Parkinson’s disease (PD) is the second largest degenerative disease that has affected a large number of people worldwide [
In 2000, Fénelon et al. systematically described the minor hallucinatory phenomena that consequently prompted attention to MH [
Major hallucinations include well-structured visual hallucinations (VHs) and hallucinations in other senses, such as auditory, olfactory, gustatory, and tactile [
Although MHs are now recognized to be closely associated with well-structured VHs [
Patients with PD (
The subjects were categorized into eight strata, namely, no hallucination, isolated minor hallucination, isolated major hallucination, isolated delusion, and the combination of these psychiatric symptoms, on the basis of their response to the Hallucinations and Psychosis item of the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part 1:
All participants signed informed written consent and provided clinical data. This study was approved by the local Ethics Committee of the Brain Hospital Affiliated to Nanjing Medical University and was conducted in accordance with the principles outlined in the Declaration of Helsinki.
All PD patients were interviewed using a standard questionnaire to collect basic information, including age, gender, marriage, education level, body mass index (BMI), allergies, history of smoking and drinking, history of drinking tea and coffee, daily exercise, hypertension, diabetes, lacunar infarction, family history of PD, predominance of motor symptoms, age of PD onset, disease duration, and use of antiparkinsonian medicine. Daily levodopa equivalent dose (LEDD) was also calculated [
Motor function was assessed using the Unified Parkinson’s Disease Rating Scale motor subscales (UPDRS III) and the Hoehn and Yahr (H-Y) scale. UPDRS III was tested twice; the first assessment was performed after antiparkinsonian medication was stopped for at least 24 h (controlled release agent discontinued for at least 72 hours), and the patients fasted overnight (OFF state); the second was conducted 1 hour after the patients were administered with levodopa at 1.5 times their regular morning dose (ON state) [
The characteristics of MHs were assessed in more detail in the PD-MH group by using a questionnaire comprising 12 items. Based on our previous questionnaire [
All continuous variables were presented as
Among the 262 patients with PD recruited in our study, 102 (38.9%) experienced MHs, including 74 patients (28.2%) with isolated MHs and 28 patients (10.7%) with combined MHs. Isolated major hallucinations and delusions were presented in 14 (5.3%) and 1 (0.4%) patients, respectively. Up to 32 (12.2%) patients had more than one kind of psychiatric symptoms. The remaining 141 (53.8%) reported having no hallucinations or delusion. The result is shown in Figure
Prevalence of psychotic symptoms in the cohort. Of the 262 patients with PD recruited in our study, 102 (38.9%) experienced MHs. This included 74 patients (28.2%) with isolated MHs and 28 patients (10.7%) with combined MHs. Fourteen (5.3%) and one (0.4%) patients experienced isolated major hallucinations and delusions, respectively. Among the population, 32 (12.2%) had more than one kind of psychiatric symptoms. The remaining 141 (53.8%) reported having no hallucinations or delusion.
Characteristics and contents of minor hallucination.
Presence hallucination | Passage hallucination | Visual illusion | ||||
---|---|---|---|---|---|---|
Object misidentification | Pareidolia | Kineptosia | Sum | |||
Number | 28 (23.0%) | 35 (28.7%) | 24 (19.7%) | 17 (13.9%) | 18 (14.8%) | 59 (48.4%) |
Appearance time | ||||||
Daytime | 15 (53.6%) | 24 (68.6%) | 11 (45.8%) | 11 (64.7%) | 8 (44.4%) | 30 (50.8%) |
Nighttime | 7 (25.0%) | 4 (11.4%) | 8 (33.3%) | 2 (11.8%) | 8 (44.4%) | 18 (30.5%) |
Both | 6 (21.4%) | 7 (20.0%) | 5 (20.8%) | 4 (23.5%) | 2 (11.1%) | 11 (18.6%) |
Lighting | ||||||
Bright | 7 (25.0%) | 12 (34.3%) | 6 (25.0%) | 8 (47.1%) | 7 (38.9%) | 21 (35.6%) |
Dim | 18 (64.3%) | 18 (51.4%) | 17 (70.8%) | 8 (47.1%) | 9 (50.0%) | 34 (57.6%) |
Dark | 2 (7.1%) | 4 (11.4%) | 0 (0.0%) | 1 (5.9%) | 2 (11.1%) | 3 (5.1%) |
Variable | 1 (3.6%) | 1 (2.9%) | 1 (4.2%) | 0 (0.0%) | 0 (0.0%) | 1 (1.7%) |
Environment | ||||||
Indoor | 24 (85.7%) | 24 (68.6%) | 18 (75.0%) | 16 (94.1%) | 16 (88.9%) | 50 (84.7%) |
Outdoor | 1 (3.6%) | 9 (25.7%) | 4 (16.7%) | 1 (5.9%) | 0 (0.0%) | 5 (8.5%) |
Variable | 3 (10.7%) | 2 (5.7%) | 2 (8.3%) | 0 (0.0%) | 2 (11.1%) | 4 (6.8%) |
Onset | ||||||
Sudden | 23 (82.1%) | 33 (94.3%) | 24 (100.0%) | 14 (82.4%) | 18 (100.0%) | 56 (94.9%) |
Gradual | 5 (17.9%) | 2 (5.7%) | 0 (0.0%) | 3 (17.6%) | 0 (0.0%) | 3 (5.1%) |
Lasting time | ||||||
Seconds | 23 (82.1%) | 35 (100.0%) | 17 (70.8%) | 13 (76.5%) | 15 (83.3%) | 45 (76.3%) |
Minutes | 5 (17.9%) | 0 (0.0%) | 7 (29.2%) | 4 (23.5%) | 3 (16.7%) | 14 (23.7%) |
Frequency | ||||||
Daily | 5 (17.9%) | 4 (11.4%) | 10 (41.7%) | 6 (35.3%) | 4 (22.2%) | 20 (33.9%) |
1–6 times/week | 20 (71.4%) | 19 (54.3%) | 8 (33.3%) | 6 (35.3%) | 9 (50.0%) | 23 (39.0%) |
<1/week | 3 (10.7%) | 12 (34.3%) | 6 (25.0%) | 5 (29.4%) | 5 (27.8%) | 16 (27.1%) |
Duration | ||||||
<1 month | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (5.9%) | 0 (0.0%) | 1 (1.7%) |
1 month-1 year | 15 (53.6%) | 19 (54.3%) | 11 (45.8%) | 9 (52.9%) | 11 (61.1%) | 31 (52.5%) |
>1 year | 13 (46.4%) | 16 (45.7%) | 13 (54.2%) | 7 (41.2%) | 7 (38.9%) | 27 (45.8%) |
Premotor | ||||||
Yes | 3 (10.7%) | 10 (28.6%) | 7 (29.2%) | 3 (17.6%) | 4 (22.2%) | 14 (23.7%) |
No | 25 (89.3%) | 25 (71.4%) | 17 (70.8%) | 14 (82.4%) | 14 (77.8%) | 45 (76.3%) |
Clarity | ||||||
Sharp | 1 (3.6%) | 4 (11.4%) | 3 (12.5%) | 3 (17.6%) | 4 (22.2%) | 10 (16.9%) |
Blurry | 26 (92.9%) | 31 (88.6%) | 21 (87.5%) | 13 (76.5%) | 14 (77.8%) | 48 (81.4%) |
Variable | 1 (3.6%) | 0 (0.0%) | 0 (0.0%) | 1 (5.9%) | 0 (0.0%) | 1 (1.7%) |
Size | ||||||
Normal | 26 (92.9%) | 31 (88.6%) | 23 (95.8%) | 16 (94.1%) | 18 (100.0%) | 57 (96.6%) |
Miniaturized | 2 (7.1%) | 3 (8.6%) | 0 (0.0%) | 1 (5.9%) | 0 (0.0%) | 1 (1.7%) |
Magnified | 0 (0.0%) | 0 (0.0%) | 1 (4.2%) | 0 (0.0%) | 0 (0.0%) | 1 (1.7%) |
Variable | 0 (0.0%) | 1 (2.9%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
Stereotyped | ||||||
Yes | 12 (42.9%) | 23 (65.7%) | 14 (58.3%) | 10 (58.8%) | 11 (61.1%) | 35 (59.3%) |
No | 13 (46.4%) | 10 (28.6%) | 9 (37.5%) | 7 (41.2%) | 6 (33.3%) | 22 (37.3%) |
Cannot describe | 3 (10.7%) | 2 (5.7%) | 1 (4.2%) | 0 (0.0%) | 1 (5.6%) | 2 (3.4%) |
Color | ||||||
Black and white | 24 (85.7%) | 30 (85.7%) | 15 (62.5%) | 11 (64.7%) | 6 (33.3%) | 32 (54.2%) |
Multiple colors | 4 (14.3%) | 5 (14.3%) | 9 (37.5%) | 6 (35.3%) | 12 (66.7%) | 27 (45.8%) |
Content | ||||||
Familiar lived people | 4 (14.3%) | 1 (2.9%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
Unfamiliar people | 22 (78.6%) | 18 (51.4%) | 12 (50.0%) | 11 (64.7%) | 0 (0.0%) | 23 (39.0%) |
Deceased relatives | 0 (0.0%) | 1 (2.9%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
Animals | 0 (0.0%) | 6 (17.1%) | 3 (12.5%) | 5 (29.4%) | 2 (11.1%) | 10 (16.9%) |
Objects | 1 (3.6%) | 3 (8.6%) | 8 (33.3%) | 1 (5.9%) | 16 (88.9%) | 25 (42.4%) |
Cannot describe | 1 (3.6%) | 6 (17.1%) | 1 (4.2%) | 0 (0.0%) | 0 (0.0%) | 1 (1.7%) |
MHs were described from three aspects: external factors, temporal factors, and contents. The three different types of MHs were consistent in external factors: they could appear at any time, lighting condition, and environment but are more likely to appear indoor during the day when the light is dim (more than 50%). In terms of temporal factors, MHs often persisted for seconds, with a mode of sudden onset and quick disappearance (more than 70%). The frequency of MHs ranged from daily to less than once a week. Most MHs happened 1 ~ 6 times per week; however, 41.7% of object misidentification happened every day. Until they were included in this study, the patients experienced almost all types of MHs for more than 1 month, and some even existed for many years. Compared with the disease duration of PD, 22.1% of MHs started before the onset of the first Parkinsonian motor symptoms. In the case of content, many of the MHs were somewhat blurred (more than 76.4%) and were normal in size (more than 88.5%). Presence hallucinations were described to be a feeling that an unfamiliar person (78.6%) or a familiar lived person (14.3%) is standing behind, often when the patient is focusing on a task. These “people” can be different or wearing different clothes each time, but the colors are mostly monotonous (85.7%). Among the subjects with passage hallucinations, almost all experienced a fleeting image passing that is recognized as an unfamiliar person (51.4%), an animal (17.1%), or an object (8.6%). This kind of flashing image is often stereotyped and without specific color, thus causing the patients to look back. Occasionally because of the flashing too fast, some patients cannot even describe the image (17.1%). Object misidentifications referred to misidentifying an object as a person because of certain similarities in form. The “person” is also stereotyped and without specific color. Pareidolias involved either unfamiliar people (64.7%) or animals (29.4%), and patients usually report seeing a human face or a small animal in a patterned bed sheet or a painting. Kineptosias refer to stationary objects seen in motion, and 66.7% of these illusions have the same color as the original object.
Table
Demographic parameters in the PD-MH and PD-NH patients.
PD-total | PD-MH | PD-NH | Value | ||
---|---|---|---|---|---|
Number, | 215 (100%) | 74 (34.4%) | 141 (65.6%) | ||
Age, y, | 4931 | 0.509a | |||
Gender, | |||||
Male | 107 (49.8%) | 39 (52.7%) | 68 (48.2%) | 0.389 | 0.533b |
Female | 108 (50.2%) | 35 (47.3%) | 73 (51.8%) | ||
Percentage of live alone, | 21 (9.8%) | 4 (5.4%) | 17 (12.1%) | 2.436 | 0.119b |
Education, | |||||
Illiterate | 31 (14.4%) | 8 (10.8%) | 23 (16.3%) | 5202.5 | 0.971b |
Primary school | 31 (14.4%) | 12 (16.2%) | 19 (13.5%) | ||
Middle school | 108 (50.2%) | 41 (55.4%) | 67 (47.5%) | ||
College or above | 45 (20.9%) | 13 (17.6%) | 32 (22.7%) | ||
BMI, | -0.471 | 0.638c | |||
Allergies, | 32 (14.9%) | 9 (12.2%) | 23 (16.3%) | 0.66 | 0.417b |
Smoker, | 59 (27.4%) | 21 (28.4%) | 38 (27.0%) | 0.05 | 0.824b |
Alcohol intake, | 28 (13.0%) | 11 (14.9%) | 17 (12.1%) | 0.338 | 0.561b |
Drinking tea, | 41 (19.1%) | 15 (20.3%) | 26 (18.4%) | 0.105 | 0.745b |
Drinking coffee, | 14 (6.5%) | 7 (9.5%) | 7 (5.0%) | 1.603 | 0.247b |
Daily exercise, | 111 (51.6%) | 37 (50.0%) | 74 (52.5%) | 0.12 | 0.729b |
Hypertension, | 80 (37.2%) | 26 (35.1%) | 54 (38.3%) | 0.208 | 0.649b |
Diabetes, | 31 (14.4%) | 11 (14.9%) | 20 (14.2%) | 0.018 | 0.893b |
Lacunar infarction, | 81 (37.7%) | 26 (35.1%) | 55 (39.0%) | 0.31 | 0.578b |
Family history of PD, | 23 (10.7%) | 7 (9.5%) | 16 (11.3%) | 0.181 | 0.67b |
Predominance of motor symptoms, | |||||
None | 19 (8.8%) | 7 (9.5%) | 12 (8.5%) | 1.179 | 0.555b |
Left | 101 (47.0%) | 31 (41.9%) | 70 (49.6%) | ||
Right | 95 (44.2%) | 36 (48.6%) | 59 (41.8%) | ||
Age of onset, y, | 4548 | 0.122a | |||
Disease duration, y, | 4121 | ||||
PD treatment | |||||
Levodopa, | 158 (73.5%) | 62 (83.8%) | 96 (68.1%) | 6.139 | |
Dopamine agonists, | 122 (56.7%) | 49 (66.2%) | 73 (51.8%) | 4.125 | |
MAO-B inhibitors, | 29 (13.5%) | 12 (16.2%) | 17 (12.1%) | 0.72 | 0.396b |
COMT inhibitors, | 32 (14.9%) | 14 (18.9%) | 18 (12.8%) | 1.45 | 0.228b |
Amantadine, | 40 (18.6%) | 17 (23.0%) | 23 (16.3%) | 1.422 | 0.233b |
Benzhexol, | 15 (7.0%) | 6 (8.1%) | 9 (6.4%) | 0.223 | 0.637b |
LEDD, mg, | 4323 | ||||
H-Y stage, | 4447 | 0.063a | |||
UPDRS III on, | 5149.5 | 0.876a | |||
UPDRS III off, | 4646 | 0.187a |
aMann-Whitney
The nonmotor symptoms of PD-MH and PD-NH groups are summarized in Table
Clinical characteristics of the PD-MH and PD-NH patients.
PD-total | PD-MH | PD-NH | Value | Adjusted valueb | Adjusted | ||
---|---|---|---|---|---|---|---|
NMS-Quest, | 3157 | 23.154 | |||||
PDSS, | 3691.5 | 7.486 | |||||
MoCA, | 5080.5 | 0.752a | 0.675 | 0.412a | |||
Visuospatial/executive, | 4915 | 0.478a | 0.776 | 0.379a | |||
Naming, | 4836.5 | 0.166a | 1.028 | 0.312a | |||
Attention, | 5095.5 | 0.724a | 0.347 | 0.556a | |||
Language, | 4948 | 0.389a | 1.241 | 0.267a | |||
Abstraction, | 4930.5 | 0.447a | 0.773 | 0.380a | |||
Delayed memory, | 5061.5 | 0.714a | 0.007 | 0.931a | |||
Orientation, | 5119.5 | 0.751a | 0.084 | 0.773a | |||
HAMA, | 4302.5 | 3.624 | 0.058a | ||||
HAMD, | 4961 | 0.554a | 0.180 | 0.672a | |||
PDQ39, | 4074.5 | 5.485 | |||||
RBDSQ, | 3741.5 | 9.114 |
aMann-Whitney
Logistic regression analysis in Table
Logistic regression analyses for independent predictors of minor hallucinations.
OR | 95% CI | ||
---|---|---|---|
Disease duration | 0.984 | 0.913-1.061 | 0.672 |
Levodopa | 0.569 | 0.234-1.382 | 0.213 |
Dopamine agonists | 0.801 | 0.386-1.664 | 0.552 |
PDSS | 0.988 | 0.976-0.999 | |
MoCA | 1.043 | 0.978-1.112 | 0.201 |
HAMD | 0.952 | 0.885-1.024 | 0.189 |
RBDSQ | 1.136 | 1.018-1.268 | |
PDQ39 | 1.014 | 1.000-1.029 |
a Significant results are highlighted in italic (
PDP is a continuum progression that begins with MHs, then evolves to major hallucinations with insight, gradual insight loss, and eventually turns to delusions. The chronological sequence of psychotic symptom is consistent with the Braak pathology of Lewy bodies from the brainstem to the forebrain systems [
Visual illusion was the most common type of MHs in patients with PD, followed by passage hallucinations and presence hallucinations. In particular, object misidentification was the most common type of visual illusion, followed by kineptosia and pareidolia. Two or more types of MHs occurring as comorbidity are highly common. These minor phenomena are typically described to be blurred, stereotyped, and normal-sized. Presence hallucinations are likely to have unfamiliar people standing nearby, and passage hallucinations have animals or objects passing by. Object misidentifications were described as misidentifying an object as an unfamiliar person or another object. Pareidolias were reported as seeing a specific human face or an animal from a complex pattern. Kineptosia mainly involves objects. Presence hallucinations and passage hallucinations are more likely to be in black and white, whereas visual illusions can be polychromatic. These three MH phenomena generally varied in contents but usually occur indoors when the light is dim during the day. These events often appear suddenly, last a few seconds, and occur more than once a week.These phenomena began more than 1 month ago and some even began before the onset of motor symptoms. The MHs presented in the premotor phase have advanced the spectrum of PDP, which was thought to only appear in advanced stage of PD [
In this study, the patients with MHs showed differences in disease duration and LEDD, especially levodopa and dopamine agonists, which are not independent predictors of MHs. This result was consistent with previous findings [
Numerous articles have proved that RBD and MHs are both relevant, and RBD is a predictor of MHs [
PDSS was also found to be closely associated with MHs in this population. Compared with the nonhallucinators, the minor hallucinators suffered more from sleep disturbance, a dependent risk factor of MHs. Pappert et al. [
The relationship between cognitive impairment and well-structured VHs has been verified [
MHs were not correlated with depressive symptoms in our population, and this result is consistent with previous findings [
As a relatively subtly symptom in PD, MH has always been clinically ignored. Minor phenomena are intermittent but are likely to recur and continue [
This study has some limitations. First, rather than cross-section research, a longitudinal study is suitable for observing the natural course of MHs because this phenomenon gradually progresses to severe psychotic symptoms. A long-term follow-up will be conducted for this cohort to observe their psychotic state and the effects of disease duration, PD medications, emotions, and RBD on the outcome. Second, the relatively small sample number of 262 may narrow the strength of the identified relationships that were evidenced in the study. Third, a unified assessment scale must be established to fully and comprehensively evaluate the clinical characteristics of MHs.
A high prevalence of MHs was observed in patients with PD. Patients with MHs have greater burden in a range of nonmotor symptoms and life quality than those without hallucinations. This study provides evidence that MHs are mainly associated with RBD, sleep quality, and health-related life quality. Whether MHs are related to disease duration, PD medication, cognitive impairment, and depression must be further investigated. Future studies focused on MHs, which was overlooked before, need to confirm and expand the related clinical factors, which will offer strategies to improve the life quality of patients with PD.
The data supporting the findings of this study are included in the article; further inquiries can be directed to the corresponding author.
The study was approved by the Ethics committee of Nanjing Brain Hospital Affiliated to Nanjing Medical University. All procedures followed the declaration of Helsinki.
Informed consent was obtained from all subjects involved in the study.
The authors declare that they have no conflicts of interest.
LZ, JY, and MZ conceived and designed the research. LZ and JY obtained the fundings. MZ, RG, SZ, YB, ZW, XJ, BS, YP, and JZ collected the data. MZ, JY, YP, and ZW conducted the data analysis. MZ and RG drafted the manuscript. All authors contributed to the article and approved the submitted version. LZ and JY share last authorship.
We thank the patients and their families for their participation in the study. This work was supported by the Special Funds of the Jiangsu Provincial Cadre Health Projects (grant numbers BJ20005 and BJ17006), the Jiangsu Provincial Key Research and Development Program (grant numbers BE2018610 and BE2019612), the Nanjing Medical Science and Technology Development Foundation (grant number QRX17026), and the Nanjing Rehabilitation Medicine Center Project (grant number is not available).