Lack of Research and Way of Measuring Visual Hallucinations in Parkinson’s Hinders Its Treatment, Study Says

visual hallucinations

Research into the best ways of managing visual hallucinations in patients with Parkinson’s disease over the long term is severely limited and affecting treatment, a review study has found.

In particular, the lack of a universal rating scale renders data interpretation and comparison between studies difficult. To overcome this limitation, researchers propose the creation of a specific scale suitable to monitoring the effects of pharmacological and non-pharmacological treatments for visual hallucinations.

The study, “Management of visual hallucinations in dementia and Parkinson’s disease,” was published in International Psychogeriatrics.

Visual hallucinations — seeing something that is not real — is a common symptom of Parkinson’s and other types of dementia, including Alzheimer’s diseasedementia with Lewy bodies and frontotemporal dementia. These symptoms can be quite disturbing for patients, and are associated with rapid cognitive decline and increased mortality.

Although a large number of pharmacological and non-pharmacological therapies have been proposed to treat such hallucinations, an optimal management strategy is yet to be found.

This systematic review examined the prevalence and risk factors of visual hallucinations, as well as rating scales and therapeutic approaches that have been proposed to monitor and minimize their occurrence.

After a thorough literature search in the PubMed database, a total of 89 relevant studies (11 meta-analyses, 34 randomized controlled trials, six other trials, and a number of relevant review articles) were selected.

Previous studies estimated the prevalence of visual hallucinations for Alzheimer’s disease to range from 3% to 76%, and from 22% to 38% in people with Parkinson’s disease.

The high variability in prevalence, especially in Alzheimer’s disease “may be due to the setting of the study population (clinic vs. nursing home) and differences in who the informant is; whether patient, relative, or professional,” the researchers wrote.

Among Parkinson’s patients, the biggest challenge to determining prevalence of visual hallucinations seems to be separating “the contribution of dopaminergic and anticholinergic drugs from that of the disease.”

In dementia with Lewy bodies and frontotemporal dementia patients, prevalence is estimated to be 15-20% and 14.4%, respectively.

Non-pharmacological strategies have been proposed mainly as a first-line treatment for visual hallucinations. However, solid evidence from controlled trials that might demonstrate therapeutic benefit specifically for visual hallucinations is lacking.

“[R]eviewers have recommended increased socialization, as well as improving lighting and reducing visual triggers, but admit this because they are useful and inexpensive rather than based on trial evidence,” the researchers wrote.

Antipsychotics — both typical and atypical — are commonly used to treat psychosis and depression, but when used in patients with dementia are associated with a series of adverse side effects, including increased risk of stroke and death. Still, these medicines may continue to be prescribed off-label to these patients, mostly due to a lack of better alternatives.

In Parkinson’s disease, several antipsychotic treatments have been tested over the last few years. While some, like melperone and Zyprexa (olanzapine), clearly failed to ease psychosis and delusions, Clozaril (clozapine) and Nuplazid (pimavanserin) were seen to treat psychosis and hallucinations without impairing patients’ motor functions. The effects of others, like Seroquel (quetiapine), vary substantially across studies and are difficult to interpret.

In any case, these medications — even Nuplazid, the only medication approved by the U.S. Food and Drug Administration (FDA) for Parkinson’s delusions and hallucinations — “still carry the same black box warning as other antipsychotics for older people with dementia” and should be used with caution.

One of the key limitations encountered by the researchers that affects not only data interpretation, but also its generation, was the lack of a specific universal rating scale to assess visual hallucinations. Rather, symptoms tend to be “grouped together as all ‘hallucinations’ or ‘psychosis’. This over simplifies symptoms and prevents an understanding of what treatments may or may not work,” they said.

“We recommend the development of a specific scale suitable for natural history and treatment studies of VH, and for larger multi-site studies of both non-pharmacological and pharmacological treatments for VH [visual hallucinations],” the researchers concluded.

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How Hallucinations Affect Patients and Caregivers Over Disease Course Focus of Study

hallucinations and disease

Visual hallucinations can be common in Parkinson’s patients and others with dementia, but the degree of distress they cause is greatly influenced by the person’s ability to understand and consider them — and have the cognitive resources to do so, a study reports.

Likewise, the tailored support given patients needs to reflect their ability to understand and manage this disease symptom.

The research, “Visual hallucinations in dementia and Parkinson’s disease: A qualitative exploration of patient and caregiver experiences,” was published in the International Journal of Geriatric Psychiatry.

Visual hallucinations — seeing something that others cannot — are a typical manifestation of Parkinson’s disease psychosis, and of dementias like those associated with Alzheimer’s, vascular diseases, and Lewy body dementia (LBD).

Antipsychotic medications like Nuplazid (pimavanserin) — an approved treatment for Parkinson’s psychosis, developed by Acadia Pharmaceuticals — and Clozaril (clozapine), approved to treat severe schizophrenia but used off-label for these patients, have been found to ease symptoms of Parkinson’s disease psychosis without impairing motor function in double-blind, placebo-controlled clinical trials.

But not all psychosis patients can use these medications.

Visual hallucinations are linked to diminished well-being, greater caregiver burden and poorer functional skills, as well as higher rates of nursing home admissions and faster cognitive impairment. How such outcomes might be prevented or slowed in psychosis patients, however, is largely unexplored.

Researchers used qualitative methods to understand the needs, experiences, and coping strategies of Parkinson’s and dementia  patients with visual hallucinations, and their impact on caregivers.

They interviewed 11 such Parkinson’s patients and 10 with dementia, and people who served as informal caregivers (9 for Parkinson’s and 11 for dementia patients).

Most patients reported having  hallucinations for at least one year, the researchers wrote. A difference noted: Parkinson’s patients tended to see images of people and animals not actually present, while dementia patients “tended to experience people or ‘presence’ hallucinations.”

Patients were asked about their experiences and interpretations of such hallucinations, their impact on relationships and daily life, and information or support they had asked for or received regarding them.

Caregivers were asked to reflect upon their own reactions and any support they might have received.

All patients were assessed for vision, cognition, and motor function skills.

“Differences in the VH [visual hallucinations] experience between persons with dementia and PD were less striking than the overall similarities across conditions at equivalent stages of cognitive and insight impairment,” the researchers wrote.

Patients reported disease aspects such as loss of independence [related to motor decline] and depression as more concerning and difficult than hallucinations, while those with poorer cognitive abilities voiced greater distress with visual hallucinations.

Three overall themes emerged in the study:

  • Insight (comprehension) and distress: The better understanding a patient had of visual hallucinations (i.e., recognizing them as a disease symptom), the less threaten they felt by them, and the more able they were to accept them as part of their life.
  • Caregiving reactions: Caregivers’ reactions were closely related to a patient’s ability to understand hallucinations.  When they felt patients knew they were not real, a simple reassurance was a sufficient reaction. As patients declined, managing visual hallucinations become more challenging.
  • Discussions and support:  Patients generally avoided discussing or seeking support for visual hallucinations because of feelings of being “abnormal,” and the possible stigma they carried. Others either did not think them an important disease symptom, or doubted such discussions would not achieve anything and bring relief.

An ability to understand and distinguish a visual hallucination from reality — called “insight” by the research team — influenced how the threat of such hallucinations was perceived and whether acceptance occurred over time. Reactions to visual hallucinations and coping strategies varied as insights changed with disease progression.

Of note, acceptance came mainly through self-realization and through discussions with caregivers.

“Irrespective of the clinical context, tailored support is required that takes into account the [patient’s] degree of insight and cognitive function,” the researchers wrote.

“Support in early stages should focus on raising awareness of VH, symptom disclosure, stigma reduction, and contact with others affected. In later stages, the focus shifts to informal caregiver needs and a flexible approach to reassuring those affected,” they added.

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Source: Parkinson's News Today

Axovant’s Parkinson’s Therapy Shows Promise but Alzheimer’s Candidate Falls Short, Phase 2 Trials Show

Promsing Parkinson's therapy

An Axovant Sciences therapy for Parkinson’s disease showed signs of effectiveness, but an Alzheimer’s treatment did not, according to separate Phase 2 clinical trials.

Nelotanserin, the therapy candidate for Parkinson’s disease dementia (PDD) associated with hallucinations and for Dementia with Lewy Bodies (DLB), appeared safe as well as displaying signs of effectiveness, according to a Phase 2 trial (NCT02871427).

Meanwhile, intepirdine, a therapy candidate for Alzheimer’s and DLB, failed to meet its objectives in the Phase 2b HEADWAY trial (NCT02669433) and a pilot Phase 2 study (NCT02910102) that focused on walking and balance.

In the HEADWAY trial, 24-week administration of 35 mg or 70 mg of intepirdine in DLB patients did not produce statistically significant improvements in their movement, cognitive, and global functions, in comparison with placebo-treated patients.

Intepirdine has been well tolerated in all of its studies. But the poor effectiveness results did not come as a surprise. That’s because Axovant announced last year that the Phase 3 MINDSET study (NCT02585934) showed that intepirdine failed to help mild-to-moderate Alzheimer’s patients who were receiving background donepezil therapy.

Concerning the impact of intepirdine in dementia patients with gait and balance problems, 35 mg of intepirdine failed to improve gait speed.

“Based on the totality of intepirdine data to date, there is no evidence to support its further development,” David Hung, chief executive officer of Axovant, said in a news release.

In the case of nelotanserin, researchers looked at the safety of the drug in DLB and PDD patients experiencing visual hallucinations in a pilot Phase 2 study.

Preliminary results revealed nelotanserin seemed to decrease dementia progression in Parkinson’s patients.

Now, when researchers looked at 19 of the DLB patients in the Phase 2 hallucination trial, they reported that nelotanserin improved their movement scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) by 4 points.

After seeing the data, the team analyzed a subset of patients who scored 8 or more, an indication of more severe psychotic symptoms, in the Scale for the Assessment of Positive Symptoms — Parkinson’s Disease (SAPS-PD).

They found that 40 mg of nelotanserin for two weeks, followed by 80 mg for two weeks, resulted in a 1.21-point improvement in SAPS-PD.

After these positive results, “we intend to discuss a larger confirmatory nelotanserin study with the FDA that is focused on DLB patients with motor deficits and more severe baseline psychotic symptoms,” Hung said. “Separately, we will be working with Roivant to build our pipeline to develop other new therapies for patients with neurological conditions who so desperately need them.”

In future trials, Axovant said it may also analyze nelotanserin’s effect on DLB and PDD psychotic symptoms.

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Source: Parkinson's News Today