Nonmotor Aspects of Parkinson's Disease

Review Article Non-Motor Aspects of Parkinson’s Disease By Leora L. Borek, MD, Melissa M. Amick, PhD, and Joseph H. Friedman, MD ABSTRACT Parkinson’s฀disease฀is฀primarily฀considered฀ to฀be฀a฀movement฀disorder฀and฀is฀defined฀by฀ its฀motor฀signs.฀Yet,฀the฀behavioral฀manifestations฀of฀the฀disease฀are฀often฀more฀debilitating฀ than฀ its฀ motor฀ complications.฀This฀ review฀will฀focus฀on฀the฀non-motor฀aspects฀ of฀ Parkinson’s฀ disease,฀ including฀ mood,฀ psychosis,฀cognitive,฀sleep,฀fatigue,฀apathy,฀ delirium,฀and฀repetitive฀disorders,฀that฀may฀ occur.฀The฀phenomenology,฀pathology,฀and฀ treatment฀of฀the฀behavioral฀symptoms฀of฀ Parkinson’s฀disease฀will฀be฀discussed.฀ CNS฀Spectr.฀2006;11(7)541-554 INTRODUCTION Parkinson’s฀disease฀is฀defined฀by฀its฀motor฀ dysfunction.฀There฀are฀several฀different฀sets฀ of฀criteria฀for฀the฀diagnosis฀but฀all฀center฀ around฀the฀presence฀of฀the฀following฀problems:฀tremor฀at฀rest,฀rigidity,฀hypokinesia฀ (bradykinesia฀or฀akinesia),฀the฀presence฀of฀ gait,฀posture฀or฀balance฀changes฀typical฀of฀ the฀disorder,฀the฀absence฀of฀atypical฀features,฀ and฀the฀absence฀of฀an฀alternative฀explanation,฀ such฀as฀medications,฀strokes,฀or฀toxins.1฀There฀ Needs Assessment Parkinson’s฀disease฀has฀been฀important฀in฀the฀development฀of฀the฀field฀of฀neuropsychiatry.฀฀Behavioral฀symptoms฀are฀an฀important฀source฀of฀distress฀for฀many฀patients฀ with฀the฀disease.฀This฀review฀will฀focus฀on฀the฀findings฀of฀recent฀research฀and฀treatment฀of฀the฀most฀common฀behavioral฀manifestations฀of฀the฀disease.฀ Learning Objectives At฀the฀end฀of฀this฀activity,฀the฀participant฀should฀be฀able฀to:฀ •฀List฀the฀most฀common฀sleep฀disorders฀in฀Parkinson’s฀disease. •฀฀Give฀examples฀of฀neuropsychological฀testing฀that฀are฀useful฀in฀predicting฀dementia฀in฀Parkinson’s฀disease. •฀฀Understand฀the฀association฀between฀depression,฀anxiety฀and฀motor฀features฀of฀ Parkinson’s฀disease. •฀฀Understand฀the฀role฀of฀dopaminergic฀medication฀in฀psychosis฀and฀appropriate฀ treatment. Target Audience: Neurologists฀and฀psychiatrists CME Accreditation Statement: The฀Mount฀Sinai฀School฀of฀Medicine฀is฀ accredited฀by฀the฀Accreditation฀Council฀for฀Continuing฀Medical฀Education฀to฀provide฀ Continuing฀Medical฀Education฀for฀physicians.฀฀฀ The฀Mount฀Sinai฀School฀of฀Medicine฀designates฀this฀educational฀activity฀for฀a฀maximum฀of฀3฀AMA฀PRA฀Category฀1฀Credit(s)TM.฀฀Physicians฀should฀only฀claim฀credit฀commensurate฀with฀the฀extent฀of฀their฀participation฀in฀the฀activity.฀ It฀is฀the฀policy฀of฀Mount฀Sinai฀School฀of฀Medicine฀to฀ensure฀objectivity,฀balance,฀ independence,฀transparency,฀and฀scientific฀rigor฀in฀all฀CME-sponsored฀educational฀ activities.฀฀ Faculty Disclosure Policy Statement:฀All฀faculty฀participating฀in฀the฀ planning฀or฀implementation฀of฀a฀sponsored฀activity฀are฀expected฀to฀disclose฀to฀the฀ audience฀any฀relevant฀financial฀relationships฀and฀to฀assist฀in฀resolving฀any฀conflict฀of฀ interest฀that฀may฀arise฀from฀the฀relationship.฀฀Presenters฀must฀also฀make฀a฀meaningful฀disclosure฀to฀the฀audience฀of฀their฀discussions฀of฀unlabeled฀or฀unapproved฀drugs฀ or฀devices.฀This฀information฀will฀be฀available฀as฀part฀of฀the฀course฀material.฀ This฀activity฀has฀been฀peer-reviewed฀and฀approved฀by฀Eric฀Hollander,฀MD,฀chair฀at฀ Mount฀Sinai฀School฀of฀Medicine.฀Review฀Date:฀June฀20,฀2006. To Receive Credit for This Activity: Read฀this฀article,฀and฀the฀two฀ CME-designated฀accompanying฀articles,฀reflect฀on฀the฀information฀presented,฀ and฀then฀complete฀the฀CME฀quiz฀found฀on฀pages฀557฀and฀558.฀To฀obtain฀credits,฀ you฀should฀score฀70%฀or฀better.฀Termination฀date:฀July฀31,฀2008.฀The฀estimated฀ time฀to฀complete฀this฀activity฀is฀3฀hours. Dr. Borek is geriatric psychiatrist in the department of geriatric psychiatry at Brown University School of Medicine in Providence, Rhode Island. Dr. Amick is clinical neuropsychologist in the department of psychiatry and human behavior at Brown University Medical School. Dr. Friedman is clinical professor in the department of clinical neurosciences at Brown University School of Medicine. Disclosures: Dr. Borek does not have an affiliation with or financial interest in any organization that might pose a conflict of interest. Dr. Amick receives research support from Janssen. Dr. Friedman is a consultant for ACADIA, AstraZeneca, and Ovation; and he receives research support from Novartis. Submitted for publication: December 20, 2005, and accepted on June 15, 2006. Please direct all correspondence to: Leora L. Borek, MD, 90 Brown Street, Providence, RI 02906; Tel: 781-883-4755; E-mail: [email protected]. CNS Spectr 11:7 (Suppl 7) © MBL Communication Inc. 541 July 2006 Review Article is฀no฀diagnostic฀test฀for฀Parkinson’s฀disease.฀It฀is฀ only฀at฀autopsy฀that฀we฀can฀definitively฀confirm฀ the฀diagnosis฀with฀the฀presence฀of฀certain฀specific฀changes.฀And฀although฀James฀Parkinson 2฀ declared฀that฀the฀senses฀and฀intellect฀were฀intact,฀ the฀behavioral฀consequences฀of฀the฀disease฀are฀ its฀most฀devastating฀problem. There฀are฀a฀number฀of฀behavioral฀issues฀associated฀with฀Parkinson’s฀disease฀and฀because฀they฀ are฀so฀prevalent฀and฀stereotypic,฀it฀is฀this฀disorder฀that฀has฀probably฀been฀the฀most฀important฀ in฀the฀development฀of฀the฀field฀of฀neuropsychiatry.฀The฀issue฀of฀whether฀depression฀is฀intrinsic฀ or฀reactive฀has฀been฀a฀significant฀focus฀of฀attention.฀However,฀the฀most฀problematic฀issues฀have฀฀ been฀dementia฀and฀psychosis.฀ There฀are฀several฀behavioral฀problems฀in฀ Parkinson’s฀disease฀(Table),฀some฀intrinsic,฀some฀ reactive,฀and฀others฀iatrogenic.฀Complicating฀our฀ understanding,฀however,฀has฀been฀the฀increasing฀ knowledge฀of฀dementia฀with฀Lewy฀(DLB)฀bodies,฀ which฀may฀simply฀be฀one฀end฀of฀the฀Parkinson’s฀ disease฀spectrum฀or฀a฀different฀but฀related฀disease,฀but฀whose฀overlap฀with฀Parkinson’s฀disease฀confounds฀clinical฀studies. DEPRESSION Depression฀is฀one฀of฀the฀most฀common฀behavioral฀symptoms฀of฀Parkinson’s฀disease,฀with฀an฀ estimated฀prevalence฀of฀40%฀to฀50%.3-5 ฀Minor฀ depression฀and฀dysthymia฀account฀for฀a฀large฀ proportion฀of฀symptoms.3,6,7฀Diagnosing฀depression฀in฀Parkinson’s฀disease฀is฀often฀a฀challenge,฀ as฀the฀clinical฀symptoms฀of฀depression฀may฀be฀ mistaken฀for฀those฀of฀Parkinson’s฀disease,฀such฀ as฀flat฀affect,฀psychomotor฀slowing,฀sleep฀disturTABLE. Behavioral Problems in Parkinson’s Disease Intrinsic Iatrogenic Depression฀ Anxiety฀ Dementia฀ Executive฀dysfunction฀ Sleep฀disorders฀ Fatigue฀ Apathy฀ Akathisia฀ Weight฀loss฀ Pain Hallucinosis฀ Psychosis฀ Affective฀cycling฀ ฀฀฀฀(on-off฀motor฀fluctuations)฀ Sedation฀ Compulsions Borek฀LL,฀Amick฀M,฀Friedman฀JH.฀CNS฀Spectr.฀Vol฀11,฀No฀7.฀2006. CNS Spectr 11:7 (Suppl 7) © MBL Communication Inc. 542 bance,฀fatigue,฀and฀decreased฀libido.฀Depression฀ in฀Parkinson’s฀disease฀is฀reported฀to฀be฀qualitatively฀different฀from฀primary฀major฀depression฀in฀ that฀depressed฀Parkinson’s฀disease฀patients฀have฀ greater฀rates฀of฀anxiety,฀pessimism,฀irrationality,฀and฀less฀guilt฀and฀self-reproach฀compared฀to฀ depressed฀non-Parkinson’s฀disease฀patients.3,8,9฀ ฀T he฀etiology฀of฀depression฀in฀Parkinson’s฀ disease฀is฀unknown฀but฀may฀have฀a฀biological฀ basis฀and฀involve฀neuronal฀loss฀and฀a฀reduction฀ in฀ brain฀ catecholamines. 10 ฀ Postmortem฀ findings฀of฀Parkinson’s฀disease฀patients฀with฀a฀ history฀of฀depression฀show฀decreased฀numbers฀ of฀serotonin฀(5-HT)฀neurons฀in฀the฀dorsal฀raphe฀ nucleus 11 ฀and฀reduced฀dopamine฀neurons฀in฀ the฀ventral฀tegmental฀area฀compared฀to฀nondepressed฀Parkinson’s฀disease฀patients.12฀There฀is฀ a฀reported฀lowering฀of฀the฀major฀5-HT฀metabolite฀5-hydroxyindoleacetic฀acid฀in฀the฀cerebrospinal฀fluid฀in฀depressed฀but฀not฀nondepressed฀ Parkinson’s฀disease฀patients,฀suggesting฀a฀role฀of฀ 5-HT฀deficiency฀in฀depression.13฀Deep฀brain฀stimulation฀in฀the฀subthalamic฀nucleus฀is฀reported฀ to฀have฀antidepressant,฀depressant,฀and฀maniainducing฀effects฀in฀Parkinson’s฀disease฀patients,14฀ implicating฀the฀subthalamic฀nucleus฀in฀mood฀ disorders.฀Depression฀may฀also฀predate฀motor฀ symptoms,15฀suggesting฀a฀biochemical฀alteration฀ in฀Parkinson’s฀disease฀depression.฀ Depression฀in฀Parkinson’s฀disease฀may฀also฀ be฀“reactive”฀and฀result฀from฀the฀psychosocial฀ stress฀of฀having฀an฀incurable,฀debilitating฀disease.฀ Parkinson’s฀disease฀patients฀are฀faced฀with฀many฀ challenges,฀including฀adjustment฀to฀the฀loss฀of฀ physical฀ability฀and฀the฀consequences฀this฀may฀ bring,฀such฀as฀job฀loss,฀marital฀discord,฀and฀social฀ isolation.฀Patients฀who฀are฀diagnosed฀at฀an฀early฀ age฀may฀be฀particularly฀susceptible฀to฀developing฀depression฀since฀they฀often฀have฀more฀significant฀career฀and฀financial฀disruptions.฀Patients฀ with฀early-onset฀Parkinson’s฀disease฀(<55฀years฀of฀ age)฀have฀higher฀rates฀of฀depression฀compared฀ to฀those฀diagnosed฀with฀Parkinson’s฀disease฀at฀ a฀later฀age. 16,17 ฀In฀one฀study, 18 ฀depression฀was฀ more฀common฀in฀Parkinson’s฀disease฀patients฀ than฀in฀matched฀controls฀but฀rates฀did฀not฀differ฀ in฀patients฀with฀rheumatoid฀arthritis.฀In฀addition,฀ in฀the฀Parkinson’s฀disease฀and฀arthritis฀groups,฀ depression฀was฀associated฀with฀the฀severity฀of฀ illness฀and฀functional฀disability. 18฀Studies฀comparing฀ depression฀ in฀ Parkinson’s฀ disease฀ to฀ control฀medical฀populations 19-22 ฀have฀reported฀ conflicting฀outcomes,฀with฀some฀studies฀reportJuly 2006 Review Article ing฀ Parkinson’s฀ disease฀ patients฀ to฀ be฀ more฀ depressed฀than฀equally฀disabled฀control฀subjects.฀ It฀is฀likely฀that฀for฀individual฀patients฀there฀is฀often฀ both฀an฀intrinsic฀and฀reactive฀component. ฀An฀association฀between฀depression฀and฀particular฀clinical฀features฀of฀Parkinson’s฀disease฀has฀been฀ reported.฀Depression฀has฀been฀found฀to฀be฀higher฀ in฀patients฀with฀the฀akinetic฀rigid฀type฀of฀Parkinson’s฀ disease฀compared฀to฀the฀tremor-predominant฀ type 3,19 ฀and฀in฀patients฀with฀right฀sided฀motor฀ symptoms.3,16฀Cognitive฀impairment฀is฀associated฀ with฀depression฀in฀Parkinson’s฀disease฀patients.฀ One฀study 2 0 ฀found฀that฀cognitively฀impaired฀ patients฀had฀an฀increased฀risk฀of฀developing฀major฀ depression.฀Conversely,฀depression฀is฀related฀to฀a฀ more฀rapid฀cognitive฀decline฀in฀Parkinson’s฀disease฀ patients.23฀An฀association฀between฀depression฀and฀ greater฀motor฀disease฀severity฀in฀Parkinson’s฀disease฀has฀been฀reported.16,24 Depression฀is฀often฀clinically฀underrecognized฀ and฀undertreated฀and฀is฀not฀as฀well฀studied฀as฀ the฀motor฀aspects฀of฀the฀disease. 25฀ Depression฀ contributes฀significantly฀to฀disability฀in฀Parkinson’s฀ disease 7,26 ฀and฀has฀been฀found฀to฀be฀the฀most฀ important฀impairing฀factor฀for฀the฀quality฀of฀life฀in฀ Parkinson’s฀disease฀patients,฀even฀after฀accounting฀for฀motor฀disease฀severity.27,28฀ There฀is฀a฀lack฀of฀systematic฀clinical฀trials฀ evaluating฀the฀efficacy฀of฀antidepressants฀in฀ depressed฀Parkinson’s฀disease฀patients.฀A฀recent฀ meta-analysis29฀found฀a฀paucity฀of฀antidepressant฀ studies฀and฀no฀difference฀between฀active฀treatment฀and฀placebo฀in฀Parkinson’s฀disease฀depression.฀Treatment฀is฀complicated฀by฀the฀potential฀ increased฀sensitivity฀to฀adverse฀side฀effects฀of฀ antidepressants฀as฀well฀as฀drug-drug฀interactions฀from฀the฀medications฀the฀patient฀is฀already฀ taking.฀As฀autonomic฀dysfunction฀is฀integral฀to฀ Parkinson’s฀disease,฀tricyclic฀antidepressants฀ (TCAs)฀can฀aggravate฀orthostatic฀hypotension฀and฀ its฀anticholinergic฀side฀effects฀can฀worsen฀cognition,฀dry฀mouth,฀and฀constipation.฀These฀same฀ anticholinergic฀effects,฀however,฀may฀be฀used฀to฀ advantage฀and฀reduce฀drooling฀and฀inhibit฀an฀ overactive฀bladder.฀Serotonin฀selective฀reuptake฀ inhibitors฀(SSRIs)฀are฀better฀tolerated,฀with฀fewer฀ side฀effects฀and฀are฀typically฀the฀first฀choice฀for฀an฀ antidepressant.฀There฀are฀rare฀reports฀that฀SSRIs฀ worsen฀motor฀symptoms30-33฀but฀this฀is฀generally฀ not฀the฀case.34-38฀There฀is฀a฀small฀but฀increased฀ risk฀for฀developing฀5-HT฀syndrome฀when฀using฀ selegiline฀in฀combination฀with฀SSRIs฀or฀TCAs.39฀ Electroconvulsive฀therapy฀is฀beneficial฀in฀patients฀ CNS Spectr 11:7 (Suppl 7) © MBL Communication Inc. 543 with฀medication-refractory฀depression฀and฀usually฀improves฀motor฀function.40,41฀Psychotherapy฀ can฀be฀helpful฀for฀patients฀with฀mild฀depression฀ who฀have฀difficulty฀coping฀with฀their฀illness.฀As฀ depression฀occurs฀frequently฀in฀Parkinson’s฀disease฀and฀contributes฀to฀disability,฀it฀is฀important฀ to฀screen฀for฀this฀condition฀as฀effective฀management฀of฀depression฀is฀likely฀to฀improve฀the฀quality฀of฀life฀for฀Parkinson’s฀disease฀patients.฀ The฀Geriatric฀Depression฀Scale฀and฀Hamilton฀ Rating฀Scale฀for฀Depression 42 ฀are฀useful฀rating฀ scales฀that฀can฀distinguish฀between฀depressed฀ and฀nondepressed฀Parkinson’s฀disease฀patients.฀ Patients฀are฀generally฀started฀on฀an฀SSRI฀unless฀ particular฀side฀effects,฀as฀previously฀discussed,฀are฀ desired.฀For฀example,฀mirtazepine฀is฀highly฀sedating,฀increases฀appetite,฀and฀may฀improve฀tremor,฀ making฀it฀the฀drug฀of฀choice฀for฀a฀depressed,฀tremulous฀Parkinson’s฀disease฀patient฀who฀has฀nocturnal฀sleep฀problems฀and฀is฀losing฀weight.฀ ANXIETY Anxiety฀disorders฀are฀prevalent฀in฀Parkinson’s฀ disease฀and฀are฀reported฀to฀occur฀in฀up฀to฀40%฀of฀ patients.43,44฀The฀most฀common฀anxiety฀disorders฀ in฀Parkinson’s฀disease฀are฀panic฀disorder,฀generalized฀anxiety฀disorder,฀and฀social฀phobia. 45,46฀ Anxiety฀frequently฀coexists฀with฀depression฀in฀ Parkinson’s฀disease฀patients.46,47 Anxiety฀ disorder s฀ tend฀ to฀ appear฀ after฀ the฀diagnosis฀of฀Parkinson’s฀disease฀is฀established. 45,47,48 ฀They฀occur฀frequently฀in฀patients฀ who฀experience฀“on-off”฀motor฀fluctuations,46,47฀ especially,฀during฀the฀“off”฀phase. 45,47-49 ฀In฀one฀ study, 49 ฀the฀magnitude฀of฀the฀increase฀in฀anxiety฀level฀during฀“off”฀periods฀correlated฀with฀ the฀change฀in฀parkinsonian฀symptoms.฀Another฀ study50฀found฀that฀anxiety฀improved฀significantly฀ from฀the฀“off”฀to฀“on”฀state฀but฀then฀worsened฀ when฀dyskinesias฀were฀present.฀Such฀studies฀ suggest฀that฀anxiety฀may฀be฀a฀reaction฀to฀motor฀ symptoms.฀Alternatively,฀changes฀in฀neurotransmitters฀may฀occur฀during฀parkinsonian฀motor฀ fluctuations฀and฀contribute฀to฀anxiety.฀Alterations฀ in฀5-HT฀and฀norepinephrine฀are฀believed฀to฀play฀ important฀roles฀underlying฀anxiety฀in฀Parkinson’s฀ disease. 48,49 ฀While฀some฀studies 45,51 ฀have฀not฀ found฀a฀relationship฀between฀anxiety฀and฀motor฀ fluctuations,฀this฀clearly฀occurs฀in฀some฀patients.฀ Anxiety฀ is฀ an฀ uncommon฀ side฀ effect฀ of฀ Parkinson’s฀disease฀medications฀unless฀motor฀ fluctuations฀develop.฀While฀some฀studies 47,48฀ report฀an฀increase฀in฀anxiety฀and฀panic฀attacks฀ July 2006 Review Article in฀patients฀on฀levodopa฀(L-dopa)฀therapy,฀other฀ studies45,46,49฀failed฀to฀find฀a฀significant฀correlation฀ between฀anxiety฀and฀antiparkinsonian฀medication฀and฀some฀have฀found฀that฀L-dopa52,53฀and฀pergolide54฀reduce฀anxiety. The฀optimal฀pharmacologic฀treatment฀for฀anxiety฀in฀Parkinson’s฀disease฀patients฀has฀not฀been฀ established.฀Treatment฀should฀take฀into฀account฀ comorbid฀psychiatric฀and฀medical฀conditions,฀ such฀as฀depression฀and฀dementia,฀that฀may฀influence฀the฀type฀of฀medication฀used฀to฀treat฀anxiety.฀ There฀have฀been฀no฀randomized,฀controlled฀treatment฀trials฀of฀anxiety฀medication฀in฀Parkinson’s฀ disease.฀Commonly฀used฀medications฀include฀ SSRIs,฀benzodiazepines,฀TCAs,฀and฀buspirone.฀ Citalopram฀was฀found฀to฀be฀helpful฀for฀anxiety฀ in฀a฀small฀open-label฀trial฀treating฀depression.55฀ As฀most฀patients฀with฀Parkinson’s฀disease฀are฀ elderly฀and฀susceptible฀to฀falls,฀benzodiazepines฀ should฀be฀used฀with฀caution.฀Cognitive-behavioral฀therapy฀may฀have฀a฀role฀in฀alleviating฀anxiety฀symptoms฀in฀Parkinson’s฀disease.฀ PSYCHOSIS Psychosis฀is฀not฀considered฀a฀primary฀symptom฀ of฀idiopathic฀Parkinson’s฀disease.฀While฀there฀are฀ case฀reports฀from฀the฀pre-L-dopa฀era฀of฀psychosis฀ in฀Parkinson’s฀disease฀patients,฀the฀inability฀to฀reliably฀discriminate฀post-encephalitic฀parkinsonism฀ from฀idiopathic฀Parkinson’s฀disease฀and฀the฀lack฀ of฀recognition฀of฀the฀numerous฀parkinsonian฀disorders฀that฀are฀not฀idiopathic฀Parkinson’s฀disease฀ make฀these฀reports฀suspect.56฀The฀occurrence฀of฀ psychotic฀symptoms฀in฀an฀untreated฀Parkinson’s฀ disease฀patient฀would฀constitute฀an฀“atypical”฀ feature,฀casting฀doubt฀on฀the฀diagnosis. Psychosis฀in฀Parkinson’s฀disease฀may฀occur฀ as฀part฀of฀a฀delirium฀or฀with฀a฀clear฀sensorium.57฀ In฀either฀case,฀the฀predominant฀symptoms฀are฀ hallucinations฀and฀delusions.58,59฀These฀are฀fairly฀ stereotypic,฀with฀visual฀hallucinations฀predominating฀and฀the฀delusions฀are฀paranoid฀in฀nature.฀ A฀particularly฀unsettling฀and฀common฀hallucination฀is฀that฀of฀spousal฀infidelity,฀both฀for฀male฀ and฀female฀patients.58,60,61฀The฀occurrence฀of฀psychotic฀symptoms฀has฀proven฀to฀be฀the฀single฀ most฀important฀precipitant฀for฀nursing฀home฀ placement฀in฀Parkinson’s฀disease฀patients฀and฀ the฀most฀stressful฀problem฀for฀caretakers,฀outweighing฀the฀severity฀of฀motor฀dysfunction.62,63฀ The฀only฀clear฀risk฀factor฀for฀the฀development฀of฀ psychosis฀has฀been฀dementia,฀although฀depression,฀sleep฀disorders฀of฀various฀types,฀axial฀verCNS Spectr 11:7 (Suppl 7) © MBL Communication Inc. 544 sus฀appendicular฀motor฀symptoms,฀and฀the฀use฀ of฀a฀greater฀number฀of฀anti-Parkinson’s฀disease฀ drugs฀have฀been฀suggested.฀Psychosis,฀like฀hallucinosis,฀tends฀to฀be฀persistent.59฀It฀is฀also฀a฀bad฀ prognostic฀indicator.60-66฀Patients฀who฀are฀psychotic฀have฀an฀increased฀rate฀of฀nursing฀home฀ placement฀and฀a฀significantly฀increased฀mortality฀ rate.62-64,66,67฀How฀much฀of฀the฀symptomatology฀ may฀be฀due฀to฀dementia฀is฀uncertain฀since฀the฀ Parkinson’s฀disease฀drugs฀can฀only฀rarely฀be฀discontinued.68฀In฀studies฀of฀drug฀holidays,69฀a฀technique฀used฀3฀decades฀ago฀in฀which฀all฀Parkinson’s฀ disease฀medications฀were฀withdrawn฀for฀several฀ days,฀the฀psychotic฀symptoms฀resolved฀during฀ the฀time฀off฀the฀drugs,฀and฀did฀not฀resume฀when฀ low฀doses฀of฀the฀drugs฀were฀reinstituted,฀but฀did฀ recur฀when฀the฀drug฀doses฀started฀to฀increase.69฀ DLB฀and฀Parkinson’s฀disease฀with฀dementia฀and฀ psychosis฀are฀distinguishable฀only฀if฀the฀dementia฀develops฀before฀or฀within฀1฀year฀of฀the฀motor฀ symptoms,฀or฀if฀hallucinations฀develop฀unrelated฀ to฀medication. 70 ฀Treatment฀focuses฀on฀reducing฀the฀Parkinson’s฀disease฀medications฀to฀their฀ lowest฀level฀that฀allows฀an฀acceptable฀degree฀of฀ motor฀function฀and฀then฀adding฀an฀antipsychotic฀ if฀psychotic฀symptoms฀persist.59 Based฀on฀the฀experience฀of฀polypharmacy฀ in฀the฀treatment฀of฀epilepsy,฀most฀researchers57,59฀believe฀that฀it฀is฀better฀to฀reduce฀and฀then฀ eliminate฀as฀many฀drugs฀as฀possible฀rather฀than฀ maintaining฀low฀doses฀of฀several฀drugs.฀Virtually฀ all฀Parkinson’s฀disease฀experts71฀would฀recommend฀stopping฀anticholinergic฀medication฀first.฀ The฀other฀drugs,฀in฀the฀order฀of฀stopping฀priority,฀are฀amantadine฀and฀monoamine฀oxidase฀ inhibitors,฀dopamine฀agonists,฀and฀then,฀L-dopa.฀ Catechol-O-methyl฀transferase฀inhibitors฀do฀ not฀enter฀the฀brain฀in฀significant฀amounts฀and฀ add฀to฀the฀symptoms฀only฀by฀increasing฀L-dopa฀ availability.฀L-dopa฀produces฀the฀largest฀motor฀ effect฀with฀the฀least฀mental฀side฀effects฀of฀any฀of฀ the฀Parkinson’s฀disease฀medications. Although฀quetiapine฀has฀been฀the฀first-line฀ treatment฀of฀choice฀for฀psychosis฀in฀Parkinson’s฀ disease,59,72,73฀this฀is฀based฀entirely฀on฀open-label฀ data฀and฀anecdotal฀experience.74฀There฀have฀been฀ two฀published฀placebo-controlled฀trials฀of฀quetiapine฀in฀Parkinson’s฀disease฀and฀neither฀found฀ the฀drug฀to฀be฀effective.75,76฀Both,฀however,฀did฀ report฀that฀quetiapine฀had฀no฀deleterious฀effect฀ on฀motor฀function.฀Clozapine฀has฀been฀proven฀ effective฀in฀two฀double-blind,฀placebo-controlled฀ multicenter฀trials. 77,78 ฀In฀both฀trials,฀the฀mean฀ July 2006 Review Article dose฀was฀low฀(25฀mg/day฀in฀the฀United฀States฀ trial,฀37฀mg/day฀in฀the฀French฀study)฀and฀the฀ effect฀was฀the฀same,฀with฀significant฀improvement฀in฀psychosis฀without฀worsening฀of฀motor฀ function.฀In฀the฀US฀trial,฀clozapine฀was฀shown฀ to฀have฀significant฀benefit฀on฀tremor฀without฀ worsening฀ of฀ other฀ symptoms฀ and฀ signs฀ of฀ Parkinson’s฀disease.฀This฀supports฀several฀other฀ reports฀on฀the฀beneficial฀effect฀of฀clozapine฀on฀ tremor฀in฀Parkinson’s฀disease.77-79฀Unfortunately,฀ the฀potential฀side฀effect฀of฀agranulocytosis฀is฀not฀ dose-related฀so฀that฀the฀same฀monitoring฀rules฀ need฀to฀be฀used฀as฀with฀higher฀doses.79฀There฀is฀ limited฀open-label฀data฀on฀ziprasidone.80-82฀One฀ trial80฀reported฀benefit฀using฀the฀oral฀preparation฀ of฀the฀drug.฀Another฀found฀mild฀motor฀worsening฀in฀some฀patients฀and฀some฀psychiatric฀benefit.81฀The฀third฀observed฀clinical฀improvement฀ in฀psychosis฀without฀harmful฀motor฀decline฀ using฀the฀injectable฀formulation฀of฀the฀drug. 82฀ The฀other฀atypicals฀have฀had฀negative฀effects฀ on฀ motor฀ function.฀ Reports฀ on฀ risperidone฀ have฀been฀mixed,฀with฀some฀reports฀describing฀motor฀decline,83,84฀and฀others฀reporting฀good฀ tolerance.85,86฀Since฀risperidone฀clearly฀produces฀ parkinsonism฀in฀schizophrenia฀in฀a฀dose-related฀ manner,฀it฀is฀likely฀that฀some฀Parkinson’s฀disease฀ patients฀cannot฀tolerate฀it.฀Olanzapine฀has฀been฀ the฀subject฀of฀several฀double-blind,฀placebo-controlled฀trials,87-89฀all฀of฀which฀demonstrated฀significant฀motor฀decline฀and฀little฀antipsychotic฀ benefit.฀Quetiapine฀has฀been฀reported฀to฀be฀free฀ of฀motor฀effects฀in฀Parkinson’s฀disease,฀but฀while฀ the฀open-label฀studies฀have฀shown฀significant฀ antipsychotic฀benefit,฀the฀two฀double-blind฀controlled฀trials฀have฀not. 75,76 ฀Finally,฀aripiprazole฀ has฀been฀reported฀in฀two฀open-label฀prospective฀trials90,91฀to฀cause฀motor฀worsening฀in฀some฀ Parkinson’s฀disease฀patients฀even฀at฀doses฀<5฀ mg/day,฀although฀improving฀psychosis฀in฀some. The฀authors฀(LLB,฀JHF)฀treat฀psychosis฀initially฀with฀quetiapine,฀starting฀with฀12.5฀or฀25฀mg฀ QPM.฀We฀escalate฀daily,฀depending฀on฀response.฀ If฀quetiapine฀is฀not฀successful,฀we฀stop฀it฀and฀ begin฀clozapine฀at฀6.25฀or฀12.5฀mg฀at฀bedtime. ฀฀H allucinations฀occur฀in฀about฀one฀third฀of฀ drug-treated฀patients฀with฀Parkinson’s฀disease.9296 ฀This฀figure฀is฀derived฀from฀studies฀performed฀ in฀both฀the฀US฀and฀Europe.฀In฀almost฀all฀cases,฀ there฀are฀visual฀hallucinations,฀although฀auditory฀hallucinations฀may฀occur.58,94,97,98฀Other฀types฀ of฀hallucinations฀are฀considerably฀less฀common.99,100฀The฀hallucinations฀are฀fairly฀stereotypic฀ CNS Spectr 11:7 (Suppl 7) © MBL Communication Inc. 545 and฀are฀much฀different฀than฀the฀hallucinations฀ that฀ occur฀ in฀ primary฀psychiatric฀disorders,฀ primarily,฀because฀the฀images฀usually฀have฀ no฀emotional฀content,฀but฀also฀because฀most฀ patients฀have฀insight,฀and฀recognize฀the฀unreality฀of฀the฀image.฀The฀hallucinations฀are฀typically฀ of฀people,฀but฀may฀be฀of฀animals,฀such฀as฀dogs,฀ cats฀and฀insects. 94,95 ฀Occasionally,฀objects฀are฀ hallucinated,฀such฀as฀statues฀or฀trucks.฀The฀hallucinations฀tend฀to฀be฀constant฀from฀episode฀ to฀episode,฀so฀that฀the฀same฀group฀of฀people฀ is฀seen฀each฀time,฀typically฀wearing฀the฀same฀ clothing.฀The฀hallucinated฀images฀usually฀ignore฀ the฀patient,฀even฀when฀the฀patient฀tries฀to฀attract฀ their฀ attention.฀The฀ images฀ may฀ gesture฀ or฀ appear฀to฀talk฀among฀themselves,฀but฀generate฀ no฀sound.฀Visual฀hallucinations฀are฀more฀common฀in฀the฀evening,฀but฀are฀often฀seen฀during฀ the฀day.฀In฀many฀cases,฀the฀hallucinations฀are฀ better฀seen฀or฀only฀seen฀in฀a฀lighted฀portion฀of฀a฀ dark฀room,฀than฀in฀the฀twilight.฀ The฀following฀are฀illustrative฀cases฀we฀have฀ encountered฀in฀our฀clinic.฀One฀patient฀reported฀ seeing฀three฀little฀girls฀wearing฀ballet฀costumes,฀ dancing฀in฀her฀driveway฀as฀she฀washed฀dishes฀ in฀the฀evening.฀Another฀patient฀was฀angry฀at฀a฀ man฀who฀stood฀directly฀in฀front฀of฀the฀television,฀blocking฀the฀screen.฀Auditory฀hallucinations฀occur฀primarily฀in฀patients฀who฀also฀have฀ visual฀hallucinations.58,98฀They฀may฀take฀the฀form฀ of฀the฀visual฀hallucinations฀talking฀but฀more฀ often฀occur฀in฀a฀separate฀setting.฀The฀patient฀ hears฀indistinct฀voices฀or฀music฀coming฀from฀ another฀part฀of฀the฀house฀or฀down฀the฀street.฀ All฀the฀medications฀used฀to฀treat฀Parkinson’s฀ disease฀have฀the฀potential฀to฀induce฀hallucinations฀and฀it฀appears฀that฀the฀hallucinations฀do฀ not฀differ฀as฀a฀function฀of฀which฀drug฀is฀taken.101฀ While฀studies฀of฀hallucinators 66 ฀do฀not฀reveal฀ differences฀in฀drug฀intake,฀double-blinded฀studies฀comparing฀dopamine฀agonist฀monotherapy฀ to฀L-dopa฀monotherapy฀clearly฀demonstrate฀ that฀hallucinations฀are฀more฀likely฀to฀occur฀with฀ the฀dopamine฀agonist.฀ The฀only฀confirmed฀risk฀factor฀for฀the฀development฀of฀hallucinations฀has฀been฀dementia.฀Age,฀ drug฀dose,฀drug฀type,฀duration฀of฀disease,฀and฀ gender฀have฀not฀been฀shown฀to฀be฀risk฀factors.฀ Autopsy฀studies102฀have฀demonstrated฀that฀visual฀ hallucinations฀are฀clearly฀related฀to฀the฀presence฀ of฀Lewy฀bodies฀and฀that฀patients฀with฀parkinsonian฀conditions฀who฀do฀not฀have฀Lewy฀bodies฀at฀ autopsy฀are฀unlikely฀to฀have฀had฀hallucinations.102฀ July 2006 Review Article In฀DLB฀patients,฀visual฀hallucinations฀correlate฀with฀ DEMENTIA AND the฀presence฀of฀Lewy฀bodies฀in฀the฀amygdala.102,103฀ PARKINSON’S DISEASE Visual฀hallucinations฀are฀predictive฀of฀the฀developA฀significant฀percentage฀of฀Parkinson’s฀disease฀ ment฀of฀dementia. patients฀will฀experience฀cognitive฀decline฀severe฀ enough฀to฀meet฀criteria฀for฀dementia.฀This฀section฀ will฀briefly฀review฀the฀prevalence,฀risk฀factors,฀and฀ COGNITIVE DEFICITS IN pattern฀of฀cognitive฀dysfunction฀in฀patients฀with฀ NON-DEMENTED PARKINSON’S Parkinson’s฀disease.฀ DISEASE PATIENTS ฀฀Prevalence,฀frequency,฀and฀incidence฀of฀dementia฀ Parkinson’s฀disease฀is฀a฀neurodegenerative฀disor114,115 vary฀widely฀across฀studies, ฀in฀part฀due฀to฀differder฀that฀was฀once฀thought฀to฀affect฀only฀motor฀funcences฀in฀sample฀size,฀attrition,฀differences฀in฀patient฀ tioning.฀It฀is฀well฀recognized฀that฀this฀disease฀process฀ disrupts฀functions฀across฀multiple฀cognitive฀domains.฀ population,฀study฀design,฀and฀criteria฀for฀diagnosing฀ While฀there฀can฀be฀considerable฀variability฀among฀ dementia฀in฀Parkinson’s฀disease฀patients.฀In฀a฀review฀ individuals,฀Parkinson’s฀disease฀patients฀in฀the฀early฀ of฀studies฀published฀between฀1984–2001฀on฀the฀prev114 stage฀of฀the฀disease฀do฀not฀typically฀demonstrate฀ alence฀and฀frequency฀of฀Parkinson’s฀disease, ฀the฀ impairments฀in฀the฀areas฀of฀language,฀recognition฀ clinic/hospital฀cohort฀frequency฀ranged฀from฀6%฀to฀ memory,฀and฀praxis.฀By฀contrast,฀mild฀impairments฀ 29%,฀whereas฀the฀prevalence฀was฀relatively฀higher฀ in฀visual฀spatial฀abilities,฀free฀recall฀memory,฀working฀ in฀community฀based฀studies,฀ranging฀between฀ memory,฀attention,฀and฀bradyphrenia฀are฀often฀doc- 12%฀and฀41%.฀Strikingly,฀a฀more฀recent฀report฀of฀ 115 umented.104-106฀Deficient฀performance฀on฀tasks฀requir- Norwegian฀Parkinson’s฀disease฀patients ฀indicated฀ ing฀executive฀functions,฀such฀as฀set฀shifting,฀internal฀ that฀the฀8-year฀prevalence฀of฀dementia฀was฀78.2%.฀ control฀of฀attention,฀sequencing,฀and฀temporal฀order- In฀a฀study฀of฀New฀York฀City฀patients,฀individuals฀with฀ ing,฀are฀also฀observed฀in฀this฀group.104,105,107,108฀Many฀of฀ Parkinson’s฀disease฀were฀1.7฀times฀more฀likely฀to฀ the฀cognitive฀deficits฀observed฀in฀Parkinson’s฀disease฀ develop฀dementia฀compared฀to฀an฀age-฀and฀edu116 patients฀resemble฀impairments฀demonstrated฀by฀ cation-matched฀control฀group. ฀By฀contrast,฀studies฀conducted฀in฀Norway฀and฀England฀report฀that฀ patients฀with฀damage฀to฀the฀frontal฀lobes.฀ ฀฀T he฀cognitive฀impairments฀characteristic฀of฀ Parkinson’s฀disease฀patients฀are฀5.9฀and฀5.1฀times,฀ 115,117 Parkinson’s฀disease฀patients฀are฀typically฀attributed฀ respectively,฀more฀likely฀to฀develop฀dementia. The฀reliable฀identification฀of฀Parkinson’s฀disease฀ to฀striato-nigral฀degeneration;฀that฀is,฀the฀biochemical฀changes฀related฀to฀dopamine฀loss฀within฀the฀ patients฀at฀risk฀of฀developing฀dementia฀is฀imporbasal฀ganglia.฀Postmortem฀biochemical฀analysis฀ tant฀to฀patients,฀caregivers,฀and฀physicians฀for฀treathas฀shown฀that฀depletion฀of฀dopamine฀in฀the฀head฀ ment฀and฀long-term฀planning,฀especially฀since฀the฀ of฀the฀caudate฀was฀profound,฀with฀<4%฀remaining฀ presence฀of฀dementia฀is฀a฀significant฀predictor฀of฀ compared฀to฀non-Parkinson’s฀disease฀samples. 109฀ nursing฀home฀placement.61฀Increasing฀age117-120฀and฀ The฀caudate฀is฀part฀of฀several฀basal฀ganglia฀thala- hallucinations115,117฀have฀been฀identified฀as฀unique฀ mocortical฀circuits฀involving฀different฀regions฀of฀the฀ predictors฀of฀dementia.฀Findings฀are฀mixed฀for฀other฀ prefrontal฀cortex.110-112฀This฀connectivity฀pattern฀sug- variables,฀such฀as฀disease฀severity117-121฀and฀low฀levgests฀that฀in฀Parkinson’s฀disease฀patients,฀the฀pre- els฀of฀formal฀education.117,119฀Depression,117,118,120,122฀ frontal฀cortex฀may฀be฀functionally฀deafferented฀due฀ gender,117-119฀and฀longer฀duration฀of฀illness118,119฀appear฀ to฀reduced฀dopamine฀availability฀in฀the฀striatum.฀ to฀be฀unrelated.฀ Neuropsychological฀measures฀of฀frontal฀system฀ Dysregulation฀of฀the฀frontal฀lobes฀is฀frequently฀cited฀ as฀the฀explanation฀for฀a฀range฀of฀cognitive฀impair- functions฀and฀memory฀have฀also฀been฀found฀to฀ ments฀documented฀in฀non-demented฀Parkinson’s฀ predict฀conversion฀to฀dementia.฀In฀the฀domain฀of฀ disease฀patients.฀Additionally,฀other฀neurotransmit- executive฀function,฀performance฀on฀the฀Stroop฀ ter฀systems฀necessary฀for฀intact฀cognitive฀function- interference฀test, 119,121 ฀verbal฀fluency, 119,120 ฀digit฀ ing฀(ie,฀aspects฀of฀memory฀and฀attention)฀are฀also฀ span฀backwards฀from฀the฀Wechsler฀Memory฀Scaledisrupted฀by฀the฀neuropathology฀of฀Parkinson’s฀dis- Revised,122฀perseverative฀errors฀on฀the฀Wisconsin฀ ease,฀including฀the฀cholinergic฀networks,฀noradren- Card฀Sorting฀Test, 120 ฀and฀identities฀and฀oddities฀ ergic฀system,฀and฀reductions฀in฀5-HT.113฀In฀sum,฀the฀ from฀the฀Mattis฀Dementia฀Rating฀Scale 120 ฀were฀ cognitive฀deficits฀observed฀in฀Parkinson’s฀disease฀ the฀best฀predictors฀of฀dementia.฀In฀the฀domain฀ are฀likely฀due฀to฀a฀disruption฀of฀multiple฀neurotrans- of฀memory,฀immediate฀and฀delayed฀recall฀from฀a฀ mitter฀systems฀impacting฀the฀functions฀of฀the฀frontal฀ selective฀reminding฀task,120฀encoding฀and฀recognition฀from฀the฀California฀Verbal฀Learning฀Test,122฀ lobes฀and฀their฀cortical฀projections. CNS Spectr 11:7 (Suppl 7) © MBL Communication Inc. 546 July 2006 Review Article and฀the฀memory฀subtests฀of฀the฀Cambridge฀ Examination฀for฀Mental฀Disorders฀of฀the฀Elderly฀ section฀B฀(CAMCOG)117฀were฀identified฀as฀unique฀ predictors฀of฀conversion฀to฀dementia.฀Hobson฀ and฀colleagues117฀also฀report฀that฀the฀language฀ subtest฀of฀the฀CAMCOG฀was฀predictive฀of฀incident฀dementia,฀while฀other฀studies฀do฀not฀confirm฀that฀language฀skills฀relate฀to฀Parkinson’s฀ disease฀dementia. 120,122 ฀As฀larger฀studies฀with฀ more฀precise฀neuropsychological฀batteries฀are฀ conducted,฀the฀identification฀of฀cognitive฀markers฀for฀dementia฀may฀clarify฀both฀the฀nature฀and฀ causes฀of฀Parkinson’s฀disease฀dementia. Neuropathological฀findings฀have฀shown฀that฀ the฀diagnosis฀of฀Parkinson’s฀disease฀dementia฀ may฀suggest฀the฀presence฀of฀an฀additional฀neurological฀disease,฀such฀as฀Alzheimer’s฀disease,฀ Pick’s฀disease,฀progressive฀supranuclear฀palsy,฀ corticobasal฀ganglionic฀disease,฀multi-system฀ atrophy,฀DLB,฀or฀frontal฀temporal฀dementia.123฀For฀ example,฀in฀a฀sample฀of฀31฀patients฀who฀developed฀dementia฀after฀onset฀of฀Parkinsonism,123฀ autopsy฀revealed฀that฀29%฀had฀neuropathological฀ findings฀consistent฀with฀Alzheimer’s฀disease,฀10%฀ to฀26%฀had฀evidence฀of฀DLB,฀6%฀had฀vascular฀ changes฀within฀the฀basal฀ganglia,฀and฀55%฀had฀ no฀identifiable฀cause฀of฀dementia.฀A฀more฀recent฀ study฀using฀α-synuclein฀immunohistochemical฀ analysis114฀reported฀that฀12฀out฀of฀13฀patients฀had฀ findings฀of฀DLB฀as฀the฀primary฀pathological฀cause฀ for฀dementia,฀one฀patient฀was฀judged฀to฀have฀progressive฀supranuclear฀palsy฀and฀none฀met฀criteria฀for฀Alzheimer’s฀disease.฀In฀a฀larger฀study฀of฀ Parkinson’s฀disease฀dementia฀neuropathology฀ (n=88),124฀it฀was฀also฀observed฀that฀few฀patients฀ met฀pathological฀criteria฀for฀Alzheimer’s฀disease,฀ whereas฀cognitive฀status฀was฀linearly฀related฀to฀ the฀number฀of฀Lewy฀bodies฀present. D u e ฀ t o ฀ t h e ฀ c o m m o n ฀ c o - o c c u rr e n c e ฀ o f฀ Parkinson’s฀disease฀dementia,฀Alzheimer’s฀disease,฀and฀DLB฀neuropathology,฀cognitive฀profiles฀are฀used฀to฀distinguish฀Parkinson’s฀disease฀ dementia฀from฀Alzheimer’s฀disease฀and฀DLB.฀To฀ aid฀in฀the฀differentiation฀of฀Parkinson’s฀disease฀ dementia฀from฀Alzheimer’s฀disease,฀differences฀ focus฀on฀the฀amnestic฀quality฀of฀memory฀loss฀ typical฀of฀Alzheimer’s฀disease฀patients฀relative฀to฀ the฀“dysexecutive฀syndrome”฀of฀Parkinson’s฀disease฀patients,฀in฀which฀acquisition฀and฀delayed฀ recall฀are฀disrupted,฀while฀recognition฀memory฀ remains฀intact.125฀To฀aid฀in฀the฀differentiation฀of฀ Parkinson’s฀disease฀from฀DLB,฀the฀Lewy฀Body฀ Consensus฀Workshop 70 ฀recommends฀that฀flucCNS Spectr 11:7 (Suppl 7) © MBL Communication Inc. 547 tuations฀in฀attention,฀visual฀hallucinations,฀and฀ parkinsonism฀are฀consistent฀with฀DLB,฀whereas฀ patients฀who฀develop฀dementia฀after฀12฀months฀ of฀extrapyramidal฀signs฀are฀better฀characterized฀ as฀having฀Parkinson’s฀disease฀dementia. 70,126฀ Despite฀these฀recently฀proposed฀guidelines,฀it฀is฀ likely฀that฀behavioral฀studies฀of฀Parkinson’s฀disease฀dementia฀may฀have฀included฀some฀patients฀ who฀met฀pathological฀criteria฀for฀Alzheimer’s฀ disease฀or฀DLB,฀which฀may฀explain฀some฀of฀the฀ inconsistencies฀noted฀in฀previous฀studies.105฀ Parkinson’s฀disease฀dementia฀cognitive฀profiles฀can฀be฀variable,฀considering฀that฀dementia฀ may฀indicate฀a฀comorbid฀neurological฀illness.฀ Zakzanis฀and฀Freedman127฀conducted฀a฀meta-analysis฀reviewing฀83฀studies฀on฀the฀neuropsychological฀performance฀of฀non-demented฀patients฀ with฀Parkinson’s฀disease฀and฀Parkinson’s฀disease฀ dementia฀patients฀relative฀to฀age-equivalent฀control฀groups.฀Of฀the฀seven฀cognitive฀domains฀identified,฀the฀Parkinson’s฀disease฀dementia฀patients฀ differed฀most฀from฀the฀control฀participants฀in฀the฀ domains฀of฀manual฀dexterity,฀cognitive฀flexibility,฀abstraction,฀and฀delayed฀recall฀(presented฀in฀ rank฀order,฀effect฀sizes:฀2.4–1.8). 127 ฀By฀contrast,฀ relative฀to฀the฀control฀group,฀the฀non-demented฀ Parkinson’s฀disease฀patients฀performed฀more฀ poorly฀in฀the฀domains฀of฀delayed฀recall฀and฀manual฀dexterity฀(effect฀sizes:฀1.3–0.8).127฀In฀general,฀ this฀meta-analysis฀found฀that฀Parkinson’s฀disease฀ dementia฀patients฀demonstrate฀more฀severe฀ impairments฀in฀similar฀cognitive฀domains฀relative฀ to฀non-demented฀Parkinson’s฀disease฀patients,฀ which฀is฀dissimilar฀to฀other฀degenerative฀disorders฀ involving฀cortical฀functions.฀ While฀prevalence,฀frequency,฀and฀incidence฀of฀ dementia฀vary,฀it฀is฀possible฀to฀conclude฀that฀a฀ significant฀portion฀of฀Parkinson’s฀disease฀patients฀ will฀develop฀dementia.฀Future฀prospective฀longitudinal฀studies฀linking฀neuropsychological฀performance฀to฀neuropathologic฀confirmation฀of฀clinical฀ diagnosis฀are฀necessary฀to฀determine฀the฀relationship฀between฀early฀cognitive฀changes฀and฀ the฀development฀of฀dementia฀as฀well฀as฀to฀better฀ define฀the฀cognitive฀phenotypes฀of฀Parkinson’s฀ disease฀dementia,฀Alzheimer’s฀disease,฀and฀DLB. Rivastigmine฀is฀the฀only฀cognition฀enhancing฀ agent฀tested฀in฀Parkinson’s฀disease฀dementia฀on฀ a฀large฀scale.฀It฀is฀equally฀or฀more฀effective฀in฀ Parkinson’s฀disease฀than฀in฀Alzheimer’s฀disease,฀ and฀does฀not฀cause฀motor฀worsening. 128฀Many฀ small฀studies 129-131฀of฀the฀cholinesterase฀inhibitors฀support฀these฀results.฀Therefore,฀we฀advoJuly 2006 Review Article cate฀their฀use,฀so฀long฀as฀they฀are฀discontinued฀ if฀they฀produce฀no฀benefit.฀While฀published฀data฀ clearly฀supports฀rivastigmine,฀there฀is฀no฀reason,฀ a฀priori,฀to฀believe฀that฀any฀one฀of฀these฀drugs฀is฀ more฀helpful฀than฀another. of฀consciousness,฀marked฀declines฀in฀cognitive฀performance,฀increased฀confusion,฀and฀disorientation฀ from฀baseline฀are฀the฀hallmark฀signs.฀In฀psychotic฀ patients,฀baseline฀memory,฀orientation,฀and฀cognition฀are฀unimpaired.138 OTHER BEHAVIORAL SYNDROMES SLEEP Probably฀the฀most฀important฀naturally฀occurring฀ behavioral฀syndrome฀is฀apathy.฀This฀is฀a฀common฀ disorder,฀affecting฀>10%฀of฀Parkinson’s฀disease฀ patients.132,133฀Apathy฀is฀particularly฀common฀in฀ depressed฀Parkinson’s฀disease฀patients฀and฀seems฀ to฀be฀increased฀in฀demented฀patients.133฀Apathy,฀of฀ course,฀bothers฀the฀caregivers฀and฀family฀and฀not฀ the฀patient,฀so฀it฀is฀usually฀a฀complaint฀that฀is฀not฀ spontaneously฀mentioned฀by฀the฀patient.฀This฀type฀ of฀information฀has฀to฀be฀determined฀by฀direct฀questioning฀of฀the฀patient฀or฀the฀family.฀It฀is฀distressing฀ for฀family฀members฀to฀observe฀a฀formerly฀vibrant฀ person฀spend฀endless฀hours฀sitting฀in฀front฀of฀the฀ television,฀not฀caring฀if฀it฀is฀on฀or฀off฀or฀what฀program฀is฀playing.฀Apathy฀is฀believed฀to฀be฀a฀prefrontal฀lobe฀dysfunction134฀and฀has฀no฀known฀treatment.฀ It฀is฀related฀to฀fatigue฀in฀that฀both฀are฀amotivational฀ syndromes฀and฀patients฀may฀confuse฀the฀two.฀As฀ there฀is฀no฀known฀effective฀treatment฀for฀apathy฀ in฀Parkinson’s฀disease,฀we฀believe฀in฀treatment฀ with฀antidepressants฀in฀the฀hope฀that฀the฀apathy฀ is฀part฀of฀a฀depressive฀syndrome.฀Stimulant฀medication฀may฀have฀a฀role฀but฀has฀not฀been฀tested฀in฀ Parkinson’s฀disease฀for฀this฀indication. Although฀emotional฀lability฀has฀been฀reported฀ to฀occur฀in฀40%฀of฀Parkinson’s฀disease฀patients,135฀ we฀believe฀that฀is฀an฀overestimate.฀Most฀cases฀ of฀emotional฀incontinence฀involve฀sadness,฀with฀ inappropriate฀tearfulness,฀such฀as฀crying฀during฀ a฀sad฀movie฀in฀a฀manner฀that฀is฀embarrassing฀ and฀different฀from฀the฀premorbid฀personality.฀ Inappropriate฀laughter฀is฀much฀less฀common136฀ but฀both฀are฀equally฀embarrassing.฀Usually,฀the฀ emotional฀state฀is฀a฀gross฀exaggeration฀of฀what฀ the฀patient฀is฀feeling฀but฀sometimes฀the฀affect฀ is฀completely฀at฀odds฀with฀the฀patient’s฀mood.฀ Tearfulness฀is฀sometimes฀treated฀with฀an฀SSRI฀ but฀recent฀data฀on฀dextromethorphan, 137 ฀combined฀with฀quinidine฀to฀allow฀greater฀drug฀levels฀ to฀reach฀the฀brain,฀has฀demonstrated฀that฀pseudobulbar฀affect฀may฀be฀partly฀controlled. Delirium฀is฀common฀in฀Parkinson’s฀disease฀ patients฀due฀to฀their฀comorbid฀medical฀problems฀ and฀multiple฀medications.฀Distinguishing฀delirium฀ from฀drug-induced฀psychosis฀may฀be฀difficult,฀ especially฀in฀a฀demented฀patient.฀Fluctuating฀levels฀ Sleep฀disorders฀are฀common฀in฀Parkinson’s฀ disease฀and฀are฀estimated฀to฀occur฀in฀60%฀to฀ 98%฀ of฀ patients. 13 9 - 14 3 ฀ Sleep฀ disturbances฀ in฀ Parkinson’s฀disease฀include฀sleep฀fragmentation,฀daytime฀somnolence,฀sleep฀apnea,฀restless฀ legs฀syndrome฀(RLS),฀nightmares,฀and฀rapid฀eye฀ movement฀behavior฀disorder฀(RBD).144-149 Frequent฀nighttime฀awakenings฀are฀the฀most฀ common฀sleep฀complaint฀among฀Parkinson’s฀disease฀patients.139,143-145,150฀Sleep฀fragmentation฀was฀ found฀to฀occur฀three฀times฀more฀frequently฀in฀ Parkinson’s฀disease฀patients฀than฀in฀healthy฀agematched฀controls฀(38.9%฀versus฀12%).139฀A฀study฀ using฀polysomnography151฀found฀that฀Parkinson’s฀ disease฀patients฀not฀taking฀antiparkinsonian฀ medication฀had฀significantly฀less฀total฀sleep฀time฀ and฀sleep฀efficiency,฀more฀frequent฀awakenings,฀ and฀greater฀overall฀waking฀time฀compared฀to฀ controls.฀A฀number฀of฀factors฀may฀contribute฀ to฀difficulties฀maintaining฀sleep฀in฀Parkinson’s฀ disease฀patients.฀These฀include฀bladder฀hyperactivity,฀sleep฀apnea,฀tremors,฀inability฀to฀turn฀ over฀in฀bed,฀painful฀leg฀cramps,฀nightmares,฀and฀ RBD.143-145,152฀Several฀studies139,153-157฀found฀depression฀to฀be฀significantly฀associated฀with฀sleep฀ disturbances฀in฀the฀Parkinson’s฀disease฀population.฀In฀a฀community-based฀study,139฀depression,฀ rather฀than฀stage฀of฀Parkinson’s฀disease,฀was฀the฀ strongest฀predictor฀of฀disturbed฀sleep.฀In฀a฀study฀ examining฀mood฀and฀sleep฀in฀Parkinson’s฀disease฀ patients฀attending฀a฀movement฀disorders฀clinic,157฀ researchers฀found฀depression฀to฀be฀significantly฀ associated฀with฀poor฀sleep฀quality.฀Anxiety฀may฀ interfere฀with฀sleep฀onset฀and฀contribute฀to฀nighttime฀arousals.฀Antiparkinsonian฀medication฀may฀ have฀an฀influence฀on฀sleep฀in฀Parkinson’s฀disease฀ patients.฀Stimulation฀of฀dopaminergic฀neurons฀is฀ associated฀with฀arousal฀and฀suppression฀of฀rapid฀ eye฀movement฀(REM)฀sleep. 158,159฀One฀study 160฀ found฀that฀the฀daily฀dose฀of฀levodopa฀or฀use฀of฀a฀ dopamine฀agonist฀was฀the฀strongest฀predictor฀of฀ sleep฀disturbance. Excessive฀daytime฀sleepiness฀(EDS)฀commonly฀occurs฀in฀patients฀with฀Parkinson’s฀disease.฀Studies฀have฀found฀daytime฀somnolence฀to฀ be฀more฀common฀in฀Parkinson’s฀disease฀patients฀ CNS Spectr 11:7 (Suppl 7) © MBL Communication Inc. 548 July 2006 Review Article compared฀to฀controls.161,162฀EDS฀is฀associated฀with฀ more฀advanced฀disease฀and฀dopaminergic฀medication162,163฀as฀well฀as฀longer฀duration฀of฀disease฀ and฀male฀gender.157,163฀Potential฀contributing฀factors฀to฀EDS฀may฀include฀intrinsic฀abnormalities฀ in฀Parkinson’s฀disease,฀concurrent฀medical฀illness,฀ sedating฀medication,฀and฀the฀effects฀of฀nocturnal฀ sleep฀disturbance.฀Sleep฀attacks฀(sudden,฀irresistible฀onset฀of฀sleep฀without฀awareness฀of฀falling฀ asleep)฀have฀been฀described฀in฀patients฀taking฀ dopamine฀agonists.164-167฀The฀term฀“sleep฀attack”฀ has฀been฀disputed฀and฀an฀alternative฀view฀is฀that฀ Parkinson’s฀disease฀patients฀fall฀asleep฀because฀ they฀are฀continuously฀sleepy฀(ie,฀they฀have฀EDS)฀ and฀are฀placed฀in฀situations฀in฀which฀resistance฀ to฀sleep฀is฀decreased฀(ie,฀periods฀of฀inactivity).168฀ Sleep฀attacks฀are฀reported฀to฀occur฀with฀all฀dopaminergic฀medication165฀and฀while฀their฀frequency฀ is฀unknown,฀they฀are฀considered฀rare.฀฀ ฀B oth฀ central฀ and฀ obstructive฀ sleep฀ apnea฀ have฀ been฀ described฀ in฀ Parkinson’s฀ disease฀ patients.169,170฀While฀some฀studies170,171฀report฀sleep฀ apnea฀to฀be฀more฀common฀in฀Parkinson’s฀disease฀patients฀compared฀to฀controls,฀other฀studies172,173฀found฀no฀significant฀differences.฀Sleep฀ apnea฀is฀known฀to฀increase฀with฀age174฀ and฀it฀is฀ unclear฀whether฀sleep฀apnea฀in฀Parkinson’s฀disease฀patients฀is฀a฀reflection฀of฀the฀disease฀process฀ or฀of฀age,฀as฀most฀Parkinson’s฀disease฀patients฀are฀ elderly.฀RLS฀may฀occur฀more฀often฀in฀Parkinson’s฀ disease฀patients฀compared฀to฀the฀control฀population.175,176฀RLS฀is฀characterized฀by฀an฀urge฀to฀move฀ the฀limbs,฀associated฀with฀an฀unpleasant฀sensation,฀that฀is฀worsened฀by฀rest฀and฀relieved฀with฀ activity.177฀While฀sleep฀apnea฀disrupts฀sleep฀continuity,฀RLS฀results฀in฀sleep-onset฀insomnia.฀ Other฀sleep฀disturbances฀in฀the฀Parkinson’s฀ disease฀population฀include฀nightmares฀and฀RBD.฀ Nightmares฀are฀associated฀with฀nocturnal฀awakening฀and฀contribute฀to฀disturbed฀sleep.฀The฀ frequency฀of฀nightmares฀in฀Parkinson’s฀disease฀ patients฀is฀estimated฀to฀be฀between฀5.7%฀and฀ 53.3%.152,157,178฀An฀association฀between฀nightmares฀ and฀dopaminergic฀medication 152,178 ฀has฀been฀ reported฀but฀it฀is฀unclear฀whether฀this฀represents฀ a฀causal฀association฀or฀a฀parallel฀progression฀of฀ the฀motor฀and฀behavioral฀aspects฀of฀the฀disease.฀ RBD฀is฀characterized฀by฀a฀loss฀of฀muscle฀atonia฀during฀REM฀sleep฀and฀prominent฀motor฀ activity฀associated฀with฀dream฀mentation. 179฀ Patients฀enact฀their฀dreams,฀which฀are฀often฀violent฀in฀nature฀and฀involve฀being฀chased,฀attacked,฀ or฀defending฀oneself฀from฀attack.฀RBD฀may฀be฀ CNS Spectr 11:7 (Suppl 7) © MBL Communication Inc. 549 idiopathic฀or฀associated฀with฀neurodegenerative฀diseases฀affecting฀the฀brainstem.฀RBD฀has฀ a฀male฀predominance157,180-182฀and฀is฀associated฀ with฀longer฀duration฀of฀Parkinson’s฀disease.157,180฀ It฀affects฀up฀to฀one฀third฀of฀Parkinson’s฀disease฀ patients157,182,183฀and฀can฀lead฀to฀significant฀injuries฀to฀both฀the฀patient฀and฀sleeping฀partner.181 The฀ management฀ of฀ sleep฀ disorder s฀ in฀ Parkinson’s฀disease฀involves฀identifying฀and฀ treating฀the฀underlying฀cause.฀This฀includes฀ assessing฀for฀any฀concurrent฀medical฀or฀psychiatric฀factors฀that฀may฀contribute฀to฀the฀problem.฀ We฀recommend฀the฀Epworth฀Sleepiness฀Scale184฀ for฀ measuring฀ daytime฀ somnolence.฀Actual฀ diagnoses฀of฀sleep฀disorders฀require฀an฀overnight฀polysomnogram.฀When฀evaluating฀elderly฀ patients฀with฀Parkinson’s฀disease,฀it฀is฀important฀ to฀consider฀that฀both฀quantitative฀and฀qualititative฀changes฀occur฀in฀sleep฀with฀normal฀aging.185฀ Counseling฀patients฀in฀sleep฀hygiene฀measures฀ may฀be฀helpful฀and฀if฀not฀successful,฀pharmacologic฀approaches฀should฀be฀considered.฀Sleep฀ apnea฀may฀require฀a฀continuous฀positive฀airway฀pressure฀mask,฀although฀these฀are฀often฀not฀ well฀tolerated.฀Occasionally,฀a฀jaw฀prosthesis฀or฀ minor฀surgical฀procedure฀can฀be฀helpful.฀RBD฀ responds฀well฀to฀low฀doses฀of฀clonazepam฀given฀ at฀bedtime.฀Bladder฀problems฀may฀be฀insurmountable,฀as฀sedatives฀may฀result฀in฀bedwetting.฀Restricting฀fluid฀intake฀prior฀to฀bedtime฀is฀ recommended.฀Sedating฀drugs,฀such฀as฀diphenhydramine,฀trazodone,฀quetiapine,฀mirtazapine,฀ and฀benzodiazepines,฀may฀be฀helpful฀in฀treating฀ insomnia.฀Occasionally,฀anti-soporifics,฀such฀as฀ modafinil฀100–400฀mg฀QAM฀or฀amphetamines,฀ can฀be฀helpful฀in฀improving฀daytime฀wakefulness,฀thus฀reducing฀daytime฀naps,฀leading฀to฀ better฀nocturnal฀sleeping.฀ FATIGUE Fatigue฀is฀a฀common฀problem฀in฀virtually฀every฀ medical,฀neurologic,฀and฀psychiatric฀disorder.186,187฀ Its฀importance฀in฀neurological฀diseases,฀however,฀ has฀been฀recognized฀only฀in฀the฀past฀2฀decades฀ or฀so188฀and฀has฀largely฀focused฀on฀multiple฀sclerosis.189฀It฀is฀a฀frequent฀symptom฀in฀Parkinson’s฀ disease฀and฀is฀poorly฀understood. 190-195 ฀There฀ are฀two฀major฀categories฀of฀fatigue:฀mental฀and฀ physical,฀although฀others฀have฀been฀described.196฀ Physical฀fatigue฀is฀subdivided฀into฀central฀and฀ peripheral฀components.190 ฀Most฀studies191-194 ฀of฀ fatigue฀have฀not฀distinguished฀between฀the฀two,฀ which฀are฀often฀present฀together.฀In฀several฀studJuly 2006 Review Article ies฀performed฀in฀the฀US฀and฀Europe,฀the฀following฀observations฀were฀made:฀~50%฀of฀patients฀ attending฀a฀Parkinson’s฀disease฀center฀suffer฀ from฀fatigue, 191,192,195 ฀considerably฀higher฀than฀ control฀populations,฀and฀about฀one฀third฀of฀all฀ Parkinson’s฀disease฀patients฀consider฀fatigue฀their฀ most฀severe฀Parkinson’s฀disease-related฀problem,฀worse฀than฀their฀motor฀problems.191฀Fatigue฀ is฀unrelated฀to฀motor฀disability฀and฀is฀encountered฀early฀in฀the฀disease,฀usually฀before฀the฀diagnosis฀is฀made.฀It฀has฀a฀different฀character฀than฀ the฀fatigue฀experienced฀prior฀to฀the฀onset฀of฀ Parkinson’s฀disease.฀In฀a฀recent฀study฀restricted฀to฀ subjects฀with฀newly฀diagnosed,฀mild฀Parkinson’s฀ disease,฀who฀agreed฀to฀participate฀in฀a฀large฀ multicentered,฀ placebo-controlled฀ drug฀ trial฀ (hence,฀a฀highly฀restricted,฀motivated,฀and฀mildly฀ impaired฀cohort),฀one฀third฀of฀patients฀suffered฀ from฀fatigue.197฀Fatigue฀was฀mildly฀responsive฀to฀ L-dopa฀compared฀to฀placebo.197฀There฀is,฀otherwise,฀little฀data฀on฀the฀effects฀of฀medications฀on฀ fatigue.198฀While฀fatigue฀is฀associated฀with฀depression,฀it฀is฀almost฀as฀common฀in฀populations฀that฀ exclude฀patients฀with฀depression฀or฀sleep฀disorders.199฀It฀should฀be฀noted฀that฀depression,฀which฀ is฀common฀in฀Parkinson’s฀disease,฀confounds฀our฀ ability฀to฀understand฀fatigue฀since฀fatigue฀is฀one฀ of฀the฀core฀diagnostic฀symptoms฀used฀to฀diagnose฀depression฀in฀the฀Diagnostic฀and฀Statistical฀ Manual,฀Fourth฀Edition.200 While฀sleep฀disorders฀may฀overlap฀with฀fatigue,฀ it฀appears฀that฀Parkinson’s฀disease฀patients฀are฀ able฀to฀distinguish฀the฀tiredness฀they฀experience฀ from฀sleep฀impairment,฀from฀the฀experience฀they฀ denote฀by฀the฀term฀“fatigue.”201 ฀฀T here฀is฀no฀known฀gender฀predilection฀or฀ particular฀set฀of฀motor฀impairments฀associated฀with฀fatigue.฀Parkinson’s฀disease฀worsens฀motor฀efficiency฀so฀that฀patients฀require฀ more฀ energy฀ to฀ breathe฀ and฀ exercise฀ than฀ normal฀controls. 202-205฀However,฀no฀difference฀ was฀ found฀ in฀ exercise฀ efficiency฀ between฀ fatigued฀and฀non-fatigued฀Parkinson’s฀disease฀ patients.206฀Fatigued฀patients฀were฀less฀active,฀ demonstrated฀reduced฀endurance,฀and฀did฀not฀ require฀more฀energy฀per฀unit฀of฀work.206 ฀฀There฀have฀been฀few฀reports฀on฀the฀long-term฀ outcome฀of฀fatigue฀in฀Parkinson’s฀disease.195,207฀ Fatigue฀worsens฀over฀time,฀but฀the฀prevalence฀ of฀fatigue฀seems฀to฀increase฀only฀mildly.฀The฀little฀data฀that฀exists฀suggests฀that฀fatigue฀appears฀ early฀in฀the฀course,฀possibly฀predating฀onset฀of฀ motor฀symptoms,฀and฀does฀not฀resolve.฀While฀ CNS Spectr 11:7 (Suppl 7) © MBL Communication Inc. 550 some฀patients฀develop฀fatigue฀later,฀and฀some฀ improve,฀ most฀ fatigued฀ Parkinson’s฀ disease฀ patients฀remain฀fatigued฀throughout฀their฀lifetime.฀ There฀is฀no฀data฀suggesting฀that฀these฀patients฀ suffer฀from฀severe฀tremor฀or฀medication-induced฀ dyskinesias,฀which฀may฀cause฀fatigue. ฀฀฀There฀is฀no฀known฀treatment฀for฀fatigue฀ unless฀an฀etiology,฀such฀as฀anemia,฀hypothyroidism,฀or฀depression,฀is฀identified. REPETITIVE DISORDERS The฀recognition฀that฀dopamine฀agonists฀may฀ induce฀pathological฀gambling฀in฀Parkinson’s฀disease฀patients฀who฀were฀never฀so฀inclined, 208-210฀ helped฀place฀the฀problem฀of฀drug-induced฀repetitive฀behaviors฀into฀an฀interesting฀perspective.211฀ When฀L-dopa฀was฀first฀introduced,฀there฀was฀an฀ interest฀in฀its฀potential฀aphrodisiac฀properties.฀This฀ was฀difficult฀to฀interpret,฀given฀the฀circumstances฀ of฀formerly฀“frozen”฀people฀recovering฀mobility.฀ However,฀there฀have฀been฀reports฀on฀compulsive฀ sexual฀activity฀linked฀to฀L-dopa212,213฀and฀overeating,212฀but฀these฀have฀been฀few.฀A฀few฀reports฀on฀ “punding”฀then฀emerged,214,215฀showing฀a฀connection฀to฀certain฀repetitive฀behaviors฀seen฀primarily฀ in฀amphetamine฀and฀cocaine฀addicts.฀Compulsive฀ behaviors฀are฀thought฀to฀relieve฀inner฀anxiety฀in฀ that฀the฀performance฀of฀a฀stereotypic฀action฀as฀ part฀of฀a฀compulsive฀disorder฀presumably฀relieves฀ inner฀stress.฀It฀is฀unclear฀if฀this฀is฀the฀same฀for฀ punders.฀They฀find฀satisfaction฀in฀performing฀their฀ rituals,฀and฀become฀irritable฀when฀interrupted,฀ but฀do฀not฀suffer฀from฀an฀underlying฀anxiety฀disorder.฀Punding฀may฀arise฀as฀the฀“loss฀of฀inhibition฀ of...฀automatic฀habits.”211 The฀connection฀between฀dopaminergic฀drugs฀ and฀repetitive฀behaviors฀is฀unclear.฀In฀the฀case฀ of฀pathological฀gambling,฀there฀appears฀to฀be฀a฀ connection฀to฀dopamine฀agonists,฀particularly฀ pramipexole,฀but฀this฀may฀simply฀represent฀a฀ sampling฀bias฀as฀most฀cases฀are฀reported฀from฀ the฀US,฀where฀pramipexole฀is฀the฀leading฀dopamine฀ agonist.฀ However,฀ Kurlan 2 16 ฀ described฀ patients฀who฀developed฀their฀behavior฀after฀ being฀on฀stable฀doses฀of฀medication,฀without฀resolution฀on฀reducing฀the฀drug฀dose.฀Furthermore,฀ the฀behavior฀does฀not฀respond฀to฀antipsychotic฀ medication,฀as฀might฀be฀expected฀with฀a฀dopamine฀excess฀disorder.216฀Nor฀does฀it฀respond฀well฀ to฀SSRIs,216฀as฀do฀typical฀obsessive-compulsive฀ disorders.฀Our฀own฀experience฀has฀been฀that฀ reducing฀or฀eliminating฀the฀dopamine฀agonist฀ usually฀leads฀to฀resolution฀of฀the฀behavior.฀ July 2006 Review Article NON-BEHAVIORAL CHANGES ฀ o ฀ i n t r i n s i c ฀ o r ga n ฀ ch a n g e s ฀ o c c u r ฀ i n฀ N Parkinson’s฀ disease.฀There฀ are฀ autonomic฀ problems฀and฀skin฀changes,฀but฀none฀are฀specific฀to฀Parkinson’s฀disease.฀ T h e ฀ m o s t ฀ c o m m o n ฀ s k i n ฀ c h a n g e s ฀ i n฀ Parkinson’s฀disease฀are฀increased฀oiliness฀and฀ a฀fungal฀infection฀causing฀seborrheic฀dermatitis.฀The฀former฀predisposes฀to฀the฀latter฀so฀that฀ they฀occur฀in฀the฀same฀areas,฀typically,฀the฀forehead,฀malar฀and฀chin฀regions฀of฀the฀face.฀The฀ skin฀becomes฀erythematous฀and฀scaly,฀and฀dandruff฀is฀common.฀ ฀฀Autonomic฀changes฀may฀be฀as฀problematic฀ as฀the฀behavioral฀changes.217,218฀Perhaps฀the฀single฀most฀bothersome฀problem฀is฀constipation.฀ Lewy฀bodies฀have฀been฀found฀in฀the฀myenteric฀ plexus฀and฀there฀is฀most฀likely฀a฀loss฀of฀dopaminergic฀cells฀throughout฀the฀gut฀that฀contributes฀ to฀constipation.฀This฀does฀not฀respond฀to฀dopaminergic฀medication,฀however.฀The฀next฀most฀ common฀problem฀is฀orthostatic฀hypotension฀ due฀to฀direct฀involvement฀of฀the฀autonomic฀ganglia฀by฀the฀disease฀process,฀often฀exacerbated฀ by฀medications.฀Bladder฀hyperactivity,฀causing฀ frequency฀and฀urgency,฀is฀common฀and฀complicates฀preexisting฀bladder฀disorders฀caused฀by฀ prostatism฀or฀childbirth.฀Although฀cardiac฀innervation฀is฀affected฀by฀Parkinson’s฀disease,฀this฀is฀ rarely฀a฀clinical฀problem.219฀Bowel฀incontinence฀ is฀not฀a฀direct฀effect฀of฀Parkinson’s฀disease. Smell฀is฀affected฀early฀in฀Parkinson’s฀disease฀ but฀is฀rarely฀a฀clinical฀complaint.฀Muller฀and฀colleagues220฀have฀convincingly฀demonstrated฀that฀ the฀olfactory฀tubercle฀is฀the฀first฀brain฀location฀ affected฀by฀Parkinson’s฀disease฀so฀that฀diminished฀smell฀and฀its฀attendant฀problem,฀reduced฀ taste,฀are฀harbingers฀of฀the฀disease. CONCLUSION Although฀ the฀ majority฀ of฀ patients฀ with฀ Parkinson’s฀disease฀are฀primarily฀treated฀for฀their฀ motor฀signs,฀the฀behavioral฀manifestations฀of฀ the฀disease฀are฀often฀significant฀and฀contribute฀ to฀disability.฀Physicians฀should฀be฀aware฀of฀the฀ need฀to฀evaluate฀for฀the฀neuropsychiatric,฀cognitive,฀and฀sleep฀complications฀of฀Parkinson’s฀disease.฀Early฀recognition฀of฀non-motor฀symptoms฀ is฀essential฀as฀effective฀treatment฀can฀reduce฀ morbidity฀and฀improve฀the฀quality฀of฀life฀of฀ Parkinson’s฀disease฀patients.฀CNS CNS Spectr 11:7 (Suppl 7) © MBL Communication Inc. 551 REFERENCES 1.฀ Hughes฀ AJ,฀ Daniel฀ SE,฀ Kilford฀ L,฀ Lees฀ AJ.฀ Accuracy฀ of฀ clinical฀ diagnosis฀ of฀ idiopathic฀ Parkinson’s฀ disease:฀ a฀ clinico-pathological฀ study฀ of฀ 100฀ cases.฀ J฀ Neurol฀ Neurosurg฀Psychiatry.฀1992;55:181-184. 2.฀ Parkinson฀J.฀An฀Essay฀on฀the฀Shaking฀Palsy.฀฀London,฀England:฀Sherwood,฀Neely฀ and฀Jones;฀1817. 3.฀ Cummings฀ JL.฀ Depression฀ and฀ Parkinson’s฀ disease:฀ a฀ review.฀ Am฀ J฀ Psychiatry.฀ 1992;149:443-454. 4.฀ Dooneief฀G,฀Mirabello฀E,฀Bell฀K,฀Marder฀K,฀Stern฀Y,฀Mayeux฀R.฀An฀estimate฀of฀the฀incidence฀of฀depression฀in฀idiopathic฀Parkinson’s฀disease.฀Arch฀Neurol.฀1992;49:305-307. 5.฀ Zesiewicz฀ TA,฀ Gold฀ M,฀ Chari฀ G,฀ Hauser฀ RA.฀ Current฀ issues฀ in฀ depression฀ in฀ Parkinson’s฀disease.฀Am฀J฀Geriatr฀Psychiatry.฀1999;7:110-118. 6.฀ Tandberg฀E,฀Larsen฀JP,฀Aarsland฀D,฀Cummings฀JL.฀The฀occurrence฀of฀depression฀in฀ Parkinson’s฀disease.฀A฀community-based฀study.฀Arch฀Neurol.1996;53:175-179. 7.฀ Liu฀CY,฀Wang฀SJ,฀Fuh฀JL,฀Lin฀CH,฀Yang฀YY,฀Liu฀HC.฀The฀correlation฀of฀depression฀with฀ functional฀activity฀in฀Parkinson’s฀disease.฀J฀Neurol.฀1997;244:493-498. 8.฀ Slaughter฀JR,฀Slaughter฀KA,฀Nichols฀D,฀Holmes฀SE,฀Martens฀MP.฀Prevalence,฀clinical฀manifestations,฀etiology,฀and฀treatment฀of฀depression฀in฀Parkinson’s฀disease.฀J฀ Neuropsychiatry฀Clin฀Neurosci.฀2001;13:187-196. 9.฀ Henderson฀R,฀Kurlan฀R,฀Kersun฀JM,฀Como฀P.฀Preliminary฀examination฀of฀the฀comorbidity฀ of฀ anxiety฀ and฀ depression฀ in฀ Parkinson’s฀ disease.฀ J฀ Neuropsychiatry฀ Clin฀ Neurosci.฀1992;4:257-264. 10.฀McDonald฀ WM,฀ Richard฀ IH,฀ DeLong฀ MR.฀ Prevalence,฀ etiology,฀ and฀ treatment฀ of฀ depression฀in฀Parkinson’s฀disease.฀Biol฀Psychiatry.฀2003;54:363-375. 11.฀Paulus฀W,฀Jellinger฀K.฀The฀neuropathologic฀basis฀of฀different฀clinical฀subgroups฀of฀ Parkinson’s฀disease.฀J฀Neuropathol฀Exp฀Neurol.฀1991;50:743-755. 12.฀Brown฀ AS,฀ Gershon฀ S.฀ Dopamine฀ and฀ depression.฀ J฀ Neural฀ Transm฀ Gen฀ Sect.฀ 1993;91:75-109. 13.฀Mayeux฀R,฀Stern฀Y,฀Cote฀L,฀Williams฀JB.฀Altered฀serotonin฀metabolism฀in฀depressed฀ patients฀with฀Parkinson’s฀disease.฀Neurology.฀1984;34:642-646. 14.฀Takeshita฀S,฀Kurisu฀K,฀Trop฀L,฀Arita฀K,฀Akimitsu฀T,฀Verhoeff฀NP.฀Effect฀of฀subthalamic฀ stimulation฀on฀mood฀state฀in฀Parkinson’s฀disease:฀evaluation฀of฀previous฀facts฀and฀ problems.฀Neurosurg฀Rev.฀2005;28:179-186. 15.฀Starkstein฀SE,฀Preziosi฀TJ,฀Bolduc฀PL,฀Robinson฀RG.฀Depression฀in฀Parkinson’s฀disease.฀J฀Nerv฀Ment฀Dis.฀1990;178:27-31. 16.฀Cole฀SA,฀Woodard฀JL,฀Juncos฀JL,฀Kogos฀JL,฀Youngstrom฀EA,฀Watts฀RI.฀Depression฀and฀ disability฀in฀Parkinson’s฀disease.฀J฀Neuropsychiatry฀Clin฀Neurosci.฀1996;8:20-25. 17.฀Kostic฀VS,฀Filipovic฀SR,฀Lecic฀D,฀Momcilovic฀D,฀Sokic฀D,฀Sternic฀N.฀Effect฀of฀age฀ at฀ onset฀ on฀ frequency฀ of฀ depression฀ in฀ Parkinson’s฀ disease.฀ J฀ Neurol฀ Neurosurg฀ Psychiatry.฀1994;57:1265-1267. 18.฀Gotham฀AM,฀Brown฀RG,฀Marsden฀CD.฀Depression฀in฀Parkinson’s฀disease:฀a฀quantitative฀and฀qualitative฀analysis.฀J฀Neurol฀Neurosurg฀Psychiatry.฀1986;49:381-389. 19.฀Starkstein฀SE,฀Petracca฀G,฀Chemerinski฀E,฀et฀al.฀Depression฀in฀classic฀versus฀akinetic-rigid฀Parkinson’s฀disease.฀Mov฀Disord.฀1998;13:29-33. 20.฀Tandberg฀E,฀Larsen฀JP,฀Aarsland฀D,฀Laake฀K,฀Cummings฀JL.฀Risk฀factors฀for฀depression฀in฀Parkinson’s฀disease.฀Arch฀Neurol.฀1997;54:625-630. 21.฀Menza฀ M,฀ Marin฀ H,฀ Kaufman฀ K,฀ Mark฀ M,฀ Lauritano฀ M.฀ Citalopram฀ treatment฀ of฀ depression฀in฀Parkinson’s฀disease:฀the฀impact฀on฀anxiety,฀disability,฀and฀cognition.฀J฀ Neuropsychiatry฀Clin฀Neurosci.฀2004;16:315-319. 22.฀Ehmann฀ TS,฀ Beninger฀ RJ,฀ Gawel฀ MJ,฀ Riopelle฀ RJ.฀ Depressive฀ symptoms฀ in฀ Parkinson’s฀ disease:฀ a฀ comparison฀ with฀ disabled฀ control฀ subjects.฀ J฀ Geriatr฀ Psychiatry฀Neurol.฀1990;3:3-9.฀ 23.฀Starkstein฀SE,฀Mayberg฀HS,฀Leiguarda฀R,฀Preziosi฀TJ,฀Robinson฀RG.฀A฀prospective฀ longitudinal฀ study฀ of฀ depression,฀ cognitive฀ decline,฀ and฀ physical฀ impairments฀ in฀ patients฀with฀Parkinson’s฀disease.฀J฀Neurol฀Neurosurg฀Psychiatry.฀1992;55:377-382. 24.฀Schrag฀A,฀Jahanshahi฀M,฀Quinn฀NP.฀What฀contributes฀to฀depression฀in฀Parkinson’s฀ disease?฀Psychol฀Med.฀2001;31:65-73. 25.฀Shulman฀LM,฀Taback฀RL,฀Rabinstein฀AA,฀Weiner฀WJ.฀Non-recognition฀of฀depression฀ and฀other฀non-motor฀symptoms฀in฀Parkinson’s฀disease.฀Parkinsonism฀Relat฀Disord.฀ 2002;8:193-197. 26.฀Weintraub฀D,฀Moberg฀PJ,฀Duda฀JE,฀Katz฀IR,฀Stern฀MB.฀Effect฀of฀psychiatric฀and฀ other฀nonmotor฀symptoms฀on฀disability฀in฀Parkinson’s฀disease.฀J฀Am฀Geriatr฀Soc.฀ 2004;52:784-788. 27.฀Schrag฀A,฀Jahanshahi,฀M,฀Quinn฀N.฀What฀contributes฀to฀quality฀of฀life฀in฀patients฀ with฀Parkinson’s฀disease?฀J฀Neurol฀Neurosurg฀Psychiatry.฀2000;69:308-312. 28.฀ Kuopio฀ A,฀ Marttila฀ RJ,฀ Helenius฀ H,฀ Toivonen฀ M,฀ Rinne฀ UK.฀ The฀ quality฀ of฀ life฀ in฀ Parkinson’s฀disease.฀Mov฀Disord.฀2000;15:216-223. 29.฀Weintraub฀D,฀Morales฀KH,฀Moberg฀PJ,฀et฀al.฀Antidepressant฀studies฀in฀Parkinson’s฀ disease:฀a฀review฀and฀meta-analysis.฀Mov฀Disord.฀2005;20:1161-1169. 30.฀Simons฀JA.฀Fluoxetine฀in฀Parkinson’s฀disease.฀Mov฀Disord.฀1996;11:581-582. 31.฀Steur฀EN.฀Increase฀of฀Parkinson฀disability฀after฀fluoxetine฀medication.฀Neurology.฀ 1993;43:211-213. 32.฀Jimenez-Jimenez฀ FJ,฀ Tejeiro฀ J,฀ Martinez-Junquera฀ G,฀ Cabrera-Valdivia฀ F,฀ Alarcon฀J,฀Garcia-Albea฀E.฀Parkinsonism฀exacerbated฀by฀paroxetine.฀Neurology.฀ 1994;44:2406. July 2006 Review Article 64.฀฀Low-dose฀ clozapine฀ for฀ the฀ treatment฀ of฀ drug-induced฀ psychosis฀ in฀ Parkinson’s฀ 33.฀Hesselink฀JM.฀Serotonin฀and฀Parkinson’s฀disease.฀Am฀J฀Psychiatry.฀1993;150:843-844. disease.฀The฀Parkinson฀Study฀Group.฀N฀Engl฀J฀Med.฀1999;340:757-763. 34.฀฀Caley฀ CF,฀ Friedman฀ JH.฀ Does฀ fluoxetine฀ exacerbate฀ Parkinson’s฀ disease?฀ J฀ Clin฀ 65.฀฀Pramipexole฀vs฀levodopa฀as฀initial฀treatment฀for฀Parkinson฀disease:฀a฀randomized฀ Psychiatry.฀1992;53:278-282. controlled฀trial.฀Parkinson฀Study฀Group.฀JAMA.฀2000;284:1931-1938.฀ 35.฀Rampello฀ L,฀ Chiechio฀ S,฀ Raffaele฀ R,฀ Vecchio฀ I,฀ Nicoletti฀ F.฀ The฀ SSRI,฀ citalopram,฀ 66.฀฀Factor฀ SA,฀ Feustel฀ PJ,฀ Friedman฀ JH,฀ et฀ al.฀ Longitudinal฀ outcome฀ of฀ Parkinson’s฀ improves฀ bradykinesia฀ in฀ patients฀ with฀ Parkinson’s฀ disease฀ treated฀ with฀ L-dopa.฀ disease฀patients฀with฀psychosis.฀Neurology.฀2003;60:1756-1761. Clin฀Neuropharmacol.฀2002;25:21-24. 67.฀฀Pollak฀P,฀Tison฀F,฀Rascol฀O,฀et฀al.฀Clozapine฀in฀drug฀induced฀psychosis฀in฀Parkinson’s฀ 36.฀Dell’Agnello฀G,฀Ceravolo฀R,฀Nuti฀A,฀et฀al.฀SSRIs฀do฀not฀worsen฀Parkinson’s฀disease:฀evidisease:฀ a฀ randomised,฀ placebo฀ controlled฀ study฀ with฀ open฀ follow฀ up.฀ J฀ Neurol฀ dence฀from฀an฀open-label,฀prospective฀study.฀Clin฀Neuropharmacol.฀2001;24:221-227. Neurosurg฀Psychiatry.฀2004;75:689-695. 37.฀Ceravolo฀R,฀Nuti฀A,฀Piccinni฀A,฀et฀al.฀Paroxetine฀in฀Parkinson’s฀disease:฀effects฀on฀ 68.฀Fernandez฀HH,฀Trieschmann฀ME,฀Okun฀MS.฀Rebound฀psychosis:฀effect฀of฀discontinumotor฀and฀depressive฀symptoms.฀Neurology.฀2000;55:1216-1218. ation฀of฀antipsychotics฀in฀Parkinson’s฀disease.฀Mov฀Disord.฀2005;20:104-105. 38.฀Gony฀M,฀Lapeyre-Mestre฀M,฀Montastruc฀JL;฀French฀Network฀of฀Regional฀Pharmacovigilance฀ 69.฀฀฀Friedman฀ JH.฀ ‘Drug฀ holidays’฀ in฀ the฀ treatment฀ of฀ Parkinson’s฀ disease.฀ A฀ brief฀ Centers.฀ Risk฀ of฀ serious฀ extrapyramidal฀ symptoms฀ in฀ patients฀ with฀ Parkinson’s฀ disease฀ review.฀Arch฀Intern฀Med.฀1985;145:913-915.฀ receiving฀antidepressant฀drugs:฀a฀pharmacoepidemiologic฀study฀comparing฀serotonin฀reup70.฀McKeith฀IG,฀Dickson฀DW,฀Lowe฀J,฀et฀al.฀Diagnosis฀and฀management฀of฀dementia฀with฀ take฀inhibitors฀and฀other฀antidepressant฀drugs.฀Clin฀Neuropharmacol.฀2003;26:142-145. Lewy฀bodies:฀third฀report฀of฀the฀DLB฀Consortium.฀Neurology.฀2005;65:1863-1872. 39.฀Richard฀IH,฀Kurlan฀R,฀Tanner฀C,฀et฀al.฀Serotonin฀syndrome฀and฀the฀combined฀use฀ 71.฀ Chou฀ KL,฀ Fernandez฀ HH.฀ Combating฀ psychosis฀ in฀ Parkinson’s฀ disease:฀ the฀ use฀ of฀ of฀deprenyl฀and฀an฀antidepressant฀in฀Parkinson’s฀disease.฀Parkinson฀Study฀Group.฀ antipsychotic฀drugs.฀Expert฀Opin฀Investig฀Drugs.฀2006;15:339-349. Neurology.฀1997;48:1070-1077฀. 72.฀Dewey฀RB฀Jr,฀O’Suilleabhain฀PE.฀Treatment฀of฀drug-induced฀psychosis฀with฀quetiap40.฀Aarsland฀D,฀Larsen฀JP,฀Waage฀O,฀Langeveld฀JH.฀Maintenance฀of฀electroconvulsive฀ ine฀and฀clozapine฀in฀Parkinson’s฀disease.฀Neurology.฀2000;55:1753-1754. therapy฀for฀Parkinson’s฀disease.฀Convuls฀Ther.฀1997;13:274-277. 73.฀Morgante฀L,฀Epifanio฀A,฀Spina฀E,฀et฀al.฀Quetiapine฀and฀clozapine฀in฀parkinsonian฀ 41.฀Moellentine฀C,฀Rummans฀T,฀Ahlskog฀JE,฀et฀al.฀Effectiveness฀of฀ECT฀in฀patients฀with฀ patients฀with฀dopaminergic฀psychosis.฀Clin฀Neuropharmacol.฀2004;27:153-156. parkinsonism.฀J฀Neuropsychiatry฀Clin฀Neurosci.฀1998;10:187-193. 74.฀Miyasaki฀JM,฀Shannon฀K,฀Voon฀V,฀et฀al.฀Practice฀Parameter:฀evaluation฀and฀treat42.฀Weintraub฀D,฀Oehlberg฀KA,฀Katz฀IR,฀Stern฀MB.฀Test฀characteristics฀of฀the฀15-item฀ ment฀of฀depression,฀psychosis,฀and฀dementia฀in฀Parkinson’s฀disease฀(an฀evidencegeriatric฀ depression฀ scale฀ and฀ Hamilton฀ depression฀ scale฀ in฀ Parkinson’s฀ disease.฀ based฀ review):฀ report฀ of฀ the฀ Quality฀ Standards฀ Subcommittee฀ of฀ the฀ American฀ Am฀J฀Geriatr฀Psychiatr.฀2006;14:169-175. Academy฀of฀Neurology.฀฀Neurology.฀2006;66:996-1002. 43.฀฀Richard฀IH,฀Schiffer฀RB,฀Kurlan฀R.฀Anxiety฀and฀Parkinson’s฀disease.฀J฀Neuropsychiatry฀ 75.฀฀Ondo฀ WG,฀ Tintner฀ R,฀ Vuong฀ KD,฀ Lai฀ D,฀ Ringholz฀ G.฀ A฀ double-blind,฀ placebo-conClin฀Neurosci.฀1996;8:383-392. CNS Spectr 11:7 (Suppl 7) © MBL trolled,฀unforced฀titration฀parallel฀trial฀of฀quetiapine฀for฀dopaminergic฀induced฀hal44.฀Walsh฀K,฀Bennett฀G.฀Parkinson’s฀disease฀and฀anxiety.฀Postgrad฀Med฀J.฀2001;77:89-93. Communication July 2006 lucinations฀in฀Parkinson’s฀disease.฀Mov฀Disord.฀2005;20:958-963. 45.฀฀Stein฀ MB,฀ Heuser฀ IJ,฀ Juncos฀ JL,฀ Uhde฀ TW.฀ Anxiety฀ disorders฀ in฀ patients฀ with฀ Inc. 76.฀฀Rabey฀JM,฀Prokhorov฀T,฀Miniovich฀A,฀Klein฀C.฀฀The฀effect฀of฀quetiapine฀in฀Parkinson’s฀ Parkinson’s฀disease.฀Am฀J฀Psychiatry.฀1990;147:217-220. disease฀(PD)฀psychotic฀patients:฀a฀double-blind฀labeled฀study฀of฀3฀months฀duration.฀฀ 46.฀Menza฀MA,฀Robertson-Hoffman฀DE,฀Bonapace฀AS.฀Parkinson’s฀disease฀and฀anxiety:฀ Mov฀Disord.฀฀2005;฀20(suppl฀10):S46.฀฀ comorbidity฀with฀depression.฀Biol฀Psychiatry.฀1993;34:465-470. 77.฀฀Friedman฀JH,฀Koller฀WC,฀Lannon฀MC,฀Busenbark฀K,฀Swanson-Hyland฀E,฀Smith฀D.฀ 47.฀Henderson฀R,฀Kurlan฀R,฀Kersun฀JM,฀Como฀P.฀Preliminary฀examination฀of฀the฀comorBenztropine฀ versus฀ clozapine฀ for฀ the฀ treatment฀ of฀ tremor฀ in฀ Parkinson’s฀ disease.฀ bidity฀ of฀ anxiety฀ and฀ depression฀ in฀ Parkinson’s฀ disease.฀ J฀ Neuropsychiatry฀ Clin฀ Neurology.฀1997;48:1077-1081. Neurosci.฀1992;4:257-264. 78.฀฀Jansen฀ EN.฀ Clozapine฀ in฀ the฀ treatment฀ of฀ tremor฀ in฀ Parkinson’s฀ disease.฀ Acta฀ 48.฀Vazquez฀A,฀Jimenez-Jimenez฀FJ,฀Garcia-Ruiz฀P,฀Garcia-Urra฀D.฀“Panic฀attacks”฀in฀ Neurol฀Scand.฀1994;89:262-265. Parkinson’s฀disease.฀A฀long-term฀complication฀of฀levodopa฀therapy.฀Acta฀Neurol฀ 79.฀฀Alvir฀ JM,฀ Lieberman฀ JA,฀ Safferman฀ AZ,฀ Schwimmer฀ JL,฀ Schaaf฀ JA.฀ ClozapineScand.฀1993;87:14-18. induced฀agranulocytosis.฀Incidence฀and฀risk฀factors฀in฀the฀United฀States.฀N฀Engl฀J฀ 49.฀฀Siemers฀ ER,฀ Shekhar฀ A,฀ Quaid฀ K,฀ Dickson฀ H.฀ Anxiety฀ and฀ motor฀ performance฀ in฀ Med.฀1993;329:162-167. Parkinson’s฀disease.฀Mov฀Disord.฀1993;8:501-506. 80.฀฀Gomez-Esteban฀JC,฀Zarranz฀JJ,฀Velasco฀F,฀et฀al.฀Use฀of฀ziprasidone฀in฀parkinsonian฀ 50.฀Menza฀MA,฀Sage฀J,฀Marshall฀E,฀Cody฀R,฀Duvoisin฀R.฀Mood฀changes฀and฀“off-on”฀ patients฀with฀psychosis.฀Clin฀Neuropharmacol.฀2005;28:111-114. phenomena฀in฀Parkinson’s฀disease.฀Mov฀Disord.฀1990;5:148-151. 81.฀฀Michelli฀ F,฀ Taubenslag฀ N,฀ Gatto฀ E,฀ Scorticati฀ MC.฀ Ziprasidone฀ and฀ psychosis฀ in฀ 51.฀Nissenbaum฀H,฀Quinn฀NP,฀Brown฀RG,฀Toone฀B,฀Gotham,฀AM,฀Marsden฀CD.฀Mood฀ Parkinson฀disease.฀Clin฀Neuropharmacol.฀2005;28:254. swings฀associated฀with฀the฀“on-off”฀phenomenon฀in฀Parkinson’s฀disease.฀Psychol฀ 82.฀฀Oechsner฀M,฀Korchounov฀A.฀Parenteral฀ziprasidone:฀a฀new฀atypical฀neuroleptic฀for฀ Med.฀1987;17:899-904. emergency฀treatment฀of฀psychosis฀in฀Parkinson’s฀disease?฀Hum฀Psychopharmacol.฀ 52.฀฀Maricle฀ RA,฀ Nutt฀ JG,฀ Valentine฀ RJ,฀ Carter฀ JH.฀ Dose-response฀ relationship฀ of฀ 2005;20:203-205. levodopa฀with฀mood฀and฀anxiety฀in฀fluctuating฀Parkinson’s฀disease:฀a฀double-blind,฀ 83.฀฀Ford฀B,฀Lynch฀T,฀Greene฀P.฀Risperidone฀in฀Parkinson’s฀disease.฀Lancet.฀1994;344:฀681. placebo-controlled฀study.฀Neurology.฀1995;45:1757-1760. 84.฀฀Rich฀SS,฀Friedman฀JH,฀Ott฀BR.฀Risperidone฀versus฀clozapine฀in฀the฀treatment฀of฀psy53.฀฀Fetoni฀ V,฀ Soliveri฀ P,฀ Monza฀ D,฀ Testa฀ D,฀ Girotti฀ F.฀ Affective฀ symptoms฀ in฀ multiple฀ chosis฀in฀six฀patients฀with฀Parkinson’s฀disease฀and฀other฀akinetic-rigid฀syndromes.฀ system฀atrophy฀and฀Parkinson’s฀disease:฀response฀to฀levodopa฀therapy.฀J฀Neurol฀ J฀Clin฀Psychiatry.฀1995;56:556-559. Neurosurg฀Psychiatry.฀1999;66:541-544. 85.฀฀Mohr฀ E,฀ Mendis฀ T,฀ Hildebrand฀ K,฀ De฀ Deyn฀ PP.฀ Risperidone฀ in฀ the฀ treatment฀ of฀ 54.฀Arnold฀G,฀Gasser฀T,฀Storch฀A,฀et฀al.฀High฀doses฀of฀pergolide฀improve฀clinical฀global฀ dopamine-induced฀psychosis฀in฀Parkinson’s฀disease:฀an฀open฀pilot฀trial.฀Mov฀Disord.฀ impression฀in฀advanced฀Parkisnon’s฀disease:฀a฀preliminary฀open฀label฀study.฀Arch฀ 2000;15:1230-1237. Gerontol฀Geriatr.฀2005;41:239-253. 86.฀฀Meco฀ G,฀ Alessandria฀ A,฀ Bonifati฀ V,฀ Giustini฀ P.฀ Risperidone฀ for฀ hallucinations฀ in฀ 55.฀฀Menza฀ M,฀ Marin฀ H,฀ Kaufman฀ K,฀ Mark฀ M,฀ Lauritano฀ M.฀ Citalopram฀ treatment฀ of฀ levodopa-treated฀Parkinson’s฀disease฀patients.฀Lancet.฀1994;343:1370-1371. depression฀in฀Parkinson’s฀disease:฀the฀impact฀on฀anxiety,฀disability,฀and฀cognition.฀J฀ 87.฀฀Goetz฀ CG,฀ Blasucci฀ LM,฀ Leurgans฀ S,฀ Pappert฀ EJ.฀ Olanzapine฀ and฀ clozapine:฀ Neuropsychiatry฀Clin฀Neurosci.฀2004;16:315-319. comparative฀ effects฀ on฀ motor฀ function฀ in฀ hallucinating฀ PD฀ patients.฀ Neurology.฀ 56.฀฀Fenelon฀ G,฀ Goetz฀ CG,฀ Karenberg฀ A.฀ Hallucinations฀ in฀ Parkinson’s฀ disease฀ in฀ the฀ 2000;55:789-794. prelevodopa฀era.฀฀Neurology.฀2006;66:93-98. 88.฀฀Ondo฀ WG,฀ Levy฀ JK,฀ Vuong฀ KD,฀ Hunter฀ C,฀ Jankovic฀ J.฀ Olanzapine฀ treatment฀ for฀ 57.฀฀Friedman฀JH.฀The฀management฀of฀the฀levodopa฀psychoses.฀Clin฀Neuropharmacol.฀ dopaminergic-induced฀hallucinations.฀Mov฀Disord.฀2002;17:1031-1035. 1991;14:283-295. 89.฀฀Breier฀ A,฀ Sutton฀ VK,฀ Feldman฀ PD,฀ et฀ al.฀ Olanzapine฀ in฀ the฀ treatment฀ of฀ dopami58.฀฀Chou฀KL,฀Messing฀S,฀Oakes฀D,฀Feldman฀PD,฀Breier฀A,฀Friedman฀JH.฀Drug-induced฀ metic-induced฀ psychosis฀ in฀ patients฀ with฀ Parkinson’s฀ disease.฀ Biol฀ Psychiatry.฀ psychosis฀in฀Parkinson฀disease:฀phenomenology฀and฀correlations฀among฀psychosis฀ 2002;52:438-445. rating฀instruments.฀Clin฀Neuropharmacol.฀2005;28:215-219. 90.฀฀Fernandez฀HH,฀Trieschmann฀ME,฀Friedman฀JH.฀Aripiprazole฀for฀drug-induced฀psychosis฀ 59.฀฀Friedman฀JH,฀Factor฀SA.฀Atypical฀antipsychotics฀in฀the฀treatment฀of฀drug-induced฀ in฀Parkinson฀disease:฀preliminary฀experience.฀Clin฀Neuropharmacol.฀2004;27:4-5. psychosis฀in฀Parkinson’s฀disease.฀Mov฀Disord.฀2000;15:201-211. 91.฀฀Friedman฀JH,฀Berman฀R,฀Carson฀W,฀et฀al฀฀Low฀dose฀aripiprazole฀for฀the฀treatment฀ 60.฀฀Aarsland฀ D,฀ Larsen฀ JP,฀ Karlsen฀ K,฀ Lim฀ NG,฀ Tandberg฀ E.฀ Mental฀ symptoms฀ in฀ of฀ drug฀ induced฀ psychosis฀ in฀ Parkinson’s฀ disease.฀ Poster฀ presented฀ at:฀ Ninth฀ Parkinson’s฀disease฀are฀important฀contributors฀to฀caregiver฀distress.฀Int฀J฀Geriatr฀ International฀ Congress฀ of฀ Parkinson’s฀ Disease฀ and฀ Movement฀ Disorders.฀ March฀ Psychiatry.฀1999;14:866-874. 5-8,฀2005;฀New฀Orleans,฀La. 61.฀฀Aarsland฀D,฀Larsen฀JP,฀Tandberg฀E,฀Laake฀K.฀Predictors฀of฀nursing฀home฀placement฀ 92.฀฀Sanchez-Ramos฀ JR,฀ Ortoll฀ R,฀ Paulson฀ GW.฀ Visual฀ hallucinations฀ associated฀ with฀ in฀ Parkinson’s฀ disease:฀ a฀ population-based,฀ prospective฀ study.฀ J฀ Am฀ Geriatr฀ Soc.฀ Parkinson฀disease.฀Arch฀Neurol.฀1996;53:1265-1268. 2000;48:938-942. 93.฀฀Holroyd฀S,฀Currie฀L,฀Wooten฀GF.฀Prospective฀study฀of฀hallucinations฀and฀delusions฀in฀ 62.฀฀Goetz฀ CG,฀ Stebbins฀ GT.฀ Risk฀ factors฀ for฀ nursing฀ home฀ placement฀ in฀ advanced฀ Parkinson’s฀disease.฀J฀Neurol฀Neurosurg฀Psychiatry.฀2001;70:734-738. Parkinson’s฀disease.฀Neurology.฀1993;43:2227-2229. 94.฀Fenelon฀G,฀Mahieux฀F,฀Huon฀R,฀Ziegler฀M.฀Hallucinations฀in฀Parkinson’s฀disease:฀ 63.฀฀Goetz฀CG,฀Stebbins฀GT.฀Mortality฀and฀hallucinations฀in฀nursing฀home฀patients฀with฀ prevalence,฀phenomenology฀and฀risk฀factors.฀Brain.฀2000;123฀(pt฀4):733-745. advanced฀Parkinson’s฀disease.฀Neurology.฀1995;45:669-671. CNS Spectr 11:7 (Suppl 7) © MBL Communication Inc. 552 July 2006 Review Article 95.฀Barnes฀ J,฀ David฀ AS.฀ Visual฀ hallucinations฀ in฀ Parkinson’s฀ disease:฀ a฀ review฀ and฀ phenomenological฀survey.฀J฀Neurol฀Neurosurg฀Psychiatry.฀2001;70:727-733. 96.฀฀Graham฀JM,฀Grunewald฀RA,฀Sagar฀HJ.฀Hallucinosis฀in฀idiopathic฀Parkinson’s฀disease.฀J฀Neurol฀Neurosurg฀Psychiatry.฀1997;63:434-440. 97.฀฀Aarsland฀ D,฀ Ballard฀ C,฀ Larsen฀ JP,฀ McKeith฀ I.฀ A฀ comparative฀ study฀ of฀ psychiatric฀ symptoms฀in฀dementia฀with฀Lewy฀bodies฀and฀Parkinson’s฀disease฀with฀and฀without฀ dementia.฀Intl฀J฀Ger฀Psychiatry.฀2001:16:528-536. 98.฀฀Inzelberg฀ R,฀ Kipervasser฀ S,฀ Korczyn฀ AD.฀ Auditory฀ hallucinations฀ in฀ Parkinson’s฀ disease.฀฀J฀Neurol฀Neurosurg฀Psychiatry.฀1998;64:533-535. 99.฀฀฀Fenelon฀G,฀Thobois฀S,฀Bonnet฀AM,฀Broussolle฀E,฀Tison฀F.฀Tactile฀hallucinations฀in฀ Parkinson’s฀disease.฀J฀Neurol.฀2002;249:1699-1703. 100.฀฀Tousi฀ B,฀ Frankel฀ M.฀ Olfactory฀ and฀ visual฀ hallucinations฀ in฀ Parkinson’s฀ disease.฀ Parkinsonism฀Relat฀Disord.฀2004;10:253-254. 101.฀฀Goetz฀ CG,฀ Tanner฀ CM,฀ Klawans฀ HL.฀ Pharmacology฀ of฀ hallucinations฀ induced฀ by฀ long-term฀drug฀therapy.฀Am฀J฀Psychiatry.฀1982;139:494-497. 102.฀฀Williams฀DR,฀Lees฀AJ.฀Visual฀hallucinations฀in฀the฀diagnosis฀of฀idiopathic฀Parkinson’s฀ disease:฀a฀retrospective฀autopsy฀study.฀Lancet฀Neurol.฀2005:4:605-610. 103.฀฀Harding฀ AJ,฀ Stimson฀ E,฀ Henderson฀ JM,฀ Halliday฀ GM.฀ Clinical฀ correlates฀ of฀ selective฀pathology฀in฀the฀amygdala฀of฀patients฀with฀Parkinson’s฀disease.฀Brain.฀ 2002;25:2431-245. 104.฀฀Pillon฀B.฀Neuropsychological฀assessment฀for฀management฀of฀patients฀with฀deep฀ brain฀stimulation.฀Mov฀Disord.฀2002;17:S116-S122. 105.฀฀Stout฀JC,฀Johnson฀SA.฀Cognitive฀impairment฀and฀dementia฀in฀basal฀ganglia฀disorders.฀Curr฀Neurol฀Neurosci฀Rep.฀2005;5:355-363. 106.฀฀Cronin-Golomb฀A,฀Amick฀MM.฀Spatial฀abilities฀in฀aging,฀Alzheimer’s฀disease,฀and฀ Parkinson’s฀disease.฀In:฀Boller฀F,฀Cappa฀S,฀eds.฀Aging฀and฀Dementia.฀Amsterdam,฀ Netherlands:฀Elsevier;฀2001:119-144. 107.฀฀Saint-Cyr฀JA,฀Trepanier฀LL.฀Neuropsychologic฀assessment฀of฀patients฀for฀movement฀disorder฀surgery.฀Mov฀Disord.฀2000;15:771-783. 108.฀฀Owen฀AM.฀Cognitive฀dysfunction฀in฀Parkinson’s฀disease:฀the฀role฀of฀frontostriatal฀ circuitry.฀Neuroscientist.฀2004;10:525-537. 109.฀฀Kish฀SJ,฀Shannak฀K,฀Hornykiewicz฀O.฀Uneven฀pattern฀of฀dopamine฀loss฀in฀the฀striatum฀of฀patients฀with฀idiopathic฀Parkinson’s฀disease.฀Pathophysiologic฀and฀clinical฀ implications.฀N฀Engl฀J฀Med.฀1988;318:876-880.฀ 110.฀฀Middleton฀FA,฀Strick฀PL.฀Basal฀ganglia฀output฀and฀cognition:฀evidence฀from฀anatomical,฀behavioral,฀and฀clinical฀studies.฀Brain฀Cogn.฀2000;42:183-200.฀ 111.฀฀Middleton฀FA,฀Strick฀PL.฀Basal฀ganglia฀and฀cerebellar฀loops:฀motor฀and฀cognitive฀ circuits.฀Brain฀Res฀Brain฀Res฀Rev.฀2000;31:236-250.฀ 112.฀฀Clower฀DM,฀Dum฀RP,฀Strick฀PL.฀Basal฀ganglia฀and฀cerebellar฀inputs฀to฀‘AIP’.฀Cereb฀ Cortex.฀2005;15:913-920. 113.฀฀Fernandez฀HH,฀Shinobu฀L.฀Dementia฀and฀psychosis.฀In:฀Pahwa฀R,฀Lyons฀K,฀Koller฀ W,฀ eds.฀ Therapy฀ of฀ Parkinson’s฀ Disease.฀ 3rd฀ ed.฀ rev.฀ expanded.฀ New฀ York,฀ NY:฀ Marcel฀Dekker฀Inc.;฀2004:399-423. 114.฀฀Apaydin฀H,฀Ahlskog฀JE,฀Parisi฀JE,฀Boeve฀BF,฀Dickson฀DW.฀Parkinson฀disease฀neuropathology:฀later-developing฀dementia฀and฀loss฀of฀the฀levodopa฀response.฀Arch฀ Neurol.฀2002;59:102-112. 115.฀฀Aarsland฀ D,฀ Andersen฀ K,฀ Larsen฀ JP,฀ Lolk฀ A,฀ Kragh-Sorensen฀ P.฀ Prevalence฀ and฀ characteristics฀ of฀ dementia฀ in฀ Parkinson฀ disease:฀ an฀ 8-year฀ prospective฀ study.฀ Arch฀Neurol.฀2003;60:387-392. 116.฀฀Marder฀ K,฀ Tang฀ MX,฀ Cote฀ L,฀ Stern฀ Y,฀ Mayeux฀ R.฀ The฀ frequency฀ and฀ associated฀risk฀factors฀for฀dementia฀in฀patients฀with฀Parkinson’s฀disease.฀Arch฀Neurol.฀ 1995;52:695-701.฀ 117.฀฀Hobson฀P,฀Meara฀J.฀Risk฀and฀incidence฀of฀dementia฀in฀a฀cohort฀of฀older฀subjects฀ with฀Parkinson’s฀disease฀in฀the฀United฀Kingdom.฀Mov฀Disord.฀2004;19:1043-1049.฀ 118.฀฀Hughes฀TA,฀Ross฀HF,฀Musa฀S,฀et฀al.฀A฀10-year฀study฀of฀the฀incidence฀of฀and฀factors฀ predicting฀dementia฀in฀Parkinson’s฀disease.฀Neurology.฀2000;54:1596-1602. 119.฀฀Mahieux฀ F,฀ Fenelon฀ G,฀ Flahault฀ A,฀ Manifacier฀ MJ,฀ Michelet฀ D,฀ Boller฀ F.฀ Neuropsychological฀ prediction฀ of฀ dementia฀ in฀ Parkinson’s฀ disease.฀ Neurology.฀ 1998;64:178-183. 120.฀฀Levy฀G,฀Jacobs฀DM,฀Tang฀MX,฀et฀al.฀Memory฀and฀executive฀function฀impairment฀ predict฀dementia฀in฀Parkinson’s฀disease.฀Neurology.฀2002;17:1221-1226. 121.฀฀Janvin฀CC,฀Aarsland฀D,฀Larsen฀JP.฀Cognitive฀predictors฀of฀dementia฀in฀Parkinson’s฀ disease:฀ a฀ community-based,฀ 4-year฀ longitudinal฀ study.฀ J฀ Geriatr฀ Psychiatry฀ Neurol.฀2005;18:149-154. 122.฀฀Woods฀ SP,฀ Troster฀ A.฀ Prodromal฀ frontal/executive฀ dysfunction฀ predicts฀ incident฀ dementia฀in฀Parkinson’s฀disease.฀J฀Int฀Neuropsychol฀Soc.฀2003;9:17-24. 123.฀฀Hughes฀AJ,฀Daniel฀SE,฀Kilford฀L,฀Lees฀AJ.฀Accuracy฀of฀clinical฀diagnosis฀of฀idiopathic฀ Parkinson’s฀ disease:฀ a฀ clinico-pathological฀ study฀ of฀ 100฀ cases.฀ J฀ Neurol฀ Neurosurg฀Psychiatry.฀1992;55:181-184. 124.฀฀Braak฀H,฀Rub฀U,฀Jansen฀Steur฀EN,฀Del฀Tredici฀K,฀de฀Vos฀RA.฀Cognitive฀status฀correlates฀ with฀neuropathologic฀stage฀in฀Parkinson฀disease.฀Neurology.฀2005;64:1404-1410. 125.฀฀Pillon฀B,฀Boller฀F,฀Levy฀R,฀Dubois฀B.฀Cognitive฀deficits฀and฀dementia฀in฀Parkinson’s฀ disease.฀In:฀Boller฀F,฀Cappa฀S,฀eds.฀Aging฀and฀Dementia.฀Amsterdam,฀Netherlands:฀ Elsevier;฀2001:311-372. CNS Spectr 11:7 (Suppl 7) © MBL Communication Inc. 553 126.฀฀McKeith฀ IG,฀ Ballard฀ CG,฀ Perry฀ RH,฀ et฀ al.฀ Prospective฀ validation฀ of฀ consensus฀ criteria฀ for฀ the฀ diagnosis฀ of฀ dementia฀ with฀ Lewy฀ bodies.฀ Neurology฀ 2000;54:1050-1058. 127.฀฀Zakzanis฀KK,฀Freedman฀M.฀A฀neuropsychological฀comparison฀of฀demented฀and฀nondemented฀patients฀with฀Parkinson’s฀disease.฀Appl฀Neuropsychol.฀1999;6:129-146. 128.฀฀Emre฀M,฀Aarsland฀D.฀Albanese฀A,฀et฀al.฀Rivastigmine฀for฀dementia฀associated฀with฀ Parkinson’s฀disease.฀N฀Eng฀J฀Med.฀2004;351:2509-2518. 129.฀฀Ravina฀ B,฀ Putt฀ M,฀ Siderowf฀ A,฀ et฀ al.฀ Donepezil฀ for฀ dementia฀ in฀ Parkinson’s฀ disease:฀a฀randomized,฀double฀blind,฀placebo฀controlled,฀crossover฀study.฀J฀Neurol฀ Neurosurg฀Psychiatry.฀2005;76:934-939. 130.฀฀Aarsland฀D,฀Hutchinson฀M,฀Larsen฀JP.฀฀Cognitive,฀psychiatric฀and฀motor฀response฀ to฀ galantamine฀ in฀ Parkinson’s฀ disease฀ with฀ dementia.฀ Int฀ J฀ Geriatr฀ Psychiatry.฀ 2003;18:937-941. 131.฀฀Giladi฀N,฀Shabai฀H,฀Gurevitch฀T,฀Benbunan฀B,฀Anca฀M,฀Korczyn฀AD.฀฀Rivastigmine฀ (Exelon)฀ for฀ dementia฀ in฀ patients฀ with฀ Parkinson’s฀ disease.฀ Acta฀ Neurol฀ Scand.฀ 2003;108:368-373. 132.฀฀Starkstein฀SE,฀Mayberg฀HS,฀Preziosi฀TJ,฀Andrezejewski฀P,฀Leiguarda฀R,฀Robinson฀ RG.฀Reliability,฀validity,฀and฀clinical฀correlates฀of฀apathy฀in฀Parkinson’s฀disease.฀J฀ Neuropsychiatry฀Clin฀Neurosci.฀1992;4:134-139. 133.฀฀Luck฀GC,฀Brown฀RG.฀Apathy฀in฀Parkinson’s฀disease.฀J฀Neurol฀Neurosurg฀Psychiatry.฀ 2002;73:636-642. 134.฀฀Levy฀ R,฀ Dubois฀ B.฀ Apathy฀ and฀ the฀ functional฀ anatomy฀ of฀ the฀ prefrontal฀ cortexbasal฀ganglia฀circuits.฀Cereb฀Cortex.฀2005฀Oct฀5;฀[Epub฀ahead฀of฀print].฀ 135.฀฀฀Madeley฀P,฀Biggins฀CA,฀Boyd฀JL,฀et฀al.฀Emotionalism฀in฀Parkinson’s฀disease.฀Ir฀J฀ Psychol฀Med.฀1992;9:24-25. 136.฀฀Marsh฀L,฀McDonald฀WM,฀Cummings฀J,฀Ravina฀B;฀NINDS/NIMH฀Work฀Group฀on฀Depression฀ and฀Parkinson’s฀Disease.฀Provisional฀diagnostic฀criteria฀for฀depression฀in฀Parkinson’s฀disease:฀report฀of฀an฀NINDS/NIMH฀Work฀Group.฀Mov฀Disord.฀2006;21:148-158. 137.฀฀Schiffer฀R,฀Pope฀LE.฀Review฀of฀pseudobulbar฀affect฀including฀a฀novel฀and฀potential฀ therapy.฀J฀Neuropsychiatr฀Clin฀Neurosci.฀2005;17:447-454. 138.฀฀Brust฀JCM,฀Delirium.฀In:฀Jeste฀DV,฀Friedman฀JH,฀eds.฀Psychiatry฀for฀Neurologists.฀ Humana฀Press:฀Boston,฀Mass;฀2005:307-312. 139.฀฀Tandberg฀E,฀Larsen฀JP,฀Karlsen฀K.฀A฀community-based฀study฀of฀sleep฀disorders฀in฀ patients฀with฀Parkinson’s฀disease.฀Mov฀Disord.฀1998;13:895-899. 140.฀฀Partinen฀M.฀Sleep฀disorder฀related฀to฀Parkinson’s฀disease.฀J฀Neurol.฀1997;244(4฀ suppl฀1):S3-S6. 141.฀฀Nausieda฀PA,฀Weiner฀WJ,฀Kaplan฀LR,฀Weber฀S,฀Klawans฀HL.฀Sleep฀disruption฀in฀ the฀course฀of฀chronic฀levodopa฀therapy:฀an฀early฀feature฀of฀the฀levodopa฀psychosis.฀Clin฀Neuropharmacol.฀1982;5:183-194. 142.฀฀van฀Hilten฀JJ,฀Weggeman฀M,฀van฀der฀Velde฀EA,฀Kerkhof฀GA,฀van฀Dijk฀JG,฀Roos฀RA.฀ Sleep,฀excessive฀daytime฀sleepiness฀and฀fatigue฀in฀Parkinson’s฀disease.฀J฀Neurol฀ Transm฀Park฀Dis฀Sect.฀1993;5:235-244. 143.฀฀Lees฀ AS,฀ Blackburn฀ NA,฀ Campbell฀ VL.฀ The฀ nighttime฀ problems฀ of฀ Parkinson’s฀ disease.฀Clin฀Neuropharmacol.฀1988;11:512-519. 144.฀฀Thorpy฀MJ.฀Sleep฀disorders฀in฀Parkinson’s฀disease.฀Clin฀Cornerstone.฀2004;6(suppl฀ 1A):S7-S15. 145.฀฀Friedman฀ JH,฀ Chou฀ KL.฀ Sleep฀ and฀ fatigue฀ in฀ Parkinson’s฀ disease.฀ Parkinsonism฀ Relat฀Disord.฀2004;10(suppl฀1):S27-S35. 146.฀฀Garcia-Borreguero฀D,฀Larrosa฀O,฀Bravo฀M.฀Parkinson’s฀disease฀and฀sleep.฀ Sleep฀ Med฀Rev.฀2003;7:115-129. 147.฀฀Larsen฀JP,฀Tandberg฀E.฀Sleep฀disorders฀in฀patients฀with฀Parkinson’s฀disease.฀CNS฀ Drugs.฀2001;15:267-275. 148.฀฀Adler฀ CH,฀ Thorpy฀ MJ.฀ Sleep฀ issues฀ in฀ Parkinson’s฀ disease.฀ Neurology.฀ 2005;64(suppl฀3):S12-S20. 149.฀฀Grandas฀ F,฀ Iranzo฀ A.฀ Nocturnal฀ problems฀ occurring฀ in฀ Parkinson’s฀ disease.฀ Neurology.฀2004;63(suppl฀3):S8-S11. 150.฀฀Comella฀CL.฀Sleep฀disturbances฀in฀Parkinson’s฀disease.฀Curr฀Neurol฀Neurosci฀Rep.฀ 2003;3:173-180. 151.฀฀Wetter฀TC,฀Collado-Seidel฀V,฀Polmacher฀T,฀Yassouridis฀A,฀Trenkwalder฀C.฀Sleep฀and฀ periodic฀leg฀movement฀patterns฀in฀drug-free฀patients฀with฀Parkinson’s฀disease฀and฀ multiple฀system฀atrophy.฀Sleep.฀2000;฀23:361-367. 152.฀฀Kumar฀S,฀Bhatia฀M,฀Behari฀M.฀Sleep฀disorders฀in฀Parkinson’s฀disease.฀Mov฀Disord.฀ 2002;17:775-781. 153.฀฀Starkstein฀SE,฀Preziosi฀TJ,฀Robinson฀RG.฀Sleep฀disorders,฀pain฀and฀depression฀in฀ Parkinson’s฀disease.฀Eur฀Neurol.฀1991;31:352-355. 154.฀฀Goetz฀CG,฀Wilson฀RS,฀Tanner฀CM,฀Garron฀DC.฀Relationships฀among฀pain,฀depression฀and฀sleep฀alterations฀in฀Parkinson’s฀disease.฀Adv฀Neurol.฀1987;45:345-347. 155.฀฀Caap-Ahlgren,฀ Dehlin฀ O.฀ Insomnia฀ and฀ depressive฀ symptoms฀ in฀ patients฀ with฀ Parkinson’s฀ disease.฀ Relationship฀ to฀ health-related฀ quality฀ of฀ life.฀ An฀ interview฀ study฀of฀patients฀living฀at฀home.฀Arch฀Gerontol฀Geriatr.฀2001;32:23-33. 156.฀฀Happe฀ S,฀ Ludemann฀ P,฀ Berger฀ K;฀ FAQT฀ study฀ investigators.฀ The฀ association฀ between฀disease฀severity฀and฀sleep-฀related฀problems฀in฀patients฀with฀Parkinson’s฀ disease.฀Neuropsychobiology.฀2002;46:90-96. 157.฀฀Borek฀ LL,฀ Kohn฀ R,฀ Friedman฀ JH.฀ Mood฀ and฀ sleep฀ in฀ Parkinson’s฀ disease.฀ J฀ Clin฀ Psychiatry.฀2006;67:958-963. July 2006 Review Article 158.฀฀Ongini฀ E,฀ Caporali฀ MG,฀ Massotti฀ M.฀ Stimulation฀ of฀ dopamine฀ D-1฀ receptors฀ by฀ SKF฀ 38393฀ induces฀ EEG฀ desynchronization฀ and฀ behavioral฀ arousal.฀ Life฀ Sci.฀ 1985;37:2327-2333. 159.฀฀Trampus฀M,฀Ferri฀N,฀Monopoli,฀Ongini฀E.฀The฀dopamine฀D1฀receptor฀is฀involved฀in฀ the฀regulation฀of฀REM฀sleep฀in฀the฀rat.฀Eur฀J฀Pharmacol.฀1991;194:189-194. 160.฀฀van฀Hilten฀B,฀Hoff฀JI,฀Middelkoop฀HA,฀et฀al.฀Sleep฀disruption฀in฀Parkinson’s฀disease.฀ Assessment฀by฀continous฀activity฀monitoring.฀Arch฀Neurol.฀1994;51:922-928. 161.฀฀Factor฀ SA,฀ McAlarney฀ T,฀ Sanchez-Ramos฀ JR,฀ Weiner฀ WJ.฀ Sleep฀ disorders฀ and฀ sleep฀effect฀in฀Parkinson’s฀disease.฀Mov฀Disord.฀1990;5:280-285. 162.฀฀Tandberg฀E,฀Larsen฀JP,฀Karlsen฀K.฀Excessive฀daytime฀sleepiness฀and฀sleep฀benefit฀ in฀Parkinson’s฀disease:฀a฀community-based฀study.฀Mov฀Disord.฀1999;14:922-927. 163.฀฀Ondo฀WG,฀Dat฀Vuong฀K,฀Khan฀H,฀Atassi฀F,฀Kwak฀C,฀Jankovic฀J.฀Daytime฀sleepiness฀ and฀other฀sleep฀disorders฀in฀Parkinson’s฀disease.฀Neurology.฀2001;57:1392-1396. 164.฀฀Frucht฀S,฀Rogers฀JD,฀Greene฀PE,฀Gordon฀MF,฀Fahn฀S.฀Falling฀asleep฀at฀the฀wheel:฀ motor฀vehicle฀mishaps฀in฀persons฀taking฀pramipexole฀and฀ropinirole.฀Neurology.฀ 1999;52:1908-1910. 165.฀฀Ferreira฀JJ,฀Galitzky฀M,฀Montastruc฀JL,฀Rascol฀O.฀Sleep฀attacks฀and฀Parkinson’s฀ disease฀treatment.฀Lancet.฀2000;15:1333-1334. 166.฀฀Schapira฀AH.฀Sleep฀attacks฀(sleep฀episodes)฀with฀pergolide.฀Lancet.฀2000;355:1332-1333. 167.฀฀Hauser฀RA,฀Gauger฀L,฀Anderson฀WM,฀Zesiewicz฀TA.฀Pramipexole-induced฀somnolence฀and฀episodes฀of฀daytime฀sleep.฀Mov฀Disord.฀2000;15:658-663. 168.฀฀Olanow฀ CW,฀ Schapira฀ AH,฀ Roth฀ T.฀ Waking฀ up฀ to฀ sleep฀ episodes฀ in฀ Parkinson’s฀ disease.฀Mov฀Disord.฀2000;15:212-215. 169.฀฀Askenasy฀JJ.฀Sleep฀disturbances฀in฀Parkinsonism.฀J฀Neural฀Transm.฀2003;110:125-150.฀ 170.฀฀Hardie฀RJ,฀Efthimiou฀J,฀Stern฀GM.฀Respiration฀and฀sleep฀in฀Parkinson’s฀disease.฀J฀ Neurol฀Neurosurg฀Psychiatry.฀1986;49:1326. 171.฀฀Maria฀B,฀Sophia฀S,฀Michalis฀M,฀et฀al.฀Sleep฀breathing฀disorders฀in฀patients฀with฀ idiopathic฀Parkinson’s฀disease.฀Respir฀Med.฀2003;97:1151-1157. 172.฀฀Happe฀S,฀Schrodl฀B,฀Faltl฀M,฀Muller฀C,฀Auff฀E,฀Zeitlhofer฀J.฀Sleep฀disorders฀and฀depression฀in฀patients฀with฀Parkinson’s฀disease.฀Acta฀Neurol฀Scand.฀2001;104:275-280. 173.฀฀Ferini-Strambi฀ L,฀ Franceschi฀ M,฀ Pinto฀ P,฀ Zucconi฀ M,฀ Smirne฀ S.฀ Respiration฀ and฀ heart฀rate฀variability฀during฀sleep฀in฀untreated฀Parkinson฀patients.฀Gerontology.฀ 1992;38:92-98. 174.฀฀Ancoli-Israel฀S,฀Kripke฀DF,฀Klauber฀MR,฀et฀al.฀Morbidity,฀mortality฀and฀sleep-disordered฀breathing฀in฀community฀dwelling฀elderly.฀Sleep.฀1996;19:277-282. 175.฀฀Ondo฀WG,฀Vuong฀KD,฀Jankovic฀J.฀Exploring฀the฀relationship฀between฀Parkinson’s฀ disease฀and฀restless฀legs฀syndrome.฀Arch฀Neurol.฀2002;59:421-424. 176.฀฀Krishnan฀PR,฀Bhatia฀M,฀Behari฀M.฀Restless฀legs฀syndrome฀in฀Parkinson’s฀disease:฀ a฀case-controlled฀study.฀Mov฀Disord.฀2003;18:181-185. 177.฀฀Allen฀ RP,฀ Picchietti฀ D,฀ Hening฀ WA,฀ Trenkwalder฀ C,฀ Walters฀ AS,฀ Montplaisi฀ J;฀ Restless฀Legs฀Syndrome฀Diagnosis฀and฀Epidemiology฀workshop฀at฀the฀National฀ Institute฀of฀Health;฀International฀Restless฀Legs฀Syndrome฀Study฀Group.฀Restless฀ legs฀ syndrome:฀ diagnostic฀ criteria,฀ special฀ considerations,฀ and฀ epidemiology.฀ A฀ report฀from฀the฀restless฀legs฀syndrome฀diagnosis฀and฀epidemiology฀workshop฀at฀ the฀National฀Institutes฀of฀Health.฀Sleep฀Med.฀2003;4:101-119. 178.฀฀Sharf฀ B,฀ Moskovitz฀ C,฀ Lupton฀ MD,฀ Klawans฀ HL.฀ Dream฀ phenomena฀ induced฀ by฀ chronic฀levodopa฀therapy.฀J฀Neural฀Transm.฀1978;43:143-151. 179.฀฀The฀ International฀ Classification฀ of฀ Sleep฀ Disorders,฀ Revised:฀ Diagnostic฀ and฀ Coding฀Manual.฀฀Rochester,฀Minn:฀American฀Academy฀of฀Sleep฀Medicine;฀2001. 180.฀฀Schenck฀CH,฀Mahowald฀MW.฀REM฀sleep฀behavior฀disorder:฀clinical,฀developmental฀and฀neuroscience฀perspectives฀16฀years฀after฀its฀formal฀identification฀in฀SLEEP.฀ Sleep.฀2002;25:120-138. 181.฀฀Olson฀ EJ,฀ Boeve฀ BF,฀ Silber฀ MH.฀ Rapid฀ eye฀ movement฀ sleep฀ behaviour฀ disorder:฀ demographic,฀clinical฀and฀laboratory฀findings฀in฀93฀cases.฀Brain.฀2000;123:331-339. 182.฀฀Scaglione฀ C,฀ Vignatelli฀ L,฀ Plazzi฀ G,฀ et฀ al.฀ REM฀ sleep฀ behaviour฀ disorder฀ in฀ Parkinson’s฀disease:฀a฀questionnaire-based฀study.฀Neurol฀Sci.฀2005;25:316-321. 183.฀฀Gagnon฀JF,฀Bedard฀MA,฀Fantini฀ML,฀et฀al.฀REM฀sleep฀behavior฀disorder฀and฀REM฀ sleep฀without฀atonia฀in฀Parkinson’s฀disease.฀Neurology.฀2002;59:585-589. 184.฀฀Johns฀MW.฀A฀new฀method฀for฀measuring฀daytime฀sleepiness:฀the฀Epworth฀sleepiness฀scale.฀Sleep.฀1991;14:540-545. 185.฀฀Swift฀ CG,฀ Shapiro฀ CM.฀ ABC฀ of฀ sleep฀ disorders.฀ Sleep฀ and฀ sleep฀ problems฀ in฀ elderly฀people.฀BMJ.฀1993;306:1468-1471. 186.฀฀Kirk฀J,฀Douglass฀R,฀Nelson฀E,฀et฀al.฀Chief฀complaint฀of฀fatigue:฀a฀prospective฀study.฀ J฀Fam฀Pract.฀1990;30:33-39. 187.฀Swain฀MG.฀Fatigue฀in฀chronic฀disease.฀Clin฀Sci฀(Lond).฀2000;99:1-8. 188.฀฀Krupp฀ LB,฀ Pollina฀ DA.฀ Mechanisms฀ and฀ management฀ of฀ fatigue฀ in฀ progressive฀ neurological฀disorders.฀Curr฀Opin฀Neurol.฀1996;9:456-460. 189.฀฀Krupp฀LB.฀Fatigue฀in฀Multiple฀Sclerosis:฀A฀Guide฀to฀Diagnosis฀and฀Management.฀ New฀York,฀NY:฀Demos฀Medical฀Publishing;฀2004. CNS Spectr 11:7 (Suppl 7) © MBL Communication Inc. 554 190.฀฀Lou฀ JS,฀ Kearns฀ G,฀ Oken฀ B,฀ Sexton฀ G,฀ Nutt฀ J.฀ Exacerbated฀ physical฀ fatigue฀ and฀ mental฀fatigue฀in฀Parkinson’s฀disease.฀Mov฀Disord.฀2001;16:190-196. 191.฀฀Friedman฀J,฀Friedman฀H.฀Fatigue฀in฀Parkinson’s฀disease.฀Neurology.฀1993;43:2016-2018. 192.฀฀van฀Hilten฀JJ,฀Hoogland฀G,฀van฀der฀Velde฀EA,฀Middelkoop฀HA,฀Kerkhof฀GA,฀Roos฀ RA.฀Diurnal฀effects฀of฀motor฀activity฀and฀fatigue฀in฀Parkinson’s฀disease.฀J฀Neurol฀ Neurosurg฀Psychiatry.฀1993;56:874-877. 193.฀฀Abe฀K,฀Takanashi฀M,฀Yanagihara฀T.฀Fatigue฀in฀patients฀with฀Parkinson’s฀disease.฀ Behav฀Neurol.฀2000;12:103-106. 194.฀฀Herlofson฀K,฀Larsen฀JP.฀Measuring฀fatigue฀in฀patients฀with฀Parkinson’s฀disease– the฀Fatigue฀Severity฀Scale.฀Eur฀J฀Neurol.฀2002;9:595-600. 195.฀฀Alves฀G,฀Wentzel-Larsen฀T,฀Aarsland฀D,฀Larsen฀JP.฀Progression฀of฀motor฀impairment฀ and฀ disability฀ in฀ Parkinson฀ disease:฀ a฀ population-based฀ study.฀ Neurology.฀ 2005;65:1436-1441. 196.฀฀Smets฀ EM,฀ Garssen฀ B,฀ Bonke฀ B,฀ De฀ Haes฀ JC.฀ The฀ Multidimensional฀ Fatigue฀ Inventory฀ (MFI)฀ psychometric฀ qualities฀ of฀ an฀ instrument฀ to฀ assess฀ fatigue.฀ J฀ Psychosom฀Res.฀1995;39:315-325. 197.฀฀Shiffito฀G,฀Friedman฀JH,฀Oakes฀D,฀et฀al.฀Fatigue฀in฀ELLDOPA.฀Poster฀presented฀at:฀ the฀World฀Parkinson฀Congress.฀Feb฀22-26,฀2006;฀Washington,฀DC. 198.฀฀Abe฀ K,฀ Takanashi฀ M,฀ Yanagihara฀ T,฀ Sakoda฀ S.฀ Pergolide฀ mesilate฀ may฀ improve฀ fatigue฀in฀patients฀with฀Parkinson’s฀disease.฀Behav฀Neurol.฀2001;13:117-121. 199.฀฀Herlofson฀K,฀Larsen฀JP.฀The฀influence฀of฀fatigue฀on฀health-related฀quality฀of฀life฀in฀ patients฀with฀Parkinson’s฀disease.฀Acta฀Neurol฀Scand.฀2003;107:1-6. 200.฀฀Diagnostic฀and฀Statistical฀Manual฀of฀Mental฀Disorders.฀4th฀ed.฀Washington,฀DC:฀ American฀Psychiatric฀Association;฀1994. 201.฀฀Brown฀ RG,฀ Dittner฀ A,฀ Findley฀ L,฀ Wessely฀ SC.฀ The฀ Parkinson฀ fatigue฀ scale.฀ Parkinsonism฀Relat฀Disord.฀2005;11:49-55.฀ 202.฀฀Levi฀S,฀Cox฀M,฀Lugon฀M,฀Hodkinson฀M,฀Tomkins฀A.฀Increased฀energy฀expenditure฀ in฀Parkinson’s฀disease.฀BMJ.฀1990;301:1256-1257. 203.฀฀Markus฀HS,฀Cox฀M,฀Tomkins฀AM.฀Raised฀resting฀energy฀expenditure฀in฀Parkinson’s฀ disease฀and฀its฀relationship฀to฀muscle฀rigidity.฀Clin฀Sci฀(Lond).฀1992;83:199-204. 204.฀฀Broussolle฀E,฀Borson฀F,฀Gonzalez฀de฀Suso฀JM,฀et฀al.฀Increase฀of฀energy฀expenditure฀ in฀Parkinson’s฀disease.฀Rev฀Neurol฀(Paris).฀1991;147:46-51. 205.฀฀Tzelepis฀GE,฀McCool฀FD,฀Friedman฀JH,฀Hoppin฀FG฀Jr.฀Respiratory฀muscle฀dysfunction฀in฀Parkinson’s฀disease.฀Am฀Rev฀Resp฀Dis.฀1988;138:266-271. 206.฀฀Garber฀ CE,฀ Friedman฀ JH.฀ Effects฀ of฀ fatigue฀ on฀ physical฀ activity฀ and฀ function฀ in฀ patients฀with฀Parkinson’s฀disease.฀Neurology.฀2003;60:1119-1124. 207.฀฀Friedman฀JH,฀Friedman฀H.฀Fatigue฀in฀Parkinson’s฀disease:฀a฀nine-year฀follow-up.฀ Mov฀Disord.฀2001;16:1120-1122. 208.฀฀Driver-Dunckley฀ E,฀ Samanta฀ J,฀ Stacy฀ M.฀ Pathological฀ gambling฀ associated฀ with฀ dopamine฀agonist฀therapy฀in฀Parkinson’s฀disease.฀Neurology.฀2003;61:422-423. 209.฀฀Serrano-Duenas฀M.฀Chronic฀dopamimetic฀drug฀addiction฀and฀pathologic฀gambling฀ in฀patient฀with฀Parkinson’s฀disease-presentation฀of฀four฀cases.฀Ger฀J฀Psychiatry.฀ 2002;5:62-66. 210.฀฀Dodd฀ ML,฀ Klos฀ KJ,฀ Bower฀ JH,฀ Geda฀ YE,฀ Josephs฀ KA,฀ Ahlskog฀ JE.฀ Pathological฀ gambling฀ caused฀ by฀ drugs฀ used฀ to฀ treat฀ Parkinson฀ disease.฀ Arch฀ Neurol.฀ 2005;62:1377-1381. 211.฀฀Voon฀V.฀Repetition,฀repetition,฀and฀repetition:฀compulsive฀and฀punding฀behaviors฀in฀ Parkinson’s.฀Mov฀Disord.฀2004;19:367-370. 212.฀฀Nirenberg฀MJ,฀Waters฀C.฀Compulsive฀eating฀and฀weight฀gain฀related฀to฀dopamine฀ agonist฀use.฀Mov฀Disord.฀2006;21:524-529. 213.฀฀Klos฀ KJ,฀ Bower฀ JH,฀ Josephs฀ KA,฀ Matsumoto฀ JY,฀ Ahlskog฀ JE.฀ Pathological฀ hypersexuality฀ predominantly฀ linked฀ to฀ adjuvant฀ dopamine฀ agonist฀ therapy฀ in฀ Parkinson’s฀ disease฀ and฀ multiple฀ system฀ atrophy.฀ Parkinsonism฀ Relat฀ Disord.฀ 2005;11:381-386. 214.฀Friedman฀JH.฀Punding฀on฀levodopa.฀Biol฀Psychiatry.฀1994;36:350-351. 215.฀Fernandez฀HH,฀Friedman฀JH.฀Punding฀on฀L-dopa.฀Mov฀Disord.฀1999;14:836-838. 216.฀฀Kurlan฀ R.฀ Disabling฀ repetitive฀ behaviors฀ in฀ Parkinson’s฀ Disease.฀ Mov฀ Disord.฀ 2004;19:433-437. 217.฀฀Magerkurth฀C,฀Cshnitzer฀R,฀Braune฀S.฀Symptoms฀of฀autonomic฀failure฀in฀Parkinson’s฀ disease:฀Prevalence฀and฀impact฀on฀daily฀life.฀Clin฀Auton฀Res.฀2005;15:76-82. 218.฀฀Dewey฀RB฀Jr.฀Autonomic฀dysfunction฀in฀Parkinson’s฀disease.฀Neurol฀Clin.฀2004;22(3฀ suppl):S127-S139. 219.฀฀Orimo฀S,฀Amino฀T,฀Itoh฀Y,฀et฀al.฀Cardiac฀sympathetic฀denervation฀precedes฀neuronal฀loss฀in฀the฀sympathetic฀ganglia฀in฀Lewy฀body฀disease.฀Acta฀Neuropathol฀(Berl).฀ 2005;109:583-588. 220.฀฀Muller฀CM,฀De฀Vos฀RA,฀Maurage฀CA,฀Thal฀DR,฀Tolnay฀M,฀Braak฀H.฀Staging฀of฀sporadic฀Parkinson’s฀disease-related฀alpha-synuclein฀pathology:฀inter-฀and฀intra-rater฀ reliability.฀J฀Neuropath฀Exp฀Neurol.฀2005;64:623-628. July 2006