Validation of a cataplexy questionnaire in 983 sleep-disorders patients.

Our goal was to validate a self-administered narcolepsy questionnaire focusing on cataplexy. Nine hundred and eight three consecutive subjects entering the Stanford Sleep Disorder Clinic completed the questionnaire. Clinic physicians reported on the presence or absence of "clear-cut" cataplexy. Responses to 51 cataplexy-related questionnaire items were compared between subjects with clear-cut cataplexy (n = 63) and all other patients (n = 920). As previously reported, a large portion of the non-narcoleptic population was found to experience muscle weakness with various intense emotions (1.8% to 18.0%) or athletic activities (26.2% to 28.8%). Factor analysis and Receiver Operating Characteristic Curve (ROC) analysis were used to determine the most predictive items for clear-cut cataplexy. Most strikingly, cataplexy was best differentiated from other types of muscle weakness when triggered by only three typical situations: "when hearing and telling a joke," "while laughing," or "when angry." Face or neck, rather than limbs, were also more specifically involved in clear-cut cataplexy. Other items, such as length of attacks, bilaterality, and alteration in consciousness, were poorly predictive. A simple decision tree was constructed to isolate high-(91.7%) and low-(0.6%) risk groups for cataplexy. This questionnaire will be used to increase diagnostic consistency across clinical centers, thus providing more homogenous subject pools for clinical and basic research studies.

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.

Familial aspects of narcolepsy-cataplexy in the Czech Republic.

A group of 153 probands with narcolepsy included 38 subjects (24.8%) with a familial incidence of excessive daytime sleepiness (EDS). In 15 cases (9.8%), at least one additional family member suffered from narcolepsy-cataplexy; only EDS was present in the remaining 23 cases (15.0%). One thousand eighty-two relatives were evaluated. The percentage of first degree relatives affected with narcolepsy-cataplexy was 2.28% (1.20% if only clinically confirmed cases were accounted); the adequate value for second degree relatives was 1.49%. The occurrence of EDS exceeded these values several times (4.28% in first degree relatives, 6.57% in second degree relatives). The vertical mode of transmission was found in most families. Human leukocyte antigen (HLA) typing was performed in six families with multiple-case incidence of narcolepsy. Forty-one blood samples were analyzed (12 patients with narcolepsy, 7 with only EDS, 2 with sleep apnea syndrome, and 20 healthy relatives). HLA DR2+ and DQB1*0602+ were found in only 8 out of 12 narcoleptic patients with cataplexy and in six out of seven patients with isolated attacks of sleepiness. These findings support the hypothesis that there is a common genetic basis for narcolepsy associated with cataplexy and "monosymptomatic" forms of narcolepsy and suggest the existence of non-major histocompatibility complex (MHC) susceptibility factors for narcolepsy.

DQB1*0602 and DQA1*0102 (DQ1) are better markers than DR2 for narcolepsy in Caucasian and black Americans.

In the present study, we tested 19 Caucasian and 28 Black American narcoleptics for the presence of the human leucocyte antigen (HLA) DQB1*0602 and DQA1*0102 (DQ1) genes using a specific polymerase chain reaction (PCR)-oligotyping technique. A similar technique was also used to identify DRB1*1501 and DRB1*1503 (DR2). Results indicate that all but one Caucasian patient (previously identified) were DRB1*1501 (DR2) and DQB1*0602/DQA1*102 (DQ1) positive. In Black Americans, however, DRB1*1501 (DR2) was a poor marker for narcolepsy. Only 75% of patients were DR2 positive, most of them being DRB1*1503, but not DRB1*1501 positive. DQB1*0602 was found in all but one Black narcoleptic patient. The clinical and polygraphic results for this patient were typical, thus confirming the existence of a rare, but genuine form of DQB1*0602 negative narcolepsy. These results demonstrate that DQB1*0602/DQA1*0102 is the best marker for narcolepsy across all ethnic groups.

Desmethyl metabolites of serotonergic uptake inhibitors are more potent for suppressing canine cataplexy than their parent compounds.

Our series of pharmacological studies on canine narcolepsy has suggested that the adrenergic systems are more critically involved in the regulation of cataplexy than the serotonergic and dopaminergic systems. This, however, is an apparent contradiction to data obtained in human patients, which show that chronic oral administration of serotonergic uptake inhibitors, such as clomipramine, zimelidine and fluoxetine, is effective in reducing cataplexy. To explore this discrepancy, we have assessed the anticataplectic effects of various serotonergic uptake inhibitors and their active desmethyl metabolites on canine cataplexy. We found that the anticataplectic effect of the desmethyl metabolites, which are usually more potent for in vitro adrenergic uptake inhibition, was more potent and developed more rapidly than the effect of the parent compounds. Furthermore, the anticataplectic potency was positively correlated to the adrenergic uptake inhibition and was negatively correlated with serotonergic uptake inhibition among the 10 compounds tested. These results are consistent with our hypothesis of a preferential involvement of the adrenergic system in the control of cataplexy. Our results also suggest that the anticataplectic effect of "selective" serotonergic uptake inhibitors in human narcolepsy might be mediated by their less selective active metabolites.

Heterozygosity at the canarc-1 locus can confer susceptibility for narcolepsy: induction of cataplexy in heterozygous asymptomatic dogs after administration of a combination of drugs acting on monoaminergic and cholinergic systems.

Narcolepsy is a genetically determined disorder of sleep characterized by excessive daytime sleepiness and abnormal manifestations of REM sleep that affects both humans and animals. Although its exact pathophysiologic mechanisms remain undetermined, recent experiments have demonstrated that in both humans and canines, susceptibility genes are linked with immune-related genes. A striking difference, however, is that the genes thought to be involved in the human pathology are autosomal dominant, whereas canine narcolepsy in Dobermans is transmitted as a single autosomal recessive gene with full penetrance (canarc-1). In this study, we have examined the development of narcoleptic symptoms in homozygous narcoleptic, heterozygous, and control Dobermans. Animals were behaviorally observed until 5 months of age and then treated at weekly intervals with cataplexy-inducing compounds that act on cholinergic or monoaminergic systems (alone and in combination). Our data indicate that cataplexy can be induced in 6-month-old asymptomatic heterozygous animals, but not in control canines, with a combination of drugs that act on the monoaminergic and cholinergic systems. This demonstrates that disease susceptibility may be carried by heterozygosity at the canarc-1 locus. Our data further suggest that cataplexy, a model of REM sleep atonia, is centrally regulated by a balance of activity between cholinergic and monoaminergic neurons.

Further characterization of the alpha-1 receptor subtype involved in the control of cataplexy in canine narcolepsy.

We have demonstrated previously that central noradrenergic mechanisms, especially postsynaptic alpha-1 receptors, are critically involved in the regulation of cataplexy, a pathological manifestation of rapid eye movement sleep atonia in narcolepsy. However, it has been shown recently that alpha-1 receptors constitute a heterogeneous population of binding sites, which is encoded by several distinct genes. In light of these findings, we investigated the possibility that the effect of alpha-1 compounds on cataplexy found in our previous study is mediated more specifically by certain alpha-1 receptor subtypes than by other subtypes. We therefore examined the effects of eight selective alpha-1 antagonists and five agonists on canine cataplexy and compared these with the affinities of the same compounds for the canine central alpha-1a and alpha-1b subtypes. The affinities of the compounds for the alpha-1 receptor subtypes were assessed by using [3H]prazosin receptor binding in combination with a 5-methylurapidil (an alpha-1a selective ligand) mask. Six of the eight alpha-1 antagonists tested exacerbated canine cataplexy, whereas all five agonists tested suppressed cataplexy. Furthermore, the potency (ED50 values) of the compounds on cataplexy significantly correlated with the affinity of the compounds for the alpha-1b binding site. These results are consistent with our earlier implication of the alpha-1 receptor mechanisms in the control of cataplexy and further suggest a specific involvement of the alpha-1b receptor subtype in these mechanisms.

Canine cataplexy is preferentially controlled by adrenergic mechanisms: evidence using monoamine selective uptake inhibitors and release enhancers.

Narcolepsy is currently treated with anti-depressants to control REM-related symptoms such as cataplexy and with amphetamine-like stimulants for the management of sleepiness. Both stimulant and antidepressant drugs presynaptically enhance monoaminergic transmission but both classes of compounds lack pharmacological specificity. In order to determine which monoamine is selectively involved in the therapeutic effect of these compounds, we examined the effects of selective monoamine uptake inhibitors and release enhancers on cataplexy using a canine model of the human disorder. A total of 14 compounds acting on the adrenergic (desipramine, nisoxetine, nortriptyline, tomoxetine, viloxazine), serotoninergic (fenfluramine, fluoxetine, indalpine, paroxetine, zimelidine) and dopaminergic (amfonelic acid, amineptine, bupropion, GBR 12909) systems were tested. Some additional compounds interesting clinically but with less pharmacological selectivity, i.e., cocaine, dextroamphetamine, methylphenidate, nomifensine and pemoline, were also included in the study. All compounds affecting noradrenergic transmission completely suppressed canine cataplexy at low doses in all dogs tested, whereas compounds which predominantly modified serotoninergic and dopaminergic transmission were either inactive or partially active at high doses. Our results demonstrate the preferential involvement of adrenergic systems in the control of cataplexy and, presumably, REM sleep atonia. Our findings also demonstrate that canine narcolepsy is a useful tool in assessing the pharmacological specificity of antidepressant drugs.

DQB1-0602 (DQw1) is not present in most nonDR2 Caucasian narcoleptics.

Human narcolepsy is a genetically determined disorder of sleep strongly associated with the human leucocyte antigens (HLA) DR2 and DQw1. In black narcoleptic patients, susceptibility for narcolepsy is more closely related to a specific gene subtype of DQw1, DQB1-0602, than to DR2. About 30% of black narcoleptic patients are nonDR2, but all carry the HLA DQB1-0602 gene. In the present study, we have tested caucasian nonDR2 cataplectic patients (6 sporadic cases and 7 familial cases from 3 multiplex families) for the presence of the HLA DQB1-0602 and DQA1-0102 (DQw1) using a specific polymerase chain reaction (PCR)-oligotyping technique. None of the patients was DQB1-0602 or DQA1-0102 positive, thus proving that, in caucasians, DQB1-0602 and DQA1-0102 (DQw1) are not prerequisites for the diagnosis of narcolepsy. Further studies with more patients are warranted to exclude the possibility that a few caucasian patients carry rare haplotypes with DQB1-0602 independently of DR2.

Dopamine D2 mechanisms in canine narcolepsy.

Narcolepsy is a sleep disorder characterized by abnormal manifestations of rapid-eye-movement (REM) sleep and excessive daytime sleepiness. Using a canine model of the disease, we found that central D2 antagonists suppressed cataplexy, a form of REM-sleep atonia occurring in narcolepsy, whereas this symptom was aggravated by D2 agonists. The effect on cataplexy was stereospecific for the S(-) enantiomer of sulpiride (a D2 antagonist) and the R(+) enantiomer of 3-PPP (a D2 agonist). There was also a significant correlation between the in vivo pharmacological potency and in vitro drug affinity for D2 receptors (but not for D1 and alpha 2 receptors) among the seven central D2 antagonists tested. Selective D1 compounds were also tested; however, the results were inconsistent because both antagonists and agonists generally suppressed cataplexy. Our current results demonstrate that central D2-type receptors are critically involved in the control of cataplexy and REM sleep. Furthermore, the finding that small doses of D2 antagonists suppressed cataplexy and induced behavioral excitation, while small doses of D2 agonists aggravated cataplexy and induced sedation, suggests that this effect is mediated presynaptically. However, considering the fact that selective dopamine reuptake inhibitors did not modify cataplexy and that our previous pharmacological results demonstrated a preferential involvement of the noradrenergic system in the control of cataplexy, we believe that the effect of D2 compounds on cataplexy is mediated secondarily via the noradrenergic systems.