Applying generalizability theory to examine assessments of subjective cognitive complaints: whose reports should we rely on - participant versus informant?

OBJECTIVES: This study aimed to apply the generalizability theory (G-theory) to investigate dynamic and enduring patterns of subjective cognitive complaints (SCC), and reliability of two widely used SCC assessment tools. DESIGN: G-theory was applied to assessment scales using longitudinal measurement design with five assessments spanning 10 years of follow-up. SETTING: Community-dwelling older adults aged 70-90 years and their informants, living in Sydney, Australia, participated in the longitudinal Sydney Memory and Ageing Study. PARTICIPANTS: The sample included 232 participants aged 70 years and older, and 232 associated informants. Participants were predominantly White Europeans (97.8%). The sample of informants included 76 males (32.8%), 153 females (65.9%), and their age ranged from 27 to 86 years, with a mean age of 61.3 years (SD = 14.38). MEASUREMENTS: The Memory Complaint Questionnaire (MAC-Q) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). RESULTS: The IQCODE demonstrated strong reliability in measuring enduring patterns of SCC with G = 0.86. Marginally acceptable reliability of the 6-item MAC-Q (G = 0.77-0.80) was optimized by removing one item resulting in G = 0.80-0.81. Most items of both assessments were measuring enduring SCC with exception of one dynamic MAC-Q item. The IQCODE significantly predicted global cognition scores and risk of dementia incident across all occasions, while MAC-Q scores were only significant predictors on some occasions. CONCLUSIONS: While both informants' (IQCODE) and self-reported (MAC-Q) SCC scores were generalizable across sample population and occasions, self-reported (MAC-Q) scores may be less accurate in predicting cognitive ability and diagnosis of each individual.

Association of plasma C-reactive protein with ischaemic stroke: a Mendelian randomization study.

BACKGROUND AND PURPOSE: Elevated C-reactive protein (CRP) is associated with an increased risk of ischaemic stroke (IS). However, the causality of this association is uncertain. The aim is to investigate whether genetically raised plasma CRP concentration levels are associated with IS on the basis of the Mendelian randomization method. METHODS: Based on the National Center for Biotechnology Information single nucleotide polymorphism (SNP) database, the Chinese online genetic database as well as previously published studies, four CRP-associated SNP alleles (rs1130864, rs1205, rs876537 and rs3093059) with minor allele frequency ≥0.15 were selected and the concentration levels of CRP were measured in 378 first-ever IS patients and 613 healthy controls. RESULTS: Three SNPs were chosen and used as instrumental variables. The adjusted odds ratios (ORs) [95% confidence interval (95% CI)] of IS per addition of the modelled allele were 1.07 (0.79-1.45) for rs876537, 0.99 (0.73-1.35) for rs1205 and 1.08 (0.71-1.65) for rs3093059. The OR (95% CI) of IS for plasma CRP ≥2.0 mg/l was 2.19 (1.06-4.53) compared with <2.0 mg/l. The adjusted OR (95% CI) of IS per genetically predicted 10% higher CRP concentration, based on the three SNPs as the instruments, was 1.02 (0.94-1.11). Furthermore, similar results were obtained with adjusted ORs (95% CI) of 1.00 (0.88-1.13) and 1.04 (0.93-1.16), respectively, for large-artery atherosclerosis and small-artery occlusion per genetically predicted 10% higher CRP concentration. CONCLUSIONS: This Mendelian randomization study provides no clear support that elevated CRP concentration is causally associated with the risk of IS.

Burden of neurodegenerative diseases in the Eastern Mediterranean Region, 1990-2016: findings from the Global Burden of Disease Study 2016.

BACKGROUND AND PURPOSE: The Eastern Mediterranean Region (EMR) is experiencing a demographic shift towards rapid aging at a time of political unrest. We aimed to estimate the burden of neurodegenerative disorders and its relationship with sociodemographic index in the EMR countries from 1990 to 2016. METHODS: Using data from the Global Burden of Disease Study 2016, we calculated country-specific trends for prevalence, mortality, disability-adjusted life-years (DALY), years of life lost and years lived with disability (YLD) for Alzheimer's disease/other dementias and Parkinson's disease in the EMR during 1990-2016. RESULTS: In the EMR, the age-standardized prevalence rate of Alzheimer's disease/other dementias and Parkinson's disease was estimated at 759.8/100 000 (95% uncertainty intervals, 642.9-899.9) and 87.1/100 000 (95% uncertainty intervals, 69.8-108.2) people in 2016, demonstrating 0.01% and 42.3% change from 1990, respectively. Neurodegenerative disorders contributed to 5.4% of total DALY and 4.6% of total YLD among the older EMR population (70 years of age or older in 2016). Age-standardized DALY due to Parkinson's disease were strongly correlated with the sociodemographic index level (r = 0.823, P < 0.001). The YLD:DALY ratio of neurodegenerative diseases declined during this period in the low-income but not the high-income EMR countries. CONCLUSIONS: Our findings demonstrated an increasing trend in the burden of dementias and Parkinson's disease in most EMR countries between 1990 and 2016. With aging of the EMR populations, countries should target the modifiable risk factors of neurodegenerative diseases to control their increasing burden.

MLC901 (NeuroAiD II™) for cognition after traumatic brain injury: a pilot randomized clinical trial.

BACKGROUND AND PURPOSE: Treatments to facilitate recovery after traumatic brain injury (TBI) are urgently needed. We conducted a 9-month pilot, randomized placebo-controlled clinical trial to examine the safety and potential effects of the herbal supplement MLC901 (NeuroAiD II™) on cognitive functioning following TBI. METHODS: Adults aged 18-65 years at 1-12 months after mild or moderate TBI were randomized to receive MLC901 (0.8 g capsules 3 times daily) or placebo for 6 months. The primary outcome was cognitive functioning as assessed by the CNS Vital Signs online neuropsychological test. Secondary outcomes included the Cognitive Failures Questionnaire, the Rivermead Post-concussion Symptom Questionnaire (neurobehavioral sequelae), Quality of Life after Brain Injury, Hospital Anxiety and Depression Scale, Modified Fatigue Impact Scale and extended Glasgow Outcome Scale (physical disability). Assessments were completed at baseline and at 3-, 6- and 9-month follow-up. Linear mixed-effects models were conducted, with the primary outcome time-point of 6 months. RESULTS: A total of 78 participants [mean age 37.5 ± 14.8 years, 39 (50%) female] were included in the analysis. Baseline variables were similar between groups (treatment group, n = 36; control group, n = 42). Linear mixed-effects models controlling for time, group allocation, repeated measurements, adherence and baseline assessment scores revealed significant improvements in complex attention (P = 0.04, d = 0.6) and executive functioning (P = 0.04, d = 0.4) at 6 months in the MLC901 group compared with controls. There were no significant differences between the groups for neurobehavioral sequelae, mood, fatigue, physical disability or overall quality of life at 6 months. No serious adverse events were reported. CONCLUSIONS: MLC901 was safe and well tolerated post-TBI. This study provided Class I/II evidence that, for patients with mild to moderate TBI, 6 months of MLC901 improved cognitive functioning.

Prevalence, natural course and predictors of depression 1 year following traumatic brain injury from a population-based study in New Zealand.

OBJECTIVE: Depression is common post-TBI, yet has not been studied longitudinally, nor at a population level. This study examined prevalence of depression in a population-based sample across the first year post-TBI. DESIGN AND METHODS: Prospective follow-up of 315 adults (>16 years) with assessments (Hospital Anxiety Depression Scale, DSM-IV criteria) at 1-, 6- and 12-months post-TBI. Demographic and injury-related predictors of depression at 1-year post-TBI were also explored. RESULTS: The number of individuals identified as depressed reduced significantly between baseline and 12-months post-TBI from 21-12.4% using the HADS and 49-34% using DSM-IV criteria; with only 10 of the 28 individuals initially meeting criteria on the HADS continuing to do so at 12-month follow-up. Meeting HADS depression criteria was linked to pre-morbid depression and/or anxiety; while those meeting DSM-IV criteria were older, but not significantly so. CONCLUSIONS: The findings suggest depression is common post-TBI and that clinicians/researchers use caution in its diagnosis, as existing criteria have significant overlap with common TBI sequels.

Enzogenol for cognitive functioning in traumatic brain injury: a pilot placebo-controlled RCT.

BACKGROUND AND PURPOSE: Enzogenol, a flavonoid-rich extract from Pinus radiata bark with antioxidant and anti-inflammatory properties has been shown to improve working memory in healthy adults. In traumatic brain injury (TBI), oxidation and inflammation have been linked to poorer cognitive outcomes. Hence, this phase II, randomized controlled trial investigated safety, compliance and efficacy of Enzogenol for improving cognitive functioning in people following mild TBI. METHODS: Sixty adults, who sustained a mild TBI, 3-12 months prior to recruitment, and who were experiencing persistent cognitive difficulties [Cognitive Failures Questionnaire (CFQ) score > 38], were randomized to receive Enzogenol (1000 mg/day) or matching placebo for 6 weeks. Subsequently, all participants received Enzogenol for a further 6 weeks, followed by placebo for 4 weeks. Compliance, side-effects, cognitive failures, working and episodic memory, post-concussive symptoms and mood were assessed at baseline, 6, 12 and 16 weeks. Simultaneous estimation of treatment effect and breakpoint was effected, with confidence intervals (CIs) obtained through a treatment-placebo balance-preserving bootstrap procedure. RESULTS: Enzogenol was found to be safe and well tolerated. Trend and breakpoint analyses showed a significant reduction in cognitive failures after 6 weeks [mean CFQ score, 95% CI, Enzogenol versus placebo -6.9 (-10.8 to -4.1)]. Improvements in the frequency of self-reported cognitive failures were estimated to continue until week 11 before stabilizing. Other outcome measures showed some positive trends but no significant treatment effects. CONCLUSIONS: Enzogenol supplementation is safe and well tolerated in people after mild TBI, and may improve cognitive functioning in this patient population. This study provides Class IIB evidence that Enzogenol is well tolerated and may reduce self-perceived cognitive failures in patients 3-12 months post-mild TBI.

The spectrum captured: a methodological approach to studying incidence and outcomes of traumatic brain injury on a population level.

OBJECTIVE: Drawing on the experience of conducting the Brain Injury Incidence and Outcomes New Zealand in the Community study, this article aims to identify the issues arising from the implementation of proposed guidelines for population-based studies of incidence and outcomes in traumatic brain injury (TBI). STUDY DESIGN AND SETTING: All new cases of TBI (all ages and severities) were ascertained over a 1-year period, using overlapping prospective and retrospective sources of case ascertainment in New Zealand. All eligible TBI cases were invited to participate in a comprehensive assessment at baseline and at 1-month follow-up. RESULTS: Our experience to date has revealed the feasibility of case ascertainment methods. Consultation with community health services and professionals resulted in feasible referral pathways to support the identification of TBI cases. 'Hot pursuit' methods of recruitment were essential to ensure complete case ascertainment for this population with few additional cases of TBI identified through cross-checks. CONCLUSION: This review of proposed guidelines in relation to practical study methodology provides a framework for future comparable population-based epidemiological studies of TBI incidence and outcomes in developed countries.

Auckland Stroke Outcomes Study. Part 1: Gender, stroke types, ethnicity, and functional outcomes 5 years poststroke.

BACKGROUND: Studying long-term stroke outcomes including body functioning (neurologic and neuropsychological impairments) and activity limitations and participation is essential for long-term evidence-based rehabilitation and service planning, resource allocation, and improving health outcomes in stroke. However, reliable data to address these issues is lacking. METHODS: This study (February 2007-December 2008) sourced its participants from the population-based incidence study conducted in Auckland in 2002-2003. Participants completed structured self-administered questionnaires, and a face-to-face interview including a battery of neuropsychological tests. Logistic regression analysis was used to analyze associations between and within functional outcomes and their potential predictors. RESULTS: Of 418 5-year stroke survivors, two-thirds had good functional outcome in terms of neurologic impairment and disability (defined as modified Rankin Score <3), 22.5% had cognitive impairment indicative of dementia, 20% had experienced a recurrent stroke, almost 15% were institutionalized, and 29.6% had symptoms suggesting depression. Highly significant correlations were found between and within various measurements of body functioning (especially neuropsychological impairments), activity, and participation. Age, dependency, and depression were independently associated with most outcomes analyzed. CONCLUSIONS: The strong associations between neuropsychological impairment and other functional outcomes and across various measurements of body functioning, activity, and participation justify utilizing a multidisciplinary approach to studying and managing long-term stroke outcomes. Observed gender and ethnic differences in some important stroke outcomes warrant further investigations.

Auckland Stroke Outcomes Study. Part 2: Cognition and functional outcomes 5 years poststroke.

BACKGROUND: Understanding the extent of long-term neuropsychological deficits poststroke and their contribution to functional outcomes is essential for evidence-based rehabilitation and resource planning, and could improve stroke outcomes. However, most existing neuropsychological stroke data are not population-based, examine limited outcomes, and have short-term follow-up. METHODS: This population-based long-term stroke follow-up study examined associations between neuropsychological deficits (memory, executive function, information processing speed [IPS], visuoperceptual/construction ability, language), depression, and a range of functional outcomes and their interrelationships 5 years poststroke. RESULTS: The greatest proportion of the 307 participants exhibited neuropsychological functioning within the average range, and about 30%-50% performed at lower levels on most measures; few performed above the average range. Deficits were most common in executive functioning and IPS, and 30.4% of participants were depressed. While correlation analyses indicate all cognitive domains are significantly related to functional outcomes, multiple regression analyses showed that only IPS and visuoperceptual ability made significant independent contributions to functional outcomes over and above age, depression, and current Barthel Index. Depression also made a significant and independent contribution to functional outcomes. CONCLUSION: A considerable proportion of 5-year stroke survivors experience neuropsychological deficits, with these being more likely to involve IPS and executive functioning. Visuoperceptual/construction abilities, visual memory, and IPS were independently associated with handicap, disability, and health-related quality of life over and above contributions made by age, depression, and stroke severity, suggesting these areas are important targets for rehabilitation to improve overall stroke recovery and should be evaluated in future randomized controlled trials.

Does cigarette smoking exacerbate the effect of total cholesterol and high-density lipoprotein cholesterol on the risk of cardiovascular diseases?

OBJECTIVE: To explore whether an interaction between smoking and serum total cholesterol (TC) and/or decreased levels of serum high-density lipoprotein cholesterol (HDLC) exists for any major subtype of cardiovascular disease. DESIGN: An individual participant overview of 34 cohort studies. SETTING: The Asia-Pacific region. PARTICIPANTS: People aged >or=20 years without a particular condition or risk factor. MEAN OUTCOME MEASURES: Hazard ratios (HRs) and 95% confidence intervals (CIs) for both TC and HDLC by smoking status were estimated using Cox proportional hazard models adjusted for age and systolic blood pressure and stratified by study and sex. RESULTS: During follow-up (median 4.0 years), 3298 coronary heart disease (CHD) and 4318 stroke events were recorded. For CHD, the HR (95% CI) for an additional 1.06 mmol/l increment in TC was greater in current smokers than in non-smokers: 1.54 (1.43 to 1.66) versus 1.38 (1.30 to 1.47); p = 0.02. Similarly, the HR (95% CI) for an additional 0.40 mmol/l decrement in HDLC was greater in current smokers than in non-smokers: 1.67 (1.35 to 2.07) versus 1.28 (1.10 to 1.49); p = 0.04. The positive association of TC with ischaemic stroke, and the negative association of TC with haemorrhagic stroke, were broadly similar for current smokers and non-smokers. Similarly, the risks of both the subtypes of stroke remained broadly unchanged as HDLC decreased in both current smokers and non-smokers. CONCLUSIONS: Smoking exacerbated the effects of both TC and HDLC on CHD, although no interaction between smoking and TC or HDLC existed for either of the subtypes of stroke.

Calcium antagonists for aneurysmal subarachnoid haemorrhage.

BACKGROUND: Secondary ischaemia is a frequent cause of poor outcome in patients with subarachnoid haemorrhage (SAH). Its pathogenesis has been incompletely elucidated, but vasospasm probably is a contributing factor. Experimental studies have suggested that calcium antagonists can prevent or reverse vasospasm and have neuroprotective properties. OBJECTIVES: To determine whether calcium antagonists improve outcome in patients with aneurysmal SAH. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched April 2006), MEDLINE (1966 to March 2006) and EMBASE (1980 to March 2006). We handsearched two Russian journals (1990 to 2003), and contacted trialists and pharmaceutical companies in 1995 and 1996. SELECTION CRITERIA: Randomised controlled trials comparing calcium antagonists with control, or a second calcium antagonist (magnesium sulphate) versus control in addition to another calcium antagonist (nimodipine) in both the intervention and control groups. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data and assessed trial quality. Trialists were contacted to obtain missing information. MAIN RESULTS: Sixteen trials, involving 3361 patients, were included in the review; three of the studies were of magnesium sulphate in addition to nimodipine. Overall, calcium antagonists reduced the risk of poor outcome: the relative risk (RR) was 0.81 (95% confidence interval (CI) 0.72 to 0.92); the corresponding number of patients needed to treat was 19 (95% CI 1 to 51). For oral nimodipine alone the RR was 0.67 (95% CI 0.55 to 0.81), for other calcium antagonists or intravenous administration of nimodipine the results were not statistically significant. Calcium antagonists reduced the occurrence of secondary ischaemia and showed a favourable trend for case fatality. For magnesium in addition to standard treatment with nimodipine, the RR was 0.75 (95% CI 0.57 to 1.00) for a poor outcome and 0.66 (95% CI 0.45 to 0.96) for clinical signs of secondary ischaemia. AUTHORS' CONCLUSIONS: Calcium antagonists reduce the risk of poor outcome and secondary ischaemia after aneurysmal SAH. The results for 'poor outcome' depend largely on a single large trial of oral nimodipine; the evidence for other calcium antagonists is inconclusive. The evidence for nimodipine is not beyond all doubt, but given the potential benefits and modest risks of this treatment, oral nimodipine is currently indicated in patients with aneurysmal SAH. Intravenous administration of calcium antagonists cannot be recommended for routine practice on the basis of the present evidence. Magnesium sulphate is a promising agent but more evidence is needed before definite conclusions can be drawn.

Risk factors for Alzheimer's disease in Russia: a case-control study.

No reliable data on risk factors of Alzheimer's disease (AD) are available in Russia. We aimed to evaluate the relative importance of various putative environmental and medical risk factors of AD in a Russian population. We conducted a hospital-based case-control study. Two hundred and sixty consecutive AD patients and an equal number of cognitive impairment-free control subjects matched for sex, age, level of education and place of birth selected from nursing homes and other long-term healthcare facilities in the Novosibirsk region for the period from 1998 to 2002 were examined. A conditional logistic regression analysis was employed to calculate odds ratios (OR) and corresponding 95% confidence intervals (CI) for various putative risk factors. Of the 260 patients with AD, 187 (72%) were females. Patients' age varied from 40 to 89 years (mean +/- SD: 69.2 +/- 7.7 years). The majority of the patients (77%) had secondary education and 12% had university education. Risk factors independently associated with AD were family history of parkinsonism among first-degree relatives (OR = 4.2; 95% CI 1.2-15.1), hypothyroidism (OR = 2.7; 95% CI 1.1-6.7), and history of head trauma with loss of consciousness (OR = 1.7; 95% CI 1.0-2.8). The most important risk factors for AD in the Russian community are family history of parkinsonism, hypothyroidism and a history of head trauma with loss of consciousness. These findings have implications for developing preventive strategies of AD.

Corticosteroids for aneurysmal subarachnoid haemorrhage and primary intracerebral haemorrhage.

BACKGROUND: Corticosteroids, particularly dexamethasone, are commonly used for treatments in patients with subarachnoid haemorrhage (SAH) and primary intracerebral haemorrhage (PICH) despite the lack of evidence. OBJECTIVES: This review aimed: (1) to determine whether corticosteroid therapy reduces the proportion of patients who die or have a poor outcome at one to six months after the onset of SAH or PICH; (2) to determine whether corticosteroid therapy reduces the frequency of delayed cerebral ischaemia (DCI) in patients with SAH; (3) to determine the frequency of adverse effects of corticosteroid therapy in patients with SAH or PICH within six months of the onset of the event. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched November 2003). In addition, we searched MEDLINE (1966 to March 2004) and EMBASE (1980 to March 2004), and searched reference lists of relevant studies identified. We also made an attempt to identify any relevant ongoing and published or unpublished studies by contacting trialists and pharmaceutical companies. SELECTION CRITERIA: We sought to identify all randomised or quasi-randomised clinical trials of corticosteroid therapy, in patients with SAH or PICH, that have a placebo or standard strategy arm as control. Patients of any age and either gender with clinically (bed-side) diagnosed PICH and cerebrospinal fluid documented SAH were included in the analysis. The data were analysed both separately and combined for computed tomography (CT)/magnetic resonance imaging (MRI)/autopsy/angiography verified patients. DATA COLLECTION AND ANALYSIS: Data extracted from eligible clinical trials included: (1) death and poor outcome (death, severe disability, or vegetative state) within the first one to six months of the event onset (primary outcomes); (2) development of delayed cerebral ischaemia (as defined by the trialists) in patients with SAH; and (3) adverse effects of the treatment during the scheduled treatment or follow-up period (secondary outcomes). A pooled estimate of the effect size was computed, and the test for heterogeneity between trial results was carried out using The Cochrane Collaboration's Review Manager software, RevMan 4.2. Intention-to-treat analysis was carried out whenever possible. MAIN RESULTS: Eight trials that fulfilled the eligibility criteria were identified, with a total of 256 randomised patients in three SAH trials, and 206 patients in five PICH trials. The studies differed substantially with regard to the study populations and drugs, and methodological quality. The number of patients allocated to either hydrocortisone or fludrocortisone acetate treatment in patients with SAH, or to dexamethasone treatment in patients with PICH, was too small to make any definitive conclusions (confidence intervals were wide for any of the outcome estimates). AUTHORS' CONCLUSIONS: Overall, there is no evidence of a beneficial or adverse effect of corticosteroids in patients with either SAH or PICH. Confidence intervals are wide and include clinically significant effects in both directions.

Calcium antagonists for aneurysmal subarachnoid haemorrhage.

BACKGROUND: Secondary ischaemia is a frequent cause of poor outcome in patients with subarachnoid haemorrhage (SAH). Its pathogenesis has not been elucidated yet, but may be related to vasospasm. Experimental studies have indicated that calcium antagonists can prevent or reverse vasospasm and have neuroprotective properties. Several types of calcium antagonists have been studied in several clinical trials. OBJECTIVES: To determine whether calcium antagonists improve outcome in patients with aneurysmal SAH. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (September 2003). In addition, we searched MEDLINE (1966 to October 2003) and EMBASE (1980 to October 2003), handsearched two Russian journals (1990 to 2003) and contacted trialists and pharmaceutical companies (in 1995 and 1996) to identify further studies. SELECTION CRITERIA: All unconfounded, truly randomised controlled trials comparing any calcium antagonist with control. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted the data and assessed trial quality. Trialists were contacted to obtain missing information. MAIN RESULTS: We analysed 12 trials totalling 2844 patients with SAH (1396 in the treatment group and 1448 in the control group). The drugs analysed were: nimodipine (eight trials, 1574 patients), nicardipine (two trials, 954 patients), AT877 (one trial, 276 patients) and magnesium (one trial, 40 patients). Overall, calcium antagonists reduced the risk of poor outcome: relative risk (RR) 0.82 (95% confidence interval (CI) 0.72 to 0.93); the absolute risk reduction was 5.1%, the corresponding number of patients needed to treat to prevent a single poor outcome event was 20. For oral nimodipine alone the RR was 0.70 (0.58 to 0.84). The RR of death on treatment with calcium antagonists was 0.90 (95% CI 0.76 to 1.07), that of clinical signs of secondary ischaemia 0.67 (95% CI 0.60 to 0.76), and that of CT or MR confirmed infarction 0.80 (95% CI 0.71 to 0.89). AUTHORS' CONCLUSIONS: Calcium antagonists reduce the risk of poor outcome and secondary ischaemia after aneurysmal SAH. The results for 'poor outcome' depend largely on a single large trial with oral nimodipine; the evidence for nicardipine, AT877 and magnesium is inconclusive. The evidence for nimodipine is not beyond every doubt, but given the potential benefits and modest risks of this treatment, against the background of a devastating natural history, oral nimodipine (60 mg every 4 hours) is currently indicated in patients with aneurysmal SAH. Intravenous administration of calcium antagonists cannot be recommended for routine practice on the basis of the present evidence.

Circulatory volume expansion therapy for aneurysmal subarachnoid haemorrhage.

BACKGROUND: Secondary ischaemia is a frequent complication after aneurysmal subarachnoid haemorrhage (SAH), and responsible for a substantial proportion of patients with poor outcome after SAH. The cause of secondary ischaemia is unknown, but hypovolaemia and fluid restriction are important risk factors. Therefore, volume expansion therapy (hypervolaemia) is frequently used in patients with SAH to prevent or treat secondary ischaemia. OBJECTIVES: To determine the effectiveness of volume expansion therapy for improving outcome in patients with aneurysmal SAH. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched September 2003). In addition we searched MEDLINE (1966 to January 2004) and EMBASE (1980 to January 2004) and contacted trialists to identify further published and unpublished studies. SELECTION CRITERIA: All randomised controlled trials of volume expansion therapy in patients with aneurysmal SAH. We also sought controlled trials based on consecutive groups of patients quasi-randomly allocated to treatment or control group and included these in the analysis if the two groups were well comparable with regard to major prognostic factors. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted the data and assessed trial quality. Trialists were contacted to obtain missing information. MAIN RESULTS: We identified three trials. One truly randomised trial and one quasi-randomised trial with comparable baseline characteristics for both groups were included in the analyses. Volume expansion therapy did not improve outcome (Relative Risk (RR) 1.0; 95% Confidence Interval (CI) 0.5 to 2.2), nor the occurrence of secondary ischaemia (RR 1.1; 95% CI 0.5 to 2.2). Hypervolaemia tended to increase the rate of complications (RR 1.8; 95% CI 0.9 to 3.7) In another quasi-randomised trial, outcome assessment was done only at the day of operation (7 to 10 days after SAH). In the period before operation, treatment resulted in a reduction of secondary ischaemia (RR 0.33; 95% CI 0.11 to 0.99) and case fatality (RR 0.20; 95% CI 0.07 to 1.2). REVIEWERS' CONCLUSIONS: The effects of volume expansion therapy have been studied properly in only two trials of patients with aneurysmal SAH, with very small numbers. At present, there is no sound evidence for the use of volume expansion therapy in patients with aneurysmal SAH.

Teaching of neuroepidemiology in Europe: time for action.

Many epidemiological and clinical studies in Europe, especially in Eastern Europe and countries in transition, are of poor methodological quality because of lack of background knowledge in clinical epidemiology methods and study designs. The only way to improve the quality of epidemiological studies is to provide adequate undergraduate and/or postgraduate education for the health professionals and allied health professions. To facilitate this process, the European Federation of Neurological Societies (EFNS) Task Force on teaching of clinical epidemiology in Europe was set up in October 2000. Based on analyses of the current teaching and research activities in neuroepidemiology in Europe, this paper describes the Task Force recommendations aimed to improve these activities.

Subarachnoid haemorrhage occurrence exhibits a temporal pattern - evidence from meta-analysis.

The aim of the present meta-analysis was to determine a temporal pattern of occurrence of subarachnoid haemorrhage (SAH). A MEDLINE 1966-2001 and EMBASE (1980-2001) literature search and hand search of relevant references were performed for population-based incidence studies that reported the time of SAH occurrence. Data from all identified relevant studies were combined into a pooled rate ratio (RR), with corresponding 95% confidence intervals (CI) using the Mantel-Haenszel method. Overall, eight population-based studies were included in the analysis. A total of 2533 first-ever cases of SAH were reported in the studies identified. Risk of SAH occurrence was the highest in the period between 6 am and 12 am (RR = 3.19; 95% CI 3.03-3.36; early morning as a reference variable) and between 12 p.m. and 6 p.m. (RR = 2.63; 95% CI 2.47-2.80), in winter and spring (RR = 1.10; 95% CI: 1.02-1.17; and RR = 1.07; 95% CI: 1.01-1.13, respectively; summer as a reference variable) and on Sunday (RR = 1.22; 95% CI 1.09-1.37; Monday as a reference variable). The evidence suggests that occurrence of SAH exhibits a seasonal (winter and spring) peak, diurnal (late morning peak) and daily (Sunday peak) pattern. It is suggested that the occurrence of some major acute vascular events (total ischaemic strokes, intracerebral haemorrhage and myocardial infarction) may be influenced by common triggering factors.

Calcium antagonists for aneurysmal subarachnoid haemorrhage.

BACKGROUND: Secondary ischaemia is a frequent cause of poor outcome in patients with subarachnoid haemorrhage. Its pathogenesis has not been elucidated yet, but may be related to vasospasm. Experimental studies have indicated that calcium antagonists can prevent or reverse vasospasm. Calcium antagonists have been studied in several trials, but data are conflicting. There is no overview concerning all available calcium antagonists. OBJECTIVES: To determine whether calcium antagonists improve outcome in patients with aneurysmal subarachnoid haemorrhage (SAH). SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched November 2001). In addition, we handsearched two Russian journals (1990-1995) and contacted trialists and pharmaceutical companies to identify further studies SELECTION CRITERIA: All completed, unconfounded, truly randomised controlled trials comparing any calcium antagonist with control, within ten days of SAH onset. Eleven trials that met the inclusion criteria were included in the overview. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted the data and assessed trial quality. Trialists were contacted to obtain missing information MAIN RESULTS: We analysed 11 trials totaling 2804 randomised patients with subarachnoid haemorrhage (1376 in the treatment and 1428 in the control group). The drugs analysed were: nimodipine (eight trials, 1574 patients), nicardipine (two trials, 954 patients), and AT877 (one trial, 276 patients). In 92% of the patients aneurysms were confirmed by angiography or autopsy. Overall, calcium antagonists significantly reduced the risk of poor outcome after subarachnoid haemorrhage: relative risk (RR) 0.82 (95% CI 0.72 to 0.93); the absolute risk reduction was 5.1%, the corresponding number of patients needed to treat to prevent a single poor outcome event is 20. For oral nimodipine alone the RR was 0.69 (0.58 to 0.84). The RR of death on treatment with calcium antagonists was 0.94 (95% CI 0.80 to 1.10), that of ischaemic neurological deficits 0.67 (95% CI 0.59 to 0.76), and that of CT-scan documented cerebral infarction 0.80 (95% CI 0.71 to 0.89). REVIEWER'S CONCLUSIONS: Calcium antagonists reduce the proportion of patients with poor outcome and ischaemic neurological deficits after aneurysmal SAH. The results for 'poor outcome' are statistically robust, but depend largely on one large trial with oral nimodipine; the evidence for nicardipine and AT877 is inconclusive. The evidence for nimodipine is not beyond every doubt, but given the potential benefits and modest risks associated with this treatment, against the background of a devastating natural history, oral nimodipine (60 mg every 4 hours) is indicated in patients with aneurysmal SAH. Intravenous administration of calcium antagonists cannot be recommended on the basis of the present evidence. For oral nimodipine uncertainty remains regarding the (dis)advantages in patients in poor clinical condition on admission or in patients with established cerebral ischaemia, the optimal dose and time window, the question whether other types of calcium antagonists offer better protection and the intermediate factors through which nimodipine exerts its beneficial effect after aneurysmal SAH.