Etiology and Treatment Approach for Visual Hallucinations in PD Dementia

Visual hallucinations are a common symptom of Parkinson’s disease dementia. These can cause delusions and violent behaviors that can be significant burdens on patients and caregivers. The cause of visual hallucinations is considered to be the dysregulation of the default mode network due to the presence of Lewy bodies in the cortex and the degeneration of dopaminergic and cholinergic neurons. Dopaminergic agents, especially non-ergoline dopamine agonists, can exacerbate visual hallucinations. Reducing the dosage can ameliorate symptoms in many cases; however, this frequently worsens parkinsonism. In contrast, the administration of cholinesterase inhibitors is effective and rarely worsens motor symptoms. In advanced cases, antipsychotic drugs are required; clinical studies have shown that some drugs are beneficial while the adverse events are acceptable. An optimal treatment protocol should be selected depending on the patient’s condition. Galantamine binds to the nicotinic receptors and allosterically enhances their response to acetylcholine.


Introduction
Advanced Parkinson's disease (PD) patients often have dementia due to widespread Lewy bodies in the cerebrum [1]. Lewy bodies are inclusion bodies consisting of a protein, named alpha-synuclein [2]. In Parkinson's disease dementia (PDD), visual hallucinations (VH), defined as hallucinations accompanied by delusions, which are abnormal beliefs that are endorsed by patients as real, that persist in spite of evidence to the contrary, and that are not part of a patient's culture or subculture, are a common symptom as in dementia with Lewy bodies (DLB) [3]. VH can cause delusions and violent behavior that can be a considerable burden on patients and their caregivers [4][5][6]; therefore, optimal treatments are indispensable.
In the early stages of PD, VH are usually a simple presentation like blurred moving images [3]. Complex VH, which are consisting of well-organized unreal visual perception, appear as the disease progresses. In a study of early-stage patients within 7 years from onset, VH were found in 17% during 4-year follow-up [7]. On the other hand, the lifetime incidence was reported as 50% [8].
The main form of treatment is the adjustment of medication dosage. In many cases, a reduction of the dose of dopaminergic agents ameliorates symptoms [2]. In contrast, the administration of antidementia medications, especially cholinesterase inhibitors, is an effective alternative that can relieve VH without worsening motor symptoms [2]. However, antipsychotic agents are required for some patients [2]. In this chapter, we review previous studies on drug management to propose a clinical approach for treating VH in PDD patients.

Etiology of visual hallucinations
Visual identification of objects processes from the occipital lobes to the temporal lobes [9]. The object is recognized when this visual information is linked to memories. It is considered that this linking occurs partly in a network called the default mode network (DMN) [3,10]. The DMN is activated when a person does not focus on any task in particular [3,11]. The DMN comprises multiple parts of the brain such as the medial prefrontal cortex, precuneus, posterior cingulate cortex, inferior parietal cortex, and lateral temporal cortex (Figure 1) [12]. In contrast, the network activated by attention-demanding tasks is called the task-positive network (TPN) [3,11], which includes the lateral frontal cortex, superior parietal cortex, insula cortex, and frontal operculum cortex [12]. The TPN modulates the DMN, and it is hypothesized that overactivity of the DMN causes VH (Figure 2) [3].
Findings from a pathological study are consistent with this hypothesis. One study compared Lewy body deposits in patients with and without VH [13]. Patients with VH had more accumulation of Lewy bodies at many sites, and the most statistically significant difference was seen in the frontal cortex. Most of this area is part of the TPN, and the damage incurred by Lewy bodies can lead to the dysregulation of the DMN.
Furthermore, dopaminergic and cholinergic agents can affect VH [14]. Dopaminergic neurons and cholinergic neurons are associated with visual recognition. The prefrontal cortex and striatum receive dopaminergic stimulation and control attention and working memory [15][16][17][18][19]. The nucleus basalis of Meynert projects acetylcholine across the entire cerebral cortex [20]. These are related to the TPN; therefore, dopaminergic or cholinergic dysfunction can cause dysregulation of the DMN.
Although the pathophysiology of VH is not fully understood, it is reasonable to adjust dopaminergic agents and administer antidementia drugs to treat VH of PDD patients.

Management of dopaminergic agents
Most PDD patients with VH use dopaminergic agents (e.g., levodopa, dopamine agonists, monoamine oxidase inhibitors, catechol-O-methyltransferase inhibitors, or amantadine) to ameliorate motor symptoms. However, these drugs may exacerbate VH in patients with PDD [14]. This exacerbation is considered to be due to the overactivity of the mesolimbic system caused by an unnatural dopaminergic stimulation. Of course, other drugs, such as anticholinergics, antidepressants, and N-methyl-D-aspartate (NMDA) antagonists, can cause VH; however, these are less frequently used, and most of them have a low risk [3,14]. Thus, reducing the dose of dopaminergic agents ameliorates the symptoms of VH.
Not all patients require VH treatment since, in some mild cases, patients can understand that VH are unreal. In such cases, motor symptom treatment is prioritized; therefore, dopaminergic agents can be continued. Goetz et al. evaluated the prognosis of PD patients who have VH with insight [21]. Eighty-one percent of the patients progressed to VH without insight during 3-year follow-up (Figure 3). If VH cause delusions or violent behavior, doses of dopaminergic agents should be reduced. However, abruptly discontinuing them can cause severe rigidity and rhabdomyolysis, possibly leading to neuroleptic malignant syndrome [22,23]; thus, gradual tapering is recommended.
Among dopaminergic agents, non-ergoline dopamine agonists pose a greater risk of VH than do others [24], which have different dopamine receptor binding profiles compared with dopamine [25]. It is considered that this profile difference causes VH. Four non-ergoline dopamine agonists, pramipexole, ropinirole, rotigotine, and apomorphine, received U.S. Food and Drug Administration (FDA) approval as PD treatment agents and are globally used. In PDD patients with VH using these drugs, a reduction in the dose is recommended. In particular, slow tapering is strongly recommended to avoid dopamine agonist withdrawal syndrome [26]. This syndrome can cause miscellaneous symptoms, such as anxiety,

Brain network process of linking visual input to memories. DMN properly links visual information input to memories under regulation by TPN (A). DMN links visual information input to inappropriate memories without adequate regulation by TPN (B).
depression, irritability, fatigue, nausea, pain, and suicidal ideation [27,28]. Careful monitoring is required after reducing drug dosage, since patients can show symptoms even during slow tapering [27,29].
Reducing dopaminergic agents worsens motor symptoms in most cases. Since most PDD patients are in the advanced disease stage, worsening bradykinesia due to the drug reduction can lead to fatal complications such as pneumonia [30]. Therefore, it may be necessary to change from a high-risk drug to a relatively safe drug rather than merely reduce it (e.g., non-ergoline dopamine agonist replacement by levodopa). However, all dopaminergic agents can cause VH [3,14], and deterioration of motor functions may be unavoidable in some cases. This is a trade-off situation, and it is necessary to comprehensively consider the balance of all symptoms and adjust the optimal prescription for each patient [31].

Therapeutic drugs 4.1 Overview of therapeutic drugs
Several studies have reported the therapeutic effects of antidementia and antipsychotic drugs on VH. There are two types of globally used antidementia drugs, cholinesterase inhibitors and NMDA receptor antagonists. We reviewed key previous studies on these drugs. Cholinesterase inhibitors reduce VH and mostly do not worsen parkinsonism [32][33][34][35][36][37][38][39][40][41][42][43]. They can be used as first-line drugs. Although there is no study showing that memantine ameliorates VH sufficiently, it may improve cognitive function [44]. It can be used as an additional drug. Antipsychotic drugs should be used in a minimal dose due to high risks of mortality and adverse events [45]. However, some of them reduce VH without causing intolerable adverse events [46,47]. They should be used for cases that are difficult to control.
Hereafter, we will explain the studies on and detailed characteristics of these drugs and propose a treatment strategy.
Rivastigmine was the first cholinesterase inhibitor that showed a reduction in VH in DLB patients in a randomized controlled trial (RCT) [36]. It not only inhibits acetylcholinesterase but also suppresses butyrylcholinesterase [50]. It was suggested that this dual inhibition may be beneficial for the long-term treatment of Alzheimer's disease (AD) [51,52]. As half of the PDD patients have AD pathology [53], this pharmacological characteristic may also be preferable for PDD treatment. A large double-blind RCT suggested that rivastigmine ameliorates VH as well as cognitive function in PDD patients [39]. In this study, significant improvements in both neuropsychiatric inventory (NPI) and mini-mental state examination (MMSE) scores were observed. Although it caused a significantly high frequency of gastrointestinal adverse events, a transdermal patch is available [54], which is less likely to cause gastrointestinal events [55]. Another study compared rivastigmine effect on PDD patients with and without VH [42]. The cognitive function improvement was greater in patients with VH. These previous studies suggest rivastigmine is beneficial for PDD patients with VH.
Donepezil is a selective acetylcholinesterase inhibitor and delays the hydrolysis of acetylcholine in the brain neuronal synapses [56]. Stinton et al. performed a systematic review and meta-analysis of donepezil studies for PDD patients [32]. They compared MMSE scores between donepezil and placebo groups in four doubleblind RCTs [34,38,41,43]. Donepezil group showed better scores, but without significant difference. They found significantly better scores of NPI [38,41], which suggests a possibly beneficial effect of donepezil on VH. The most frequent adverse event was gastrointestinal symptoms [34,38,41,43]. In the largest study, 21% of the donepezil group patients experienced nausea, and the frequency was significantly higher than in the placebo group [41]. However, no discontinuation rate difference was found. Mori et al. performed a double-blind RCT of donepezil for DLB patients [35]. In this study, the experimental group had fewer VH and significant improvement of NPI. Furthermore, a positron emission tomography study showed a significant change of glucose metabolism in occipital lobes after administration of donepezil [33]. Although we need to be aware of the side effects, donepezil is a reasonable choice for VH treatment. We have summarized the RCTs of donepezil in Table 1.
Galantamine is another acetylcholinesterase inhibitor commonly used. It is also an allosteric potentiating ligand for nicotinic acetylcholine receptors [56,57]. (The pharmacological characteristics of each cholinesterase inhibitor are described in Figure 4.) We did not find a double-blind RCT for galantamine. However, a small open-label controlled trial showed significant amelioration of VH, as well as MMSE and NPI scores [37]. The drug-related adverse events were seen in 30% of the experimental group, and the most frequent one was drooling. Edwards et al. performed a 24-week open-label study on DLB patients [40]. This study suggested that galantamine ameliorates VH similar to rivastigmine and donepezil in DLB patients. Galantamine is a possible option in PDD patients with VH, based on these studies.
Cholinesterase inhibitors generally ameliorate VH without worsening motor symptoms. Each of them has a different advantage, and they should as such be selected depending on the patient's condition. Donepezil is the most clinically studied drug, and its efficacy is reliable [34,38,41,43]. Besides, the administration burden is small since it requires oral intake only once a day due to its long elimination half-life [58]. In contrast, galantamine requires oral administration twice daily [59]. However, it can ameliorate agitation and disinhibition due to its nicotinic effect [60]. The most remarkable benefit of rivastigmine is the availability of the transdermal patch [54]. It can be administered to patients who refuse oral intake.

Memantine
Memantine is an antidementia drug that blocks NMDA receptors [61]. It is approved for clinical use in North America, Latin America, Europe, the Middle East, Asia, and Oceania. Many RCTs and meta-analytic studies have demonstrated the beneficial effect of memantine in AD patients [62][63][64][65][66]. In contrast, according to a meta-analysis of three RCTs of PDD and DLB patients, no significant amelioration of cognitive function or VH was found [32,[67][68][69]. However, another metaanalysis reported a small but significant improvement in the score of clinicians' global impression of change [44]. Memantine has very few drug-related adverse events [67][68][69], and it can be used as an additional treatment for cognitive function improvement. However, findings from a case series suggested that memantine may exacerbate VH [70]. As other NMDA antagonists, such as ketamine, can cause hallucinations, memantine may have a similar effect [3]. Although the evidence suggesting exacerbation of VH is limited with most RCTs reporting no significant deterioration [67][68][69], memantine should be used with caution.

Antipsychotic agents
Antipsychotic agents compromise dopaminergic function and ameliorate psychiatric symptoms including VH. They should be used in a minimal dose owing to high risks of mortality and adverse events in these patients [45]. However, several studies have reported the beneficial effect of atypical antipsychotic agents.
A systematic review suggested that clozapine is efficacious in the treatment of psychosis in PD patients [46]. Two double-blind placebo-controlled RCTs were performed, and both studies showed significant amelioration of psychosis without worsening of motor symptoms [71,72]. One of them showed significant alleviation of VH [72]. However, in a 12-week open-label extension study of these RCTs, one withdrawal out of 108 patients due to leukocytopenia was registered [73,74]. Clozapine leukocytopenia can be fatal, and weekly blood sampling is required for several months according to each country's regulation [75]. In addition, it may cause myocarditis and hyperglycemia [76,77]. Therefore, clozapine is clinically useful but requires monitoring. Quetiapine is possibly useful for VH in PD patients, but the evidence is insufficient [46]. Five double-blind placebo-controlled RCTs were performed [78][79][80][81][82]. No significant amelioration of psychiatric symptoms was demonstrated in four studies [78][79][80][81]. However, one study showed significant improvement of the clinical global impression scale and the hallucination item of the brief psychiatric rating scale scores [82]. In addition, two RCTs compared effects of quetiapine and clozapine, and both were almost equally effective on psychosis [83,84]. No worsening of motor symptoms was seen in all of these studies. Quetiapine is possibly beneficial for PDD patients with VH. However, it should be used cautiously because it is associated with risks of arrhythmia and hyperglycemia [85,86]. We have summarized the quetiapine studies in Table 2.
Pimavanserin is a serotonin 5-HT2A agonist without dopaminergic affinity [87]. A systematic review reported it effective in the treatment of PD psychosis [46], and it is the only drug that has FDA approval for the PD psychosis treatment. A double-blind, placebo-controlled RCT showed significantly better amelioration of VH and other psychiatric symptoms compared with that in the placebo group [88]. A subgroup analysis revealed that it was also efficacious and safe for cognitively impaired patients; therefore, it may be useful for PDD patients [89]. However, ten out of 105 experimental patients discontinued the treatment due to adverse events. Six of these patients experienced psychosis. In addition, pimavanserin may prolong the QT interval, and thus, it should not be used in patients with arrhythmias [90]. Pimavanserin administration requires caution and careful monitoring for psychiatric adverse events.
Other antipsychotic agents (e.g., olanzapine, risperidone, or aripiprazole) lack evidence of the beneficial effect on VH or other psychiatric symptoms. If other antipsychotic agents, especially typical ones, are required, they should be administered for as short a period as possible.

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Treatment strategy
In mild cases, the administration of cholinesterase inhibitors is the first option. When VH are troublesome, modification of dopaminergic agent is recommended. If VH are not controlled by dopaminergic agent modification and cholinesterase inhibitors, antipsychotic agents are recommended. We propose a treatment plan in light of these findings (Figure 5). The optimal treatment will be different for each patient and should be selected depending on the patient's condition.

Conclusion
VH are a frequent symptom in PDD. The lifetime incidence was reported as 50% [8]. VH can cause delusions and violent behavior that can be a considerable burden on patients and their caregivers [4][5][6]; therefore, optimal treatments are indispensable. The cause of VH is hypothesized to be linked to the overactivity of the DMN [3]. Dopaminergic or cholinergic dysfunction is associated with dysregulation of the DMN. It is reasonable to adjust dopaminergic agents and administer antidementia drugs to treat the VH of PDD patients.
Reducing dopaminergic drug dosage can ameliorate symptoms [2]. However, this frequently worsens motor symptoms. The administration of cholinesterase inhibitors is effective and rarely worsens parkinsonism [2].
Antipsychotic agents should be used in a minimal dose because of adverse events [45]. However, several studies have reported that clozapine and pimavanserin can ameliorate VH without worsening motor symptoms [46]. Although there is not sufficient evidence, quetiapine is possibly useful too [46].
An optimal treatment plan should be selected depending on the patient's condition.

Conflict of interest
The authors declare no conflict of interest.
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