Valoración del sueño mediante actigrafía en niños con trastornos del sueño y con déficit de atención y/o hiperactividad (TDAH)papel de la melatonina y ácidos grasos de la serie omega-3

Resum

Background: Sleep disorders are one of the most frequent reasons for consulting the paediatrician, with a prevalence ranging between 13% and 27% in children aged 4 to 12 years, depending on the different reviewed reports (1-3). Moreover, it is well-known their participation as a comorbidity in children diagnosed with Attention Deficit/Hyperactivity Disorder (ADHD) according to the criteria established by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). Sleeps disorders and ADHD are found together in 55% of cases (4). This comorbidity may be primary or secondary, as a consequence of the effect produced by psychostimulant medication (Methylphenidate/MPH) (5-8). At present, new chemical compounds with less adverse effects are being developed to be used as possible therapies for ADHD and related comorbidities (9). Among them, it should be mentioned the omega (ω)-3 fatty acids, due to their possible beneficial effects on cognition and health (10-12), and the melatonin, on account of its functions as a sleep inductor, a synchroniser of biological rhythms and a neuronal protector (13-17). Objectives: Under these premises, the present project was developed with the following aims: a) To define the sleep-wake patterns and its association with the circadian variation of urinary 6-sulfatoxymelatonin (aMT6s) levels in 2 groups of patients. One group of healthy children (Control Group: C-G), who did not have any sleep difficulties nor endocrine problems. The other group was composed of children diagnosed with different sleep disorders according to the International Classification of Sleep Disorders (ICSD) (Group with Sleep Disorders: SD-G). b) To analyse the efficacy of a therapeutic trial with melatonin in those patients of SD-G who showed a low production or a disordered secretion of aMT6s. c) To assess the short-term efficacy and the tolerability of a therapeutic combination of MPH, melatonin and ω-3 fatty acids in patients with ADHD. Serum fatty acid profile was monitored and changes in sleep patterns were analysed by using the actigraphy and a neural network model. Material: All participants of our study were assisted at the Paediatrics Clinical Management Unit (CMU) of San Cecilio University Hospital (Hospital Complex), Granada (Spain). 1) Patients of the C-G and the SD-G were referred to the Paediatric Neurology Unit and the General Paediatric Section from the different primary care centres of the province. Participants of the C-G met the common characteristic of being healthy children in relation to the complete medical record and the physical examination that were initially done. All of them had only a mild illness, which was transient and did cause no significant repercussions on the general health of the patient. In relation to the patients of the SD-G, they had to comply with the criterion of being diagnosed with a sleep disorder according to the ICSD, provided that such disorder was not a consequence of other neurological or endocrine-metabolic problems. 124 children aged 4 to 15 were included in both groups (64 boys/60 girls in the C-G and 65 boys/59 girls in the SD-G). 2) Patients suspected of having ADHD were referred to the Paediatric Neurology Unit of our hospital. A clinical record based on the interviews with the patient/parents and the information provided from the school, was completed to confirm the diagnosis. After the physical and neurological examinations, a psychometric assessment of the patient was conducted: the Kaufman Brief Intelligence Test (K-BIT), the Wechsler Intelligence Scale for Children 4th edition (WISC-IV) and an anxiety/depression symptom screening (Children’s Depression Inventory or CDI, Spence Children’s Anxiety Scale or SCAS). Other questionnaires, like the NICHQ Vanderbilt Assessment Scale (parent and teacher versions) and the inventory to evaluate the executive functions (BRIEF, Behavior Rating Inventory of Executive Functions) were completed at the beginning as well. Only those patients who strictly complied with the selection criteria were invited to participate in the study. Inclusion criteria included to have a confirmed diagnosis of ADHD, in absence of other endocrine, metabolic or neurological illnesses, and to receive no type of long-term pharmacological treatment. The presence of heart or cardiovascular disease, glaucoma, psychotic disorder, a severe pathology that required polymedication or a mild, moderate or severe intellectual disability (intelligence quotient under 70), were considered as exclusion criteria. 40 ADHD patients aged 7-15 years (27 boys/13 girls) were finally included. Among them, 22 patients (55%) were classified as an ADHD Inattentive, 16 (40%) as an ADHD Combined and the other 2 patients were diagnosed with an ADHD Hyperactive-Impulsive Type. K-BIT/WISC-IV scores showed a medium IQ in 22 patients (55%), low-medium IQ in 15 of them (37.50%) and a high IQ in the remaining 3 patients (7.50%). Methods: An open-label clinical trial designed in 2 phases was conducted in order to comply with our objectives. 1) Patients of the C-G and the SD-G were recruited during the first phase. An actigraphic assessment of sleep18 (The Actiwatch Activity Monitoring System®, propiedad de CamNtech Ltd.) and a determination by radioimmunoassay (RIA) of melatonin and aMT6s levels in plasma and urine, respectively, were initially carried out in these patients. The measurements were repeated after 3 months of treatment with melatonin (dose of 3 mg daily, 30 minutes before bedtime) in those patients of SD-G who initially showed disturbances in melatonin production and/or melatonin secretion. 2) Patients with a confirmed diagnosis of ADHD were included throughout the second phase of the study (group before treatment or BT-G). An uninterrupted actigraphic assessment of sleep for 1 week was carried out in them, as well as a serum fatty acid profile analysis by gas chromatography and an assessment of attention by using the Magallanes Scale of Visual Attention (MSVA). A combination of MPH (1 mg/kg/day), melatonin (1mg/day) and ω-3 fatty acids (docosahexaenoic acid or DHA 250 mg + eicosapentaenoic acid or EPA 70 mg) were administered to those ADHD patients who met the criteria to receive pharmacological treatment. After 1 month of treatment, the same measurements were repeated in order to establish a comparative analysis before/after treatment. The comparisons between actigraphic results were made by using a neural network model. All parents/patients provided their written informed consent to participate in the study, as well as all procedures were carried out in accordance with the Helsinki Declaration for human research. Results: 1) In the first phase of the study, the actigraphic analysis showed statistically significant differences (p < 0.001) between the C-G and the SD-G for the following sleep parameters: sleep end, actual sleep time, actual wake time, sleep efficiency, sleep latency and wake bouts. Diurnal average excretion of aMT6s in urine was significantly higher in patients of the SD-G, whereas nocturnal and 24-hour excretions of aMT6s were significantly lower in relation to the C-G. Fourteen patients of the SD-G with disturbances in the production and/or secretion of melatonin were selected for the therapeutic trial with melatonin. After 3 months of treatment, a statistically significant increase of plasma and urinary melatonin values was observed, even higher than those ones in the SD-G. These changes were accompanied by an improvement of actigraphic results. 2) In the second phase of the study, no statistically significant differences were observed in relation to somatometric parameters and the blood test general values between the groups before (BT-G) and after treatment (AT-G). The only significant difference in regard to the actigraph results was an increased actual sleep time (p < 0.040) among patients of the AT-G. In addition, the neural network was not able to classify the actigraphic data of medicated and not medicated patients as different categories. The fatty acid analysis showed a significant decrease of some ω-6 fatty acids, like arachidonic acid (p < 0.030), as well as an (not statistically significant) increase by 4% and 30% of DHA and EPA levels, respectively. The quality of attention index (in regard to MSVA results) was significantly higher in the AT-G (p < 0.026). In general, an improvement of ADHD symptoms was observed and corroborated by parents, teachers and paediatricians after 1 month of treatment (MPH + melatonin + DHA/EPA). The medication was adequately tolerated by all patients. Discussion: a) Actigraphy as a diagnostic tool for sleep disorders in paediatric patients in general, and in children with ADHD in particular: As we observed, actigraphy provided sleep patterns of the different groups of patients (C-G, SD-G, BT-G, AT-G) according to the information of previous studies (18). Actigraphic results showed an adequate correlation with objective data provided by melatonin levels (19). The differences between sleep patterns of the C-G and the SD-G were clearly reflected in the actigraphic analysis, as well as the improvement associated to the normalised production and the circadian regulation of melatonin secretion after the therapeutic administration of this indolamine. In the case of the second phase of the project (BT-G and AT-G), sleep difficulties identified by actigraphy will be furtherly confirmed (last phase of the project), as it would be expected, with the use of a definitive diagnostic tool (gold standard) like polysomnography (PSG). In contrast to the PSG, actigraphy has several advantages. It provides non invasive sleep records and reliable measurements (20) with an ease of use that make it a feasible instrument for the screening of sleep disorders in children in general, and in paediatric patients with ADHD in particular. b) Sleep difficulties in patients with ADHD. Role of melatonin and the influence of psychostimulant medication: At present, sleep induction is the most accepted property of melatonin, and together with its excellent safety profile, allow us to consider it as a therapeutic alternative specially interesting in the case of paediatric populations (21). The study conducted throughout the first phase of the project (C-G and SD-G) showed the utility of melatonin administration in intrinsic sleep disorders caused by circadian rhythm disturbances, low melatonin production or phase maladjustment. Within paediatric populations, a relevant group of candidates for melatonin therapy is composed by children with ADHD (22). The findings of different studies have suggested that diurnal and nocturnal melatonin productions are really increased in children with ADHD. Therefore, the cause of an insufficient action of melatonin in these children might be a rise of its catabolism (23-25). On the one hand, the increase of melatonin production would be caused by decreased concentrations of the neurotransmitter gamma-aminobutyric acid (GABA), which would act as a circadian secretion regulator (26-28). On the other hand, it would be produced by a rise of diurnal extrapineal secretion (29). However, the investigation conducted by Molina-Carballo et al.23 reveals the presence of similar plasma concentrations of melatonin between ADHD patients and healthy children. This finding does not appear to be consistent with the hypothesis of an increased production. As we may note, the question in relation to the physiopathology of sleep disorders in patients with ADHD does not have a conclusive answer yet. Thus, more investigations in this regard are required. In relation to psychostimulant medication, MPH causes a reduction of serum serotonin (5-HT) concentrations in the evening and of diurnal melatonin levels, as it has been reported by Cubero-Millán et al. (24). Likewise, MPH leads to an increase of nocturnal melatonin concentrations together with a decreased urinary excretion of aMT6s. This circumstance suggests that psychostimulant medication has an influence on melatonin catabolism by promoting an alternative route of metabolisation. c) Therapeutic effects of melatonin on sleep problems of ADHD patients: In the case of children with ADHD, clinical trials reveal the property of melatonin to significantly reduce the sleep latency and prolong the actual sleep duration (30). When it is administered jointly with MPH, melatonin is able to improve the sleep disturbances caused by psychostimulant medication (31,32). Some examples are the comparisons between the BT-G and the AT-G in relation to the actigraphic results. As we can observe, the mean values of actigraphic parameters barely changed after 1 month of treatment with melatonin + MPH, except in the case of the actual sleep time, which was significantly longer in the AT-G. The comparative analysis was corroborated by a neural network model, which demonstrated the similarity of both sleep patterns and classified them as the same category after operating with different sized networks (5 and 10 neurons). After 1 month of melatonin administration, the tolerability was adequate in all patients and no severe side effects were reported. Other possible benefit of combining melatonin and MPH is that the first one appears to act as a neuroprotective agent by avoiding the toxic effects induced by psychostimulants on brain metabolism (33,34). Psychostimulant agents promote the production of free radicals and the transcription of the enzyme nitric oxide synthase (NOS) (35,36). Some examples are the continuous investigations conducted by our research group in relation to the neuroprotective and antioxidant benefits obtained with the use of melatonin in children (37-41). d) Considerations regarding the fatty acid profile in our group of ADHD patients: Despite numerous evidences provided by literature (42) and in spite of being one of the most studied possible alternative treatments for ADHD (43), therapeutic administration of ω-3 fatty acids to children with ADHD is a controversial aspect of the nutritional and therapeutic recommendations for these patients. In our work we tested a combination of DHA/EPA in which we have some experience on account of its tolerability and its relative low dose. We considered beforehand that this formulation might be useful for ADHD patients. Obviously, the definitive estimation in relation to the possible beneficial effects will be reached in the future, when the project is finished and we have the possibility to evaluate the complete patient cohort after 2-year follow-up period, recruit new patients and to modify the dose throughout the study. This is the reason why we firmly believe that obtaining preliminary data provides an initial reference regarding clinical effects (beneficial), tolerability (excellent) and possible serum changes of the different fatty acids (44). The proportions used in this investigation (70 mg of EPA and 250 mg of DHA) are in line with the recommended ω-3 daily intake in paediatric populations (45,46). Nevertheless, the current blood ω-6/ω-3 ratio in western population is around 12/1 or even higher, far from the values (4/1 or 2/1) recommended by the FAO/WHO (47), with the consequent risk of atherosclerosis and neuroinflammation. Due to this reason, ω-3 long-chain polyunsaturated fatty acid (ω-3 LC-PUFA) intake is advised by a large number of authors and international agencies in order to ensure a proper brain development and optimal cognitive and visual functions. A good example are the clinical studies conducted in the last years, which are focused on the impact of ω-3 LC-PUFAs supplementation on cognitive function and behaviour of healthy children (48-55). However, it should be considered that overall results depend, to a large extent, on the combinations of LC-PUFAs and the relative concentration of each one of them (56). Whereas positive results using different quantitative and qualitative combinations of ω-3 fatty acids were reported in healthy children (54,55),a combination of EPA+ DHA (ω-3) and/or gamma-linolenic acid (GLA, ω-6) in decreasing quantities might be the most appropriate one in ADHD patients. This information was reported in the studies conducted by Richardson (57), Sinn (58) and Johnson (59), the clinical trials by Gustafsson (60), Huss (61), Manor et al. (62) or the metaanalysis by Bloch and Qawasmi (63). In our study, it was observed a slight but not statistically significant decrease of ω-6/ω-3 index. This finding invites us to think about possible changes in the administered dose. As a matter of fact, the proportions of EPA/DHA have been modified throughout the subsequent phase of the project in order to improve the aforementioned protective functions against disease (44). In addition, it should be considered that the initial monitoring took place only 1 month after treatment. For the time being, tolerability was excellent in our study. No severe side effects were reported and no patients were withdrawn from the study due to safety problems. In this phase of our investigation, proportions of EPA and DHA were different (250 mg DHA, 70 mg EPA), so comparisons must be necessarily relative (44). Nevertheless, we found benefits for ADHD symptoms, school performance and sleep efficiency (44). Throughout the further follow-up, we expect to obtain more information in relation to dose adjustment, proportions of ω-3/ω-6 fatty acids, tolerability as well as medium and long-term therapeutic effects (64). Conclusions: a) Sleep disorders have a considerable prevalence in childhood, particularly in children with ADHD. Taking this reason into consideration, they should be investigated in each patient referred to the Unit with the suspicious of ADHD. b) Actigraphy represents a reliable and pragmatic instrument in order to carry out an initial screening of sleep problems in paediatric populations. c) Melatonin is an innocuous and effective therapeutic resource in patients who show sleep disorders associated to disturbances of melatonin production rhythm. d) In children with ADHD and sleep disorders, whether primary sleep disorder or secondary ones to the effect of psychostimulant medication (methylphenidate/MPH), melatonin has been demonstrated to be equally effective. e) ω-3 fatty acids might represent an adjuvant therapy in ADHD and enhance the effects of MPH and melatonin. In any case, by testing different combinations of ω-3 fatty acids throughout a medium and long-term follow-up of these patients (last phase of the project), is expected to provide more evidences in relation to the preliminary results obtained in this experience.