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PubMed1997

Pharmacological aspects of human and canine narcolepsy.

Narcolepsy-cataplexy is a disabling neurological disorder that affects 1/2000 individuals. The main clinical features of narcolepsy, excessive daytime sleepiness and symptoms of abnormal REM sleep (cataplexy, sleep paralysis, hypnagogic hallucinations) are currently treated using amphetamine-like compounds or modafinil and antidepressants. Pharmacological research in the area is facilitated greatly by the existence of a canine model of the disorder. The mode of action of these compounds involves presynaptic activation of adrenergic transmission for the anticataplectic effects of antidepressant compounds and presynaptic activation of dopaminergic transmission for the EEG arousal effects of amphetamine-like stimulants. The mode of action of modafmil is still uncertain, and other neurochemical systems may offer interesting avenues for therapeutic development. Pharmacological and physiological studies using the canine model have identified primary neurochemical and neuroanatomical systems that underlie the expression of abnormal REM sleep and excessive sleepiness in narcolepsy. These involve mostly the pontine and basal forebrain cholinergic, the pontine adrenergic and the mesolimbic and mesocortical dopaminergic systems. These studies confirm a continuing need for basic research in both human and canine narcolepsy, and new treatments that act directly at the level of the primary defect in narcolepsy might be forthcoming.

Animals↗
PubMed2004

Sleep, sleep disorders and hypocretin (orexin).

Narcolepsy is a disabling neurologic condition affecting 1 in 2000 individuals, characterized by sleepiness, cataplexy, and transitions from wakefulness into rapid-eye-movement sleep. Current treatments include amphetamine-like stimulants and antidepressants. Human narcolepsy is HLA-associated, multigenic, and environmentally influenced. Positional cloning was used to isolate narcolepsy genes in canine families with autosomal recessive narcolepsy transmission. Three mutations in the G-protein-coupled hypocretin (orexin) receptor-2 (Hcrtr-2) gene were identified. In humans, most cases of narcolepsy are not linked to hypocretin (Hcrt) ligand or receptor mutations but are associated with undetectable cerebrospinal fluid Hcrt-1 levels. A single Hcrt gene/narcolepsy mutation was identified in narcoleptic patients. Hcrt-1 is wake-promoting in vivo, and studies in sporadic human narcolepsy indicate a loss of brain Hcrt-1 and Hcrt-2 and a disappearance of Hcrt-1-containing cells in the hypothalamus. Narcolepsy with cataplexy may therefore be due to Hcrt deficiency. The HLA association in humans suggests possible autoimmune activity against hypothalamic Hcrt-containing cells. Hypocretins may also have roles in regulating normal sleep, appetite, neuroendocrine function and energy metabolism, uniquely positioning them as a link between multiple important behaviors. Abnormal Hcrt transmission is also found in neurologic disorders featuring excessive daytime sleepiness and/or hypothalamic abnormalities. Pharmacologic manipulations of Hcrts may have multiple therapeutic applications.

Alleles↗
PubMed1981

Life effects of narcolepsy in 180 patients from North America, Asia and Europe compared to matched controls.

A questionnaire survey has been made of the life effects of narcolepsy in 180 patients, 60 each from North American, Asian and European populations, with 180 similarly distributed age and sex matched controls. Life-effects were attributed by the patients to the primary symptoms of excessive daytime drowsiness, sleep attacks, cataplexy, vivid hypnagogic hallucinations and sleep paralysis, and also to other frequent symptoms such as visual problems (blurring, diplopia) and memory impairment. Occupational problems were prevalent (over 75%) and included statistically significant deleterious effects upon performance, promotion, earning capacity, fear of or actual job loss and increased disability insurance. Driving was greatly affected and patients fell asleep at the wheel more frequently (66%), had near or actual accidents from drowsiness or falling asleep at the wheel (67%), and could experience cataplexy (29%) or sleep paralysis (12%) while driving. Work or home accidents attributed to sleepiness or sleep (49%) or related to smoking (49%) were much more common in patients. There were also deleterious effects on education, recreation and personality related to disease. Narcolepsy can produce a variety of life-effects probably more serious and pervasive than, for instance, those of epilepsy, therefore emphasizing the importance of early diagnosis and treatment.

Accidents↗
PubMed2003

CSF hypocretin measures in patients with obstructive sleep apnea.

The majority of patients with narcolepsy-cataplexy were reported to have very low cerebrospinal fluid (CSF) hypocretin-1 (orexin-A) levels. The hypocretin-1 levels of secondary excessive daytime sleepiness (EDS) disorders are not known. In this study, we found that CSF hypocretin levels in the patients with obstructive sleep apnea syndrome were within the control range. The low hypocretin levels seem to reflect only the presence of cataplexy and DR2 positive in narcoleptics but not EDS itself.

Adult↗
PubMed2001

Narcoleptic canines display periodic leg movements during sleep.

Periodic leg movements during sleep (PLMS) is a high prevalent sleep disorder of unknown etiology. The disease is pharmacologically treated with dopaminergic agonists (i.e. D2/D3 agonists) and opiates. Periodic leg movements during sleep often occur in narcoleptic patients. We observed that narcoleptic canines, like narcoleptic humans, also exhibit jerky, unilateral or bilateral slow leg movements during sleep. The movements in dogs are characterized by repetitive dorsiflexions of the ankle, lasting 0.5-1.5 s, and occur at regular intervals of 3-20 s, thus showing similarities to PLMS in humans. The observation that D2/D3 agonists aggravate cataplexy in narcoleptic dogs suggests that altered dopaminergic regulation in canine narcolepsy may play a critical role in both cataplexy and PLMS. Our canines may therefore be an invaluable resource in PLMS research.

Animals↗
PubMed2001

Idiopathic Hypersomnia.

In contrast to narcolepsy and the Kleine-Levin syndrome, idiopathic hypersomnia is a recently described sleep disorder. Absence of associated clinical features such as cataplexy or megaphagia and characteristic polysomnographic features such as sleep-onset REM episodes render positive diagnosis more uncertain in idiopathic hypersomnia than in the fwo former conditions. Consequently there has been an unfortunate tendency to label all difficult to classify cases of excessive daytime sleepiness as idiopathic hypersomnia. At present due to the description of new disorders such as upper airway resistance syndrome, narcolepsy without cataplexy, delayed sleep phase syndrome, all of which were formerly confused with idiopathic hypersomnia and the clear identification of a "polysymptomatic" or "classic" form of idiopathic hypersomnia, the limits of the disorder become more precise. Still there are a number of cases of isolated excessive daytime sleepiness with no prolonged night sleep, no difficulty waking up, which lay between narcolepsy and genuine idiopathic hypersomnia. Thus there is a definite need to further develop laboratory investigations to help identify and classify these cases. Moreover pathophysiology and pathogenesis are still in their infancy and efforts have to be pursued in this direction. Treatment has not made consistent progress except for the use of a new wake promoting compound, modafinil, which has not yet been evaluated in controlled studies.

Journal Article↗
PubMed1995

Tranylcypromine in narcolepsy.

The narcolepsy syndrome consists of excessive daytime somnolence, cataplexy, hallucinations, and sleep paralysis. Data on the effects of tranylcypromine are scant. We report on a patient with severe narcolepsy in whom administration of tranylcypromine led to freedom from hallucinations, nightmares, sleep paralysis, and rapid eye movements (REM), with considerable amelioration of cataplexy and increased daytime alertness. Muscle atonia and low-voltage desynchronized cortical activity during REM sleep did not change. Tranylcypromine warrants further study in narcolepsy.

Adult↗
PubMed2006

The adult form of Niemann-Pick disease type C.

Niemann-Pick disease type C (NPC) is a fatal neurovisceral lipid storage disease of autosomal inheritance resulting from mutations in either the NPC1 (95% of families) or NPC2 gene. The encoded proteins appear to be involved in lysosomal/late endosomal transport of cholesterol, glycolipids and other molecules but their exact function is still unknown. The clinical spectrum of the disease ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. Based upon a comprehensive study of 13 unrelated adult patients diagnosed in France over the past 20 years as well as the analysis of the 55 other cases published since 1969, we have attempted to delineate the major clinical, radiological, biochemical and genotypic characteristics of adult NPC. Overall, mean age at onset (+/-SD) of neuropsychiatric symptoms was 25 +/- 9.7 years. The diagnosis of NPC was established after a mean delay of 6.2 +/- 6.4 years and the mean age at death (calculated from 20 cases) was 38 +/- 10.2 years. Major clinical features included cerebellar ataxia (76%), vertical supranuclear ophthalmoplegia (VSO, 75%), dysarthria, (63%), cognitive troubles (61%), movement disorders (58%), splenomegaly (54%), psychiatric disorders (45%) and dysphagia (37%). Less frequent signs were epilepsy and cataplexy. During the course of the disease, clinical features could be subdivided into (i) visceral signs (hepatomegaly or splenomegaly), (ii) cortical signs (psychiatric cognitive disorders and epilepsy); and (iii) deep brain signs (VSO, ataxia, movement disorders, dysarthria, dysphagia, cataplexy) which exhibited different evolution patterns. Asymptomatic and non-evolutive visceral signs were often noticed since early childhood (38.5% of our patients), followed by mild cortical signs in childhood (learning difficulties) and early adulthood (62% of cases among which 38% were psychiatric disorders). Deep brain signs were observed in 96% of patients and were usually responsible for death. In general, there was a good correlation between clinical signs and the localization of brain atrophy on MRI. The 'variant' biochemical phenotype characterized by mild abnormalities of the cellular trafficking of endocytosed cholesterol was over-represented in the adult form of NPC and seemed associated with less frequent splenomegaly in childhood and lesser psychiatric signs. Involvement of the NPC1 gene was shown in 33 families and of the NPC2 gene in one. Improving the knowledge of the disease among psychiatrists and neurologists appears essential since emerging treatments should be more efficient at the visceral or cognitive/psychiatric stages of the disease, before the occurrence of widespread deep brain neurological lesions.

Adolescent↗
PubMed1994

Modafinil: a double-blind multicentric study.

Modafinil is a central putative alpha-1 postsynaptic agonist with vigilance-promoting properties. Fifty narcoleptics (33 male and 17 female) participated in a multicentric study aimed at assessing the effects of the compound on night sleep, feeling on awakening, excessive daytime sleepiness and cataplexy. Modafinil was administered in a double-blind cross-over design at a daily dosage of 300 mg versus placebo. The duration of the study was 12 weeks, including a 2-week "run in" period with placebo, a first 4-week treatment period with either modafinil or placebo, a 2-week wash-out period with placebo and a second 4-week treatment period with either placebo or modafinil. Daily evaluation was based on a sleep log, visual analog scales, a sleep questionnaire and a clinical global index. Sleep laboratory evaluation took place on nights 1, 28, 42 and 70. It included 1 night of polysomnography preceded by a questionnaire on therapeutic and side effects, and a maintenance of wakefulness test (MWT). Sleep logs did not show any modification of night sleep, but a reduction of daytime sleepiness and sleep. Feeling on awakening was not modified. An overall benefit was noted by physicians as well as by patients. MWT disclosed a positive effect of modafinil on excessive daytime sleepiness. Cataplexy was not modified.

Adult↗
PubMed1994

Narcolepsy in children.

The clinical and polygraphic characteristics of narcolepsy in children were established on the analysis of 97 reported cases in children (including 12 personal cases). In idiopathic narcolepsies (77 cases) narcoleptic attacks occurred in 97% of the cases, cataplexy in 80.5%, hypnagogic hallucination in 39% and sleep paralysis in 29%; 13% of the children had the tetrad; dyssomnia was a prominent feature. Polygraphic data showed no significant differences between adults and children. In symptomatic narcolepsies (20 cases): cataplexy was the prominent feature occurring in 95% of the cases, 26% of the children had status cataplecticus; in these narcoleptic-cataplectic syndromes there was often an absence of polygraphic evidence of narcolepsy. Symptomatic narcolepsy should be suspected in cases where narcolepsy is detected in preteenage children, where cataplectic attacks are abnormally frequent, where there is an absence of polygraphic evidence of classical narcolepsy (although this criterion may not apply in the case of younger children) or where human leukocyte antigen typing for DR2 is negative. An association with a Niemann-Pick disease type C was found in 12 out of the 20 symptomatic cases, this association merits further study.

Catalepsy↗
PubMed1997

HLA haplotypes, polysomnography, and pedigrees in a case series of patients with narcolepsy.

An ongoing study of the genetics of narcolepsy ascertains families through a case series of narcoleptic probands using diagnostic criteria consisting of 1) clinical history of excessive somnolence, 2) a mean sleep latency on the multiple sleep latency test (MSLT) of less than 7.9 minutes, 3) the rapid eye movement (REM) sleep-related symptom of cataplexy, 4) nocturnal polysomnography ruling out sleep apnea syndrome, and 5) two or more transitions to REM sleep on the MSLT. All probands and first-degree relatives received clinical and laboratory evaluations as well as human leukocyte antigen (HLA) typing. Demographic characteristics of the 32 probands are as follows: 17 males and 15 females; mean age was 42.1 years (range 13-70 years). The polysomnographic data confirmed daytime sleepiness and increased tendency for REM sleep for the 32 probands. Nocturnal polysomnographic results are as follows: sleep latency, 3.2 minutes; total sleep time, 442 minutes. MSLT results are as follows: sleep latency, 3.1 minutes; REM latency, 6.9 minutes; number of REM periods, 3.2. HLA typing revealed the presence of the HLA haplotypes, DRB1*15 and DQB1*0602, in 21 narcoleptic probands, with two African-Americans having the DQB1*0602 but not the DRB1*15 allele. Among the 57 relatives of the 32 probands, 1/31 females and 7/26 males were found to be affected with narcolepsy (p < 0.02), which suggests a higher diagnostic rate in male relatives. The 21 probands who were positive for the DRB1*15 and DQB1*0602 haplotypes did not differ from the 10 probands who were negative for these alleles in terms of their nocturnal sleep parameters, MSLT findings, or clinical presentation. Three families with multiple individuals affected with narcolepsy are presented. Two families have more than one affected individual who does not have the high-risk HLA haplotype. In one of these families, the disease is segregating independently of any HLA haplotype. In the third family, there is cosegregation with HLA DRB1*15 and DQB1*0602. One family contains a pair of DNA-confirmed, monozygotic twins with narcolepsy who are discordant for cataplexy and have the HLA DR14(Dw9)/DQB1*0503 and DR4(Dw4)/DQB1*0302 haplotypes.

Adolescent↗
PubMed2002

The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study.

STUDY OBJECTIVES: To determine the age- and sex-specific incidence rates and prevalence of narcolepsy in a United States community. DESIGN: The records-linkage system of the Rochester Epidemiology Project was utilized to ascertain all patients with narcolepsy seen in Olmsted County, Minnesota between 1960 and 1989. Age- and sex-specific incidence rates were calculated, using census data. Prevalence of narcolepsy on January 1,1985 was calculated. SETTING: N/A. PATIENTS OR PARTICIPANTS: Community patients diagnosed with narcolepsy by a validated set of diagnostic criteria. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The incidence rate per 100,000 persons per year was 1.37 (1.72 for men and 1.05 for women). The incidence rate was highest in the 2nd decade, followed in descending order by the 3rd, 4th and 1st decades. The prevalence on January 1, 1985 was 56.3 per 100,000 persons. Approximately 36% of prevalence cases did not have cataplexy. CONCLUSIONS: Narcolepsy is not a rare disorder. It appears to be commoner in men. It originates most commonly in the 2nd decade. Narcolepsy without cataplexy is an important subgroup, warranting further study.

Adolescent↗
PubMed2003

Narcolepsy-like symptoms in a patient with down syndrome and without obstructive sleep apnea.

OBJECTIVE: The study reports on a 33-year-old Caucasian female with Down syndrome and narcolepsy-like symptoms. METHOD: After medical and genetic screening, docturnal polysomnography followed by a Multiple Sleep Latency Test and HLA typing were performed. The patient was medication free and reported a number of cataplexy attacks everyday. Each time that she came to the sleep disorders clinic, she was observed to have cataplexy. She also felt extremely drowsy. A mean sleep latency of 8.8 minutes with 4 sleep-onset rapid eye movement periods in the Multiple Sleep Latency Test, with no other sleep disorder that accounts for the symptoms, was obtained. The patient was DQB1*0301, DQB1*0602, as revealed by the last high-resolution serologic typing.

Adult↗
PubMed2003

Emotional information processing in patients with narcolepsy: a psychophysiologic investigation.

OBJECTIVES: Cataplexy is the key symptom of the narcoleptic syndrome. It is usually triggered by emotions, which play an important role in the manifestation and severity of the disease. Accordingly, we compared the psychophysiologic effects on patients with narcolepsy and healthy subjects of processing visual stimuli that have established emotional valences. METHOD: Eight drug-free patients with narcolepsy with severe cataplexy and 8 controls were studied. Fifty-four color pictures (pleasant, neutral, and unpleasant) selected from the International Affective Picture System were presented on a monitor to the subjects. The effects of exposure to the pictures were assessed in muscular (corrugator, zygomatic and mylohyoid electromyographic activity), autonomic (blood pressure, heart rate, and skin conductance responses) cognitive (scalp-recorded event-related potentials), and subjective (valence, arousal, and dominance by Self-Assessment Manikin) systems. RESULTS: The autonomic, muscular, and cognitive systems showed an attenuated reaction to visual stimuli in patients compared to controls. Furthermore, patients with narcolepsy showed the lowest responses when unpleasant pictures were presented. CONCLUSIONS: Our data suggest that, compared to the group of healthy subjects, patients with narcolepsy suffer from a temporal disadvantage in input processing, in particular, of unpleasant stimuli. The drawback exhibited by these patients suggests reduced reactivity of the aversive motivational system responsible for negative or unpleasant emotions.

Adult↗
PubMed2003

Month of birth as a risk factor for narcolepsy.

STUDY OBJECTIVES: A loss of hypocretin neurons has been observed in human narcolepsy; however, the cause of this disorder is still unknown. While family history and genetic factors are important individual risk factors for narcolepsy, environmental factors also contribute to the pathogenesis of the disease. The aim of the study was to find out whether there is a seasonality of month of birth in narcoleptic patients. DESIGN: Diagnosis of narcolepsy with cataplexy was based on International Classification of Sleep Disorders criteria with clinical, standard polysomnographic, and Multiple Sleep Latency Test features. PATIENTS AND SETTING: The birth dates of 886 patients with a clear-cut diagnosis of narcolepsy with cataplexy from 3 large narcolepsy databases (352 from Montpellier-France, 157 from Montreal-Canada, and 377 from Stanford-United States of America) were compared with those of 35,160,522 subjects from the general population. MEASUREMENTS AND RESULTS: Patients with narcolepsy had a significantly different seasonality of month of birth compared to that of the general population. The monthly distribution of birth yielded a peak in March with a maximal odds ratio at 1.45 and a trough in September with a minimal odds ratio at 0.63. No gender or country of origin differences were observed. CONCLUSIONS: A birth seasonality in the development of narcolepsy suggests the presence of environmental factors acting in combination with genetic factors during the fetal or perinatal period, in terms of an autoimmune process targeting the hypocretin system.

Birth Rate↗
PubMed2005

Analysis of hypocretin (orexin) antibodies in patients with narcolepsy.

STUDY OBJECTIVES: We tested the hypothesis that patients with narcolepsy have serum antibodies specific for preprohypocretin and its derivatives. DESIGN: We tested sera from strictly diagnosed HLA DQB1*0602-positive narcoleptic patients with cataplexy for evidence of autoantibodies against human preprohypocretin, hypocretin 1 and 2, N-terminal leader and C-terminal peptides of preprohypocretin using enzyme-linked immunosorbent assays (ELISA). These results were compared to samples from nonnarcoleptic psychiatric and sleep apnea controls. Laboratory personnel were blinded to subject status. SETTING: Narcoleptic patients and nonnarcoleptic controls were recruited from the Mayo Clinic facilities in Rochester, Minnesota; Scottsdale, Arizona; and Jacksonville, Florida. Laboratory testing was conducted in the Mayo Psychogenomic Laboratory at the Rochester Mayo Clinic. PARTICIPANTS: A sample of 34 narcoleptic patients and 49 nonnarcoleptic controls. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: ELISA measurements were in optical density. Primary analyses were of the entire narcoleptic and control groups for each potential antigen, and none of the differences reached P values required for significance after Bonferroni adjustment. Secondary analyses by age and sex yielded P values that were significant after Bonferroni adjustment in only 2 cases, but further statistical analyses cast doubt on the veracity of these differences. In all cases where a significant difference was recorded, the hypothesis was not supported because the control optical density reading was higher than the narcoleptic values. CONCLUSIONS: These ELISA assay results do not support the hypothesis that HLA DQB1*0602-positive narcolepsy with cataplexy is associated with serum antibodies against preprohypocretin or its cleavage products.

Autoantibodies↗
PubMed2006

A randomized trial evaluating the effectiveness of sodium oxybate therapy on quality of life in narcolepsy.

STUDY OBJECTIVES: To evaluate the efficacy of sodium oxybate versus placebo to improve quality of life in patients with narcolepsy. DESIGN: A multicenter, double-blind, placebo-controlled trial. SETTING: Outpatient facility of 42 sleep centers in the United States, Canada, and Europe. PARTICIPANTS: Study participants were 285 patients with narcolepsy, 16 to 75 years of age, with a median Epworth Sleepiness Scale score of 18, a Maintenance of Wakefulness Test sleep latency of 9.56 minutes, and experiencing symptoms of narcolepsy, including cataplexy and excessive daytime sleepiness with recurrent sleep episodes almost daily for at least 3 months at the time of enrollment. INTERVENTIONS: Subjects were gradually withdrawn from narcolepsy medications used for cataplexy, including antidepressants. Subsequently, participants were randomly assigned to receive 4.5, 6.0, or 9.0 g per day of sodium oxybate or placebo taken in two equally divided doses upon retiring to bed and again 2.5 to 4 hours later for 4 weeks during the stable dosing phase. MEASUREMENTS AND RESULTS: The change in quality of life following the administration of sodium oxybate was measured with the Functional Outcomes of Sleep Questionnaire. The nightly administration of sodium oxybate produced significant dose-related improvements in the Total Functional Outcomes of Sleep Questionnaire score, as well as in the Activity Level, General Productivity, Vigilance, and Social Outcomes subscales. CONCLUSIONS: The nocturnal administration of sodium oxybate in patients with narcolepsy was associated with statistically significant and clinically relevant improvements in functional status, an important component of quality of life.

Adjuvants, Anesthesia↗
PubMedDate not supplied

Successful treatment of post-traumatic narcolepsy with methylphenidate: a case report.

Narcolepsy is a rare sequela of brain injury. We report the case of a 27-yr-old male with post-traumatic narcolepsy who was successfully treated with methylphenidate. This patient sustained moderate brain injury from a motorcycle accident. Subsequently, he manifested the classic tetrad of narcolepsy: cataplexy, excessive daytime sleepiness, sleep paralysis, and hypnogogic hallucinations. There was no premorbid seizure or sleep disorder. There was no family history of sleep disorders. Polysomnography and Multiple Sleep Latency Test confirmed the diagnosis of narcolepsy. Sleep latency (time to sleep onset), rapid eye movement sleep latency (time from sleep onset to rapid eye movement sleep onset), and mean multiple sleep latency were all pathologically shortened (2.5, 66, and 1.2 min, respectively). Twenty-four hour electroencephalographic monitoring and magnetic resonance imaging of the brain were normal, as were serum chemistries. Treatment with caffeine was unsuccessful. He was then started on methylphenidate, 10 mg twice daily, which was increased to 30 mg twice daily over a 4-mo period. Cataplexy and excessive daytime sleepiness started to improve 1 mo after adjustments in methylphenidate dosing. Six months after the initiation of methylphenidate therapy, the patient is completely asymptomatic.

Adult↗