Sleep and Neurologic Disorders

Chapter 

31 

Sleep and Neurologic Disorders

Chapter Points • AD is the most common cause of dementia and can be associated with the irregular sleep-wake rhythm disorder and sundowning. In early AD, there is a decrease in stage N3. In late AD, there is a decrease in REM sleep and an increase in the REM latency. • OSA is common in AD patients and, if successfully treated with CPAP, can improve sleep quality and mood as well as slow the rate of cognitive decline. • Donepezil (Aricept), a cholinesterase inhibitor, is used in AD to improve cognition but is often associated with insomnia. Morning dosing is suggested to minimize sleep disturbance. Some studies have suggested that evening doses of rivastigmine and galantamine can improve sleep quality. Cholinesterase inhibitors and cholinergic medications in general tend to increase REM sleep. Rivastigmine has been reported to cause RBD in AD patients. • PSP is characterized by vertical gaze palsy and prominent sleep-maintenance insomnia (worse than in AD) and nocturia. PSP patients have a large reduction in the amount of REM sleep. PSG will often show absence of vertical eye movements during REM sleep. RBD occurs in approximately 13% to 30% of PSP patients. • The sleep of patients with PD is impaired by rigidity, tremor (tends to resolve with sleep onset), dyskinesias, OSA, RBD, and nocturnal hallucinations. Patients with PD can manifest excessive daytime sleepiness even if OSA is not present. Modafinil may be helpful, although the published evidence is conflicting. • PD+ disorders are manifested by parkinsonism (bradykinesia and rigidity), no or decreased response to levodopa, sensitivity to dopamine blockers, and a more rapid course than PD. PD+ disorders include PSP, DLBD, and MSA. • Patients with DLBD have prominent dementia much earlier in the disease course compared with PD. The patients frequently have visual hallucinations and are exquisitely sensitive to dopamine blockers (can

develop severe rigidity). The RBD is common in patients with DLBD. • MSA patients have various amounts of striatonigral degeneration (rigidity and bradykinesia), olivopontocerebellar degeneration (cerebellar dysfunction, ataxia, falls), and autonomic dysfunction (erectile dysfunction, orthostatic hypotension, bladder dysfunction). The RBD is very common in MSA patients. • Stridor (especially during sleep) is a well-known manifestation of MSA and denotes a poor prognosis. • FFI is a familial autosomal dominant prion disease with progressive insomnia and dementia. PET shows a characteristic absent or very low activity of the thalamus. • There is a high prevalence of sleep apnea in patients who have had a recent stroke. OSA is the most common form of sleep apnea but central sleep apnea (including CSB) can occur. If OSA is present, this is associated with a worse prognosis but CPAP treatment can improve outcomes.

SLEEP AND NEURODEGENERATIVE DISORDERS Sleep complaints are very common in patients with neurodegenerative disorders (Box 31–1). Some basic knowledge about these disorders is essential for the sleep clinician. The major neurodegenerative disorders are discussed briefly with an emphasis on the effects on sleep.

Synucleopathies The synucleopathies are chronic and progressive disorders associated with a decline in cognitive, behavioral, and autonomic functions.1,2 The two major categories are taupathies and alpha synucleopathies (Table 31–1). The taupathies are disorders associated with intracellular disposition of abnormally phosphorylated tau (a microtubule-associated protein) usually expressed as neurofibrillary tangles, neurophil threads, and abnormal tau filaments (Pick bodies). Tau 631

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BOX 31–1 

BOX 31–2 

Sleep Disorders in Neurodegenerative Disorders

Major Dementias

• Insomnia—sleep onset, sleep maintenance, fragmented sleep • Hypersomnia • Sleep apnea syndromes • Hypersomnia due to the neurologic disorder • Excessive nocturnal motor activity (including RBD) • Circadian rhythm disorders • Sundowning

• Alzheimer’s disease (60–80%) • Diffuse Lewy body dementia (20%) • Others (vascular, metabolic)

RBD = rapid eye movement sleep behavior disorder.

TABLE 31–1 

Neurodegenerative Disorders TAUPATHIES

ALPHA SYNUCLEOPATHIES

• Alzheimer’s disease (AD) • Parkinson’s disease (PD) • Progressive supranuclear • Diffuse Lewy body dementia palsy (PSP) (DLBD) • Corticobasal degeneration • Multiple system atrophy (CBD) (MSA) • Frontotemporal dementia (FTD) • Pick’s disease

proteins are involved in maintaining the cell shape and serve as tracks for axonal transport. The taupathy disorders include Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD), and Pick’s disease. Alpha synuclein is a protein that helps in the transportation of dopamine-laden vesicles from the cell body to the synapses. The alpha synucleopathies include Parkinson’s disease (PD), diffuse Lewy body dementia (DLBD), and multiple system atrophy (MSA).

Dementias Dementia is defined as a clinical syndrome characterized by acquired loss of cognitive and emotional abilities severe enough to interfere with daily functioning.1,2 In evaluating any patients with dementia, it is important to rule out treatable causes including medication side effects, hypothyroidism, vitamin B12 deficiency, depression, and occult obstructive sleep apnea (OSA). Pseudodementia of the elderly is due to depression and can be associated with a short rapid eye movement (REM) latency and high REM density. In contrast, patients with AD tend to have a low REM density, long REM latency, and a reduction in the amount of REM sleep. AD is by far the most common cause of dementia with DLBD the next most common (Box 31–2).

Alzheimer’s Disease AD is the most common cause of dementia (>60% of dementias). The diagnosis is one of exclusion. The hallmark is a

gradual onset of short-term memory problems. The APO4E genotype is a risk factor for AD. Sleep disturbance worsens in parallel with cognitive dysfunction. Patients with AD suffer from sundowning (Box 31–3), which is defined as nocturnal exacerbation of disruptive behavior or agitation in older patients. This is likely the most common cause of institutionalization in patients with AD. Some of the key points concerning AD are listed in Box 31–4. Etiology of Sleep Disturbances in AD  A number of factors may

contribute to sleep disturbance in AD. Degeneration of neurons in a number of areas including the optic nerve, retinal ganglion cells, and suprachiasmatic nucleus may contribute to circadian rhythm disturbances in AD.3–5 These patients may manifest the irregular sleep-wake rhythm disorder. Institutional factors can worsen circadian rhythm disorders by decreasing normal zeitgebers (light and activity) and disturbing nocturnal sleep (noise). Poor sleep hygiene including daytime sleeping and decreased physical activity may also impair sleep-wake rhythms.

Sleep Disturbances in AD  A number of sleep disturbances are present in AD and vary with the course of the illness (Table 31–2). Early in the illness, there is disruption of sleep-wake rhythms, nocturnal awakenings, and decreased stage N3 sleep. Late in the disease course, there is a reduction in REM sleep and increased REM latency as well as excessive daytime sleepiness. Whereas both OSA and medications can contribute to daytime sleepiness in AD patients, sleepiness can occur simply as a manifestation of AD. The disruption of the sleep-wake rhythms manifests itself with large amounts of daytime sleep and often an irregular sleep-wake rhythm disorder. As noted previously, there is degeneration of both the suprachiasmatic nucleus (SCN) neurons and the pineal neurons. Recently, a decrease in melatonin MT1 receptors in the SCN has been demonstrated.5 This could be one reason for the poor response to melatonin in AD. A large multicenter trial of melatonin did not show an improvement in elderly patients in group facilities.6 A recent study in AD found that combined bright light and melatonin decreased aggressive behavior and modestly improved sleep efficiency and decreased nocturnal restlessness.7 OSA in AD  OSA is common among patients with AD, and several studies have suggested that continuous positive airway pressure (CPAP) treatment of AD patients with OSA can slow the deterioration of cognition and improve sleep and mood.8

Chapter 31    Sleep and Neurologic Disorders

BOX 31–3 

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BOX 31–5 

Sundowning Definition: Nocturnal exacerbation of disruptive behavior or agitation in older patients Factors • Early bedtime • Use of sedatives • Advanced cognitive impairment • Associated medical conditions

BOX 31–4 

Alzheimer’s Disease • Most common cause of dementia (60% of cases of dementia) • Progressive intellectual deterioration in middle to late adult life • RBD much less common than in other causes of dementia • Sundowning common • Treatment is with cholinergic medications RBD = rapid eye movement sleep behavior disorder.

TABLE 31–2 

Sleep Disturbance in Alzheimer’s Disease EARLY AD

LATE AD

Disruption of sleep-wake rhythms

Reduction in REM

Increased nocturnal awakenings

Increased REM latency

Decreased stage N3

EDS and daytime napping— not associated with OSA or medications

AD = Alzheimer’s disease; EDS = excessive daytime sleepiness; OSA = obstructive sleep apnea; REM = rapid eye movement.

Treatment of AD  Patients with AD have reduced cerebral pro-

duction of choline acetyl transferease, which leads to a decrease in acetylcholine synthesis and impaired cortical cholinergic function. Cholinergic medications (cholinesterase inhibitors) are used to treat AD and are beneficial.9 However, cholinergic medications can cause sleep disturbance. The cholinergic medications used to treat AD include donepezil (Aricept), rivastigmine (Excelone), and galantamine (Razadyne, formerly Reminyl). The dosage of the medications is listed in Appendix 31–1. The cholinesterase inhibitors tend to increase REM sleep. Memantine (Namenda), an N-methyl-D-aspartate (NMDA) receptor antagonist, is approved for treatment of moderate to severe AD. It is thought to prevent excitotoxicity from excessive glutamate actions at NMDA receptors that can cause neuronal dysfunction. Memantine’s side effects

Sleep Disturbance in Progressive Supranuclear Palsy • Sleep disturbance present in most patients (>50%) • Insomnia is the most common sleep disorder (more severe than in AD or PD). • RBD occurs (13–30%)—tends to start concomitantly or soon after onset of PSP (unlike RBD in PD, which starts BEFORE manifestations of motor and cognitive dysfunction). • Factors leading to insomnia • Immobility in bed. • Difficulty with transfer. • Frequent nocturia. AD = Alzheimer’s disease; PD = Parkinson’s disease; PSP = progressive supranuclear palsy; RBD = rapid eye movement sleep behavior disorder.

include hallucinations and dizziness (most common side effect). Treatment with memantine can be combined with a cholinesterase inhibitor. Some studies have shown a benefit from combined treatment. Medication-Induced Insomnia in AD  Donepezil (Aricept) up to

10 mg has been associated with incident insomnia up to 18%. Morning dosing of donepezil is recommended to minimize insomnia. Whereas donepezil is a once-a-day medication, rivastigmine is bid to tid and must be titrated up slowly. Rivastigmine and galantamine have more gastrointestinal side effects than donepezil. The sleep of some AD patients may improve with evening doses of galantamine or rivastigmine.10,11 Stahl and coworkers10 reviewed the results of double-blind studies of galantamine and found no higher incidence of sleep side effects than with placebo. Rivastigmine improved sleep complaints in some studies.11,12 Whereas cholinesterase inhibitors have been reported to improve rapid eye movement sleep behavior disorder (RBD) in idiopathic RBD patients, rivastigmine has been reported to cause RBD in patients with AD.13

Progressive Supranuclear Palsy PSP is characterized by supranuclear extraocular gaze palsy. Manifestations include a pseudobulbar palsy (upper neuron lesion to corticobulbar tract with dysarthria and choking), akinetic rigidity, ataxic gait and falling, limb and axial rigidity, and frontal lobe type dementia. There is a lack of response to dopaminergic medications.1,2 Sleep disturbance will be present in most patients (Box 31–5). Insomnia is the most common complaint (worse than in AD or PD). Patients have an absence or a drastic reduction in REM sleep. Nocturia is a common problem. One study comparing patients with AD and PSP found unsuspected OSA in approximately 50% of both groups.14,15 A high and nearly equal percentage of both groups had REM sleep without atonia. However, clinical RBD was less common in PSP than in PD (7/20 vs. 13/20). If RBD is present in PSG,

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it presents concomitantly with other findings. In contrast, RBD can occur many years before the onset of PD. Physical Examination  Impaired voluntary vertical gaze espe-

cially in downward direction is an early finding.

Epidemiology in PSP  Patients with PSP have a mean age of 63

and the mean survival from symptoms is 9 years.

Histology  Tau-positive neurofibrillary tangles are present in multiple subcortical nuclei including the locus coeruleus. There is relative preservation of the hippocampus and cortex. Sleep in PSP  PSP patients have severe sleep-maintenance

insomnia (worse than PD). Sleep complaints in PSP include an increased sleep latency, increased arousals, increased awakening frequency, decreased REM sleep, and increased REM latency.14,15

Polysomnography in PSP  Polysomnography (PSG) reveals

absence of vertical eye movements during REM sleep. Horizontal movements are present but are slower.

Corticobasal Degeneration CBD is a neurodegenerative disorder characterized by progressive asymmetrical rigidity, apraxia, and other findings reflecting cortical and basal ganglia dysfunction.1,2 Taupositive astrocytic threads and oligodendral coiled bodies are noted. Apraxia is characterized by loss of the ability to execute or carry out learned purposeful movements, despite having the desire and the physical ability to perform the movements. It is a disorder of motor planning, which may be acquired or developmental but may not be caused by incoordination.

Frontotemporal Dementia FTD is a type of cortical dementia resembling AD.1,2 It is characterized by insidious onset, early loss of insight, social decline, emotional blunting, relative preservation of perception and memory, perseverance, and echolalia. Computed tomography (CT) or magnetic resonance imaging (MRI) shows frontal or anterior temporal atrophy.

Parkinsonism Syndromes (PD, PD+) The term parkinsonism is used to refer to a group of manifestations including tremor, rigidity, bradykinesia, and postural instability. Parkinsonism is found in both PD and Parkinson Plus (PD+) disorders (Box 31–6).16,17 The PD+ disorders include those characterized by parkinsonism and other manifestations. The PD+ disorders include PSP, DLBD, and MSA. Of note, the brains of PD patients do have Lewy bodies (LBs), but in DLBD, the distribution of LBs is more dense and more diverse. DLBD patients have more prominent dementia than noted in patients with PD. The dementia

BOX 31–6 

Disorders Associated with Parkinsonism Parkinsonism = tremor, rigidity, bradykinesia, and postural instability Disorders with parkinsonism • PD—also known as idiopathic parkinsonism • PD+—disorders with parkinsonism + other manifestations • PSP • CBD • DLBD • MSA • Medication side effects (dopamine blockers) • Wilson’s disease (hereditary copper accumulation)— presents in younger patients with parkinsonism features, diagnosis by slit lamp examination showing KayserFleischer rings CBD = corticobasal degeneration; DLBD = diffuse Lewy body dementia; MSA = multiple system atrophy; PD = Parkinson’s disease; PSP = progressive supranuclear palsy.

of DLBD also present much earlier in the course of the disease than the dementia associated with PD. However, there is overlap between PD and DLBD. The PD+ disorders tend to progress more quickly than PD. The typically antiParkinson’s medications are either less effective or completely ineffective in PD+ disorders. PD+ patients are also very sensitive to dopamine blockers. Differential Diagnosis of Parkinsonism

1. Essential tremor—responds to beta blocker, worse on intention, improved with alcohol. 2. Wilson’s disease—a disorder of hereditary copper accumulation. The typical presentation is a young person who has parkinsonian features. Diagnosis is by performing a slit lamp examination for Kayser-Fleischer rings.

Parkinson’s Disease PD is also called primary parkinsonism or idiopathic PD. The term idiopathic means “no secondary systemic cause.” The etiology of PD is partially understood and, in this sense, is not truly idiopathic. PD is a chronic neurodegenerative disorder associated with a loss of dopaminergic neurons (substantia nigra and other sites). It is characterized by bradykinesia (slowing of physical movement), akinesia (loss of physical movement), rigidity, resting tremor, postural instability, and a good response to levodopa (LD; Box 31–7).16,17 The disorder often starts unilaterally. Movements are slow and reduced facial expressiveness is noted (masklike facies) with infrequent blinking and a monotonous voice. Gait is slow and shuffling with small steps. The tremor in PD is a resting tremor—maximal when limb is at rest and disappearing with voluntary movement and sleep. Secondary symptoms may include cognitive dysfunction and subtle language problems.

Chapter 31    Sleep and Neurologic Disorders

BOX 31–7 

Parkinson’s Disease Manifestations • Resting tremor (pill rolling). • Gabellar reflex (sensitive but not specific)—breakdown of frontal lobe inhibition. • Masklike facies. • Small handwriting (micrographia). • Walking without arm swinging. • Flexed forward posture when walking with small shuffling steps. • RBD in 20–30%—often precedes PD manifestations— sometimes by 10 years. • Insomnia in 50%. • OSA. OSA = obstructive sleep apnea; PD = Parkinson’s disease; RBD = rapid eye movement sleep behavior disorder.

Nonmotor manifestations of PD include sleep disorders, dementia, orthostatic hypotension, oily skin, and seborrheic dermatitis. The sleep disorders in PD can occur secondary to medication side effects but are also a primary manifestation of PD. PD patients have a sixfold increased risk of dementia. Physical findings in PD include resting pill rolling tremor, gabellar tap (tap of forehead elicits continued blinking [a frontal lob sign]), and cogwheel rigidity (joint stiffness and increased muscle tone). Imaging of the central nervous system (MRI, CT scan) is typically normal. The neuropathology of PD includes the presence of LBs. A major component of LB is alpha synuclein. Secondary parkinsonism can occur secondary to drugs such as dopamine blockers (phenothiazines and butyrophenones) or head trauma. Differential Diagnosis of PD

1.  Essential tremor—Responds to beta blocker, worse on intention, improved with alcohol. 2. PD+ disorders—If cognitive dysfunction occurs early in the disease course of a patient with parkinsonism, DLBD would be suspected. If early postural instability + supranuclear gaze palsy is prominent early, the PSP should be suspected. If autonomic dysfunction is prominent early (erectile dysfunction or syncope), MSA should be suspected. 3. CBD—If CT or MRI shows prominent asymmetry with patchy changes and cortical deficits (apraxia) are prominent, CBD should be suspected. Treatment of PD  A detailed discussion of the treatment of PD

is beyond the scope of this chapter. A very comprehensive and useful discussion of PD is recommended.18 A number of different medications have been used to treat PD (Table 31–3). The usual treatment of PD is with levodopa/carbidopa (LD/CD). CD prevents peripheral metabolism of LD to dopamine, thus reducing side effects and allowing for more LD to reach the central nervous system. Patients may respond to LD/CD but have a number of reported problems. “On times” refers to periods of time when symptoms go away or

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improve markedly. “Off times” refers to periods of time when symptoms return. “Wearing off time” refers to times when symptoms are under less control. Dyskinesias, manifested by sudden jerky or uncontrolled movements of the limbs and neck, are side effects of LD/CD treatment. Dystonias consisting of abnormal posture or cramps of the extremities or trunk can occur. Dopamine agonists (DAs) are less likely to cause dyskinesia but have some dose-dependent side effects of their own. In low doses, DAs tend to cause sleepiness or promote sleep. Ropinirole or pramipexole have dopamine D2/D3 receptor activity and can stimulate autoreceptors to decrease dopamine release. In high doses, DAs can cause insomnia, frequent awakenings, and a reduction in the amount of stage N3. Another serious side effect of DA treatment of PD patients is the often unpredictable sudden onset of severe daytime sleepiness. Catechol-O-methyl transferase (COMT) inhibitors have also been used as adjunctive medications in PD. This enzyme is involved in degrading neurotransmitters including dopamine. The COMT inhibitors available include entacapone (Comtan) and tolcapone (Tasmar). Entacapone is only peripherally active, whereas tolcapone is active in both the peripheral and the central nervous system. Tolcapone can be hepatotoxic, whereas entacapone is not. These medications can permit LD to last longer or maintain higher levels of effectiveness. Anticholinergic agents are typically used in younger patients without cognitive impairment in whom tremor is the major feature. The concept behind the use of these agents is that PD has upset the cholinergic-dopaminergic balance in the basal ganglia due to loss of dopaminergic neurons. Anticholinergic drugs restore the balance. The anticholinergic drugs do not work for other PD manifestations. LD can also help tremor. The two anticholinergic drugs most commonly used include trihexyphenidyl (Artane) and benzotropine (Cogentin). Trihexyphenidyl is started at 0.5 to 1  mg bid and gradually increased to 2  mg tid as tolerated. Benzotropine is used in doses of 0.5 to 2  mg bid. Side effects of these medications including memory impairment and hallucinations limit their use. The anticholinergic side effects include dry mouth, constipation, and urinary retention. Of note, LD improves tremor as well as rigidity and can be used to treat tremor in patients not tolerating anticholinergic medications. Amantadine is an antiviral agent that can improve rigidity, akinesia, or tremor in approximately two thirds of patients. The mechanism of action is unknown. The usual dose of amantadine is 100 to 200 mg one to three times daily. The dose should be lower in patients with renal failure. The starting dose of amantadine is 100 mg daily with slow increases as tolerated. Side effects include confusion, hallucinations, insomnia, and nightmares. Selegiline (Deprenyl, Eldepryl), a selective monoamine oxidase B (MAO-B) inhibitor, is approved for use in PD patients as an adjunct to LD because it modestly increases the percent of “on” time in advanced PD patients. When used

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TABLE 31–3 

Medications Used to Treat Parkinson’s Disease Dopamine precursor LD/CD 10/100, 25/100, 25/100

• Very effective for akinetic symptoms or tremor. Start 12 of 25/100 tid, titrate up to 25/100 tid.

SR LD/CD (25/100, 50/200 ER)

• Poorly and slowly absorbed, 30% higher dose needed for same effect. • Very low dose of SR can cause nausea owing to inadequate CD.

DAs

• Less likely than LD to cause dyskinesias. • Can cause sudden episodes of severe sleepiness. • Dopamine dysregulation syndrome. • Some recommend using DAs in younger patients as “neuroprotective.”

Ropinirole (Requip) Pramipexole (Mirapex) COMT Inhibitors

Tolcapone (Tasmar) Entacapone (Comtan)

• These medications prolong the effect of LD and can allow a reduction in dose. COMT inhibition reduces the peripheral methylation of LD or dopamine, which increases the plasma half-life of LD; thus, prolongs action of LD. • Entacapone—peripheral inhibition of COMT. • Tolcapone—peripheral and central inhibition of COMT. • Tolcapone—deaths from hepatotoxicity.

Amantadine

• Antiviral. • May improve rigidity, akinesia, and tremor. • Monotherapy or combined with LD.

Trihexyphenidyl (Artane) Benzotropine (Cogentin)

• For younger patients with predominant tremor. • Side effects include cognitive impairment and typical anticholinergic side effects (dry mouth, urinary retention, constipation).

MAOI (segiline)

• MAO-B inhibitor • Modest benefit; can be used with LD to reduce motor fluctuations.

CD = carbidopa; COMT = catechol-O-methyl transferase; DAs = dopamine agonists; ER = extended-release; LD = levodopa; MAO = monoamine oxidase; MAOI = monoamine oxidase inhibitor; SR = sustained release.

alone at 5 mg bid, it is well tolerated. When used with LD, it can increase dopaminergic side effects. Some clinicians use selegiline at a lower dose in combination with LD to decrease motor fluctuations. Other clinicians use selegiline as a putative neuroprotective therapy. There is controversy about which dopaminergic medication is most appropriate for initiation of treatment of PD. The most common approach is to start with LD/CD if symptoms are significant. LD/CD is particularly effective for rigidity. However, patients taking LD/CD can develop dyskinesias. This tends to happen if patients have been on the medication for years or if high doses are used. If a patient on LD/CD develops dyskinesias, she or he can be switched to a DA. Conversely, some clinics recommend starting a DA as initial dopaminergic treatment. It is possible that DAs have a neuroprotective effect not present with LD/CD. Sleep-Related Manifestations of PD  Patients with PD have a

number of sleep-related manifestations and disturbances (Table 31–4).19,20 Treating the nocturnal manifestations of PD can be challenging.

Sleep Disturbance Due to Motor Manifestations  Patients with PD

have motor symptoms including tremor that are worse during wakefulness (Fig. 31–1) and usually decrease or are abolished with sleep. The tremor often stops with the onset

of alpha activity during drowsiness even before the onset of stage N1 or N2. Tremor is rare during stage N3. However, in some patients, motor manifestations persist during sleep. Examples of motor findings associated with sleep include repeated eye blinking at onset of sleep, blepharospasm at the onset of REM sleep, and prolonged tonic contractions of limb extensor or flexor muscles during non–rapid eye movement (NREM) sleep. Because of rigidity, patients with PD have difficulty changing body position during the night. Early morning akinesia and painful off dystonia can be problematic. LD/CD has a short duration of action. The DAs have a longer duration of action and may be useful in patients with motor manifestations during sleep. in PD  Excessive daytime sleepiness (EDS) not due to OSA or medications is a well-known phenomenon in PD. Sleep attacks were once thought due to side effects from DAs. Most recent studies suggest medications used to treat PD may worsen EDS but that the underlying disease process is the most common cause of EDS in PD. Studies have reported 50% loss of hypocretin neurons in patients with PD.21 Treatment of EDS not due to OSA in PD patients includes modafinil, bupropion, and traditional stimulants. Fatigue can also be a major complaint. The American Academy of Sleep Medicine (AASM) practice parameters for treatment of central hypersomnia22 state that modafinil may

Daytime Sleepiness

Chapter 31    Sleep and Neurologic Disorders



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TABLE 31–4 

Sleep Disturbance in Parkinson’s Disease PATHOPHYSIOLOGY

MANIFESTATION

TREATMENT

Changes in cholinergic and monoaminergic systems

Impaired wake-sleep control Decreased REM sleep

Cautious use of sedating antidepressants and hypnotics

Bradykinesia and rigidity

Decreased body shifts during sleep → discomfort and increased awakenings Impaired ability to use the bathroom

Sustained-release LD/CD or DAs

Tremor

Arousals Insomnia

Sustained release CD/LD or DAs

Drug-induced dyskinesia

Jerks, arousals

Decrease evening LD/CD or DAs

Abnormal motor control of respiratory and upper airway muscles

OSA (BMI often normal)

CPAP

RBD

• Disturbed REM sleep • Injury to self or bed partner • RBD • May precede other findings by years • Prevalence 15–30%

• Clonazepam • Melatonin • ?Dopamine agonists

PLMS, RLS

Arousals, difficult sleep onset

Dopamine agonists

Depression and anxiety

Insomnia Difficulty with sleep onset Early AM awakening

Cautious use of hypnotics and antidepressants

Dementia

Nocturnal confusional episodes

Quetiapine Aricept

BMI = body mass index; CD = carbidopa; CPAP = continuous positive airway pressure; DAs = dopamine agonists; LD = levodopa; OSA = obstructive sleep apnea; PLMS = periodic limb movements during sleep; RBD = rapid eye movement sleep behavior disorder; REM = rapid eye movement; RLS = restless legs syndrome. Adapted from Comella CL: Sleep disorders in Parkinson’s disease. Curr Treat Options Neurol 2008;10:215–221.

be an effective treatment of daytime sleepiness in PD. However, the evidence from studies of the effects of modafinil in PD is somewhat conflicting. A study by Ondo and colleagues23 found no significant improvement in the Epworth Sleepiness Scale (ESS; subjective sleepiness). A study by Hogl and associates24 found an improvement in the ESS but no increase in the sleep latency on the maintenance of wakefulness test (MWT). An uncontrolled study by Nieves and Lang25 found improvement in the ESS with modafinil in PD patients. Another study investigated whether modafinil would improve fatigue in PD. Using a double-blind, placebocontrolled design, Lou and coworkers26 noted no improvement in fatigue symptoms, no improvement in ESS, and some improvement in finger tapping. In summary, even though the evidence is less than totally convincing, a trial of modafinil is indicated if daytime sleepiness is a significant problem for a patient with PD. Of course, the possibility of OSA should be eliminated. As noted previously, treatment with DAs can be associated with sudden attacks of severe daytime sleepiness. One case report found that the addition of modafinil to DA therapy reduced the severity of this DA side effect.27

can be the earliest manifestation, occurring many years before other PD symptoms and signs. In general, treatment options for RBD in PD are similar to those for idiopathic RBD. DAs have been reported to be effective treatment of RBD in some patients. Nocturnal hallucinations can occur in PD and disturb sleep. A recent study compared sleep between groups of PD patients with and without visual hallucinations. Whereas both groups slept poorly, the group with visual hallucinations had much poorer sleep.28 Drug-induced psychosis is a major problem in PD. It can occur in up to 22% and is a major cause of placing patients in a chronic care facility. Treatments have included reducing the dose of anti-Parkinson’s medication, adding a neuroleptic drug, or discontinuing PD treatment for a period of time. Low-dose clozapine was found effective even if antiParkinson’s medications were still taken and did not worsen tremor. In this study, doses of 6.25 to 50 mg were used (far lower than the 300–900 mg used for schizophrenia). The drug can cause leukopenia.29 Quetiapine has also been effective for drug-induced psychosis but can cause problems with glucose control and oversedation.30

Nocturnal Behavior: RBD, Nocturnal Hallucinations, Nocturnal Psychosis  RBD occurs in 20% to 40% of patients with PD. It

Dementia in PD  A study found modest benefit from donepezil and the drug did not cause worsening of PD.31 Another study

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Chapter 31    Sleep and Neurologic Disorders

1234 E1-M2 E2-M2 F3-M2 1 sec

F4-M1 C3-M2 C4-M1 O1-M2

O2-M1 EMG1-EMG2 R Leg1 - R Leg2 L Leg1 - L Leg2 Nasal pressure Chest Abdomen SpO2

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ECG1-ECG2 11:33:27 PM

11:33:32 PM

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FIGURE 31–1  A 30-second tracing during wakefulness in a patient with Parkinson’s disease shows a classic 4-Hz tremor noted in the chin electromyogram (EMG). RLeg1-RLeg2 and LLeg1-LLeg2 are the right and left anterior tibial EMG derivations. ECG = electrocardiogram; SpO2 = pulse oximetry.

has reported some benefit from memantine in patients with PD with dementia or DLBD.32

Diffuse Lewy Body Dementia DLBD is also known as dementia with Lewy bodies (DLB), Lewy body dementia, or diffuse Lewy body disease. DLBD is a type of dementia characterized anatomically by the presence of Lewy bodies, clumps of alpha synuclein and ubiquitine proteins in neurons. In this disorder, loss of cholinergic neurons results in cognitive dysfunction and loss of dopamine neurons results in parkinsonism (Box 31–8). If dementia occurs more than 1 year after other symptoms in PD, the disorder is called PD with dementia. If dementia occurs within the first year of parkinsonism, the diagnosis is DLBD. DLBD tends to progress much more rapidly than PD. Manifestations of DLBD  The major manifestations of DLBD33

include (1) fluctuating cognition with great variation in attention and alertness from day to day and hour to hour, (2) recurrent visual hallucination (75% of patients with DLBD), (3) motor features of parkinsonism (tremor less common in DLBD than in PD), (4) RBD (50–75%), and (5) problems with orthostasis, including repeated falls, syncope (fainting),

and transient loss of consciousness. The RBD can have an onset years before the other manifestations of DLBD (similar to PD). Visual Hallucinations  The most common reported hallucina-

tion is of people or animals. The patient may misinterpret what he or she sees. For example, the patient may open a drawer full of socks but see snakes.

to DA Blockers  An important characteristic of DLBD is exquisite sensitivity to dopamine blockers. When given dopamine blockers, patients with DLBD can develop life-threatening rigidity or malignant neuroleptic syndrome. Anticholinergic drugs such as benadryl or hytrin can worsen dementia.

Sensitivity

Dementia Variant  A variant of DLB and RBD but without par-

kinsonism or hallucinations has been reported. This disorder may be a variant of DLBD.34

Multiple System Atrophy MSA is a neurodegenerative disorder characterized by a combination of parkinsonism, dysautonomia, cerebellar dysfunction, and features of pyramidal tract dysfunction (Box

Chapter 31    Sleep and Neurologic Disorders



31–9).35 Some patients have more prominent dysfunction in one category. MSA is sometimes divided into three separate conditions (Table 31–5). These include (1) striatonigral degeneration, (2) olivopontocerebellar degeneration, and (3) progressive autonomic failure (Shy-Drager syndrome). A BOX 31–8 

Diffuse Lewy Body Dementia • Fluctuating cognition and alertness. • Visual hallucinations in 70%. • Orthostasis and frequent falls. • Motor manifestations of parkinsonism (rigidity, tremor less common than in PD). • Onset of dementia within 1 year of symptoms of parkinsonism. • RBD is very common (50–80%). • Life-threatening rigidity with dopamine blockers. PD = Parkinson’s disease; RBD = rapid eye movement sleep behavior disorder.

639

recent consensus conference35 recommended new MSA terminology and the term Shy-Drager was not used in this classification, although it is widely used in the literature. Symptoms

1. Autonomic dysfunction (erectile dysfunction, bladder control—urgency, incomplete emptying, constipation, abnormal breathing during sleep, orthostatic hypotension). 2. Parkinsonism = rigidity ± tremor, bradykinesia, and postural instability. The tremor of MSA is irregular and usually not a pill rolling tremor as seen in PD. 3. Gait ataxia (poor coordination/unsteady walking) may be a presenting symptom. Ataxia of speech (cerebellar dysarthria) is also common and manifested by slow and slurred speech and sudden uncontrolled alterations in loudness of voice. Epidemiology of MSA  The typical age of onset of MSA is 50

to 60 years. The disease course is fairly rapid with onset to death in about 9 years. The disorder progresses more rapidly than PD.

Diagnosis  The second consensus conference on MSA defined

BOX 31–9 

Manifestations of Multiple System Atrophy • Age of onset 50–60 years. • Onset to death in 9 years. • Not seen: hallucinations and dementia. • Orthostatic hypotension a major problem. • Variants • Striatonigral degeneration—rigidity, bradykinesis. • Olivopontocerebellar atrophy—prominent ataxia, postural instability. • Shy-Drager—autonomic dysfunction. • Stridor—poor prognostic sign, normal awake laryngeal examination does not exclude. • Sleep disorders very common (>70%). • RBD very common (80–95% of patients). • OSA. OSA = obstructive sleep apnea; RBD = rapid eye movement sleep behavior disorder.

two categories of MSA based on the predominant symptoms at the time of evaluation35:

1. MSA-P—MSA with predominant parkinsonism (also called striatonigral degeneration, parkinsonian variant). 2. MSA-C—MSA with predominant cerebellar features. MSA in which cerebellar features predominate is also called sporadic olivopontocerebellar atrophy. Pathology of MSA  The pathology of MSA involves alpha

synuclein oligodendral inclusions in the brainstem, cerebellum, and spinal cord. Glial cytoplasmic inclusions (PappLantos bodies) appear in the brain centers involved with control of movement, balance, and autonomic control centers.

Vocal Cord Palsy and Stridor in MSA  Stridor may occur in up

to 30% of patients with MSA. It can be much worse during

TABLE 31–5 

Classifications of Multiple System Atrophy CHARACTERISTICS

1996 CONSESNUS CONFERENCE

2007 CONSENSUS CONFERENCE

Striatonigral degeneration

Predominantly Parkinson’s type symptoms

MSA-P

MSA-P

Sporadic OPCA

Progressive ataxia of gait, limbs, and speech (cerebellar dysarthria)

MSA-C

MSA-C

Shy-Drager syndrome

Characterized by parkinsonism + pronounced failure of the autonomic nervous system

MSA-A

No longer used

MSA = multiple system atrophy; OPCA = sporadic olivopontocerebellar atrophy. From Gillman S, Wenning P, Low PA, et al: Second consensus statement of the diagnosis of multiple system atrophy. Neurology 2008;71:670–676.

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sleep. A normal laryngeal examination during wakefulness does not rule out the problem.36 The presence of stridor is associated with a poor prognosis (compared with MSA patients without stridor) and has traditionally been managed by tracheostomy. Recently, CPAP has been used to assist with stridor at night.36,37 Patients with MSA often have OSA as well as worsening stridor during sleep. The etiology of stridor is controversial but is likely due to overactivity of the vocal cord adductors (close vocal cords) and underactivity of vocal cord abductors (posterior cricoarytenoid muscles [PCAs]). A neuropathy of the recurrent laryngeal nerves that innervate the PCA muscles may be involved. The syndrome of stridor in many patients is a dystonia rather than vocal cord paralysis. In others, there is complete vocal cord immobility. Sudden death has been reported in MSA patients with stridor even though treated with tracheostomy or CPAP.37,38 Central Apnea and Cheyne-Stokes Breathing  Central apnea,

nocturnal hypoventilation, and Cheyne-Stokes breathing (CSB) have been reported in MSA, especially in patients with prominent autonomic features.39

Treatment of MSA  The treatment of MSA is mostly supportive. There is usually no or only a short initial response to LD. Patients with stridor can be treated with CPAP or tracheostomy (although sudden death can still occur at night).

Other Neurodegenerative Disorders Fatal Familial Insomnia Fatal familial insomnia (FFI) is a familial autosomal dominant prion disorder associated with the D178N mutation and methionine-methionine genotype at codon 129 in the prion protein gene on chromosome 20.40,41 Of note, the D178N mutation and valine-valine genotype at codon 129 are associated with familial Creutzfeldt-Jakob disease (CJD). Topography of Degeneration Methionine-methionine genotype at codon 129 produces dorsomedial and anteroventral thalamic dysfunction, whereas the valine-valine genotype of CJD is associated with more general cortical involvement. FFI Manifestations FFI manifestations include insomnia, dementia, ataxia, dysarthria, dysautonomia, hallucinations, and hypersomnolence. The duration from onset to death varies from a few months to 4 years. Diagnosis The International Classification of Sleep Disorders, 2nd edition (ICSD-2), diagnostic criteria for FFI are listed in Box 31–10. The PSG in FFI reveals severe disruption of the sleepwake cycle, loss of sleep spindles, reduction in stage N3 and stage R, as well as reduced sleep efficiency. REM sleep without atonia can occur.

Positron Emission Tomography Scan Positron emission tomography (PET) reveals nearly absent or very low activity of the thalamus. Summary FFI should be considered in any patient with prominent sleep-wake disturbance and dementia. Treatment is supportive.

Sleep Disturbances in Stroke Important points concerning stroke and sleep are listed in Box 31–11. SDB occurs in 50% to 70% of stroke patients (defined by apnea-hypopnea index [AHI] > 10/hr).42–46 Central sleep apnea including CSB can be noted, especially soon after stroke, but tends to decrease with time. CSB in some chronic stroke patients is associated with heart failure.45,46 Other patients with stroke and central sleep apnea have occult heart failure.47 OSA is the most common BOX 31–10 

Fatal Familial Insomnia—Diagnostic Criteria A. Complaint of insomnia is initially present and becomes progressively more severe. B. Progressive autonomic hyperactivity with pyrexia, hypersalivation, hyperhydrosis, cardiac and respiratory dysfunction, tremor-like muscle activity. C. Polysomnographic monitoring demonstrates i. Loss of sleep spindles. ii. Loss of slow wave sleep. iii. Dissociated REM sleep. D. The disorder is not better explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder. OR E. A missense GAC to AAC mutation at codon 17 of the PRNP gene (d178N) co-segregating with the methionine polymorphism at codon 129 of the PRNP on the mutated allele is found (this mutation is absent in sporadic fatal familial insomnia). REM = rapid eye movement. Adapted from International Classification of Sleep Disorders, 2nd ed. Westchester, IL: American Academy of Sleep Medicine, 2005.

BOX 31–11 

Stroke and Sleep Apnea • OSA > CSA are common in patients after CVA. • If OSA is present, adequate treatment may improve outcome. • CPAP treatment is often challenging, especially in nonsleepy patients. • Incidence of stroke increased in men with mild to moderate OSA. CSA = central sleep apnea; CVA = cerebrovascular accident; OSA = obstructive sleep apnea.



disorder following a cerebrovascular accident (CVA). OSA also tends to improve with time, but a substantial number of patients still have OSA at 2 to 3 months after stroke. However, the presence of sleep apnea following a CVA raises questions about the temporal relationship with stroke. Does brain damage from CVA cause sleep apnea or did sleep apnea precede the stroke? If so, is the presence of sleep apnea an independent risk factor for the development of a CVA? The Sleep Heart Health Study did show an increased risk of having a CVA (prevalence) if OSA is present.48 In a recently published study, Redline and colleagues49 evaluated the Sleep Heart Health data and found an increased risk for incident ischemic stroke in men with mild to moderate OSA. In this study, data were adjusted for a number of confounders that complicate the analysis including obesity. If there is a causal role for OSA in stroke, what are the mechanisms? OSA could predispose a patient to atherosclerosis, hypertension, and early morning hemoconcentration. These factors would increase the risk of stroke. During sleep apnea, there are increases in intracranial pressure (ICP)50 and decreases in cerebral blood flow.51 There is an increase in ICP with each apneic event and the rise tends to be correlated with the length of apnea. The increase in ICP is thought secondary to increases in central venous pressure, systemic pressure, and cerebral vasodilatation from rises in arterial partial pressure of carbon dioxide (PaCO2) during events. Because cerebral perfusion is proportional to the mean arterial pressure (MAP)—ICP, increases in ICP may reduce perfusion pressure even if MAP also rises. Studies of cerebral blood flow velocity using Doppler monitoring have shown that flow velocity increases in early apnea, then has approximately a 25% fall below baseline at end apnea.51 There is some evidence that the presence of OSA in patients who have suffered a CVA is a poor prognostic sign regardless of whether OSA precedes or follows the CVA. Good and associates52 found that the Barthel index (a multifaced scale measuring mobility and activities of daily living that is used to assess patients after stroke) was significantly lower in patients with OSA and CVA compared with those with no evidence of OSA after CVA. The presence of OSA was determined at discharge and the Barthel index was lower at 3 and 12 months in the OSA-CVA group. Martinez-Garcia and coworkers53 found that CPAP treatment reduced mortality in patients found to have OSA following an ischemic stroke. This study suggests that physicians need to be more aggressive about ruling out OSA in patients with a recent CVA. Unfortunately, CPAP adherence following CVA is often very suboptimal. After stroke, other sleep-wake disorders may impair recovery. Insomnia can occur but treatment should be cautious unless sleep apnea is excluded. Daytime sleepiness can occur even if sleep apnea is not present. Poststroke hypersomnia can be found after subcortical (caudate-putamen), thalamomesencephalic, medial pontomedullary, and cortical strokes. In one study, up to 12% of patients developed newonset restless legs syndrome after stroke.54 Pontine-tegmental strokes can lead to RBD.

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641

CLINICAL REVIEW QUESTIONS 1. In which of the following dementias is RBD relatively uncommon? A. PSP. B. AD. C. PD. D. MSA. E. DLBD. 2. What neurodegenerative disorder is not an alpha synucleinopathy? A. PSP. B. MSA. C. PD. D. DLBD. 3. Which of these neurodegenerative disorders is frequently associated with stridor? A. PD. B. AD. C. PSP. D. DLBD. E. MSA. 4. In which of the following disorders is sundowning a prominent feature? A. AD. B. PD. C. PSP. D. MSA. 5. Which of the following is NOT a PD+ disorder? A. PSP. B. AD. C. MSA. D. DLB. 6. Which of the following is true about PD+ disorders compared with PD? A. There is a good response to LD. B. They have a slower downhill course than PD. C. They are very sensitive to dopamine blockers. D. Dementia is less common early. 7. Which of the following is true about patients with DLBD? A. Dopamine blockers can cause life-threatening rigidity. B. Dementia starts about 2 years after rigidity and loss of balance. C. Visual hallucinations occur in 5%. D. They respond well to LD.

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Answers 1. B.  RBD is uncommon in AD. RBD is very common in PD, DLB, and MSA and tends to precede other neurologic manifestations. RBD occurs in about 13% of PSP patients and tends to start concomitantly with other manifestations. 2. A.  PSP is a tau disorder. 3. E.  MSA is associated with stridor. 4. A.  Sundowning is common in AD. 5. B.  AD is not a PD+ disorder. 6. C.  PD+ patients are very sensitive to dopamine blockers. They have a more rapid course than those with PD, they have minimal response to LD, and dementia can be prominent early (DLBD). 7. A.  Dopamine blockers can cause life-threatening rigidity. Visual hallucinations are very common—up to 70%.

REFERENCES 1. Chokroverty S: Sleep and neurodegenerative diseases. Semin Neurol 2009;29:446–468. 2. Avidan AY: Sleep and neurological problems in the elderly. Sleep Med Clin 2006;1:273–292. 3. Hofman MA, Swaab DF: Living by the clock: the circadian pacemaker in older people. Ageing Res Rev 2006:5:33–51. 4. Wu Y, Swaab DF: Disturbance and strategies for reactivation of the circadian rhythm system in aging and Alzheimer’s disease. Sleep Med 2007;8:623–636. 5. Zee PC, Vitiello MV: Circadian rhythm sleep disorder: irregular sleep-wake rhythm type. Sleep Med Clin 2009;4:213–218. 6. Singer C, Tractenberg RE, Kaye J, et al: A multicenter, placebocontrolled trial of melatonin of sleep disturbance in Alzheimer’s disease. Sleep 2003;26:893–901. 7. Riemersma-van der Lek RF, Swaab DF, Twisk J: Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities. JAMA 2008;299: 2647–2655. 8. Cooke JR, Ayalon L, Palmer BW, et al: Sustained use of CPAP slows deterioration of cognition, sleep, and mood in patients with Alzheimer’s disease and obstructive sleep apnea: a preliminary study. J Clin Sleep Med 2009;5:305–309. 9. Birks J: Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 2006;1:CD005593. 10. Stahl SM, Markowitz JS, Papadopoulos G, Sadik K: Examination of nighttime sleep-related problems during doubleblind, placebo-controlled trials of galantamine in patients with Alzheimer’s disease. Curr Med Res Opin 2004;20: 517–524. 11. Gauthier S, Juby A, Dalziel W, et al, EXPLORE Investigators: Effects of rivastigmine on common symptomatology of Alzheimer’s disease (EXPLORE). Curr Med Res Opin 2010;26: 1149–1160. 12. Grossberg G, Irwin P, Satlin A, et al: Rivastigmine in Alzheimer’s disease: efficacy over two years. Am J Geriatr Psychiatry 2004;12:420–431. 13. Yeh SB, Yeh PY, Schenck CH: Rivastigmine-induced REM sleep behavior disorder (RBD) in a 88-year-old man with Alzheimer’s disease. J Clin Sleep Med 2010;15:192–195.

14. Sixel-Döring F, Schweitzer M, Mollenhauer B, Trenkwalder C: Polysomnographic findings, video-based sleep analysis and sleep perception in progressive supranuclear palsy. Sleep Med 2009;10:407–415. 15. Arnulf I, Merino-Andreu M, Bloch F, et al: REM sleep behavior disorder and REM sleep without atonia in patients with progressive supranuclear palsy. Sleep 2005;28:349–354. 16. Jankovic J: “Parkinson’s disease”: Clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008;79:368–376. 17. Reichmann H: Clinical criteria for the diagnosis of Parkinson’s disease. Neurodegener Dis 2010;7:284–290. 18. Olanow CW, Watts RL, Koller WC: An algorithm for the management of Parkinson’s disease (2001): treatment guidelines. Neurology 2001;56:1–88. 19. Comella CL: Sleep disorders in Parkinson’s disease. Curr Treat Options Neurol 2008;10:215–221. 20. Manni R, Terzaghi M, Repetto A, et al: Complex paroxysmal nocturnal behaviors in Parkinson’s disease. Mov Disord 2010;25:985–990. 21. Thannickal TC, Lai YY, Siegel JM: Hypocretin (orexin) cell loss in Parkinson’s disease. Brain 2007;130:1586–1595. 22. Morgenthaler TI, Kapur VK, Brown TM, et al, Standards of Practice Committee of the AASM: Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007;30:1705–1711. 23. Ondo WG, Fayle F, Atassi F, Jankovic J: Modafinil for daytime somnolence in Parkinson’s disease: double-blind, placebocontrolled parallel trial. J Neurol Neurosurg Psychiatry 2005;76: 1636–1639. 24. Hogl B, Saletu M, Brandauer E, et al: Modafinil for the treatment of daytime sleepiness in Parkinson’s disease: a doubleblind, randomized, crossover, placebo-controlled polygraphic trial. Sleep 2002;25:905–909. 25. Nieves AV, Lang AE: Treatment of excessive daytime sleepiness in patients with Parkinson’s disease with modafinil. Clin Neuropharmacol 2002;25:111–114. 26. Lou JS, Dimitrov DM, Park BS, et al: Using modafinil to treat fatigue in Parkinson disease: a double-blind, placebo-controlled pilot study. Clin Neuropharmacol 2009;32:305–310. 27. Hauser RA, Walha MN, Anderson WM: Modafinil treatment of pramipexole associated somnolence. Mov Disord 2000; 15:1269–1271. 28. Barnes J, Connelly V, Wiggs L, et al: Sleep patterns in Parkinson’s disease patients with visual hallucinations. Int J Neurosci 2010;120:564–569. 29. Parkinson Study Group: Low-dose clozapine for the treatment of drug induced psychosis in Parkinson’s disease. N Engl J Med 1999;340:757–763. 30. Juri C, Chana P, Tapia J, et al: Quetiapine for insomnia in Parkinson disease: results from an open label trial. Clin Neuropharmacol 2005;28:185–187. 31. Trieschmann MM, Reichwein S, Simuni T: Donepezil for dementia in Parkinson’s disease: a randomised, double-blind, placebo-controlled, crossover study. J Neurol Neurosurg Psychiatry 2005;76:934–939. 32. Emre M, Tsolaki M, Bonuccelli U, et al, on behalf of the 11018 Study Investigators: Memantine for patients with Parkinson’s disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010; 9:969–977; Epub 2010;August 20. 33. McKeith JG, Galasko D, Kosaka K, et al: Consensus guideline for the clinical and pathological diagnosis of dementia with Lewy bodies: report of Consortium on DLB International Workshop. Neurology 1996;47:1113–1124. 34. Ferman T, Boeve B, Smith G, et al: Dementia with Lewy bodies may present as dementia with REM sleep behavior disorder without parkinsonism or hallucinations. J Int Neuropsychol Soc 2002;8:907–914.

35. Gillman S, Wenning P, Low PA, et al: Second consensus statement of the diagnosis of multiple system atrophy. Neurology 2008;71:670–676. 36. Iranzo A: Management of sleep-disordered breathing in multiple system atrophy. Sleep Med 2005;6:297–300. 37. Kuźniar TJ, Morgenthaler TI, Prakash UBS, et al: Effects of continuous positive airway pressure on stridor in multiple system atrophy—sleep laryngoscopy. J Clin Sleep Med 2009; 5:65–67. 38. Silber MH, Levine S: Stridor and death in multiple system atrophy. Mov Disord 2000;15;699–714. 39. Sadaoka T, Kakitsub N, Fujiwara Y, et al: Sleep-related breathing disorders in patients with multiple system atrophy and vocal fold palsy. Sleep 1996;19:479–484. 40. Lugaresi E, Tobler I, Montagna P, et al: Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med 1986;315:997–1003. 41. Montagna P, Gambetti P, Cortelli P, Lugaresi E: Familial and sporadic fatal insomnia. Lancet Neurol 2003;2:167–176. 42. Hermann DM, Bassetti CL: Sleep-related breathing and sleep wake disturbances in ischemic stroke. Neurology 2009;73: 1313–1322. 43. Turkington P, Bamfor J, Wanklyn P, et al: Prevalence and predictors of upper airway obstruction in the first 24 hours after acute stroke. Stroke 2002;33:2037–2041. 44. Para O, Arboix A, Bechichi S, et al: Time course of sleep-related breathing disorders in first-ever stroke or transient ischemic attack. Am J Respir Crit Care Med 2000;161:375–380. 45. Siccoli MM, Valko PO, Hermann DM, Bassetti CL: Central periodic breathing during sleep in 74 patients with acute ischemic stroke—neurogenic and cardiogenic factors. J Neurol 2008;255:1687–1692.

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643

46. Hermann DM, Siccoli M, Kirov P, et al: Central periodic breathing during sleep in ischemic stroke. Stroke 2007;38: 1082–1084. 47. Nopmaneejumruslers C, Kaneko Y, Hajek V, et al: CheyneStokes respiration in stroke: relationship to hypocapnia and occult cardiac dysfunction. Am J Respir Crit Care Med 2005;171:1048–1052. 48. Shahar E, Whitney CW, Redline S, et al: Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163:19–25. 49. Redline S, Yenokyan G, Gottlieb DJ, et al: Obstructive sleep apnea-hypopnea and incident stroke: the Sleep Heart Health study. Am J Respir Crit Care Med 2010;182:269–277. 50. Sugita Y, Susami I, Yoshio T, et al: Marked episodic elevation of cerebral spinal fluid pressure during nocturnal sleep in patients with sleep apnea hypersomnia syndrome. Electroencephalogr Clin Neurophysiol 1985;60:214–219. 51. Balfors EM: Impairment of cerebral perfusion during obstructive sleep apneas. Am J Respir Crit Care Med 1994;150: 1587–1591. 52. Good DC, Henkle JQ, Gelber D, et al: Sleep disordered breathing and poor functional outcome after stroke. Stroke 1996; 27:252–259. 53. Martinez-Garcia MA, Soler-Cataluna JJ, Ejarque-Martinez L, et al: Continuous positive airway pressure treatment reduces mortality in patients with ischemic stroke and obstructive sleep apnea: a five-year follow-up. Am J Respir Crit Care Med 2008;180:36–41. 54. Lee SJ, Kim JS, Song IU, et al: Post-stroke restless legs syndrome and lesion location. Anatomical considerations. Mov Disord 2008;24:77–84.

Appendix 

31-1 

Medications Used to Treat Alzheimer’s Disease STARTING DOSE

MAINTENANCE DOSE

COMMENTS

5 mg po qd Increase after 4–6 wk

10 mg qd

Given in AM

4.6 mg/24 hr 1.5 mg bid

Rash, fewer side effects than pill Give with meals

Galantamine Immediate release

Increase to 9.5 mg/24 hr after 4 wk Increase in 1.5-mg increments bid every 2–4 wk until 6 mg bid

4 mg bid

Extended release

8 mg qd

Increase in 4-mg increments monthly until 12 mg bid Increase in 8-mg increments monthly until 24 mg daily

Cholinesterase Inhibitors Donepezil Rivastigmine Patch Pill

Neuroprotective

Give with meals

Memantine (Namendia) an NMDA receptor antagonist. Can cause hallucinations and dizziness (most common side effect). Can be used with cholinesterase inhibitors.

NMDA = N-methyl-d-aspartate.

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