Hélène Bastuji

An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: Studies in orexin−/− mice and patients

Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy, direct onsets of rapid eye movement (REM) sleep from wakefulness (DREMs) and deficiency of orexins, neuropeptides that promote wakefulness largely via activation of histamine (HA) pathways. The hypothesis that the orexin defect can be circumvented by enhancing HA release was explored in narcoleptic mice and patients using tiprolisant, an inverse H(3)-receptor agonist. In narcoleptic orexin(-/-) mice, tiprolisant enhanced HA and noradrenaline neuronal activity, promoted wakefulness and decreased abnormal DREMs, all effects being amplified by co-administration of modafinil, a currently-prescribed wake-promoting drug. In a pilot single-blind trial on 22 patients receiving a placebo followed by tiprolisant, both for 1 week, the Epworth Sleepiness Scale (ESS) score was reduced from a baseline value of 17.6 by 1.0 with the placebo (p>0.05) and 5.9 with tiprolisant (p<0.001). Excessive daytime sleep, unaffected under placebo, was nearly suppressed on the last days of tiprolisant dosing. H(3)-receptor inverse agonists could constitute a novel effective treatment of EDS, particularly when associated with modafinil.

Brain processing of stimulus deviance during slow-wave and paradoxical sleep: a study of human auditory evoked responses using the oddball paradigm.

Auditory evoked potentials (AEPs) to frequent (90%) and deviant (10%) tones were recorded during both wakefulness and all-night sleep in eight drug-free volunteers. During presleep waking (10:00–11:00 p.m.), deviant stimuli elicited, in all subjects, a prominent “P300” wave of parieto-central topography, culminating at 344 ms (average), which was absent in response to frequent tones. This “presleep P300” was delayed and reduced relative to values obtained during full wakefulness (3:00–7:00 p.m.) in a control group. Passage from waking to sleep stage I was characterized by a progressive attenuation and delay of the P300 wave in response to deviant stimuli, without major changes in AEP morphology as compared to the waking state. Thus, in terms of cognitive evoked potentials (EPs), sleep stage I appeared more as a “weak” state of wakefulness than a true phase of sleep. During sleep stages II, III, and IV, both frequent and deviant tones evoked AEPs that closely resembled K-complexes. Responses to rare stimuli were four-to-five times larger than those to frequent tones, this likely being the result of K-complex habituation to monotonous stimuli. During paradoxical sleep (PS), AEP morphology again became comparable to that of wakefulness. Notably, a “P3” wave with similar topography as the waking P300 appeared in response to deviant stimuli exclusively. Thus, even though the brain seems able to detect stimulus deviance during all sleep stages, only during stage I and PS were the electrophysiological counterparts of deviance detection comparable to those of the waking state. Our results support the view that PS is not a state of “sensory isolation”; failure to respond to external stimuli during this stage may depend upon mechanisms occurring only after the sensory input has undergone cognitive analysis.

Thalamic deactivation at sleep onset precedes that of the cerebral cortex in humans

Thalamic and cortical activities are assumed to be time-locked throughout all vigilance states. Using simultaneous intracortical and intrathalamic recordings, we demonstrate here that the thalamic deactivation occurring at sleep onset most often precedes that of the cortex by several minutes, whereas reactivation of both structures during awakening is synchronized. Delays between thalamus and cortex deactivations can vary from one subject to another when a similar cortical region is considered. In addition, heterogeneity in activity levels throughout the cortical mantle is larger than previously thought during the descent into sleep. Thus, asynchronous thalamo-cortical deactivation while falling asleep probably explains the production of hypnagogic hallucinations by a still-activated cortex and the common self-overestimation of the time needed to fall asleep.

Pitolisant, an Inverse Agonist of the Histamine H3 Receptor: An Alternative Stimulant for Narcolepsy-Cataplexy in Teenagers With Refractory Sleepiness

ObjectiveNarcolepsy is a rare disabling sleep disorder characterized by excessive daytime sleepiness and cataplexy (sudden loss of muscle tone). Drugs such as pitolisant, which block histamine H3 autoreceptors, constitute a newly identified class of stimulants because they increase brain histamine and enhance wakefulness in animal and human adult narcolepsy. MethodsWe report our experience with the off-label use of pitolisant in 4 teenagers with narcolepsy/cataplexy with severe daytime sleepiness, refractory to available treatments (modafinil, methylphenidate, mazindol, sodium oxybate, and D-amphetamine). ResultsAll teenagers developed their disease during childhood (11.3 ± 2.4 years; 50% boys) and were 17.3 ± 0.8 years old at the time of pitolisant therapy. Pitolisant treatment was increased from 10 to 30 mg (n = 1) and 40 mg (n = 3). The adapted Epworth Sleepiness Score decreased from 14.3 ± 1.1 to 9.5 ± 2.9 (P = 0.03) with pitolisant alone to 7 ± 3.4 when combined with mazindol (n = 1), methylphenidate (n = 1), or sodium oxybate plus modafinil (n = 1). Mean sleep onset latency increased from 31 ± 14 minutes to 36 ± 8 minutes (P = 0.21) on the maintenance of wakefulness test. The severity and frequency of cataplexy were slightly improved. Adverse effects were minor (insomnia, headache, hot flushes, leg pain, and hallucinations) and transitory, except for insomnia, which persisted in 2 teenagers. The benefit was maintained after a mean of 13 months. ConclusionsPitolisant could constitute an acceptable alternative for the treatment of refractory sleepiness in teenagers with narcolepsy.

Laser evoked responses to painful stimulation persist during sleep and predict subsequent arousals

&NA; We studied behavioural responses and 32‐channel brain potentials to nociceptive stimuli during all‐night sleep in 12 healthy subjects, using sequences of thermal laser pulses delivered over the dorsum of the hand. Laser stimuli less than 20 dB over perception threshold had clear awakening properties, in accordance with the intrinsic threatening value of nociceptive signals. Even in cases where nociceptive stimulation did not interrupt sleep, it triggered motor responses in 11% of trials. Only four subjects reported dreams, and on morning questionnaires there was no evidence of incorporation to dreams of nociceptive stimuli. Contrary to previous reports suggesting the absence of cortical nociceptive responses during sleep, we were able to record brain‐evoked potentials to laser (LEPs) during all sleep stages. Sleep LEPs were in general attenuated, but their morphology was sleep‐stage‐dependent: in stage 2, the weakened initial response was often followed by a high‐amplitude negative wave with typical features of a K‐complex. During paradoxical sleep (PS) LEP morphology was similar to that of waking, but frontal components showed strong attenuation, consistent with the reported frontal metabolic deactivation. A late positive component (450–650 ms) was recorded in both stage 2 and PS, the amplitude of which was significantly enhanced in trials that were followed by an arousal. This response appeared functionally related to the P3 wave, which in waking subjects has been associated to conscious perception and memory encoding.

Detection of verbal discordances during sleep.

We used an electrophysiological marker of linguistic discordance, the N400 wave, to investigate how linguistic and pseudo-linguistic stimuli are categorised during sleep as compared to waking. During wakefulness, signs of discordance detection were, as expected, greater for pseudo-words than for real but semantically incongruous words, relative to congruous words. In sleep stage 2 all signs of hierarchic process of discordance disappeared. A new hierarchic process reappeared in paradoxical sleep, which differed from that of waking, responses to pseudo-words being similar to those to congruous words. Linguistic absurdity appears to be accepted in a different manner during paradoxical sleep than during waking, and this might explain why absurd contents are so naturally incorporated into otherwise plausible dream stories.

Sleep/wake abnormalities in patients with periodic leg movements during sleep: factor analysis on data from 24-h ambulatory polygraphy.

>Periodic Leg Movements (PLM) in sleep occur in a wide variety of sleep/wake disorders but their relationship with sleep disturbance, and notably with the concomitant existence of a ‘restless legs’ syndrome (RLS) remains unclear. We performed 24‐h ambulatory polygraphy in a population of 54 consecutive, unselected patients with PLMs (Colemans index greater than 5/h) who complained of different sleep disorders. A Principal Component Analysis (PCA) was conducted on seven variables from the sample, namely PLM index, patients age, sleep stage changes per hour, sleep depth index (SWS+PS/TST), diurnal sleep time, number of awakenings exceeding 2 min and presence of a RLS. PCA yielded four independent factors. The PLM index and the changes of sleep stage clustered in a single factor, linking therefore sleep fragmentation to the frequency of PLMs. The second factor appeared to reflect a circadian sleep/wake disorder, combining diurnal sleep time with the number of long night awakenings. The third factor was mainly loaded by the patients’ age and the sleep depth index, thus reflecting a well known relationship. Finally, the variable reflecting the existence of a RLS appeared isolated in a single factor, independent from the three previously described. These results confirm and extend the link between PLMs and sleep fragmentation, as well as the recently described dissociation between PLMs and diurnal somnolence. On the other hand, our analysis suggests that in PLM patients the concomitant existence of a RLS is not related to the frequency of occurrence of PLMs, at least when these latter are quantified independently of their arousal index.

BAEP latency changes during nocturnal sleep are not correlated with sleep stages but with body temperature variations

Serial BAEPs and polysomnograms were recorded during nocturnal sleep in 8 normal subjects. Wave V latency and the I-V interval were found to increase significantly during stages II, III + IV and paradoxical sleep when compared to waking. Trend curves of BAEP latencies showed that these shifts were independent of sleep stages and reversed at the end of the night. BAEP changes were found to be related to physiological hypothermia during the night.

Functional dissociation of the early and late portions of human K-complexes.

We analyzed K-complexes (KCs) evoked during sleep stage II by the subjects own name and by other names. KCs were composed either of four consecutive waves (full KCs, N2-P3-N3-P4) or of the two first components only (N2–P3). The amplitude of the late phase of KCs (N3–P4) was identical to all stimuli; conversely, own names enhanced selectively the N2–P3 waves, whether they were or not part of a full KC. Two independent phenomena appear to coexist during a full KC, one being connected to the physical characteristics of the stimulus (N3–P4) and the other to its intrinsic significance. This latter may appear either within a full KC or in isolation, and in this case it is reminiscent of the N200-P300 complex observed in wakefulness.

Prevalence of papilloedema in patients with sleep apnoea syndrome: a prospective study

The association of papilloedema (PO) with respiratory diseases and especially obstructive sleep apnoea (OSA) syndrome has been emphasised in many reports. The pathophysiology could rely on the episodic increase of intracranial pressure related to apnoeic episodes during night sleep. Nevertheless, prevalence of papilloedema in patient with OSA syndrome remains unknown. As this information could improve diagnosis and therapeutic strategies, the aim of the present study was to investigate the prevalence of PO in an OSA syndrome population. From 95 successive, recently diagnosed OSA patients, 35 answered a questionnaire about visual symptoms and underwent fundoscopic examination. Visual symptoms suggestive of PO were present in 40% of the patients, but none had PO. As a conclusion, PO does not seem to be frequently associated with OSA syndrome and systematic screening of PO in these patients does not seem to be warranted. Nevertheless, patients with visual complaints evocative of papilloedema should have their eye fundus checked since the association between OSA and PO exists. Further studies, including more patients, might be useful to establish which patients are at particular risk for this complication.