Michel Lecendreux

Nonpharmacological interventions for ADHD: systematic review and meta-analyses of randomized controlled trials of dietary and psychological treatments

OBJECTIVE Nonpharmacological treatments are available for attention deficit hyperactivity disorder (ADHD), although their efficacy remains uncertain. The authors undertook meta-analyses of the efficacy of dietary (restricted elimination diets, artificial food color exclusions, and free fatty acid supplementation) and psychological (cognitive training, neurofeedback, and behavioral interventions) ADHD treatments. METHOD Using a common systematic search and a rigorous coding and data extraction strategy across domains, the authors searched electronic databases to identify published randomized controlled trials that involved individuals who were diagnosed with ADHD (or who met a validated cutoff on a recognized rating scale) and that included an ADHD outcome. RESULTS Fifty-four of the 2,904 nonduplicate screened records were included in the analyses. Two different analyses were performed. When the outcome measure was based on ADHD assessments by raters closest to the therapeutic setting, all dietary (standardized mean differences=0.21-0.48) and psychological (standardized mean differences=0.40-0.64) treatments produced statistically significant effects. However, when the best probably blinded assessment was employed, effects remained significant for free fatty acid supplementation (standardized mean difference=0.16) and artificial food color exclusion (standardized mean difference=0.42) but were substantially attenuated to nonsignificant levels for other treatments. CONCLUSIONS Free fatty acid supplementation produced small but significant reductions in ADHD symptoms even with probably blinded assessments, although the clinical significance of these effects remains to be determined. Artificial food color exclusion produced larger effects but often in individuals selected for food sensitivities. Better evidence for efficacy from blinded assessments is required for behavioral interventions, neurofeedback, cognitive training, and restricted elimination diets before they can be supported as treatments for core ADHD symptoms.

Sleep in children with attention-deficit/hyperactivity disorder: meta-analysis of subjective and objective studies

OBJECTIVE To perform a meta-analysis of subjective (i.e., based on questionnaires) and objective (i.e., using polysomnography or actigraphy) studies comparing sleep in children with attention-deficit/hyperactivity disorder (ADHD) versus controls. METHOD We searched for subjective and objective sleep studies (1987-2008) in children with ADHD (diagnosed according to standardized criteria). Studies including subjects pharmacologically treated or with comorbid anxiety/depressive disorders were excluded. RESULTS Sixteen studies, providing 9 subjective and 15 objective parameters and including a total pooled sample of 722 children with ADHD versus 638 controls, were retained. With regard to subjective items, the meta-analysis indicated that children with ADHD had significantly higher bedtime resistance (z = 6.94, p <.001), more sleep onset difficulties (z = 9.38, p <.001), night awakenings (z = 2.15, p =.031), difficulties with morning awakenings (z = 5.19, p <.001), sleep disordered breathing (z = 2.05, p =.040), and daytime sleepiness (z = 1.96, p =.050) compared with the controls. As for objective parameters, sleep onset latency (on actigraphy), the number of stage shifts/hour sleep, and the apnea-hypopnea index were significantly higher in the children with ADHD compared with the controls (z = 3.44, p =.001; z = 2.43, p =.015; z = 3.47, p =.001, respectively). The children with ADHD also had significantly lower sleep efficiency on polysomnography (z = 2.26, p =.024), true sleep time on actigraphy (z = 2.85, p =.004), and average times to fall asleep for the Multiple Sleep Latency Test (z = 6.37, p <.001) than the controls. CONCLUSIONS The children with ADHD are significantly more impaired than the controls in most of the subjective and some of the objective sleep measures. These results lay the groundwork for future evidence-based guidelines on the management of sleep disturbances in children with ADHD.

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.

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.

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.

Elevated Tribbles homolog 2–specific antibody levels in narcolepsy patients

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis showed that sera from narcolepsy patients with cataplexy had higher Trib2-specific antibody titers compared with either normal controls or patients with idiopathic hypersomnia, multiple sclerosis, or other inflammatory neurological disorders. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2-3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. High Trib2-specific antibody titers correlated with the severity of cataplexy. Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus. Thus, we have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder.

Attention-Deficit/Hyperactivity Disorder (ADHD) and Obesity: A Systematic Review of the Literature

Recent studies suggest a possible comorbidity between Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity. To gain insight into this potential association, we performed a systematic review of the literature excluding case reports, non-empirical studies, and studies not using ADHD diagnostic criteria. Empirically based evidence suggests that obese patients referred to obesity clinics may present with higher than expected prevalence of ADHD. Moreover, all reviewed studies indicate that subjects with ADHD are heavier than expected. However, data on the prevalence of obesity in subjects with ADHD are still limited. As for the mechanisms underlying the potential association between ADHD and obesity, ADHD might lead to obesity via abnormal eating behaviors, impulsivity associated with binge eating might contribute to ADHD in obese patients, or, alternatively, both obesity and ADHD might be the expression of common underlying neurobiological dysfunctions, at least in a subset of subjects. In patients with obesity and ADHD, both conditions might benefit from common therapeutic strategies. Further empirically based studies are needed to understand the potential comorbidity between obesity and ADHD, as well as the possible mechanisms underlying this association. This might allow a more appropriate clinical management and, ultimately, a better quality of life for patients with both obesity and ADHD.

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.

Kleine–Levin syndrome: A systematic study of 108 patients

Kleine–Levin syndrome is a rare disorder characterized by relapsing‐remitting episodes of hypersomnia, cognitive disturbances, and behavioral disturbances, such as hyperphagia and hypersexuality.

Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15–25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 × 10−8). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 × 10−43) and DRB1*1301-DQB1*0603 (P < 3 × 10−7). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 × 10−14). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.