Predictable Risk Factors for the Feeling of Presence in Patients with Parkinson's Disease

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Authors:  Hiroshi Kataoka and Satoshi Ueno

Article first published online:   16 SEP 2015 | DOI: 10.1002/mdc3.12233


Abstract

Background

The detailed relations between feeling of presence (FOP) and hallucinations remain uncertain in Parkinson's disease (PD). The prospective studies of risk factors predicting the onset of FOP have yet to be reported on. We prospectively investigated risk factors for FOP to identify factors related to the development of first-onset hallucinations from FOP in patients with PD who were followed up for 2 years.

Methods

From among the 100 consecutive patients, we registered 78 patients with PD. Once every 1 to 3 months, the same sole interviewer personally asked these patients during 2 years of follow-up. Seventeen independent variables were evaluated using multivariate logistic regression analysis using forced entry.

Results

Seventeen patients newly presented with FOP. In 7 patients, hallucinations developed after the onset of FOP. Twenty-six patients newly presented with visual hallucinations. On multivariate logistic regression analysis, the score for UPDRS part 4 (odds ratio [OR] = 1.413;P = 0.049; 95% confidence interval [CI] = 1.002–1.991) and an increase in dose of antiparkinsonian medications (OR = 0.132; P = 0.033; 95% CI = 0.021–0.846) were related to onset of FOP. Zung depression score (P = 0.017) differed significantly between patients who had FOP without hallucinations and those who had FOP with hallucinations (39.2 ± 5.21 and 46.25 ± 2.86, respectively).

Conclusion

Motor complications and increasing doses of antiparkinsonian medications may predict onset of FOP, and depression might be helpful for predicting the future development of hallucinations from FOP.

A feeling of presence (FOP) is defined as the vivid sensation that somebody (distinct from oneself) is present nearby when nobody is actually there, and FOP is not considered to indicate the presence of hallucinations.[1] FOP often occurs when hallucinations are imperfectly developed.[2] Hallucinations remain problematic in Parkinson's disease (PD). However, the detailed relations between FOP and hallucinations remain uncertain. FOP is important for two main reasons: to reassure the patient that FOP is not uncommon in PD (and that they are not terrible hallucinations) and to have the physician realize that increasing PD medication may induce hallucinations and hence such symptoms are a warning. Studies of FOP in PD are scant, and only one cross-sectional study has provided clinical descriptions of FOP.[2] To our knowledge, prospective studies of risk factors predicting the onset of FOP have yet to be reported on. We therefore prospectively investigated risk factors for FOP to identify factors related to the development of first-onset hallucinations from FOP in patients with PD who were followed up for 2 years.

Patients and Methods

We initially screened 100 consecutive patients who fulfilled the UK Parkinson's Disease Society Brain Bank criteria.[3] First, we had the patients complete diary questionnaires for 4 weeks (Fig. S1) to exclude patients who had hallucinations or who had dementia or higher brain dysfunction that would preclude following our instructions. The clinical diary included a total of 10 questions and inquired about hallucinations (item 9), vivid nightmares (items 1 and 2), dream-enactment behavior (items 3, 4, 5, and 7), and sleep fragments associated with vivid dreams (item 8). Items 3, 5, 7, and 9 were asked to both the patients and their bed partners. The patients wrote their responses to the questions after awakening in the morning. If a patient had drunk alcohol the previous night (item 10), we did not use their responses for that night. If they did not remember any dream or the experienced dreams could be not judged as nightmares, we did not use the responses associated with dreams. Patients who responded that they had hallucinations (item 9) were excluded. Patients who were given quetiapine, clozapine, rivastigmine, donepezil, galanthamine, yokukansan, or neuroleptic medications were excluded. Patients who had received DBS surgery or a previous diagnosis of schizophrenia, as well as patients who had a history of hallucinations, were also excluded. Severity of PD was graded according to the scores on parts III and IV of the UPDRS.[4] Cognition function was assessed with the Mini–Mental Status Examination (MMSE). Quality of patient health was evaluated with the 8-item Short-Form Health Survey (SF-8). The Brief Fatigue Inventory (BFI), Zung depression score, Zung anxiety score, and Parkinson's Disease Sleep Scale (PDSS) were also performed. Daily dose of antiparkinsonian agents was converted into the equivalent dose of levodopa as follows: 100 mg of standard l-dopa = 140 mg of controlled release l-dopa = 10 mg of bromocriptine = 1 mg of pergolide = 1.5 mg of cabergoline = 5 mg of ropinirole = 1 mg of pramipexole = 10 mg of selegiline.[5, 6] No patient received rotigotine. The same sole interviewer conducted all evaluations.

From among the 100 patients, we registered 78 patients with PD (Fig. 1). Once every 1 to 3 months, the same sole interviewer personally asked the following questions, as reported previously[1]: “Do you sometimes feel the presence of somebody, animals, shadows, or others when no one is there? If you sensed them, were they not distinct former subjects, such as persons or animals, and were they not dreams?” The same sole interviewer promptly obtained responses from all patients. At the same time, the interviewer interviewed the patients to inquire about the presence or absence and the frequency of hallucinations in the visual, auditory, tactile, and olfactory domains. As for hallucinations, the interviewer also asked the patients' caregivers. If discordant responses were obtained, the sole interviewer used best judgment to assign a point score. During 2 years of follow-up, we excluded patients who showed evidence of epilepsy, stroke, transient ischemic attacks, or who were admitted to the hospital because of physical problems, such as cardiac failure or pulmonary infection, or who had undergone surgical intervention. In addition, during follow-up, no patient had mental impairment, impaired consciousness, dementia, or impaired higher brain dysfunction, such as inattention or agnosia, which would have precluded following our instructions. Ten patients who did not complete this study and another 10 who newly had hallucinations without FOP were excluded, and the remaining 58 were included in data analysis (Fig. 1).

image

Figure 1. Selection procedure for analyzing patients.






Statistical Analysis

A total of 17 variables were evaluated: Independent variables were categorized as (1) age, (2) sex, (3) disease duration, (4) l-dopa equivalent dose (LED), (5) H & Y stage, (6) total UPDRS score, (7) UPDRS part III, (8) UPDRS part IV, (9) MMSE, (10) Zung depression score, (11) Zung anxiety score, (12) BFI, (13) SF-8, (14) sum score of items on PDSS (excluding items 6 and 7, associated with dream and hallucinations, respectively, which were rated from the direction of good to bad sleep), (15) dream-enactment behavior (absent = 0, present = 1), (16) nightmares (absent = 0, present = 1), and (17) increased doses of antiparkinsonian medications, such as dopamine agonists, trihexyphenidyl, amantadine, and zonisamide (absent = 0, present = 1). Variables that were significantly related to falling on univariate logistic regression analysis (P < 0.05) were entered into multivariate logistic regression analysis using forced entry. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Correlations of each variable were also evaluated by Spearman's rank-correlation test. To analyze the statistical significance of differences in these variables between groups, categories were evaluated by the Mann–Whitney U test, followed by Fisher's exact probability test (Fig. 1). SPSS software (Version 18; SPSS, Inc., Chicago, IL) was used for statistical analysis.

Results

During 2 years of follow-up, 5 patients newly presented with FOP without hallucinations, and 12 patients had both FOP and hallucinations. In 7 of the 12 latter patients, hallucinations developed after the onset of FOP (Table 1). During the 6 months before the onset of FOP, the dose of rotigotine, ropinirole, or entacapone was increased in 4 patients, and treatment with zonisamide, selegiline, or entacapone was begun in 3 patients. Three patients received stable doses of antiparkinsonian medications during the 2 years of follow-up. FOP of humans was most common, and FOP occurred more often in the evening or night (Table 2). Most episodes of FOP were short and not terrible. Insight was preserved in all patients. Some episodes of FOP preceded visual hallucinations of subjects similar to those associated with FOP (Table 3). Three subjects had terrible FOP. A 74-year-old man and a 73-year-old woman initially had only FOP lasting for seconds in the night and, subsequently, hallucinations including the same subject (human or cat) as FOP occurred. The man felt that he was being chased by someone, and the woman felt the presence of a cat running beside the patient. Another 72-year-old woman had FOP of humans or animals lasting for several seconds in the night, but hallucinations did not develop. She felt terrible because she felt that she was being closely watched by someone. During 2 years of follow-up, 22 patients newly presented with visual hallucinations, and 4 patients had both visual and auditory hallucinations. Zung depression score (P = 0.017) differed significantly between patients who had FOP without hallucinations and those who had FOP with hallucinations (39.2 ± 5.21 and 46.25 ± 2.86, respectively). Zung depression score (P = 0.051) differed slightly, but not significantly between patients who had FOP without hallucinations and those who had FOP followed by the later development of hallucinations (39.2 ± 5.21 and 46 ± 2.94, respectively).

Table 1. Clinical characteristics of patients with FOP and antiparkinsonian medications
Patient no. Clinical features at entry FOP Antiparkinsonian treatments
Age/sex Disease duration (m) UPDRS Part 3 UPDRS Part 4 MMSE Accompanied by Hs Developed to Hs later Increased dose used until FOPa Addiction of drugs until FOPa Increased or addiction during 2 years

1aPD: Parkinson's disease, UPDRS: Unified Parkinson's Disease Rating Scale, MMSE: Mini-Mental State Examination, During 6 months until the onset of FOP.

2bIncreased the dose and discontinued.

3m, months.

1 63/M 61 40 0 30 Rotigotine [1 m] Rotigotine, pramipexole
2 64/M 80 40 9 30
3 83/M 34 18 9 25 Zonisamide [1 m] Zonisamide
4 60/F 3 24 0 29 Selegiline, l-dopa
5 72/M 51 30 0 27 l-dopa, rotigotine, ropinirole, istradefylline, pramipexoleb, cabergolineb
6 72/F 11 27 0 29 + Zonisamide
7 69/M 30 21 0 30 + Rotigotine [1 m] Rotigotine, l-dopa
8 73/F 145 32 8 27 + Ropinirole [3 m] Ropinirole, zonisamide
9 68/F 100 41 7 23 + Rotigotine, pramipexole, l-dopa
10 71/F 91 12 1 29 + Zonisamide, pramipexole
11 74/M 57 29 1 29 +
12 71/M 9 35 1 30 +
13 74/M 103 15 0 28 + Selegiline [5 m] Selegiline
14 73/M 29 40 1 27 + l-dopa, rotigotine, zonisamide
15 81/F 61 26 0 30 + Trihexyphenidyl
16 69/M 30 10 1 29 + Ropinirole, selegiline
17 81/F 72 11 1 23 + Entacapone[1 m] Entacapone[4 m] Entacapone, l-dopa
 
Table 2. Detailed contents of FOP in patients with PD
  n = 17 (%)
What FOP
Human 12 (70)
Animal 5 (29)
Shadows 2 (11)
Other 1 (5)
Time
Evening 6 (35)
Night 13 (76)
Daytime 2 (11)
Frequency
Everyday 4 (23)
Several times per week 8 (47)
Once per week 0
Once per month 2 (11)
Rarely 3 (17)
Duration
Seconds 16 (94)
Minutes 1 (5)
Hours 0
Location
Indoor 16 (94)
Outdoor 3 (17)
Emotional impact
Not minded 10 (58)
Unpleasant 4 (23)
Terrible 3 (17)
 
Table 3. Patients in whom FOP developed to visual hallucinations
Patient no. Age/sex FOP Subsequent hallucinations
6 72/F Human Human
7 69/M Cat Human
8 73/F Human, cat, shadows Cat
9 68/F Human, shadows Human
11 74/M Human Human
12 71/M Shadows Human
13 74/M Insect Insect
 

Risk Factors for FOP

On multivariate logistic regression analysis, the score for UPDRS part 4 (OR = 1.413; P = 0.049; 95% CI = 1.002–1.991) and an increase dosed of antiparkinsonian medications (OR = 0.132; P = 0.033; 95% CI = 0.021–0.846) were related to onset of FOP (Table 4). There were no significant interactions between these predictive factors. Furthermore, when we additionally entered disease duration,[7] reported to be a significant risk factor for hallucinations, into multivariate logistic regression analysis, the results similarly showed that the score for UPDRS part 4 or an increased dose of antiparkinsonian medications was related to onset of FOP (OR = 1.412; P = 0.05; 95% CI = 1.001–1.992 and OR = 0.131; P = 0.033; 95% CI = 0.02–0.847, respectively). None of the 17 independent variables studied differed significantly between patients with and those without FOP.

Table 4. Independent predictors of FOP
  Crude OR (95% CI) P value Adjusted OR (95% CI)a P value

1aAdjusted for H & Y stage, Total UPDRS score, UPDRS part 3 and 4, MMSE, and increase of antiparkinsonian medications.

2bP < 0.05.

Age (years) 0.809 (0.646–1.014) 0.065    
Sex 0.97 (0.17–6.306) 1.036    
Disease duration (months) 1.009 (0.985–1.034) 0.461    
LED 1.00 (0.992–1.008) 0.976    
H & Y stage 0.091 (0.009–0.882) 0.039b 3.243 (0.831–12.659) 0.09
Total UPDRS score 1.254 (1.009–1.56) 0.042b 0.891 (0.779–1.019) 0.092
UPDRS part 3 0.724 (0.555–0.944) 0.017b 1.178 (0.993–1.397) 0.06
UPDRS part 4 0.552 (0.319–0.955) 0.034b 1.413 (1.002–1.991) 0.049b
Zung depression score 0.874 (0.719–1.064) 0.179    
Zung anxiety score 1.166 (0.883–1.541) 0.279    
BFI 0.994 (0.926–1.067) 0.876    
SF-8 0.983 (0.775–1.28) 0.9    
MMSE 0.478 (0.251–0.91) 0.025b 1.439 (0.994–2.084) 0.054
PDSS 1.002 (0.997–1.007) 0.408    
Nightmares 4.591 (0.534–39.503) 0.165    
Dream-enactment behaviors 5.549 (0.343–89.773) 0.228    
Increase of antiparkinsonian medications 70.822 (2.333–2150.39) 0.014b 0.132 (0.021–0.846) 0.033b
 

Risk Factors for New Hallucinations

We studied 68 patients, including the 10 who were excluded because they newly had hallucinations without FOP, to determine whether FOP is a risk factor for new onset of hallucinations. We included the variable “FOP” in a multivariate analysis in addition to the 17 independent variables. Only FOP was a significant risk factor for new onset of hallucinations on univariate logistic regression analysis (OR = 21.497; P = 0.006; 95% CI = 2.429–190.284). In addition, when we included disease duration, UPDRS part 4, and an increase dose of antiparkinsonian medications in multivariate logistic regression analysis, FOP (P = 0.001) was related to new onset of hallucinations.

Discussion

FOP has been increasingly recognized to commonly occur in association with the increased availability and use of dopaminergic treatment, and FOP and hallucinations have been investigated in cross-sectional studies.[1] FOP is now accepted as part of the spectrum of psychotic symptoms in the new diagnostic criteria for PD-associated psychosis.[8] Our study represents the first time to prospectively investigate nonhallucinators and identified 17 patients in whom FOP newly developed. The estimated rate of FOP in our study was 29%, which is lower than that in previous studies, reporting rates of 30% to 44%.[1, 9] The higher rate of FOP in previous studies might be attributed to the fact that hallucinators were included in these previous cross-sectional studies. Consistent with the findings of previous studies, most cases of FOP were short-lived, not terrible, and occurred indoors in the evening or night. The insight of FOP was preserved, and many patients felt the presence of humans.[1] A previous study reported that 1 patient felt the presence of a former pet dog,[1] but such former subjects were not reported by any patient in our study.

The score for UPDRS part 4 and an increased dose of antiparkinsonian medications were found to be independent risk factors for FOP. UPDRS part 4 mainly evaluates dyskinesia and motor fluctuations, and these motor complications are well-documented side effects of long-term l-dopa treatment and have been reported to be risk factors for hallucinations.[8, 10] Although the total daily LED was not a risk factor for hallucinations in many studies,[7, 10] these studies did not evaluate whether the dose of antiparkinsonian medications was increased during follow-up, in contrast to our study. Our study showed that many patients with FOP were receiving increased doses of antiparkinsonian drugs. One cross-sectional study reported that a higher daily LED is an independent predictor of FOP and suggested a specific facilitating role of dopaminergic therapy in the development of FOP.[1] It is not surprising that both the UPDRS part 4 score and an increased dose of antiparkinsonian medications were identified as risk factors for FOP in our study because increasing doses of dopaminergic drugs can cause motor complications or evoke hallucinations.

Patients with FOP are more likely to have visual illusions and hallucinations than patients without FOP.[1] Our study showed that the Zung depression score differed among patients with FOP, patients with FOP accompanied by hallucinations, and patients with FOP followed by the subsequent development of hallucinations, but this factor was not a significant predictor of FOP on multivariate analysis. Several studies have shown that patients with visual hallucinations[8, 11] or with minor hallucinations/illusions[7] have higher depression scores than patients without hallucinations. Depression may sometimes trigger or aggravate hallucinations associated with other conditions.[12]In another study, hallucinators with a disease duration of >5 years had fewer depressive symptoms than nonhallucinators.[13] The relation between hallucinations and depression thus remains unclear.[7] Patients who had FOP of a deceased relative were not more depressed than patients with other types of FOP,[1] but differences among subgroups of patients as found in our study were not mentioned. Depression might be a predictor of the development of hallucinations from FOP, but this remains to be confirmed.

We validated fatigue by using the BFI, but fatigue was not found to be a risk for FOP on multivariate logistic regression analysis. We did not use the Parkinson's fatigue scale in a specific questionnaire designed for patients with PD.[14] This scale includes the presence of not only physical, but also mental fatigue, which can influence the FOP or hallucinations. Depression can trigger or aggravate hallucinations,[12] and the present study evaluated depression by means of the Zung depression score. The Quick Inventory of Depressive Symptomatology includes 16 items and is in accord with the Diagnostic and Statistical Manual of Mental Disorders.[15] The Hamilton depression score has been frequently used as a tool for evaluating depression.[16] These questionnaires can play an important role in better investigating the association of depression with FOP.

Most episodes of FOP were not terrible, and insight was preserved. FOP may not be problematic for patients or caregivers, but some episodes were associated with the subsequent onset of visual hallucinations similar to the subjects of FOP. Motor complications and increasing doses of antiparkinsonian medications may predict the onset of FOP, and depression might be helpful for predicting the future development of hallucinations from FOP. To avoid the progression of FOP to hallucinations, depression should be monitored, and any increase in the dose of dopaminergic medication should be very gradual.

 

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