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At least 19 recordsLinked to original sources
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↗
PubMed1998

Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. US Modafinil in Narcolepsy Multicenter Study Group.

Narcolepsy is a central nervous system disorder characterized by excessive daytime sleepiness and cataplexy. This placebo-controlled, double-blind, randomized, parallel-group, 18-center study assessed the efficacy and safety of modafinil, a new wake-promoting drug for treating sleepiness in narcolepsy. Subjects with narcolepsy (n = 283) received daily modafinil, 200 or 400 mg, or placebo, for 9 weeks, followed by an open-label treatment period. Subjective sleepiness was measured with the Epworth Sleepiness Scale. Objective sleepiness was assessed with the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test. Level of illness was measured with the Clinical Global Impression of Change. Modafinil significantly reduced all measures of sleepiness and was associated with significant improvements in level of illness. Medication-related adverse experiences were few, dose-dependent, and mostly rated mild to moderate. Modafinil taken once daily was a very well tolerated and effective wake-promoting agent in the treatment of excessive daytime somnolence associated with narcolepsy. Modafinil demonstrated an excellent safety profile for up to 40 weeks of open-label treatment and efficacy was maintained, suggesting that tolerance will not develop with long-term use. Modafinil is a pharmacologically and clinically promising compound for the treatment of pathological daytime somnolence.

Adolescent↗
PubMedDate not supplied

[Narcolepsy and the psychiatric tableau. A specific form of narcolepsy?].

Narcolepsy is a well-known hypersomnia. Nevertheless narcolepsy in which the hallucinatory component is unusually prominent may lead to a false diagnosis of schizophrenia syndrome. This aspect is illustrated by the case of Miss B. who appears like a psychotic patient without dissociation syndrome and with a hysterical personality. Are the narcoleptics with psychiatric disorders a peculiar sub-type of narcolepsy? Fourty-five percent of our eleven narcoleptics patients have an associated psychiatric disorder. Most of them are depressive. Surprisingly fourty percent of our patients are non-DR2 at the Human Leucocyte Antigen typing. Furthermore seventy five percent of them have an associated psychiatric disorder. This would mean a peculiar sub-type of narcolepsy.

Adolescent↗
PubMed2000

Differences in electroencephalogram power densities between genuine narcolepsy and secondary narcolepsy.

Diagnosing narcolepsy is not always simple. Some patients secondarily show narcoleptic tetrad through irregular sleep patterns or psychotic diseases. The power densities of daytime electroencephalograms in genuine narcolepsy and secondary narcolepsy were analysed and compared. Electroencephalogram power densities for a 6.5-h period after waking in genuine narcoleptic patients were lower than those of secondary narcoleptic patients in the 11.0-12.5 Hz bands. Arousal levels may be lower in genuine narcoleptic patients than in secondary narcoleptic patients. Spectral analysis may be useful in clarifying differences between the two groups.

Adolescent↗
PubMed1993

The positive diagnosis of narcolepsy and narcolepsy's borderland.

We studied the validity of cataplexy and number of sleep-onset rapid-eye-movement periods (SOREMPs) during one Multiple Sleep Latency Test (MSLT) as determinants of narcolepsy in 306 subjects with excessive daytime sleepiness not related to obstructive sleep apnea or other known syndromes. The subgroup defined by a history of cataplexy was the most homogeneous in clinical and polygraphic variables. However, only 83% of these subjects had two or more SOREMPs in one MSLT. The subgroup defined by two or more SOREMPs included many patients without cataplexy. A disproportionate number of these subjects were older women whose chances of developing cataplexy are remote. This group of older women had a higher number of periodic leg movements during sleep than the other groups. Patients with both cataplexy and two or more SOREMPs have the greatest chance of being DR2 DQw1 positive. Thus, the combination of history of cataplexy and two or more SOREMPs is the best clinical determinant of narcolepsy. However, two or more SOREMPs is a poorer discriminant of narcolepsy than history of cataplexy.

Adolescent↗
PubMed2003

[HLA-DRB and -DQB allele contribution to narcolepsy susceptibility in Chinese patients with narcolepsy].

OBJECTIVES: To study the association of narcolepsy with HLA class II alleles in Chinese narcoleptic patients. METHODS: 31 patients with narcolepsy underwent brain computed tomography (CT) scan and magnetic resonance imaging (MRI) testing. All patients received a MSLT test following a routine night's sleep, and serological HLA typing for HLA DR(2). 21 patients received PCR-SSP HLA DR and DQ typing. RESULTS: All patients had sleepiness and cataplexy. There was no evidence for other functional or structural diseases. Sleep paralysis was elicited in 45%; hypnagogic hallucinations, in 61%. Mean sleep latency on MSLT was 2.1 min +/- 1.3 min; sleep-onset rapid eye movement (SOREM) occurred during 2/5 naps in 30 of 31 patients. The average number and latency of SOREM episodes were 4.2 +/- 1.0 episodes and 4.0 min +/- 1.8 min, respectively. All patients but one were HLA DR(2) positive and 86% were HLADRB(1) * 1501-HLADQB(1)*0602 positive. CONCLUSIONS: HLA DR(2) and HLADQw6 are markers for narcolepsy-cataplexy in Chinese.

Adolescent↗
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↗
PubMed2000

Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy: US Modafinil in Narcolepsy Multicenter Study Group.

OBJECTIVE: This is one of two separate clinical trials to evaluate the efficacy and safety of modafinil, a novel wake-promoting agent, in patients with excessive daytime sleepiness (EDS) associated with narcolepsy. METHODS: In this 9-week, randomized, placebo-controlled, double-blind, 21-center clinical trial, patients were randomized to receive fixed daily doses of modafinil 200 mg, modafinil 400 mg, or placebo. A placebo-controlled, 2-week treatment discontinuation phase was included to evaluate the effects of withdrawal on patients who had been receiving modafinil. A total of 271 patients who were naive to modafinil received study medication in the 9-week trial and 240 patients received study medication in the discontinuation phase. RESULTS: Treatment with modafinil resulted in significant improvement in two objective measures of EDS: the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test. Additionally, patient self-assessment of sleepiness was significantly improved, as measured by the Epworth Sleepiness Scale, and level of illness was significantly reduced on the independent clinician assessment, the Clinical Global Impression of Change. Nighttime sleep, monitored by nocturnal polysomnography, was not adversely effected with modafinil treatment compared with placebo treatment. The most frequent adverse experience was headache, which was not significantly greater for modafinil than placebo. During treatment discontinuation, individuals who had been receiving modafinil experienced a return of their EDS to baseline levels. During treatment discontinuation, patients did not experience symptoms associated with amphetamine withdrawal syndrome. For up to 9 weeks of daily use there was no evidence for the development of dependence at the dose levels studied. CONCLUSION: The data indicate that modafinil has an excellent safety profile and is very well tolerated. Modafinil is an effective treatment for excessive daytime sleepiness in narcolepsy and shows continued efficacy with up to 9 weeks of daily use.

Adolescent↗
PubMedDate not supplied

The neurobiology of narcolepsy-cataplexy syndrome.

The pathophysiology of narcolepsy is closely related to the abnormalities of REM sleep that are the electrophysiologic signature of the syndrome. Evidence from studies of canine narcolepsy and postmortem human narcoleptic brain tissue provide strong evidence that cholinergic and monoaminergic systems involved in REM sleep regulation are abnormal in narcolepsy but the primary neurochemical abnormality has not yet been determined. There is now conclusive evidence that a genetic basis is required for all or almost all cases of narcolepsy. In the vast majority of narcoleptics, a gene closely linked to the HLA-DR/DQ region appears to confer narcoleptic susceptibility, but the penetrance of the gene is low and additional environmental and perhaps genetic factors are required to express the disease. In a minority of narcoleptics, there may be a second autosomal dominant gene not linked to HLA-DR2 that facilitates the occurrence of narcolepsy. This gene may be related to the mu-immunoglobulin heavy-chain switch-like segment that has been implicated in canine narcolepsy. There appear to be at least two narcoleptic phenotypes associated with the narcoleptic susceptibility gene or genes: narcolepsy-cataplexy syndrome and monosymptomatic narcolepsy, or narcolepsy with REM sleep abnormalities but without cataplexy. Idiopathic hypersomnia without cataplexy or REM sleep abnormalities may represent a third phenotype, although most cases of idiopathic hypersomnia are probably unrelated to the HLA-D linked gene. The link between the genetic basis of narcolepsy and its neurochemical abnormalities is still entirely unknown. Although the hypothesis that a transient immune-mediated reaction leads to a permanent alteration of monoaminergic function is appealling, there is no direct evidence to support this hypothesis. Several important questions concerning the neurobiology of narcolepsy remain to be answered. What is the specific gene in the HLA-D region that is linked to human narcolepsy and what are the products or functions of the gene that predispose to narcolepsy? Does the human mu-switch region contain genetic material homologous to the 85-kb band linked to canarc-1 that predisposes to narcolepsy? What are the environmental factors required for expression of the disease in susceptible individuals and do they incite immunologic processes? Which of the neurochemical abnormalities are primary, which are secondary or compensatory, and how do they relate to the predisposing genetic and environmental elements? Additional familial, genetic, and neurochemical studies over the next decade should lead to more complete understanding of the neurobiology of narcolepsy and ultimately to better treatments for this chronic disabling disease.

Animals↗
PubMed2002

The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias.

CONTEXT: Narcolepsy, a neurological disorder affecting 1 in 2000 individuals, is associated with HLA-DQB1*0602 and low cerebrospinal fluid (CSF) hypocretin (orexin) levels. OBJECTIVES: To delineate the spectrum of the hypocretin deficiency syndrome and to establish CSF hypocretin-1 measurements as a diagnostic tool for narcolepsy. DESIGN: Diagnosis, HLA-DQ, clinical data, the multiple sleep latency test (MSLT), and CSF hypocretin-1 were studied in a case series of patients with sleep disorders from 1999 to 2002. Signal detection analysis was used to determine the CSF hypocretin-1 levels best predictive for International Classification of Sleep Disorders (ICSD)-defined narcolepsy (blinded criterion standard). Clinical and demographic features were compared in narcoleptic subjects with and without low CSF hypocretin-1 levels. SETTING: Sleep disorder and neurology clinics in the United States and Europe, with biological testing performed at Stanford University, Stanford, Calif. PARTICIPANTS: There were 274 patients with narcolepsy; hypersomnia; obstructive sleep apnea; restless legs syndrome; insomnia; and atypical hypersomnia cases such as familial cases, narcolepsy without cataplexy or without HLA-DQB1*0602, recurrent hypersomnias, and symptomatic cases (eg, Parkinson disease, depression, Prader-Willi syndrome, Niemann-Pick disease type C). The subject group also included 296 controls (healthy and with neurological disorders). INTERVENTION: Venopuncture for HLA typing, lumbar puncture for CSF analysis, primary diagnosis using the International Classification of Sleep Disorders, Stanford Sleep Inventory for evaluation of narcolepsy, and sleep recording studies. MAIN OUTCOME MEASURES: Diagnostic threshold for CSF hypocretin-1, HLA-DQB1*0602 positivity, and clinical and polysomnographic features. RESULTS: HLA-DQB1*0602 frequency was increased in narcolepsy with typical cataplexy (93% vs 17% in controls), narcolepsy without cataplexy (56%), and in essential hypersomnia (52%). Hypocretin-1 levels below 110 pg/mL were diagnostic for narcolepsy. Values above 200 pg/mL were considered normal. Most subjects with low levels were HLA-DQB1*0602-positive narcolepsy-cataplexy patients. These patients did not always have abnormal MSLT. Rare subjects without cataplexy, DQB1*0602, and/or with secondary narcolepsy had low levels. Ten subjects with hypersomnia had intermediate levels, 7 with narcolepsy (often HLA negative, of secondary nature, and/or with atypical cataplexy or no cataplexy), and 1 with periodic hypersomnia. Healthy controls and subjects with other sleep disorders all had normal levels. Neurological subjects had generally normal levels (n = 194). Intermediate (n = 30) and low (n = 3) levels were observed in various acute neuropathologic conditions. CONCLUSIONS: Narcolepsy-cataplexy with hypocretin deficiency is a genuine disease entity. Measuring CSF hypocretin-1 is a definitive diagnostic test, provided that it is interpreted within the clinical context. It may be most useful in cases with cataplexy and when the MSLT is difficult to interpret (ie, in subjects already treated with psychoactive drugs or with other concurrent sleep disorders).

Adult↗
PubMed2005

Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system.

Human narcolepsy is a chronic sleep disorder affecting 1:2000 individuals. The disease is characterized by excessive daytime sleepiness, cataplexy and other abnormal manifestations of REM sleep, such as sleep paralysis and hypnagogic hallucinations. Recently, it was discovered that the pathophysiology of (idiopathic) narcolepsy-cataplexy is linked to hypocretin ligand deficiency in the brain and cerebrospinal fluid (CSF), as well as the positivity of the human leukocyte antigen (HLA) DR2/DQ6 (DQB1*0602). The symptoms of narcolepsy can also occur during the course of other neurological conditions (i.e. symptomatic narcolepsy). We define symptomatic narcolepsy as those cases that meet the International Sleep Disorders Narcolepsy Criteria, and which are also associated with a significant underlying neurological disorder that accounts for excessive daytime sleepiness (EDS) and temporal associations. To date, we have counted 116 symptomatic cases of narcolepsy reported in literature. As, several authors previously reported, inherited disorders (n=38), tumors (n=33), and head trauma (n=19) are the three most frequent causes for symptomatic narcolepsy. Of the 116 cases, 10 are associated with multiple sclerosis, one case of acute disseminated encephalomyelitis, and relatively rare cases were reported with vascular disorders (n=6), encephalitis (n=4) and degeneration (n=1), and hererodegenerative disorder (three cases in a family). EDS without cataplexy or any REM sleep abnormalities is also often associated with these neurological conditions, and defined as symptomatic cases of EDS. Although it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, review of the literature reveals numerous unquestionable cases of symptomatic narcolepsy. These include cases with HLA negative and/or late onset, and cases in which the occurrences of the narcoleptic symptoms are parallel with the rise and fall of the causative disease. A review of these cases (especially those with brain tumors), illustrates a clear picture that the hypothalamus is most often involved. Several cases of symptomatic cataplexy (without EDS) were also reported and in contrast, these cases appear to be often associated with non-hypothalamic structures. CSF hypocretin-1 measurement were also carried out in a limited number of symptomatic cases of narcolepsy/EDS, including narcolepsy/EDS associated with tumors (n=5), head trauma (n=3), vascular disorders (n=5), encephalopathies (n=3), degeneration (n=30), demyelinating disorder (n=7), genetic/congenital disorders (n=11) and others (n=2). Reduced CSF hypocretin-1 levels were seen in most symptomatic narcolepsy cases of EDS with various etiologies and EDS in these cases is sometimes reversible with an improvement of the causative neurological disorder and an improvement of the hypocretin status. It is also noted that some symptomatic EDS cases (with Parkinson diseases and the thalamic infarction) appeared, but they are not linked with hypocretin ligand deficiency. In contrast to idiopathic narcolepsy cases, an occurrence of cataplexy is not tightly associated with hypocretin ligand deficiency in symptomatic cases. Since CSF hypocretin measures are still experimental, cases with sleep abnormalities/cataplexy are habitually selected for CSF hypocretin measures. Therefore, it is still not known whether all or a large majority of cases with low CSF hypocretin-1 levels with CNS interventions, exhibit EDS/cataplexy. It appears that further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiological mechanisms for the occurrence of EDS and cataplexy.

Child↗
PubMed2003

Clinical aspects and pathophysiology of narcolepsy.

UNLABELLED: Narcolepsy is a chronic debilitating sleep disorder first described in the late 19th century. It is characterized by two major symptoms, excessive daytime sleepiness and cataplexy, and two so-called auxiliary symptoms, hypnagogic hallucinations and sleep paralysis. The final diagnosis relies on polysomnography showing the presence of sleep onset rapid eye movement periods (SOREMPs) during the multiple sleep latency test. The presence of HLA DQA1*0102-DQB1*0602 is supportive of the diagnosis. The pathophysiology of the disorder is still unknown but an imbalance between monoamines and acetylcholine is generally accepted. Recent findings in narcoleptic dogs, a natural model of narcolepsy, and in knockout mice revealed that a mutation of type 2 hypocretin receptor plays a major role in the etiology of narcolepsy. Up to now, no mutation has been found in humans except a case of early onset and atypical narcolepsy. However, a marked reduction of hypocretin type 1 has been found in the cerebrospinal fluid (CSF) of a majority of patients and a global loss of hypocretins was noted in post-mortem brain tissue of narcoleptic subjects. Conversely, no hypocretin neuron degeneration has been observed in the genetic form of narcolepsy in dogs but no trace of hypocretin was seen in the brain or the CSF in cases of sporadic canine narcolepsy. This suggests that different hypocretinergic mechanisms are involved in sporadic and genetic forms of canine narcolepsy. Treatment has not evolved significantly over the last few years. However, new drugs, such as hypocretin agonists, are currently being developed. SIGNIFICANCE: After the discovery of the type 2 hypocretin receptor mutation in canine narcolepsy and the finding of a CSF hypocretin-1 deficiency in human narcolepsy, the major stream of research has involved the hypocretinergic system. However, other lines of research deserve to be pursued simultaneously, in view of comprehensive advancements in the understanding of narcolepsy.

Animals↗
PubMed1986

HLA-DR2 and Dw2 in narcolepsy and in other disorders of excessive somnolence without cataplexy.

Studies on HLA antigens were conducted in several patient populations with the following findings: (a) All 135 Japanese narcoleptic patients, eight of whom were considered to have "symptomatic" narcolepsy, were found to be HLA-DR2 and HLA-DQw1 positive. All 17 members of a subgroup of the original population were also found to be HLA-Dw2-positive. It was concluded that HLA-DR2 is a prerequisite for the development of narcolepsy and that the diagnosis of narcolepsy can be excluded if HLA-DR2 or HLA-Dw2 is negative. The distinction between idiopathic and symptomatic narcolepsy needs to be reconsidered. (b) Haplotype studies in three families with narcoleptic members enabled detection of children at high risk for narcolepsy. (c) Of the 54 patients with disorders of excessive daytime sleepiness other than narcolepsy, those with essential hypersomnia (EHS) had a higher frequency of HLA-DR2; the others had a lower frequency. The DR2-positive EHS group could include members with an incomplete form of narcolepsy; the DR2-negative EHS group had disorders essentially different from narcolepsy, although both positive and negative groups manifested hypnagogic hallucinations, sleep paralysis, and sleep onset REMs. Two further studies were conducted in subgroups of the original narcoleptic population studied. In a subgroup of 30 patients who underwent lymphocyte subset studies, no T-cell abnormalities were detected; it is unlikely that an autoimmune mechanism is involved in the development of narcolepsy. In a subgroup of 33 narcoleptic patients, Southern's blot analysis of DNA using a DQ beta probe revealed three specific restriction fragments. Further studies are necessary to locate the DNA locus that carries the susceptibility gene for narcolepsy.

Alleles↗
PubMed1996

Perspectives in narcolepsy research and therapy.

Narcolepsy with associated cataplexy is a disabling sleep disorder that affects 0.05% of the general population. Whereas narcolepsy-cataplexy is largely considered as etiologically homogeneous, hypersomnias without cataplexy represent a very heterogeneous group of clinical entities that must be thoroughly explored before final diagnosis of narcolepsy is given. A typical treatment for narcolepsy-cataplexy associates amphetamine-like stimulants for sleepiness and antidepressant therapy for abnormal rapid eye movement sleep (cataplexy, sleep paralysis, and hypnagogic hallucinations). This treatment is purely symptomatic and involves activation of central dopaminergic and adrenergic activity respectively. Genetic research indicates a role for the immune system rather than abnormalities in monoaminergic or cholinergic systems as the primary cause for narcolepsy. Human narcolepsy is tightly associated with HLA-DQB1*0602; canine narcolepsy is linked with a DNA segment with high homology with the human immunoglobulin mu-switch segment, and the onset of canine narcolepsy is associated with increased microglial expression of major histocompatibility complex DQ and DR molecules. Taken together with the lack of direct evidence for an autoimmune process in narcolepsy, these results may suggest the existence of novel neuroimmune interactions in narcolepsy and open new perspectives in the treatment of this disabling disorder.

Adrenergic Agonists↗