Brief Report

Hallucinations, Sleep Fragmentation, and Altered DreamPhenomena in Parkinson’s Disease

Eric J. Pappert, MD, Christopher G. Goetz, MD, Francie G. Niederman, BSN, *Rema Raman, MS, and*Sue Leurgans, PhD

Departments of Neurological Sciences and *Preventive Medicine, Rush-Presbyterian-St. Luke’s Medical Center,Chicago, Illinois, U.S.A.

Summary: In a series of consecutively randomized outpa-tients who had Parkinson’s disease (PD), we examined theassociation of three behaviors: sleep fragmentation, altereddream phenomena, and hallucinations/illusions. Using a log-linear model methodology, we tested the independence of eachbehavior. Sixty-two percent of the subjects had sleep fragmen-tation, 48% had altered dream phenomena, and 26% hadhallucinations/illusions. Eighty-two percent of the patients withhallucinations/illusions experienced some form of sleep disor-der. The three phenomena were not independent. The interac-tion between sleep fragmentation and altered dream phenom-ena was strongly statistically significant. Likewise, a signifi-

cant interaction existed between altered dream phenomena andhallucinations/illusions. No interaction occurred between sleepfragmentation and hallucinations/illusions. Sleep fragmenta-tion, altered dream phenomena, and hallucinations/illusions inPD should be considered distinct but often overlapping behav-iors. The close association between altered dream phenomenaand hallucinations suggests that therapeutic interventionsaimed at diminishing dream-related activities may have a spe-cific positive impact on hallucinatory behavior.Key Words:Hallucinations—Illusions—Sleep fragmentation—Dreamphenomenon—Parkinson’s disease.

Hallucinations and illusions are a common complica-tion of the chronic pharmacologic treatment of idiopathicParkinson’s disease (PD) occurring in approximately onethird of patients.1,2 Whereas the pathogenesis, patho-physiology, and natural history of hallucinations and il-lusions are not fully understood,2 this serious complica-tion limits drug therapy of motor disability and is a sig-nificant risk factor for permanent nursing homeplacement3 and its related increased mortality.4 Promi-nent abnormalities of sleep hygiene5 and altered dreamphenomena6 are also commonly encountered in PD.Some investigators have suggested that sleep disruptionsand altered dream phenomena are linked to hallucina-tions either as precursors or comorbid features.7 Inde-

pendence of these three phenomena has not been for-mally tested. Because sleep disorders are potentiallytreatable, a full delineation of their relationship to hallu-cinations has implications for understanding pathogen-esis and therapy.

METHODS

Patient Selection

Outpatients with the diagnosis of idiopathic PD (basedon the presence of at least three of the following features:rest tremor, bradykinesia, rigidity, and postural refleximpairment) and a Hoehn and Yahr stage of two or threewhile ‘‘on’’ qualified for study participation. Patientswith clinical evidence of non-idiopathic PD, includingdiffuse Lewy body disease and Alzheimer’s disease aswell as clinically significant stroke, were excluded. Ad-ditional patient eligibility criteria required the use oflevodopa/carbidopa, with or without other medications,levodopa responsiveness, and the availability of a spouse

Received April 9, 1998; revision received September 15, 1998. Ac-cepted September 17, 1998.

Address correspondence and reprint requests to Eric J. Pappert, MD,at the Movement Disorders Section, Department of Neurological Sci-ences, Rush-Presbyterian-St. Luke’s Medical Center, 1725 W. HarrisonSt., Suite 1106, Chicago, IL 60612, U.S.A.

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or 24-hour caretaker. All patients gave informed consentfor the questionnaire study as approved by the Rush-Presbyterian-St. Luke’s Medical Center Human Investi-gation Committee.

Study Design

Using a computerized randomization scheme, outpa-tient clinic times of six movement disorders specialists ata tertiary care center were randomly chosen over a6-month period. Patients who were scheduled at thesetimes were recruited to participate with their spouse/caretaker in a structured interview if they met the patientselection criteria and had not been previously recruited.The interview assessed the presence or absence, severity,and characteristics of three behavioral abnormalities overthe previous 30 days: sleep fragmentation (nocturnalawakenings unrelated to voiding); altered dream phe-nomena (vivid dreams, nightmares, and reports sugges-tive of rapid eye movement [REM] behavioral disorderor night terrors); and hallucinations/illusions (visual, au-ditory, tactile, or gustatory false experiences in the set-ting of a clear sensorium). Hallucinations/illusions werestudied irrespective of patient insight into their occur-rence. The interviews occurred with both the patient andspouse/caregiver present, and when discordant answerswere obtained, the sole interviewer used best clinicaljudgment to record a single response. The interview alsogathered demographic information on age, gender, dis-ease duration, motor disability (Schwab and Englandscale), and current medications. A Unified Parkinson’sDisease Rating Scale (UPDRS) motor score was ob-tained. After the interview, patients were classified onthe following criteria that covered the past 30 days: sleepfragmentation, defined as an average of at least twoawakenings per night; altered dream phenomena, definedas an average of at least two occurrences per week; andhallucinations/illusions, defined as an average of at leastone occurrence per week.

Data Analysis

Log-linear models were fit to a 2 × 2 × 2three-waytable classifying the presence or absence of sleep frag-mentation, altered dream phenomena, and hallucinations/illusions. Log-linear models were selected because thevariables (presence or absence) were discrete and thestudy focused on associations among variables, not onpredictions of presence or absence of one variable basedon presence or absence of another. Log-likelihoods wereobtained for the models corresponding to independenceof the three factors, interactions of one pair of factors,interactions of two pairs of factors, interactions of allpairs of factors, and three-way interactions. Statistical

tests, using thex2 distribution of the difference in devi-ances of nested models, were used to select a final model.To assess differences among the subgroups in demo-graphic features and medications, we used chi-squaredtests or Fisher’s exact test as appropriate for categoricalvariables and Wilcoxon rank sum tests for continuousvariables.

RESULTS

PatientsOf the 384 clinic visits selected for potential patient

recruitment, 142 PD patients met medical and neurologicstudy eligibility criteria; 126 (74 men) participated in thisstudy. Fifteen patients who met medical and neurologicentry criteria were excluded because of a lack of a spouseor 24-hour caretaker. The age (mean ± standard deviation[SD]) of participating patients was 57.4 ± 11.4 yrs(range, 35–85 yrs) with a mean duration of parkinsoniansymptoms of 10.0 ± 6.6 yrs (range, 1–36 yrs). The me-dian parkinsonian severity while ‘‘on’’ was Hoehn andYahr stage 2 (range, 2–3) and while ‘‘off’’ 4 (range,2–5). Mean UPDRS obtained at the time of the interviewwas 28.3 ± 10.2 and mean Schwab and England 85.3 ±7.4. Patients had been treated with levodopa/carbidopafor an average of 9.2 (± 5.6 SD) yrs with an averagelevodopa dose of 521.3 (± 345.9 SD) mg/day (range,100–2000 mg/day). Other medications included dopa-mine agonists in 57, anticholinergic drugs in 17, selege-line in 74, amantadine in 23, antidepressant drugs in 24,and neuroleptics in three.

Prevalence of Study BehaviorsSixty-two percent of the sample had sleep fragmenta-

tion, 48% had altered dream phenomena, and 26% hadhallucinations/illusions. Thirty-seven percent had bothsleep fragmentation and altered dream phenomena, 18%had both sleep fragmentation and hallucinations/illusions, and 17% had altered dream phenomena andhallucinations/illusions. Fourteen percent experienced allthree behaviors and 22% experienced none. Eighty-twopercent of the patients with hallucinations/illusions ex-perienced some form of sleep disorder, 15% with sleepfragmentation only, 12% with altered dream phenomenaonly, and 55% with both sleep fragmentation and altereddream phenomena (Fig. 1).

Behavioral Associations and Interactions

The three phenomena were not independent (x2 418.04, df4 4, p < 0.00001). The interaction betweensleep fragmentation and altered dream phenomena wasstrongly statistically significant (x2 4 11.26, df 4 1,p 4 0.00079). Likewise, a significant interaction existed

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between altered dream phenomena and hallucinations/illusions (x2 4 6.28, df4 1, p4 0.012). When the twointeractions were included in the model, both the sleepfragmentation-altered dream phenomena and the altereddream phenomena–hallucinations/illusions interactionsretained their significance. The combined two-way inter-action model showed no lack of fit in that the proportionsin each cell were adequately explained by these two in-teractions and no statistical evidence for a more complexinterrelationship existed (x2 4 0.50, p4 0.48). No in-teraction occurred between sleep fragmentation andhallucinations/illusions (x2 4 1.09, p4 0.30). Based onthe log-linear model with two interactions, altered dreamphenomena were associated individually with sleep frag-mentation and with hallucinations/illusions, but the lattertwo behaviors were conditionally independent once thestatus of altered dream phenomena was controlled.

Influence of Demographic Features and MedicationsWhereas patient age, gender, and parkinsonian disabil-

ity (UPDRS and Schwab and England disability score)did not separate the behavioral subgroups, PD durationwas significantly different in distribution (p < 0.01). Spe-cifically, older patients predominated in the subgroupwithout any behavioral abnormalities. Additionally, pre-sent use of levodopa, dopamine agonists, antidepres-sants, bedtime Sinemet-CR (DuPont Pharma, Wilming-ton, DE, U.S.A.), sedatives, and neuroleptics did not in-

fluence behavioral group assignment, but selegeline (p <0.001), amantadine (p < 0.0001), and anticholinergicdrugs (p < 0.004) were unequally distributed. Specifi-cally, all subjects on selegeline had at least one behav-ioral abnormality. All those on amantadine had halluci-nations, and in subjects on anticholinergic drugs thecombination of sleep fragmentation and altered dreamphenomena was rare (Table 1).

DISCUSSIONSleep fragmentation, altered dream phenomena, and

hallucinations/illusions should not be considered isolated

FIG. 1. Distribution of Parkinson’sdisease patients among the three be-havioral domains (not drawn toscale). Text presents data as percent-ages.

TABLE 1. Significant differences in medication use

Drug(no. of subjects) p

Nobehavioral

abnormality(%)

SF(%)

ADP(%)

SF andADP (%)

H/I withor without

otherbehaviors

(%)

Selegeline (73)<0.001

0 0 13 33 12No selegeline (53) 9 28 0 0 6

Amantadine (22)<0.0001

0 0 0 0 18No amantadine

(104) 9 28 13 33 0

Anticholinergics(17)

<0.00424 18 18 6 34

No anticholinergics(109) 6 29 12 38 15

ADP, altered dream phenomena; H/I, hallucinations/illusions; SF, sleepfragmentation.

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and independent behaviors in PD patients. Among thesethree behaviors, we found two significant associations:the presence of sleep fragmentation was closely linked toaltered dream phenomena and altered dream phenomenawere linked to the presence of hallucinations/illusions. Aprior study by Nausieda et al. linked hallucinations withthe general category of sleep disruption and found thatsubjects with hallucinations were likely to have con-comitant sleep disorders.7 Their subject group was simi-larly derived as ours, and their prevalence of sleep alter-ations was comparable. Their study design differed fun-damentally from ours in that they focused on overallrelationships between sleep disorders and hallucinationsand did not concentrate on specific roles of sleep frag-mentation and altered dream phenomena. Because ourinterview incorporated questions specifically related tothe three primary behaviors of focus and the study in-cluded patients with and without these behaviors, wewere able to examine all possibilities of associationsamong these behaviors without bias. Like Nausieda etal., we found that most patients (82% in our study versus98% in the Nausieda study) with hallucinations had someform of sleep problem. The numerical difference mayrelate, at least in part, to interview techniques. We foundthat particular emphasis needed to be placed on the dis-tinction between nocturnal hallucinations/illusions dur-ing the waking state compared with vivid dreams andthat without careful questioning, patients frequentlytermed a nocturnal event a dream even when they werefully awake.

The observation that altered dream phenomena wasassociated with two different and independent behaviors,on the one hand sleep fragmentation and on the otherhallucinations/illusions, suggests that this behavior is ofparticular clinical significance in PD. Because of thecross-sectional design of the study, we cannot commenton whether altered dream phenomena precede andthereby predict a risk for the other behaviors. Clearly,however, our data argue strongly against the concept ofan additive continuum of behaviors that starts with sleepdisruption, later includes altered dream phenomena, andfinally has accompanying hallucinations/illusions.8

Rather, we suggest two other possibilities: first, the pri-mary behavior of pathophysiological importance in PD isaltered dream phenomena and this behavior can evolveinto two different and unrelated syndromes. Alterna-tively, sleep fragmentation and hallucinations/illusionsmay be part of a behavioral continuum but the individualbehaviors are not additive at any one time. As such,patients may experience combined sleep fragmentationand altered dream phenomena at one point in their illnessbut later progress to altered dream phenomena with

hallucinations/illusions in the absence of prominent sleepfragmentation. A longitudinal study design would ad-dress this issue.

The focus of our study was the association or inde-pendence of three behaviors in PD and as such was notan epidemiological survey of incidence or prevalence.We recognize that our tertiary care patient populationmay represent an overestimate of these behaviors com-pared with a general PD population. Such patients, how-ever, provide an excellent opportunity to study the asso-ciations among the chosen target behaviors. Our inter-view questionnaire required between 5 and 20 minutes,depending on the presence or absence of specific behav-iors, and its ease of administration suggests its use for avariety of future research efforts. We derived the ques-tionnaire primarily from other rating interviews used bysleep physicians and psychiatrists.9,10For sleep fragmen-tation, altered dream phenomena, and hallucinations/illusions, the questions were presented to the patient andcaregiver simultaneously and the single evaluator usedbest clinical judgment to arrive at one answer.

The anatomic and neurochemical substrates of sleepfragmentation, altered dream phenomena, and hallucina-tions/illusions are incompletely understood. Dopaminer-gic and serotonergic changes involving the substantianigra and dorsal raphe, respectively, have been presumedto influence these behaviors, although consistent patternsfor all the behaviors have not been delineated.11 Animalstudies demonstrate that during wakefulness dopaminer-gic and serotonergic activities increase, during slow-wave sleep dorsal raphe activity increases and substantianigral activity decreases, and during REM sleep the re-verse pattern occurs. Specifically related to PD, Birk-mayer and Riederer12 documented increased central se-rotonin levels in eight of nine brain regions in halluci-nating PD patients at autopsy, and agents that blockcentral 5-HT receptors, like ondansetron, are effectiveantihallucinatory drugs in PD.13 Clozapine, a novel neu-roleptic agent effective in decreasing hallucinations andpromoting sleep, shares combined receptor antagonistproperties for dopaminergic and serotonergic systems.14

Similar to the motoric complications of PD, behavioraldysfunction can relate to both progressive disease andmedication effects. Because this study was cross-sectional in design, we cannot specifically dissect therelative contributions of disease and drugs to our results.The fact that levodopa use, dopamine agonist exposure,and Sinemet-CR use did not differ among the groupsargues against a primary dopaminergic role in the phar-macology of these behaviors. The three drugs that wereunequally distributed, anticholinergics, selegeline, and

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amantadine, all act, at least in part, on nondopaminergicpharmacology.

Currently available treatments for hallucinations in PDare limited because traditional antipsychotic agents (neu-roleptics) exacerbate parkinsonism, and the primarynovel neuroleptic, clozapine, is associated with blooddyscrasias. The close association between altered dreamphenomena and hallucinations suggests that therapeuticinterventions aimed at diminishing dream-related activi-ties may have a positive impact on hallucinatory behav-ior. Available therapeutic measures include drugs likebenzodiazepines for REM behavioral disorder and tricy-clic agents for other sleep disruptions. Their impact onhallucinations in PD have not been specifically studied.Because hallucinations are associated with a high risk fornursing home placement3 and its consequent associatedmortality,4 and because hallucinations persist without in-tervention,15 assertive therapies are justified.

Acknowledgment: This study was supported in part by theUnited Parkinson Foundation.

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