Melatonin has membrane receptor-independent hypnotic action on neurons: an hypothesis.

Melatonin, which is known to have sleep-promoting properties, has no morpho-physiological barriers and readily enters neurons and their subcellular compartments from both the blood and cerebrospinal fluid. It has multiple receptor-dependent and receptor-independent functions. Sleep is a neuronal function, and it can no longer be postulated that one or more anatomical structures fully control sleep. Neurons require sleep for metabolically driven restorative purposes, and as a result, the process of sleep is modulated by peripheral and central mechanisms. This is an important finding because it suggests that melatonin should have intracellular sleep-inducing properties. Based on recent evidence, it is proposed that melatonin induces sleep at the neuronal level independently of its membrane receptors. Thus, the hypnotic action of melatonin and the mechanisms involving the circadian rhythms are separate neurological functions. This is contrary to the presently accepted view.

The role of the thalamus in sleep, pineal melatonin production, and circadian rhythm sleep disorders.

The thalamus has a strong nonphotic influence on sleep, circadian rhythmicity, pineal melatonin production, and secretion. The opening of the sleep gate for nonrapid eye movement sleep is a thalamic function but it is assisted by melatonin which acts by promoting spindle formation. Thus, melatonin has a modulatory influence on sleep onset and maintenance. A remarkable similarity exists between spindle behavior, circadian rhythmicity, and pineal melatonin production throughout life. Together, the thalamic and chronobiological control of sleep leads to a new and improved understanding of the pathophysiology of circadian rhythm sleep disorders and also of the principles of sleep hygiene interventions.

Autism spectrum disorder in children with and without epilepsy: impact on social functioning and communication.

AIM: To compare developmental and psychological functioning in two groups of children with autism spectrum disorder (asd), one with epilepsy and one without. METHODS: Sixty 7-17-year-old children in each group were recruited through a range of services in order to screen as representative a sample as possible. Parents were interviewed using the diagnostic interview for social and communication disorders (DISCO-11), and children were clinically examined and their medical histories assessed. RESULTS: The asd and epilepsy (asd+e) group demonstrated a substantially more even gender ratio, with a greater proportion of girls. They were more likely to have received later asd diagnoses and additional medical diagnoses. They also showed more motor difficulties, developmental delays and challenging behaviours, but were no more likely to be aloof and passive. The asd-only group experienced more abnormal fascinations with objects and used brief glances as a means of eye contact more than the asd+e group. CONCLUSION: Results support important between-group differences with diagnostic and therapeutic implications. asds often present atypically in children with seizures. However, both groups showed widely varying social and linguistic presentations.

A report: the definition and classification of cerebral palsy April 2006.

For a variety of reasons, the definition and the classification of cerebral palsy (CP) need to be reconsidered. Modern brain imaging techniques have shed new light on the nature of the underlying brain injury and studies on the neurobiology of and pathology associated with brain development have further explored etiologic mechanisms. It is now recognized that assessing the extent of activity restriction is part of CP evaluation and that people without activity restriction should not be included in the CP rubric. Also, previous definitions have not given sufficient prominence to the non-motor neurodevelopmental disabilities of performance and behaviour that commonly accompany CP, nor to the progression of musculoskeletal difficulties that often occurs with advancing age. In order to explore this information, pertinent material was reviewed on July 11-13, 2004 at an international workshop in Bethesda, MD (USA) organized by an Executive Committee and participated in by selected leaders in the preclinical and clinical sciences. At the workshop, it was agreed that the concept 'cerebral palsy' should be retained. Suggestions were made about the content of a revised definition and classification of CP that would meet the needs of clinicians, investigators, health officials, families and the public and would provide a common language for improved communication. Panels organized by the Executive Committee used this information and additional comments from the international community to generate a report on the Definition and Classification of Cerebral Palsy, April 2006. The Executive Committee presents this report with the intent of providing a common conceptualization of CP for use by a broad international audience.

Clinical and MRI correlates of cerebral palsy: the European Cerebral Palsy Study.

CONTEXT: Magnetic resonance imaging (MRI) findings have been reported for specific clinical cerebral palsy (CP) subgroups or lesion types but not in a large population of children with all CP subtypes. Further information about the causes of CP could help identify preventive strategies. OBJECTIVE: To investigate the correlates of CP in a population sample and compare clinical findings with information available from MRI brain studies. DESIGN AND SETTING: Cross-sectional, population-based investigative study conducted in 8 European study centers (North West London and North East London, England; Edinburgh, Scotland; Lisbon, Portugal; Dublin, Ireland; Stockholm, Sweden; Tübingen, Germany; and Helsinki, Finland). PARTICIPANTS: Five hundred eighty-five children with CP were identified who had been born between 1996 and 1999; 431 children were clinically assessed and 351 had a brain MRI scan. MAIN OUTCOME MEASURES: Standardized clinical examination results, parental questionnaire responses, MRI results, and obstetric, genetic, and metabolic data from medical records. RESULTS: Important findings include the high rate of infections reported by mothers during pregnancy (n = 158 [39.5%]). In addition, 235 children (54%) were born at term while 47 children (10.9%) were very preterm (<28 weeks). A high rate of twins was found, with 51 children (12%) known to be from a multiple pregnancy. Clinically, 26.2% of children had hemiplegia, 34.4% had diplegia, 18.6% had quadriplegia, 14.4% had dyskinesia, 3.9% had ataxia, and 2.6% had other types of CP. Brain MRI scans showed that white-matter damage of immaturity, including periventricular leukomalacia (PVL), was the most common finding (42.5%), followed by basal ganglia lesions (12.8%), cortical/subcortical lesions (9.4%), malformations (9.1%), focal infarcts (7.4%), and miscellaneous lesions (7.1%). Only 11.7% of these children had normal MRI findings. There were good correlations between the MRI and clinical findings. CONCLUSIONS: These MRI findings suggest that obstetric mishaps might have occurred in a small proportion of children with CP. A systematic approach to identifying and treating maternal infections needs to be developed. Multiple pregnancies should be monitored closely, and the causes of infant stroke need to be investigated further so preventive strategies can be formulated. All children with CP should have an MRI scan to provide information on the timing and extent of the lesion.

Neurophysiology of circadian rhythm sleep disorders of children with neurodevelopmental disabilities.

This article reviews circadian rhythm sleep disorders (CRSDs) of children with neurodevelopmental disabilities. These sleep disturbances frequently occur in this population but they are misunderstood and under diagnosed. The causes and features of CRSD in children with brain disorders differ in many ways from those seen in typically developing children. It is the brain, including the eyes, which regulates sleep and circadian rhythmicity by modulating pineal melatonin production/secretion and when there is significant brain damage, the sleep/wake patterns may be modified. In most instances CRSD are not disorders of the suprachiasmatic nuclei because these small hypothalamic structures only adjust their functions to the changing photic and non-photic modulatory influences. Each form of CRSD is accompanied by characteristic changes in serum melatonin levels and clinical features. When nocturnal melatonin production/secretion is inappropriately timed or impaired in relation to the environment, timed melatonin replacement therapy will often be beneficial. In this review an attempt is made to clarify the neurophysiological mechanisms underlying the various forms of CRSD because without understanding the photic and non-photic influences on sleep, these sleep disorders can not be fully characterized, defined or even appropriately treated. In the future, the existing definitions for the different forms of CRSD should be modified by experts in pediatric sleep medicine in order to include children with neurodevelopmental disabilities.

Cerebral modulation of circadian sleep-wake rhythms.

The objective of this prospective observational study was to assess the association between dysrhythmia of EEG background (disturbance of cerebral connectivity) and sleep difficulties. Sixty children, aged 4 to 12 years, participated. Hospital records were reviewed, and sleep histories were obtained by interviewing the parents. EEGs of 39 subjects were normal, showed epileptiform activity, and/or mild to moderate background dysrhythmia. Severe unilateral dysrhythmia was noted in 6 and bilaterally in 15 EEGs, with all 15 children having profound neurodevelopmental disabilities and 14 of these 15 having long-standing severe chaotic sleep/wake patterns. Thus, there was a highly significant association between EEG evidence of severe bilateral dysrhythmia and chronic sleep/wake dysregulation. Unilateral dysrhythmia was not associated with sleep difficulties. This study delineates a specific sleep disorder in a group of children with marked neurodevelopmental disabilities and offers insight into how disturbed cerebral connectivity impacts the thalamocortical dynamics relating to neurodevelopmental disabilities, sleep, and melatonin production.

Long-term sleep disturbances in children: a cause of neuronal loss.

Short-term sleep loss is known to cause temporary difficulties in cognition, behaviour and health but the effects of persistent sleep deprivation on brain development have received little or no attention. Yet, severe sleep disorders that last for years are common in children especially when they have neurodevelopmental disabilities. There is increasing evidence that chronic sleep loss can lead to neuronal and cognitive loss in children although this is generally unrecognized by the medical profession and the public. Without the restorative functions of sleep due to total sleep deprivation, death is inevitable within a few weeks. Chronic sleep disturbances at any age deprive children of healthy environmental exposure which is a prerequisite for cognitive growth more so during critical developmental periods. Sleep loss adversely effects pineal melatonin production which causes disturbance of circadian physiology of cells, organs, neurochemicals, neuroprotective and other metabolic functions. Through various mechanisms sleep loss causes widespread deterioration of neuronal functions, memory and learning, gene expression, neurogenesis and numerous other changes which cause decline in cognition, behaviour and health. When these changes are long-standing, excessive cellular stress develops which may result in widespread neuronal loss. In this review, for the first time, recent research advances obtained from various fields of sleep medicine are integrated in order to show that untreated chronic sleep disorders may lead to impaired brain development, neuronal damage and permanent loss of developmental potentials. Further research is urgently needed because these findings have major implications for the treatment of sleep disorders.

Sleep Health Issues for Children with FASD: Clinical Considerations.

This article describes the combined clinical experience of a multidisciplinary group of professionals on the sleep disturbances of children with fetal alcohol spectrum disorders (FASD) focusing on sleep hygiene interventions. Such practical and comprehensive information is not available in the literature. Severe, persistent sleep difficulties are frequently associated with this condition but few health professionals are familiar with both FASD and sleep disorders. The sleep promotion techniques used for typical children are less suitable for children with FASD who need individually designed interventions. The types, causes, and adverse effects of sleep disorders, the modification of environment, scheduling and preparation for sleep, and sleep health for their caregivers are discussed. It is our hope that parents and also researchers, who are interested in the sleep disorders of children with FASD, will benefit from this presentation and that this discussion will stimulate much needed evidence-based research.

Evidence supporting the use of melatonin in short gestation infants.

Pineal melatonin regulates circadian rhythms and influences sleep. Melatonin also has protective actions against tissue damage from free-radicals and other toxins. Evidence is presented that this indoleamine is involved in pre- and postnatal brain (and ocular) development and intrauterine growth. In the absence of maternal melatonin, short gestation infants have a prolonged period of melatonin deficiency. Melatonin supplementation, which has a benign safety profile, may help reduce complications in the neonatal period that are associated with short gestation. We believe that this treatment might result in a wide range of health benefits, improved quality of life and reduced healthcare costs.

Proposed definition and classification of cerebral palsy, April 2005.

Because of the availability of new knowledge about the neurobiology of developmental brain injury, information that epidemiology and modern brain imaging is providing, the availability of more precise measuring instruments of patient performance, and the increase in studies evaluating the efficacy of therapy for the consequences of injury, the need for reconsideration of the definition and classification of cerebral palsy (CP) has become evident. Pertinent material was reviewed at an international symposium participated in by selected leaders in the preclinical and clinical sciences. Suggestions were made about the content of a revised definition and classification of CP that would meet the needs of clinicians, investigators, and health officials, and provide a common language for improved communication. With leadership and direction from an Executive Committee, panels utilized this information and have generated a revised Definition and Classification of Cerebral Palsy. The Executive Committee presents this revision and welcomes substantive comments about it.

Long-term evaluation of the impact of the h1-receptor antagonist cetirizine on the behavioral, cognitive, and psychomotor development of very young children with atopic dermatitis.

The impact of the prolonged use of cetirizine at high dose (0.25 mg/kg twice a day over 18 mo) on behavior and cognitive ability was examined in a double-blind, randomized, placebo-controlled trial (ETAC-Early Treatment of the Atopic Child) designed to establish whether it was possible to prevent young children (1-2 y old at study entry) with atopic dermatitis from developing asthma. Well-validated and standardized measures of behavior (Behavior Screening Questionnaire) and cognition (McCarthy Scales of Children's Abilities) were used. In addition, the ages of attainment of psychomotor milestones were established. These measures were taken between an average of 32 and 53 mo of age, both during the study treatment with cetirizine or placebo and after the study treatment had been discontinued. The Behavior Screening Questionnaire was completed at least once on approximately 300 children in each group and on approximately 200 children on five occasions. The McCarthy Scales of Children's Abilities were administered to approximately 100 in each group at three different times. There were no significant differences between the cetirizine and placebo groups on either of the behavior and cognition measures or in psychomotor milestones during or after the study treatment. These findings suggest that there are no adverse effects on behavior or learning processes associated with the prolonged use of cetirizine in young children with atopic dermatitis.