Malcolm Man-Son-Hing

Diagnosis and treatment of dementia: 5. Nonpharmacologic and pharmacologic therapy for mild to moderate dementia

Background: Practising physicians frequently seek advice on the most effective interventions for dementia. In this article, we provide practical guidance on nonpharmacologic and pharmacologic interventions for the management of mild to moderate dementia based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. Methods: We developed evidence-based guidelines using systematic literature searches, with specific criteria for the selection and quality assessment of articles, and a clear and transparent decision-making process. We selected articles published from January 1996 to December 2005 that dealt with the management of mild to moderate stages of Alzheimer disease and other forms of dementia. Recommendations based on the literature review were drafted and voted on. Consensus required 80% or more agreement by participants. Subsequent to the conference, we searched for additional articles published from January 2006 to April 2008 using the same major keywords and secondary search terms. We graded the strength of the evidence using the criteria of the Canadian Task Force on Preventive Health Care. Results: We identified 1615 articles, of which 954 were selected for further study. From a synthesis of the evidence in these studies, we made 48 recommendations for the management of mild to moderate dementia (28) and dementia with a cerebrovascular component (8) as well as recommendations for addressing ethical issues (e.g., disclosure of the diagnosis) (12). The updated literature review did not change these recommendations. An exercise program is recommended for patients with mild to moderate dementia. Physicians should decide whether to prescribe a cholinesterase inhibitor on an individual basis, balancing anticipated benefits with the potential for harm. For mild mood and behavioural concerns, nonpharmacologic approaches should be considered first. Interpretation: Although the available therapies for dementia can help with the management of symptoms, there is a need to develop more effective interventions.

Clinical utility of office-based cognitive predictors of fitness to drive in persons with dementia: A systematic review.

OBJECTIVES: To perform a systematic review of evidence available regarding in‐office cognitive tests that differentiate safe from unsafe drivers with dementia.

Systematic Review of Driving Risk and the Efficacy of Compensatory Strategies in Persons with Dementia

OBJECTIVES: To determine whether persons with dementia are at greater driving risk and, if so, to estimate the magnitude of this risk and determine whether there are efficacious methods to compensate for or accommodate it.

Predictors of Driving Ability Following Stroke: A Systematic Review

Abstract Background and Purpose: The objective of this review is to identify the most consistent predictors of driving ability post stroke. Method: A computerized search of numerous databases from 1966 forward was completed. Measured outcomes included voluntary driving cessation or results of on-road driving evaluation. Studies were evaluated using the Newcastle-Ottawa Quality Assessment Scale. Results: 17 eligible studies were identified. The most useful screening tests were tests assessing cognitive abilities. These included the Trail Making A and B tests, the Rey–Osterreith Complex Figure Design, and the Useful Field of View Test. Conclusion: Cognitive tests that assess multiple cognitive domains relevant to driving appear to have the best reproducibility in predicting fitness to drive in stroke patients.

Determination of the clinical importance of study results

Formal statistical methods for analyzing clinical trial data are widely accepted by the medical community. Unfortunately, the interpretation and reporting of trial results from the perspective of clinical importance has not received similar emphasis. This imbalance promotes the historical tendency to consider clinical trial results that are statistically significant as also clinically important, and conversely, those with statistically insignificant results as being clinically unimportant. In this paper, we review the present state of knowledge in the determination of the clinical importance of study results. This work also provides a simple, systematic method for determining the clinical importance of study results. It uses the relationship between the point estimate of the treatment effect (with its associated confidence interval) and the estimate of the smallest treatment effect that would lead to a change in a patient’s management. The possible benefits of this approach include enabling clinicians to more easily interpret the results of clinical trials from a clinical perspective, and promoting a more rational approach to the design of prospective clinical trials.

Meta-analysis of efficacy of quinine for treatment of nocturnal leg cramps in elderly people

Abstract Objective: To assess quantitatively the efficacy of quinine (as quinine sulphate) compared with placebo in the treatment of nocturnal leg cramps. Design: A meta-analysis of six randomised, double blind, crossover trials. Setting: Randomised trials that were available as of April 1994. Subjects: A total of 107 general ambulatory patients who suffered from regular nocturnal leg cramps from six clinical trials. Results: Data from individual patients were used to calculate point estimates and 95% confidence intervals for each of the outcome measures reported by these studies. Treatment with quinine resulted in a significant reduction in the number of cramps for a four week period compared with placebo (8.83 fewer cramps; 95% confidence interval 4.16 to 13.49). Treatment with quinine reduced the number of nights with cramps by 27.4% (24.0% to 30.8%) compared with placebo. Treatment did not produce a significant change in the severity or duration of individual nocturnal leg cramps. Side effects were uncommon. Conclusions: The results indicate that quinine can prevent nocturnal leg cramps in general ambulatory populations. Given the possible serious side effects of treatment with quinine, the benefits and risks in patients taking this drug should be closely monitored. Key messages Key messages The results of this meta-analysis show that quinine sulphate is more effective than placebo in reducing the number of cramps experienced by patients This analysis also suggests that dosing is cumulative, therefore a trial of at least four weeks of quinine may be necessary to show a beneficial effect Quinine should be taken on a regular as opposed to as needed basis as it could not be shown definitively to reduce the severity or duration of an individual cramp

Management of mild to moderate Alzheimer’s disease and dementia

The authors were charged with making a series of evidence‐based recommendations that would provide concrete advice on all aspects of the management of mild to moderate stages of dementia and Alzheimers disease (AD). The recommendations were primarily targeted to primary care physicians practicing in Canada. The assigned topic area did not include either the assessment of a patient with suspected dementia or the prevention of AD and other dementias. An extensive examination of the available literature was conducted. Explicit criteria for grading the strength of recommendations and the level of evidence supporting them were used. The 28 evidence‐based recommendations agreed on are presented in this article.

Diagnosis and treatment of dementia: 4. Approach to management of mild to moderate dementia

Background: The management of mild to moderate dementia presents complex and evolving challenges. Practising physicians are often uncertain about the appropriate approaches to issues such as the disclosure of the diagnosis, driving and caregiver support. In this article, we provide practical guidance on management based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. Methods: We developed evidence-based guidelines using systematic literature searches, with specific criteria for the selection and quality assessment of articles, and a clear and transparent decision-making process. We selected articles published from January 1996 to December 2005 that dealt with the management of mild to moderate stages of Alzheimer disease and other forms of dementia. Recommendations based on the literature review were drafted and voted on. Consensus required 80% or more agreement by participants. Subsequent to the conference, we searched for additional articles published from January 2006 to April 2008 using the same major keywords and secondary search terms. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care. Results: We identified 1615 articles, of which 954 were selected for further study. From a synthesis of the evidence in these studies, we made 48 recommendations for the management of mild to moderate dementia (28) and dementia with a cerebrovascular component (8) as well as recommendations for addressing ethical issues (e.g., disclosure of the diagnosis) (12). The updated literature review did not change these recommendations. In brief, patients and their families should be informed of the diagnosis. Although the specifics of managing comorbid conditions might require modification, standards of care and treatment targets would not change because of a mild dementia. The use of medications with anticholinergic effects should be minimized. There should be proactive planning for driving cessation, since this will be required at some point in the course of progressive dementia. The patients ability to drive should be determined primarily on the basis of his or her functional abilities. An important aspect of care is supporting the patients primary caregiver. Interpretation: Much has been learned about the care of patients with mild to moderate dementia and the support of their primary caregivers. There is a pressing need for the development, and dissemination, of collaborative systems of care.

Key methodological features of randomized controlled trials of Alzheimer's disease therapy. Minimal clinically important difference, sample size and trial duration.

Background: The results of clinical trials are routinely presented in terms of statistical significance, which may or may not indicate clinical significance. Analysis of the minimal clinically important difference (MCID) of cognitive scales has received little attention to date. Objectives: By reviewing the key methodological features (sample size, duration, statistical and clinical significance) of clinical trials examining the efficacy of tacrine in the treatment of Alzheimer’s disease (AD), we assessed their ability to detect clinically important changes in cognition. Design: The value for the MCID of the Mini-Mental State Examination (MMSE) was determined by surveying specialists in neurology and geriatric medicine. This value was then used to interpret the clinical significance of the results of published randomized controlled trials (RCTs) assessing the efficacy of tacrine in the treatment of AD and to retrospectively determine their optimal sample size and trial duration. Results: The mean survey MCID for the MMSE was 3.72 (95% confidence interval 3.50–3.95) points. Only 2 of 12 tacrine RCTs using the MMSE found a statistically significant difference in MMSE scores for patients taking tacrine compared with those taking placebo. These improvements were not clinically significant when compared with the survey MMSE MCID. For parallel trials of tacrine in AD, the smallest sample size and minimum trial duration required to demonstrate a clinically significant difference were calculated to be 53 subjects and 1 year, respectively. Five of the 7 parallel trials met the required sample size; however, none of them met the criteria for trial duration. Conclusions: When using the MMSE as an outcome measure, no tacrine trial reported results that were clinically significant as perceived by clinicians working with dementia patients. Application of a range of plausible MCIDs to the parallel design RCTs also demonstrated that 2 of 7 of these trials did not have sufficient sample size, and none had sufficient duration of treatment to reliably detect clinically meaningful changes in cognition. Future clinical trials in this area will need to incorporate the evolving knowledge of MCIDs in order to increase their chance of detecting clinically relevant results.

Quinine for nocturnal leg cramps: a meta-analysis including unpublished data.

AbstractOBJECTIVE: With respect to the use of quinine for the treatment of nocturnal leg cramps, to determine whether the findings of a previously performed meta-analysis of published data are altered with the addition of unpublished data, and whether publication bias is present in this area. DESIGN: A meta-analysis of eight (four published and four unpublished) randomized, double-blind, placebo-controlled trials, seven of which had a crossover design. SETTING: Randomized trials that were available as of July 1997. SUBJECTS: Ambulatory patients (659) who suffered from regular nocturnal leg cramps. MAIN RESULTS: When individual patient data from all crossover studies were pooled, persons had 3.60 (95% confidence interval [CI] 2.15, 5.05] fewer cramps in a 4-week period when taking quinine compared with placebo. This compared with an estimate of 8.83 fewer cramps (95% CI 4.16, 13.49) from pooling published studies alone. The corresponding relative risk reductions were 21% (95% CI 12%, 30%) and 43% (95% CI 21%, 65%), respectively. Compared with placebo, the use of quinine was associated with an increased incidence of side effects, particularly tinnitus. Publication bias is present in the reporting of the efficacy of quinine for this indication, as almost all published studies reported larger estimates of its efficacy than did unpublished studies. CONCLUSIONS: This study confirms that quinine is efficacious in the prevention of nocturnal leg cramps. However, its benefit may not be as large as reported from the pooling of published studies alone. Given the side effect profile of quinine, nonpharmacologic therapy (e.g., regular passive stretching of the affected muscle) is the best first-line treatment. For persons who find this ineffective and whose quality of life is significantly affected, a trial of quinine is warranted. Prescribing physicians must closely monitor the risks and benefits in individual patients. Publication bias is present in this area even though there is controversy about the role of quinine in the treatment of leg cramps. To minimize the possibility of this bias, persons performing medication-related meta-analyses should seek high-quality unpublished data from drug regulatory agencies and pharmaceutical companies.