Reviews for Primary Care - Fall 2007 - (Page 42) Insomnia and Neurological Disorders continued Circadian Rhythm Disruption Atrophy of the SCN APOE4 genotype Degeneration of cholinergic neurons in the nucleus basalis of Meynert Degeneration of respiratory neurons: Degeneration of the brainstem respiratory neurons and the supramedullary respiratory pathways Degeneration of the Perilocus coeruleus Degeneration of the supraspinal autonomic neurons pedunculopontine tegmental and laterodorsal tegmental nuclei Reduced REMsleep % REM without atonia RBD Autonomic dysfunction Increased risk for sleep-disordered breathing Figure 2. Pathophysiology of sleep disturbances in neurodegenerative disorders: direct mechanisms. The broken arrow demonstrates a hypothetical relationship. RBD, rapid eye movement sleep behavior disorder; REM, rapid eye movement; SCN, suprachiasmatic nucleus. Modified from Figure 1 in Avidan A. Sleep in dementia and other neurodegenerative disorders. In: Culebras A, ed. Sleep Disorders and Neurologic Diseases, 2nd ed. New York: Taylor & Francis Group; submitted for publication. risk for additional sleep disturbances, such as obstructive sleep apnea (OSA) and periodic limb movement disorder of sleep (PLMS), which occur at higher incidence with aging. Many of these sleep disruptions can cause considerable caregiver burden and may put the patient at increased risk for institutionalization.6,7 Alzheimer’s Disease In Alzheimer’s disease (AD), degeneration of the neurons of the SCN may be responsible for the circadian rhythm abnormalities seen in sundowning syndrome, and may be a cofactor in inducing insomnia and other sleep-wake schedule disturbances (Figure 2).1,2 The severity of circadian rhythm disturbances was correlated with the severity of dementia.8,9 Polysomnographic recordings in patients with dementia consistently demonstrate increased diffuse slow wave activity, decreased sleep efficiency, and reversal of circadian rhythmicity. This reversal is the second most common cause of institutionalization after incontinence.10 Direct mechanisms of insomnia in AD are related to the degeneration of the cholinergic neurons in the nucleus basalis of Meynert, pedunculopontine tegmental, laterodorsal tegmental nuclei, and noradrenergic neurons of the brainstem, which may be responsible for decreased rapid eye movement (REM) sleep in AD patients.1,2 Indirect mechanisms of sleep disruption in AD include medicationrelated side effects; underlying psychiatric diagnosis, such as mood disorders; increasing incidence of PLMS in elderly AD patients; and agerelated alterations in sleep. Insomnia may be complicated by agents prescribed for the specific management of underlying neurodegenerative dis- eases. Targeted pharmacotherapy for AD can precipitate insomnia. A prime example is tacrine (a centrally acting cholinesterase inhibitor), which is notorious for causing insomnia. Patients with AD and dementias suffer from mood disturbances that can induce insomnia.11,12 Insomnia is also a common and unpleasant side effect of antidepressant therapy. Other indirect mechanisms include general medical diseases affecting the cardiovascular and respiratory systems and environmental factors such as insufficient or dim light and excessive environmental noise in nursing homes or other long-term-care institutions (Figure 1). Patients with AD have significant sleep architecture abnormalities. The hallmarks include reduction in sleep efficiency, increase in non-REM stage 1 sleep, increase in arousal and awakening frequency, decrease in total sleep time, and reduction in sleep spindles and K complexes. A profound disruption in sleep-wake rhythmicity occurs primarily early, at the onset of the disease. Sleep fragmentation subsequently leads to increased daytime sleepiness; nocturnal insomnia; nocturnal wandering; increases in cognitive decline, number of daytime naps, time in bed and time spent awake in bed, and frequency of nocturnal wandering; disorientation; and confusion.2,13-18 Later, as the disease progresses, patients with AD manifest more dramatic reduction of REM sleep, increased REM sleep latency, and a marked alteration of the circadian rhythm, resulting in sleepiness.1 In fact, sleep and cognitive dysfunction are positively correlated in AD. The treatment of sleep problems in AD involves a combined multidisciplinary approach including a behavioral approach, pharmacotherapy, and in some cases, light therapy. As a general rule, the time in bed should be 42 VOL. 1 NO. 1 2007 REVIEWS FOR PRIMARY CARE
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