Original Research Paper

Risk factors for visual hallucinations in patients with Parkinson’s disease Roˆmulo Lopes Gama1, Veralice Meireles Sales de Bruin1, Pedro Felipe Carvalhedo de Bruin1, Daniel Gurgel Fernandes Ta´vora1, Emily Moura˜o Soares Lopes1, Iago Farias Jorge1, Lia Rita Azeredo Bittencourt2, Sergio Tufik3 1

Universidade Federal do Ceara, Fortaleza, Brazil, 2Department of Psychobiology, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil Aim: Parkinson’s disease (PD) patients frequently present visual hallucinations (VHs) that have been associated with depression, old age, and cognitive impairment. Sleep abnormalities are also related to these factors. The aim of this study is to evaluate risk factors, particularly sleep alterations, associated with VHs in PD. Methods: This is a cross-sectional evaluation of consecutive patients from a Movement Disorder’s clinics. Patients were clinically evaluated, and behavioral questionnaires were applied in a face-to-face interview. Results: Among 100 PD patients (67% male, mean age 5 65.0 ¡ 10.4), VHs were present in 28% of cases; individuals with VHs had worse sleep quality (Pittsburgh Sleep Questionnaire Index) and more severe sleep disturbances [Parkinson’s Disease Sleep Scale (PDSS)]. Logistic regression analysis showed that vivid dreams and Unified Parkinson’s Disease Rating Scale (UPDRS) I scores (i.e., mentation, behavior, and mood symptoms) are independently associated with VHs. Our data show that the presence of vivid dreams is associated with VHs in PD and reaffirm that VHs are linked to cognitive impairment. Conclusions: Investigating vivid dreams may help the identification of VHs in PD. Identifying vivid dreams can be hard considering that patients may fail to report symptoms for the fear of the stigma associated with psychosis and dementia.

Keywords: Parkinson’s disease, Visual hallucinations, Vivid dreams, Sleep, Mental dysfunction

Introduction Hallucinations are sensory perceptions in the absence of a suitable external stimulus and can manifest as visual, auditory, olfactory, or tactile phenomena.1 When the patient recognizes the false nature of the hallucination, the term pseudo-hallucination is used.2 Visual hallucinations (VHs) occur within a broad spectrum of medical conditions that include retinal disease, migraine, acute stroke, side effects related to drugs, neurodegenerative diseases, abuse of alcohol, or other substances, toxic-metabolic encephalopathy, and psychiatric illness.3 Patients with Parkinson’s disease (PD) may have different forms of hallucinations, and the most frequent being VHs. Usually, they occur in more advanced stages of the disease and estimated prevalence range between 8.8% and 44%.4 Frequently, PD patients who have VHs present a high Hoehn and Yahr (HY) stage5 or greater disease severity as assessed by the activities of daily living, a sub scale of the Unified Parkinson’s Disease Rating Scale (UPDRS).6 FurtherCorrespondence to: Veralice M. S. de Bruin, Departamento de Medicina, Universidade Federal do Ceara´ Rua Cel Nunes de Melo 1315 CEP 60.430-270, Fortaleza, Ceara´, Brazil. Email: [email protected]

ß W. S. Maney & Son Ltd 2014 DOI 10.1179/1743132814Y.0000000418

more, VHs in PD are of clinical importance, as many studies show an association between VHs, cognitive decline, and increased mortality.7 Despite reports that higher doses of levodopa and other antiparkinsonian agents, such as dopamine agonists or anticholinergics, have been associated with VHs in individual cases, a direct cause and effect relationship between a specific drug and VHs remains controversial.8 Few studies have demonstrated an association between VHs and higher doses of dopaminergic drugs9 or the association with a specific profile of drug such as dopaminergic agonists or selegiline.10,11 Taking all this evidence together, it is reasonable to consider that identifying risk factors associated with VHs is important and may guide clinical diagnosis and therapeutic measures. The objective of this study is to evaluate risk factors, particularly sleep alterations, associated with VHs in PD.

Methods Participants and ethical considerations One hundred patients with a clinical diagnosis of PD were consecutively recruited from the Movement

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Disorders Outpatient Clinic at the University Hospital of the Universidade Federal do Ceara´, Brazil. Patients were recruited among a population of 152 patients: 28 were too old or had difficulty with verbal communication, 10 refused to collaborate, and 14 lived in remote areas and were considered as non-compliant with the follow-up. The protocol was analyzed and approved by the Ethics Committee (HU-UFC No. 045.0607).

Study design and measurements This was a cross-sectional investigation of VHs in patients with PD, HY I–III. The evaluations were performed over a period of 12 months (July 2010– July 2011). Specific questionnaires were all measured concurrently in a face-to-face interview by two trained medical staff. Patients were excluded if they had any severe comorbidity and were not competent to provide their informed consent. Demographic data, habits, and comorbidities were recorded using a standardized questionnaire. We used the Parkinson’s Disease Sleep Scale (PDSS), a 15-item visual analog scale that quantifies various aspects of nocturnal disabilities and sleep problems in PD; this scale has also been validated in Brazil.12 A PDSS score #100 defined troublesome nocturnal symptoms and a cut-off of ,5 for each item indicates sleep impairment.13,14 Subjective sleep quality was evaluated by the Pittsburgh Sleep Quality Index (PSQI). Patients were also questioned whether dreaming was frequent, vivid, and sometimes terrifying. Vivid dreams were considered present when patients reported any occurrence of this kind in the last 30 days. The PSQI has seven components, each one dealing with a major aspect of sleep: subjective quality of sleep, sleep onset latency, sleep duration, sleep efficiency, and the presence of sleep disturbances. Individuals with a total PSQI score greater than five were considered poor sleepers.15 Daytime somnolence was assessed by the Epworth Sleepiness Scale (ESS), a questionnaire containing eight items that ask about the expectation of dozing in eight hypothetical situations. An ESS score of 10 or more indicates excessive daytime sleepiness.16 Both the PSQI15 and ESS17 have been validated in Brazil. Disease severity was investigated by the UPDRS, Parts I (mentation, behavior, and mood), II (selfevaluation of the activities of daily life), III (clinicianscored motor evaluation), and IV and V (HY stage severity). Depressive symptoms were evaluated by the Beck Depression Inventory (BDI) and were defined as present if the score was §10.18 The Hospital Anxiety and Depression Scale was also used.19 The levodopa equivalent dose (LED) was determined.20 We routinely questioned the patients on the presence of the types of hallucinatory phenomena during the previous 3 months: minor hallucinations/illusions;

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VHs; and auditory hallucinations. None of the patients had previously received a diagnosis of schizophrenia or other psychiatric condition.

Statistical analysis Descriptive statistics are presented as mean ¡ standard deviation, range, and frequency (% values). Fisher’s exact test for categorical variables, Mann–Whitney U test for continuous variables and Student’s t-test for normally distributed data with equal variances were used to identify variables that were associated with VHs. Stepwise multiple regression procedures were used to determine the best predictive model. Variables with P , 0.2 were all included as potential predictor variables; a P , 0.05 was required for a variable to be retained in the final model. Statistical analysis was carried out using SPSS for Windows, version 16.0. Statistical significance was set at P , 0.05.

Results One hundred patients, 67 men and 33 women, aged from 45 to 80 years (mean age 65.0 ¡ 10.4 years) were evaluated. Visual hallucinations were observed in 28% of patients (mean age: 66.2 ¡ 10.6 years). No differences in relation to gender, age at examination, age at disease onset, and disease duration were found. Family history of PD, present in 29% of cases, was also similar between groups. Reports of vivid dreams were more common in PD patients with VHs (P 5 0.01). Dyskinesia, excessive daytime sleepiness, sudden sleep onset, and postural instability were not significantly different between cases with and without VHs. Diabetes (25%) and hypertension (47.2%) were not different between groups (Table 1). Unified Parkinson’s Disease Rating Scale measures Part 1 that evaluates valuation of mentation, behavior, and mood were significantly more impaired in PD patients with VHs (P , 0.005). Sleep quality (PSQI) and sleep disorders (PDSS) were also more impaired in patients with VHs (P 5 0.001) (Table 2). Logistic regression analysis showed that the presence of vivid dreams (P 5 0.007) and higher scores (worse) of the UPDRS Part I (P 5 0.000) were independently associated with VHs (Table 3).

Discussion Our results show that VHs are independently associated with the presence of vivid dreams and with worse mentation, behavior, and mood symptoms (UPDRS I). In line with our results, Goetz et al.21 showed an association between hallucinations and concurrent vivid dreams; however, they also showed that sleep fragmentation or vivid dreams had no predictive influence on the future development of hallucinations. Goetz22 concluded that hallucinations and global sleep disorders were distinct behavioral abnormalities with different patterns of progression.

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Table 1 Clinical demographic characteristics of patients with PD (N 5 100) according to the presence/absence of hallucinations All cases, N 5 100

Variables Gender (M/F), n (%) Age, years, Mean (SD) Age at onset, years, Mean (SD) Disease duration, years, Mean (SD) Family history of PD, n (%) LED, Mean (SD) Dyskinesia, n (%) Vivid dreams, n (%) EDS, n (%) Sudden sleep onset, n (%) Postural instability, n (%) Diabetes, Yes/No, n (%) Arterial Hypertension, n (%)

67/33 65.0 (10.4) 58.1 (11.7) 6.8 (5.3) 29/71 707.1 (305.2) 37/63 58/42 27/73 38/60 34/66 22/78 49/51

PD without visual hallucinations (VHs), N 5 72 49/23 64.6 57.8 6.5 21/51 704.5 27/45 37/35 17/55 24/47 22/50 18/54 34/38

PD with VHs, N 5 28

(68/32)) (10.3) (11.2) (5.0) (41) (358.0) (37.5/62.5) (51.4/48.6) (23.6/76.4) (33.3/66.7) (30.5/69.5) (25/75) (47.2/52.8)

18/10 66.2 58.7 7.4 8/20 720.8 10/18 21/7 10/18 13/15 13/15 4/24 15/13

P value 0.47a 0.50b 0.74b 0.45b 0.80a 0.91b 0.97a 0.01a,* 0.19a 0.11a 0.15a 0.37a 0.81a

(64.3/35.7) (10.6) (12.9) (6.1) (40) (199.0) (35.7/64.3) (75/25) (35.7/64.3) (46.4/53.6) (42.8/57.2) (14.3/75.7) (53.5/46.5)

M/F: male/female; PD: Parkinson’s disease; LED: levodopa equivalent dose; EDS: excessive daytime sleepiness; aFisher exact test; b Student’s test; *P , 0.05.

Table 2 Behavioral questionnaires according to the presence/absence of hallucinations

All cases, N 5 100

Variables UPDRS I range, mean (SD) UPDRS II range, mean (SD) UPDRS III range, mean (SD) UPDRS IV range, mean (SD) PSQI range, mean (SD) PDSS range, mean (SD) Epworth range, mean (SD) BDI II range, mean (SD)

0–11, 4.5 (2.8) 1–38, 17.5 (9.9) 0–52, 19.4 (12.6) 0–11, 2.7 (3.1) 2–19, 10.1 (4.2) 26–143, 89.1 (28.0) 0–22, 8.5 (4.5) 0–52, 18.2 (10.9)

Parkinson’s disease (PD) without hallucinations, N 5 72

PD with hallucinations, N 5 28

P value

0–10, 3.5 (2.2) 1–38, 16.0 (9.2) 0–52, 17.9 (11.8) 0–11, 2.5 (3.1) 2–18, 9.3 (3.9) 40–143, 95.5 (25.9) 1–18, 8.2 (4.1) 0–52, 17.2 (10.4)

3–11, 7.3 (2.5) 3–37, 21.4 (10.9) 2–47, 23.3 (11.0) 0–11, 3.4 (3.3) 4–19, 12.8 (4.1) 26–120, 71.9 (26.7) 0–22, 9.0 (5.5) 3–49, 21.9 (11.6)

0.000** 0.05 0.10 0.19 0.001** 0.001** 0.59 0.05

UPDRS: Unified Parkinson’s Disease Rating Scale; PSQI: Pittsburgh Sleep Quality Index; PDSS: Parkinson’s Disease Sleep Scale; BDI: beck depression inventory. Mann–Whitney test *P , 0.05; **P , 0.01.

Table 3 Stepwise multiple regression analysis for predictors of visual hallucinations (VHs)

Variables Step 1 Disease duration Vivid dreams PDSS UPDRS I UPDRS II UPDRS III BDI HAD-anxiety Step 2 Vivid dreams UPDRS I UPDRS III BDI Step 3 Vivid dreams UPDRS I

95.0% Confidence interval

Stand. B of coefficient

Wald

P value

OR

0.03 1.40 20.03 0.58 0.05 0.03 0.03 0.12

0.05 6.51 10.44 21.0 4.91 0.02 3.25 5.73

0.53 0.02* 0.35 0.001** 0.53 0.25 0.24 0.64

0.95 47.5 .97 4.49 0.93 0.91 0.92 0.93

[0.80–1.11] [1.58–265.3] [0.93–1.02] [1.83–11.03] [0.75–1.15] [0.77–1.07] [0.82–1.05] [0.71–1.22]

3.59 1.47 20.07 20.07

4.74 11.00 1.06 1.48

0.02* 0.000** 0.02* 0.15

18.8 4.30 0.88 0.92

[1.58–133.9] [1.95–9.46] [0.79–0.98] [0.83–1.02]

2.35 0.66

7.32 19.8

0.007** 0.000**

10.5 1.94

[2.3–47.9] [1.44–2.59]

UPDRS: Unified Parkinson’s Disease Rating Scale; PDSS: Parkinson’s Disease Sleep Scale; BDI: Beck Depression Inventory; HAD: Hospital anxiety and depression scale; Stepwise multiple regression analysis *P , 0.05; **P , 0.01.

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Our results indicate that the presence of vivid dreams is associated with VHs and questioning about vivid dreams is important for the detection of VHs in PD patients. The appearances of formed VHs in PD are predominantly of people, animals, or objects, and less often of inanimate objects.23 Classic VHs are typically well formed, the figures can be mobile and are usually of brief duration, lasting only minutes. They occur frequently in low light conditions or in the evening or night, often when patients are resting and alone. Additionally, due to their repetitive and stereotyped character, the figures become familiar to the patient. Other types of hallucinations such as auditory, olfactory, and tactile are rarer, or later, when they take the form of bodily contact with animal or person.24 It has been shown that VHs are correlated with anxiety, major depression,25 old age, and cognitive impairment.26–28 In fact, studies about the relationship between depression, psychosis, and hallucinations with VHs have yielded inconsistent results. Most investigators found a positive association,29–31 while others found that this association was not maintained in multivariate analysis32 or was negative. Furthermore, sleep disorders are important risk factors for the development of psychosis, a condition associated with VHs in PD.33 Importantly, vivid dreams also manifest in several other neurological conditions such as cerebrovascular disease, senile dementia, and central nervous system infections. In this study, worse mentation as evaluated by the UPDRS I was associated with VHs. Interestingly, severity of psychotic symptoms in PD patients, as measured by the UPDRS thought disorder has been associated with the severity of cognitive impairment and with sleep disturbance.29 The association between cognitive impairment and VHs may be due to a parallel pathophysiological process and could be an expression of a common endpoint of neurodegeneration. Of note, the progression of cognitive decline has been more rapid in PD patients with VHs than in those without.34 However, it is unclear how independent cognitive changes and VHs are as regarding the pathologic process. Our data show that patients with VHs had worse sleep quality and more sleep disturbances; however, we do not confirm an independent association between VHs and sleep disorders or sleep quality as assessed by the PDSS and PSQI scales, respectively. Visual hallucinations were not associated with age at examination, age at onset, disease duration, and greater motor impairment. These findings may be related to the fact that clinical manifestations are pleomorphic in PD.35,36 The less than predictable evolution of disease severity in PD is a common observation. The development of VHs is the result of complex mechanism that integrates visual input, processing,

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and interpretation through limbic and temporal regions.37 In connection with VHs, a reduced gray matter volumes in the temporal cortex, stronger activation in subcortical centers, reduced control by dorsolateral prefrontal cortex, aberrant activation from emotional attention centers (rostral ventral anterior cingulate), and attenuated activation of the dorsal anterior cingulated, supplementary motor area, and cerebellum are thought to be involved.38,39 Gama et al.40 showed that the operculum-insula network may be part of an imagery cortical release phenomenon and play an important role in the manifestation of hallucinations and cognitive dysfunction in PD. Patients with VHs tend to be in advanced stage of the disease and suffer general cognitive impairment, with frontal dysfunction and memory deterioration.41 The present findings confirm a link between cognitive decline and VHs. Hallucinations in PD can be clinically occult and not unlikely can be covered by the patient’s fear of the stigma associated with psychosis and dementia. Likewise, visual dysfunction may be missed in routine neurological examination.42 Matsui et al.43 demonstrated a close relationship between impaired visual acuity and VHs in PD; it has been proposed that impaired visual acuity and VHs involve similar pathological processes. Our data show that the presence of vivid dreams is associated with VHs in PD and reaffirm that VHs is linked to cognitive impairment. Interrogating about vivid dreams may help the identification of VHs in PD. This is important considering that VHs in PD can be clinically occult, probably hidden by the patient for fear of the stigma associated with psychosis and dementia.

Disclaimer Statements Contributors Written by Roˆmulo Lopes Gama, Veralice Meireles Sales de Bruin, and Iago Farias Jorge. Reviewed by Veralice Meireles Sales de Bruin, Pedro Felipe Carvalhedo de Bruin, Daniel Gurgel Fernandes Ta´vora, Lia Rita Azeredo Bittencourt, and Sergio Tufik. Funding Conselho Nacional de Pesquisa (CNPq), Fortaleza, Brazil. Conflicts of interest The authors do not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Ethics approval The work has been seen and approved by all authors, and it is not under appreciation elsewhere. All authors are in agreement with this submission and it has been approved by the Ethical Committee.

Acknowledgements This work was partially supported in part by MCT/ CNPq.

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Risk factors for visual hallucinations in patients with Parkinson's disease.

Parkinson's disease (PD) patients frequently present visual hallucinations (VHs) that have been associated with depression, old age, and cognitive imp...
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