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.

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.

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.

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.

Is mechanical embolectomy performed in nonanesthetized patients effective?

BACKGROUND AND PURPOSE: In centers performing endovascular treatment for patients with AIS, there is variability in placing patients under general anesthesia. Nonanesthetized patients might move during the procedure leading to complications and prolonging the time to revascularization due to lack of cooperation. However, general anesthesia can lead to a delay of the procedure, an inability to assess the patient during the procedure, and fluctuations of blood pressure. Our center does not routinely either use general anesthesia or sedate patients. We report our experience with nonanesthetized patients undergoing emergent mechanical embolectomy. MATERIALS AND METHODS: We performed a retrospective analysis of 66 consecutive patients enrolled in the MERCI Registry at our center from June 2007 to June 2009. A univariate statistical analysis was performed by using the Fisher exact test for categoric variables and the Student t test for continuous variables in comparing use of general anesthesia with nonanesthetized patient demographics, procedural times, procedural complications, good outcome, and mortality. RESULTS: Nine patients (13.6%) were placed under general anesthesia, and 57 (86.4%) were awake. Higher baseline NIHSS scores and older age were statistically associated with general anesthesia. No significant difference occurred between groups in the time to groin puncture or procedural times. Revascularization rates were 77% for general anesthesia patients and 70% for nonanesthetized patients (P = .331). The nonanesthetized group had better outcomes, but we did not control these outcomes for other factors. Complications were much more frequent in the general anesthesia patients (22%) than in the nonanesthetized patients (3.5%) (P = .0288). CONCLUSIONS: Performing mechanical embolectomy in nonanesthetized patients at our institution does not prolong procedure time, decrease revascularization rates, increase complication rates, or decrease good outcome. Mechanical embolectomy in nonanesthetized patients is effective and should be considered an option in the treatment of the patient with AIS.

Acutely ruptured intracranial saccular aneurysms treated with stent assisted coiling: complications and outcomes in 42 consecutive patients.

BACKGROUND: Antiplatelet agents are required to prevent thromboembolic complications from recently deployed intracranial stents, yet they carry a risk of bleeding complications that may be serious in patients with recent subarachnoid hemorrhage. METHOD: Consecutive patients at a single institution who had ruptured intracranial saccular aneurysms treated with stent assisted coiling were retrospectively reviewed. Our primary outcomes were ischemic stroke related to the stent and bleeding complications possibly related to antithrombotic therapy. Secondary outcomes included 3 month follow-up National Institute of Health Stroke Scale (NIHSS) scores and modified Rankin Scale (mRS) scores. RESULTS: 44 aneurysms in 42 patients were treated. Seven patients experienced ischemic strokes during their hospitalization. Five ischemic strokes were secondary to vasospasm; one was definitely related to thrombus formation within the stent and one was possibly related to the stent. Two patients had asymptomatic intracranial hemorrhages and one patient had a symptomatic intracranial hemorrhage. Patients with Hunt and Hess grades I-II (n=25) experienced no stent associated ischemic strokes or symptomatic intracranial hemorrhages. The two stent associated ischemic strokes and one symptomatic intracranial hemorrhage occurred in patients with Hunt and Hess grades III-V (n=17) and patients with external ventricular drains (EVDs) (n=17). Only one patient had disability at the 3 month follow-up that was possibly related to the stent (mRS score of 3 and NIHSS score of 2). CONCLUSION: These data suggest that higher grade hemorrhage patients, especially those with EVDs, are at greater risk for ischemic stroke and/or bleeding complications than lower grade patients. However, the complications had a small impact on mid-term disability outcomes in this cohort.

Pathological laughter and crying: a link to the cerebellum.

Patients with pathological laughter and crying (PLC) are subject to relatively uncontrollable episodes of laughter, crying or both. The episodes occur either without an apparent triggering stimulus or following a stimulus that would not have led the subject to laugh or cry prior to the onset of the condition. PLC is a disorder of emotional expression rather than a primary disturbance of feelings, and is thus distinct from mood disorders in which laughter and crying are associated with feelings of happiness or sadness. The traditional and currently accepted view is that PLC is due to the damage of pathways that arise in the motor areas of the cerebral cortex and descend to the brainstem to inhibit a putative centre for laughter and crying. In that view, the lesions 'disinhibit' or 'release' the laughter and crying centre. The neuroanatomical findings in a recently studied patient with PLC, along with new knowledge on the neurobiology of emotion and feeling, gave us an opportunity to revisit the traditional view and propose an alternative. Here we suggest that the critical PLC lesions occur in the cerebro-ponto-cerebellar pathways and that, as a consequence, the cerebellar structures that automatically adjust the execution of laughter or crying to the cognitive and situational context of a potential stimulus, operate on the basis of incomplete information about that context, resulting in inadequate and even chaotic behaviour.

Trypsin and chymotrypsin inhibitor of Vigna unguiculata seeds--involvement of tyrosyls in its interaction with proteases.

When trypsin and chymotrypsin inhibitor of Vigna unguiculata seeds (black-eyed pea trypsin and chymotrypsin inhibitor, BTCI) combines with beta-trysin, 4.0, 4.5, 5.0, 5.8, and 6.6 tyrosyl residues are shielded from reaction with N-acetylimidazole, at reagent/protein molar ratios of 60, 120, 200, 350 and 500, respectively. This may result from the presence of tyrosyl residues in the zone of contact between enzyme and inhibitor. In the interaction of BTCI and alpha-chymotrypsin, only 0.6 tyrosyl residues are shielded from the reaction with N-acetylimidazole, at a 500-fold reagent molar excess.