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PubMed2006

Molecular genetics and treatment of narcolepsy.

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy. The hypocretin/orexin deficiency is likely to be the key to its pathophysiology in most of cases although the cause of human narcolepsy remains elusive. Acting on a specific genetic background, an autoimmune process targeting hypocretin neurons in response to yet unknown environmental factors is the most probable hypothesis in most cases of human narcolepsy with cataplexy. Although narcolepsy presents one of the tightest associations with a specific human leukocyte antigen (HLA) (DQB1*0602), there is strong evidence that non-HLA genes also confer susceptibility. In addition to a point mutation in the prepro-hypocretin gene discovered in an atypical case, a few polymorphisms in monoaminergic and immune-related genes have been reported associated with narcolepsy. The treatment of narcolepsy has evolved significantly over the last few years. Available treatments include stimulants for hypersomnia with the quite recent widespread use of modafinil, antidepressants for cataplexy, and gamma-hydroxybutyrate for both symptoms. Recent pilot open trials with intravenous immunoglobulins appear an effective treatment of cataplexy if applied at early stages of narcolepsy. Finally, the discovery of hypocretin deficiency might open up new treatment perspectives.

Animals↗
PubMed2006

Correlates of sleep-onset REM periods during the Multiple Sleep Latency Test in community adults.

The diagnosis of narcolepsy without documented cataplexy is based on the observation of two or more sleep-onset REM periods (SOREMPs) during the Multiple Sleep Latency Test (MSLT). We report on the prevalence and correlates of SOREMPs in the community-based Wisconsin Sleep Cohort Study. MSLTs were conducted following nocturnal polysomnography (NPSG) and daily sleep diaries in 289 males and 267 females (age 35-70, 97% Caucasians). Multiple SOREMPs were observed in 13.1% of males and 5.6% of females. An MSLT mean sleep latency < or =8 min and > or =2 SOREMPs (diagnostic of narcolepsy) was observed in 5.9% (males) and 1.1% (females), all without cataplexy. Because of significant sex interactions, analyses were stratified by sex. Increased prevalence of HLA-DQB1*0602, a marker of narcolepsy, was observed in males but not in females with > or =2 SOREMPs. Males with multiple SOREMPs compared with those with no SOREMPs had shorter rapid eye movement (REM) latency during NPSG, were sleepier on the MSLT and reported increased sleepiness, hypnagogic hallucinations and cataplexy-like symptoms, suggesting a narcolepsy-like phenotype. In males only, the occurrence of SOREMPs increased with shift work and some indirect markers of sleep restriction, such as shorter sleep a day before NPSG. SOREMPs were unrelated to age, body mass index, depression (Zung Scale), anxiety (State-Trait Anxiety Scale) and the number of apnea and hypopnea events per hour of sleep (AHI), but were associated with decreased mean lowest oxygen saturation in males. Finally, we found that both males and females with SOREMPs reported taking more antidepressants, but those were of the types known not to suppress REM sleep. These results suggest a high prevalence of narcolepsy without cataplexy, as defined by the International Classification of Sleep Disorders, and/or a large number of false-positives for the MSLT.

Adult↗
PubMed1994

Neuropharmacology and neurochemistry of canine narcolepsy.

It is believed that narcolepsy involves abnormalities of rapid eye movement (REM) sleep, especially of REM sleep atonia. Compelling evidence suggests that the regulation of REM sleep and REM sleep atonia involves a reciprocal interaction of cholinergic and monoaminergic systems. Using our canine model of narcolepsy and a pharmacological approach, we have previously demonstrated a similar interaction in the regulation of cataplexy. Global activation of cholinergic or monoaminergic transmission aggravates or suppresses canine cataplexy, respectively. We have also identified the subtypes of monoaminergic and cholinergic receptors specifically involved in this interaction. Cataplexy is aggravated by activation of the cholinergic system via M2 stimulation, as well as deactivation of the catecholaminergic systems by either blockade of postsynaptic alpha-1b receptors or stimulation of alpha-2 or D2 inhibitory autoreceptors. These pharmacological results correspond to previously identified neurochemical abnormalities in canine narcolepsy, such as significant increases in M2 receptors in the pons, alpha-1 receptors in the amygdala, alpha-2 receptors in the locus coeruleus and D2 receptors in the amygdala and nucleus accumbens, when compared to control animals. Using local perfusion of active compounds, we have further demonstrated that cholinoceptive sites in the pontine reticular formation, as well as in the basal forebrain, are involved in the regulation of cataplexy. Although the specific sites of action of the monoaminergic compounds remain unknown, the results of our pharmacological and neurochemical studies to date suggest that a widespread hyperactivity of cholinergic systems within the central nervous system together with a hypoactivity of catecholaminergic systems underlie the pathophysiology of narcolepsy.

Acetylcholine↗
PubMed1998

Neuronal activity in the cholinoceptive basal forebrain of freely moving narcoleptic dobermans.

Cholinergic stimulation in the basal forebrain (BF) triggers cataplexy in canine narcolepsy. Extracellular single unit recordings in the BF were carried out in freely moving narcoleptic dogs to study the neuronal mechanisms mediating cataplexy induction in the BF. Among the 64 recorded neurons, 12 were wake-active, three were slow wave sleep (SWS)-active, 17 were wake-/REM-active, 11 were REM sleep-active, three were cataplexy-active, and the other 18 were state-independent. Systemic administration of physostigmine, a cholinesterase inhibitor, induces status cataplecticus, decreases SWS and increases acetylcholine levels in the BF. Firing of most of the state-dependent neurons in the BF was significantly modified by physostigmine. Some of these neurons may thus mediate sleep stage changes or the effect on cataplexy observed after cholinergic stimulation in the BF.

Acetylcholine↗
PubMed1983

The effect of gammahydroxybutyrate on the H-reflex: pilot study.

Gammahydroxybutyrate (GHB) promotes cataplexy when given during the day, but decreases the incidence of daytime cataplexy when given at night. To understand the effects of GHB on this form of motor inhibition, we studied its actions on the H- and F-responses. The H-response is attenuated or abolished during cataplexy. GHB markedly inhibited the H-reflex response in normal and narcoleptic subjects, whether or not sleep was induced. It had no effect on the F-response. Prolonged motor inhibition at night by GHB may raise the threshold for inhibition during the day, accounting for the decrease in daytime cataplexy. The failure to affect the F-response suggests that GHB has a presynaptic site of action.

Adult↗
PubMed1998

Investigations into the neurologic basis of narcolepsy.

The understanding of narcolepsy has been enhanced by neurophysiologic investigations in humans and by pharmacologic and biochemical studies using the canine model of narcolepsy. Repetitive microsleeps have a more deleterious effect on performance than several short complete naps during the day. Under normal living conditions, the nocturnal sleep of narcoleptic patients is disrupted, and the spectral analysis of central EEG leads shows less delta power density per epoch than it does in age-matched controls, who have an absence or decrease of the usual decay in delta power across the night. Cataplexy is associated with a drop in H-reflex, even during partial cataplectic attacks. Monitoring of heart rate and intra-arterial blood pressure during cataplexy in humans shows a decrease in heart rate and an increase in blood pressure with onset of cataplexy, but the change in heart rate is secondary to the change in blood pressure. Investigations of narcoleptic Doberman pinschers have implicated several neurotransmitters in the brainstem and amygdala. In vivo dialysis and in situ injections of carbachol indicate that the pontine reticular formation is not the only muscarinic cholinergic region involved, but data support the existence of a multisynaptic descending pathway involved in the muscle atonia of cataplexy. Carbachol injections into the basal forebrain induce status cataplecticus. Experimental findings suggest a hypersensitivity of the overall muscarinic cholinergic system and that this hypersensitive cholinergic system is linked to the limbic system. An increase in the postsynaptic D2 dopaminergic receptor is observed in the amygdala of narcoleptic dogs compared with controls, with impairment of dopamine release. The associated findings suggest that an abnormal cholinergic-dopaminergic interaction could underlie the pathophysiology of narcolepsy.

Animals↗
PubMed2002

[Status cataplecticus induced by abrupt withdrawal of clomipramine].

INTRODUCTION: Cataplexy is one of the main narcoleptic symptoms and is characterized by sudden loss of muscle tone triggered by emotional stimuli while consciousness is mantained. Clomipramine is an effective treatment of cataplexy. Cataplexy that occurs repeatedly for hours or days is referred to as status cataplecticus. PATIENTS: We report three adults with narcolepsy in whom cataplexy was chronically and effectively treated with clomipramine (75-150 mg/day). For diverse reasons, these three patients had an abrupt withdrawal of clomipramine, and after 2-9 days patients showed an invalidant status cataplecticus characterized by a marked increase of the frequency, duration and severity of their cataplectic attacks that were now elicited by mild emotional stimuli. After introduction of anticataplectic agents (clomipramine in two patients and fluoxetine in one patient), status cataplecticus was resolved in less than a week. CONCLUSION: In patients with narcolepsy, abrupt withdrawal of chronic treatment with clomipramine may be associated with status cataplecticus. This condition may be resolved with the reintroduction of anticataplectic agents.

English Abstract↗
PubMed2006

Narcolepsy in Saudi Arabia. Demographic and clinical perspective of an under-recognized disorder.

OBJECTIVE: To assess the clinical and polysomnographic features of narcolepsy in Saudis. METHODS: All patients diagnosed to have narcolepsy in the Sleep Disorders Center at King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia between March 1998 and December 2005 based on the International Classifications of Sleep Disorders Diagnostic and Coding Manual criteria were included. A data entry form collecting the demographic, clinical features, medications, referring specialty, prior diagnoses and daytime sleepiness was used. All patients underwent polysomnography followed by multiple sleep latency. RESULTS: Forty-seven patients with a mean age of 28.9 +/- 1.9 years were included. The mean age at onset of symptoms was 20.5 +/- 1.4 years. The interval between symptoms onset and diagnosis was 8.4 +/- 1.2 years. While 22 (46.8%) of the patients were referred to the sleep disorders clinic by different specialties, 25 (53.2%) patients sought an appointment in the sleep disorders clinic directly. Only 3 patients were referred with the correct diagnosis. Nocturnal sleep quality was worse in narcoleptics with cataplexy compared to those without cataplexy. CONCLUSION: Saudi patients with narcolepsy have the same clinical presentation as reported in the Western literature. Narcoleptics with cataplexy had disturbed quality compared to narcoleptics without cataplexy. A long time was reported between symptoms onset and diagnosis, which may reflect the under-recognition of the problem among physicians.

Adolescent↗
PubMed1993

[Narcolepsy in horses].

Narcolepsy is an incurable non-progressive disease of the central nervous system. In humans, narcolepsy causes excessive drowsiness during the day (sometimes a sleep-attack occurs), cataplexy (sudden loss of muscle tone), hallucinations, and sleep paralysis. In the horse and other mammals cataplexy is the most frequently observed symptom. Excessive drowsiness can occur but is harder to observe. Cataplexy is caused by a fragmentation of the REM sleep. The etiology of narcolepsy is still subject to debate, partly because normal sleeping patterns are poorly understood. In humans and certain breeds of dogs a hereditary background has been demonstrated. In Shetland ponies the disease runs in certain families. The role of trauma and infection is the subject of debate. Cataplexy (which can be induced by physostigmine injection) confirms the diagnosis. Several drugs are available for the treatment of narcolepsy in humans. However there are a few data on the results of treatment of narcolepsy in the horse.

Animals↗
PubMed2005

Narcolepsy and disorders of excessive somnolence.

Recent studies provide valid criteria that help differentiate idiopathic narcolepsy from other disorders of excessive daytime somnolence [3]. Research to date suggests that idiopathic narcolepsy might properly be considered a disorder of excessive sleepiness with dysfunctional REM-sleep mechanisms, clinically evidenced as cataplexy and electrophysiologically recognized as SOREMPs. Given these criteria, a diagnosis can generally be made using a combination of history, PSG, and MSLT. Traditionally, the medical treatment of idiopathic narcolepsy has centered on a two-drug regimen (stimulants for sleepiness and TCAs for cataplexy and auxiliary symptoms). Some newer medications are proving efficacious for sleepiness with minimal adverse effects, whereas others may provide a single-drug regimen that simultaneously addresses sleepiness and cataplexy [18]. New research has allowed some experts to hypothesize that idiopathic narcolepsy may be the result of a genetic predisposition to autoimmune disease [176]. It is possible that aberrant genetic coding of elements in the hypocretin/orexin systems allows a sensitivity to inducible and possibly virally mediated changes, which leave cells in the lateral hypothalamus susceptible to autoimmune attack [96]. As such, genetic screening of high-risk individuals might eventually rationalize the prophylactic use of immunosuppressants in some instances. In the future, for atypical cases(poorly responsive to therapy), genetic, CSF, and brain imaging studies, and possibly even neuronal transplantation may prove beneficial in the assessment and treatment of idiopathic narcolepsy.

Cataplexy↗
PubMed2000

Implication of dopaminergic mechanisms in the wake-promoting effects of amphetamine: a study of D- and L-derivatives in canine narcolepsy.

Using a canine model of narcolepsy and selective DA and NE uptake inhibitors, we have recently shown that DA uptake inhibition promotes wakefulness, while NE uptake inhibition inhibits rapid eye movement sleep and cataplexy. In order to further delineate the respective roles of the dopaminergic and noradrenergic systems in the pharmacological control of symptoms of narcolepsy, we compared the potency of amphetamine isomers (D- and L-amphetamines) and a derivative (L-methamphetamine) on wakefulness and cataplexy. Their respective effects on these narcolepsy symptoms were then compared with their in vivo effects on extracellular DA levels in the caudate and NE levels in the frontal cortex during local drug perfusion in narcoleptic dogs. Polygraphic recordings demonstrated that D-amphetamine was about twice as potent as L-amphetamine, and was six times more potent than L-methamphetamine in increasing wakefulness and reducing slow-wave sleep. D-Amphetamine and L-amphetamine were equipotent in reducing rapid eye movement sleep and cataplexy, and L-methamphetamine was about half as potent as L- and D-amphetamines. D-Amphetamine was found to be more potent in increasing DA efflux than L-amphetamine, and L-methamphetamine was found to have little effect on DA efflux; there was no significant difference in the potencies of the three derivatives on NE efflux. The potencies of these amphetamines on wakefulness correlated well with DA, but not NE, efflux in the brain of narcoleptic dogs during local drug perfusion. Our current results further exemplify the importance of the DA system for the pharmacological control of electroencephalogram arousal and suggest that increased DA transmission mediates the wake-promoting effects of amphetamine-like stimulants.

Amphetamine↗
PubMed1996

Narcolepsy-like symptoms among adult twins.

The genetic architecture of narcolepsy is poorly known. Genetic and environmental components of symptoms characteristic of narcolepsy, excessive sleepiness and cataplexy were assessed in a population-based sample of middle-aged like-sexed twin pairs. Questionnaire assessment of the 11-item Ullanlinna Narcolepsy Scale (UNS), a validated screening instrument for narcolepsy [J. Sleep Res. (1994) 3, 52-59] and two subscales (sleepiness and cataplexy-like symptoms) was obtained from both twins of 3785 pairs aged 33-60 y (541 male MZ pairs, 1089 male DZ pairs, 781 female MZ and 1374 female DZ pairs) from the population-based Finnish Twin Cohort. For the UNS scores, the intraclass correlation for male MZ pairs was 0.365 and for male DZ pairs 0.072, while for female pairs the MZ correlation was 0.375 and for DZ pairs 0.155. Structural equation model fitting indicated that a model with additive and non-additive genetic effects, and idiosyncratic environmental effects best accounted for the pattern of twin resemblance in both men and women. Genetic effects accounted for 35% (in men) and for 39% (in women) of total phenotypic variance in UNS. Analysis of the subscales suggested that there may be a greater genetic component to the sleepiness subscale, while environmental components play more of a role in the development of cataplexy-like symptoms. Further investigation of the complex genetic architecture of narcolepsy and its symptoms is warranted.

Adolescent↗
PubMed1976

Evaluation of short-term and long-term treatment of the narcolepsy syndrome with clomipramine hydrochloride.

Clinical examinations, questionnaires, and 24- or 36-hour polygraphic recordings were performed on 21 adult patients with the narcolepsy syndrome to investigate the short- and long-term effects of clomipramine HCL. Cataplexy was improved by the medication, but tolerance was observed 4 1/2 months of treatment. Clomipramine HCL induced significant changes in the sleep EEG, chin EMG, and EOG. In two patients, clomipramine HCL caused a nocturnal myoclonia that produced insomnia. Sexual side effects were seen with clomipramine HCL, particularly in males. A combination of clomipramine HCL and L-Dopa apparently prevented this difficulty in one patient. A rebound of cataplexy was seen during the 15 days following withdrawal of the drug. Methysergide maleate was found to be ineffective on cataplexy in four patients.

Adult↗
PubMed1998

Presentation of narcolepsy after 40.

To advance understanding of the clinical spectra of narcolepsy, we retrospectively reviewed the histories and clinical and polysomnographic features of 41 consecutive patients in whom this diagnosis was established in our center over 3 years. A total of 51% presented after the age of 40 years. Among the older patients, three subpopulations were noted: 1) narcolepsy/cataplexy with presentation delayed because of mild disease severity or misdiagnosis; 2) narcolepsy/cataplexy with diagnosis delayed until late-life expression of cataplexy; and 3) narcolepsy lacking cataplexy with later-life onset of excessive daytime sleepiness. Clinical, polysomnographic, and multiple sleep latency test assessments of rapid eye movement sleep dyscontrol and sleepiness were unrelated to age. This analysis identified older patients lacking cataplexy as the least severely affected narcoleptic subgroup. Narcolepsy, a continuum of phenotypes and severities that masks its recognition, should be considered in the differential diagnosis of sleepiness or transient loss of muscle tone in older patients.

Adult↗
PubMed1976

Narcolepsy. Diagnosis and treatment.

Narcolepsy may affect as many as 200,000 Americans. The illness involves a neurologic defect in the regulation of sleep and wakefulness. The chief symptoms are sleepiness, inappropriate sleep episodes, and cataplexy. A characteristic history of cataplexy establishes the diagnosis. Narcoleptic patients also frequently complain of hypnagogic hallucinations, sleep paralysis, blackouts (or automatic behavior), and disturbed nocturnal sleep. Narcolepsy usually develops in adolescence and is a life-long illness. Symptoms may also appear in young children who may be misdiagnosed as hyperactive or psychotic. No completely satisfactory treatment is available at the present time. The current treatments of choice are methylphenidate (for sleepiness and sleep episodes) and imipramine (for cataplexy). Medication dosages must be adjusted for individual patients. A careful history of the illness can rule out hypothyroidism, hypoglycemia, and epilepsy. Sleep apnea is a serious complication of narcolepsy and may be life threatening.

Adolescent↗
PubMed2005

Symptoms of narcolepsy in children misinterpreted as epilepsy.

Differentiating an epileptic seizure from some other paroxysmal event is a common challenge in clinical practice. Many paroxysmal events mimic epileptic seizures and misdiagnosis can have disastrous consequences. Incorrectly identifying an event as an epileptic seizure can lead to unnecessary investigations and instigation of inappropriate treatment regimes. We report five patients referred to regional Paediatric Neuroscience Centres for investigation of events initially suspected of being epileptic seizures. All five patients were subsequently diagnosed as having narcolepsy. Suspected diagnoses were absence epilepsy (four patients), generalized epilepsy with astatic seizures (two patients) and focal epileptic seizures (two patients). Diagnostic confusion arose because lack of responsiveness due to excessive sleepiness was mistaken for epileptic absences, and cataplexy was confused with a variety of seizure types. In each case, videotape recording of clinical events aided in making the diagnosis of cataplexy. At presentation, all five children had excessive daytime sleepiness with cataplexy. Following correct diagnosis and appropriate management, an improvement in symptoms was reported in all cases. Narcolepsy/cataplexy should be included in the differential diagnoses of paroxysmal disorders, particularly if there are associated sleep symptoms or behavioural difficulties. It is important to take a sleep history when evaluating any disorder of the central nervous system.

Attention Deficit Disorder with Hyperactivity↗
PubMed1984

[Narcoleptic syndrome].

Only in the last century was the narcoleptic syndrome recognized as a distinct entity fundamentally different from epilepsy. It is characterized by increased daytime sleepiness, usually as short sleep attacks, and by cataplexy. The latter is reflected in attacks of fully or incompletely developed loss of muscle tone, and in distressing akinetic states (so-called sleep paralysis) which chiefly occur in transition states between wake and sleep. In about half the patients, excessive daytime sleepiness may manifest itself in twilight states of lowered vigilance with automatic behaviour and amnesia. Many narcoleptics suffer from hallucinations, which may occur as they are falling asleep, during sleep paralysis, cataplectic attacks, and daytime sleepiness. Knowledge of the pathogenesis of narcoleptic disturbances is still incomplete but has been essentially widened by the discovery of paradoxical sleep, because cataplexy, sleep paralysis and hypnagogic hallucinations may now be interpreted as dissociated paradoxical sleep phenomena. The treatment of narcolepsy comprises advice in appropriate daily regimen, nutrition and vocational orientation as well as medication by stimulating agents for hypersomnolence and by tricyclic drugs for cataplexy.

Arousal↗
PubMedDate not supplied

Narcolepsy. Signs, symptoms, differential diagnosis, and management.

Narcolepsy is a chronic neurologic disorder characterized by excessive daytime sleepiness and cataplexy and less often by hypnagogic hallucinations and sleep paralysis. While patients report excessive daytime sleepiness and cataplexy as the more frequent symptoms of this condition, excessive daytime sleepiness is generally believed to be the most debilitating. Narcolepsy often is undiagnosed or misdiagnosed for a variety of reasons. Although confirmation of an initial diagnosis requires monitoring of physiologic variables conducted at a sleep center by specialists, the primary care physician has a critical role in the identification and management of this incurable affliction. This article provides recommendations for the diagnosis and management of narcolepsy. The cataplexy associated with narcolepsy can be managed with tricyclic antidepressants. The excessive sleepiness is managed with stimulants but newer agents, such as modafinil, which will be marketed as Provigil, and selegiline hydrochloride, with fewer adverse effects and less abuse potential, may offer means of promoting daytime wakefulness. Groups such as the National Sleep Foundation, Washington, DC, and the Narcolepsy Network, Cincinnati, Ohio, can provide patients with needed support and information.

Diagnosis, Differential↗