Ying Li1, Shan Hai, Yan Zhou, Bi Rong Dong. 1. Center of Geriatrics and Gerontology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, China, 610041.
Abstract
BACKGROUND: Rarer dementias include Huntington's disease (HD), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), frontotemporal dementia (FTD), dementia in multiple sclerosis (MS) and progressive supranuclear palsy (PSP). Cholinesterase inhibitors, including donepezil, galantamine and rivastigmine, are considered to be the first-line medicines for Alzheimer's disease and some other dementias, such as dementia in Parkinson's disease. Cholinesterase inhibitors are hypothesised to work by inhibiting the enzyme acetylcholinesterase (AChE) which breaks down the neurotransmitter acetylcholine. Cholinesterase inhibitors may also lead to clinical improvement for rarer dementias associated with neurological conditions. OBJECTIVES: To assess the efficacy and safety of cholinesterase inhibitors for cognitive impairment or dementia associated with neurological conditions. SEARCH METHODS: We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register, CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, several trial registries and grey literature sources in August 2013. SELECTION CRITERIA: We included randomised, double-blind, controlled trials assessing the efficacy of treatment of rarer dementias associated with neurological conditions with currently marketed cholinesterase inhibitors. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and quality of trials, and extracted data. We used the standard methodological procedures of the Cochrane Collaboration. MAIN RESULTS: We included eight RCTs involving 567 participants. Six studies used a simple parallel-group design; the other two consisted of an open-label treatment period followed by a randomised phase. All trials were well concealed for allocation and double-blind, however the sample sizes of most trials were small. All trials used placebo as control. We performed meta-analyses for some outcomes in patients with MS. For all other conditions, results are presented narratively.Two trials included patients with HD; one found that cholinesterase inhibitor use in the short-term had no statistically significant impact on the cognitive portion of the Alzheimer Disease Assessment Scale (ADAS-Cog; 1 study, WMD 1.00, 95% CI -1.66 to 3.66, P = 0.46; low quality evidence), Unified Huntington's Disease Rating Scale (UHDRS) Verbal Fluency Test (1 study, WMD -1.20, 95% CI -7.97 to 5.57, P = 0.73; low quality evidence), UHDRS Symbol Digit Modalities Test (SDMT; 1 study, WMD 2.70, 95% CI -0.95 to 6.35, P = 0.15; low quality evidence) and other psychometric tests. The other study found that cholinesterase inhibitor use in the medium-term improved the results of the verbal fluency test (1 study, WMD 6.43, 95% CI 0.66 to 12.20, P = 0.03; moderate quality evidence) and California Verbal Learning Test - Second Edition (CVLT-II) Recognition Task (1 study, WMD 2.42, 95% CI 0.17 to 4.67, P = 0.04; moderate quality evidence). There was no statistically significant difference between groups on the SDMT (1 study, WMD -0.31, 95% CI -7.77 to 7.15, P = 0.94; moderate quality evidence), CVLT-II trials 1-5 (1 study, WMD -2.09, 95% CI -11.65 to 7.47, P = 0.67; moderate quality evidence), short-delay recall (1 study, WMD 0.35, 95% CI -2.87 to 3.57, P = 0.83; moderate quality evidence), or long-delay recall (1 study, WMD -0.14, 95% CI -3.08 to 2.80, P = 0.93; moderate quality evidence), and other psychometric tests.Four trials included patients with MS; one found no differences between the cholinesterase inhibitors (short-term) and placebo groups on the Wechsler Memory Scales general memory score (1 study, WMD 0.90, 95% CI -0.52 to 2.32, P = 0.22; low quality evidence). The three other trials found that, in the medium-term - cholinesterase inhibitors improved the clinician's impression of cognitive change (2 studies, OR 1.96, 95% CI 1.06 to 3.62, P = 0.03; high quality evidence). However, the treatment effect on other aspects of cognitive change were unclear, measured by the Selective Reminding Test (3 studies, WMD 1.47, 95% CI -0.39 to 3.32, P = 0.12; high quality evidence), patient's self-reported impression of memory change (2 studies, OR 1.67, 95% CI 0.93 to 3.00, P = 0.08; high quality evidence) and cognitive change (1 study, OR 0.95, 95% CI 0.45 to 1.98, P = 0.89; high quality evidence), clinician's impression of memory change (1 study, OR 1.50, 95% CI 0.59 to 3.84, P = 0.39; moderate quality evidence), other psychometric tests, and activities of daily living - patient reported impact of multiple sclerosis activities (1 study, WMD -1.18, 95% CI -3.02 to 0.66, P = 0.21; low quality evidence).One study on patients with CADASIL found a beneficial effect of cholinesterase inhibitors on the Executive interview, and Trail Making Test parts A and B. The impact of cholinesterase inhibitors on the Vascular ADAS-Cog score (1 study, WMD 0.04, 95% CI -1.57 to 1.65, P = 0.96; high quality evidence), the Clinical Dementia Rating Scale Sum of Boxes (1 study, WMD -0.09, 95% CI -0.48 to 0.03, P = 0.65; high quality evidence) Disability Assessment for Dementia scale (1 study, WMD 0.58, 95% CI -2.72 to 3.88, P = 0.73; moderate quality evidence), and other measures was unclearOne study included patients with FTD. This trial consisted of an open-label treatment period followed by a randomised, double-blind, placebo-controlled phase. No data of primary outcomes were reported in this study.In the included studies, the most common side effect was gastrointestinal symptoms. For all conditions, compared to the treatment group, the placebo group experienced significantly less nausea (6 studies, 44/257 vs. 22/246, OR 2.10, 95% CI 1.22 to 3.62, P = 0.007; high quality evidence), diarrhoea (6 studies, 40/257 vs. 13/246, OR 3.26, 95% CI 1.72 to 6.19, P = 0.0003; moderate quality evidence) and vomiting (3 studies, 17/192 vs. 3/182, OR 5.76, 95% CI 1.67 to 19.87, P = 0.006; moderate quality evidence). AUTHORS' CONCLUSIONS: The sample sizes of most included trials were small, and some of the results were extracted from only one study. There were no poolable data for HD, CADASIL and FTD patients and there were no results for patients with PSP. Current evidence shows that the efficacy on cognitive function and activities of daily living of cholinesterase inhibitors in people with HD, CADASIL, MS, PSP or FTD is unclear, although cholinesterase inhibitors are associated with more gastrointestinal side effects compared with placebo.
RCT Entities:
BACKGROUND: Rarer dementias include Huntington's disease (HD), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), frontotemporal dementia (FTD), dementia in multiple sclerosis (MS) and progressive supranuclear palsy (PSP). Cholinesterase inhibitors, including donepezil, galantamine and rivastigmine, are considered to be the first-line medicines for Alzheimer's disease and some other dementias, such as dementia in Parkinson's disease. Cholinesterase inhibitors are hypothesised to work by inhibiting the enzyme acetylcholinesterase (AChE) which breaks down the neurotransmitter acetylcholine. Cholinesterase inhibitors may also lead to clinical improvement for rarer dementias associated with neurological conditions. OBJECTIVES: To assess the efficacy and safety of cholinesterase inhibitors for cognitive impairment or dementia associated with neurological conditions. SEARCH METHODS: We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register, CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, several trial registries and grey literature sources in August 2013. SELECTION CRITERIA: We included randomised, double-blind, controlled trials assessing the efficacy of treatment of rarer dementias associated with neurological conditions with currently marketed cholinesterase inhibitors. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and quality of trials, and extracted data. We used the standard methodological procedures of the Cochrane Collaboration. MAIN RESULTS: We included eight RCTs involving 567 participants. Six studies used a simple parallel-group design; the other two consisted of an open-label treatment period followed by a randomised phase. All trials were well concealed for allocation and double-blind, however the sample sizes of most trials were small. All trials used placebo as control. We performed meta-analyses for some outcomes in patients with MS. For all other conditions, results are presented narratively.Two trials included patients with HD; one found that cholinesterase inhibitor use in the short-term had no statistically significant impact on the cognitive portion of the Alzheimer Disease Assessment Scale (ADAS-Cog; 1 study, WMD 1.00, 95% CI -1.66 to 3.66, P = 0.46; low quality evidence), Unified Huntington's Disease Rating Scale (UHDRS) Verbal Fluency Test (1 study, WMD -1.20, 95% CI -7.97 to 5.57, P = 0.73; low quality evidence), UHDRS Symbol Digit Modalities Test (SDMT; 1 study, WMD 2.70, 95% CI -0.95 to 6.35, P = 0.15; low quality evidence) and other psychometric tests. The other study found that cholinesterase inhibitor use in the medium-term improved the results of the verbal fluency test (1 study, WMD 6.43, 95% CI 0.66 to 12.20, P = 0.03; moderate quality evidence) and California Verbal Learning Test - Second Edition (CVLT-II) Recognition Task (1 study, WMD 2.42, 95% CI 0.17 to 4.67, P = 0.04; moderate quality evidence). There was no statistically significant difference between groups on the SDMT (1 study, WMD -0.31, 95% CI -7.77 to 7.15, P = 0.94; moderate quality evidence), CVLT-II trials 1-5 (1 study, WMD -2.09, 95% CI -11.65 to 7.47, P = 0.67; moderate quality evidence), short-delay recall (1 study, WMD 0.35, 95% CI -2.87 to 3.57, P = 0.83; moderate quality evidence), or long-delay recall (1 study, WMD -0.14, 95% CI -3.08 to 2.80, P = 0.93; moderate quality evidence), and other psychometric tests.Four trials included patients with MS; one found no differences between the cholinesterase inhibitors (short-term) and placebo groups on the Wechsler Memory Scales general memory score (1 study, WMD 0.90, 95% CI -0.52 to 2.32, P = 0.22; low quality evidence). The three other trials found that, in the medium-term - cholinesterase inhibitors improved the clinician's impression of cognitive change (2 studies, OR 1.96, 95% CI 1.06 to 3.62, P = 0.03; high quality evidence). However, the treatment effect on other aspects of cognitive change were unclear, measured by the Selective Reminding Test (3 studies, WMD 1.47, 95% CI -0.39 to 3.32, P = 0.12; high quality evidence), patient's self-reported impression of memory change (2 studies, OR 1.67, 95% CI 0.93 to 3.00, P = 0.08; high quality evidence) and cognitive change (1 study, OR 0.95, 95% CI 0.45 to 1.98, P = 0.89; high quality evidence), clinician's impression of memory change (1 study, OR 1.50, 95% CI 0.59 to 3.84, P = 0.39; moderate quality evidence), other psychometric tests, and activities of daily living - patient reported impact of multiple sclerosis activities (1 study, WMD -1.18, 95% CI -3.02 to 0.66, P = 0.21; low quality evidence).One study on patients with CADASIL found a beneficial effect of cholinesterase inhibitors on the Executive interview, and Trail Making Test parts A and B. The impact of cholinesterase inhibitors on the Vascular ADAS-Cog score (1 study, WMD 0.04, 95% CI -1.57 to 1.65, P = 0.96; high quality evidence), the Clinical Dementia Rating Scale Sum of Boxes (1 study, WMD -0.09, 95% CI -0.48 to 0.03, P = 0.65; high quality evidence) Disability Assessment for Dementia scale (1 study, WMD 0.58, 95% CI -2.72 to 3.88, P = 0.73; moderate quality evidence), and other measures was unclearOne study included patients with FTD. This trial consisted of an open-label treatment period followed by a randomised, double-blind, placebo-controlled phase. No data of primary outcomes were reported in this study.In the included studies, the most common side effect was gastrointestinal symptoms. For all conditions, compared to the treatment group, the placebo group experienced significantly less nausea (6 studies, 44/257 vs. 22/246, OR 2.10, 95% CI 1.22 to 3.62, P = 0.007; high quality evidence), diarrhoea (6 studies, 40/257 vs. 13/246, OR 3.26, 95% CI 1.72 to 6.19, P = 0.0003; moderate quality evidence) and vomiting (3 studies, 17/192 vs. 3/182, OR 5.76, 95% CI 1.67 to 19.87, P = 0.006; moderate quality evidence). AUTHORS' CONCLUSIONS: The sample sizes of most included trials were small, and some of the results were extracted from only one study. There were no poolable data for HD, CADASIL and FTDpatients and there were no results for patients with PSP. Current evidence shows that the efficacy on cognitive function and activities of daily living of cholinesterase inhibitors in people with HD, CADASIL, MS, PSP or FTD is unclear, although cholinesterase inhibitors are associated with more gastrointestinal side effects compared with placebo.