Hallucinations occur in 20–40% of Parkinson's disease (PD) patients receiving symptomatic therapy 1. Although potentially treatable by anti-parkinsonian drug adjustments and the use of atypical antipsychotics 2, hallucinations have been associated with unfavorable clinical outcomes such as nursing home placement and increased mortality 34.

Hallucinations, like other non-motor features of PD, are not well recognized in routine clinical practice, either in primary or in secondary care, and are frequently missed during consultations 5. Standardized PD rating scales such as the Unified Parkinson's disease Rating Scale (UPDRS) part I 6 have low sensitivity to detect hallucinations and other psychotic symptoms7. Symptom and disease specific instruments such as the Parkinson's Psychosis Rating Scale (PPRS), 8 the non-motor symptom questionnaire (NMSQuest) 5 or the Parkinson's Disease-Psychosocial questionnaire (SCOPA-PS) 9 assess hallucinations only in a few sub-items. Other PD specific instruments that may offer a more detailed characterization of hallucinations, such as the Rush Parkinson's Disease Behavioral Interview 10 are not easily administered in the busy clinical settings and generic rating scales/questionnaires that were designed to address organic brain psychosis and/or neuropsychiatric manifestations (ie the Neuropsychiatric Inventory 11) are of limited use in characterizing PD-associated hallucinations.

To date there is no instrument that allows for a focused, comprehensive assessment of the characteristics of hallucinations in PD for the clinician or for use as a research outcome measure. We therefore developed the University of Miami Parkinson's disease Hallucinations Questionnaire (UM-PDHQ), a 20-item questionnaire to be used as a screening instrument to assess hallucinations in PD. This pilot study, part of an initiative begun at the University of Miami, Miller School of Medicine sought to quantify the type and presence of hallucinations in a clinic population while controlling for disease factors, depression, anxiety and medication.

Hallucinations in PD have received growing attention since the introduction of chronic treatments of dopamine restoration which increased their frequency from 5% in the pre-L-dopa era 212223 to around 40% in chronically treated patients at least 3 years into their disease 1. Hallucinations may be considered a characteristic of α-synucleinopathies, a group of diseases associated with excessive accumulation of α-synuclein in the CNS that includes PD, dementia with Lewy bodies and multiple system atrophy 2425 and a red flag for Lewy body pathology 26.

Although there is an extensive literature in this area, lack of consistency and standardization of assessment approaches has significantly biased comparison data across studies and made it difficult to conclude about prevalence rates, content, classification, risk factors and treatment outcomes 1. Only recently a set of diagnostic criteria for psychotic symptoms that include hallucinations in PD, were proposed by a panel of NIH-sponsored experts. This working group highlighted the lack of relevant instruments/scales 27. Few studies i.e. 2829 have used validated scales or structured interviews, including the UPDRS I thought disorder subscale score 6 and the Rush Parkinson's Disease Behavioral Interview 10 respectively. Our study confirmed previous findings that showed that the UPDRS thought disorders subscale is not considered the most sensitive instrument to detect psychotic symptoms in PD 7. The Rush Behavioral interview primarily assesses the severity of hallucinations of all modalities focusing on frequency in the past month: severity score: 0 = none, 1 = less than once weekly, 2 = once or twice weekly, 3 = at least three times weekly and does not ascertain detailed information about the type and nature of hallucinations. Severe hallucinations are defined as a score of 3. To this end we developed the UM-PDHQ to systematically study hallucinatory experiences in PD in an outpatient clinic setting.

The UM-PDHQ confirmed previous findings on the prevalence of hallucinations; the prevalence in our cohort (44.3%) was similar to other clinic-based prospective studies and somewhat higher than previously reported in community studies 3031. Studies focusing on a single hallucinatory modality, mainly visual 3233, have consistently reported lower prevalence of hallucinations as they fail to consider auditory, olfactory, somatic and gustatory modalities. Among hallucinators, the cumulative percentage of reported non-visual modalities was 54.8%.

In PD, hallucinatory experiences tend to be present intermittently, lasting seconds to minutes at a time 34. Their frequency can vary, but most studies register the presence of hallucinations when they occur at least one time per week. Often, they occur several times per day 27. The typical hallucinatory experience in our clinic-based cohort was that of a non-threatening, familiar or unfamiliar solid, real sized, colored or colorless human body that appeared suddenly anytime during the day and disappeared a few seconds later. Little animals and insects were also common. A variety of other non-typical hallucinatory sensations were very frequently described. Therefore one should not consider hallucinatory experiences in PD uniform. Simplistic classifications such as benign-malignant, simple-complex or minor-major should be avoided until a scaling method has been developed and validated. We also found that hallucinations were unrelated to light cycle in the majority of patients. Previous reports have suggested that hallucinations tend to occur during times of low ambient stimulation, most typically in the evening or when the patient is alone in a quiet environment 27.

Hallucinations lacking a visual component were reported in 7 out of 70 patients with an overall prevalence of 10%. Several other systematic prospective studies have pointed out the increased frequency of non-visual hallucinatory modalities in PD 3536. Their content may vary considerably 3738. Non-visual hallucinations may often consist of whispers or music, as opposed to the threatening voices reported in schizophrenia; however, some cases of threatening auditory hallucinations have been reported in PD 39. Tactile, olfactory and gustatory hallucinations have also been reported; however less commonly, and they tend to co-occur with visual hallucinations 4041.

There were no differences detected between hallucinators and non-hallucinators in demographic and neuropsychiatric profiles. Confirming previous observations from our group, hallucinations interfered with activities of daily living and were related to more severe symptomatology as measured by the UPDRS 32. As expected, hallucinators were more frequently prescribed antipsychotics. Although cognitive impairment and dementia have been frequently reported as risk factors for hallucinations in PD 31 no such association (as measured by the MMSE score) was detected in our study. Our results are in line with those of another interview-based prospective study that found no association between MMSE scores and hallucinations at the conclusion of a 4-year study 29. In our cohort loss of insight regarding hallucinatory experiences was unrelated to cognitive status. Loss of insight has been associated with the "continuum hypothesis" that suggests a progression of psychotic symptoms from sleep disturbances to hallucinatory experiences to full-blow psychosis 42. However, our findings on insight and spontaneous remission of hallucinations in 9/31 (29%) of patients coupled with lack of a REM behavior sleep disorder in some hallucinators 4344 suggest that this theory may not apply for all patients. In using only the MMSE as our measure of cognitive status, we did not examine particular cognitive domains that may have differentiated hallucinators from non-hallucinators. BDI scores and BAI scores were not significantly different between hallucinators and non-hallucinators. It is unclear from our data whether the higher prevalence of antidepressant use among hallucinators who were distressed by their hallucinations as compared to those not distressed was either a contributor to or a cause of the distress.

Our study has certain limitations; the UM-PDHQ in its current form does not provide an overall score of severity and is not a graded or rating instrument. Instead, it is a screening tool designed to draw attention to the presence of hallucinations and initiate further investigation. In our study cognitive status was assessed using the MMSE which is a brief screening measure that is known to be less sensitive to subcortical functions 45. However, examining the relationship between cognitive decline and hallucinations was beyond the scope of this pilot study. We are currently collecting more detailed neuropsyhological data in a larger cohort of patients to examine this important question.

Using the UM-PDHQ during a structured interview we were able to define in depth the key characteristics of hallucinations in a pilot cohort of PD patients. Future directions include the validation of the questionnaire and the development of a disease and symptom rating scale for severity of hallucinations. The UM-PDHQ may be modified in the future as additional data become available. Valid criteria for psychotic symptoms in PD combined with disease specific questionnaires and scales may provide the necessary endpoints that meet regulatory needs for future clinical trials on the subject.

Unified Parkinson's disease Rating Scale: UPDRS; Parkinson's Psychosis Rating Scale: PPRS; Non-motor symptom questionnaire: NMSQuest; Parkinson's Disease-Psychosocial questionnaire: SCOPA-PS; University of Miami Parkinson's disease Hallucinations Questionnaire: UM-PDHQ; Tremor-dominant PD: TD and Postural Instability/Gait-Dominant (PIGD); Activities of Daily Living: ADL; Beck Anxiety Inventory: BAI; Beck Depression Inventory – Second Edition: BDI-II; Mini Mental Status Examination: MMSE.

The authors declare that they have no competing interests.

Conception and design of the Questionnaire: SP, HK, AS, BL. Acquisition of data: SP, HK, AS, CS, BKS, DN, AG, BL. Analysis and interpretation of data: SP, HK, AS, CS, BKS, DN, AG, BL. Drafting the manuscript: SP, HK. Revising it critically for important intellectual content: SP, HK, AS, CS, BKS, DN, AG, BL.