Non-pharmacological interventions for Lewy body dementia: a systematic review

Lewy body dementia (consisting of dementia with Lewy bodies and Parkinson's disease dementia) is a common neurodegenerative disease characterised by visual hallucinations, fluctuating attention, motor disturbances, falls, and sensitivity to antipsychotics. This combination of features presents challenges for pharmacological management. Given this, we sought to review evidence for non-pharmacological interventions with patients with Lewy body dementia and their carers. Bibliographic databases were searched using a wide range of search terms and no restrictions were placed on study design, language, or clinical setting. Two reviewers independently assessed papers for inclusion, rated study quality, and extracted data. The search identified 21 studies including two randomised controlled trials with available subgroup data, seven case series, and 12 case studies. Most studies reported beneficial effects of the interventions used, though the only sizeable study was on dysphagia, showing a benefit of honey-thickened liquids. Given the heterogeneity of interventions and poor quality of the studies overall, no quantitative synthesis was possible. Overall, identified studies suggested possible benefits of non-pharmacological interventions in Lewy body dementia, but the small sample sizes and low quality of studies mean no definite recommendations can be offered. Our findings underscore the clear and urgent need for future research on this topic.


Introduction
Lewy body dementia is a common neurodegenerative disease in older people (Walker et al. 2015). It is responsible for 5-25% of diagnosed cases of dementia (Vann Jones & O'Brien, 2014), giving it a likely prevalence of around 1% in people over 65 years old (Ballard et al. 2013). The disease is characterised by fluctuations in attention and alertness, recurrent visual hallucinations, and parkinsonian motor features . It is broadly considered to consist of two related disordersdementia with Lewy bodies and Parkinson's disease dementiathat are distinguished by the relative timing of when cognitive and motor symptoms appear. Dementia with Lewy bodies is diagnosed if dementia develops either prior to parkinsonian motor symptoms or within 1 year of their onset. By contrast, Parkinson's disease dementia is diagnosed if dementia develops after 1 year of parkinsonian motor symptoms. The two disorders share a common underlying pathophysiology, but likely vary in the sequence by which brain areas underpinning cognition and motor function are affected (Aarsland et al. 2009;McKeith, 2009).
Lewy body dementia poses a number of challenges for clinical management that differ from those of other dementias. People with Lewy body dementia typically experience visual hallucinations and may be more likely to have delusions than people with other types of dementia (Ballard et al. 1999;Aarsland et al. 2007;Brodaty et al. 2015). These types of symptoms can be very distressing to both patients and their carers, and are a risk factor for early institutionalisation (Black & Almeida, 2004;Brodaty et al. 2014). Pharmacological management, however, is limited because of the condition's adverse sensitivity to neuroleptics (antipsychotic drugs) (McKeith et al. 1992;Aarsland et al. 2005;Ballard et al. 2013). Antidepressants also appear to be poorly tolerated (Culo et al. 2010) with no clear evidence that they are effective for treating mood disturbances in this population (Ballard et al. 2013;Stinton et al. 2015), though further research is needed. At the same time, patients typically have parkinsonian motor disturbances and treatment responses are limited by the fact that some antiparkinson medications can exacerbate psychotic symptoms . People with Lewy body dementia are also prone to falls, which further increases the risks of using medications that exacerbate orthostatic hypotension, impair cognition, or otherwise predispose to falls.
Finally, people with Lewy body dementia may undergo faster cognitive decline , require higher costs of care (Murman et al. 2003;Boström et al. 2007;Vossius et al. 2014), result in greater caregiver burden (Svendsboe et al. 2016), and progress more quickly to death (Oesterhus et al. 2014) than people with Alzheimer's disease and other dementias.
Despite these challenges and the relatively high prevalence of the disease, the evidence base for intervention strategies remains unclear. A previous systematic review and meta-analysis of pharmacological treatments for Lewy body dementia identified a lack of high-quality evidence for commonly used drugs in this population, though found evidence for efficacy of cholinesterase inhibitors (Stinton et al. 2015). Another systematic review evaluated the benefits of exercise in Lewy body dementia and likewise found little high-quality research (Inskip et al. 2016). There is, however, no synthesis of evidence for non-pharmacological options more generally for people with Lewy body dementia. Such options have been shown to be helpful in other types of dementia (Brodaty & Arasaratnam, 2012;Livingston et al. 2014;Orgeta et al. 2015), but are likely to be especially important in Lewy body dementia given the risks of medications in this population. In this paper, we addressed this issue and reviewed studies that assessed non-pharmacological interventions for patients with Lewy body dementia.

Method
The protocol for this systematic review was registered at PROSPERO (registration number CRD42016050492).

Eligibility criteria
The review focused on primary research that assessed a nonpharmacological intervention for either patients with Lewy body dementia or carers of such patients. The review considered studies evaluating non-pharmacological interventions in the broader categories of dementia or Parkinson's disease if the results of a Lewy body dementia subgroup were available. Studies that were confounded by a concurrent pharmaceutical intervention (i.e. medication initiated at the same time as a non-pharmacological intervention or given to one group in a study but not the other) were excluded. There were no other restrictions on study design and no requirements for a comparator group. There were also no restrictions on language, time period, or clinical context in which the study was conducted.

Search strategy
The search identified studies through bibliographic databases, trial registers, and the grey literature. Bibliographic databases and trial registers included the following: Medline (1946-present);PreMedline, PubMed;EMBASE (1974-present), Scopus, Web of Science (1900-current); PsychInfo (1806-present); CINAHL (1981-present) ; 1929-present); Social work Abstracts (1968present); and the National Association of Social Workers (NASW) clinical register (14th edition). The grey literature was searched using such resources as SIGLE (System for Information on Grey Literature in Europe), NTIS (National Technical Information Service) database, and PsychEXTRA (1908-present).
In addition to bibliographic database searches, the reference lists of papers included in the review and previous systematic reviews on both Lewy body dementia and non-pharmacological interventions were checked for relevant papers. Advice was also sought from experts in the field.

Study selection
Two reviewers (MHC and LQ) independently assessed search results for inclusion by title and abstract. All articles deemed relevant by either reviewer were obtained in full. Both reviewers then independently evaluated full-text articles for inclusion. Any disagreements were resolved through discussion or, if necessary, with a third reviewer (JTO).

Data extraction
Two reviewers independently extracted relevant data from publications using a standardised form. This included participant details (e.g. demographics, number, recruitment, clinical context, dementia severity), intervention type, study design, measures, and results. Qualitative data were also collated.
The primary outcomes were measures of cognition, function, neuropsychiatric symptoms, and motor symptoms. The secondary outcomes were measures of any other clinically relevant outcomes, such as quality of life, carer burden, financial costs, other symptoms (sleep or autonomic disturbances), and objective endpoints (e.g. falls, hospitalisation, institutionalisation, mortality). Secondary outcomes also included the perceived acceptability of treatments, reported side effects, and dropout rates (a measure of treatment acceptability).

Quality assessment
Two reviewers independently assessed study quality and risk of bias using standardised tools. These included the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies (Effective Public Health Practice Project, 2007;Armijo-Olivo et al. 2012) and the NICE Methodology Checklist: Qualitative Studies (NICE, 2016). Any disagreements were resolved through discussion.

Data synthesis
Although a quantitative synthesis of findings using meta-analytic techniques was originally intended, this was not possible due to the small sample sizes and poor quality of the included studies. As a result, only a descriptive synthesis was provided.

Search results
The search identified 73 093 publications, of which 30 419 were unique and 42 674 were duplicates. Of these, 76 were considered by one or both reviewers to be potentially relevant and obtained in full. In turn, 21 studies were found eligible for inclusion (a flow diagram in PRISMA format is shown in Fig. 1). The included studies consisted of 12 case studies (Kung & O'Connor, 2002;Loher et al. 2002;Graff et al. 2006;Cheston et al. 2007;Huh et al. 2008;Freund et al. 2009;Ciro et al. 2013;Gil-Ruiz et al. 2013;Tabak et al. 2013;Dawley, 2015;Hsu et al. 2015;Ricciardi et al. 2015), seven case series (Rasmussen et al. 2003;Rochester et al. 2009;Takahashi et al. 2009;Ota et al. 2012;Elder et al. 2016;Yamaguchi et al. 2016)two of which were reported in the same paper (Takahashi et al. 2009)and two randomised controlled trials (Logemann et al. 2008;Telenius et al. 2015). Both randomised trials focused on the broader conditions of dementia and/or Parkinson's disease but had separate results for a Lewy body dementia subgroup available. One case report was reported in two separate papers (Freund et al. 2009;Barnikol et al. 2010); our descriptive synthesis focused on the more detailed of these papers (Freund et al. 2009). A further case report on electroconvulsive therapy was excluded (Fujiwara et al. 2004) because of a concurrent pharmacological intervention. Twelve studies focused on dementia with Lewy bodies (Kung & O'Connor, 2002;Rasmussen et al. 2003;Cheston et al. 2007;Huh et al. 2008;Takahashi et al. 2009;Ota et al. 2012;Ciro et al. 2013;Gil-Ruiz et al. 2013;Hsu et al. 2015;Telenius et al. 2015;Yamaguchi et al. 2016), eight focused on Parkinson's disease dementia (Loher et al. 2002;Graff et al. 2006;Logemann et al. 2008;Freund et al. 2009;Rochester et al. 2009;Tabak et al. 2013;Dawley, 2015;Ricciardi et al. 2015), and one included patients from both groups (Elder et al. 2016). A summary of studies is shown in Table 1.

Quality assessment
Of the 21 studies, 19 were rated as poor quality due to their small sample size, uncertainties about recruitment, and the lack of a control group. One randomised controlled trial, which focused on exercise in nursing homes for patients with dementia (Telenius et al. 2015), was evaluated as poor quality with respect to Lewy body dementia specifically (it only included four participants with the condition and these participants did not complete all tasks) (Inskip et al. 2016). The other randomised controlled trial (Logemann et al. 2008), which investigated dietary fluid and postural interventions for dysphagia, was evaluated as moderate quality. This study, however, was limited by its lack of blinding and the fact that it relied on measures of immediate efficacy in a research setting, without any longer term follow-up or measures of real-world effectiveness. It was also limited by the absence of a control group that did not receive a treatment, making it difficult to establish the absolute effectiveness of the interventions.

Participants
The total number of participants across the included studies was 195. This comprised 44 patients with dementia with Lewy bodies and 151 patients with Parkinson's disease dementia (of whom, 132 were from one study; Logemann et al. 2008). Demographic information was not consistently reported. It was not provided for the subgroup of 132 patients with Parkinson's disease dementia in the largest study (Logemann et al. 2008) and for two case series (Ota et al. 2012;Yamaguchi et al. 2016)altogether 140 participants. Of the data available (n = 55), the mean age of participants was 70.6 years (S.D. = 8.2) and included 27 males and 28 females. Measures of patients' cognition and dementia severity were lacking from the majority of reports. Of the 21 studies, nine recruited participants from nursing homes or hospitals, five recruited participants from the community, and seven did not report participants' residential status. One of the studies that recruited participants from nursing homes examined the effect of an intervention on both a patient with dementia with Lewy bodies and her carers (Huh et al. 2008).

Effectiveness of interventions
Given the heterogeneity of interventions and the poor quality of the research evidence, no quantitative synthesis was possible. A descriptive summary of individual studies is provided in Table 1.
All studies reported some effectiveness of their respective intervention. The strongest evidence came from the randomised Psychological Medicine control trial that assessed interventions to prevent fluid aspiration in participants with dysphagia (Logemann et al. 2008). This trial compared honey-thickened fluids, nectar-thickened fluids, and a chin-down posture in 132 patients with Parkinson's disease dementia (see Table 1). It found that the use of honey-thickened fluids was superior to the other two methods in preventing fluid aspiration as measured by videofluorographic swallow studies.
Four small uncontrolled studies (Kung & O'Connor, 2002;Rasmussen et al. 2003;Takahashi et al. 2009;Yamaguchi et al. 2016)involving 22 participants in totalfound that electroconvulsive therapy had some effectiveness in treating depression in dementia with Lewy bodies. In one of these studies, two patients exhibited confusion immediately after electroconvulsive therapy (Rasmussen et al. 2003); in another study, an unspecified number displayed signs of autonomic dysfunction, though without any lasting effects (Takahashi et al. 2009). No other adverse events were reported. Another three case studies of deep brain stimulation (Loher et al. 2002;Freund et al. 2009;Ricciardi et al. 2015) identified benefits in either cognition or motor symptoms depending on the location of stimulation in patients with Parkinson's disease dementia. All three studies used different brain locations for stimulation. None of these studies reported adverse effects.
Other individual studies variously reported benefits of carer education for reducing agitation (Huh et al. 2008); psychological interventions for reducing distress around visual hallucinations (Ota et al. 2012); physical exercise to improve gait and function (Tabak et al. 2013;Telenius et al. 2015); gait cueing to improve gait speed (Rochester et al. 2009); environmental modification to reduce the distress associated with mirrored selfmisidentification delusion (Gil-Ruiz et al. 2013); music therapy to reduce agitation (Hsu et al. 2015); simulated presence to reduce distress (Cheston et al. 2007); occupational therapy interventions to improve functional ability (Graff et al. 2006;Ciro et al. 2013); physical therapy to improve gait (Dawley, 2015); dietary fluid and postural interventions to prevent aspiration (Logemann et al. 2008); transcranial magnetic stimulation to reduce depression (Takahashi et al. 2009); and transcranial direct current stimulation to improve attention (Elder et al. 2016) (see Table 1). For all these studies, however, limitations in their design, including small sample sizes, lack of blinding, and lack of adequate controls, mean that it is not possible to rule out confounding, selection  bias, experimenter expectancy, publication bias, and other causes for the reported effects.

Discussion
The systematic review identified very little research on nonpharmacological interventions in Lewy body dementia. No randomised control trials focusing specifically on Lewy body dementia were identified and the majority of research consisted of case studies and case series. Of the studies identified, the best quality evidence came from a randomised control trial that focused on preventing fluid aspiration in Parkinson's disease patients with dysphagia (Logemann et al. 2008). As already noted, however, even this study was limited by the fact that it only examined the immediate effects of interventions in an experimental context and did not assess longer term effectiveness in more naturalistic settings. Overall, given the heterogeneity of interventions, small sample sizes, and poor quality of research, no treatment recommendations can be offered. The lack of research in this area is in contrast to the large amount of research on non-pharmacological interventions in other types of dementia (Brodaty & Arasaratnam, 2012;Livingston et al. 2014;Orgeta et al. 2015;Livingston & Cooper, 2017;Seeher & Brodaty, 2017). It is consistent, though, with what has been found in other systematic reviews on Lewy body dementia (Hindle et al. 2013;Stinton et al. 2015;Inskip et al. 2016). Despite the lack of research, however, nonpharmacological interventions are likely to be important in the management of Lewy body dementia. As already noted, pharmacological treatment of psychotic symptoms and movement disturbances in this condition is limited by the difficulties patients have tolerating first-line medications.
At the same time, there is evidence for the effectiveness of nonpharmacological interventions for similar symptoms in other conditions. In the case of psychosis, for example, multi-factorial interventions, including physical activity, occupational therapy, and music therapy, have some evidence of effectiveness in other types of dementia (Brodaty & Arasaratnam, 2012;Chen et al. 2014). In the case of motor disturbances, interventions such as exercise and gait training have been found to be effective in Parkinson's disease (Bloem et al. 2015). There is also strong evidence that nonpharmacological interventions are effective at ameliorating symptoms that are common across different dementias (Brodaty & Arasaratnam, 2012;Livingston et al. 2014;Orgeta et al. 2015;Seeher & Brodaty, 2017). Caregiver education, training, and support, for example, have been shown to reduce both carers' distress and patients' neuropsychiatric symptoms (Brodaty & Arasaratnam, 2012;Seeher & Brodaty, 2017). Likewise, psychological interventions, such as cognitive behavioural therapy, have been shown to reduce patients' depression (Orgeta et al. 2015). Finally, organised activities, music therapy, and sensory stimulation have been shown to reduce patients' agitation (Livingston et al. 2014). All of these interventions could be investigated more systematically in Lewy body dementia.
Altogether, the review highlights the clear and urgent need for research in this area. Possible barriers to this include challenges establishing the diagnosis and distinguishing it from other dementias Vann Jones & O'Brien, 2014); the limited research resources devoted to Lewy body dementia as opposed to other neurodegenerative conditions; and the general lack of funding for non-pharmacological interventions. Each of these, however, is not insurmountable. The use of multicentre registries or networks of centres with expertise in Lewy body dementia, for example, could help to address the problem of recruitment. Given the prevalence of the disease, its disproportionately high social and economic burden (Murman et al. 2003;Boström et al. 2007;Vossius et al. 2014;Svendsboe et al. 2016), and the limited suitability of medications, future research into non-pharmacological interventions is important to improving management at both individual and population levels.