SLEEP

Billiard,, M.;Besset,, A.;Montplaisir,, J.;Laffont,, F.;Goldenberg,, F.;Weill, J., S.;Lubin,, S.

doi: 10.1093/sleep/17.suppl_8.S107pmid: 7701191

Summary 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. Modafinil, Alpha adrenergic agonist, Maintenance of wakefulness testing, Sleepiness, Cataplexy This content is only available as a PDF. © 1994 American Sleep Disorders Association and Sleep Research Society

Nishino,, Seiji;Reid, Malcolm, S.;Dement, William, C.;Mignot,, Emmanuel

doi: 10.1093/sleep/17.suppl_8.S84pmid: 7701206

Summary 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 α-lb receptors or stimulation of a-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, a-1 receptors in the amygdala, a-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. Canine narcolepsy, Cataplexy, REM sleep, Cholinergic systems, Monoaminergic systems, Receptor subtypes This content is only available as a PDF. © 1994 American Sleep Disorders Association and Sleep Research Society

Partinen,, M;Hublin,, C;Kaprio,, J;Koskenvuo,, M;Guilleminault,, C

doi: 10.1093/sleep/17.suppl_8.S13pmid: 7701193

Summary The genetic basis of narcolepsy is reflected by the strong association to human leukocyte antigen DR2 (most specifically to DQB1-0602) and the occasional familial occurrence, with several modes of transmission. At present, 12 monozygotic pairs with at least one affected twin have been reported. Of the three pairs considered concordant, the only well-documented pair is DR2 negative. Of the nine discordant pairs five are well documented, and all of these are DR2 positive. We performed a questionnaire study using a validated measure of narcoleptic symptoms (the Ullanlinna narcolepsy scale or UNS). The questionnaire was sent to 2,191 monozygotic twin pairs included in the Finnish Twin Cohort. In 225 pairs neither of the twins responded. In 1,550 pairs both twins responded, but in the answers of 228 pairs there were some missing data concerning the UNS items. Not a single case suggestive of narcolepsy was found. Narcolepsy in monozygotic twins is very rare. These facts support the hypothesis of a multifactorial etiology with a strong influence of nongenetic environmental factors. Twins, Narcolepsy, Inheritance, Environmental factors This content is only available as a PDF. © 1994 American Sleep Disorders Association and Sleep Research Society

Parkes,, David

doi: 10.1093/sleep/17.suppl_8.S93pmid: 7701207

Article PDF first page preview Close This content is only available as a PDF. © 1994 American Sleep Disorders Association and Sleep Research Society

Laffont,, F.;Mayer,, G.;Minz,, M.

doi: 10.1093/sleep/17.suppl_8.S113pmid: 7701192

Summary The efficacy of modafinil, a psychostimulant drug acting on postsynaptic a-\ adrenergic receptors, as a treatment for excessive daytime sleepiness was studied in 123 patients. Subjects included 94 narcoleptic patients (76 with cataplexy), 23 hypersomnia patients and 6 patients with disrupted nocturnal sleep (DNS) and excessive daytime sleepiness (EDS). Clinical efficacy of the treatment on each symptom (EDS, cataplexy and DNS) was evaluated on a four-point scale from excellent to absent. The effectiveness of modafinil as a treatment for EDS was excellent in 17% of all patients, good in 63%, fair in 17% and absent in 3%. The incidence of side effects was rather low (14 of 123 patients) and most of them disappeared (11 patients) when doses were reduced. Résumé L'efficacité du modafinil, molécule psychostimulante agissant de façon postsynaptique sur les réepteurs a-1, est étudiée sur 123 patients se plaignant de somnolence diurne. La population comprend 94 patients narcoleptiques dont 76 présentent des cataplexies, 23 patients hypersomniaques et 6 patients présentant des troubles du sommeil nocturne associés à une somnolence diurne. L'effet sur les différents symptômes (somnolence diurne, cataplexie et troubles du sommeil nocturne) est apprécié cliniquement au moyen d'une échelle à quatre niveaux. Sur l'ensemble de la population traitée par le modafinil, celui-ci a été jugé: très efficace par 17% des patients, efficace par 63% des patients, moyennement efficace par 17% des patients et sans efficacité par 3% des patients. Des effets secondaires bénins ont été observés chez 14 patients sur 123, pour 11 d'entre eux, ceux-ci ont disparu après diminution de la posologie. Modafinil, Excessive daytime sleepiness, Disrupted nocturnal sleep, Narcolepsy, Cataplexy This content is only available as a PDF. © 1994 American Sleep Disorders Association and Sleep Research Society

Mignot,, E.;Bell, R., A.;Rattazzi,, C.;Lovett,, M.;Grumet, F., C.;Dement, W., C.

doi: 10.1093/sleep/17.suppl_8.S68pmid: 7701203

Summary Canine narcolepsy is an animal model of the human disorder that is transmitted as a single autosomal recessive gene with full penetrance (canarc-1) in Dobermans and Labradors. In previous experiments, we have identified a very tight linkage marker for canarc-1. This marker, a 0.85-kb band cross reacting with a human μ-switch Heavy-Chain Immunoglobulin probe (maximum logarithm of odds [LOD] score Zmax = 10.8 at 0% recombination), has now been cloned and sequenced. The gene, composed of GC rich repeats, is 75% homologous to the human μ-switch gene and is similar in organization to immunoglobulin switch genes. Curiously, however, this μ-switchlike segment appears to be unlinked with other switchlike polymorphisms detected at high stringency with the human μ-switch probe. Because in most animal species all switch genes are located within 300-500 kb and show tight linkage in families, this result suggests two possible hypotheses: 1) Our 0.85 kb is a true immunoglobulin switch segment, but the map of the canine Variable Heavy-Chain loci is organized in unlinked clusters, or 2) our 0.85-kb segment is not an immunoglobulin switch segment and is located elsewhere in the genome in all species. We are now using chromosome walking and Yeast Artificial Chromosome Cloning techniques, together with corresponding studies in humans to identify the pathological gene. Résumé La narcolepsie canine est une maladie qui se transmet de façon autosomale recessive. En 1991, nous avons identifié un marqueur génétique pour cette maladie (LOD score actuel: 10.8 à 0% de recombination). II s'agit d'un segment de 850 pairs de bases homologue au gène Immunoglobuline μ-switch. Ce marqueur a maintenant été cloné et séquencé. II est composé de segments de 79-82 pairs de bases répétés dix fois. Sa structure est très riche en GC et est homologue à 75% avec le gène μ-switch humain. Curieusement, ce segment n'est pas lié génetiquément avec les autres polymorphismes reconnus par le gène μ-switch humain. Chez toutes les autres espèces étudiées à ce jour, tous les gènes switch sont localisés à proximité et sont très liés génétiquement. Ce résultat pourrait done avoir deux explications possibles: 1) Le segment de 850 pairs de bases n'est pas un gène Immunoglobuline mais représente un nouveau gène localisé à un autre endroit du génome. 2) Le segment de 850 pairs de base est un gène immunoglobuline switch mais la carte génomique de ce locus chez le chien est organisés en plusieurs secteurs non liées génétiquement. Des études de clonage sont en cours pour répondre à ces questions. Narcolepsy, Cataplexy, Switch, Immunoglobulin Narcolepsie, Cataplexie, Switch, Immunoglobuline This content is only available as a PDF. © 1994 American Sleep Disorders Association and Sleep Research Society

Mitler, Merrill, M.

doi: 10.1093/sleep/17.suppl_8.S103pmid: 7701190

Summary This paper briefly reviews sleep laboratory studies on the treatment efficacy of methylphenidate, pemoline, dextroamphetamine and methamphetamine. The literature indicates that 1) methylphenidate, dextroamphetamine, pemoline and methamphetamine objectively improve somnolence as measured by the Multiple Sleep Latency or Maintenance of Wakefulness Tests (MSLT or MWT); 2) pemoline, at doses up to 112.5 mg, is less effective in controlling somnolence than methylphenidate, dextroamphetamine and methamphetamine; 3) there are dosedependent improvements in performance that parallel MSLT and MWT data; and 4) at the highest doses of stimulants studied to date, narcoleptics, although improved, still did not function on MSLT or MWT and most performance tests at levels comparable to those of control subjects. Future research designs should address issues of placebo effect, practice effects and the degree to which alertness and performance measures can be pharmacologically brought up to levels comparable to those of normal control subjects. Narcolepsy, Multiple Sleep Latency Test, Maintenance of Wakefulness Test, Methylphenidate, Dextroamphetamine, Pemoline, Methamphetamine This content is only available as a PDF. © 1994 American Sleep Disorders Association and Sleep Research Society

Challamel,, Marie-Josèphe;Mazzola,, Maria-Elena;Nevsimalova,, Sona;Cannard,, Christine;Louis,, Jacqueline;Revol,, Michel

doi: 10.1093/sleep/17.suppl_8.S17pmid: 7701194

Summary 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. Narcolepsy, Cataplexy, Children, Symptomatic narcolepsy, Sleep polygraphy This content is only available as a PDF. © 1994 American Sleep Disorders Association and Sleep Research Society

Billiard,, M.;Pasquié-Magnetto,, V.;Heckman,, M.;Carlander,, B.;Besset,, A.;Zachariev,, Z.;Eliaou, J., F.;Malafosse,, A.

doi: 10.1093/sleep/17.suppl_8.S54pmid: 7701201

Summary Out of a population of 188 unrelated narcoleptic probands, we identified 14 probands (7.44%) with a family history of narcolepsy, 23 (12.23%) with a family history of isolated repeated episodes of naps and/or lapses into sleep and 151 (80.31%) without a family history of either condition. Clinical, polysomnographic or zygotic differences could not be evidenced in the three groups. Empirical risk for narcolepsy was 40.7 times greater among first-degree relatives of narcoleptics than in the general population. Narcolepsy and the condition characterized by isolated repeated episodes of naps and/or lapses into sleep have a common genetic component. This finding has important implications. Indeed, when the latter condition is included in the spectrum of narcolepsy, the empirical risk figure is relatively close to that expected in cases of simple mode of inheritance. A trend in favor of a more frequent transmission through mothers than fathers is emphasized. Narcolepsy, Family study, Inheritance, Aggregation, Empirical risk This content is only available as a PDF. © 1994 American Sleep Disorders Association and Sleep Research Society

Orellana,, C.;Villemin,, E.;Tafti,, M.;Carlander,, B.;Besset,, A.;Billiard,, M.

doi: 10.1093/sleep/17.suppl_8.S50pmid: 7701200

Summary A multifactorial etiology for narcolepsy has been postulated, stressing the importance of environmental factors in the clinical onset of the condition. Our study evaluated the occurrence of stressful life events in the year preceding the onset of narcolepsy. Fifty narcoleptic and 50 control subjects completed a life event questionnaire (the Schedule of Recent Experiences). The proportion of narcoleptic subjects reporting the presence of life events in the year preceding the onset of narcolepsy was significantly greater than the proportion of control subjects reporting life events in the corresponding year. Moreover the weight of life events was increased in narcoleptic subjects in comparison with controls. In conclusion life events seem to be increased in narcoleptic subjects in the year preceding the onset of their condition. However a number of other factors could not be taken into consideration, which limits the full significance of these data. Narcolepsy, Environmental factors, Life events This content is only available as a PDF. © 1994 American Sleep Disorders Association and Sleep Research Society