Sleep Disorders in Neurologic Practice: A Case-based Approach.

Sleep disorders are common in neurology practice, but are often undiagnosed and untreated. Specific patient cohorts, such as older adults, patients residing in nursing homes, and patients with underlying chronic neurologic and psychiatric disorders, are at particular risk. If these sleep problems are not properly evaluated and managed the patient may experience exacerbation of the underlying neurologic disorder. This article highlights some of the key sleep disorders relevant to practicing neurologists, emphasizing hypersomnolence, insomnia, and sleep-related movement disorders in the setting of neurologic disorders to enhance the tools available for evaluation, and discusses management strategies.

Extended wakefulness: compromised metabolics in and degeneration of locus ceruleus neurons.

Modern society enables a shortening of sleep times, yet long-term consequences of extended wakefulness on the brain are largely unknown. Essential for optimal alertness, locus ceruleus neurons (LCns) are metabolically active neurons that fire at increased rates across sustained wakefulness. We hypothesized that wakefulness is a metabolic stressor to LCns and that, with extended wakefulness, adaptive mitochondrial metabolic responses fail and injury ensues. The nicotinamide adenine dinucleotide-dependent deacetylase sirtuin type 3 (SirT3) coordinates mitochondrial energy production and redox homeostasis. We find that brief wakefulness upregulates SirT3 and antioxidants in LCns, protecting metabolic homeostasis. Strikingly, mice lacking SirT3 lose the adaptive antioxidant response and incur oxidative injury in LCns across brief wakefulness. When wakefulness is extended for longer durations in wild-type mice, SirT3 protein declines in LCns, while oxidative stress and acetylation of mitochondrial proteins, including electron transport chain complex I proteins, increase. In parallel with metabolic dyshomeostasis, apoptosis is activated and LCns are lost. This work identifies mitochondrial stress in LCns upon wakefulness, highlights an essential role for SirT3 activation in maintaining metabolic homeostasis in LCns across wakefulness, and demonstrates that extended wakefulness results in reduced SirT3 activity and, ultimately, degeneration of LCns.

Effects of chronic sleep fragmentation on wake-active neurons and the hypercapnic arousal response.

STUDY OBJECTIVES: Delayed hypercapnic arousals may occur in obstructive sleep apnea. The impaired arousal response is expected to promote more pronounced oxyhemoglobin desaturations. We hypothesized that long-term sleep fragmentation (SF) results in injury to or dysfunction of wake-active neurons that manifests, in part, as a delayed hypercapnic arousal response. DESIGN: Adult male mice were implanted for behavioral state recordings and randomly assigned to 4 weeks of either orbital platform SF (SF4wk, 30 events/h) or control conditions (Ct4wk) prior to behavioral, histological, and locus coeruleus (LC) whole cell electrophysiological evaluations. MEASUREMENTS AND RESULTS: SF was successfully achieved across the 4 week study, as evidenced by a persistently increased arousal index, P < 0.01 and shortened sleep bouts, P < 0.05, while total sleep/wake times and plasma corticosterone levels were unaffected. A multiple sleep latency test performed at the onset of the dark period showed a reduced latency to sleep in SF4wk mice (P < 0.05). The hypercapnic arousal latency was increased, Ct4wk 64 ± 5 sec vs. SF4wk 154 ± 6 sec, P < 0.001, and remained elevated after a 2 week recovery (101 ± 4 sec, P < 0.001). C-fos activation in noradrenergic, orexinergic, histaminergic, and cholinergic wake-active neurons was reduced in response to hypercapnia (P < 0.05-0.001). Catecholaminergic and orexinergic projections into the cingulate cortex were also reduced in SF4wk (P < 0.01). In addition, SF4wk resulted in impaired LC neuron excitability (P < 0.01). CONCLUSIONS: Four weeks of sleep fragmentation (SF4wk) impairs arousal responses to hypercapnia, reduces wake neuron projections and locus coeruleus neuronal excitability, supporting the concepts that some effects of sleep fragmentation may contribute to impaired arousal responses in sleep apnea, which may not reverse immediately with therapy.

C/EBP homologous binding protein (CHOP) underlies neural injury in sleep apnea model.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with cognitive impairment and neuronal injury. Long-term exposure to intermittent hypoxia (LTIH) in rodents, modeling the oxygenation patterns in sleep apnea, results in NADPH oxidase 2 (Nox2) oxidative injury to many neuronal populations. Brainstem motoneurons susceptible to LTIH injury show uncompensated endoplasmic reticulum stress responses with increased (CCAAT/enhancer binding protein homologous protein (CHOP). We hypothesized that CHOP underlies LTIH oxidative injury. In this series of studies, we first determined whether CHOP is upregulated in other brain regions susceptible to LTIH oxidative Nox2 injury and then determined whether CHOP plays an adaptive or injurious role in the LTIH response. To integrate these findings with previous studies examining LTIH neural injury, we examined the role of CHOP in Nox2, hypoxia-inducible factor-1α (HIF-1α) responses, oxidative injury and apoptosis, and neuron loss. DESIGN: Within/between mice subjects. SETTING: Laboratory setting. PARTICIPANTSSUBJECTS: CHOP null and wild-type adult male mice. INTERVENTIONS: LTIH or sham LTIH. MEASUREMENTS AND MAIN RESULTS: Relative to wild-type mice, CHOP-/- mice conferred resistance to oxidative stress (superoxide production/ carbonyl proteins) in brain regions examined: cortex, hippocampus, and motor nuclei. CHOP deletion prevented LTIH upregulation of Nox2 and HIF-1α in the hippocampus, cortex, and brainstem motoneurons and protected mice from neuronal apoptosis and motoneuron loss. CONCLUSIONS: Endogenous CHOP is necessary for LTIH-induced HIF-1α, Nox2 upregulation, and oxidative stress; CHOP influences LTIH-induced apoptosis in neurons and loss of neurons. Findings support the concept that minimizing CHOP may provide neuroprotection in OSA.

Sleep-disordered breathing.

PURPOSE OF REVIEW: This article introduces readers to the clinical presentation, diagnosis, and treatment of sleep-disordered breathing and reviews the associated risk factors and health consequences. RECENT FINDINGS: Sleep-disordered breathing is associated with significant impairments in daytime alertness and cognitive function as well as adverse health outcomes. The initial treatment of choice is positive airway pressure. Improvements in technology and mask delivery systems have helped to make this treatment more comfortable and convenient for many patients. SUMMARY: Sleep-disordered breathing, particularly in the form of obstructive sleep apnea, is highly prevalent in the general population and has important implications for neurology patients. Sleep-disordered breathing is characterized by repetitive periods of cessation in breathing, termed apneas, or reductions in the amplitude of a breath, known as hypopneas, that occur during sleep. These events are frequently associated with fragmentation of sleep, declines in oxygen saturation, and sympathetic nervous system activation with heart rate and blood pressure elevation. Obstructive sleep apnea, which represents cessation of airflow, develops because of factors such as anatomic obstruction of the upper airway related to obesity, excess tissue bulk in the pharynx, and changes in muscle tone and nerve activity during sleep. Central sleep apnea represents cessation of airflow along with absence or significant reduction in respiratory effort during sleep and is more commonly found in the setting of congestive heart failure, neurologic disorders, or cardiopulmonary disease.

Daytime sleepiness in obesity: mechanisms beyond obstructive sleep apnea--a review.

Increasing numbers of overweight children and adults are presenting to sleep medicine clinics for evaluation and treatment of sleepiness. Sleepiness negatively affects quality of life, mental health, productivity, and safety. Thus, it is essential to comprehensively address all potential causes of sleepiness. While many obese individuals presenting with hypersomnolence will be diagnosed with obstructive sleep apnea and their sleepiness will improve with effective therapy for sleep apnea, a significant proportion of patients will continue to have hypersomnolence. Clinical studies demonstrate that obesity without sleep apnea is also associated with a higher prevalence of hypersomnolence and that bariatric surgery can markedly improve hypersomnolence before resolution of obstructive sleep apnea. High fat diet in both humans and animals is associated with hypersomnolence. This review critically examines the relationships between sleepiness, feeding, obesity, and sleep apnea and then discusses the hormonal, metabolic, and inflammatory mechanisms potentially contributing to hypersomnolence in obesity, independent of sleep apnea and other established causes of excessive daytime sleepiness.

SIRT1 regulation of wakefulness and senescence-like phenotype in wake neurons.

Wake neurons in the basal forebrain and brainstem provide critical inputs to optimize alertness and attention. These neurons, however, evidence heightened vulnerability to a diverse array of metabolic challenges, including aging. SIRT1 is an nicotinamide adenine dinucleotide responsive deacetylase serving diverse adaptive responses to metabolic challenges, yet this metabolic rheostat may be downregulated under conditions of significant oxidative stress. We hypothesized that SIRT1 might serve as a critical neuroprotectant for wake neurons in young animals but that this protectant would be lost upon aging, rendering the neurons more vulnerable to metabolic insults. In this collection of studies, we first established the presence of nuclear SIRT1 in wake neurons throughout the forebrain and brainstem. Supporting functional and behavioral roles for SIRT1 in wake-active neurons, transgenic whole animal, and conditional loss of brain SIRT1 in the adult mouse impart selective impairments in wakefulness, without disrupting non-rapid eye movement or rapid eye movement sleep. Populations of wake neurons, including the orexinergic, locus ceruleus, mesopontine cholinergic, and dopaminergic wake neurons, evidence loss of dendrites and neurotransmitter synthesis enzymes and develop accelerated accumulation of lipofuscin, consistent with a senescence-like phenotype in wake neurons. Normal aging results in a progressive loss of SIRT1 in wake-active neurons, temporally coinciding with lipofuscin accumulation. SIRT1 is a critical age-sensitive neuroprotectant for wake neurons, and its deficiency results in impaired wakefulness.

Review of sleep disorders.

Sleep disorders are common and may result in significant morbidity. Examples of the major sleep disturbances in primary care practice include insomnia; sleep-disordered breathing, such as obstructive sleep apnea; central nervous system hypersomnias, including narcolepsy; circadian rhythm sleep disturbances; parasomnias, such as REM sleep behavior disorder; and sleep-related movement disorders, including restless legs syndrome. Diagnosis is based on meticulous inventory of the clinical history and careful physical examination. In some cases referral to a sleep laboratory for further evaluation with polysomnography, a sleep study, is indicated.