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PubMed1997

Effects of thyrotropin-releasing hormone and its analogs on daytime sleepiness and cataplexy in canine narcolepsy.

The therapeutic potential of thyrotropin-releasing hormone (TRH) and TRH analogs in narcolepsy, a sleep disorder characterized by abnormal rapid eye movement (REM) sleep and daytime sleepiness, was examined using the canine model. The effects of TRH and the biologically stable TRH analogs CG3703, CG3509, and TA0910 on daytime sleep and cataplexy, a symptom of abnormal REM sleep, were assessed using polysomnographic recordings and the food elicited cataplexy test (FECT), respectively. CG3703 (100 and 400 microg/kg, i.v.) and TA0910 (100 and 400 microg/kg, i.v.) significantly increased wakefulness and decreased sleep in narcoleptic canines, whereas TRH (400 and 1600 microg/kg, i.v.) had no significant effect. TRH (25-1600 microg/kg, i.v.) and all three TRH analogs, CG3703 (6. 25-400 microg/kg, i.v., and 0.25-16 mg/kg, p.o.), CG3509 (25-1600 microg/kg, i.v.), and TA0910 (25-1600 microg/kg, i.v.), significantly reduced cataplexy in canine narcolepsy. These compounds did not produce any significant side effects during behavioral assays, nor did they alter free T3 and T4 levels in serum even when used at doses that completely suppressed cataplexy. Although more work is needed to establish the mode of action of TRH analogs on alertness and REM sleep-related symptoms, our results suggest a possible therapeutic application for TRH analogs in human sleep disorders.

Animals↗

PubMed2000

The use of citalopram in resistant cataplexy.

Background: Cataplexy is a disabling component of the narcolepsy tetrad that is sometimes resistant to standard treatment.Case reports: Three of our patients with narcolepsy, including one who had post-traumatic narcolepsy, suffered from intractable cataplexy with failure of treatment with established drugs due to unacceptable side-effects.Results: We explored the use of citalopram (Celexa), the newest and most specific of the serotonin reuptake inhibitors, and were successful in treating cataplexy without significant side-effects. Stimulant drugs remained necessary for controlling symptoms of excessive drowsiness.Conclusions: Citalopram was effective in relieving the symptoms of resistant cataplexy in out patients.

Journal Article↗

PubMed1994

Stability of cataplexy over several months--information for the design of therapeutic trials.

Twenty-seven narcoleptic patients severely affected with cataplexy completed four symptom diaries over a 4-month period in order to clarify some of the controversies surrounding assessment of anticataplectic medications. The home diary method was found to be a viable model for the assessment of anticataplectic activity. Assessment of reliability in 1-, 2-, 3-, 4-, 5- and 10-day intervals indicated that reliability increases with the number of days included. A 10-day design was found to be optimal. Reliability decreased, however, with each successive diary over the 4-month period. Power analysis indicates that two groups of 30-40 subjects in a parallel design, or one group of 30-40 subjects in a crossover design, would be sufficient to demonstrate a significant therapeutic anticataplectic effect in most cases. A "first diary effect" was observed, suggesting that a training period prior to the actual trial might improve reliability. Whether the patient was treated or untreated with stimulant medications did not affect severity or fluctuation of cataplexy, suggesting that both groups of patients could be included in therapeutic trials. No time-of-day fluctuation was observed in the daily distribution of cataplexy attacks. Sudden increases in cataplexy were often, although not always, caused by unusual emotional events or sleepiness. The finding of a long-lasting "precataplectic" feeling or "aura" pointed to the need to carefully clarify the symptom prior to beginning a therapeutic trial.

Catalepsy↗

PubMed1997

Central administration of vitamin B12 aggravates cataplexy in canine narcolepsy.

Experimental evidence in canine narcolepsy suggests that central cholinergic systems are critically involved in the regulation of cataplexy, an abnormal manifestation of REM sleep atonia. In the current study, we found that intracerebroventricular perfusion of methyl-B12, (10(-5)-10(-2) M), significantly aggravated cataplexy and enhanced REM sleep in narcoleptic dogs. Choline, a direct precursor of acetylcholine, was also found to aggravate cataplexy, while cyano-B12, a vitamin B12 analog without methyl donating abilities, had no effect on cataplexy. Since both methyl-B12 and choline are reported to enhance acetylcholine synthesis, enhancement of the biosynthesis of acetylcholine may be involved in the effects observed in canine narcolepsy. Our results suggest that central administration of methyl-B12 has the potential to modulate both normal and pathological REM sleep.

Analysis of Variance↗

PubMed1993

Treatment of narcolepsy-cataplexy syndrome with the new selective and reversible MAO-A inhibitor brofaromine-a pilot study.

Eighteen narcoleptic patients were treated in a single-blind study with brofaromine, a new selective and reversible MAO-A-inhibitor. After a drug-free period of seven days, brofaromine was administered for two weeks. Patients were treated with 75 mg brofaromine for the first week and with 150 mg brofaromine for the second week of the study. After an adaptation night nocturnal sleep EEGs were recorded under placebo before brofaromine was given, one week later under 75 mg, and another week later under 150 mg brofaromine. Excessive daytime sleepiness (EDS) was evaluated under placebo at the beginning of the study, under 75 mg at the end of the first week, and under 150 mg brofaromine at the end of the second week by means of the Multiple Sleep Latency Test (MSLT) and the Maintenance of Wakefulness Test (MWT). The number of cataplexies was protocolled by the patients. Compared to placebo the administration of 150 mg brofaromine led to a significant increase of sleep latency in the MLST as well as in the MWT. REM sleep was significantly suppressed in the nocturnal sleep EEG, in the MSLT and in the MWT. The number of cataplexies protocolled by the patient was significantly decreased under 150 mg of brofaromine compared to placebo. Improvement of vigilance and cataplexy occurred in dose-dependent manner. No serious side effects were observed. The results of the present single-blind study indicate that brofaromine seems to be a well-tolerated and effective drug for the treatment of excessive daytime sleepiness and cataplexy in narcoleptic patients.

Journal Article↗

PubMed1975

Treatment of Cataplexy with Clomipramine.

A new antodepressant drug, clomipramine hydrochloride, closely related to imipramine hydrochloride, was used to treat four patients suffering from cataplexy, sleep paralysis, and hypnagogic hallucinations. Attacks of cataplexy were associated with rapid-eye-movement (REM) electroencephalographic patterns. Cloripramine, in doses of 25 to 75 mg/day, completely stopped all attacks of cataplexy, sleep paralysis, and hypnagogic hallucinations within 48 hours of initial therapy. The patients have been free of symptoms for periods of 10 to 21 months. Side effects included impotence in the male patients, but no hematologic, cardiovascular, hepatic, or renal toxic effects were observed. Available evidence suggests that such drugs inhibit those brain stem systems that control the toxic components of REM sleep.

Adult↗

PubMed1989

Efficacy of gamma-hydroxybutyrate versus placebo in treating narcolepsy-cataplexy: double-blind subjective measures.

The efficacy of gamma-hydroxybutyrate (GHB) versus placebo for treating narcolepsy was evaluated in 20 patients with narcolepsy, 10 men and 10 women, using a double-blind counterbalanced crossover design. Each patient completed a daily sleep-wake log and questionnaire during a 14-day baseline, a 29-day placebo period, a 29-day GHB period (50 mg GHB/kg/night given 25 mg/kg h.s. and 25 mg/kg 3 hr later), and a 6-day washout period after each treatment. Cataplexy frequency was significantly lower during GHB treatment than during placebo treatment (p = 0.022). Compared to baseline values, the number of cataplexy attacks per day declined by 52% and 69% during GHB treatment weeks 1 and 4, respectively. The number of subjective arousals from sleep was less with GHB than with placebo (p = 0.035), and the number of sleep attacks was not significantly different during GHB versus placebo treatment. GHB did not have a significant effect on subjective estimates of sleep onset latency, total sleep time, Stanford Sleepiness Scale ratings at morning wake-up, methylphenidate usage, or the number of naps per day. The results indicate that GHB is efficacious for reducing the frequency of cataplexy attacks and subjective nocturnal arousals in patients with narcolepsy within the first 4 weeks of treatment.

Adolescent↗

PubMed1976

Effects of imipramine, chlorimipramine, and fluoxetine on cataplexy in dogs.

Four narcoleptic dogs with cataplexy were given trials with the serotonin uptake blockers imipramine and chlorimipramine (known to be effective in treating cataplexy in humans). An even more selective serotonin uptake blocker, fluoxetine, was also tested. Injections of placebo, test compound, and placebo were given respectively on 3 successive days. Anticataplectic effects were measured approximately 30 min, 3 hr, and 6 hr postinjection by recording elapsed time and number of cataplectic episodes during the dogs' attempts to eat ten pieces of a desired food presented in a standard fashion. Imipramine (1 mg/kg) and fluoxetine (1.5 and 3.0 mg/kg)significantly improved performance, while chlorimipramine (0.5-5 mg/kg) had no clear effect. Data were not totally consistent with the notion that serotonin uptake blockers improve cataplexy in dogs, since chlorimipramine was not effective in these animals.

Animals↗

PubMed2005

Cerebral perfusion abnormality in narcolepsy with cataplexy.

To investigate abnormal cerebral perfusion in narcoleptics with cataplexy, 25 narcoleptics with cataplexy and 25 normal controls were enrolled in this study. Cerebral perfusion was measured by brain single photon emission computed tomography (SPECT) using 99mTc-ethylcysteinate dimer. Patients and normal controls had not received any medication prior to the SPECT scan. Differences in cerebral perfusion between narcoleptics and normal controls were subjected to statistical parametric mapping (SPM) analysis. Overnight polysomnography and multiple sleep latency test (MSLT) were performed in all patients. Brain SPECT was carried out on all patients and normal controls during the waking state. Clinical symptoms and MSLT results of all patients are in accord with the International Classification of Sleep Disorders criteria for narcolepsy. MSLT showed a short mean sleep latency (1.69 +/- 1.0 min) and 2-5 sleep onset REM periods in individual patient. SPM analysis of brain SPECT showed hypoperfusion of the bilateral anterior hypothalami, caudate nuclei, and pulvinar nuclei of thalami, parts of the dorsolateral/ventromedial prefrontal cortices, parahippocampal gyri, and cingulate gyri in narcoleptics [P < 0.05 by Student's t test with false discovery rate (FDR) correction]. Significant hypoperfusion in the white matter of frontal and parietal lobes was also noted in narcoleptics. This study shows reduced cerebral perfusion in subcortical structures and cortical areas in narcoleptics. The distribution of abnormal cerebral perfusion is concordant with the pathway of the cerebral hypocretin system and may explain the characteristic features of narcolepsy, i.e., cataplexy, emotional lability, and attention deficit.

Adolescent↗

PubMed2004

Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice.

Narcolepsy-cataplexy is a neurological disorder associated with the inability to maintain wakefulness and abnormal intrusions of rapid eye movement sleep-related phenomena into wakefulness such as cataplexy. The vast majority of narcoleptic-cataplectic individuals have low or undetectable levels of orexin (hypocretin) neuropeptides in the cerebrospinal fluid, likely due to specific loss of the hypothalamic orexin-producing neurons. Currently available treatments for narcolepsy are only palliative, symptom-oriented pharmacotherapies. Here, we demonstrate rescue of the narcolepsy-cataplexy phenotype of orexin neuron-ablated mice by genetic and pharmacological means. Ectopic expression of a prepro-orexin transgene in the brain completely prevented cataplectic arrests and other abnormalities of rapid eye movement sleep in the absence of endogenous orexin neurons. Central administration of orexin-A acutely suppressed cataplectic behavioral arrests and increased wakefulness for 3 h. These results indicate that orexin neuron-ablated mice retain the ability to respond to orexin neuropeptides and that a temporally regulated and spatially targeted secretion of orexins is not necessary to prevent narcoleptic symptoms. Orexin receptor agonists would be of potential value for treating human narcolepsy.

Animals↗

PubMed2001

Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups.

Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles-DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy.

Black or African American↗

PubMed2004

The month-of-birth pattern in narcolepsy is moderated by cataplexy severity and may be independent of HLA-DQB1*0602.

OBJECTIVES: A March peak and a September trough in the birth pattern of narcolepsy patients with clear-cut cataplexy was recently reported. The objectives of the present study were to determine whether the month-of-birth pattern would (a) vary with the presence and severity of cataplexy and (b) differ for patients positive and negative for HLA-DQB1*0602. DESIGN: Cross-sectional survey with data obtained from the clinical trials assessing the safety and efficacy of modafinil in the treatment of narcolepsy. SETTING: Sleep clinics throughout the United States. PATIENTS: A group of 530 narcolepsy patients diagnosed based on the International Classification of Sleep Disorders using clinical histories, nocturnal polysomnography, and Multiple Sleep Latency Tests. INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: A surplus of March births and a fall-off in September births was found in narcolepsy relative to the general population. This finding was only observed when cataplexy was moderate or severe. The month-of-birth pattern was similar for HLA-DQB1*0602 positive and negative patients. A March birth and HLA-DQB1*0602 positivity were independent risk factors in a logistic regression analysis. CONCLUSIONS: Environmental events during development may influence narcolepsy severity or the likelihood of developing the disease.

Adult↗

PubMed1986

Heart rate and blood pressure changes associated with cataplexy in canine narcolepsy.

Blood pressure and heart rate were monitored in narcoleptic dogs by means of a chronically implanted catheter placed in the descending aorta. Changes in these variables were recorded during spontaneously occurring cataplectic episodes. We found no reliable change in blood pressure associated with cataplexy onset. However, heart rate showed a marked increase prior to the onset of cataplexy, with peak heart rates being reached at or shortly after the disappearance of muscle tone. Autonomic events correlated with increased heart rate may contribute to the triggering of cataplexy in narcoleptics.

Animals↗

PubMed1996

Thalidomide, a hypnotic with immune modulating properties, increases cataplexy in canine narcolepsy.

Thalidomide is a sedative hypnotic that was widely used in the 1950s but was withdrawn due to its teratogenic properties. The compound has recently been reintroduced as an immune modulating agent. Thalidomide significantly aggravates canine cataplexy, a pathological manifestation of rapid eye movement (RFM) sleep atonia seen in narcolepsy. This compound also increases REM sleep and slow wave sleep in these animals. In vitro receptor binding and enzyme assays demonstrate that thalidomide does not bind to or enzymatically modulate the neurotransmitter systems reported to be involved in the regulation of cataplexy. Thalidomide may therefore affect cataplexy through its immune modulation properties. Further studies on the mechanisms of action of thalidomide should increase our understanding of the pathophysiology of this disabling disorder.

Animals↗

PubMed1976

Unilateral cataplexy associated with systemic lupus erythematosus.

A patient with systemic lupus erythematosus (SLE) developed attacks of unilateral cataplexy precipitated by laughter. Unilateral cataplexy has not been described previously in detail and its association with SLE is unique. The clinical details, investigations, and diagnostic criteria are discussed and a causal relationship between cataplexy and SLE is suggested.

Adult↗

PubMed1980

Fluvoxamine and clomipramine in the treatment of cataplexy.

Fluvoxamine 25-200 mg daily and clomipramine 25-200 mg daily were given for separate three week periods to 18 subjects with narcolepsy and cataplexy. Both drugs improved cataplexy but not narcolepsy. Fluvoxamine was less active than clomipramine, but both drugs abolished cataplexy in individual subjects. Gastrointestinal side effects prevented treatment with fluvoxamine in five subjects. All patients completed the clomipramine phase of the trial, but two men complained of delayed ejaculation. Fluvoxamine is a more potent inhibitor of 5-hydroxytryptamine (5-HT) reuptake in some systems, but not in others. It is therefore uncertain whether the greater anticataplectic effect of clomipramine is due to a greater inhibition of 5-HT reuptake or to other mechanisms.

Adult↗

PubMed1996

Narcolepsy-cataplexy and loss of sphincter control.

We describe the case of a 34-year-old man who presented intermittent faecal incontinence as a manifestation of cataplexy. The patient's sleep history was positive for the full narcoleptic tetrad (sleep attacks, cataplexy, sleep paralysis and hypnagogic hallucinations) while extensive neuropsychiatric work up was negative for any neurologic or psychiatric illness. Repeat polysomnograms (including a polysomnogram with a full seizure montage) were positive for pathologic sleepiness, but there was no evidence of a seizure disorder. The course of the patient's symptomatology and the favourable response of his symptoms to stimulants and imipramine support the theory that his intermittent loss of sphincter control is part of his narcolepsy-cataplexy.

Adult↗

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↗