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    Parkinson's disease and nonmotor dysfunction Parkinson's disease and nonmotor dysfunction Document Transcript

    • 245R.F. Pfeiffer and I. Bodis-Wollner (eds.), Parkinson’s Disease and Nonmotor Dysfunction,Current Clinical Neurology, DOI 10.1007/978-1-60761-429-6_17,© Springer Science+Business Media New York 2013M.L. Moro-de-Casillas, M.D. • D.E. Riley, M.D.(*)Neurological Institute, University Hospitals andCase Western Reserve University School of Medicine,11100 Euclid Ave, Cleveland, OH 44106, USAe-mail: David.Riley@uhhospitals.org17AbstractThe International Classification of Sleep Disorders (ICSD) defines insom-nia simply as “difficulty in initiating and/or maintaining sleep”. Otherdefinitions exist, and there is no clear consensus in this matter. The coreelements of insomnia are an inadequate quantity or quality of sleep, withboth nocturnal and daytime consequences. Traditionally, insomnia hasbeen subgrouped into sleep-onset insomnia, sleep-maintaining insomnia,and insomnia with early morning awakening; however, there is extensiveoverlap, and most insomniacs fit into more than one subgroup.Sleep disorders, particularly in the elderly, are strongly associated withincreased morbidity and mortality, significant limitations in activities ofdaily living, and impaired quality of life. Aside from the obvious compli-cations of daytime fatigue and somnolence, insomniacs have an increasedincidence of psychiatric disorders such as depression and anxiety, increaseduse of over-the-counter medications and alcohol, and a higher incidence ofaccidents and unemployment. Chronic sleep loss has multisystem conse-quences and may represent a risk factor for obesity, insulin resistance, andType 2 diabetes. However, the brunt of negative effects of sleep depriva-tion is borne by the brain. Chronic insomnia independently predicts inci-dent cognitive decline in older men, but it also has been suggested thatsome degree of apparent age-related cognitive decline may be due to treat-able insomnia.Insomnia in Parkinson’s DiseaseMaria L. Moro-de-Casillas and David E. Riley
    • 246 M.L. Moro-de-Casillas and D.E. RileyKeywordsNocturia • Insomnia • Melatonin • Bromocriptine • Restless legs syndrome• Unified Parkinson’s Disease Rating Scale • Nighttime awakenings •Sleep fragmentation • PRIAMO • International Classification of SleepDisordersIntroductionThe International Classification of SleepDisorders (ICSD) defines insomnia simply as“difficulty in initiating and/or maintaining sleep”[1]. Other definitions exist, and there is no clearconsensus in this matter. The core elements ofinsomnia are an inadequate quantity or quality ofsleep [2], with both nocturnal and daytime conse-quences. Traditionally, insomnia has been sub-grouped into sleep-onset insomnia,sleep-maintaining insomnia, and insomnia withearly morning awakening; however, there isextensive overlap, and most insomniacs fit intomore than one subgroup [3].Sleep disorders, particularly in the elderly,are strongly associated with increased morbid-ity and mortality, significant limitations inactivities of daily living, and impaired qualityof life [2]. Aside from the obvious complica-tions of daytime fatigue and somnolence,insomniacs have an increased incidence ofpsychiatric disorders such as depression andanxiety [4], increased use of over-the-countermedications and alcohol, and a higher inci-dence of accidents and unemployment [5].Chronic sleep loss has multisystem conse-quences and may represent a risk factor forobesity, insulin resistance, and Type 2 diabetes[6]. However, the brunt of negative effects ofsleep deprivation is borne by the brain [7].Chronic insomnia independently predicts inci-dent cognitive decline in older men [8], but italso has been suggested that some degree ofapparent age-related cognitive decline may bedue to treatable insomnia [9].Insomnia is the most frequently reported sleepproblem in the USA and in industrialized nationsworldwide [10]. Bixler et al. reported an overallprevalence of insomnia of 42 % in a sample of1,006 subjects aged 18–80 [11]. Women are 1.3times more likely than men to report insomniasymptoms [12]. The elderly (>65 years old) havea prevalence rate of sleep difficulty 1.5 timeshigher than that of adults younger than 65 [13].Schubert et al. found that almost half (49 %) ofan older population (ages 53–97) reported at leastone insomnia trait (difficulty getting to sleep,difficulty returning to sleep after waking up, orrepeated awakenings) occurring at least five timesa month [14].The economic burden of insomnia on societyis enormous [15]; the annual per person cost ofuntreated insomnia in the United States civilianlabor force exceeds $1,000 [16]. In a Canadianstudy, the largest proportion of insomnia-relatedexpenses was attributable to work absences andreduced productivity. Indirect costs includedhealthcare consultations, prescription and over-the-counter medications, as well as alcohol usedas a sleep aid [17].Against this background, and with the addedconsideration that insomnia is highly dependenton subjective reporting [18], it is difficult todetermine the contribution of superimposed ill-ness to the problem of insomnia in affectedpatients. Nevertheless, insomnia has been associ-ated with many medical conditions, includingneurodegenerative disorders such as Alzheimer’sdisease and Parkinson’s disease (PD) [19].Nonmotor manifestations of PD, including sleepdisorders, have a major impact on the quality oflife of patients and their families [20]. The mostimportant nonmotor complaints associated withpoor quality of life in PD patients are depression,apathy, and insomnia [21].
    • 24717 Insomnia in Parkinson’s DiseaseSleep PhysiologyThe recognition of the state of sleep is based onboth behavioral and physiologic criteria [22]. Thebehavioral criteria include eye closure, reducedresponsiveness to environmental stimuli,decreased or absent movement, and a reversiblyunconscious state [23]. Physiologically, sleepnormally proceeds through cycles of five stages.The first four, collectively known as nonrapid eyemovement sleep (NREM sleep), are numberedconsecutively and represent progressively deeperstates of somnolence. They account for 75–80 %of sleep time in a healthy adult. During thesephases, electroencephalography (EEG) displaysvarying amounts of high-voltage slow activityand delta waves (1–4 Hz), with characteristicsleep spindles (12–14 Hz) and K-complexes dur-ing stage II. Recent nomenclature has combinedstages III and IV and divided NREM sleep intoN1, N2, and N3 stages [24]. The fifth (fourth)stage of sleep is characterized by rapid eye move-ments (hence the term, REM sleep), atonia, low-voltage fast brain activity, cardiorespiratoryirregularities, and dreaming [23]. Sleep cycleslast 90–100 min, and a normal sleep period hasfour to six cycles. The duration of REM sleepincreases from the first to the last cycle, and at theend of the sleep period can persist for as long as1 h. With aging, important changes in sleep struc-ture occur, including decreased total nocturnalsleep time, reduced delta sleep, delayed onset ofsleep, reduced REM sleep, and reduced thresholdfor arousal [25]. Probably the most characteristicchange is a phase advance of the normal circa-dian rhythm, which results in earlier sleep onset,accompanied by earlier awakening in the morn-ing [26]. Interference with the initiation, orderlyprogression, and completion of normal cycles ofsleep results in insomnia.The sleep cycle is regulated by a variety ofneurochemical/neuroendocrine systems and isthe result of active and passive mechanisms,under genetic and molecular regulation [27].Multiple monoamines, including dopamine (DA),serotonin, norepinephrine, and histamine, as wellas acetylcholine and the neuropeptide, hypocre-tin [28], appear to be involved in the modulationof the sleep–wake cycle. Serotonin and DA bothfunction to promote waking and to inhibit slow-wave sleep and/or rapid eye movement sleep[29]. The most prominent pathways utilizing DAinclude the mesostriatal, mesocortical, andmesolimbic systems. Midbrain dopaminergicneurons may have the potential to influence thal-amocortical neuron excitability, and theoreticallythe sleep/wake state, through connections withthe striatum and through extensive collaterals tothe thalamus [30]. Neural mechanisms closelyrelated to behavioral states have been associatedwith the modulation of “burst-firing” patterns ofdopaminergic neurons [31]. REM sleep depriva-tion may produce a significant increase in striatalDA levels, suggesting that sleep deprivation caninduce plasticity in the mesostriatal DA system[32]. DA activity is itself under the influence of acircadian rhythm [33]. The rest/activity cycle ofDrosophila has features in common with that ofmammals [34]. Kume et al. reported that a certainDrosophila line with a mutation in the DA trans-porter gene has abnormally high levels of activityand reduced sleep, providing evidence that dop-aminergic signals regulate arousal [35].Hypocretin neurons are exclusively located inthe lateral and perifornical regions of the hypo-thalamus. They project widely through the cen-tral nervous system (CNS) including the locusceruleus, septal nuclei, thalamus, and substantianigra, where they have an excitatory effect onseveral arousal systems, including autonomic,metabolic, and neuroendocrine [36]. Studies ofhypocretin levels in the cerebrospinal fluid (CSF)of patients with PD have conflicted [37–39]. In apostmortem study of 11 patients with PD and fivecontrols, Thannickal et al. reported massive lossof hypocretin cells in the hypothalamus of PDpatients; the severity of loss of hypocretin corre-lated with the clinical stage of PD [40]. Theauthors postulated that loss of hypocretin cellsmay be the cause of narcolepsy-like symptoms ofPD. Loss of these cells occurs prior to onset ofdrug treatment in many PD patients. Politis et al.reported reductions of hypothalamic D2-receptoravailability using positron emission tomographywith (11)C-raclopride in PD patients [41].
    • 248 M.L. Moro-de-Casillas and D.E. RileyHowever, the results could not determine whetherthis reduction was disease related, due to chronicexposure to levodopa, or both. There are distinctpatterns of release of various hormones (includ-ing cortisol, growth hormone, and corticotrophin)during the sleep cycle, with the potential exis-tence of common regulatory pathways of thesleep EEG and the nocturnal hormone secretion[42, 43].There is consensus that both abnormalsleep and impaired daytime alertness occur in themajority of PD patients [44]; clinical observa-tions of sleepiness in PD further support the roleof DA in the sleep–wake cycle [31]. The effectsof levodopa and DA agonists on sleep [45] alsopoint toward a role of dopaminergic systems insleep. Thus it is not surprising that most PDpatients experience difficulties with sleep due tothe disease, its treatment, or both [46].Insomnia in Parkinson’s DiseaseSleep disorders are a common problem in patientswith PD [47–49]. Their frequency appears to behigher than that expected from the effects of agealone [50]. Prevalence figures for sleep disordersin PD range from 40 to 98 % [51, 52].Polysomnographic data in PD patients demon-strate a wide variety of findings (1) light frag-mented sleep [53], (2) decreased sleep efficiencies[54],(3)increasedwakefulness[54],(4)decreasedamounts of REM sleep [54], (5) increased REMsleep latencies [55], (6) fragmented REM sleep[54], (7) increased frequency of arousals [54], (8)decreased amounts of sleep spindles [55, 56], (9)poorly formed K complexes [55, 56], and (10)increased muscle activity in REM sleep (REMwithout atonia) [54]. It is evident that both themacro- and microstructure of sleep are affectedin this group of patients.The PRIAMO study found that 98.6 % ofpatients with PD (n=1,072) reported nonmotorsymptoms [57]. Insomnia was reported by 37 %;other commonly reported symptoms that couldalter sleep patterns included fatigue, anxiety, andleg pain. Sleep disturbances can occur at any stageof PD but are more common as the disease pro-gresses; this suggests a direct relation betweenimpaired sleep and severity of disease [51, 58]. Aprospective longitudinal cohort study of nocturnalsleeping problems in patients with PD over 8 yearsfound that more than 50 % of patients reportedinsomnia [59]. Patients with insomnia had higherdepression scores and were often female. Similarfindings were also reported by Verbaan et al., whofound higher insomnia rates in female patients anda strong relation between nighttime sleep prob-lems and depression [60]. Porter et al. reportedthat 22 % of 122 PD patients had marked sleepdisturbances, with the most common symptomsbeing sleep fragmentation and nocturia [61].Insomnia was an important and independent pre-dictor of poor health-related quality of life in apopulation-based cohort of patients with PD [62].The most common form of insomnia in PDpatients is that of frequent nocturnal awakenings,also known as sleep fragmentation [55]. Factoret al. studied sleep complaints, as well as the effectof sleep on motor symptoms, through a question-naire survey in 78 patients with PD (median age67 years old; average disease duration 6.7 years)and 43 elderly controls (median age 63) [50]. Sleepinitiation problems occurred frequently in bothgroups, with no significant difference betweenthem, but sleep fragmentation was more commonin PD patients (88.5 % in PD vs. 74.4 % in the con-trol group). In a community-based study, Tandberget al. found that the most common sleep com-plaints reported by 245 patients with PD weresleep fragmentation and early awakening [52]. Inthis study, patients with PD reported sleep disor-ders significantly more frequently than patientswith diabetes and healthy control subjects, with athird of the PD patients rating their overall night-time problem as moderate to severe. Anotherstudy, comparing 90 PD patients with 71 age-matched healthy subjects, showed a high preva-lence of sleep disturbances in both groups (81 %of PD patients vs. 92 % controls) [63]. There wereno differences between the groups regarding theprevalence of disturbances of sleep initiation ormaintenance; however, those PD patients whoexperiencedsleepmaintenancedifficultiesreporteda significantly greater number of awakenings.Kumar et al. reported the frequency and natureof sleep disturbances in 149 PD patients and 115
    • 24917 Insomnia in Parkinson’s Diseaseage-matched controls [51]. They found that 42 %of PD patients reported sleep problems, com-pared with 12 % of a healthy control population.Insomnia was reported by 39.6 % of patients butonly 5 % of the control group. Within the PDgroup, those patients with sleep complaints had alonger duration of disease, higher UnifiedParkinson’s Disease Rating Scale (UPDRS)scores and were receiving higher doses oflevodopa. They also had longer sleep latenciesthan those without sleep problems. Nighttimeawakenings were significantly associated withrigidity and Hoehn and Yahr (H&Y) scores.The frequency of sleep initiation difficulties inPD patients is not as well established as that ofsleep maintenance. Most studies have not docu-mentedsignificantdifferencesbetweenPDpatientsand control subjects [50, 52, 63]. However, Kaleset al. found sleep initiation problems to be a prom-inent problem in PD patients [46].Although it has been suggested that sleepdeprivation influences DA systems [64], dataconcerning the effects of sleep deprivation onmotor symptoms in PD patients are scarce andcontroversial. Bertolucci et al. reported improve-ment in rigidity, bradykinesia, gait, and posturedisturbances lasting 2 weeks after a single nightof total sleep deprivation (TSD) in 12 patientswith PD [65]. These results supported the posi-tive effects of REM sleep deprivation shown inan animal model of PD [66]. However, beneficialresults are not universal. Fifteen patients with PDunderwent one night of TSD, one night of partialsleep deprivation (PSD), and one control night ofnormal sleep. Mean UPDRS motor scores andtapping velocities did not show any substantialeffect of sleep deprivation [64]. Only four patientsafter PSD showed an improvement in their motorscore of greater than 20 % compared with thescore after normal sleep.Contributing FactorsThe etiology of light and fragmented sleep in PDis multifactorial [48, 67]. Treated patients withmore advanced disease typically experiencewearing off of antiparkinsonian medication effectat night, resulting in recurrence of tremor, rigid-ity, and akinesia and increased sleep latency.Rigidity and akinesia both contribute to inabilityto turn in bed, which has been rated as the mosttroublesome nocturnal symptom, affecting 65 %of 220 PD patients in one study [68]. Multiplemotor symptoms persist during sleep and inter-fere with its normal physiology [69]. During lightsleep, PD tremor can reappear [70]. The effect ofsleep on involuntary movements (dyskinesia) inPD and other movement disorders was studied byFish et al. [71]. They reported that dyskinesia inPD was most likely to occur after awakenings orin stage one sleep; this movement was very rareduring the deeper phases of sleep. The movementthat occurred without awakenings was usuallypreceded by arousal phenomena and, rarely, bysleep spindles or slow waves.Repetitive muscle contractions can occur dur-ing NREM sleep. Askenasy et al. reported thatNREM sleep transforms the waking “alternating”parkinsonian tremor into subclinical repetitivemuscle contractions [72]. Their amplitude andduration decreased as NREM sleep progressedand disappeared during REM sleep. Additionalmotor abnormalities that contribute to sleep frag-mentation include dystonia, which can lead topain [68], blinking and blepharospasm [69, 70],painful leg cramps [68], and fragmentary myo-clonus [73].A common complaint of PD patients is fre-quent urination, and nocturia was the most com-mon form of nighttime disability in a group of220 PD patients [68]. In this study, 79 % of thepatients had to “visit the lavatory” during thenight, and one-third needed to urinate three ormore times. When nocturnal urinary frequency iscompounded with the inability to walk withoutassistance (as in, for example, 35 % of these 220patients) [68], nocturia can represent a majorsource of stress and disability in PD. Urinary fre-quency in PD may be due to disease-related dys-autonomiaortoage-relatedurologicabnormalitiesand can increase patients’ morbidity, as it exposesthem to frequent falls and consequent injuries,including fractures [73], and further immobility.Dhawan et al. explored the nature and range ofsleep dysfunction in early, untreated PD (mean
    • 250 M.L. Moro-de-Casillas and D.E. RileyH&Y 1.9), and advanced PD (mean H&Y 3.4)[74]. Logistic regression analysis showed thatnocturia, cramps, dystonia, tremor, and daytimesomnolence were significantly impaired in drug-naïve PD patients compared with controls.Coexisting psychiatric and medical disorderscan also affect sleep in PD patients. Depressionmay play an important role in modulating normalsleep architecture [47], and early-morning awak-ening with inability to return to sleep is a funda-mental symptom of depression. The highprevalence of depression in PD patients makes itan important consideration in the differentialdiagnosis of insomnia. Depression is discussed indetail in an earlier chapter.Other disturbances of sleep that can contributeto insomnia, namely REM sleep behavior disor-der and sleep-related breathing disorders, aredetailed elsewhere in this volume. Other PD non-motor symptoms discussed elsewhere that mayaffect the ability to sleep restfully include pain,anxiety, and hallucinosis.Restless Legs SyndromeThe restless legs syndrome (RLS) is character-ized by an irresistible urge to move the limbs that(1) becomes evident or is accentuated in the eve-ning and at nighttime, (2) occurs when the legsare rested (sitting or lying down) and is relievedby moving the legs or walking, and (3) is accom-panied by paresthesias or dysesthesias variouslydescribed as creeping, crawling, itching, burning,pulling, aching, restless, tingling, cramping, orother sensations [75]. The onset is unilateral in40–50 % of cases. The legs are almost alwaysinvolved, but the arms may be affected as well in25–50 %. The majority of patients also experi-ence periodic limb movements in sleep (PLMS),and many display similar dyskinesias whileawake. Symptoms tend to increase with age. RLSmay affect as much as 5 % of the population, and10 % of those over 65. The main effect of RLS onsleep is sleep latency insomnia (i.e., delaying theonset of sleep), but RLS may also cause frag-mented, nonrestorative sleep, and occasionallyexcessive daytime sleepiness.Many cases are idiopathic or hereditary.However, as with insomnia in general, RLS is acommon disorder that appears to be even morecommon when associated with a variety ofchronic illnesses, including PD. Approximately20 % of PD patients report symptoms consistentwith RLS; in over 70 % of these cases, the onsetof PD precedes or occurs concomitantly with thedevelopment of RLS [76]. Some PD patientsclearly relate their RLS symptoms to the devel-opment of motor symptoms when the benefitfrom their medications wears off [77, 78]. Gunalet al. identified five such instances among 72 con-secutive PD patients with motor fluctuations [79].By contrast, Tan et al. could not find any PDpatients with RLS in a survey of 125 consecutivepatients [80], although the same authors reporteda prevalence of RLS of only 0.6 % in their gen-eral population. Möller et al. reviewed the asso-ciation between the two disorders and concludedthere was an increased risk of RLS in PD, albeitslight [81].It is important to identify RLS because of itshigh rate of response to treatment. Systematicsurvey of PD patients indicates that the majorityof affected individuals will not volunteer symp-toms of RLS [76]. In patients in whom the symp-toms of RLS fluctuate in tandem with motormanifestations of PD, patients may assume thatsuch symptoms are typical of “off” periods andnot a distinct experience. Thus, such historicalinformation must be actively and specificallysought in order to establish the diagnosis ofRLS.Effects of Antiparkinsonian TreatmentPharmacological agents used in the treatment ofPD may play a role as a cause of sleep disorders[45, 48, 82]. Dopaminergic medications haveprominent effects on both circadian rhythmsand sleep–wake modulatory systems [69]. Theeffects of levodopa on sleep are nonspecific,exerted through pre- and postsynaptic mecha-nisms, as well as through interaction with dif-ferent neurotransmitters [69]. Levodopasuppresses REM sleep and delays REM sleep
    • 25117 Insomnia in Parkinson’s Diseaselatency [45, 83]; it has improved daytime vigi-lance in narcoleptic patients [84]. In a question-naire study, the use and duration of levodopatherapy in patients with PD were associatedwith a higher frequency of sleep disruption, withsleep fragmentation being the most commonsleep complaint [85].Bromocriptine has induced changes in sleeparchitecture similar to levodopa, including shorterREM sleep, superficial sleep, and prolongation ofREM sleep latency, in PD patients [86]. Pergolide,bromocriptine, and apomorphine produce “bipha-sic effects” (opposite effects at low and highdoses) on sleep architecture in rats [87]. At lowdoses, they decrease wakefulness and increaseNREM sleep. The newer nonergoline dopaminer-gic agonists, ropinirole and pramipexole, alsoaffect sleep physiology. At lower doses, D3 ago-nists increase NREM and REM sleep and reducelocomotion in rats; with higher doses, D2/D3agonists improve locomotion, without majorsedation [88]. In one study, ropinirole was shownto improve sleep efficiency and total sleep time infive patients with chronic insomnia secondary toRLS [89]. The potential clinical effect of DAagonists and levodopa to induce “sleep attacks”is discussed in a succeeding chapter. Selegilinecan suppress REM sleep [90]. Puca et al. reportedan increase in sleep spindle activity in parkinso-nian patients following administration of amanta-dine [91].Treatment of Insomnia in Parkinson’sDiseaseThe first step in the management of insomnia inPD is correct identification of contributing fac-tors. A detailed history provided by the patient,and any bedmate or caregiver, is crucial. Forthose with complicated or varying sleep prob-lems, the use of a symptom diary could be useful.In some instances, diagnostic testing with poly-somnography might be necessary. Successfultreatment of sleep disturbances in PD patientscan postpone their institutionalization, allow thecaregiver better sleep, and improve quality of life[73, 92].If a specific cause for insomnia is found, itshould be treated first [3]. Comorbid conditionssuch as nocturia, sleep apnea, RLS, anxiety, anddepression should be addressed, as their treat-ment will likely improve sleep quality. Generalsleep hygiene rules should be recommended asappropriate to each individual. Some of theseinstructions include (1) reduce excessive time inbed; (2) increase exercise and physical activity;(3) curtail caffeine intake; (4) observe a fixedwake-up time; (5) avoid naps; (6) avoid caffeine,alcohol, or heavy meals before bedtime; (7) limitfluid intake after 17:00 h; (8) use available aidsfor getting in and out of bed; and (9) make medi-cations, water, and a bathroom or commode chaireasily accessible [3, 69, 73]. Sleep hygiene rulesshould be instituted no more than one at a time toenhance compliance. Behavioral therapy, throughstimulus control, sleep restriction, and sleephygiene education, plays an important role in thetreatment of insomnia [69, 73, 93]. Other non-pharmacologic measures, such as bright lighttherapy or chronotherapy, may be beneficial [92,93].Insomnia in a parkinsonian patient shouldalways prompt careful reassessment of dopamin-ergic therapy. Adjustment of dosages must becarefully individualized. In some patients, exces-sive dosages of dopaminergic medications shouldbe avoided at night. Levodopa can have an arousaleffect, potentiate wakefulness, and enhance sleepfragmentation [73]. On the other hand, increasesin dopaminergic medications may improve sleepsignificantly by improving motor symptoms, andspecifically tremor and akinesia. Activity andimmobility during sleep were recorded by meansof a wrist monitor in 84 PD patients and 83 age-and sex-matched normal controls [94]. In mild-to-moderate disease, levodopa and DA agonistswere disruptive to sleep by virtue of their effectson sleep regulation. However, in individuals withmore severe PD, the drugs had beneficial effectson nocturnal disability [94]. The effects on sleepof other medications, such as anticholinergics,selegiline, and amantadine, should also beconsidered.Use of hypnotics usually is not indicated, asthe role of these medications is primarily in the
    • 252 M.L. Moro-de-Casillas and D.E. Rileytreatment of acute insomnia, and in chronicinsomnia there is a risk of dependence [69, 73]. Ifbenzodiazepines are used, short-acting ones arepreferred; those with a long half-life can producedaytime sedation, dozing, and disturbances inperceptual skills [3, 73]. Newer, nonbenzodiaz-epine hypnotic agents have been well accepted inthe treatment of insomnia in the general popula-tion. Zolpidem and zaleplon have hypnosedativeactions comparable with those of benzodiaz-epines, but they display specific properties. Theyshare a short plasma half-life (zaleplon 1 h andzolpidem 5 h) and a limited duration of actionand are less sedating than benzodiazepines [95].A double-blind placebo-controlled trial of zolpi-dem in ten PD patients suggested that it may behelpful for parkinsonian motor symptoms as wellas insomnia [96].The role of melatonin in the treatment ofinsomnia in the general population is controver-sial [3]. Its use in PD requires furtherinvestigation.Nocturia frequently causes sleep disruption inPD patients. Oral anticholinergic agents, such asoxybutynin and tolterodine, may providesufficient antispasmodic effects on the urinarybladder, and both are available in sustained-release preparations for nighttime dosing.Suchowersky et al. found intranasal desmopres-sin to be a safe and effective tool for nocturnalpolyuria in PD [97].RLS fortunately shares with PD a responsive-ness to dopaminergic medication, and DA ago-nists are particularly appropriate in themanagement of RLS because of the greater ten-dency of levodopa to produce augmentation [98].Other agents effective in the treatment of RLSinclude gabapentin, clonazepam, and opiates.Sleep architecture in PD may improve withsubthalamic nucleus (STN) stimulation [99], withpallidotomy [100], or with combined STN–pedunculopontine nucleus stimulation [101]. Inten insomniac patients with PD on dopaminergictherapy, STN improved nighttime akinesia by60 %, suppressed axial dystonia, and increasedtotal sleep time by 47 % and sleep efficiency by36 % [99]. It also decreased the duration of wake-fulness after sleep. Periodic leg movements andmotor behavior during REM sleep were notinfluenced by stimulation [99].ConclusionInsomnia is a common complaint, and one of themost important determinants of quality of life, inPD patients. The most common form of insomniain PD patients is frequent nocturnal awakenings.Insomnia may be a direct complication of PD orits treatment or a by-product of other complica-tions such as depression, nocturia, and RLS.Proper management of insomnia involvesidentification and treatment of contributing fac-tors, careful assessment of the regimen of anti-parkinsonian medications, institution of goodsleep hygiene measures, and judicious use ofhypnotic medication.References1. American Sleep Disorders Association. The interna-tional classification of sleep disorders: diagnostic andcoding manual. Rochester, MN: American SleepDisorders Association; 1997.2. Polo-Kantola P. Sleep problems in midlife and beyond.Maturitas. 2011;68(3):224–32.3. Hauri PJ. Insomnia. Clin Chest Med. 1998;19(1):157–68.4. Gillin JC. Are sleep disturbances risk factors for anxi-ety, depressive and addictive disorders? Acta PsychiatrScand Suppl. 1998;393:39–43.5. Hossain JL, Shapiro CM. The prevalence, cost impli-cations, and management of sleep disorders: an over-view. Sleep Breath. 2002;6(2):85–102.6. Spiegel K, Knutson K, Leproult R, Tasali E, VanCauter E. Sleep loss: a novel risk factor for insulinresistance and Type 2 diabetes. J Appl Physiol.2005;99(5): 2008–19.7. Colrain IM. Sleep and the brain. Neuropsychol Rev.2011;21(1):1–4.8. Cricco M, Simonsick EM, Foley DJ. The impact ofinsomnia on cognitive functioning in older adults. JAm Geriatr Soc. 2001;49(9):1185–9.9. Altena E, Ramautar JR, Van Der Werf YD, VanSomeren EJ. Do sleep complaints contribute to age-related cognitive decline? Prog Brain Res. 2010;185:181–205.10. Sateia MJ, Doghramji K, Hauri PJ, Morin CM.Evaluation of chronic insomnia. An AmericanAcademy of Sleep Medicine review. Sleep.2000;23(2):243–308.
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