Rivastigmine for minor visual hallucinations in Parkinson's disease: A randomized controlled trial with 24 months follow-up

Tom J.M. van Mierlo; Elisabeth M.J. Foncke; the CHEVAL Study Group; Bart Post; Ben A. Schmand; Bastiaan R. Bloem; Barbera van Harten; Gerrit Tissingh; Alexander G. Munts; Rob J. de Haan; Rob M.A. de Bie

doi:10.1002/brb3.2257

Rivastigmine for minor visual hallucinations in Parkinson's disease: A randomized controlled trial with 24 months follow-up

Tom J.M. van Mierlo^*, Elisabeth M.J. Foncke, the CHEVAL Study Group, Bart Post, Ben A. Schmand, Bastiaan R. Bloem, Barbera van Harten, Gerrit Tissingh, Alexander G. Munts, Rob J. de Haan, Rob M.A. de Bie

^*Corresponding author for this work

Neurology

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Abstract

Background: Visual hallucinations are common in patients with Parkinson's disease and represent probably the major independent predictor for cognitive deterioration and nursing home placement. Objective: To investigate if treatment of minor visual hallucinations in Parkinson's disease with rivastigmine delays the progression to psychosis. Methods: A multicenter, randomized, double-blind, placebo-controlled trial was conducted which aimed to recruit 168 patients with Parkinson's disease reporting minor visual hallucinations 4 weeks before it. Important exclusion criteria were Parkinson's disease dementia, current delirium, and treatment with antipsychotics or drugs that have significant anti-cholinergic side effects. Subjects were randomized to rivastigmine capsules, 3–6 mg twice a day, or placebo for 24 months. The primary outcome was the time to Parkinson's disease psychosis, which was defined as the need to start with antipsychotics. Results: The trial was stopped prematurely because of slow recruitment. Ninety-one patients were randomized: 46 patients were assigned to rivastigmine and 45 patients to placebo. No effect of rivastigmine could be demonstrated on the transition time to psychosis or dementia during the 24-month follow-up period. After 6 months of study treatment, cognition, mood, motor performance, and non-motor performance did not differ significantly between the rivastigmine-group and the placebo-group. Conclusions: Because the study was terminated early, it was insufficiently powered to properly evaluate the primary outcome. The limited data of the study favor a wait and see approach instead of early treatment with rivastigmine in PD patients with minor VH.

Original language	English
Article number	e2257
Journal	Brain and Behavior
Volume	11
Issue number	8
Early online date	21 Jul 2021
DOIs	https://doi.org/10.1002/brb3.2257
Publication status	Published - 1 Aug 2021

Bibliographical note

Funding Information:
informationThe Netherlands Organisation for Health Research and Development (ZonMW, trial registry number NCT01856738), Stichting ParkinsonFonds, and the Parkinson Pati?nten Vereniging.We thank the participating patients, the nurses who obtained the trial measurements, and the neurologists who participated in recruiting possible participants. We thank C.G. Goetz and S. Lewis for their comments on our manuscript. Bastiaan Bloem currently serves as Editor-in-Chief for the Journal of Parkinson's Disease, serves on the editorial board of Practical Neurology and Digital Biomarkers, has received honoraria from serving on the scientific advisory board for Zambon, Biogen, UCB and Walk with Path, has received fees for speaking at conferences from AbbVie, Zambon, Roche, GE Healthcare and Bial, and has received research support from the Netherlands Organization for Scientific Research, the Michael J Fox Foundation, UCB, Abbvie, Zambon, the Stichting Parkinson Fonds, the Hersenstichting Nederland, the Parkinson's Foundation, Verily Life Sciences, Horizon 2020, the Topsector Life Sciences and Health, and the Parkinson Vereniging. Rob de Bie received unrestricted grants from ZonMw, Parkinson Vereniging, Stichting Parkinson Nederland, Lysosomal Therapeutics, Medtronic and GEHealth, all paid to the institution.

Funding Information:
We thank the participating patients, the nurses who obtained the trial measurements, and the neurologists who participated in recruiting possible participants. We thank C.G. Goetz and S. Lewis for their comments on our manuscript. Bastiaan Bloem currently serves as Editor‐in‐Chief for the , serves on the editorial board of Practical Neurology and Digital Biomarkers, has received honoraria from serving on the scientific advisory board for Zambon, Biogen, UCB and Walk with Path, has received fees for speaking at conferences from AbbVie, Zambon, Roche, GE Healthcare and Bial, and has received research support from the Netherlands Organization for Scientific Research, the Michael J Fox Foundation, UCB, Abbvie, Zambon, the Stichting Parkinson Fonds, the Hersenstichting Nederland, the Parkinson's Foundation, Verily Life Sciences, Horizon 2020, the Topsector Life Sciences and Health, and the Parkinson Vereniging. Rob de Bie received unrestricted grants from ZonMw, Parkinson Vereniging, Stichting Parkinson Nederland, Lysosomal Therapeutics, Medtronic and GEHealth, all paid to the institution. Journal of Parkinson's Disease

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© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC

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van Mierlo, T. J. M., Foncke, E. M. J., the CHEVAL Study Group, Post, B., Schmand, B. A., Bloem, B. R., van Harten, B., Tissingh, G., Munts, A. G., de Haan, R. J., & de Bie, R. M. A. (2021). Rivastigmine for minor visual hallucinations in Parkinson's disease: A randomized controlled trial with 24 months follow-up. Brain and Behavior, 11(8), Article e2257. https://doi.org/10.1002/brb3.2257

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title = "Rivastigmine for minor visual hallucinations in Parkinson's disease: A randomized controlled trial with 24 months follow-up",

abstract = "Background: Visual hallucinations are common in patients with Parkinson's disease and represent probably the major independent predictor for cognitive deterioration and nursing home placement. Objective: To investigate if treatment of minor visual hallucinations in Parkinson's disease with rivastigmine delays the progression to psychosis. Methods: A multicenter, randomized, double-blind, placebo-controlled trial was conducted which aimed to recruit 168 patients with Parkinson's disease reporting minor visual hallucinations 4 weeks before it. Important exclusion criteria were Parkinson's disease dementia, current delirium, and treatment with antipsychotics or drugs that have significant anti-cholinergic side effects. Subjects were randomized to rivastigmine capsules, 3–6 mg twice a day, or placebo for 24 months. The primary outcome was the time to Parkinson's disease psychosis, which was defined as the need to start with antipsychotics. Results: The trial was stopped prematurely because of slow recruitment. Ninety-one patients were randomized: 46 patients were assigned to rivastigmine and 45 patients to placebo. No effect of rivastigmine could be demonstrated on the transition time to psychosis or dementia during the 24-month follow-up period. After 6 months of study treatment, cognition, mood, motor performance, and non-motor performance did not differ significantly between the rivastigmine-group and the placebo-group. Conclusions: Because the study was terminated early, it was insufficiently powered to properly evaluate the primary outcome. The limited data of the study favor a wait and see approach instead of early treatment with rivastigmine in PD patients with minor VH.",

author = "{van Mierlo}, {Tom J.M.} and Foncke, {Elisabeth M.J.} and {the CHEVAL Study Group} and Bart Post and Schmand, {Ben A.} and Bloem, {Bastiaan R.} and {van Harten}, Barbera and Gerrit Tissingh and Munts, {Alexander G.} and {de Haan}, {Rob J.} and {de Bie}, {Rob M.A.} and Pieter Nederveen and Krul, {Jean Michel} and Annemarie Vlaar and Agnita Boon and Henk Berendse and Jons Verduijn and Mirthe Ponssen and {van Strien}, Teun and Nathalie Rosenberg and Jorrit Hoff and {van Hilten}, Bob and Roeland Tans and Germ Tiessens and {Van der Meulen}, Willem and Dareia Roos and {van Vugt}, Jeroen and {van Asseldonk}, Ties and {van Wensen}, Erik and Ad Vermeij and Lucile Dorresteijn and Mark Kuijf and {van Laar}, Teus and {van Kesteren}, Mirjam and Wouter Schuiling and Axel Portman and Philip Scheltens and Koos Zwinderman and Joke Dijk and Michel Hof",

note = "Funding Information: informationThe Netherlands Organisation for Health Research and Development (ZonMW, trial registry number NCT01856738), Stichting ParkinsonFonds, and the Parkinson Pati?nten Vereniging.We thank the participating patients, the nurses who obtained the trial measurements, and the neurologists who participated in recruiting possible participants. We thank C.G. Goetz and S. Lewis for their comments on our manuscript. Bastiaan Bloem currently serves as Editor-in-Chief for the Journal of Parkinson's Disease, serves on the editorial board of Practical Neurology and Digital Biomarkers, has received honoraria from serving on the scientific advisory board for Zambon, Biogen, UCB and Walk with Path, has received fees for speaking at conferences from AbbVie, Zambon, Roche, GE Healthcare and Bial, and has received research support from the Netherlands Organization for Scientific Research, the Michael J Fox Foundation, UCB, Abbvie, Zambon, the Stichting Parkinson Fonds, the Hersenstichting Nederland, the Parkinson's Foundation, Verily Life Sciences, Horizon 2020, the Topsector Life Sciences and Health, and the Parkinson Vereniging. Rob de Bie received unrestricted grants from ZonMw, Parkinson Vereniging, Stichting Parkinson Nederland, Lysosomal Therapeutics, Medtronic and GEHealth, all paid to the institution. Funding Information: We thank the participating patients, the nurses who obtained the trial measurements, and the neurologists who participated in recruiting possible participants. We thank C.G. Goetz and S. Lewis for their comments on our manuscript. Bastiaan Bloem currently serves as Editor‐in‐Chief for the , serves on the editorial board of Practical Neurology and Digital Biomarkers, has received honoraria from serving on the scientific advisory board for Zambon, Biogen, UCB and Walk with Path, has received fees for speaking at conferences from AbbVie, Zambon, Roche, GE Healthcare and Bial, and has received research support from the Netherlands Organization for Scientific Research, the Michael J Fox Foundation, UCB, Abbvie, Zambon, the Stichting Parkinson Fonds, the Hersenstichting Nederland, the Parkinson's Foundation, Verily Life Sciences, Horizon 2020, the Topsector Life Sciences and Health, and the Parkinson Vereniging. Rob de Bie received unrestricted grants from ZonMw, Parkinson Vereniging, Stichting Parkinson Nederland, Lysosomal Therapeutics, Medtronic and GEHealth, all paid to the institution. Journal of Parkinson's Disease Publisher Copyright: {\textcopyright} 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC",

year = "2021",

month = aug,

day = "1",

doi = "10.1002/brb3.2257",

language = "English",

volume = "11",

journal = "Brain and Behavior",

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TY - JOUR

T1 - Rivastigmine for minor visual hallucinations in Parkinson's disease

T2 - A randomized controlled trial with 24 months follow-up

AU - van Mierlo, Tom J.M.

AU - Foncke, Elisabeth M.J.

AU - the CHEVAL Study Group

AU - Post, Bart

AU - Schmand, Ben A.

AU - Bloem, Bastiaan R.

AU - van Harten, Barbera

AU - Tissingh, Gerrit

AU - Munts, Alexander G.

AU - de Haan, Rob J.

AU - de Bie, Rob M.A.

AU - Nederveen, Pieter

AU - Krul, Jean Michel

AU - Vlaar, Annemarie

AU - Boon, Agnita

AU - Berendse, Henk

AU - Verduijn, Jons

AU - Ponssen, Mirthe

AU - van Strien, Teun

AU - Rosenberg, Nathalie

AU - Hoff, Jorrit

AU - van Hilten, Bob

AU - Tans, Roeland

AU - Tiessens, Germ

AU - Van der Meulen, Willem

AU - Roos, Dareia

AU - van Vugt, Jeroen

AU - van Asseldonk, Ties

AU - van Wensen, Erik

AU - Vermeij, Ad

AU - Dorresteijn, Lucile

AU - Kuijf, Mark

AU - van Laar, Teus

AU - van Kesteren, Mirjam

AU - Schuiling, Wouter

AU - Portman, Axel

AU - Scheltens, Philip

AU - Zwinderman, Koos

AU - Dijk, Joke

AU - Hof, Michel

N1 - Funding Information: informationThe Netherlands Organisation for Health Research and Development (ZonMW, trial registry number NCT01856738), Stichting ParkinsonFonds, and the Parkinson Pati?nten Vereniging.We thank the participating patients, the nurses who obtained the trial measurements, and the neurologists who participated in recruiting possible participants. We thank C.G. Goetz and S. Lewis for their comments on our manuscript. Bastiaan Bloem currently serves as Editor-in-Chief for the Journal of Parkinson's Disease, serves on the editorial board of Practical Neurology and Digital Biomarkers, has received honoraria from serving on the scientific advisory board for Zambon, Biogen, UCB and Walk with Path, has received fees for speaking at conferences from AbbVie, Zambon, Roche, GE Healthcare and Bial, and has received research support from the Netherlands Organization for Scientific Research, the Michael J Fox Foundation, UCB, Abbvie, Zambon, the Stichting Parkinson Fonds, the Hersenstichting Nederland, the Parkinson's Foundation, Verily Life Sciences, Horizon 2020, the Topsector Life Sciences and Health, and the Parkinson Vereniging. Rob de Bie received unrestricted grants from ZonMw, Parkinson Vereniging, Stichting Parkinson Nederland, Lysosomal Therapeutics, Medtronic and GEHealth, all paid to the institution. Funding Information: We thank the participating patients, the nurses who obtained the trial measurements, and the neurologists who participated in recruiting possible participants. We thank C.G. Goetz and S. Lewis for their comments on our manuscript. Bastiaan Bloem currently serves as Editor‐in‐Chief for the , serves on the editorial board of Practical Neurology and Digital Biomarkers, has received honoraria from serving on the scientific advisory board for Zambon, Biogen, UCB and Walk with Path, has received fees for speaking at conferences from AbbVie, Zambon, Roche, GE Healthcare and Bial, and has received research support from the Netherlands Organization for Scientific Research, the Michael J Fox Foundation, UCB, Abbvie, Zambon, the Stichting Parkinson Fonds, the Hersenstichting Nederland, the Parkinson's Foundation, Verily Life Sciences, Horizon 2020, the Topsector Life Sciences and Health, and the Parkinson Vereniging. Rob de Bie received unrestricted grants from ZonMw, Parkinson Vereniging, Stichting Parkinson Nederland, Lysosomal Therapeutics, Medtronic and GEHealth, all paid to the institution. Journal of Parkinson's Disease Publisher Copyright: © 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC

PY - 2021/8/1

Y1 - 2021/8/1

N2 - Background: Visual hallucinations are common in patients with Parkinson's disease and represent probably the major independent predictor for cognitive deterioration and nursing home placement. Objective: To investigate if treatment of minor visual hallucinations in Parkinson's disease with rivastigmine delays the progression to psychosis. Methods: A multicenter, randomized, double-blind, placebo-controlled trial was conducted which aimed to recruit 168 patients with Parkinson's disease reporting minor visual hallucinations 4 weeks before it. Important exclusion criteria were Parkinson's disease dementia, current delirium, and treatment with antipsychotics or drugs that have significant anti-cholinergic side effects. Subjects were randomized to rivastigmine capsules, 3–6 mg twice a day, or placebo for 24 months. The primary outcome was the time to Parkinson's disease psychosis, which was defined as the need to start with antipsychotics. Results: The trial was stopped prematurely because of slow recruitment. Ninety-one patients were randomized: 46 patients were assigned to rivastigmine and 45 patients to placebo. No effect of rivastigmine could be demonstrated on the transition time to psychosis or dementia during the 24-month follow-up period. After 6 months of study treatment, cognition, mood, motor performance, and non-motor performance did not differ significantly between the rivastigmine-group and the placebo-group. Conclusions: Because the study was terminated early, it was insufficiently powered to properly evaluate the primary outcome. The limited data of the study favor a wait and see approach instead of early treatment with rivastigmine in PD patients with minor VH.

AB - Background: Visual hallucinations are common in patients with Parkinson's disease and represent probably the major independent predictor for cognitive deterioration and nursing home placement. Objective: To investigate if treatment of minor visual hallucinations in Parkinson's disease with rivastigmine delays the progression to psychosis. Methods: A multicenter, randomized, double-blind, placebo-controlled trial was conducted which aimed to recruit 168 patients with Parkinson's disease reporting minor visual hallucinations 4 weeks before it. Important exclusion criteria were Parkinson's disease dementia, current delirium, and treatment with antipsychotics or drugs that have significant anti-cholinergic side effects. Subjects were randomized to rivastigmine capsules, 3–6 mg twice a day, or placebo for 24 months. The primary outcome was the time to Parkinson's disease psychosis, which was defined as the need to start with antipsychotics. Results: The trial was stopped prematurely because of slow recruitment. Ninety-one patients were randomized: 46 patients were assigned to rivastigmine and 45 patients to placebo. No effect of rivastigmine could be demonstrated on the transition time to psychosis or dementia during the 24-month follow-up period. After 6 months of study treatment, cognition, mood, motor performance, and non-motor performance did not differ significantly between the rivastigmine-group and the placebo-group. Conclusions: Because the study was terminated early, it was insufficiently powered to properly evaluate the primary outcome. The limited data of the study favor a wait and see approach instead of early treatment with rivastigmine in PD patients with minor VH.

UR - http://www.scopus.com/inward/record.url?scp=85110976078&partnerID=8YFLogxK

U2 - 10.1002/brb3.2257

DO - 10.1002/brb3.2257

M3 - Article

C2 - 34291590

AN - SCOPUS:85110976078

SN - 2157-9032

VL - 11

JO - Brain and Behavior

JF - Brain and Behavior

IS - 8

M1 - e2257

ER -

Rivastigmine for minor visual hallucinations in Parkinson's disease: A randomized controlled trial with 24 months follow-up

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