Department of Gerontology, Geriatrics and Psychiatry, Catholic University, Rome
Alzheimer Evaluation Unit, IRCCS San Giovanni di Dio, Fatebenefratelli, Brescia, Italy
University Hospital of Geriatrics, Geneva, Switzerland
Laboratory of Epidemiology and Neuroimaging, IRCCS San Giovanni di Dio, Brescia and Fatebenefratelli Research Association, Rome
Geriatric Department, Hospital San Eugenio, Rome
Alzheimer Evaluation Unit, Institute of Neurological and Psychiatric Sciences, Rome
Department of Gerontology, Geriatrics and Psychiatry, Catholic University, Rome, Italy
Correspondence: Graziano Onder, Centro Medicina dellInvecchiamento, Università Cattolica del Sacro Cuore, L.go Francesco Vito 1, 00168 Roma, Italy. Tel: +39 06 30154341; fax: +39 06 3051911; e-mail: graziano_onder{at}rm.unicatt.it
Declaration of interest O.Z. is on the speaker bureau of Pfizer, Novartis, Janssen-Cilag and Bracco; R.B. has received honoraria from Pfizer. Funding from the Italian Ministry of Health.
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ABSTRACT |
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Aims To perform such an evaluation.
Method We randomly assigned 79 of156 patients treated with donepezil to receive a reality orientation programme. Caregivers of the treatment group were trained to offer the programme at home 3 days a week, 30 min/day, for 25 consecutive weeks, and were invited to stimulate and involve patients in reality-based communication.
Results The treatment group showed a slight improvement in
Mini-Mental State Examination (MMSE) scores (mean change +0.2, s.e.=0.4)
compared with a decline in the control group (mean change 1.1,
s.e.=0.4; P=0.02). Similarly for the Alzheimers Disease
Assessment Scale Cognition (treatment group mean change +0.4,
s.e.=0.8; control group 2.5, s.e.=0.8; P=0.01). The
intervention had an equal effecton cognition in those with mild (MMSE score
20) and moderate (score <20) dementia. No significant effect was
observed for behavioural and functional outcomes.
Conclusions Reality orientation enhances the effects of donepezil on cognition in Alzheimers disease.
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INTRODUCTION |
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METHOD |
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People were considered suitable for participation in the study if they met the National Institute of Neurological and Communicative Diseases and Stroke and the Alzheimers Disease and Related Disorders Association (NINCDSADRA) criteria for probable Alzheimers disease (McKhann et al, 1984), scored between 14 and 27 on the Mini-Mental State Examination (MMSE; Folstein et al, 1975), did not present with major aphasia or blindness, and had received pharmacological treatment with donepezil for at least 3 months. Figure 1 shows the trial profile, including data on people screened and excluded because they did not meet the eligibility criteria. Data on those not receiving pharmacological treatment with donepezil for at least 3 months were not collected. All patients participating in the CRONOS project were taking donepezil (the only cholinesterase inhibitor available in Italy at the time of the study) and were followed for at least 6 months.
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Patients and caregivers participating in the study were assessed at baseline and at the 25-week follow-up (end of the study) by personnel unaware of group allocation. Patients assessments included demographic information; cognitive function, measured with the MMSE and the Alzheimers Disease Assessment Scale Cognition (ADASCog; Rosen et al, 1984); functional status, measured with the Barthel index (Mahoney & Barthel, 1965) and Instrumental Activities of Daily Living (IADL; Lawton & Brody, 1969); behaviour (Neuropsychiatric Inventory; Cummings et al, 1994); and medications used. Caregivers assessment included demographic information; mood measured with the Hamilton Rating Scales for Depression (HRSD; Hamilton, 1967) and Anxiety (HRSA; Hamilton, 1959); quality of life (rated using the Medical Outcomes Study 36-item Short-Form General Health Survey (SF36; Tarlov et al, 1989)); and burden of care (Caregiver Burden Inventory; Novak & Guest, 1989).
In each of the participating centres, caregivers in the intervention group were trained by a team including physicians, psychologists and therapists to deliver a programme of reality orientation in patients own home. They were also provided with a manual of instruction on this therapy and specific schedules for each session. During the training meeting, a brief history of reality orientation therapy and results obtained by the use of this approach in previous studies were presented. Next the manual was read and discussed in order to answer questions raised by caregivers and to resolve any doubts. In addition, caregivers were given a detailed explanation of how to approach and stimulate the patients both during the reality orientation session and informally during the day. Finally, a simulated therapy session was presented.
Caregivers were instructed to provide three orientation sessions per week, for 25 consecutive weeks. Each session lasted about 30 min and consisted of an organised, intensive cognitive training during which the caregiver gradually presented information such as date, time and location. In the first part of the session attention was directed to personal, time and space orientation; following this, topics of general interest such as historical events and famous people, attention, memory and visuospatial exercises were introduced. Patients were prompted to give either spontaneous or cued answers, with the aid of calendars, clocks and notes. Besides the formal reality orientation sessions, caregivers were also invited to stimulate and involve patients in reality-based communication two or three times throughout the day informally, focusing on personal, time and space orientation and discussing news or topics of general interest.
The appropriate local research ethics committees granted approval. After hearing an explanation of the study, patients and caregivers who agreed to participate gave written informed consent.
We calculated that a sample size of 142 participants allows for detection of a difference of 2 points in MMSE score between study groups, with 80% power and at a 0.05 level of type I error. This calculation assumed, on the basis of a previous observation (Metitieri et al, 2001), a common standard deviation of 4 and a 10% withdrawal rate.
Statistical analysis
Differences in baseline characteristics between the treatment group and the
control group in categorical parameters were tested using Fishers exact
test. Differences between continuous variables were assessed by analysis of
variance (ANOVA) comparisons for normally distributed parameters; otherwise,
the KruskalWallis test was used. Data were analysed based on intention
to treat. Analysis of covariance (ANCOVA) was performed to compare the change
in outcome measures between treatment and control group. Analyses were
adjusted for baseline value of the outcome measure. In additional analyses, we
calculated the number of participants needed to be treated for 1 patient to
achieve one of the following outcomes: an improvement of 4 or more points in
the ADASCog score, or any improvement in the ADASCog score
(change in score 40). The number needed to treat (NNT) was calculated using
the formula described by Cook & Sackett
(1995). Finally, to explore
whether the effect of the intervention on cognitive outcomes (MMSE and
ADASCog) differed according to baseline cognitive status, we repeated
ANCOVA comparisons separately for patients with baseline MMSE scores below 20
(n=60; moderate dementia) and those with scores of 20 or over
(n=77; mild dementia). These analyses were adjusted for baseline
value of the outcome measure. A value of P<0.05 (two-tailed) was
considered statistically significant. All analyses were performed using the
Statistical Package for the Social Sciences (SPSS for Windows, version
10.0).
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RESULTS |
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The mean duration of follow-up was 25.4 weeks (s.d.=5.0). Table 2 compares changes in patient and caregiver outcomes between the two study groups, after adjusting for the baseline value of the outcome measure examined. Reality orientation appeared to have an additive beneficial effect on cognition: in the treatment group MMSE scores showed a slight improvement (0.2 points, s.e.=0.4) compared with a decline of 1.1 points (s.d.=0.4) in the control group (P=0.02). Similarly, the ADASCog score improved by 0.4 points (s.e.=0.8) in the treatment group and declined by 2.5 points (s.e.=0.8) in the control group (P=0.01). No significant difference between study groups was observed for ratings on the Neuropsychiatric Inventory (P=0.23), Barthel Index (P=0.18) and number of impaired IADL (P=0.34). In addition, we did not observe any significant difference for scores on the Neuropsychiatric Inventory sub-scales (data not shown).
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There was no difference between the two caregiver groups in terms of their decline in scores on the HRSD, HRSA, Caregiver Burden Inventory and SF36 (Table 2). No significant difference between the groups was observed in Caregiver Burden Inventory and SF36 sub-scales (data not shown).
Overall, 19% of participants in the treatment group and 11% in the control group improved by 4 or more points in the ADASCog score. When calculating the NNT for this outcome, we found that 14 people needed to be treated in order for 1 to benefit. Similarly, 45% of participants in the treatment group and 36% in the control group showed an improvement in the ADASCog score (change in score >0). In this case, 11 people needed to be treated in order for 1 to benefit.
In additional analyses we explored the effect of treatment on cognitive outcomes in patients with moderate dementia (n=60) and mild dementia (n=77). Among patients with moderate dementia, treatment was associated with an improvement in both MMSE score (1.1 points, s.e.=0.7) and ADASCog (1.8 points, s.e.=1.2), compared with a decline in these measures observed among patients in the control group (MMSE score 0.4, s.e.=0.6, P=0.12 v. treatment group; ADASCog 1.8, s.e.=1.1, P=0.03 v. treatment group). Among patients with mild dementia, both MMSE and ADASCog scores declined during the study period, but this change was less marked in the intervention group than in the control group: MMSE score: treatment group 0.4 (s.e.=0.4), control group 1.7 (s.e.=0.4), P=0.03; ADASCog score: treatment group 0.8 (s.e.=1.0), control group 2.8 (s.e.=1.1), P=0.18. No significant interaction was observed between dementia group and treatment on change in MMSE score (P=0.83) and ADASCog score (P=0.40).
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DISCUSSION |
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Our results confirm and extend to the long term the beneficial effects of reality orientation on cognitive function reported by previous trials of shorter duration (Spector et al, 2000a, 2003), and suggest an additive effect of reality orientation when combined with anticholinesterase therapy. This effect may be explained through cognitive stimulation by caregivers, which made participants more able to communicate effectively, and to respond to the environment and to other people, by reinforcing questioning, thinking and interacting ability. In addition, this cognitive training may have improved patients self-esteem through their increased ability to retain information and continuous encouragement by caregivers (Spector et al, 2003).
The size of the effect of the reality orientation programme on MMSE score (1.3 points) was smaller than we predicted; however, Jonsson et al (1999) have shown that a difference of even 1 point in MMSE score is associated with a substantial reduction in the cost of caring for patients with dementia. In addition, we failed to show any significant effect on functional and behavioural changes. Thus, if the benefit of our intervention is evaluated in the light of the main objective of psychosocial rehabilitation, its value may be limited. However, it has been suggested that the Barthel Index, IADL and behavioural measures may have low sensitivity to detect mild functional and behavioural changes related to cognitive stimulation programmes and that more sensitive outcomes (i.e. functional performance measures) might provide a superior method for longitudinal assessments (Zanetti et al, 1995; Onder et al, 2002). In this context, it should be noted that a recent Cochrane review concluded that reality orientation may have a beneficial effect on behaviour (Spector et al, 2002a), but only one of the individual trials included demonstrated a significant difference in this outcome (Baines et al, 1987). In line with these findings, previous studies on cholinesterase inhibitor therapy alone showed a lack of improvement in carers and patients functional and behavioural outcomes, despite a positive effect on cognition (Trinh et al, 2003; Courtney et al, 2004).
Comparison with other reality orientation programmes
This is, to our knowledge, the first randomised trial to assess the
effectiveness of a home-based reality orientation programme delivered by
caregivers. This study combines a formal reality orientation approach, based
on lessons given by caregivers on a regular basis during the week, with an
informal approach, based on repetition of orientation information at all times
throughout the day with no fixed schedule. Most of the clinical trials
published so far evaluated the efficacy of formal therapy given in classrooms
where groups of patients met in specialised centres on a regular basis to
engage in orientation-related activities. Compared with this latter approach,
which provides only a mass teaching of generic orientation
skills, a home-based programme of formal and informal reality orientation
delivered by caregivers offers the advantage of a more individualised
treatment (Spector et al,
2000a). In addition, continuous stimulation and
orientation to reality during the day might be a good way to retain what has
been learned during formal lessons, leading to an increment in the effect of
the formal therapy. In this context, it is noteworthy that our home-based
programme did not significantly worsen the psychological status and quality of
life of caregivers, suggesting that the higher burden of care related to the
sessions was counterbalanced by the improvements experienced by patients.
Effect of reality orientation and baseline cognitive status
We have previously shown that baseline cognitive function may influence
response to reality orientation therapy
(Zanetti et al,
2002). In this study both patients with mild dementia and those
with moderate dementia significantly benefited from the intervention, even if
the more severely affected patients had a clear gain in terms of MMSE and
ADASCog points, compared with stabilisation in scores on these measures
observed among the patients with milder dementia. This favourable response in
patients with more severe dementia seems in line with the reported effects of
anticholinesterase treatment. Indeed, Farlow et al
(2001) showed that rate of
dementia progression predicts response to cholinesterase inhibitors, and that
patients with more rapidly progressive disease might be particularly likely to
benefit from treatment with these agents. However, we cannot exclude the
possibility that our findings might be explained by a ceiling effect in this
less compromised group, whose scores in the outcome measures were already
elevated at baseline.
Reality orientation and anticholinesterase therapy
This is the first trial to evaluate the effect of reality orientation in
combination with cholinesterase inhibitor therapy. Participants entering the
study had already received treatment with donepezil for at least 3 months, the
time required for the maximum effect of this drug to be reached
(Feldman et al, 2001).
This criterion was applied to ensure the selection of a group of participants
receiving donepezil on a stable basis, to reduce the number of people leaving
treatment because of side-effects, and to avoid the beneficial response to
donepezil observed at the beginning of treatment confounding or hiding the
effects of reality orientation. It is therefore not surprising that patients
in the control group declined in cognitive outcomes despite treatment with
donepezil, since they had started taking this drug on average 7 months before
entering the study, by which time the maximum effect of cholinesterase
inhibitor therapy would be waning.
Limitations
A major limitation of this study is that the reality orientation programme
was administered by caregivers, with no guarantee that patients were receiving
the intervention as intended in the study protocol. However, a poor adherence
to study protocol would have led to a dilution of the effects, resulting in an
underestimation of the benefits of the intervention. In addition, it could be
argued that the beneficial effect of the intervention we observed may be
related to an improvement in social contact or attention in the intervention
group, and that the programme should have been compared with other
psychosocial approaches. However, a review by Spector et al
(2000b) showed that
there are no differences in the effect of alternative activities (either no
treatment or alternative social therapy) offered to control groups during
trials of reality orientation. Therefore, we concluded from our study that the
qualities of reality orientation, rather than merely the therapeutic effect of
social contact and attention, may affect patients outcomes. Another
limitation relates to the fact that data on adherence to donepezil treatment
were not collected. During the study period participants might have stopped or
changed their dosage of donepezil, and this could have influenced their level
of cognition. Finally, the rate of withdrawal in our study was 12% (19 of 156
patients), which is comparable to previous observations with shorter follow-up
periods.
In conclusion, our study shows that a home-based programme of reality orientation provided by caregivers improves cognitive function, enhancing the effect of anticholinesterase treatment alone. Future studies are needed to explore whether the benefit of reality orientation may be extended to physical function and behaviour. The addition of non-pharmacological therapy should be recommended in patients receiving cholinesterase inhibitors.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication September 14, 2004. Revision received January 24, 2005. Accepted for publication January 28, 2005.
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