Hallucinations In Parkinson's Disease Research Articles

Visual hallucinations in PD and Lewy body dementias: old and new hypotheses.

Visual Hallucinations (VH) are a common non-motor symptom of Parkinson’s Disease (PD) and the Lewy body dementias (LBD) of Parkinson's disease with dementia (PDD) and Dementia with Lewy Bodies (DLB). The origin of VH in PD and LBD is debated: earlier studies considered a number of different possible mechanisms underlying VH including visual disorders, Rapid Eye Movement (REM) Sleep Intrusions, dysfunctions of top down or bottom up visual pathways, and neurotransmitter imbalance.More recently newer hypotheses introduce, among the possible mechanisms of VH, the role of attention networks (ventral and dorsal) and of the Default Mode Network (DMN) a network that is inhibited during attentional tasks and becomes active during rest and self referential imagery.Persistent DMN activity during active tasks with dysfunctional imbalance of dorsal and ventral attentional networks represents a new hypothesis on the mechanism of VH.We review the different methods used to classify VH and discuss reports supporting or challenging the different hypothetical mechanisms of VH.

Anterior cingulate integrity: Executive and neuropsychiatric features in Parkinson's disease

Patients with advanced Parkinson's disease (PD) commonly suffer with significant executive dysfunction and concomitant visual hallucinations. Although the underlying pathophysiology remains poorly understood, numerous studies have highlighted the strong association between these neuropsychiatric features, suggesting common neural pathways. Although previous neuroimaging studies have identified widespread volume loss across a number of cortical regions, to date, no studies have utilized proton magnetic resonance spectroscopy to provide insights into how neurometabolic changes may relate to such symptoms. Twenty patients with PD and 20 healthy controls underwent spectroscopy to determine the N-acetyl aspartate/creatine (NAA/Cr) ratio, which reflects the degree of neuronal integrity in neurodegenerative diseases. Voxels were obtained from the anterior cingulate cortex (ACC), an area critical for a wide range of executive mechanisms as well as from a control volume in the posterior cingulate cortex (PCC). Compared to controls, patients with PD had lower NAA/Cr ratios in the ACC. In turn, lower NAA/Cr ratios significantly correlated with poorer executive function on tasks of attentional set-shifting and response inhibition, as well as more-severe psychotic symptoms and poorer performance on the Bistable Percept Paradigm, a neuropsychological probe of visual hallucinations. NAA/Cr ratios were significantly lower in hallucinators, compared to nonhallucinators, within the ACC, but did not differ in the PCC. These results suggest that loss of neuronal integrity within the ACC plays an important role in the pathophysiology underlying executive functioning and visual hallucinations in PD. © 2012 Movement Disorder Society.

Increased levels of 5‐HT1A receptor binding in ventral visual pathways in Parkinson's disease

Visual hallucinations are common in advanced Parkinson's disease (PD). The pathophysiology of visual hallucinations may involve enhanced serotonergic neurotransmission. The atypical antipsychotics clozapine and quetiapine, which have affinity for 5-HT(2A) and 5-HT(1A) receptors, are effective against visual hallucinations in PD. 5-HT(2A) receptors are increased in ventral visual pathways in PD patients with visual hallucinations, and we hypothesized that 5-HT(1A) receptors were also involved in visual hallucinations in PD. Autoradiographic binding using [(3) H]-WAY-100,635 and NAN-190 was performed in brain sections from 6 PD patients with visual hallucinations, 6 PD patients without visual hallucinations, and 5 age-matched controls. All PD subjects had been treated with L-dopa. Brain areas studied were the orbitofrontal, inferolateral temporal, and motor cortices, as well as the striatum, globus pallidus, substantia nigra, and thalamus. 5-HT(1A) -binding levels were dramatically increased in the ventral visual pathways of all PD patients compared with controls (0 vs 11 and 0 vs 100 nmol/mg, respectively; both P < .05). There was no significant difference in 5-HT(1A) -binding levels in PD patients with visual hallucinations compared with PD patients without visual hallucinations or with controls in any of the brain areas studied (P > .05). Gross abnormalities in 5-HT(1A) levels in ventral visual areas occurred in all PD patients exposed to L-dopa. However, as there was no difference in 5-HT(1A) -binding levels between hallucinators and nonhallucinators, alterations in 5-HT(1A) receptor levels may not contribute specifically to visual hallucinations in PD. However, the discrete anatomical distribution of rises to the ventral visual areas suggests some role in predisposing to visual hallucinations.

Hallucinations in Parkinson’s disease: cross-sectional study

The aim of this study was to estimate the prevalence and risk factors for the development of hallucinations in patients with Parkinson's disease (PD). This cross-sectional study included 180 consecutive, non-demented patients with PD. Out of them, 24 patients (13%) experienced some kind of hallucinations. Visual hallucinations were present in 22/24 (90%) subjects. Univariate logistic regression analysis has shown relationship between presence of hallucinations and the following variables: age of patients (p = 0.025), PD duration (p = 0.001), duration of levodopa treatment (p = 0.001), total daily dose of levodopa (p = 0.033), presence of levodopa-induced dyskinesia (p = 0.002) and their duration (p = 0.021), and experience of nightmares (p = 0.042). Hallucinations were also associated with higher scores of the UPDRS (p = 0.001), HDRS (p = 0.001) and the NPI total score (p = 0.001), and higher H-Y stages of the disease (p = 0.001). Multivariate regression analysis has demonstrated that the duration of PD (p = 0.024) as well as NPI total score (p = 0.002) was significant independent risk factors for hallucinations in PD.

Visual misperceptions and hallucinations in Parkinson's disease: Dysfunction of attentional control networks?

Visual misperceptions and hallucinations are a major cause of distress in patients with Parkinson's disease (PD), particularly in the advanced stages of the condition. Recent work has provided a framework for understanding the pathogenesis of these symptoms, implicating impairments from the retina to the integration of external information with preformed internal images. In this article, we propose a novel hypothesis that attempts to explain the presence of visual misperceptions and hallucinations in PD through the aberrant coordination of complimentary yet competing neural networks. We propose that hallucinations in PD reflect the relative inability to recruit activation in the dorsal attention network in the presence of an ambiguous percept, leading to overreliance on default mode network processing and salience arising from the ventral attention network. This inability is proposed to stem from improper function across cortical and subcortical structures secondary to the presence of Lewy body pathology. This hypothesis may be empirically tested by the use of targeted cognitive paradigms. In turn, this may assist our understanding of the pathophysiological mechanisms and cognitive processes contributing to visual misperceptions and hallucinations and ultimately may inform more effective treatment strategies for this troubling symptom.

The interplay of cholinergic function, attention, and falls in Parkinson's disease

Dopamine loss in the substantia nigra causes several of the motor signs seen in Parkinson's disease, but there is now increasing evidence highlighting the importance of cholinergic loss in the pathophysiology of nonmotor symptoms. The nucleus basalis of Meynert supplies the majority of the cholinergic input to the cerebral cortex, with the pedunculopontine nucleus providing many subcortical structures with acetylcholine. Both these structures undergo degeneration in Parkinson's disease (PD), with more severe loss associated with cognitive impairment. The risk of dementia in PD is greater than that in control subjects, with impairments in attention, visuospatial function, and executive control dominating. Imaging studies have demonstrated degeneration of the cholinergic system in PD, Parkinson's disease dementia, and dementia with Lewy bodies, with improvements in attention seen following the introduction of cholinesterase inhibitors. Conversely, anticholinergic drugs are associated with cognitive decline, with neuropathology studies indicating the presence of increased neurofibrillary tangles and senile plaque formation. In addition, these drugs are also known to precipitate visual hallucinations, lending support to a cholinergic basis for visual hallucinations in PD. Gait, falls, and cognition may also be related, as evidenced by the findings that fallers perform less well on test of attention than nonfallers and that greater postural instability is associated with worse scores on attention and executive function. It is therefore feasible that cognition (namely, attention), visual hallucinations, falls, and gait are subserved by acetylcholine, and this is further explored in this clinically orientated review.

Racial differences may influence the role of cholecystokinin polymorphisms in Parkinson's disease hallucinations

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Hallucinations and REM sleep behaviour disorder in Parkinson’s disease: Dream imagery intrusions and other hypotheses

REM sleep behaviour disorder (RBD) is a REM sleep-related parasomnia which may be considered a "dissociated state of wakefulness and sleep", given that conflicting elements of REM sleep (dreaming) and of wakefulness (sustained muscle tone and movements) coexist during the episodes, leading to motor and behavioural manifestations reminiscent of an enacted dream. RBD has been reported in association with α-synucleinopathies: around a third of patients with Parkinson's disease (PD) have full-blown RBD. Recent data indicate that PD patients with RBD are more prone to hallucinations than PD patients without this parasomnia. However it is still not clear why RBD in PD is associated with an increased prevalence of VHs. Data exist which suggest that visual hallucinations in PD may be the result of untimely intrusions of REM visual imagery into wakefulness. RBD, which is characterised by a REM sleep dissociation pattern, might be a condition that particularly favours such intrusions. However, other hypotheses may be advanced. In fact, deficits in attentional, executive, visuoperceptual and visuospatial abilities have been documented in RBD and found to occur far more frequently in PD with RBD than in PD without RBD. Neuropsychological deficits involving visual perception and attentional processes are thought to play an important role in the pathophysiology of VHs. On this basis, RBD in PD could be viewed as a contributory risk factor for VHs.

Visual hallucinations in Parkinson disease are associated with cholinergic dysfunction

Parkinson disease: Visual hallucinations in Parkinson disease are associated with cholinergic dysfunction

Hallucinations in Parkinson disease

Patients with Parkinson disease (PD) can experience hallucinations (spontaneous aberrant perceptions) and illusions (misinterpretations of real perceptual stimuli). Of such phenomena, visual hallucinations (VHs) and illusions are the most frequently encountered, although auditory, olfactory and tactile hallucinations can also occur. In cross-sectional studies, VHs occur in approximately one-third of patients, but up to three-quarters of patients might develop VHs during a 20-year period. Hallucinations can have substantial psychosocial effects and, historically, were the main reason for placing patients in nursing homes. Concomitant or overlapping mechanisms are probably active during VHs, and these include the following: central dopaminergic overactivity and an imbalance with cholinergic neurotransmission; dysfunction of the visual pathways, including specific PD-associated retinopathy and functional alterations of the extrastriate visual pathways; alterations of brainstem sleep-wake and dream regulation; and impaired attentional focus. Possible treatments include patient-initiated coping strategies, a reduction of antiparkinson medications, atypical neuroleptics and, potentially, cholinesterase inhibitors. Evidence-based studies, however, only support the use of one atypical neuroleptic, clozapine, and only in patients without dementia. Better phenomenological discrimination, combined with neuroimaging tools, should refine therapeutic options and improve prognosis. The aim of this Review is to present epidemiological, phenomenological, pathophysiological and therapeutic aspects of hallucinations in PD.

A questionnaire-based (UM-PDHQ) study of hallucinations in Parkinson's disease.

BackgroundHallucinations occur in 20–40% of PD patients and have been associated with unfavorable clinical outcomes (i.e., nursing home placement, increased mortality). Hallucinations, like other non-motor features of PD, are not well recognized in routine primary/secondary clinical practice. So far, there has been no instrument for uniform characterization of hallucinations in PD. To this end, we developed the University of Miami Parkinson's disease Hallucinations Questionnaire (UM-PDHQ) that allows comprehensive assessment of hallucinations in clinical or research settings.MethodsThe UM-PDHQ is composed of 6 quantitative and 14 qualitative items. For our study PD patients of all ages and in all stages of the disease were recruited over an 18-month period. The UPDRS, MMSE, and Beck Depression and Anxiety Inventories were used for comparisons.Results and DiscussionSeventy consecutive PD patients were included in the analyses. Thirty-one (44.3%) were classified as hallucinators and 39 as non-hallucinators. No significant group differences were observed in terms of demographics, disease characteristics, stage, education, depressive/anxiety scores or cognitive functioning (MMSE) between hallucinators and non-hallucinators. Single mode hallucinations were reported in 20/31 (visual/14, auditory/4, olfactory/2) whereas multiple modalities were reported in 11/31 patients. The most common hallucinatory experience was a whole person followed by small animals, insects and reptiles.ConclusionUsing the UM-PDHQ, we were able to define the key characteristics of hallucinations in PD in our cohort. Future directions include the validation of the quantitative part of the questionnaire than will serve as a rating scale for severity of hallucinations.

REM behavior disorder, hallucinations and cognitive impairment in Parkinson's disease: A two‐year follow up

In Parkinson's disease (PD) the presence of REM parasonnias as REM Behaviour Disorder (RBD) or vivid dreams/nightmares, is recognized as largely associated with hallucinations, even if the risk of the development of hallucinations seem not to depend on how long the REM parasomnias had been occurring. The aim of this study was to establish if RBDs occurring earlier than hallucinations in PD are predictive of cognitive impairment development. Three groups of PD patients: i) group 1, without RBD and without hallucinations; ii) group 2, with RBD but without hallucinations; iii) group 3, with RBD and hallucinations have been prospectively investigated at baseline and after two years throughout a clinical and neuropsychological evaluation. After two years, the group 1 continued to present normal neuropsychological tests and did not present either RBDs or hallucinations. In the group 2, the frontal impairment evidenced at baseline was confirmed; the onset of newly hallucinations was reported in a subgroup of 12 patients, who proved to be older, with a more severe executive impairment at baseline and with a more severe motor symptoms progression than those RBD patients who had not manifested hallucinations. The group 3, characterized at baseline by a more severe cognitive impairment presented, after two years, a cognitive worsening and a higher mortality rate. The longitudinal but at preliminary step investigation identified a PD subgroup of patients, in whom a common background disease profile, including the presence of RBD, could represent a "red flag" in developing further cognitive impairment.

Psychotic symptoms in Parkinson's disease

About one third of patients with Parkinson's disease (PD) experience hallucinations, mostly of a complex visual type, less often auditory or tactile. Minor hallucinatory phenomena, including sense of presence, passage hallucinations and visual illusions are frequent. Hallucinations primarily occur in a context of clear sensorium in patients with longstanding PD. They are more frequent in the evening or during the night. Insight in the hallucinatory nature of the phenomenon may be retained, partial, fluctuating, or abolished. An altered insight is common when cognitive impairment is present, and may be associated with delusions and (or) delusional misidentifications. Pharmacological factors such as dopaminergic treatment clearly trigger or increase the occurence of hallucinations in PD. However, in the recent years, emphasis has been made on disease-related factors including cognitive impairment, diurnal somnolence, visual disorders (either contrast and color discrimination impairment due to PD, or coincident ocular disorders), long duration of PD, late onset, severe axial impairment and autonomic dysfunction. The pathophysiology of hallucinations of PD is poorly understood but is likely to be multifactorial. The first steps of the treatment consist in giving information and reassurance to the patient and his/her caregiver, re-evaluating the antiparkinsonian treatment and associated medications, and evaluating the patient for mood disorder, visual impairment, and cognitive impairment. Cholinesterase inhibitors, when prescribed for associated cognitive impairment, may be beneficial on hallucinations. In the more severe forms, clozapine has been proved to be safe and effective.

Does seasonal variation affect hallucinations in PD? a longitudinal study

The objective of this study was to examine the chronobiology of visual hallucinations in Parkinson's disease (PD) patients to test whether hallucinations are more severe during darker months (winter) than summer months. We extracted longitudinal data on the UPDRS Thought Disorder (TD) score, taken as part of regular patient management on sequential visits through a 1-year cycle in hallucinating PD patients. To reduce the confounding effects of medication adjustments, analysis was restricted to patients with a baseline evaluation that did not involve a medication change. The primary outcome was the seasonal change in hallucination severity, defined as a change in TD score or neuroleptic use. Using Wilcoxon rank-sum tests, we compared the exacerbation of hallucination by season, focusing on winter (December through February) versus summer (June through August). A total of 51 hallucinating patients met entry criteria, and their longitudinal data were analyzed. There was no difference in hallucination severity with changing season; the level of wintertime exacerbation was no greater than summertime exacerbation (P = 0.42). Although hallucinations frequently develop in dimmed environments and evening hours, the darkness of wintertime does not exacerbate hallucinations in PD subjects on stable medications. Because we found no evidence of seasonal variations, we cannot recommend phototherapy or other strategies affecting chronobiological systems as research priorities to treat PD hallucinations. (c) 2006 Movement Disorder Society.

Regional Alpha-Synuclein Aggregation, Dopaminergic Dysregulation, and the Development of Drug-Related Visual Hallucinations in Parkinson's Disease

Regional Alpha-Synuclein Aggregation, Dopaminergic Dysregulation, and the Development of Drug-Related Visual Hallucinations in Parkinson's Disease

Age‐related influences on the clinical characteristics of new‐onset hallucinations in Parkinson's disease patients

The objective of this study was to determine the demographic influences on the sensory characteristics (pure visual vs. nonvisual or mixed visual/nonvisual) of new-onset hallucinations in Parkinson's disease (PD). We utilized 6-year longitudinal interview data from 60 PD patients who had never hallucinated at baseline and reinterviewed them at 6, 18, 48, and 72 months to assess the presence and type of hallucination that developed as the first form of hallucination. We analyzed data by Generalized Estimating Equations methods and by nonparametric tests. Over 6 years, 37 of 60 patients developed hallucinations, and the first hallucinations were pure visual in 18, pure nonvisual in 9, and mixed visual/nonvisual in 10. At the time of first onset of hallucinations, patients whose hallucinations were nonvisual or mixed were significantly older than those with purely visual hallucinations (mean age, 69.8+/-8.3 vs. 61.9+/-10.6; P=0.031). PD duration in the two groups, however, was statistically comparable (9.6+/-4.4 vs. 12.9+/-8.6 years). Though classically described as visual, hallucinations in PD frequently involve other sensory modalities. Age-related disinhibition may facilitate wider cortical activation in PD and potentiate aberrant signaling that invokes other types of hallucinations besides the classic visual forms.

Hallucinations in Parkinson disease in the prelevodopa era

Whether chronic hallucinations belong to the natural history of untreated Parkinson disease (PD) remains undetermined. For early authors such as Gowers or Charcot and his followers, hallucinations that occurred in the course of PD either accompanied the final phase of the disease or reflected comorbidities. However, a few authors observed that hallucinations could occur in PD patients with severe depression, confusion, or dementia. Interest in hallucinations with parkinsonism increased with the outbreak of von Economo encephalitis, as they were more frequent than in PD, provoking new pathophysiologic questions. Later studies on mental symptoms in parkinsonism were often based on series that pooled patients with PD and postencephalitic syndromes, confounding a clear analysis. It remains difficult to estimate the prevalence of hallucinations in the natural course of PD before the introduction of levodopa therapy. The lack of prospective studies, the wide early use of anticholinergics and ergots compounds, and the absence of dementia with Lewy bodies in the nosology of the time are further limitations. Even with these limitations, historical descriptions of PD from the prelevodopa era suggest that hallucinations may be part of PD itself, especially in the context of late dementia, depression, or nonspecific encephalopathy.

Regional cerebral blood flow in Parkinson disease with nonpsychotic visual hallucinations

Patients with Parkinson disease (PD) often experience visual hallucinations (VH) with retained insight (nonpsychotic) but the precise mechanism remains unclear. To clarify which neural substrates participate in nonpsychotic VH in PD, the authors evaluated regional cerebral blood flow (rCBF) changes in patients with PD and VH. The authors compared 24 patients with PD who had nonpsychotic VH (hallucinators) and 41 patients with PD who had never experienced VH (non-hallucinators) using SPECT images with N-isopropyl-p-[(123)I]iodoamphetamine. There were no significant differences in age, sex, duration of disease, doses of PD medications, Hoehn and Yahr scale, or Mini-Mental State Examination (MMSE) scores between the two groups. The rCBF data were analyzed using statistical parametric mapping (SPM). The rCBF in the right fusiform gyrus was lower in the hallucinators than in the non-hallucinators (corrected p < 0.05 at cluster levels). The hallucinators revealed higher rCBF in the right superior and middle temporal gyri than the non-hallucinators (uncorrected p < 0.001). These significant differences were demonstrated after MMSE scores and duration of disease, which are the relevant factors associated with VH, were covariated out. Nonpsychotic visual hallucinations in Parkinson disease (PD) may be associated with hypoperfusion in the right fusiform gyrus and hyperperfusion in the right superior and middle temporal gyri. These temporal regions are important for visual object recognition and these regional cerebral blood flow changes are associated with inappropriate visual processing and are responsible for nonpsychotic visual hallucinations in PD.

Association between family history of dementia and hallucinations in Parkinson disease

To identify familial risk factors for hallucinations in patients with Parkinson disease (PD). Two hundred seventy-six outpatients with PD participated in the study. The presence of hallucinations was determined using a validated questionnaire, including items regarding the occurrence of visual, auditory, or other types of hallucinations. Family history of PD and dementia was determined by a structured interview and examination of medical records and affected family members. Patients with young-onset PD (<50 years) who reported another PD patient among their siblings were tested for parkin mutations. Stepwise logistic regression was applied for the detection of risk factors. The regression model included a set of family history-related variables (family history of PD and of dementia) and a set of disease-related variables (age, age at onset of PD, stage, duration of PD and of l-dopa therapy, l-dopa dose, and number of antiparkinsonian drugs). Hallucinations were present in 32% of the 276 patients. Risk factors for hallucinations included Mini-Mental State Examination score (p < 0.0001) and positive family history of dementia (p = 0.0005). Family history of dementia and lower Mini-Mental State Examination scores are risk factors for hallucinations in Parkinson disease.

Factors associated with drug–induced visual hallucinations in Parkinson's disease

Visual hallucinations are common in medication-treated Parkinson's disease (PD) patients. Although their etiology is unknown several factors seem to be involved in their pathogenesis. The aim of this study was to identify possible risk factors and determine clinical characteristics associated with the development of visual hallucinations in PD. 166 consecutive patients fulfilling clinical criteria for PD were studied. During a semi-structured interview, demographic characteristics and clinical variables were recorded. Motor, cognitive and psychiatric status was also assessed. Patients with and without visual hallucinations were compared using non-parametric tests, and logistic regression was applied to significant data. During the month before evaluation 20.4% of our patients experienced visual hallucinations (11.4% benign, 9% malignant). Logistic regression analysis identified three factors independently associated with visual hallucinations: long duration of Parkinson's disease, dementia, and disease severity as measured by the UPDRS total score. Our findings indicate that apart from well established risk factors such as cognitive impairment and disease duration, disease severity is also important for the development of visual hallucinations in PD. Furthermore, the presence of bradykinesia and instability, the absence of tremor and the severity of rigidity and bradykinesia (limb and axial) may act as cofactors.