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A Randomized, Placebo Controlled Pilot Trial of Botulinum Toxin for Paratonic Rigidity in People with Advanced Cognitive Impairment

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A Randomized, Placebo Controlled Pilot Trial of Botulinum Toxin for Paratonic Rigidity in People with Advanced Cognitive Impairment RESEARCH ARTICLE A Randomized, Placebo Controlled Pilot Trial of Botulinum Toxin for Paratonic Rigidity in People with Advanced Cognitive Impairment Galit Kleiner-Fisman1,2,3*, Edwin Khoo4, Nikohl Moncrieffe1, Triina Forbell1, Pearl Gryfe1, David Fisman4 1. Jeff and Diane Ross Movement Disorders Clinic, Assistive Technology Clinic, Toronto, Canada, 2. Baycrest Center for Geriatric Health, University of Toronto, Toronto, Canada, 3. Department of Medicine, Division of Neurology, University of Toronto, Toronto, Canada, 4. Dalla Lana School of Public Health, University of Toronto, Toronto, Canada OPEN ACCESS *[email protected] Citation: Kleiner-Fisman G, Khoo E, Moncrieffe N, Forbell T, Gryfe P, et al. (2014) A Randomized, Placebo Controlled Pilot Trial of Botulinum Toxin for Paratonic Rigidity in People with Advanced Abstract Cognitive Impairment. PLoS ONE 9(12): e114733. doi:10.1371/journal.pone.0114733 Objective: Evaluate safety and efficacy of Incobotulinumtoxin A in elderly patients Editor: Terence J. Quinn, University of Glasgow, United Kingdom with dementia and paratonia. Received: August 22, 2014 Setting: University-affiliated hospital, spasticity management Clinic. Accepted: November 5, 2014 Participants: Ten subjects were enrolled. Inclusion criteria: 1) severe cognitive impairment 2) diagnosis of Alzheimer’s disease, vascular dementia, or Published: December 23, 2014 frontotemporal dementia, and 3) score .3 on the paratonic assessment instrument, Copyright: ß 2014 Kleiner-Fisman et al. This is an open-access article distributed under the terms with posture in an arm(s) interfering with provision of care. Exclusion criteria: 1) of the Creative Commons Attribution License, which permits unrestricted use, distribution, and alternate etiologies for increased tone and 2) injection with botulinum toxin within reproduction in any medium, provided the original the 6 months preceding the study. author and source are credited. Design: Single center, randomized, double blind, placebo-controlled, crossover Data Availability: The authors confirm that all data underlying the findings are fully available without trial with two treatment cycles of 16 weeks. Assessments occurred at 2, 6, 12 and16 restriction. All relevant data are within the paper weeks following injections. Subjects received up to 300 U of Incobotulinumtoxin A and its Supporting Information files. in arm(s). Funding: Merz Pharmaceuticals GmbH (NT-036; http://www.merz.com/company/merz_ Primary and Secondary Outcome Measures: Primary outcome measure was the pharmaceuticals/index.jsp), who supplied study modified caregiver burden scale (mCBS); exploratory secondary outcome drug and provided funding for the study, had no role in influencing study design, data collection, measures were also performed. Analysis of variance and mixed modeling data analysis or interpretation, in the writing of the manuscript, or in the decision to submit the techniques were used to evaluate treatment effects. manuscript for publication. Results: Incobotulinumtoxin A treatment produced significant improvement in Competing Interests: The principal investigator mCBS total score 21.11 (–2.04 to 20.18) (Treatment effect and 95% CI), dressing has received consulting honoraria from Merz Pharmaceuticals GmbH. None of the other authors sub-score 20.36 (–0.59 to 0.12), and cleaning under the left and right armpits sub- have a conflict of interest, financial or otherwise. score 20.5 (–0.96 to 20.04), 20.41 (–0.79 to 20.04) respectively. PROM in the left This does not alter the authors’ adherence to all PLoS ONE policies on sharing data and materials. and right elbow increased by 27.67 degrees (13.32–42.02) and 22.07 degrees PLOS ONE | DOI:10.1371/journal.pone.0114733 December 23, 2014 1/17 Botulinum Toxin for Paratonic Rigidity in Dementia (9.76–34.39) respectively. PROM in the left and right shoulder increased by 11.92 degrees (5.46–18.38) and 8.58 degrees (3.73–13.43) respectively. No significant treatment effect was found for GAS, VAS and PAINAD scales or change in time to perform care. No adverse drug reactions occurred. Conclusions: Administration of Incobotulinumtoxin A in elderly people with advanced dementia and paratonia may be an efficacious and safe treatment to increase range of motion and reduce functional burden. Further studies are needed to confirm results. Trial Registration: ClinicalTrials.Gov NCT02212119 Introduction It is frequently assumed that dementia is a disorder only of cognitive impairment; however, dementia is often accompanied by significant motor disability due in part to ‘‘paratonia’’, a form of increased muscle tone. First observed by Dupre in 1910 [1], it was characterized as ‘‘an inability to relax muscles in the setting of cognitive impairment’’. Paratonia has been estimated to be present in 5% of those with mild cognitive impairments and 100% in those with advanced dementia [2– 5]. Postulated to originate in the central nervous system, paratonia exerts its effects by increasing muscle resistance reflexively when a limb is moved passively (though can fluctuate in severity depending on level of relaxation of the person). In advanced dementia, paratonia may also exist at rest with constant muscle contraction leading to fixed postures (contractures). Some of the consequences of paratonia and fixed postures include difficulties in washing, dressing, feeding, and providing general care, to a fully dependent person increasing caregiver burden. Fixed postures may lead to skin breakdown, infection, and pain upon movement, thereby reducing comfort and quality of life. It is commonly accepted that once contractures have developed, medical treatments are futile. However, contractures may be avoided or delayed if paratonia is recognized and treated. Botulinum toxin type A (Xeomin, Botox, Dysport), is an exotoxin produced by the bacterium Clostridium botulinum. It can be used as a therapeutic intervention to selectively weaken skeletal muscle in a dose-related manner by impairing the release of acetylcholine, a neurotransmitter, at the neuromuscular junction [6]. Botulinum toxin is used widely to address other hypertonic states such as dystonia [7–10] and has been proven safe and effective for the treatment of post-stroke spasticity [11, 12]. In stroke patients with spasticity, the administration of Botulinum toxin has been shown to significantly improve the capacity to independently perform activities of daily living (ADLs) [11]. In those with severe disability requiring full care as the result of a stroke, administration of Botulinum toxin has been shown to reduce caregiver burden [12]. Injections are effective for approximately 3 months with peak effect occurring after ,4–6 weeks. Unlike orally administered tone-reducing agents that PLOS ONE | DOI:10.1371/journal.pone.0114733 December 23, 2014 2/17 Botulinum Toxin for Paratonic Rigidity in Dementia may have substantial systemic consequences, side effects of Botulinum toxin are minimal as it only has local effects. Given the safety of its use and proven effect on tone reduction in spasticity, we postulated that administration of Incobotulinum toxin A in cognitively impaired, dependent individuals with dementia exhibiting paratonic rigidity in the upper limbs would increase range of motion such that ADLs could be facilitated and discomfort and consequences of limb immobility could be delayed or prevented. Methods Subjects The protocol for this trial and supporting CONSORT checklist are available as supporting information; see S1 Checklist and S1 Protocol. Subjects were eligible for the study if 1) they had severe cognitive impairment defined as complete dependency in all ADLs; 2) diagnosed with of Alzheimer’s disease, vascular dementia, frontotemporal dementia (FTD), or mixed dementia not otherwise specified (NOS), and 3) scored .3 on the paratonic assessment instrument (PAI) [2] with consequent paratonic rigidity in one or both arm(s) interfering in the provision of care. Exclusion criteria included alternate etiologies for increased tone such as Parkinsonism, dystonia, territorial strokes or other focal neurological deficits, fixed contractures of the affected limb (assessed clinically as no mobility on passive range of motion), or injection with Botulinum toxin in the preceding 6 months. All participants were residents of a single long-term care facility. The Ethics Review Board at Baycrest Health Sciences approved the study. The study was approved on December 20th, 2010 with the first patient recruited April 11th, 2011 and the final patient recruited July 12th, 2012. The last follow-up was February 27th, 2013. All subjects had written informed consent provided by their power of attorney (POA). Prior to enrollment of the first subject, the study was registered with Health Canada, the regulatory agency overseeing clinical trials in Canada where the study was performed. Technically, the trial didn’t have to be registered with clinicaltrial.gov as our trial did not meet criteria for ‘‘applicable drug clinical trial’’ subject to section 505 of the FDC Act or section 351 of the PHS Act. The drug was manufactured outside of the US and the trial was not being conducted under an investigational new drug (IND) designation [13]. However, given that registration of all clinical trials is now required for their acceptability for publication, the trial was retrospectively registered with clinicaltrials.gov. The authors confirm that all ongoing and related trials for this drug/intervention are registered. Study Design The study
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