL = 0.9857-2.7007; p=0.0514). We found that cases were statistically much more likely than controls to have received a diagnosis for neurotic disorders (17% of cases), depression (16%), personality disorders (3%) and adjustment reaction (4%). Although the cases had twice as many doctor visits as the controls (9.3 +/- 0.97 (sem) vs. 4.8 +/- 0.17 p<0.0001), only 38% of them had received a diagnosis of narcolepsy in the year prior to sleep specialist evaluation. Neurologists had the highest "success rate" for correct diagnosis: neurologists diagnosed narcolepsy in 55% of the cases they had seen. The other medical practitioners diagnosed narcolepsy in a much smaller percentage of the cases they had seen: 23.5% for internists (excluding neurologists), 21.9% for general practitioners, 11.1% for psychiatrists, and 0% for pediatricians. CONCLUSIONS: In the year prior to documentation of narcolepsy in a sleep disorders center, patients with narcolepsy were diagnosed with a wide variety of mental and neurologic disorders. Our findings are supportive of either the coexistence of these disorders in narcolepsy patients or a high frequency of missed diagnosis by their clinicians. The latter may help explain the very long interval between onset of symptoms and correct diagnosis.

Adjustment Disorders↗
PubMed2002

ICSD diagnostic criteria for narcolepsy: interobserver reliability. Intemational Classification of Sleep Disorders.

STUDY OBJECTIVES: To estimate the reliability of the diagnosis of narcolepsy after clinical interview and polysomnographic evaluation among sleep medicine doctors, before and after training in application of the International Classification of Sleep Disorders (ICSD). SETTING: Videotaped semi-structured interviews of 10 patients complaining of daytime sleepiness of different etiologies. Questions referred to ICSD criteria for narcolepsy. A further series of 10 cases of narcolepsy without cataplexy were simulated, with at least a random one to three of the ICSD polysomnographic criteria at pathological levels. PARTICIPANTS AND DESIGN: Seventeen doctors were required to classify each videotaped case as "ascertained," "possible," or "excluded" narcolepsy, in two sessions: one before and one after discussion of ICSD criteria. The observers were invited to confirm or exclude the diagnosis of narcolepsy in the 10 simulated cases, according to the given polysomnographic findings, before and after an agreed proposal of the interpretation of ICSD polysomnographic criteria. Interobserver reliability was calculated using Kappa statistics. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Interobserver reliability of clinical judgement improved from "substantial" at baseline (Kappa 0.61) to "almost perfect" after training (Kappa 0.95). Interobserver reliability of polysomnographic findings was "fair" at baseline (Kappa 0.24), unanimous after the proposed interpretation of ICSD polysomnographic criteria. CONCLUSIONS: Baseline reliability of diagnostic judgement in suspected narcolepsy was found satisfactory among Italian sleep medicine doctors. Educational training, based on discussion of ICSD criteria, further improved agreement. Diagnosis based on polysomnographic findings, not reliable at baseline, needed a strict interpretation of ICSD criteria to attain standardization.

Adult↗
PubMed2004

A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy.

STUDY OBJECTIVES: To measure the effect of nocturnal sodium oxybate administration on sleep architecture in patients with narcolepsy. DESIGN: Open-label study. SETTING: Four accredited sleep clinics. PARTICIPANTS: 25 adult patients with narcolepsy-cataplexy. INTERVENTIONS: Patients were weaned from previously used anticataplectic medications and administered increasing nightly doses of sodium oxybate over a 10-week period: 4.5 g for 4 weeks, 6 g for 2 weeks, 7.5 g for 2 weeks, and 9 g for 2 weeks. The effect of sodium oxybate was measured using nocturnal polysomnograms, the Epworth Sleepiness Scale, the Maintenance of Wakefulness Test, and a narcolepsy symptoms questionnaire. RESULTS: The nightly administration of sodium oxybate produced dose-related increases in slow-wave sleep and delta power, rapid eye movement sleep increased initially and then decreased in a dose-related manner, nocturnal awakenings decreased, and daytime sleep latency increased. Significant improvements in daytime symptoms were measured by the Maintenance of Wakefulness Test, the Epworth Sleepiness Scale, and the narcolepsy symptom questionnaire. CONCLUSIONS: Nocturnal administration of sodium oxybate in patients with narcolepsy produces significant improvements in sleep architecture, which coincide with significant improvements in daytime functioning.

Adjuvants, Anesthesia↗
PubMed2005

Effect of genetically caused excess of brain gamma-hydroxybutyric acid and GABA on sleep.

BACKGROUND: Exogenous gamma-hydroxybutyrate (GHB) increases slow-wave sleep and reduces daytime sleepiness and cataplexy in patients with primary narcolepsy. OBJECTIVE: To examine nighttime sleep and daytime sleepiness in a 13-year-old girl homozygous for succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare recessive metabolic disorder that disrupts the normal degradation of 4-aminobutyric acid (GABA), and leads to an accumulation of GHB and GABA within the brain. METHODS: Sleep interview, nighttime polysomnography, Multiple Sleep Latency Tests, and continuous 24-hour in-lab recordings in the patient; overnight polysomnography in her recessive mother and in a 13-year-old female control. RESULTS: During quiet wakefulness, background electroencephalographic activity was slow and composed of 7-Hz activity. Sleep stage 3/4 was slightly increased (28.1% of total sleep period, norms 15%-28%), and the daytime mean sleep latency was short in the patient (3 minutes 42 seconds, norms > 8 minutes). Stage 2 spindles were infrequent in the child (0.18/minute, norms: 1.2-9.2/minute) and her mother (0.65/minute) but normal (4.6/minute) in the control. At the beginning of the second night, a tonic-clonic seizure occurred, followed by a dramatic increase in stage 3/4 sleep, that lasted 46.3 % of the total sleep period, double the normal value. The mother showed a reduced total sleep time and rapid eye movement sleep percentage. DISCUSSION: This suggests that a chronic excess of GABA and GHB induces subtle sleep abnormalities, whereas increased slow-wave sleep evoked by a sudden event (here an epileptic seizure) may be caused by a supplementary increase in GABA and GHB.

Adolescent↗
PubMed2006

Detection of autoantibodies against hypocretin, hcrtrl, and hcrtr2 in narcolepsy: anti-Hcrt system antibody in narcolepsy.

STUDY OBJECTIVES: The impairment of hypocretin neurotransmission system is considered to play a major role in the pathophysiology of narcolepsy. It has been hypothesized that autoimmune abnormalities underlie the etiology of narcolepsy, based on the tight association with HLA-DRB1*1501/ DQB1*0602. It remains unclear if autoantibodies against hypocretin receptors (hcrtrl and hcrtr2) are involved in narcolepsy. DESIGN: We have developed a novel radioligand binding assay to address this question. Sera from 181 patients with narcolepsy, 10 patients with other hypersomnias, and 91 control subjects were used. Human [35S]-Hcrt, hcrtrl, and hcrtr2 were synthesized by in vitro transcription/translation system. The immune complex of autoantibody and each [35S]-protein were immunoprecipitated and quantified using a radioligand-binding assay. RESULTS: We detected autoantibodies against hypocretin in 3 patients, hcrtrl in 1 patient, and hcrtr2 in 5 patients with narcolepsy. Positive reactions were also found against hcrtrl in 2 and hcrtr2 in 1 control subjects. No relationships were found between these autoantibodies and HLA-DRB1*1501/DQB1*0602 haplotypes, presence of cataplexy, presence of subjective nocturnal sleep disruption, or the score on the Epworth Sleepiness Scale. CONCLUSIONS: Although we have detected autoantibodies against the hypocretin neurotransmission system, our results do not support the hypothesis that autoantibody-mediated dysfunction in the hypocretin system underlies the pathophysiology of narcolepsy.

Autoantibodies↗
PubMed1986

Daytime sleep characteristics and their relationships with night sleep in the narcoleptic patient.

Thirty-six narcoleptic patients with overwhelming sleep episodes, cataplexy, and sleep onset REM (SOREM) episodes were recorded for 34 continuous hours in the laboratory starting at 2200 h and ending at 0800 h a day and a half later. There were 94 SOREM and 60 sleep onset NREM (SONREM) episodes. While SONREM episodes were evenly distributed across daytime, SOREM episodes peaked between 0800 and 1000, 1200 and 1400, and 1600 and 1800 h. The ratio of SOREM to SONREM episodes was at its highest level between 1200 and 1400 h. Correlation coefficients between night 1 and night 2 for total sleep time (TST) and percentages of sleep stages were all positive and significant, whereas between daytime and each night, they were significant for percentages of stages 1, 2, and REM. Sleep-stage distribution across the last 24 h of continuous recording indicated that although TST levels were higher than that typical of normal subjects, REM sleep and slow wave sleep followed the same circadian distribution as that observed in normal subjects. The results are interpreted as evidence that the daytime sleep of narcoleptic patients is modified, similar to their night sleep, and that SOREM episodes are influenced by a time-of-day effect which culminates between 1200 and 1400 h.

Adolescent↗
PubMed1986

Treatment of narcolepsy with gamma-hydroxybutyrate. A review of clinical and sleep laboratory findings.

Previous studies on the effects of gamma-hydroxybutyrate (GHB) on the sleep and clinical response of patients with narcolepsy are reviewed. New information on 48 patients treated with GHB for as long as 9 years is presented. These studies indicate that 2.25 to 3.00 g of GHB, taken in conjunction with a low dose of a stimulant during the day, rapidly alleviate the symptoms of narcolepsy in most patients. Tolerance does not develop to this treatment regimen; neither have any patients discontinued the treatment because of side effects. In poor responders, daytime drowsiness and not cataplexy has been the most common residual symptom. Sleep studies reveal that GHB induces REM followed by slow wave sleep. Although total sleep time at night may be unchanged, sleep is less fragmented. GHB appears to be effective because it can induce the symptoms of narcolepsy and contain them at night. It is noteworthy, therefore, that the central biochemical changes induced by GHB also appear comparable to those found naturally in narcolepsy.

Female↗
PubMed2000

Effects of lateral preoptic area application of orexin-A on sleep-wakefulness.

Deficiency of orexin, a newly discovered hypothalamic peptide, is thought to lead to abnormal sleepiness and cataplexy in both human narcolepsy and animal models of the disease. As the POA contains extensive orexin terminals and is established as a sleep/arousal regulatory site, we evaluated a hypothesis that this site is a target for the arousal-inducing effects of orexin. Orexin-A was microinjected into lateral preoptic area (IPOA) and the effects on sleep-wakefulness and brain temperature were studied. Compared to saline vehicle control, orexin-A induced an increase in wakefulness for 70 min and suppressed all sleep stages, especially SWS2 and REM for 80 and 90 min, respectively. Brain temperature was not differentially affected by orexin-A compared to saline control. The orexin-induced arousal and REM suppression are consistent with the orexin-deficiency model of narcolepsy. Our results suggest that the IPOA orexin terminal field or adjacent structures may be a locus of arousal regulation by this peptide and a substrate of sleep-wake regulatory deficits in narcolepsy.

Animals↗
PubMed2001

Attentive and preattentive processing in narcolepsy as revealed by event-related potentials (ERPs).

Narcolepsy is a neurological disorder, characterised by excessive daytime sleepiness, sleep attacks, cataplexy and abnormal manifestations of rapid eye movement sleep. Recent studies suggest that neuropsychological impairments in narcolepsy may include memory and attention deficits due to a monoaminergic or cholinergic transmitter dysfunction. To explore the nature of cognitive problems, the P300 and mismatch negativity (MMN) event-related potentials were investigated in narcoleptic patients and matched controls. Narcoleptics showed significantly increased P300 amplitudes relative to controls, especially at frontal recording sites. While control subjects exhibited typically larger MMN over the right than the left hemisphere, in particular at frontal and central electrodes, narcoleptics did not show this asymmetry. These results are interpreted as possible alterations in cognitive preattentive and attentive processing associated with altered functioning of the prefrontal cortex in narcolepsy.

Acoustic Stimulation↗
PubMed1995

Selegeline hydrochloride treatment in narcolepsy. A double-blind, placebo-controlled study.

The relative benefits of selegeline hydrochloride (2 x 5 mg, 2 x 10 mg selegeline) were studied in 30 narcoleptic patients using a randomized, double-blind, placebo-controlled design. Patients were randomly assigned to three groups (placebo and 2 x 5 mg and 2 x 10 mg selegeline). After a 2-week washout period for previous anticataplectic and stimulant medication, the study started with a 2-day period of placebo intake for each group, continued by 14 days of medication, ending with a 2-day placebo period. Outcome was measured by comparison of four polysomnographies and four multiple sleep latency tests (MSLTs) performed during the initial and the final placebo and medication period. Each MSLT day included acoustic and visual vigilance tests. Blood pressure and pulse rate were monitored daily. Patients reported daily about mood, concentration, subjective sleep time, nocturnal awakenings, nocturnal wake times, number of naps, and occurrence of symptoms of the narcoleptic tetrad. Selegeline caused dose-dependent REM suppression during nighttime sleep and naps and increase of sleep and REM latency. Under selegeline, daytime sleepiness improved significantly and the number of sleep attacks and naps as well as the frequency of cataplexy were reduced. Selegeline at a dose of a least 20 mg/day is a potent drug for the treatment of all narcoleptic symptoms.

Adolescent↗
PubMedDate not supplied

A clinical picture of child and adolescent narcolepsy.

Although narcolepsy is rarely diagnosed before adulthood, symptoms often begin much earlier and can easily mimic psychiatric disorders in children and adolescents. Clinical experience from a pediatric sleep center is reviewed in 16 consecutive cases of polysomnographically proven narcolepsy with onset of symptoms by age 13 years. Only 1 of the 16 patients presented with the classic clinical tetrad of symptoms (sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis). Behavioral and emotional disturbances were present in 12 of 16 cases, with four patients appearing to have been misdiagnosed with a psychiatric disorder before recognition of the narcolepsy. Obesity appeared as an unexpected association in this case series, with 11 of the 16 narcoleptic patients found to be overweight at the time of diagnosis. The varied clinical presentations, polysomnographic findings, family history, and associated psychiatric symptoms are described. The importance of considering narcolepsy in the differential diagnosis of any child or adolescent with excessive sleepiness is emphasized.

Adolescent↗
PubMed1990

Narcolepsy.

Narcolepsy is a neurological condition with a prevalence of up to 1 per 1,000 that is characterized by irresistible bouts of sleep. Associated features include the pathological manifestations of rapid-eye-movement (REM) sleep: cataplexy, sleep paralysis, hypnagogic hallucinations, and abnormal sleep-onset REM periods and disturbed nocturnal sleep. The condition is strongly associated with the HLA-DR2 and DQw1 phenotype. The phenomenology of narcolepsy is discussed, and diagnostic procedures are reviewed. Treatment modalities involving central nervous system stimulants for somnolence and tricyclic drugs for REM-sleep abnormalities are discussed. Sleep laboratory studies on the treatment efficacy of methylphenidate, pemoline, dextroamphetamine, protriptyline, and viloxazine are presented. Data suggest that: (1) methylphenidate and dextroamphetamine objectively improve somnolence; (2) pemoline, at doses up to 112.5 mg, is less effective in controlling somnolence but may improve certain aspects of performance; and (3) protriptyline and viloxazine are effective anticataplectic agents that produce little improvement in somnolence.

Adult↗
PubMed1996

Successful treatment of giggle incontinence with methylphenidate.

PURPOSE: Giggle incontinence, the second most common type of childhood enuresis unrelated to disease, is notoriously difficult to treat. However, the association of laughter or emotion precipitated alteration of muscle tone is suggestive of a functional relationship to cataplexy, a part of the narcoleptic syndrome complex that may respond to stimulant medication. MATERIALS AND METHODS: Two boys and 5 girls (mean age 10.9 years) with giggle incontinence, a positive family history of giggle incontinence (4 patients) and no evidence of urological disease were treated with methylphenidate for 1 to 5 years. RESULTS: All patients responded positively with complete cessation of enuresis to varying dose schedules of methylphenidate. CONCLUSIONS: These results suggest that giggle incontinence is a centrally mediated and likely hereditary disorder that may share a common pathophysiological basis with the narcolepsy/cataplexy syndrome.

Adolescent↗
PubMed1978

Reversal of chronic diabetes insipidus during treatment with protriptyline.

We have described a 13-year-old white boy with Ondine's curse, sleep apnea and cataplexy who simultaneously developed progressive hypothalamic neuroendocrine deficiencies requiring replacement therapy. The patient was treated with protriptyline, a nonsedating tricyclic antidepressant, for control of the sleep-related symptoms. An unexpected result was the apparent reversal of his chronic diabetes insipidus by protriptyline, necessitating discontinuation of lysine-vasopressin. Some possible mechanisms of action were discussed.

Adolescent↗
PubMed2004

A rare form of narcolepsy (HLA-DR2-) shows possible association with (functionally relevant) alpha-interferon gene polymorphisms.

Narcolepsy is a neuropsychiatric disease caused by complex disturbance of sleep regulation. The main symptoms comprise daytime sleepiness and cataplexy. Although the aetiology remains unclear so far, narcolepsy is genetically characterized by strong linkage to the human leukocyte antigen complex as more than 90% of the patients are typed HLA-DR2+. Recently, it has become apparent that the orexin (hypocretin) neurotransmitter system plays a key role in the pathogenesis of the disease. Canine narcolepsy is caused by mutations in the orexin receptor 2 gene, and narcoleptic patients show specifically decreased cerebrospinal fluid orexin levels. Decreased promotor activity of the prepro-orexin gene is caused by binding of alpha-interferon in vitro. To investigate the possible role of IFNA gene polymorphisms in the pathogenesis of narcolepsy, we have genotyped two single nucleotide polymorphisms in IFNA genes as well as a neighbouring microsatellite. No association was evident in the prevalent DR2+ group. Yet, the IFNA10 single nucleotide polymorphisms and the IFNA microsatellite are associated with the DR2- patient group. Thus, the pathogenetic role of interferons needs to be defined in DR2- narcolepsy.

Carrier Proteins↗
PubMed1992

Narcolepsy: pathogenesis and nursing care.

Narcolepsy is a chronic, incurable disorder affecting at least a quarter of a million Americans. It is characterized by a tetrad of symptoms, which include excessive daytime sleepiness, cataplexy, sleep paralysis and hypnogogic hallucinations. Individuals may experience severe negative psychosocial consequences associated with these symptoms. The neuropathology of narcolepsy is largely unknown. Current work implicates decreased production or utilization of norepinephrine, dopamine and serotonin in the brain, and excessively numerous or hypersensitive cholinergic receptors in the brain. Medical management includes the use of separate drug therapies to control sleep attacks and cataplectic episodes. Nursing management requires comprehensive assessment of the interplay between the patient and environment and assistance with long-term coping.

Amphetamines↗