Characteristics of Visual Hallucinations in Parkinson Disease Dementia and Dementia With Lewy Bodies

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Characteristics of Visual Hallucinations in Parkinson Disease Dementia and Dementia With Lewy Bodies Urs P. Mosimann, M.D., Elise N. Rowan Ph.D., Cassie E. Partington, M.Phil., Daniel Collerton M.Sc., Elizabeth Littlewood, B.Sc., John T. O Brien M.D., David J. Burn, M.D., Ian G. McKeith, M.D. Objective: Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) have overlapping clinical and pathologic features. Recurrent visual hallucinations (RVH) are common in both disorders. The authors have compared details of hallucination characteristics and associated neuropsychiatric features in DLB and PDD. Methods: This is a descriptive, cross-sectional study using the Institute of Psychiatry Visual Hallucinations Interview (IP-VHI) to explore self-reported frequency, duration, and phenomenology of RVH in PDD and DLB. The caregivers ratings of hallucinations and other neuropsychiatric features were elicited with the Neuropsychiatric Inventory (NPI). Results: Fifty-six patients (35 PDD; 21 DLB) with RVH were assessed. Hallucination characteristics were similar in both disorders. Simple hallucinations were rare. Most patients experienced complex hallucinations daily, normally lasting minutes. They commonly saw people or animals and the experiences were usually perceived as unpleasant. NPI anxiety scores were higher in PDD. Neuropsychiatric symptoms coexisting with hallucinations were apathy, sleep disturbance, and anxiety. Conclusions: Patients with mild to moderate dementia can provide detailed information about their hallucinations. Characteristics of RVH were similar in PDD and DLB, and phenomenology suggests the involvement of dorsal and ventral visual pathways in their generation. The coexistence of RVH with anxiety, apathy, and sleep disturbance is likely to impair patients quality of life and may have treatment implications. (Am J Geriatr Psychiatry 2006; 14:153 160) Key Words: Visual hallucinations, dementia with Lewy bodies, Parkinson disease dementia Parkinson disease dementia (PDD) is a common late feature of Parkinson disease. It has overlapping pathologic and clinical features with dementia with Lewy bodies (DLB). 1,2 Lewy body pathology is prominent in both disorders, 3 and comparative studies have found no major differences in fluctuation of Received November 5, 2004; revised April 12, 2005; accepted April 19, 2005. From the Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom (UPM, ENR, CEP, EL, JTO, DJB, IGM), and Bensham Hospital, Gateshead, United Kingdom (DC). Send correspondence and reprint requests to Dr. Urs P. Mosimann, Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne NE4 6BE, U.K. e-mail: u.p.mosimann@ncl.ac.uk 2006 American Association for Geriatric Psychiatry Am J Geriatr Psychiatry 14:2, February 2006 153

Visual Hallucinations in Dementia attention, 4 phenomenology of parkinsonism, 5 autonomic dysfunction, 6 and response to cholinergic therapy. 7,8 The current clinical distinction of PDD and DLB therefore relies mainly on the duration of parkinsonism before dementia onset. Recurrent visual hallucinations (RVH) are prevalent (60% 80%) in PDD and DLB. 1,2 They are, together with fluctuation and parkinsonism, core clinical features of DLB. 9 The few studies addressing hallucination phenomenology in both disorders have reported well-formed complex hallucinations of people, animals, or objects 10,11 but do not mention simple hallucinations of flashes, dots, or grids, commonly mentioned in eye disease. 12 Hallucination phenomenology may thus be disease-dependent and may depend on the pattern of cortical dysfunction. The latter is supported by neuroimaging studies that related hallucination phenomenology to the activation of specific cortical visual areas, e.g., the hallucination of faces was accompanied with the activation of cortical areas involved in face perception. 13,14 Given the similar perfusion changes in areas involved in visual processing, 15 similar perceptual impairments, 16 and the lack of differences in hallucination phenomenology in previous studies, 10,11 we did not expect major differences in hallucination characteristics between PDD and DLB. To date, there have been no comparative studies of detailed hallucination characteristics in PDD and DLB using the same questionnaire. This pilot study therefore used the Institute of Psychiatry Visual Hallucinations Interview (IP-VHI) 12 in both disorders. As a result of the lack of a validated questionnaire to assess hallucinations in dementia, we chose an interview previously used to assess hallucinations and eye disease. A patient interview was important, because hallucinations are subjective percepts and we were interested in establishing whether demented patients could provide phenomenologic information. The Neuropsychiatric Inventory (NPI) 17 was used to assess the caregivers reports of hallucinations and associated neuropsychiatric features. Using this inventory, previous studies found highest scores for depression, apathy, and hallucinations in PDD 10 and apathy, delusions, and hallucinations in DLB. 18 Given these differences, we hypothesized that associated neuropsychiatric features in patients with PDD and those with DLB would slightly differ. METHODS Participants All patients in the Newcastle Medical Research Council (MRC) Lewy body patient cohort with PDD or DLB 5 were asked whether they experienced RVH at their annual assessment. Visual hallucinations were defined as visual perceptions without adequate visual stimulus. 19 To be included in this study, patients had to report RVH and the informant had to complete the NPI. Fifty-six of 85 patients reported RVH. DLB was diagnosed according to Consensus guidelines 9 and patients with PDD fulfilled U.K. Parkinsons Disease Society Brain Bank Clinical Diagnostic Criteria for PD for at least 12 months, before then fulfilling Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for dementia and for DLB. 20 Diagnosis was determined by the consensus of three senior clinicians (IGM, JTO, DJB) using a method with established accuracy as determined by autopsy confirmation. 21 The only antiparkinsonian medication allowed was L-dopa monotherapy. Patients taking cholinesterase inhibitors (ChE-Is) were eligible for the study provided they had been on a stable dose for more than three months. This requirement was mainly to avoid additional research appointments during the initial treatment phase. The local research ethics committee granted approval, procedures were fully explained to patients and informants, and both gave written informed consent. Testing Procedure The IP-VHI 12 is a semistructured patient interview that explores hallucination characteristics in detail and builds on well-established neurophysiological models. 22 It was originally developed for telephone interviewing of visually impaired patients with hallucinations, i.e., Charles Bonnet Syndrome (CBS). We adapted it slightly for the use in our sample, i.e., we assessed patients face to face in the outpatient clinic and patients were encouraged to give verbatim statements about their experiences. Verbatim statements were categorized by consensus (CEP, ENR, UPM) as simple hallucinations (e.g., flashes, lines, zigzags, regular and irregular patterns, particles) or wellformed complex hallucinations. The latter were 154 Am J Geriatr Psychiatry 14:2, February 2006

Mosimann et al. grouped into the following categories: children and babies, adult family members and friends, soldiers and anonymous people, animals, machines, body parts, or letters/numbers. An outline of the questionnaire can be found in the Appendix of Santhouse et al. 12 Interviewers were not blind with regard to diagnosis. The NPI is a caregiver interview assessing delusions, hallucinations, agitation, depression, anxiety, elation, apathy, disinhibition, irritability, aberrant motor behavior, sleep, and appetite. The subquestions Does the patient talk to people who are not there and Does the patient describe seeing things not seen by others of the hallucination section were used to establish if the caregiver confirmed the presence of RVH. 17 Fluctuation was measured with the Caregiver One-Day Fluctuation Assessment Scale. 23 The Bristol Activities of Daily Living Scale (Bristol ADL) 24 was used to assess functional impairment. These three caregiver assessments were completed in the absence of the patient. The Unified Parkinsons Disease Rating Scale (UPDRS) motor section (part III) 25 and Cambridge Cognitive Examination (CAMCOG) 26 were used to quantify the severity of extrapyramidal features and global cognitive impairments, respectively. Statistical Analysis Data were analyzed using the Statistical Package for Social Sciences (SPSS version 11). The distribution of the data were examined for normality (Kolmogorov Smirnov test). Means and standard deviations (SDs) were calculated. Provided the data did not deviate from the normal distribution, parametric tests (i.e., independent-sample t-tests) were used; nonnormally distributed data were compared with Mann-Whitney U tests. Pearson chi-square was used for the comparison of frequencies and Fisher exact tests when the expected frequency of a symptom in either group was 5. All reported p values are twotailed and a p value of less than 0.05 was considered significant. RESULTS Characteristics of the sample are summarized in Table 1. Fifty-six patients (35 PDD and 21 DLB) reported RVH. The two diagnostic groups did not differ with respect to age, gender, education, cognitive scores, fluctuation or the severity of parkinsonism. The onset of parkinsonism was, as expected, earlier in the PDD group. Ninety-one percent of patients with PDD were treated with L-dopa compared with only 29% of patients with DLB (Fisher exact: p 0.0001). Fifty-seven percent of patients with DLB were taking ChE-I compared with 31% of patients with PDD (Fisher exact: p 0.092). No differences in frequency, duration, or phenomenology of RVH were found between patients who were taking L-dopa and/or ChE-I and those not on these medications. TABLE 1. Characteristics of the Sample PDD DLB Comparison Statistic [df]; p Gender (M:F) 24:11 15:6 p 0.822* Age (years) 73.7 5.9 75.4 6.4 t [54] 0.980, p 0.332 Education (years) 11.7 1.8 11.3 0.9 z [56] 0.836, p 0.403 CAMCOG (maximum 105) 63.5 13.9 62.4 13.6 t [51] 0.273, p 0.786 MMSE (maximum 30) 18.6 5.5 17.3 5.1 t [54] 0.878, p 0.384 Age of dementia onset (years) 70.0 5.9 73.3 6.9 t [43] 1.729, p 0.091 UPDRS motor III (maximum 108) 36.0 12.4 32.2 16.3 t [54] 0.978, p 0.333 Age at EPS onset (years) 64.4 9.4 71.8 7.9 t [43] 2.266, p 0.029 NPI (maximum 144) 20.3 17.2 17.7 17.7 t [54] 0.541, p 0.590 Age at hallucination onset (years) 71.2 6.0 74.9 6.8 t [39] 0.089, p 0.089 Fluctuation scale (maximum 21) 4.8 3.1 3.2 4.0 t [53] 1.607, p 0.114 Bristol ADL (maximum 60) 20.7 10.3 19.5 11.0 t [53] 0.410, p 0.684 Means and standard deviations (SDs). *Fisher exact test. Mann Whitney U test, if not specified, independent-sample t-tests. CAMCOG: Cambridge Cognitive Examination; MMSE: Mini- Mental Status Examination; UPDRS: Unified Parkinsons Disease Rating Scale; NPI: Neuropsychiatric Inventory; PDD: Parkinson disease dementia; DLB: dementia with Lewy bodies. Am J Geriatr Psychiatry 14:2, February 2006 155

Visual Hallucinations in Dementia Institute of Psychiatry Visual Hallucinations Interview Six patients (five PDD and one DLB) admitting to RVH were unable to complete the IP-VHI. The main characteristics of the remaining 50 patients (30 PDD and 20 DLB) are summarized in Table 2. Experiences of simple hallucinations in isolation were rare. RVH were commonly complex, experienced on a daily basis and lasting minutes rather than seconds or hours. Patients generally saw single, colored objects perceived in the central field of view. Hallucinated objects were static in more than 50% of cases. In addition to the main characteristics summarized in Table 2, the IP-VHI revealed that most hallucinations were opaque (PDD: 57%; DLB: 75%) rather than transparent (PDD: 37%; DLB: 10%) (Fisher exact test: p 0.088) and that hallucinations were constant (PDD: 70%; DLB: 80%) rather than changing from one thing into another (PDD: 13%; DLB: 0%) (Fisher exact test: p 0.143). Temporal palinopsia, i.e., the perseveration of a previously viewed object after a certain time, was reported in 47% of the patients with PDD and 25% of the patients with DLB (Fisher exact test: p 0.079). Spatial palinopsia, the persistence of a visual image in space, was found in 43% of the patients with PDD and 25% of the patients with DLB (Fisher exact test: p 0.129). Hallucinations were rarely precipitated by motion, e.g., by traveling in a car or train (PDD and DLB: both 10%), and they rarely moved with eye or head movements (PDD: 43%; DLB: 25%) (Fisher exact test: p 0.510). RVHs were sensitive to blinking in 40% of the patients with PDD and 30% of the patients with DLB (Fisher exact test: p 0.535) and persisted with closed eyes in 37% of the patients with PDD and 40% of patients with DLB (Fisher exact test: p 0.757). Patients normally found their hallucinations unpleasant (PDD: 43%; DLB: 45%) rather than pleasant (PDD: 3%; DLB: 10%) (Fisher exact test: p 0.565). Of patients with complex RVH (N 47), three patients (one PDD and two DLB) confirmed complex visual hallucinations by straightforward yes/no questions from the IP-VHI but were unable to give detailed descriptions of what they saw. Forty-four patients with complex visual hallucinations gave verbatim statements summarized in Table 3. Nearly two-thirds (63.6%) of the verbatim descriptions fell into more than one descriptive category. Patients reports most commonly referred to people or animals and machines. The nine patients who admitted RVH but were unable to complete the IP-VHI (N 6) or to give verbatim statements (N 3) were more cognitively impaired than patients giving a verbatim description of their hallucinations (MMSE 13.4 5.8 versus 19.1 4.6; independent-sample t-test: t 3.254, df 51, p 0.002). TABLE 2. Characteristics of Recurrent Visual Hallucinations of All Patients (30 PDD, 20 DLB) Completing the IP-VHI PDD N (%) DLB N (%) Comparison Statistic [df ]; p Hallucinations Simple 1 (3.3) 2 (10.0) Complex 16 (53.3) 14 (70.0) 2 [2] 3.366, p 0.186 Simple and complex 13 (43.3) 4 (20.0) Frequency Continuous 4 (13.3) 2 (10.0) Daily 16 (53.3) 9 (45.0) 2 [3] 1.939, p 0.585 Weekly 5 (16.7) 3 (15.0) Monthly 4 (13.3) 6 (30.0) Duration Seconds 6 (20.0) 4 (20.0) Minutes 16 (53.3) 10 (50.0) 2 [2] 0.158, p 0.924 Hours 6 (20.0) 5 (25.0) Spatial frame Single object 19 (63.3) 18 (90.0) p 0.061* Extended scene 8 (26.7) 1 (5.0) Color in color 18 (60.0) 12 (60.0) p 1.000* Location Central field 20 (66.7) 12 (60.0) p 0.522* Peripheral field 7 (23.3) 7 (35.0) Motion In motion 12 (40.0) 6 (30.0) p 0.374* Statistics are Pearson chi-square ( 2 ) test or *Fisher exact tests. PDD: Parkinson disease dementia; DLB: dementia with Lewy bodies; IP-VHI: Institue of Psychiatry Visual Hallucinations Interview. 156 Am J Geriatr Psychiatry 14:2, February 2006

Mosimann et al. TABLE 3. Phenomenology of Complex Hallucinations (28 PDD, 16 DLB) Listed in Order of Frequency of Occurrence PDD N (%) DLB N (%) Fisher Exact Tests: p Values Examples Anonymous people/soldiers 17 (60.7) 11 (68.8) 0.748 Figures sitting and standing in the house, sometimes blocking stairway; a group of people having a party; people walking in the bedroom; a line of nuns waiting to cross the road; gypsies walking around; medieval figures dressed in cloaks; a soldier on a navy ship; army marching up the lawn; gruesome elderly people without eyes; groups of people with distorted faces Friends, family members 8 (28.6) 3 (18.8) 0.719 Son sitting in a chair in the living room; son climbing out of a window; mother and daughter speaking; deceased sister Children/babies 4 (14.3) 3 (18.8) 0.692 Small boy in the bedroom shouting fire; children in bedroom cutting the bed clothes; groups of children running around Body parts 6 (21.4) 4 (25.0) 1.000 Relative s faces; a shadowy face without a body; the head of a vicious dog; three faces moving together; a ghostly phantom without a head; three-legged people; an unpleasant, red-painted face of a cartoon character without a body; heads of known people in lounge; bodies in bedroom; distorted faces Animals 13 (46.4) 4 (25.0) 0.208 Mice, rats and mice running along the skirting board; little animals, e.g., snakes on bed linen, hedgehogs in garden, and furry things on the floor; small spiders on the ceiling or the floor Machines (car, buses, airplanes) 7 (25.0) 2 (12.5) 0.450 Buses and lorries; vehicles as part of a procession; a small gray van moving; flying in an airplane; gypsies dismantling wheels from a machine Letters 4 (14.3) 0 (0.0) 0.280 Letters on the door; musical stave; musical notes; floating numbers PDD: Parkinson disease dementia; DLB: dementia with Lewy bodies. Neuropsychiatric Inventory The informants reports of neuropsychiatric symptoms are summarized in Figure 1. NPI scores (frequency multiplied by severity) did reveal differences between PDD and DLB; patients with PDD were more anxious than patients with DLB (Mann-Whitney z 2.606, N 56, p 0.009). Elation was uncommon, only being observed in three patients with DLB (Mann-Whitney z 2.277, N 56, p 0.023). No significant difference in anxiety scores was found when patients on ChE-I were compared with those off ChE-I in the PDD (Mann-Whitney z 1.147, N 35, p 0.283) and DLB groups (Mann-Whitney z 0, N 21, p 1.0). Other common symptoms, reported in more than 50% of the patients, were apathy and sleep problems. Most but not all (83.9%) informants confirmed hallucinations. Three-fourths of the caregivers were spouses, 16% were other relatives, and 9% were professional caregivers; and there was no difference in terms of caregiver type between informant-confirmed and -nonconfirmed RVH (chisquare 3.875, df 2, p 0.145). DISCUSSION This study assessed the characteristics of RVH in patients with PDD and DLB. The groups did not differ in age, gender, or dementia severity, and patients with mild to moderate dementia (MMSE 13) were able to provide phenomenologic information. Characteristics of RVH in DLB and PDD were similar. NPI scores for anxiety were higher in patients with PDD. Other common symptoms coexisting with hallucinations in both disorders were apathy and sleep disturbance. In agreement with previous studies, 10,11 most patients with PDD and those with DLB reported complex hallucinations of people, animals, Am J Geriatr Psychiatry 14:2, February 2006 157

Visual Hallucinations in Dementia FIGURE 1. Summary of NPI Scores in Patients with PDD and Those With DLB With RVH Note: Patients with PDD were more anxious than patients with DLB (Mann-Whitney z 2.606, N 56, p 0.009), and elation was only observed in three patients with DLB (Mann-Whitney z 2.277, N 56, p 0.023). Other common symptoms coexisting with hallucinations were apathy and sleep disturbance. NPI: Neuropsychiatry Inventory; PDD: Parkinson disease dementia; DLB: dementia with Lewy bodies; RVH: recurrent visual hallucinations. and objects. Simple hallucinations, i.e., flashes, lines, or patterns, solely or in combination with complex hallucinations, were uncommon (up to 20%). Santhouse et al. 12 assessed 32 visually impaired patients with RVH, i.e., CBS, using the same questionnaire and found simple hallucinations in 80% of their cases. This supports the assumption that simple hallucinations are more common in CBS and may imply that different mechanisms are involved in the generation of simple and complex hallucinations. 27 Previous neuroimaging studies have linked the occurrence of complex hallucinations to the activation of specific, specialized cortical areas. 13,14 Two interconnected visual pathways are involved in 158 Am J Geriatr Psychiatry 14:2, February 2006

Mosimann et al. higher visual processing 28 ; the ventral visual pathway is for the recognition of colors, people, and objects and the dorsal pathway for motion and overview vision. 12,22 Bearing this in mind, hallucination phenomenology in PDD and DLB suggests involvement of both pathways, because patients perceived colors, detailed objects and people, as well as motion and scenery. The lack of differences between PDD and DLB may indicate similarities in their pathophysiology. This is supported by neuroimaging studies showing similar hypoperfusion in parietal 15 and occipital brain areas 29 and the profound neurodegeneration in visual association areas in DLB and PDD. 3 Hallucinations were commonly associated with sleep disturbances, apathy, and anxiety. Whether anxiety precipitates hallucinations, simply coexists, or is a consequence of them cannot be answered with the current data. That patients considered their hallucinations as unpleasant rather than pleasant tends to support the latter assumption. 30 Patients with PDD were more anxious than patients with DLB. Because it has been shown that cholinesterase inhibitors (ChE-I) can improve anxiety in DLB, 8 higher anxiety scores in PDD could be related to fact that fewer patients with PDD were treated with ChE-I. Nevertheless, no differences were found when anxiety scores of patients on and off ChE-Is were compared in either the PDD or the DLB groups, and this makes the difference in ChE-I intake an unlikely explanation for higher anxiety scores in PDD. The IP-VHI was helpful for assessing hallucination characteristics in mildly to moderately demented patients; however, it was less effective for severely impaired patients. Patients with MMSE below 13 had difficulties providing phenomenologic information. To assess their experiences, it is therefore also necessary to question their caregivers. Unfortunately, no existing patient hallucination questionnaire has a parallel caregiver version. The extent to which caregivers can provide additional phenomenologic information needs further evaluation because in the present study, 16% of the caregivers were unaware of patients RVH. A limitation that needs to be recognized when interpreting these findings is that the psychometric properties (validity or reliability measures) of IP-VHI are unknown. This is unfortunately a general limitation for all hallucination questionnaires published so far. Another limitation in the present study is that we cannot exclude a type II error to be the reason for a lack of difference in hallucination characteristics in PDD and DLB. To our knowledge, this is the biggest, most detailed characterization of visual hallucinations in PDD and DLB to date, but the sample size is still relatively small. Considering present and previous data, 11,31 it is unlikely that hallucination content will be helpful for distinguishing PDD from DLB. Diagnosis of DLB in the current study was based on clinical guidelines using the duration of Parkinson disease before cognitive impairment to separate DLB from PDD. 9 This method has been proven accurate in previous longitudinal studies with autopsy confirmation 21 but does not completely exclude clinical misdiagnosis. Finally, only patients freely admitting RVH were included in our analysis, and thus it is possible that a selection bias was introduced by inadvertently excluding patients not disclosing them. This pilot study suggests similarities in hallucination characteristics in PDD and DLB and demonstrates the strength and limitations of existing methods for hallucination assessment. The lack of differences in hallucination phenomenology suggests similar disturbances in the visual system in the two disorders. Refined questionnaires with established psychometric properties and parallel caregiver versions are needed to quantify visual hallucinations and quantify treatment benefits. Support of this work has been provided in part by the U.K. Medical Research Council (IGM, JTO, DJB) and by the Swiss National Science Foundation and Swiss Association for Parkinsons disease (UPM). The authors thank patients and informants who made this work possible and Nicola Barnett and Debra Lett for their invaluable help with recruiting. Many thanks to Dr. D. Ffytche and Professor R. J. Howard of the Institute of Psychiatry in London for providing us with their questionnaire. References 1. McKeith I, Mintzer J, Aarsland D, et al: Dementia with Lewy bodies. Lancet Neurol 2004; 3:19 28 2. Emre M: Dementia associated with Parkinson s disease. Lancet Neurol 2003; 2:229 237 Am J Geriatr Psychiatry 14:2, February 2006 159

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