Hallucinations in Neurodegenerative Diseases

SUMMARY

Patients with neurodegenerative disease frequently experience hallucinations and illusionary perceptions. As early symptoms, hallucinations may even have diagnostic relevance (i.e., for the diagnosis of Lewy Body Dementia). In the later course of the disease, hallucinations may appear as characteristic symptoms and often constitute a particular challenge for therapeutic endeavors. Here, the distinction of disease‐inherent hallucinations from medication‐associated perceptual disturbances is particularly relevant.
Synucleinopathies and tauopathies have different risk profiles for hallucinations. In synucleinopathies hallucinations are much more frequent and phenomenology is characterized by visual, short‐lived hallucinations, with insight preserved for a long time. A “double hit” theory proposes that dysfunctionality of both associative visual areas and changes of limbic areas or the ventral striatum are required. In contrast, in tauopathies the hallucinations are more rare and mostly embedded in confusional states with agitation and with poorly defined or rapidly changing paranoia. The occurrence of hallucinations has even been proposed as an exclusion criterion for tauopathies with Parkinsonian features such as progressive supranuclear palsy. To date, treatment remains largely empirical, except the use of clozapine and cholinesterase inhibitors in synucleinopathies, which is evidence‐based. The risk of increased neuroleptic sensitivity further restricts the treatment options in patients with Lewy Body Dementia. Coping Strategies and improvement of visual acuity and sleep quality may be useful therapeutic complements.

Introduction

Hallucinations and illusionary perceptions frequently occur in different neurodegenerative diseases [1]. While illusionary perceptions result from a false interpretation of existing stimuli, hallucinations are perceptions of various sensory qualities without a correlating stimulus. As early symptoms, their diagnostic relevance is often unclear. In the later course of many neurodegenerative diseases, hallucinations frequently appear as characteristic symptoms, which make them an important focus of therapeutic endeavors. In this respect, the distinction of disease‐inherent hallucinations from medication‐associated perceptual disturbances is highly relevant. This review deals with hallucinations in common neurodegenerative diseases and the diagnostic and therapeutic challenges posed thereby. We will focus on synculeinopathies and tauopathies as these different pathophysiological entities mostly have different clinical presentations. Thus, hallucinations in synucleinopathies are much more frequent than in tauopathies [2]. The reasons for this remain only partially understood. Different disease propagation routes may be one explanation [3].

Although the abnormal accumulation of tau or alpha‐synuclein is the underlying feature for a classification scheme, there is evidence to suggest numerous overlappings and interacting mechanisms. Synuclein is a soluble protein and the gene has been mapped to chromosome 4 [4]. The synuclein family consists of four members, alpha synuclein, beta synuclein, gamma synuclein, and synoretin. Aggregated alpha synuclein is a key component of Lewy bodies [5]. Non aggregated alpha‐synuclein is localized primarily in synaptic terminals as a structural protein. In MSA, aggregated alpha‐synuclein is also a component of glial cytoplasmatic inclusions [6].

In contrast, tauopathies are marked by aggregates of protein tau, a microtubule‐associated protein involved in axonal transport. Phosphorylated tau proteins constitute neurofibrillary tangles, which define AD along with amyloid plaques. Six different isoforms of tau are known to be expressed in the human brain and they differ with respect to the number of tandem repeats in the microtubule binding region [7]. The ratio of three‐repeat tau to four‐repeat‐tau is equal in the normal brain and in AD, whereas this ratio is altered in many of the other tauopathies [8].

This essay reviews, disease by disease, prevalence, incidence, and pathogenetic concepts. Treatment options will be discussed, and if available, evidence‐based or at least expert‐opinion‐based therapeutic guidelines are presented.

Synucleinopathies

Hallucinations in Parkinson's Disease

Clinical Phenomenology and Diagnosis

Published data on prevalence of delusions and hallucinations in Parkinson's disease (PD) vary in prospective cross‐sectional studies of clinic‐based samples from 22% to 38%. In community‐based patient samples, the figures are somewhat lower (16–23%). If minor forms of hallucinations (passage hallucination and sense of presence) are considered in clinical samples, the prevalence of such phenomena increases to 40–75%[1, 9]. Longitudinal studies reveal that the point prevalence of visual hallucinations (VH) in PD increases over time, reaching 74% in a 20‐year follow‐up period.

Patients suffering from PD may present with different forms of hallucinations, the most frequent manifestation being VH in later disease stages. This primary form needs to be distinguished from hallucinations as part of a delirium, the latter often accompanied by reduced vigilance, agitation, and myoclonus. In the absence of other metabolic, toxic or inflammatory causes, delirium may be a side‐effect of medication. Dry skin, urinary retention and mydriasis suggest anticholinergic agents as possible triggers [10]. In tandem with impaired orientation, hallucinations may occur after surgical interventions, particularly when patients receive analgesic medication. Finally, hallucinations in PD patients may be a manifestation of a cooccurring—altogether different—disease.

In PD patients, VH and illusions are much more common than auditory, olfactory and tactile hallucinations. The most frequent and typical form of hallucinations in PD, often taking a chronic and repetitive course, occurs in otherwise stable patients who have been on dopaminergic treatment for years. Diagnostic criteria according to Ravina et al. [11] are listed in Table 1. VH of people and animals are predominant. They vary in intensity and are often of short duration [12, 13]. These hallucinations frequently occur in the evenings or at night [9], with darkness or reduced vigilance increasing vulnerability. As a result of the repetitive and stereotypical character of these hallucinations, habituation is fairly common. Visual illusions are also frequent, although differentiating them from hallucinations is often difficult [14]. In many cases, humans or animals are perceived within inanimate objects, e.g., a flower is mistakenly perceived as a face. So‐called passage hallucinations are brief perceptions of animals or people in the peripheral visual field. The terms presence hallucinations or extracampine hallucinations subsume the feeling of another person being present mostly on the side or behind [9]. Auditory hallucinations may range from acoasms (i.e., simple sounds like ringing or knocking) to complex scenic perceptions [9, 15]. Tactile and olfactory hallucinations are rare, the former taking the form of bodily contact with an animal or person [16], the latter being related to the distorted sense of smell [15]. In general, nonvisual hallucinations seldom occur exclusively but rather in connection with VH as “mixed” hallucinations [17]. Independent of disease duration, “mixed” hallucinations are more frequent in elderly patients, which suggests aging‐associated pathomechanisms to be a relevant factor [18]. Patients unable to maintain intellectual and/or emotional distance to hallucinations may be difficult to handle, particularly if they feel threatened and thus prompted to seek action. Such complications are more frequent in later disease stages, with cognitive impairment being more common and severe, and subsequent limitations in the ability to form rational judgments [9, 12]. Delusions and other psychotic symptoms may secondarily complicate VH. This unfavorable development seems to affect preferably patients with an early disease onset and may manifest in acts of suspicion and jealousy [19]. Patients often do not spontaneously confess their hallucinations [20]. Much like motor deficits, VH have a crucial impact on quality of life in PD, and are often responsible for patients to be hospitalized or referred to nursing homes [21, 22, 23].

Table 1.

Criteria for psychosis in Parkinson's disease [5]

At least one of the following symptoms should be present

‐ Illusions

‐ False sense of presence

‐ Hallucinations

‐ Delusions

Symptoms occur after the onset of Parkinson disease

Symptoms are recurrent or continuous for at least 1 month

No triggering psychiatric or general medical condition (for example fever, infection or following surgery)

Associated with or without

‐ Insight

‐ Dementia

‐ Specific Parkinson's disease medication

A variety of questionnaires and inventories have been used for rating hallucinations, however, most are not validated and there is no gold standard. It remains to be seen whether the new version of the Unified Parkinson's Disease Rating Scale (Table 2, [24]) provides more uniformity in diagnostics and documentation of hallucinations.

Table 2.

Questions on hallucinations in the new UPDRS questionnaire [18]

Instructions to examiner: Consider both illusions (misinterpretations of real stimuli) and hallucinations (spontaneous false sensations). Consider all major sensory domains (visual, auditory, tactile, olfactory and gustatory). Determine presence of unformed (for example, sense of presence or fleeting false impressions) as well as formed (fully developed and detailed) sensations. Rate the patients’ insight into hallucinations and identify delusions and psychotic thinking

Section 1.2 Hallucinations and psychosis

Instructions to patients (and caregivers): Over the past week have you seen, heard, smelled or felt things that were not really there? (If yes, examiner asks patient or caregiver to elaborate and probes for information)

0. Normal. No hallucinations or psychotic behavior

1. Slight: Illusions or nonformed hallucinations, but patient recognizes them without loss of insight

2. Mild: Formed hallucinations independent of environmental stimuli, no loss of insight

3. Moderate: Formed hallucinations with loss of insight

4. Severe: Patient has delusions or paranoia

Pathogenesis

Medication

Since hallucinations occur frequently under dopaminergic medication, it was first assumed‐ and maintained for a long time‐ that they are a medication‐induced symptom (“levodopa psychosis”). Within a pharmacological kindling model, chronic dopaminergic hyperstimulation leads to increased sensitivity of mesolimbic dopamine receptors [25]. In conjunction with a disease‐related reduction of presynaptic storage capacity, hypersensitive dopamine receptors are flooded with dopamine. However, in the absence of a correlation between the absolute amount of medication intake and the presence of hallucinations, it is impossible to predict a threshold which when exceeded makes hallucinations more likely to occur [25]. There is also no difference in the absolute amount of dosages between patients suffering from hallucinations or not. Interestingly, VH do not occur after intravenous challenge [26]. Anticholinergic therapy is known to cause hallucinations often accompanied by impaired vigilance [10]. Indeed, it has been suggested that when cortical acetylcholine levels are reduced, irrelevant intrinsic or extrinsic information, normally processed in parallel at a subconscious level, may enter conscious awareness in the form of hallucinations [27].

Cognition and Visuospatial Abilities

Cognitive deficits and visual impairment have been identified as pathophysiologically relevant [28]. Several lines of evidence suggest that peripheral ocular and retinal dysfunction, as well as central dysfunction of visual processing can facilitate VH in PD. PD patients show progressive deficits in color discrimination and contrast sensitivity, and in patients with VH these deficits are significantly worse than in patients without VH [29]. PD patients with VH are significantly slower in image recognition than both PD patients without VH or healthy controls. There is also evidence for decreased sustained attention [30] and deficient complex visual reality monitoring [31], both with potential triggering impact on VH. Thus in the visual object and space perception battery (VOSP), PD patients with VH perform less well on silhouette identification than PD patients without VH (silhouette agnosia). This deficit may induce compensatory but aberrant release of previously stored schemas being played out in the form of internal images.

Accompanying eye conditions may also be relevant for the pathogenesis of hallucinations in PD [31, 32]. This led to the postulation of mechanisms similar to those at work in Charles Bonnet Syndrome, which is characterized by VH in elderly patients suffering from different types of visual impairment or visual loss [33].

Another relevant risk factor for hallucinations in PD patients is dementia; vice versa, in patients suffering from hallucinations compared to patients without hallucinations earlier onset of cognitive decline was observed [34]. In nondemented PD patients reduced semantic fluency and deficient “source monitoring” have been identified as further risk factors for VH [34].

REM Sleep Behavior Disorder

Disturbed sleep‐wake rhythm and vivid dreams are frequently described by patients and often precede hallucinations, A prospective study demonstrated at most co‐occurrence of these symptoms with hallucinations but no prognostic power [35]. However, the risk for hallucinations increased in the presence of REM sleep behavior disorder (RBD) [28, 36, 37]. On the other hand, polysomnography in patients with hallucinations often reveals increased incidence of RBD [38]. Accordingly, it could be a phenomenon characterized by intrusions of REM sleep fragments into phases of wakefulness [38, 39], a hypothesis supported by studies investigating dopamine‐induced sleep‐wake cycle disturbances [40, 41, 42].

Imaging and Neuropathology

An elegant recent hypothesis proposes that a “double hit” is required for hallucinations in synucleinopathies: first, dysfunctionality of visual associative areas and, second changes of the limbic areas and the ventral striatum [23]. In patients with advanced PD or other synuceinopathies neuroradiological findings argue for a dysfunctionality of visual associative areas by showing selective reductions in gray matter volume of the lingual gyrus or Brodmann area 18 and the superior parietal lobe [43]. The involvement of other visual association areas has been shown by SPECT studies. Hypoperfusion in the fusiform gyrus and hyperperfusion in the right superior and middle temporal gyri were observed in patients with PD and VHs [44]. Concerning the second hit, the involvement of limbic areas and the ventral striatum is evidenced by both neuropathological and functional neuroimaging studies. Thinning of the retinal nerve fiber layers, visualized by optic coherence tomography has been demonstrated in patients suffering from VH thus also implicating progressive retinopathy in VH [45, 46]. Autopsy studies conducted on patients with VHs and PD showed an increased alphaSyn burden in the amygdala [47]. Studies with patients with VHs and DLB revealed increased muscarinic binding in Brodmann Area 35, which includes the posterior hippocampal formation, the parahippocampal gyrus and the lingual and fusiform gyri as well as high densities of Lewy bodies in the parahippocampal gyrus and amygdala [3, 48]. Finally, involvement of the frontal lobes in VHs in PD has been shown in a PET study, which revealed frontal hypermetabolism in patients with PD and VHs.

Animal Model of Psychotic‐Like Behavior

Evidently, animal models of psychosis have shortcomings, as they cannot reproduce the eminently subjective nature of psychotic behavior in humans. Despite these restrictions, such models may nevertheless be useful for developing novel therapeutic strategies prior to clinical studies. We are aware of only one research group led by S.H. Fox who has explored in much detail the potential usefulness of such a model [49, 50]. Marmosets lesioned by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) show abnormal psychotomimetic behaviors when treated with levodopa [51]. These behaviors can be classified into four categories: agitation, hallucinatory‐like behaviors, obsessive activity, and stereotype and can also be quantified by a rating score. More precisely the subcategory of hallucinatory‐like responses is reflected by “tracking” movements (following nonapparent stimuli for more than 10 sec) or by a “staring” attitude (the heads still or looking in one direction for extended periods) [51]. The authors found that the pharmacology of psychosis‐like behaviors in the marmoset recapitulated the pharmacology of psychosis in human PD. For instance, these behaviors were elucitated by levodopa, dopamine agonists, amantadine and reduced by atypical neuroleptics [50, 51]. Surprisingly, these behaviors were already present on day 1 of levodopa treatment and their severity did not correlate with duration of treatment [49]. The authors proposed that these findings more likely are due to an interaction between levodopa and the disease state than a consequence to sensitization to repeated dopaminergic therapy.

Treatment Strategies

It is important to first check the diagnosis so that one does not overlook an atypical Parkinsonian syndrome or another coinciding neurodegenerative disease. The search for metabolic, drug or infection‐associated causes should be mandatory [1].

Mild symptoms may be managed without specific medication encouraging the utilization of coping strategies (see Table 3) [52]. The importance of regular sleep should be pointed out to the patients. It may be helpful to leave a light on at night in order to avoid visual misinterpretations in complete darkness. If necessary, visual acuity deficits should be corrected with new glasses etc. If medication is to be reduced, drugs with the least specific effect on the disorder and the highest potential for VH, that is, anticholinergics, amantadine, and selegeline should be reduced or withdrawn first. If these steps prove insufficient, further options are either to reduce specific medication such as dopamine agonists and L‐dopa, or to initiate antipsychotic treatment. No general guidelines exist, however, thus it remains an individual decision based on balancing the severity of psychiatric versus motor symptoms and the resulting medical and psychosocial consequences. With respect to long‐term outcome, there is some evidence in favor of an early intervention with antipsychotic medication in cases of mild hallucinations [45].

Table 3.

Coping strategies for patients with Parkinson's disease and hallucinations [43]

Visual techniques

‐ Looking in another direction.

‐ Looking at another object.

‐ Focusing on the object in question more precisely.

‐ Approaching or trying to touch the hallucinations.

Cognitive techniques

‐ Patient convincing himself/herself mentally of the nonreality of the phenomenon.

‐ Waiting for the natural disappearance of the hallucinations.

‐ Turning on the light during the night.

Interactive techniques

‐ Speaking to the spouse or caregiver in order to check the nonreality of the phenomenon, to get comfort or without a specific goal.

Because of their side‐effect profile including motor disturbances, first‐generation antipsychotic drugs are obsolete. Second‐generation antipsychotics are widely used, yet efficacy has only been demonstrated for clozapine [46], with response rates of more than 80%. Clozapine does not affect the nigrostriatal neurons but preferentially interacts with the mesolimbic system. Treatment should be initiated with 6.25 to 12.5 mgs per day, and dosage may be increased by 12.5 mgs every 4 to 7 days [1]. One third of the daily dose should be given in the morning, two thirds in the evening with a maximum of 75–100 mgs per day. In‐patient settings often allow for faster increase and higher overall dosages, which may be necessary for more severely affected patients [46]. Relevant side‐effects of clozapine include sedation and orthostatic hypotension, often requiring dose reduction or smaller increments when increasing dosages. Because of the risk for agranulocytosis, clozapine‐treated patients need regular hemograms. Additional side effects as hypersalivation, influences on the immune system or a higher risk for seizures have to be considered. Effects of clozapine are usually stable and lasting. There are no sufficient data to answer the question if and when therapy may be terminated; however, this seems to be associated with an increased risk of symptom reoccurrence.

Quetiapine is also widely used against hallucinations in PD patients. However, two double‐blind randomized trials demonstrated no efficacy of the drug [53, 54] in contrast to several open‐label studies. Nevertheless, quetiapine is used in everyday clinical management. Possibly the potentially favorable effect of quetiapine is due more to its sleep promoting effect than to a specific antipsychotic effect. Therapy is usually initiated with a dosage of 12.5 to 25 mgs at night. Daily dosage may be increased by 25 mgs every third day up to a maximum daily dose of 100 to 125 mgs. If there is no significant effect, clinicians should not hesitate to initiate treatment with clozapine.

The efficacy of cholinesterase inhibitors is intriguing [55]. While the effect on cognition in PD/LBD is modest, VH have been abated in several studies [56, 57, 58]. These beneficial effects are not related to cognitive improvement, but have to be attributed to a direct effect on cholinergic activity. As mentioned above cortical cholinergic dysfunction may play a key role in the pathogenesis of hallucinations. Interestingly, hallucinations were also reported in PD in the prelevodopa era, with exclusive anticholinergic treatment.

Hallucinations in Dementia with Lewy Bodies

Clinical Phenomenology and Diagnosis

Next to AD, DLB is the second most frequent degenerative dementia in patients over 65 years [59, 60]. The presence of Lewy bodies (LB) does not itself necessarily imply a diagnosis of DLB since LB are also found in other forms of dementia as well as in healthy elderly individuals. The definite diagnosis can only be made post mortem on the basis of a neuropathological assessment. Phenomenologically, DLB is characterized by a mixed cortical and subcortical dementia with predominant deficits concerning attention, visuoconstruction and executive functions, varying in intensity. Parkinsonism usually occurs within 1 year before or after the onset of dementia. Diagnostic criteria [61] are listed in Table 5. Early VH are often responsible for suspecting DLB, as they occur in 60–80% of cases in early disease stages. Similarly to PD, hallucinations in DLB are of scenic character, rich in detail, recurrent including animals, people or schematic figures at walls [62, 63]. In contrast to PD patients, DLB patients may be more frequently affectively involved in their hallucinatory experience, thus being afraid of what they see, interacting and talking with their perceptions or trying to beat them [64].

Table 5.

Special features and treatment strategies for hallucinations in common neurodegenerative disease

	Synucleinopathies		Tauopathies
	PD	DLB	AD	FTD MSA PSP CBD
Most common clinical presentation	Visual hallucinations and visual delusions in later course of disease under dopaminergic treatment	Visual hallucinations in early stages of disease	Visual, paranoid delusions, and hallucinations	Overall rare, symptoms in less than 10% of patients
		Detailed and scenic hallucinations		Visual hallucinations and delusions
Treatment	Reduction of dopaminergic drugs	Cholinesterase‐inhibitors	second‐generation antipsychotics (risperidone, olanzapine, quetiapine, aripripazol)	second‐generation antipsychotics?
	clozapine id: 6.25–12.5 mg/d md: 75–100 mg/d	rivastigmine id: 2 × 1.5 mg/d md: 6–12 mg/d
	quetiapine id: 12.5–25 mg/d md: 100–125 mg/d	donepezil id: 5 mg/d md: 10 mg/d
		Cave: hypersensitivity to neuroleptic drugs
		second‐generation antipsychotics in lowest dosage quetiapine id 12.5 mg, clozapine id 6.25 mg
	coping strategies (Table 3)

PD, Parkinson's disease; DLB, Dementia with Lewy Bodies; AD, Alzheimer's disease; FTD, Frontotemporal Dementia; MSA, Multiple system atrophy; PSP, Progressive supranuclear palsy; CBD, Corticobasal degeneration; id, initial dose, md, maximum dose.

To allow for a clinical distinction between PD and DLB, a rather arbitrary temporal criterion, lacking a proper clinical or pathophysiological basis, was introduced: If dementia manifests within 1 year before or after the onset of the Parkinsonian syndrome, DLB is considered. In contrast, motor symptoms precede dementia by more than 12 months, a diagnosis of PD is preferred. However, some authors propose that there is indeed a continuum between PD, PD with dementia, and DLB [65]. On the other hand, the clinical distinction between AD and DLB is straightforward since in AD motor symptoms are, at the most, rather subtle and hallucinations are rare occurring only late in the course of the disease [66]. Among the delusional misidentification syndromes occurring in DLB patients [67], the Capgras syndrome is the most stressful one for the patient and his spouse, as the patient takes the spouse for a double and insults her/him as such. The sense of familiarity for the spouse's face has been lost.

Pathogenesis

LB are eosinophilic inclusion bodies, initially described in the nucleus basalis of Meynert and the nucleus dorsalis nervi vagi. Later, they were also found in numerous other cerebral areas such as the substantia nigra and the cortex. LB contain misconfigured aggregates of alpha synuclein protein. They have predominant intracellular but also neuritic localization [62]. Typical characteristics of DLB are a marked dopaminergic deficit as well as prominent cortical cholinergic deafferentiation [68].

Neuropathological research has confirmed an association between the presence of temporal lobe LB and VH, particularly if LB density is high in the inferior temporal lobe, amygdala and parahippocampus [3, 69]. Additionally, a relation exists between reduced temporal lobe cholinacetyltransferase (ChAT) activity and frequency of hallucinations [70].

Reduced metabolic activity in the primary and secondary visual cortex has been observed in functional imaging studies [48, 68]. On the other hand, areas relevant for the perception of faces show increased neural activity when faces are being hallucinated [71, 72].

The visuoperceptual dysfunction of DLB patients with VH has been found to be more pronounced than in those patients without hallucinations [64, 73]. In addition, low doses of L‐dopa or dopamine agonists trigger or increase symptoms [74]. In conclusion the “double hit” hypothesis for VH, presented above for PD patients, applies also to DLB patients as it requires involvement of the extrastriatal visual cortex and limbic or temporal areas.

Treatment Strategies

While anticholinergic drugs should be avoided altogether, dopaminergic agents should be given in a as low dosage as possible, and dosages should be increased slowly and cautiously [75] as DLB patients are particularly sensitive to VH triggered by dopaminergic medication.

With regard to potentially occurring hypersensitivity reactions to neuroleptics, these drugs must be used with great caution and with close monitoring of the patient. Neuroleptic hypersensitivity is tied to a blockade of dopamine D2 receptors by these agents and manifests as an acute exacerbation of motor symptoms in conjunction with reduced vigilance or even coma. Morbidity and mortality rates are high, with first‐generation antipsychotics in high dosages being most side effect‐prone [76]. Thus it is strongly recommended to use only second‐generation antipsychotic agents such as clozapine and quetiapine [77, 78] in the lowest dosages possible, for example, 6.25 mgs of clozapine or 12.5 mgs of quetiapine.

Cholinergic treatment usually improves patients’ condition with respect to frequency and intensity of VH. The good response of DLB patients to cholinergic therapy [79] can at least in part be explained by the fact that ChAT activity is even lower in DLB than in AD [48, 80, 81]. Cholinergic treatment results in a reduced frequency and intensity of VH and the reduction of cognitive deficits, predominantly through improved attention [82].

Notably, to date no controlled trials on the treatment of psychotic symptoms in DLB exist, which makes the choice of drug a highly individual decision. A prerequisite when using antipsychotics in DLB is, however, an extensive information of the patient about a potentially occurring hypersensitivity reaction and intense monitoring particularly at the beginning of therapy.

Tauopathies

Hallucinations in Alzheimer's Disease

Clinical Phenomenology and Diagnosis

Psychotic symptoms such as delusions and hallucinations also manifest frequently in patients with AD. The prevalence for delusions in AD ranges from 10 to 73% and for hallucinations from 21 to 49% within clinic populations and from 7 to 20% in community and clinical trials [83]. The overall incidence of onset of psychotic symptoms over a 3‐year‐period is estimated to be between 16% and 50%[84, 85, 86]. The large variety of estimations about prevalence and incidence is likely to be due to different ways in which delusions, hallucinations, and AD were diagnosed in the different studies and the resulting heterogenous study populations.

The most common hallucinations are visual (prevalence 4–59%), but auditory (1–29%), somatic, olfactory and tactile hallucinations (0.4–8%) are also reported [83].

Delusions in AD are typically of paranoid character, nonbizarre and simple. Misidentification phenomena are very common in AD. Persecutory delusions are frequently found, with delusions of theft most common [87], the occurrence of which was described with up to 28%. Typical other contents of delusions include delusional beliefs of other people stealing (27.5%), delusions that oneself is in danger (15.4%), the house is not the patient's home (5.5%), family plans to abandon him/her (4.4%), the spouse is having an affair (2.2%), an unwelcome guest is living in the house (2.2%), and media are in the house (2.2%).

The occurrence of delusions or hallucinations is reported to be related to aggressive behaviour [88, 89, 90, 91], increased wandering and purposeless activity [92], falls [90], socially inappropriate behavior [93], and worse general health [90]. They present a relevant prognostic and outcome‐associated factor [87, 94]. Hallucinations and delusions strongly contribute to early institutionalization [95], the reduction of the patients’ well‐being and increased burden for the caregiver in managing the patient. However, there is no indication for higher mortality of AD patients with psychosis [96, 97].

Delusions and hallucinations in AD patients may be assessed with good reliability and validity [83] utilizing different instruments, however, only two of them—the Columbia University Scale of Psychopathology in AD [98] and the Behavioral Rating Scale for Dementia of the Consortium to Establish a Registry for AD [99]—are especially developed for AD. For diagnostic criteria of identifying psychosis in AD see Table 4.

Table 4.

Provisional criteria for identifying psychosis in AD [140, 141]

‐ Possible or probable AD.

‐ Onset of psychotic signs and symptoms after onset of other dementia symptoms.

‐ Symptoms present at least intermittently for at least 1 month.

‐ Symptoms severe enough to cause disruption in patient's functioning.

‐ Does not occur only during a delirium.

‐ Not better accounted for by another psychotic disorder, a medical condition, effects of a drug.

‐ Associated features such as agitation, negative symptoms, or depression should be identified.

Pathogenesis

Patients with hallucinations/delusions show more severe cognitive deficits than those without [100]. They fare worse in neuropsychological tests (e.g., MMSE, Mattis Dementia Rating Scale) and display deficient verbal fluency. Neuroimaging studies suggest that AD‐associated psychosis is related to regional brain dysfunction. A fluorodesoxyglucose positron emission tomography study found that psychotic symptoms in AD were correlated with hypometabolism in the right frontal cortex [101]. Converging evidence was found in SPECT perfusion studies showing frontal hypoperfusion [102].

Histopathological studies reported structural changes in AD with particular predilection for mesial temporal limbic structures, that is, areas that have been associated with the presence of delusions and hallucinations in other organic psychotic disorders (see DLB above and [103, 104]). AD patients with psychosis also have a 2.3‐fold greater density of neocortical neurofibrillary tangles than AD patients without psychosis [105]. Histopathological studies also argued for a cholinergic/serotonergic imbalance as one cause of hallucinations or delusions in AD [106]. With regard to neurotransmitter changes reduction of the cholinacetyltransferase/serotonin ratio correlates with the intensity and frequency of hallucinations or delusions and there is also a reduction of 5‐HT6‐receptor level [107]. While there is no clear association with the presence of Apolipoprotein E4 allele, carriers of the DRD1 (Dopamine receptor D1) genetic polymorphisms as well as those with the long allele of 5‐HTTLPR, a serotonin‐transporter‐linked promotor region, may have a higher risk for psychosis [108, 109].

Treatment Strategies

In general, the treatment strategies described for synucleinopathies also apply to tauopathies. However, there are no FDA‐approved antipsychotic drugs for the specific treatment of hallucinations or delusions in AD. The use of second‐generation atypical neuroleptics is usually favored due to their relative safety. International geriatric associations also recommend only second‐generation antipsychotics as appropriate pharmacological agents to treat psychotic symptoms in AD. However, recent FDA warnings regarding the cardiac, metabolic, cerebrovascular and mortality risks associated with these drugs in elderly patients with dementia have raised serious concerns [110]. The best evidence for efficacy exists for the second‐generation antipsychotics risperidone and olanzapine although their effects are moderate [111]. There is additional evidence for modest effects of quetiapine [112] or aripirazole. A recent large multicentric, double‐blind placebo‐controlled trial [113] confirmed the superiority of risperidone and olanzapine compared to quetiapine. For ziprasidone and clozapine there are no controlled trials investigating the management of psychosis in AD. Interestingly, an association of the serotonin (5‐HT) receptor 5‐HT2a 102T/C polymorphism and response to antipsychotic treatment has been reported [114]: the T allele was related to both increased presence of delusional symptoms and treatment‐resistance to second generation antipsychotic drugs. Future developments in pharmacogenetics and pharmacogenomics may help to find individually tailored treatment approaches. The use of anticholinergic medication (e.g., for urinary tract infection) can trigger the development of psychosis in AD. Other expert opinion‐based treatment options include mood stabilizers or benzodiazepines. Several studies favor a benefit of cholinesterase Inhibitors in reducing neuropsychiatric symptoms including delusions and VH in AD as well as in DLB [115]. To a certain extent clinical observations suggest a differential effectiveness of ChE‐Inhibitors in AD and DLB, which could be due to the fact that VH occur late in AD when ChE‐inhibitors are no longer effective but early in DLB. In this context further studies are still missing. There is also no clear evidence for the prevention of VH in later courses of the disease if treatment with CHE‐inhibitors is started early [115].

Finally, nonpharmacological interventions may be attempted (e.g., brightly colored rooms, surroundings with appropriate sound modulations) and the use of coping strategies (see Table 3) should be considered as recommended by guidelines of national and international neurological associations.

Hallucinations in Frontotemporal Dementia

Clinical Phenomenology and Diagnosis

Frontotemporal lobar degeneration (FTLD) is divided in three subtypes, that is, frontotemporal dementia, semantic dementia, and progressive nonfluent aphasia. It is mainly characterized by a gradual and progressive change in behavior, personality and social conduct, while instrumental functions of perception, spatial skills, praxis, and memory are relatively well preserved. In the further course of the disease additional symptoms are impairment of executive dysfunction and language performance. Delusions and hallucinations are not part of the diagnostic criteria for FTD. Rather they are rare symptoms [116, 117, 118, 119] and their presence may even be used to differentiate FTD from DLB. However, the lack of insight that occurs in FTD may prevent the patients from recognizing hallucinations as being hallucinations so the estimated number of cases may be higher. Rare cases of De Clerambault's syndrome, also known as erotomania in FTD, have been described [120].

Pathogenesis

The main hypothesis for behavioral changes in FTD is based on a serotonergic deficit, which could be demonstrated in post mortem analyses, PET and cerebrospinal fluid [121, 122, 123, 124]. The decline of cerebral serotonin levels is associated with aggressive behavior, impulsivity, and depression [125]. In contrast, cholinergic neurotransmission remains unaffected and the Nucleus basalis Meynert does not show relevant involvement [121, 123].

Histopathological findings in FTD display a certain selectivity of neurodegeneration in supragranular layers of the temporal lobe. This may release the infragranular layers from some kind of inhibitory or regulatory control. Without these control projections originating from infragranular layers of the temporal lobes may activate association cortices in an unfavorable manner and cause hallucinations. However, as explained above, this is rarely the case.

Treatment Strategies

There is no established treatment for hallucinations/delusions in FTD‐patients. The decline of serotonin in FTD led to serotonergic therapy strategies with controversial results [126, 127, 128, 129] in open‐label or double‐blind controlled studies. The most robust findings have been reported for trazodone, with a significant improvement of behavioral symptoms such as irritability, agitation, depressive symptoms, and eating disorders. In a meta‐analysis trazodone and in second‐line SSRI are suggested to be effective in improving behavioral symptomes in FTD [130].

Because of the normal cholinergic neurotransmission there is no pathophysiological background for the use of cholinergic drugs in FTD. Therefore in case of hallucinations or psychotic symptoms FTD patients may be treated with typical or atypical neuroleptic drugs. Quetiapine seems to be an appropriate drug and a dose up to 300 mg per day is recommended [131]. Olanzapine was tested in an open study [132] and case reports about using risperidone [133] as well as aripripazole [134] have been published. None of the studies, however, reached a high level of evidence and at present firm treatment recommendations are not possible.

Hallucinations in Progressive Supranuclear Palsy and Corticobasal Degeneration

Clinical Phenomenology and Diagnosis

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are related medical conditions with Parkinsonism as one of their typical features. Both diseases have individual pathological hallmarks and autopsy is necessary for definite diagnosis. Clinical signs such as vertical supranuclear gaze palsy, prominent postural instability, falls in the first year of onset, and disease onset at age over 40 years provide the diagnosis of PSP [135]. Chronic aggressive course, asymmetric onset, the presence of higher cortical dysfunction (apraxia, cortical sensory loss, alien limb), limb or reflex dystonia, focal myoclonus, rest tremor, and severe automatic disturbances are typical clinical signs of CBD. Overall hallucinations are a rare symptom in PSP and CBD. However, if reported, VH predominate. Questionnaire‐based studies found hallucinations in 5–13% in PSP and in 5–21% in CBD [136, 137, 138]. This was echoed by two autopsy‐based studies with retrospective chart review where the prevalence was 7% for PSP and 0% for CBD [2].

Pathogenesis

PSP and CBD belong to the family of tauopathies, distinguishing them from synucleinopathies, like PD. Clinical reports have proposed that VH as well as REM sleep behavior disorder (RBD) may thus be indicative for underlying synucleinopathy [139, 140, 141, 142, 143]. However, as mentioned above, both symptoms also rarely occur in tauopathies. Thus disease localization, more than disease type, may trigger the occurrence of hallucinations or delusions [136].

Treatment Strategies

Today there is no established treatment for hallucinations in PSP or CBD patients and, if necessary, the same treatment strategies than discussed before may be applied.

Hallucinations in Multiple System Atrophy

Clinical Phenomenology and Diagnosis

Multiple system atrophy (MSA) is a sporadic and rapidly progressive neurodegenerative disorder that presents with autonomic failure in combination with Parkinsonism (Parkinsonian type of MSA with striatonigral degeneration, MSA‐P) or cerebellar ataxia (cerebellar type of MSA with olivopontocerebellar atrophy, MSA‐C) [144]. Hallucinations are a rare condition in both MSA‐P and MSA‐C. Only a few case reports describe VH as a symptom secondary to the neuropsychological changes in MSA [145]. In one study with pathologically confirmed MSA hallucinations were found in 9.5% of the patients, with predominance of mild‐to‐moderate visual and auditory symptoms [146]. Note, however, in consensus guidelines hallucinations are even listed as exclusion criteria [147].

Pathogenesis

The presence of hallucinatory symptoms in MSA has not been systematically studied. Factors that may account for the differences in the frequency and characteristics of hallucinations in MSA compared to PD may be decreased survival of MSA patients, early discontinuation of dopaminergic therapy due to loss of efficacy and different predominant disease localization [146].

Treatment Strategies

Second‐generation antipsychotics may be used, yet efficacy has not been studied.

Conclusion

Hallucinations are a common symptom in many neurodegenerative diseases and may impose severe problems both for caregivers and patients. Etiological misdiagnosis may lead to false therapeutic decisions [148]. For example, in case of DLB, the choice of an antipsychotic drug may induce a sometimes even fatal hypersensitivity reaction.

In Table 5 we summarize special features of the different conditions. Although the prevalence of hallucinations in PSP, CBD, FTD, and MSA is lower than in most reports on PD and DLB, symptoms are frequent enough to be considered within the clinical repertoire of the diseases.

Numerous factors (cognitive impairment, speech disturbances, etc.) may complicate the diagnosis of hallucinations and delusions in patients with neurodegenerative diseases. Written questionnaires are helpful and caregivers should be invited to participate in the completion of the questionnaire.

Although there is no evidence for the utilization of coping strategies (Table 3, [52]) in all different neurodegenerative diseases, it is an easy and noninvasive tool, worth to be applied.

Author Contributions

The first and second author (L.B., C.E.) contributed equally to this work and were responsible for data collection, data analysis, concept, and design. L.T., G.R.F., and N.J.D. contributed in form of data interpretation and critical revision of the article.

Conflict of Interest

The authors have no conflict of interest.