French Sleepiness Scale for Adolescents-8 items: A discriminant and diagnostic validation.

The objective of the present study was to validate the Short Version of French Sleepiness Scale for Adolescents (FSSA) with eight items (FSSA8). METHODS: A total of 384 adolescents, aged between 12 and 18 years, completed the FSSA8. These included 269 nonclinical adolescents and 115 adolescents admitted for overnight polysomnography and Multiple Sleep Latency Test (MSLT) because of suspected hypersomnia (85 patients with narcolepsy and 30 with other sleep disorders). Item response theory (IRT) assumptions were tested and psychometric properties were analysed. Matching on sex ratio and age was conducted to estimate concurrent criterion, diagnostic validity and cut-offs. RESULTS: IRT assumptions were validated confirming the one-dimensionality of the FSSA8. The latent continuum sleepiness for which the scale and its items are reliable encompassed most of the clinical subjects. FSSA8 is weakly correlated with MSLT. Distribution of scores for the nonclinical group and the clinical group differed significantly; the FSSA8 had very good screening validity in sleep disorders. The cut-off was seven points. CONCLUSION: The FSSA8 appeared to be more reliable for patients than for nonclinical participants and to be a good tool for screening excessive daytime sleepiness in sleep disorders.

[Therapeutic approaches for sleep and rhythms disorders in children with ASD]. / Approches thérapeutiques des troubles du sommeil et des rythmes chez l'enfant avec TSA.

Sleep disturbances are extremely common (40-86%) in children and adolescents, especially those with autism spectrum disorders (ASD) and are often among the first symptoms identified by parents at a very early stage of their child's development. These abnormalities are among the main parental concerns when having a child with ASD and have a significant impact on the quality of life of patients, their parents, and more broadly their siblings. Sleep disorders are essentially abnormalities of the sleep-wake rhythm - primarily sleep onset insomnia or nocturnal awakenings (with difficulty falling back to sleep). These disturbances can be accompanied by other sleep disorders, requiring notably a systematic elimination of the presence of a sleep apnea or restless legs syndrome - to ensure a personalized and efficient therapeutic approach. Physiologically, the determinants of these sleep disorders are poorly understood, even though several studies point to a significant decrease in melatonin synthesis in people with ASD. Melatonin is a hormone that facilitates falling asleep and maintaining sleep and is also involved in the endogenous synchronization of internal biological clocks. However, the causal factors of this decrease in melatonin synthesis are largely unknown, involving to a small extent the genes involved in melatonin synthesis pathway. The treatment of sleep disorders is relatively systematic: after eliminating other specific sleep disorders associated with the complaint of insomnia, as well as other possible associated comorbidities (such as seizures), a global and graduated therapeutic approach must be put in place. This treatment will be non-pharmacological as a first line, then pharmacological as a second line. A number of non-pharmacological treatment strategies for sleep disorders in typically developing children and adolescents, as well as those with ASD, have been shown to be effective. This treatment requires a combination of: 1) parental education to promote sleep development; 2) setting up bedtime rituals adapted to the child's age and particularities; 3) specific behavioral strategies including bedtime fading, gradual extinction and positive reinforcement of adapted behaviors. It is very essential that the parents are accompanied throughout this therapy. Sleep hygiene and behavioral care must also take into consideration the important role of the zeitgebers of sleep-wake rhythms, i.e. the external environmental factors involved in the synchronization of the biological clocks: regular exposure to light at adapted times, regular meal and wake-up times, social activities and times for going to school. The evidence for the effectiveness of behavioral interventions in the treatment of behavioral insomnia in the typical developmental child is strong, since 94% of children show clinically significant improvements in nighttime sleepiness and waking. By contrast, only about 25% of children with ASD are improved by an approach combining sleep hygiene and behavioral therapy. Melatonin has a special and prominent place in the drug management of sleep disorders associated with ASD. Several clinical trials have shown that melatonin is effective in treating sleep disorders in patients with ASD. This work led to the European Medicines Agency (EMA) granting marketing authorization in September 2018 for a sustained-release paediatric melatonin molecule (Slenyto®). This synthetic molecule is a prolonged release melatonin (PRM) which mimics the physiological pharmacokinetic and secretory characteristics of endogenous melatonin, having a very short blood half-life and prolonged secretion for several hours during the night. A recent study evaluated the efficacy and safety of pediatric PRM (mini-tablets) in 125 children, aged 2 to 17.5 years with mainly ASD. After 15 days on placebo, the children were randomized into two parallel groups, PRM or placebo in a double-blind design for 13 weeks. At endpoint, total sleep time was increased by an average of 57.5 minutes on PRM and only 9.14 minutes on placebo (P=0.034). This difference between the two groups was already significant after three weeks of treatment (P=0.006). Sleep latency was also improved in the PRM group (-39.6 minutes) compared to placebo (-12.51 minutes) (P=0.01). Consolidated sleep duration (uninterrupted by awakenings) was improved by 77.9 minutes for the PRM group and only 25.4 minutes for the placebo group (P<0.001). PRM was well tolerated, the most frequent side effects being headache and daytime drowsiness at the same level with PRM or placebo. In addition, the acceptability by the children for swallowing the mini-tablets was excellent (100% compliance). The efficacy and tolerability of PRM was maintained over the medium and long term in the open phase, over a total study duration of 2 years.

French consensus. Hypersomnolence: Evaluation and diagnosis.

Sleepiness is one of the most frequently reported complaints in adults and children during specialised sleep consultations. It is responsible for an alteration that can be severe in quality of life, a lowering of academic or professional performance, and domestic or work accidents. Hypersomnolence is the first cause of road accidents on the highway, responsible for a third of fatal accidents. Furthermore its presence is associated with an increased risk of morbi-mortality related to cardiovascular and neurodegenerative pathologies. Hence, its represents a real public health issue. Recent revisions in international classifications have clarified confusing terminology, and the complaint of hypersomnia has now been replaced by the terms hypersomnolence or excessive sleepiness. It is clinically defined as an excessive quantity of sleep over 24hours, and/or by an alteration in the quality of arousal defined as incapacity to maintain a satisfactory level of vigilance during the day or in the morning on awakening (defined as sleep inertia). The evaluation of sleepiness requires a rigorous clinical approach, completed by subjective and objective measurements. The Epworth Sleep Scale, Multiple Sleep Latency Tests and the Maintenance of Wakefulness Test are the most studied and used in clinical practice. However, to date, no gold standard measurement of excessive sleepiness exists, and there are no quantifiable biological markers. It is therefore important to optimise our evaluation tools, improve our pathophysiological understanding of sleepiness, and define genetic and environmental risk factors.

French consensus. Management of patients with hypersomnia: Which strategy?

Central hypersomnias principally involves type 1 narcolepsy (NT1), type 2 narcolepsy (NT2) and idiopathic hypersomnia (IH). Despite great progress made in understanding the physiopathology of NT1 with low cerebrospinal fluid hypocretin-1 levels, current treatment remains symptomatic. The same applies to NT2 and IH, for which the physiopathology is still largely unknown. Controlling excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed night-time sleep are key therapeutic targets in NT1. For IH and NT2, reducing EDS is the main objective. Based on European and American directives for the treatment of narcolepsy, we propose French recommendations for managing central hypersomnias as well as strategies in the case of drug-resistance. Stimulating treatments target EDS, and Modafinil is the first-line treatment. Other stimulants such as methylphenidate, pitolisant, and exceptionally dextro-amphetamine can be prescribed. Selective serotonin and noradrenaline reuptake inhibitor antidepressants are effective for the management of cataplexy in NT1. Sodium oxybate is an effective treatment for several symptoms, including EDS, cataplexy and disturbed night-time sleep. Treatment of central hypersomnia must also take into consideration frequent cardiovascular, metabolic and psychiatric comorbidities, particularly in NT1. New therapies are currently under study with the development of new stimulants and anti-cataplectics. The next few years will see innovative emerging therapies, based on a physiopathological approach, aiming to restore hypocretinergic transmission or to interrupt the autoimmune processes causing the loss of hypocretin neurons.

European guidelines on managing adverse effects of medication for ADHD.

The safety of ADHD medications is not fully known. Concerns have arisen about both a lack of contemporary-standard information about medications first licensed several decades ago, and signals of possible harm arising from more recently developed medications. These relate to both relatively minor adverse effects and extremely serious issues such as sudden cardiac death and suicidality. A guidelines group of the European Network for Hyperkinetic Disorders (EUNETHYDIS) has therefore reviewed the literature, recruited renowned clinical subspecialists and consulted as a group to examine these concerns. Some of the effects examined appeared to be minimal in impact or difficult to distinguish from risk to untreated populations. However, several areas require further study to allow a more precise understanding of these risks.

[Kleine-Levin syndrome: state of the art]. / Le syndrome de Kleine-Levin.

INTRODUCTION: Kleine-Levin syndrome is a rare neurological disorder (1-2 cases per million inhabitants) primarily affecting young subjects. It is characterized by relapsing-remitting episodes of hypersomnia in association with cognitive and behavioral disturbances. Case-reports, small series, meta-analysis and a recent large, prospective trio study are consistent with a homogeneous, genuine disease entity. STATE OF THE ART: Patients are mostly male (68-78%) and adolescents (81%), with mean onset at 15 years (range 4-82 years). The first episode is triggered by an infection in 72% of patients. Patients experience an average of 7-19 episodes of 10-13 days each, relapsing every 3.5 months. Episodes recur more quickly in patients with childhood onset. The median disease course is 8-14 years, with longer course in men, in patients with hypersexuality, and when onset is after age 20. During episodes, all patients have hypersomnia (with sleep lasting 15-21 heures per day), cognitive impairment (apathy, confusion, slowness, amnesia) and a specific feeling of derealization (dreamy state, altered perception). Less frequently, patients experience hyperphagia (66%), hypersexuality (53%, principally men) and depressed mood (53%, predominantly women). Patients are remarkably similar to controls between episodes regarding sleep, vigilance, mood, and eating attitude, but have increased body mass index. Structural brain imaging, evaluation of the cerebrospinal fluid and serological inflammatory markers are unremarkable. EEG slowing is notable in 70% of cases during episodes, without epileptic activity. Sleep structure varies from harmonious hypersomnia to hypo-arousal with low sleep efficiency. The brain scintigraphy may show hypoperfusion, mostly focused on the thalamic, hypothalamic and fronto-temporal areas, especially when contrasted to images obtained between episodes. Newly identified factors include increased birth and developmental problems, Jewish heritage, genetics (5% multiplex families, suggesting autosomal recessive transmission). The association of KLS with HLA-DQ2, found in a small series, is not replicated in a larger independent sample. There is no increased family history for neuropsychiatric disorders. Some stimulants (amantadine, but more rarely modafinil or amphetamins) and mood stabilizers (lithium, valproate, but not carbamazepine) have marginal efficacy. In the 10% KLS cases secondary to various genetic, inflammatory, vascular or paraneoplasic conditions, patients are older, have more frequent and longer episodes, but their clinical symptoms, disease course and treatment response are similar to primary cases. PERSPECTIVE: The most promising findings are the familial clustering and a potential Jewish founder effect, supporting a role for genetic susceptibility factors. CONCLUSION: KLS is a puzzling and disabling disease. Until its cause will be identified, disease management should be primarily supportive and educational.

[Narcolepsy with cataplexy in the child: clinical evaluation and therapeutical management]. / Narcolepsie avec cataplexie chez l'enfant : particularités cliniques et approches thérapeutiques.

Narcolepsy with cataplexy is a rare but long lasting and disabling disorder where onset often occurs during childhood. Excessive daytime sleepiness, irresistible sleep attacks, partial or complete cataplexies leading to abrupt falls without loss of consciousness are the major symptoms of the disorder together with hypnagogic hallucinations and sleep paralysis. Narcolepsy cases with childhood onset are often severe. School and social life are affected in children suffering from this condition. Due to the permanence of the disorder, long-term treatment is often required targeting sleepiness. Anticataplectic treatments may be necessary early on in the course of the disease, when considering the potential handicap created by the cataplexies and the risk of falls. There is no medication available to this day to cure the disorder. Familial education, psychological and academic support play a crucial role in the management of the symptoms and in, combination with pharmacological treatment, the quality of life in children with narcolepsy and their outcome in adulthood should lead to an improvement.

[Narcolepsy in sleepy obese children. Two case reports]. / Narcolepsie chez l'enfant obèse. À propos de 2 cas.

Narcolepsy is a disabling disorder, characterized by excessive daytime sleepiness, irresistible sleep attacks, and partial or complete cataplexy. Many cases of obesity and precocious puberty have been reported in narcoleptic children, suggesting that the deficiency of hypocretin in narcolepsy could also be implicated in appetite stimulation. We report the observations of two young girls, who were referred for obesity and who developed narcolepsy accompanied by an abrupt weight gain. In both cases, specific drugs promoted wakefulness and overweight stabilization. Narcolepsy has to be suspected in sleepy obese children and not misdiagnosed as obstructive apnea. A nocturnal polysomnography with multiple sleep latency tests should be performed to confirm the diagnosis and begin specific treatment that is effective for sleep disorders and weight gain.

Kleine-Levin syndrome: an autoimmune hypothesis based on clinical and genetic analyses.

BACKGROUND: Kleine-Levin syndrome (KLS) is a rare disorder of unknown etiology. Pathophysiologic hypotheses include a hypothalamic dysfunction and abnormalities in the central serotonin and dopamine metabolism. Several clinical symptoms also suggest an underlying autoimmune process. OBJECTIVE: To systematically investigate patients with KLS with reference to the available hypotheses. METHODS: The authors collected clinical, polysomnographic, CSF, CT, and MRI records and analyzed gene polymorphisms of HLA-DQB1, tryptophan hydroxylase (TpH), and catechol-O-methyltransferase (COMT) in 30 unrelated patients with KLS and their families. The genotype data were contrasted with data from a normal control population. RESULTS: Only human leukocyte antigen (HLA)-DQB1*0201 allele frequency was significantly increased in patients with KLS. Three patients with KLS but none of the control subjects were DQB1*0201 homozygous. Two affected subjects from the same family were DQB1*0201 homozygous. In 17 DQB1*0201 heterozygous parents, 11 (64.7%) had transmitted this allele, suggesting a preferential transmission. CONCLUSION: These findings, together with the young age at onset, the recurrence of symptoms, and the frequent infectious precipitating factors, suggest an autoimmune etiology for Kleine-Levin syndrome.

[Treatment of sleep disorders in children]. / Traitement des troubles du sommeil chez l'enfant.

Sleep disorders require careful evaluation, precise diagnosis and a systematic search for a cause before considering treatment. Hypnotics must never be prescribed directly and when necessary it must be used precautionally during a short period of time, as little is known on their long term effects in children. In addition some psychotropic drugs may lead to tolerance and addiction. Educational and behavioural therapy together with sleep hygiene, have proven to be efficient in most situations. Awaking stimulants are indicated in primary hypersomnia.

[Use of hypnotics in children: description and analysis]. / Utilisation des hypnotiques chez l'enfant: description et analyse.

BACKGROUND: Sleep disorders are frequent in pre-school children and in the French population, often leading to the prescription of hypnotics or sedatives. Therefore, this represents an important health problem in this population. PATIENTS AND METHODS: We studied the hypnotic consumption in children, aged between 1 month to 4 years (23 +/- 11.3 months), who complained of insomnia. Parents completed 203 sleep questionnaires including information on the hypnotics consumption of their offspring (112 boys and 91 girls). The questionnaire was also related to the parent's sleep patterns and hypnotics consumption. Seventy percent of the sample had received medication, at least once before the evaluation, and at any age. A positive correlation between hypnotics consumption in mothers and children, particularly boys (odds-ratio = 4.8; 1.1-8.7) was found. CONCLUSION: These data confirm the early exposition to hypnotics of children in the French population, and the existence of a familial pattern of consumption, mostly influenced by the mother. These data should permit the identification of subgroups at risk for early exposition and to encourage non-pharmacologic approaches in the treatment of insomnia in young children.

[Evaluation of excessive daytime sleepiness in child and adolescent psychopathology]. / Évaluation d'une somnolence diurne excessive en psychopathologie de l'enfant et de l'adolescent.

Childhood and adolescence are characterized by major changes in physiological, social and psychological domains. Some learning, behavior, mood or sleep disorders occurring during these ever-changing periods may lead children and teenagers to search for psychiatric care. It is then crucial to accurately determine which symptoms pertain to sleep and alertness disorders. Otherwise, some sleepy children and adolescents may be incorrectly considered as lazy, hyperactive or depressed. The evaluation of sleepiness requires a thorough physical examination (including the otorhinolaryngologic aspect), the completion of scales and brief questionnaires suited for pediatric patients, a fully completed sleep diary and in some cases biological or electrophysiological exams such as polysomnography (suited for the diagnosis of sleep apnea, narcolepsy, and periodic limb movement disorder). These investigations will help recognize excessive sleepiness, evaluate the often bi-directional links with the associated psychopathology and, should the case arise, diagnose primary sleep disorders (mostly sleep apnea in children and insufficient sleep in adolescents) and guide the adequate treatment.

Sleep and alertness in children with ADHD.

OBJECTIVE: To evaluate sleep and alertness and to investigate the presence of possible underlying sleep/wake disorders in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: After 3 nights of adaptation in a room reserved for sleep studies in the department of child psychiatry, children underwent polysomnography (PSG) followed by the Multiple Sleep Latency Test (MSLT) and reaction time tests (RT) during the daytime. Thirty boys diagnosed as having ADHD (DSM-IV), aged between 5 and 10 years, and 22 age- and sex-matched controls participated in the study. All children were medication-free and showed no clinical signs of sleep and alertness problems. RESULTS: No significant differences in sleep variables were found between boys with ADHD and controls. The mean latency period was shorter in children with ADHD. Significant differences were found for MSLT 1, 2 and 3 (p < .05). Mean reaction time was longer in children with ADHD, with significant differences in all tests (p < .05). Number and duration of sleep onsets measured by the MSLT correlated significantly with the hyperactivity-impulsivity and inattentive-passivity indices of the CTRS and CPRS. CONCLUSION: Children with ADHD were more sleepy during the day, as shown by the MSLT, and they had longer reaction times. These differences are not due to alteration in the quality of nocturnal sleep. The number of daytime sleep onsets and the rapidity of sleep-onsets measured as MSLT were found to be pertinent physiological indices to discriminate between ADHD subtypes. These results suggest that children with ADHD have a deficit in alertness. Whether this deficit is primary or not requires further studies.

High levels of nocturnal activity in children with attention-deficit hyperactivity disorder: a video analysis.

Sleep disturbances can lead to symptoms of attention-deficit hyperactivity disorder (ADHD) in children. In the present study, we compared the sleep patterns of 30 children with ADHD, with those of 19 controls matched for age (5-10 years) and sex. Sleep patterns were recorded during one night, using polysomnography (PSG) and a video system in the sleep laboratory. Both ADHD children and controls were medication free and showed no clinical signs of sleep and alertness problems. An infrared camera was used to record all types of movement, which were scored and analyzed using specific software (Observer(R) 3.0; Noldus International, The Netherlands). No significant differences in sleep variables were found between ADHD children and controls. Polysomnography data showed no significant difference between the two groups. Attention-deficit hyperactivity disorder children moved more often than controls (upper limbs, P < 0.04; lower limbs, P < 0.03; all types, P < 0.003). The duration of movements was significantly longer in ADHD children (upper limbs, P < 0.03; all types, P < 0.02). The results of the video analysis were consistent with previous findings that ADHD children have higher levels of nocturnal activity than controls. This activity concerned mostly upper and lower limb movements. Futher studies are required to determine why noctural activity does not affect sleep continuity in a more significant way and whether it should be treated specifically.

MAO-A and COMT polymorphisms and gene effects in narcolepsy.

Narcolepsy presents one of the tightest associations with a specific HLA antigen (DQB1*0602) but there is strong evidence that non-HLA genes also confer susceptibility. Recent observations have implicated the hypocretin/orexin system in narcolepsy in both humans and animals. In addition, the implication of monoaminergic systems in the pathophysiology of narcolepsy is well established and a significant association between the monoamine oxydase-A (MAO-A) gene and human narcolepsy has recently provided a possible genetic link. We investigated polymorphisms of MAO-A and catechol-O-methyltransferase (COMT) in 97 Caucasians with well-defined narcolepsy-cataplexy and sought for genotypic effects on disease symptoms. No evidence of association between genotype or allele frequencies of both MAO-A or COMT gene and narcolepsy was found. However, a sexual dimorphism and a strong effect of COMT genotype on disease severity were found. Women narcoleptics with high COMT activity fell asleep twice as fast as those with low COMT activity during the multiple sleep latency test (MSLT) while the opposite was true for men. COMT genotype also strongly affected the presence of sleep paralysis and the number of REM sleep onsets during the MSLT. In agreement with well-documented pharmacological results in canine narcolepsy, this study reports the first genetic evidence for the critical involvement of the dopaminergic and/or noradrenergic systems in human narcolepsy.

HLA and genetic susceptibility to sleepwalking.

HLA-DQB1 typing was performed in 60 Caucasian subjects with sleepwalking (SW) disorder and their families and 60 ethnically matched subjects without any diagnosed sleep disorder. A total of 21 sleepwalkers (35.0%) were DQB1*0501 positive vs eight (13.3%) controls (P = 0.0056; odds ratio = 3.5, 95% CI = 1.4-8.7). The family data for all HLA subtypes were further assessed for allelic association with SW using the transmission-disequilibrium test. A significant excess transmission was observed for DQB1*05 and *04 alleles in familial cases, strongly suggesting that a DQB1 polymorphic amino acid might be more tightly associated than any single allele. Sequence screening revealed that Ser74 in the second exon shared by all DQB1*05 and *04 was 20 times transmitted against 4 times non-transmitted (P = 0.001) in familial cases of SW. Thus, together with narcolepsy and REM sleep behavior disorder, these findings suggest that specific DQB1 genes are implicated in disorders of motor control during sleep.

CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions.

OBJECTIVE: To determine the role of CSF hypocretin-1 in narcolepsy with and without cataplexy, Kleine-Levin syndrome (KLS), idiopathic and other hypersomnias, and several neurological conditions. PATIENTS: 26 narcoleptic patients with cataplexy, 9 narcoleptic patients without cataplexy, 2 patients with abnormal REM-sleep-associated hypersomnia, 7 patients with idiopathic hypersomnia, 2 patients with post-traumatic hypersomnia, 4 patients with KLS, and 88 patients with other neurological disorders. RESULTS: 23 patients with narcolepsy-cataplexy had low CSF hypocretin-1 levels, while one patient had a normal hypocretin level (HLA-DQB1*0602 negative) and the other two had intermediate levels (familial forms). One narcoleptic patient without cataplexy had a low hypocretin level. One patient affected with post-traumatic hypersomnia had intermediate hypocretin levels. The KLS patients had normal hypocretin levels while asymptomatic, but one KLS patient (also affected with Prader-Willi syndrome) showed a twofold decrease in hypocretin levels during a symptomatic episode. Among the patients without hypersomnia, two patients with normal pressure hydrocephalus and one with unclear central vertigo had intermediate levels. CONCLUSION: Low CSF hypocretin-1 is highly specific (99.1%) and sensitive (88.5%) for narcolepsy with cataplexy. Hypocretin ligand deficiency appears not to be the major cause for other hypersomnias, with a possible continuum in the pathophysiology of narcolepsy without cataplexy and idiopathic hypersomnia. However, partial hypocretin lesions without low CSF hypocretin-1 consequences cannot be definitely excluded in those disorders. The existence of normal hypocretin levels in narcoleptic patients and intermediate levels in other rare aetiologies needs further investigation, especially for KLS, to establish the functional significance of hypocretin neurotransmission alterations.