SECTION 5 - SLEEP DISORDERS

Sleep in other Neurological Disorders

Background

Sleep disturbances and sleep disorders are commonly associated with neurological diseases, and neurological impairments of sleep reveal much about the brain circuitry involved in sleep regulation. Many neurological disorders are now recognized to cause disruptions of sleep. For example, pathological sleepiness is associated with neurological and neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and progressive supranuclear palsy. Pathological sleepiness is also associated with neuromuscular disorders such as myotonic dystrophy, inflammatory conditions such as encephalitis or multiple sclerosis, and with traumatic or ischemic injury to the brain. In addition, conditions such as REM Sleep Behavior Disorder (RBD) are recognized as precursors of Parkinson's disease. Conversely, Fatal Familial Insomnia (FFI), a prion disorder related to Creutzfeldt-Jakob disease, causes prolonged wakefulness.

Sleep is a powerful modulator of epilepsy, with some epilepsy syndromes occurring exclusively or predominantly during sleep. These include benign childhood epilepsy with centrotemporal spikes, autosomal dominant nocturnal frontal lobe epilepsy, and continuous spike-wave activity during sleep. Sleep deprivation has also been described as a risk factor for epileptic seizures, although alcohol use and work-related stress are confounding factors. Treatment of sleep disorders that fragment sleep, such as Sleep-Disordered Breathing (SDB), has improved seizure control in case series.

Sleep disorders can also occur as a consequence of treating neurological disorders. For example, pathological sleepiness may occur during treatment of Parkinson's disease and other movement disorders with dopamine-related drugs. In addition, many drugs used to treat neurological disorders can cause excessive sleepiness or wakefulness.

Sleep disorders also interact in complex ways with neurological disorders, and are frequent after head trauma, stroke, encephalitis or in association with neuromuscular disorders. For example, stroke has been shown to be associated with SDB, and SDB likely decreases potential for recovery in stroke patients. Stroke may also produce SDB by interacting with the central regulation of breathing. Similarly, the intermittent hypoxia that accompanies SDB may hasten the neurodegenerative cascade in disorders such as PD and AD.

Neurological disorders provide models for understanding sleep circuitry in the brain. In addition, understanding sleep mechanisms and disorders will be integral to treating these neurological diseases.

Progress In The Last 5 Years

- Studies of patients with Parkinson's disease reveal a range of sleep disorders, including PLMS, RBD and daytime sleepiness. These disorders are part of the disease spectrum, occur commonly, and suggest an important role for dopaminergic pathways in sleep/wake regulation. Dopamine-like drugs are useful in treating these disorders, and it is recognized that when these drugs stimulate dopamine D2/D3 receptors they can cause "attacks" of excessive sleepiness and hence result in automobile and other accidents.

- An important advance has been the empirical application of wake-promoting drugs to treat sleep disorders in various neurological conditions. The use of wake-promoting compounds in treating fatigue and sleepiness in various neurological disorders such as Parkinson's disease, head trauma and multiple sclerosis is increasing but these treatments deserve controlled study.

- Vagus nerve stimulation (VNS), an approved treatment for medically refractory epilepsy, has been shown to cause apneas and shallow breaths (hypopneas) during sleep, but these effects are ameliorated by reducing VNS stimulus frequency. In addition, VNS has been shown to reduce daytime sleepiness in epilepsy patients. These findings emphasize the interconnections of the vagus nerve with brainstem networks that regulate respiration and alertness.

- Advances in all of these disorders depend upon understanding the brain circuitry involved in sleep regulation. The last five years have seen the elucidation of important components of the wake and sleep promoting circuitry in the hypothalamus and the brainstem. Drug development is currently under way to take advantage of this new information in order to treat pathological wakefulness or sleepiness, and to cause sedation when necessary with fewer side effects.

Research Recommendations

- Evaluate the prevalence and impact of sleep disorders and disturbances in neurological conditions, such as neurodegenerative disorders (e.g. Alzheimer's disease, Parkinson's disease), movement disorders, post head trauma, encephalitis, stroke, and epilepsy. These studies should evaluate whether sleep disorders predispose to specific neurological conditions, whether neurological conditions can produce sleep disorders, and whether sleep disorders impair recovery from selected neurological disorders. Studies of sleep in animal models of neurological disorders should also be conducted.

- Study natural models of locally disrupting sleep circuits (tumors, trauma, multiple sclerosis plaques, infarcts, neurodegenerative conditions, paraneoplastic syndrome, etc.). Studies should be performed that combine imaging techniques or neuropathology with sleep/sleep disorders analyses.

- Study the impact of pharmacological and non-pharmacological neurological treatments on sleepiness and sleep (for example, in epilepsy, multiple sclerosis, Parkinson's disease).

- Study sleep and sleepiness in inflammatory states (encephalitis, infarcts, multiple sclerosis, autoimmune disorders etc.).

- Determine if sleep disruption due to sleep disorders or sleep deprivation lowers the threshold for epileptic seizures, and explore the mechanisms responsible for this effect.

- Perform controlled studies to determine if treatment of sleep disorders improves seizure control.