New approaches to understanding hallucinations in Parkinson's disease

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hallucinations in Parkinson's disease: phenomenology and possible origins. Marco Onofrj†, Astrid Thomas and Laura Bonanni. †Author for correspondence.
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New approaches to understanding hallucinations in Parkinson’s disease: phenomenology and possible origins Marco Onofrj†, Astrid Thomas and Laura Bonanni

CONTENTS Classification of visual hallucinations Classification of visual hallucinations in PD Mechanisms of visual hallucinations Mechanisms of visual hallucinations in PD Objections & criticisms Treatment Expert commentary Five-year view Financial & competing interests disclosure

The authors review current literature on hallucinations in Parkinson’s disease (PD). Recent neuropathological studies showed that hallucinations occur in synucleinopathies and are a significant predictor of Lewy Body depositions. Therefore, hallucinations are a hallmark of PD and of dementia with Lewy Bodies. Visual hallucinations are mostly complex and kinematic; preserved or disturbed insight on the nature of hallucinations is a major prognostic factor, although eventually all hallucinators will present with reduced insight. Current theories on the origin of hallucinations point to visual dysfunction, dream overflow and cognitive impairment, yet objection can be raised on each one of the putative models of hallucinations. Understanding of the origin of hallucinations is required in order to develop treatments: all treatment evaluations were focused in general on psychosis, and only clozapine obtained positive evidence-based ratings on efficacy. However, it is likely that cholinesterase inhibitors, antipsychotics and anti-5-hydroxytryptamine3 agents and drugs acting on sleep regulation will have different and perhaps opposite effects on different types of hallucinations, whether they are accompanied by disturbed insight, sleep disorders or other psychotic features. Further studies will try to separate phenomenology and responses to treatment and will investigate the relevance of concomitant sleep disorders and abnormality of frontoparietal networks involved in the attention process.

Key issues

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References

Visual hallucinations (VH) occur in a third to 40% of patients with Parkinson’s disease (PD), with the highest prevalence reported for hospital-based series [1–9]. Increased risk of mortality was reported for PD patients hospitalized or institutionalized because of hallucinations [10], suggesting that impromptu treatment of hallucinations and psychosis could be the leading cause of mortality [11]. Thus, the interest in understanding the origin, mechanism or treatment sensitivity of hallucinations has recently been revived, as several concepts which were taken for granted have been re-discussed [12]. Hallucinations in PD received growing attention when it became obvious, starting from the 1970s [13–17], that chronic dopaminomimetic treatments could trigger their onset.

Affiliations



Author for correspondence University G. D’Annunzio, Department of Neurophysiopathology, Chieti–Pescara, 65124, Pescara, Italy Tel.: +39 0853 4178 Fax: +39 0853 4178 [email protected] KEYWORDS: antipsychotic drugs, Charles Bonnet syndrome, dementia with Lewy bodies, Parkinson’s disease, peduncular hallucinosis, psychosis, REM sleep behavior disorder, visual hallucinations

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10.1586/14737175.7.12.1731

Hallucinations were thus considered to be a drug-induced phenomenon, leading to designations such as ‘dopaminomimetic psychosis’ or ‘levodopa psychosis’ [15,16,18–23], although anticholinergics could also induce analogous complications [24]. Yet, more recent studies demonstrated that dose and duration of dopaminomimetic therapy are not major risk factors for hallucinations, and that VH are not precipitated nor do they simply relate to high levels of L-dopa or to sudden changes in its plasma levels [7,25–28]. A follow-up and a prevalence study confirmed that the independent predictors of VH in PD patients are not increased dopaminomimetic therapy, but sleep disorders and visual disturbances [7].

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Furthermore, increased recognition of dementia with Lewy Bodies (DLB), with its core symptoms consisting of dementia, parkinsonism and VH [29], and the dubious distinction of PD with dementia (PDD) from DLB suggested that further studies were needed to clarify hallucinations in parkinsonisms. The identification of this clinical entity has been a major breakthrough in the understanding of parkinsonian syndromes and has led to the identification of synucleinopathies as a group of diseases including idiopathic parkinsonism, DLB and multiple system atrophy [30]. α-synuclein depositions are found in this group of diseases, and these deposits appear in the shape of LBs (intracellular α-synuclein depositions) or Lewy neurites. A recent pathophysiological theory suggested that the PD, PDD and DLB synucleinopathy is an ascending pathology, in which α-synuclein deposits are initially prominent in the brainstem, inducing rapid eye movement (REM) sleep behavior disorder (RBD), and then ascend to rostral structures, inducing parkinsonism, followed by cognitive and psychotic symptoms [31–37]. Recent neuropathological studies evidenced that VH were the strongest predictor of LBs presence and distribution in the brain of patients with parkinsonism [38,39]. The authors proposed that, “VH be added as a supportive criteria to the operational clinical criteria for the diagnosis of PD”. Therefore, VH, following this study, became a fundamental element for the correct diagnosis of PD with LBs, at contrary with previous approaches, which considered VH as drug treatment related or suggested that the presence of VH should imply a reconsideration of the diagnosis of PD. A further comment should also be that once PD definitive diagnosis was based on the finding of LBs in nigral field [40], but this approach should also be reconsidered as there is now evidence of genetic mutations causing dopa responsive PD without LBs [41]. An attempt was made to understand whether chronic hallucinations belong to the natural history of untreated PD [28] by reviewing the literature of the pre-levodopa era, in order to avoid the confounding factors of dopaminergic stimulation and drug treatment duration. Even though difficulties arising from the lack of prospective studies, the wide early use of anticholinergics and ergot compounds, and from the absence of DLB in the nosology of the time could not be overcome, the review suggested that historical descriptions of PD from the pre-levodopa era confirmed the hypothesis that hallucinations may be part of PD itself, especially when dementia or depression were concomitant. As reported in the review, the German handbooks of Psychiatry and Neurology [42,43] debated on the recognition of hallucinations in PD, a paper by Ball in 1882 described late-occurring hallucinations without insight [44] akin to the hallucinations described in recent phenomenological studies [45–47], Parant [48] and Regis [49] in earlier French literature described hallucinatory symptoms in their patients, the German König reached the conclusion that hallucinations could not be considered as incidental comorbidities [50], and it was Lewy himself who described acoustic and VH with little emotional involvement in 33% of his patient series [51].

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Recent reports and historical reviews have prompted a reconsideration of hallucinations as being dependent on the role of disease-related factors, with cognitive impairment, depression and age as contributory factors [7,52–54]. The present review will focus on phenomenology, hypothetical mechanisms and treatments. Classification of visual hallucinations

There is no agreement on classification criteria of VH and several authors attempted to categorize VH by focusing on different aspects. Before entering the different classification methods, we propose a reminder of positive spontaneous visual phenomena (PSVP) (TABLE 1) and of the two classic syndromes presenting with VH. Positive spontaneous visual phenomena

A widely comprising criterion considers VH among PSVP [55]. PSVP include phosphenes, photopsias, VH, visual distortion or illusions, kinetopias, palinopsia, polyopia and visual allesthesia. Visual hallucinations in Charles Bonnet syndrome

Charles Bonnet syndrome (CBS) indicates hallucinations associated with significant visual loss, as has been noted with visual loss caused by cataracts, maculopathy and optic neuropathy [56,57]. Specific tassellopsies and dendropsies are described in 90% of patients with CBS [58]. In this syndrome, hallucinations of faces affect 41–47%, figures affect 40–71% of patients and in 41–59% there is strong emotional interaction. Hallucinations in this syndrome are traditionally said to be lilliputian in character [59], but it is now evident that, like in PD, such miniaturization appears only in a minority of CBS patients [12]. A consistently reported feature is preserved knowledge of the unreal nature of the hallucinations, but interactions or emotional content of hallucinations are also described [1]. Classic descriptions include a lilliputian circus entering a patient’s visual field, with complex interactions including a quarrel among the various personages of the hallucinations [60–62], and a description by a physician reporting hallucination of a little pony cradled in his arm. The etiology of CBS as simply owing to visual loss is currently debated [63]. Loss of vision cannot be the sole explanation, as the majority of patients with visual loss do not experience hallucinations; hence, coexisting pathology is also called into cause [63]. Peduncular hallucinosis

Peduncular hallucinosis (PH) appears with lesions involving one of the cerebral peduncles and at least two reports have described hallucinations and hemiparkinsonism contralateral to the lesion [64,65]. VH are typically complex and vivid, “although insight is preserved and patients recognize the unreality of the images” [66]. Their vivid character is said to have a profound effect at the

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Table 1. Definitions of visual hallucinations and other visual phenomena. Visual phenomenon

Definition

Visual hallucinations

Perceptions of images not present in the visual field. Visual hallucinations are considered a “unitary pathological symptom distinct from illusion”

Complex hallucinations

Kinetic/kinematic with preserved or disturbed insight

Hypnagogic hallucinations

Appearing when falling asleep

Hypnopompic hallucinations Appearing when waking from sleep Phosphenes

Unstructured lights such as flashes, sparkles, colored dots, zigzag lines or rainbows that are black and white or colored and static or moving

Photopsias

Geometric elementary structured images, often recurring in a repetitive form

Illusions

Misinterpretation of images, with the overlap of humanoid or animal tracts or inanimate objects, as represented by the portrait of an artist experiencing hallucinations in his Parkinson’s disease, or of the distortion of images present in the visual field

Visual distortions

Illusions, as the perceived image consists of the distortion of an image that is present or was present in the visual field of the subject

Visual allesthesias

Condition in which visual images are transposed from one half of the visual field to the other, either vertically or horizontally

Micropsia

Reduced size of the object

Macropsia

Enlarged object

Pelopsia

The object appears closer than actual

Teleopsia

The object appears farther than actual

Metamorphopsia

The distortion of objects or figures, such as enlargement of particulars, for example elongated necks and fang-like dentures

Kinetopia

The illusion of movement of a static object

Palinopsia

The visual perseveration or recurrent appearance of a visual image after the stimulus has disappeared

Polyopia

The multiplication of the visual image in the visual field

Tassellopsies

Hallucinations consisting of the perception of brick-like textures in the visual field and include fortification spectra and heat waves appearing in migraine

Dendropsies

Hallucinations of tree branches (dendrons)

time [65,67], such as inducing emotional interaction. Tassellopsies and dendropsies are not seen in PH. In PH, the content of VH consists of inanimate objects, but mostly complex kinematic scenes are described. For example, in a report by one patient, the room was transformed into a train carriage into which people were walking and airplanes were flying from the ceiling [68]. Classification of visual hallucinations in PD

Different authors classify hallucinations on the basis of phenomenology [67–69] because the hallucinatory productions, even though flourishing and variegated, showed some recurrent patterns among patients. Fenelon and coauthors suggested that two types of VH are recognizable in PD: minor forms and formed VH (’elaborate’) [45]. Minor forms (minor hallucinations/illusions) include three types of phenomena: presence hallucinations (sensation of the

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presence of persons or animals somewhere close to the patient); passage hallucinations (brief vision of persons or animals passing on the sides of the visual field); and illusions (metamorphosis of an existing object). Formed hallucinations-related phenomena encompass various contents (persons, animals or objects, interacting with each other and with the patient in complex scenes). We will discuss formed hallucination contents in the section dedicated to phenomenology of VH. Blurred or formed are also possible phenomenological criteria for the definition of VH. Blurred hallucinations are described as indefinite or not fully formed images, such as presence and passage VH. Hallucinations are also described as simple or complex; simple should indicate phenomena such as photopsia or perception of static images, and complex should indicate kinetic or kinematic perceptions.

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Formed images can be inanimated or animated figures, and can be static or moving in complex interactions. When moving these images are described as kinetic and kinematic (movie like) if the scenes are particularly complex. The classification of simple/complex VH can, however, be confounding because the terms are sometimes used to design VH characterized by preserved versus disturbed insight. Preserved or disturbed insight: benign or malignant VH

VH can be described as benign or malignant [70]. The terms are applied in turn as synonymous with VH with retained insight/disrupted insight, or used to identify the proneness of the disturbance to keep stable or to progress with PD progression [70], or lastly are applied to label the nature of the disturbance as mild (not bothersome for the patient) or severe (harshly affecting the patient’s quality of life). However, this classification criterion has been challenged because hallucinations progress, and hallucinations with retained insight may be benign for the moment but they have always serious consequences. As suggested in the original paper, “the term benign hallucinations of PD should be considered generally unsound and dropped from operative vocabulary” [70]. Time of presentation during PD course

VH in PD have also been tentatively classified as early, appearing within 5 years from the onset of PD, or late [7]. Yet, this classification is debatable, as will be described later, and represents previous opinions confuted by more recent approaches (TABLE 2) [70]. Phenomenology of visual hallucinations in PD

VH are by far the most common hallucinations in PD and DLB, although acoustic [71] and haptic (tactile) hallucinations are reported in variable percentages of patients (11–19%). The majority of reports describe variegate contents of hallucinations, each dependent on the anecdotal experience of the author. An extensive phenomenological description can be found in the work by Fenelon et al [45]. VH in PD are usually formed from the very first appearance of the hallucinatory symptoms. Various descriptions report inanimate objects (leaves on the wall) [1], animated figures (children playing) [1], normal sized figures [45,46,72,73], miniature people and animals [59,74], images from daily life experience [9,45] and images from TV programs [45]. Various investigators describe commonly preserved insight, such as knowledge of the non-real nature of the images [45,46,72,75], but often accompanied by complex interaction with the hallucinations, with the parkinsonian patient inviting the hallucinatory presence to dinner [1] or trying to push away his hallucinatory bedside companion [73]. Tassellopsies, dendropsies, fortification spectra and visual distortions, such as micro-macropsies and telo-pelopsies, are never described in PD, even though a recent paper suggests that the diplopia [76–78], often reported by parkinsonian patients and currently interpreted as being due to convergent/divergent oculomotor disorders, could represent a polyopic phenomenon.

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A seasonal variation of VH occurrence has been suggested but, even though hallucinations frequently develop in dimmer environments and evening hours, the darkness of winter does not exacerbate hallucinations in PD subjects on stable medication [79]. Typical of PD are early blurred hallucinations consisting of sensation of presences, so-called ‘extracampine hallucinations’ [80] because the presence is felt at the extreme peripheral border of the visual field, or at one’s shoulders. Extracampine hallucinations were discussed in detail in a seminal paper by Critchley [81], who studied the hallucinations of the benign guardian angel or of malicious persecutors in navy soldiers marooned during the Second World War who were suffering from posttraumatic stress disorder [82]. Blurred hallucinations can also consist of sensation of sideways passage (mostly animals fleeing at the subjects sides) [45]. A frequent feature of VH in PD patients is the disappearance of the object of the hallucination under focussed attention [35]. Patients with significantly preserved cognitive functions spontaneously report that the hallucinatory images disappear when they try to focus their vision on the object. Focusing attention on VH in order to let them disappear is described as a ‘coping strategy’ useful for nonpharmacological management of the disorder [83]. In one of our studies, we described a patient frequently experiencing the hallucination of burlesque dancers moving around his bedroom armchair. The dancers disappeared whenever he tried to focus his vision and attention on details, leaving him disappointed [35]. Hallucinations can appear in combined modality: one of our PD patients with preserved cognitive function (Mini-Mental State Examination [MMSE] = 25) reported distressful, even if recognized as unreal, haptic and visual perception of long blond hairs on her arms [35]. In one of our PDD patients (MMSE = 19), haptic and VH presented the features of Ekbom delirium of infestation [35,84], with worms and lice felt and vigorously scratched. VH tend to become more complex and severe when cognitive impairment superimposes to other symptoms [45], and the indefinite borders of PDD and DLB are reached. In patients with cognitive decline, the incidence/prevalence of hallucinations is higher and hallucinations are also qualitatively different, as complex interactions with hallucinatory perceptions are described with lack of insight of the unreal nature of perceptions [3,4,7,32,45,46,52,85]. The patient interacts with “devils with blurred faces and changing size armed with blades” [45] or quarrels with the hallucinatory presence who is molesting his wife [35]. In patients with PDD or DLB, night-time hallucinations can assume the form of confusional states, defined as oniroid (oniric) confusion, status dissociatus [86] or agrypnia excitata [87]. In this confusional state, the patient interacts with hallucinations and wandering behavior is common, prompting requests for restraints, which can induce combative behaviors. Night-time confusional state in PD is a poorly described condition. It is not clear how frequent it is, as reports are only anecdotal [1], nor it is clear if nocturnal confusion with hallucinations is related to RBD. RBD is a parasomnia consisting of the

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loss of normal muscle inhibition during sleep and the enacting of dreams. During enactments the patients might fall off the bed or hurt their partner with their uncontrolled movements or by kicking and punching induced by the content of their dreams [88]. RBD is frequent in PD patients and its occurrence may precede the appearance of motor symptoms [89]. It is considered a supportive symptom for the diagnosis of DLB [29] and is considered as one of the possible causative or precipitating factor for the occurrence of VH [12]. It would seem easy to consider nocturnal confusion as an extreme example of RBD; however, REM sleep should be properly assessed by polysomnographic recording, where REM desynchronization should be evidenced. The task also seems difficult, as PDD and DLB patients have frequently abnormal EEGs with slower frequencies than in controls [29]. Predominant theta activities were shown in two studies on RBD patients with parkinsonism [90,91]; therefore, the assessment of polysomnographic studies might be difficult in these diseases and REM identification might be marred by the inscription of slow activity. A recent phenomenological analysis was performed in PDD and DLB patients, and showed that these cognitively impaired patients experienced mostly daily complex hallucinations, normally lasting minutes. Most patients commonly saw people or animals and the experiences were usually perceived as unpleasant [32]. Neuropsychiatric symptoms coexisting with hallucinations were apathy, sleep disturbances and anxiety [32]. The conclusion of these authors was that patients with mild-tomoderate dementia can provide detailed information about their hallucinations. RBD and night-time oneiroid confusion will be discussed in the paragraph about mechanisms. Mechanisms of visual hallucinations Excitation of visual pathways

Excitation is not called into cause to explain complex VH in PD. Physiological excitation has only been evoked to explain phospenes and photopsias due to activation of retinal visual circuitry because of eyeball deformation, pressure, electrical or magnetic stimulation, or cosmic rays [13,92]. Pathological excitation of cortical visual areas is considered to explain VH and visual distortion (such as metamorphopsia and micro-macropsia) of partial complex seizures originating in the temporal lobe. Complex hallucinations, however, never occur in occipital lobe epilepsy [93]. Mechanisms of visual hallucinations in PD Hyperactivity of limbic system

VH might depend on hyperactivity of mesolimbic dopamine (DA) pathways, through a mechanism akin to the one used to explain the positive symptoms of schizophrenia [12]. It has been hypothesized that denervation hypersensitivity of mesolimbic and mesocortical DA receptors may occur and that dopaminergic medications may stimulate these hypersensitive receptors, by inducing perturbations in postsynaptic peptides, to cause VH [35]. The exact neurochemical link to the dopaminergic

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system, however, is not clearly delineated and the interactions between DA and serotonin, as well as the participation of serotonin-modulated GABAergic neurons may also contribute to the pathophysiology and may be important. Chronic stimulation of DA receptors can cause persistent sensitization, causing susceptibility to the development of psychotic symptoms. This hypothesis is mostly supported by the powerful effect of antipsychotics in hallucinations, and by their antagonist activity on D2, D3, D4 receptors and 5-hydroxytryptamine (5-HT)3 receptors [94–120]. The dopaminergic agonists cocaine and amphetamine can induce psychosis, whereas the dopaminergic antagonists haloperidol and pimozide can reduce psychotic symptoms [121]. The atypical neuroleptic clozapine preferentially blocks D3 and D4 mesolimbic dopaminergic receptors and 5-HT2 receptors. Yet, the only evidence that a basal ganglia circuit abnormality can induce VH comes from a single case report of VH induced by deepbrain stimulation (DBS) of the subthalamic nuclei [122]. This report is peculiar because it is the only one describing induction of VH by DBS, among many others describing behavioral, hypomanic, dysexecutive, depressive symptoms induced by DBS, but never hallucinations [123–128]. One study showed a striking association between the distribution of temporal lobe LBs and well-formed VH [129]. Cases with VH had a high density of LB in the amygdala and parahippocampus, with early hallucinations relating to a higher density in parahippocampal and inferior temporal cortices. Serotonin is also thought to play a role in VH production. Lysergic acid diethylamide and 3,4-methylenedioxy-metamphetamine, agonists of serotonin receptors, can induce VH [122], and serotonin receptor blockade can cause psychotic symptoms. Release/disinhibition phenomena

A release phenomenon (i.e., disinhibition of neural structures, with increase in the excitability and spontaneous activity of the disinhibited neurons) is one of the core hypotheses in the mechanism of hallucinations. This mechanism is called into question to explain VH in CBS [56,57,130] and classic migraine. Tassellopsies and dendropsies, and fortification spectra or heat waves would be caused by spreading depression inhibiting the idiotypic cortex and releasing unimodal association areas. Tassellopsies and dendropsies in CBS and fortification spectra in migraine have specific orientation and spatial frequency characteristics that suggest a disinhibition of columnar structures in primary or associative visual cortex [58,92]. Based on the disinhibition theory, VH are thought to be caused by phasic increases in neural activity within the specialized visual cortex, and the type of VH is defined by the specific location of the increased activity. For example, colored hallucinations accompanied increased activity in V4 [69]. Hallucinations of landscape figures, vehicles and various other objects accompanied increased activity in the anterior ventral temporal lobe (anterior to fusiform and lingual gyri, projections of the ventral visual pathway); hallucinations of faces (or metamorphopsia of

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Table 2. Categorization of visual hallucinations. Parameter

Measurement

Rationale

Duration

Seconds; minutes; hours

In cognitively preserved PD patients, VH lasts a few seconds. In PDD-DLB patients, hallucinations last minutes to hours

Time of the day when VH occur Late-occurring; daytime; night-time

In cognitively preserved PD patients, VH are usually late-occurring. Night-time confusional state in PD is a poorly described condition. It is not clear how frequent it is nor is it clear whether nocturnal confusion with hallucinations is related to RBD

Frequency

Occasional; repeated (daily, weekly, monthly)

In cognitively preserved PD patients, the frequency of VH is usually less than one per week. They become more frequent when cognitive impairment starts to become evident. In PDD-DLB hallucinations, are daily

Relationship with treatment

Present; absent

Besides historical approach to “dopaminergic psychosis” only few reports state that VH are increased by dopamine agonists. The relationship with nondopaminergic treatments, including new drugs now under assessment, need to be investigated

Quality; occasional; recurrent

Formed; not formed; blurred; VH in PD are usually formed from the very first appearance of the detailed; static; hallucinatory symptoms. Typical of PD are early blurred hallucinations kinetic/kinematic consisting of sensation of presences, the so-called “extracampine hallucinations”. VH in PD are mostly complex and kinematic, simple VH, like the ones observed in epilepsy, migraine and CBS, are rare or absent in PD

Influence of focused attention

Irrelevant; disappearance

These phenomenological and morphological classifications should be completed by the precise description of the hallucinations and of the occasional and recurrent nature of the perceptions. A frequent feature of VH in PD patients is the disappearance of the object of the hallucination under focalized attention. This quality of VH has implications on the possible origin

Insight

Preserved; lost

Preserved or reduced insight on the non-real nature of VH is a prognostic factor, as shown by classifications in benign/malignant forms. Abnormal insight predicts the development of further behavioral disturbances

Emotional content

Absent; present

Fear, interest, curiosity, associated feelings (e.g., bothersome or haptic hallucinations) or absence of emotional interaction with detachment should be reported

Cognition

Grading

The relevance of cognitive level is a consequence of phenomenologies reported so far. Quantitative assessments with scales (e.g., MMSE, NPI and DRS-2) should accompany categorization of patients

CBS: Charles Bonnet syndrome; DLB: Dementia with Lewy bodies; DRS-2: Dementia Rating Scale-2™; MMSE: Mini-Mental State Examination; NPI: Neuropsychiatric Inventory; PD: Parkinson’s disease; PDD: PD with dementia; RBD: Rapid eye movement sleep behavior disorder; VH: Visual hallucinations.

faces) accompanied hyperactivity in the superior temporal sulcus; and increased activity in the parietal cuneus and precuneus areas (receiving projections from the dorsal visual pathway, where the reference frame that organizes the stability of the visual world across successive eye movements is located) was accompanied by perseveration and palinopsia (because of shifts of the reference frame) [55]. Cholinergic denervation causing disinhibition

The disinhibition mechanism is also called into cause in order to hypothesize a role of cholinergic denervation in the origin of VH. In DLB and PDD patients, reduction of choline acetylase and cholinesterases were shown in cholinergic nuclei of the basal forebrain and in cortical areas receiving afferent neurons from these nuclei and were more apparent than in AD [104,131,132].

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The density of muscarinic receptors was found to be less reduced in DLB-PDD than in AD, thus suggesting that DLBPDD may be more sensitive than AD to treatment with cholinesterase inhibitors [133–135], even though treatment trials did not find different outcomes in DLB-PDD as compared with AD with regard to efficacy of treatment and numbers needed to treat (responders) [136–138]. A neuropathological study suggested a strong correlation between administration of anticholinergic treatments in PDPDD and occurrence of senile plaques, which were further correlated with history of hallucinations [139]. The hypocholinergic hypothesis, with the ensuing release/disinhibition phenomenon, was supported in an extensive review [135]. According to this hypothesis, cholinergic denervation of visual associative areas should induce hallucinations because of a

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release phenomenon: cholinergic projections from the basal forebrain reach visual associative areas with their axon terminals [135]. A therapeutic trial with the cholinesterase inhibitor rivastigmine showed that hallucinations could be reduced in DLB-PDD patients by the administration of this drug [136]. Visual disturbances

Visual disturbances are part of nonmotor symptoms in PD [140]: retinal dopaminergic cells modulate contrast sensitivity of retinal ganglion cells, and hypodopaminergic states can be accompanied by blurring of spatial contrast, which can be reversed by dopaminergic drug administration [141]. In one of our studies, we showed that the contribution of visual disturbances could be, in same instances, disentangled [12]. We investigated whether hallucinations or illusions might emerge in hypodopaminergic conditions, such as end of sleep benefit and ‘off’ phases [12]. In different virtual reality experimental sets, we found that illusions, consisting of emergence of animated or human figures or inanimate objects, were frequent during hypodopaminergic states [12]. Yet, visual disorders cannot thoroughly explain the emergence of hallucinations as hypodopaminergic visual disturbances (and the accompanying abnormalities of visual evoked potentials and electroretinograms) [142,143] are corrected by

transient or chronic administration of dopaminergic therapy [12], whereas hallucinations mostly appear in chronically treated PD patient [13–19]. Dream overflow & sleep disorders

Several studies postulated links between VH and sleep disturbances. Moskowitz et al. suggested that altered dreaming is the first step in a progressive cascade of events leading to druginduced psychosis, through a mechanism involving pharmacological kindling [15]. Pharmacological kindling now appears controversial, whereas altered dreaming and sleep fragmentation [3,144] were more recently considered predictive or coincident factors for the occurrence of treatment-induced hallucinations. Later on several lines of evidence established a link between VH and RBD [39,145,146]. Comella et al. suggested that treatment-induced VH represents intrusions of REM sleep into wakefulness [145] and this hypothesis of VH as overflow dreams phenomenon was supported by further studies [1,147–150]. The relationship of VH with RBD was suggested in several studies [1,3] and in our chronic long-term study, RBD was a predictor of VH occurrence [7]. In our study, abnormal vision and RBD were treated as independent variables and cognitively intact PD patients were followed for 8 years. [7] At baseline,

PPC

DLFC Frontoparietal cortex

Pulvinar V1

V2

Pulvinar and visual cortex

V3

V4

Retina A17

Retina and visual areas

Brainstem and REM sleep regulating nuclei

Dorsal raphe nucleus

Mesopontine tegmentum Nucleus locus coeruleus

Figure 1. Multifactorial origin of visual hallucinations in Parkinson’s disease. The figure schematizes anatomical loci probably involved in visual hallucination (VH) generation in parkinsonian disorders including dementia with Lewy Bodies and Parkinsons’s Disease with dementia. The top part of the figure suggests that longitudinal (superior and inferior) frontoparietal networks, subserving visual attention, might be involved. These pathways are direct or linked by the pulvinar nucleus. The visual cortex may be disinhibited owing to insufficient cholinergic modulation or because of insufficient frontoparietal modulation: different visual areas might generate different hallucinations. Hypodopaminergic retinal conditions might also generate VH. Finally, the REM sleep ponto–geniculo–occipital regulating systems may induce VH because of dream overflow. A17: Indicates the dopaminergic retinal cells (horizontal and amacrine cells); DLFC: Dorsolateral frontal cortex; PPC: Posterior parietal cortex; REM: Rapid eye movement; V1–V4: Visual cortex 1–4.

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eight patients had visual abnormalities. In most patients, chronic dopaminergic treatment in the ‘on’ state reduced visual abnormalities to normal. At 3 and 6 years, visual abnormalities were less frequent than at baseline, whereas the prevalence of VH and RBD increased. The prevalence of hallucinations was below 40% in patients with and without visual abnormalities. Throughout the follow-up 27 patients were classified as clinically affected by RBD. At the last visit, only four patients describing hallucinations were classified among the normal sleepers [53], whereas 27 PD patients had RBD and experienced hallucinations. The Conditional Maximum Likelihood Ratio (CMLR) showed that the presence of RBD was significantly related to and predicted the development of hallucinations (p < 0.001) independently of MMSE score, H/Y stage and Unified Parkinson’s Disease Rating Scale (UPDRS) evaluation. RBD was not correlated with visual abnormalities (p < 0.7), nor were hallucinations (p < 0.2). RBD and hallucinations were related to the amount of DA agonists administered: patients who experienced both RBD and hallucinations were receiving bromocriptine equivalent 32 ± 6 mg/day, while those with neither RBD nor hallucinations were receiving bromocriptine equivalent 11 ± 6 mg/day (p < 0.001). Yet, our study described the occurrence of hallucinations in a selected patient population as patients with DLB or cognitive disturbances were specifically excluded. The prevalence of hallucinations in our patient population was less than three-quarters the prevalence reported in other studies (40–47%) where cognitive decline signs were not among exclusion criteria. As we included only PD patients who did not develop any cognitive disturbances during follow-up, our choice might have represented a selection bias. A strict relationship between RBD and VH has yet to be demonstrated. While RBD is now considered among the prominent nonmotor symptoms of synucleinopathies [31,33], as its role in PD and DLB might justify the ascending neurodegeneration hypothesis [34,36], proper studies on the relationship between RBD and VH in PD, DLB and PDD have yet to be designed and conducted. As anticipated in the phenomenology section, connections between RBD and nocturnal confusional states are also far from being elucidated, and the main question would be whether VH, RBD and nocturnal oneiric confusion are distinguishable entities or part of a continuum subserved by the same mechanisms. Despite the unclear nature of associations, the interpretation of VH as dream overflow phenomena constantly re-emerges in the literature. A recent study, for example, analyzed hypocretin (Hcrt) levels in PD patients, because of the similarity between symptoms such as sleep attacks, nocturnal insomnia, RBD, VH and depression that are consistently reported in PD [2,3,7,35,144,146–153] and in narcolepsy [154], are which are linked to a selective loss of Hcrt neurons. Loss of Hcrt cells in the anterior and posterior hypothalamus was found and correlated with Hoehn/Yahr (H/Y) stages [155]. The authors concluded that loss of Hcrt cells may be a cause of the narcolepsy-like symptoms of PD and

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may be ameliorated by treatments aimed at reversing the Hcrt deficit (i.e., modafinil). Yet, this study could not correlate Hcrt deficit with nonmotor symptoms or VH. The similarities between narcolepsy and PD nonmotor symptoms were already called into question by a study suggesting that VH in PD are expressions of symptomatic narcolepsy [1], even though in one of our studies we showed that DRD2 haplotype, which is a hallmark of narcolepsy, is irrelevantly distributed in PD patients with VH and RBD [151]. In addition, the frequent falls [33] of DLB patients have been attributed to cataplectic attacks – part of the narcoleptic syndrome – due to liberation or overflow from REM sleep control of the motor inhibition commonly accompanying REM sleep, thus adding cataplexy to dysautonomia among the causative factors of frequent falls. Recent studies found a correlation between dysautonomia and VH [156,157]. Frontal lobe dysfunction & visuocognitive disturbances

The frontal lobes are phylogenetically recent structures controlling the activity of the other heteromodal cortical areas [35,158–161]. During sleep, frontal areas are hypoactive: the lack of frontal drive is considered to explain the alogical, avolitional, amnesic, atemporal structure of thought during dreams [147]. The frontal dysfunction (dysexecutive syndrome) accompanying mental decline in PDD and DLB with reduction of inhibitory outputs might also explain the occurrence of hallucinations in these diseases, with a mechanism based again on disinhibition. A support to this hypothesis can be suggested by linking the effect of focused attention, suppressing VH in PD patients, with the theoretical solutions of the binding problem. The binding problem is the question arising from the knowledge that visual inputs are analyzed in parallel by different cortical areas, and that parallel processes should be fused at an unknown level of the cortex in order to produce perception of the visual images [161]. Thus, the binding problem investigation is addressing questions on the mechanism of visual awareness and consciousness. Hypotheses on binding problem solutions suggest that when focusing on or perceiving images a preattentive process scans a feature map, which preserves memories of previous images in parietotemporal brain regions, receiving afferents from the dorsal and ventral corticocortical visual pathway [162]. The feature map is processed in a master map (attentional matrix) or saliency map that preliminarily identifies the conspicuously noticeable elements from the preattentive scan. Following this, salient elements are analyzed in detail by spotlight (focalized) attention. The pulvinar, claustrum, superior colliculus and prefrontal cortex are the anatomical substrates of the master map and spotlight attention engagements [162]. Thus, the hypothetical solution of the binding problem highlights a role of the frontal lobes. Recent functional MRI (fMRI) studies demonstrated that dorsal and ventral frontoparietal networks [20,163,164] constitute the anatomical substrates of attention. The frontal lobe dysfunction observed in PD patients might therefore lead to an abnormal organization of the saliency map and spotlight attention.

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Hallucinations in parkinsonisms

This hypothesis adds a lack of rostral inhibitory input to visual loss and REM sleep derangement as causative mechanisms proposed in explanatory models of hallucinations. Integrative model

More recently, a new integrative model was proposed for the origin of VH. Chronic VH in PD might reflect disturbed internal/external perception dependent on visual impairment and on dysfunction of the control system for REM sleep [72]. The tentative integrative model encompasses the occurrence of hallucinations inside Hobson’s schemata of mental states [147]. Hobson schematizes states of cerebral activity in the so-called Activation–Input Source–Modulation (AIM) model, represented as a cubic frame where coordinates are three brain attributes of consciousness interacting with each other. Activation reflects the rate at which the mind can process information. Input source is a measure of the level to which the brain processes external sensory data (in waking) or from internal data sources (as in daydreaming or REM sleep). Modulation is the ratio of aminergic (noradrenergic and serotonergic) predominance in waking to cholinergic predominance in REM sleep. Based on the AIM model, hypnagogic and hypnopompic hallucinations, associated with transitions into and out of sleep, respectively, result from the REM-like enhancement of internal stimuli together with an aminergically activated waking brain. In the integrative model, visual impairment, reduced activation of primary visual cortex, abnormal activation of associative visual and frontal cortex, lack of suppression or spontaneous appearance of internally generated images through the pontogeniculo–occipital system, intrusion of dreams into wakefulness, impaired filtering capacities of the brainstem, and overactivation of mesolimbic systems contribute to VH appearance (FIGURE 1) [72]. Objections & criticisms

Objections can be raised against each one of the aforementioned models. The disinhibition theory, based on visual loss, does not explain why some kinds of hallucinations never occur in PD [63]. Furthermore, visual dysfunction in PD is corrected by dopaminergic drug administration, while VH develop chronically and are often induced by treatment. The hypocholinergic hypothesis cannot explain why RBD is relevantly related with hallucinations in PD, mostly when considering that REM sleep is dependent on high cholinergic activation [165]. According to the Hobson‘s model, REM sleep should be reduced in the hypocholinergic state [147]. It should therefore be suggested that RBD is dependent on a hypocholinergic state, related to imbalance of low cholinergic and high catecholaminergic transmission. Thus, RBD should be associated with a reduction rather than with an increase in REM sleep; a fact that has not been definitely shown. A recent study on dream content of RBD and of nightmares during RBD hypothesizes that RBD represents a regression to an ontogenetically primitive, infantile form of dreams [166]. It

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may well be that the primitive dream system involved in RBD is dependent on different neurotransmitter modulation than REM sleep [166,167]. Following this hypothesis, RBD should be reduced by cholinesterase inhibitors or cholinergic drugs, but no evidence has been produced so far. Furthermore, cholinesterase inhibitors can induce RBD [168,169]. Studies on cholinesterase inhibitor administration in early AD or mild cognitive impairment showed more frequent increments of nocturnal confusion (30%) in comparison with moderate/severe AD patients. However, RBD or nocturnal confusion was not increased following the administration of rivastigmine in PDD or DLB patients, and hallucinations decreased [170]. Against the hypothesis linking RBD with VH is also the finding that VH are rare in multiple system atrophy, while RBD is common in this disease. The phenomenology of hallucinations in PD, with their kinematic characteristics, might suggest that VH seem to be made of the “fabric of dreams” [1]. Yet, the two paradigmatic syndromes, indicating two different origins of hallucinations, such as CBS [28,56–58] and PH [171], share too many phenomenological similarities to make a simple distinction tenable: complex VH with formed images and kinematic actions with preserved insight are described in both syndromes, but consciousness of the unreal nature of perceptions can fade, as several descriptions have also reported interactions with hallucinations in CBS. The brightly colored troupe described by a patient and the little pony cradled in his arm described by a physician, both affected by CBS, are undoubtedly interpretable as dream-like images [62,63]. As an alternative interpretation, it could be suggested that any disinhibition of visual areas will lead to the appearance of dream-like images and that the interaction with these images will depend on the state of consciousness. If we hypothesize that any disinhibition of dorsal and ventral cortical visual pathways can produce dream-like hallucinations, we can attribute hallucinatory production to a final common mechanism, suggesting that hallucinations are produced in dorsal and ventral visual areas, presenting with their dream-like kinematic features when disinhibition is more widespread, and with minor features (tassellopsies, poliopsies, and extracampine and movement hallucinations) when disinhibition is only partial. By suggesting this hypothesis, the role of the frontal lobes in the production of hallucinations could be called into cause. However, this hypothesis cannot explain the reason why there are no (or very low percentages of ) reported VH in progressive supranuclear palsy (PSP) or frontotemporal dementia, where frontal dysfunction is prominent. A study on PD versus PSP patients found that hallucinations were reported in only one of 27 PSP patients who were treated with dopaminergic agents, and concluded that regional neurochemical differences in cholinergic and monoaminergic degeneration may provide possible explanations for the finding of more frequent hallucinations in PD than in PSP patients [172]. Another study reported that two of 11 PSP patients receiving chronic dopaminergic treatment developed hallucinations [173].

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The differences in the frequency of VH between PSP and PD may be explained with different regional cholinergic and monoaminergic degeneration, decreased survival of PSP compared with PD patients and early discontinuation of dopaminergic treatment due to loss of efficacy, but also by the different composition of temporoparietal areas. Furthermore, several studies performed with PET [174] or fMRI assessments of hallucinations showed hyperactivity of frontal areas accompanied by hyperactivity of occipital areas [175], thus opposing hypotheses on frontal dysfunction. More recently, longitudinal (dorsal and ventral) networks were identified by fMRI, linking frontal lobes with parietal lobes [176] and probably subserving attentional processes. These networks will obviously be investigated in PD patients with cognitive disorders and in patients with VH. Treatment

There are no systematic studies on treatment of hallucinations in PD. Treatment rationale

The choice of most appropriate treatments is based on putative mechanisms which form the basis of VH. Limbic dysfunction

Many studies are focused on psychosis, where effects on hypersexuality, compulsion, erratic behaviors and delusions are considered [177–183]. All major studies on clozapine [102104,106,111–113,115,184–186], and all minor studies on olanzapine [97–99,105,106,187,188] risperidone [100,101,189,190] and quetiapine [108–110,191–194] are focused on psychosis, and analyze hallucinations among conditions of psychosis [106,108,113,191,194]. Hallucinations are reduced by administration of typical antipsychotics such as thioridazine, and by the atypicals clozapine, olanzapine, risperidone and quetiapine; however, thioridazine, olanzapine and risperidone seriously worsen motor symptoms and should therefore be avoided [105,195]. Evidence-based (EB) reviews on the effects of atypical antipsychotics have shown that only clozapine is efficacious in the short term, while there is insufficient evidence to conclude on the long-term efficacy [196]. Clozapine treatment carries an acceptable risk with regards to safety, with the condition of weekly blood count monitoring. Therefore, clozapine was indicated as clinically useful in the short term and possibly useful for long-term management [195]. Olanzapine was described as unacceptable owing to safety risks [98]. Quetiapine was labeled with an insufficient evidence of efficacy. Risperidone was never systematically studied, but the few anecdotal reports demonstrate that its use in PD is unsafe [100,101], confirming that this drug “is not atypical in any of its motor effects” [114]. Aripiprazole also induced worsening of parkinsonism and was not considered for further clinical trials [116–120]. Even though the EB medicine classifications on treatments of psychosis were proposed in 2002, no changes in evidence were provided by recent EB reviews [196] and Cochrane databases. Therefore, only clozapine is undebated; all other drugs are not classified into sufficient evidence groups. In addition, quetiapine,

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which is currently used and advocated for treatment in several algorithms, did not receive support from recent studies. While earlier reports suggested good efficacy and safety, recent doubleblind studies showed no differences compared with placebo [185]. A recent meta-analysis, however, criticizes clozapine use and defends quetiapine [182]. Moreover, a viewpoint on psychosis in PD reports that symptoms continue or recur after antipsychotics are discontinued and symptoms may persist or recur among patients treated with antipsychotics [197]. Earlier algorithms for the treatment of psychosis aimed to reduce the dose of antiparkinsonian drugs to a level that will lead to resolution of psychosis while maintaining sufficient symptomatic motor control. This goal can be reached only in patients who present with hallucinations as an early side effect of DA agonist treatment and are at the initial stages of the disease. In such cases, withdrawal of the DA agonist drug, which is commonly the culprit of VH occurrence, can induce transient disappearance of VH. In our experience, after withdrawal of DA that had induced hallucinations, some patients remained free from VH for as long as 5 years. VH, however, recurs with disease progression [7]. In patients experiencing hallucinations in advanced forms of PD with dyskinesias and motor fluctuations, the drug withdrawal algorithm is evidently unbearable because of the occurrence of severe worsening of off time or akinetic crises [198,199]. Such patients require additional antipsychotic therapy. Despite the suggestions of the EB reviews, and in agreement with other authors [108,109], we generally attempt treatment with quetiapine, starting with 12.5 mg at night time, increasing to 25–50 mg, because quetiapine administration does not necessitate weekly blood cell counts, which are troublesome for the majority of patients. The mean dose of quetiapine used in our patient population is 37.7 mg/day, not greatly different from the 40–47 mg reported by other authors [108–110,191–194]. If quetiapine fails, we switch over to clozapine 12.5 mg, reducing to 6.25 or increasing to 50, 100 or 200 mg depending on the severity of psychotic symptoms. Five reports (from the same authors) showed that ondansetron, a 5-HT3 receptor antagonist used as a powerful antiemetic treatment in patient receiving chemotherapeutic agents, reduces hallucinations [94,95,200,201], but no systematic studies are available. We successfully used ondansetron as an antiemetic adjuvant during subcutaneous DA agonist (lisuride or apomorphine) treatment of off states and akinetic crises [198], and we have often observed a reduction of hallucinations. In one case, we successfully treated PH in a child affected by viral encephalitis. However, systematic studies need to be produced. TABLE 3 summarizes pharmacological studies on antipsychotic treatments performed in the last 5 years [108,110,114,185–188,191–194, 202–204]. We performed an electronic search for treatment of VH in PD on 16 November, 2007. A search of the electronic database MEDLINE (PubMed, 2002–2007), screened for the key words: Parkinson’s disease, hallucinations and treatment; PubMed query: (“Parkinson’s disease”) AND (hallucinations AND treatment). The full texts of all citations were obtained for study selection.

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Table 3. Recent studies on pharmacological treatments 2002-2007. Drug

Authors

Study design

n

Olanzapine vs Ondo et al. placebo 2002

Double-blind, placebo-controlled

Quetiapine

Psychosis

UPDRS

Ref.

16 4.6 ± 2.2 olanzapine

No improvement

↑ UPDRS total

[187]

Retrospective review; open-label treatment

43 (19 56.3 ± 44.9; demented) 51.3 ± 28.4 demented

Improvement; 74% nondemented; 90% demented

↑ UPDRS 25% demented

[108]

Olanzapine vs Breier et al. Double-blind, placebo 2002 (Europe) placebo-controlled

36 F/51 M

4.1 ± 2.0

± CGIS

↑ UPDRS total; ↑ UPDRS III

[188]

Olanzapine vs Breier et al . placebo 2002 (USA)

25 F/58 M

4.2 ± 2.6

± CGIS

↑ UPDRS total; ↑ UPDRS III

[188]

N/A

[204]

Reddy et al. 2002

Double-blind, placebo-controlled

Mean dosage ± in mg/day

Clonazepam

Nomura et al. Open-label 2003

8

0.5–2

↓ VH in five of eight patients

Clozapine vs quetiapine

Morgante et al. 2004

Randomized, rater-blinded, parallel group

20 F/20 M

91 ± 47 quetiapine; 26 ± 12 clozapine

Improved significantly ± UPDRS III; (p < 0.001) ↓ Dyskinesias(p