Medium-term prognosis of an incident cohort of parkinsonian patients compared to controls.

BACKGROUND: The best data on prognosis comes from population-based incident cohorts but few such cohorts exist for Parkinson's disease and atypical parkinsonism. METHODS: The PINE study is a prospective follow-up study of an incident cohort of people with degenerative or vascular parkinsonism and age-sex matched controls. Participants have annual follow-up from diagnosis until death with review of primary/secondary care records and linkage to the UK death register. Data are collected on survival, disability (dependency on others for activities of daily living) and institutionalization. Research criteria are used to guide the clinical diagnosis, which is updated annually. We compared all-cause mortality, disability and institutionalization in patients (subdivided by diagnosis) and controls, adjusted for important confounders. RESULTS: 323 incident parkinsonian patients (199 Parkinson's disease, 124 atypical parkinsonism, mean age at diagnosis 75yrs) and 262 controls (mean age 75yrs) had 1349 and 1334 person-years follow-up respectively (maximum follow-up 10 years). All outcomes were worse in parkinsonian patients than controls, especially in atypical parkinsonism (adjusted mortality hazards ratios Parkinson's disease 2.49, 95%CI 1.72-3.58, atypical parkinsonism, 6.85, 95%CI 4.78-9.81). Median survival times for Parkinson's disease and atypical parkinsonism were 7.8 and 2.7 years respectively but were very age-dependent. At three years the rates of death or dependency were controls 21%, Parkinson's disease 46%, atypical parkinsonism 96% whilst overall institutionalization rates were 5%, 15% and 55% respectively. CONCLUSION: The prognosis of Parkinson's disease and atypical parkinsonism in this unselected incident cohort was significantly worse than previously reported. This has important implications for patient management.

Motor complications in an incident Parkinson's disease cohort.

BACKGROUND AND PURPOSE: Levodopa treatment in Parkinson's disease (PD) causes motor fluctuations and dyskinesias, but few data describe their development or severity in unselected incident cohorts. METHODS: Demographic, clinical, treatment, smoking, caffeine and alcohol data from 183 people with PD were gathered from the Parkinsonism Incidence in Northeast Scotland (PINE) study, a community-based, incident cohort. With Kaplan-Meier survival analysis and Cox regression modelling the development, and severity, of dyskinesias and motor fluctuations and which factors independently influenced their onset were assessed. RESULTS: After a mean follow-up of 59 months, 39 patients (21.3%) developed motor fluctuations and 52 (28.4%) developed dyskinesias. Kaplan-Meier estimates of the probability of motor fluctuations and dyskinesias after 5 years of dopaminergic treatment were 29.2% [95% confidence interval (CI) 21.5%-38.8%] and 37.0% (95% CI 28.5%-47.1%) respectively. 19.8% developed motor fluctuations requiring treatment changes but only 4.0% (95% CI 1.5%-10.4%) developed dyskinesias requiring treatment changes by 5 years. Cumulative levodopa dose [hazard ratio (HR) 1.38 (95% CI 1.19-1.60)], female sex [HR 2.41 (1.19-4.89)] and younger age at diagnosis [HR 1.08 (1.04-1.11)] were independently associated with development of motor fluctuations. Cumulative levodopa dose [HR 1.23 (1.08-1.40)] and female sex [HR 2.51 (1.40-4.51)] were independently associated with dyskinesias. In exploratory analyses, moderate caffeine exposure was associated with fewer motor fluctuations, longer symptom duration with more dyskinesias, and tremor at diagnosis with higher rates of both complications. CONCLUSIONS: In this community-based incident PD cohort, severe dyskinesias were rare. Cumulative levodopa dose was the strongest predictor of both dyskinesias and motor fluctuations.

Pre-hospital notification is associated with improved stroke thrombolysis timing.

Intravenous thrombolysis increases disability-free survival after acute ischaemic stroke in a time-dependent fashion. We aimed to determine whether pre-hospital notification, introduction of a CT scanner near to assessment site and introduction of out-of-hours thrombolysis services affect thrombolysis timing. Methods Timings related to thrombolysis were collected between May 2012 and June 2014 at a single hospital site; these included time to stroke physician assessment, time to cranial CT imaging and door to needle time. All thrombolysed ischaemic stroke patients admitted via the emergency department were included. Ambulance services were asked to pre-notify the emergency department of any suspected stroke patient during this period. Results We studied 182 patients (48% female; mean age 74 years; 59% pre-notified). Pre-hospital notification was associated with a significantly higher rate of CT scanning within 25 minutes (60% vs 24%, odds ratio [OR] 4.7, 95% confidence interval [CI] 2.4-9.0; p<0.001), earlier stroke physician assessment (median 6 vs 32 minutes; p<0.001) and receiving thrombolysis within 60 minutes (89% vs 49%, OR 8.0, 95% CI 3.8-16.9; p<0.001). Being treated outside normal working hours did not alter thrombolysis timing. Logistic regression identified the introduction of a near-site CT scanner (OR 4.6 [95% CI 1.7-12.5]) and pre-hospital notification (OR 4.7, [95% CI 2.3-9.6]) as independent predictors of door to CT time less than or equal to 25 minutes, and pre-hospital notification (OR 11.6, [95% CI 4.9-30.3]) and stroke severity (OR 1.15 per point of NIHSS scale, [95% CI 1.08-1.23]) as predictors of door to thrombolysis time less than or equal to 60 minutes. The most common perceived timing delays were radiology-related (33%), the need to acutely lower blood pressure (15%) and obtaining consent (12%). Conclusion Pre-hospital notification is associated with earlier stroke physician review, CT imaging and delivery of thrombolysis. Referral to an out of hours thrombolysis service was not associated with additional delay.

Statistical analysis, trial design and duration in Alzheimer's disease clinical trials: a review.

BACKGROUND: The social and economic burden of Alzheimer's disease (AD) and its increasing prevalence has led to much work on new treatment strategies and clinical trials. The search for surrogate markers of disease progression continues but traditional parallel group trial designs that use well-established, but often insensitive, clinical outcome measures predominate. METHODS: We performed a systematic search across the Cochrane Library and PubMed abstracts published between January 2004 and August 2009. Information regarding the clinical trial methodology, outcome measures, intervention type and primary statistical analysis techniques was extracted and categorized, according to a standard protocol. RESULTS: We identified 149 papers describing results from clinical trials in AD containing sufficient detail for our purposes. The largest proportion (38%) presented results of trials based on tests of cognition as the primary outcome measure. The primary analysis in most papers (85%) was a univariate significance test of a single primary outcome measure. CONCLUSIONS: The majority of trials reported a comparison of baseline and end-point assessment over relatively short patient follow-up periods, using univariate statistical methods to compare differences between intervention and control groups in the primary analysis. There is considerable scope to introduce newer statistical methods and trial designs in treatment evaluations in AD.

Seizure risk from cavernous or arteriovenous malformations: prospective population-based study.

OBJECTIVES: To determine the risk of epileptic seizures due to a brain arteriovenous malformation (AVM) or cavernous malformation (CM). METHODS: In a prospective population-based study of new diagnoses of AVMs (n = 229) or CMs (n = 139) in adults in Scotland in 1999-2003, we used annual medical records surveillance, general practitioner follow-up, and patient questionnaires to quantify the risk of seizures between clinical presentation and AVM/CM treatment, last follow-up, or death. RESULTS: The 5-year risk of first-ever seizure after presentation was higher for AVMs presenting with intracranial hemorrhage or focal neurologic deficit (ICH/FND: n = 119; 23%, 95% confidence interval [CI] 9%-37%) than for incidental AVMs (n = 40; 8%, 95% CI 0%-20%), CMs presenting with ICH/FND (n = 38; 6%, 95% CI 0%-14%), or incidental CMs (n = 57; 4%, 95% CI 0%-10%). For adults who had never experienced ICH/FND, the 5-year risk of epilepsy after first-ever seizure was higher for CMs (n = 23; 94%, 95% CI 84%-100%) than AVMs (n = 37; 58%, 95% CI 40%-76%; p = 0.02). Among adults who never experienced ICH/FND and presented with or developed epilepsy, there was no difference in the proportions achieving 2-year seizure freedom over 5 years between AVMs (n = 43; 45%, 95% CI 20%-70%) and CMs (n = 35; 47%, 95% CI 27%-67%). CONCLUSIONS: AVM-related ICH confers a significantly higher risk of a first-ever seizure compared to CMs or incidental AVMs. Adults with a CM have a high risk of epilepsy after a first-ever seizure but achieve seizure freedom as frequently as those with epilepsy due to an AVM.

Medication management in people with Parkinson's disease during surgical admissions.

BACKGROUND: Patients with Parkinson's disease (PD) may experience problems in hospital, with their medication being withheld or inappropriate medication being prescribed. Since surgical admissions present particular risks, the authors examined the management of patients with PD on surgical wards. METHODS: All patients with PD admitted to surgical departments in Aberdeen Royal Infirmary during an 18-month period were identified. Medical and nursing notes were reviewed retrospectively, and drug prescription and administration were studied in detail. All documented complications were recorded. RESULTS: 59 surgical admissions (51 receiving PD medication, median duration 6 days) were studied. 71% had missed doses of PD medication, with 34% missing over 10% of prescribed doses. Values were similar for levodopa and agonists. Overall, 12% of all prescribed PD medication was missed (mean 0.7 missed doses per patient per day). No reason for missed doses was recorded in 64% of cases, while inappropriate reasons included 'out of stock' (12%) and 'nil by mouth' (8%). Centrally acting antidopaminergic drugs (mainly antiemetics) were prescribed in 41% of cases, and administered in 22%. Complications, most commonly neuropsychiatric, were documented in 69% of non-day-case admissions. CONCLUSION: Poor prescribing and incomplete drug administration are common in patients with PD on surgical wards. Measures to improve management are identified.

Recruitment bias resulted in poorer overall health status in a community-based control group.

OBJECTIVE: During a prospective community-based incidence study of parkinsonism, a control group was recruited for comparison with the incident patients. This study compared the demographic and health status of recruited vs. nonrecruited controls. STUDY DESIGN AND SETTING: For each incident patient, attempts were made to recruit an age-gender matched control from the same general practice or, failing that, from a previously identified community cohort of people aged over 64 years who had expressed an interest in taking part in future research. Recruited controls were compared with those who were approached but not recruited in terms of age, socioeconomic status, gender, several measures of health status, and survival. RESULTS: A total of 74 controls (40%) were recruited out of 186 potential controls who were approached. Recruited controls scored slightly worse than nonrecruited controls on every measure of health status, which reached statistical significance for numbers of acute prescriptions and major surgical procedures. There were no significant differences in age, gender, socioeconomic status, or survival. CONCLUSION: The control cohort was affected by recruitment bias, which suggested that recruited controls had slightly poorer health compared to nonrecruited controls. This bias may reduce differences in health when comparisons are made between the controls and the parkinsonian patients.

Differences between intracranial vascular malformation types in the characteristics of their presenting haemorrhages: prospective, population-based study.

OBJECTIVE: To determine the imaging and demographic characteristics of intracranial haemorrhages, which are subsequently found to be due to an underlying intracranial vascular malformation (IVM). METHODS: We compared the demographic and brain imaging characteristics of adults presenting with intracranial haemorrhage, subsequently found to be due to a brain arteriovenous malformation (BAVM), dural arteriovenous fistula (DAVF) or cavernous malformation (CM) in a prospective, population-based cohort of adults diagnosed for the first time with an IVM (The Scottish IVM Study (SIVMS)). RESULTS: Of the 141 adults in SIVMS who presented with intracranial haemorrhage, those with CMs presented at a younger age and were less handicapped. A total of 115 (82%) had intracerebral haemorrhage (ICH) with or without subarachnoid, intraventricular or subdural extension. ICH without extension into other compartments accounted for all CM bleeds, but only 50% of BAVM and DAVF bleeds. Median haematoma volumes differed (Kruskal-Wallis, p<0.0001): ICH due to BAVM (16.0 cm3, inter-quartile range (IQR) 4.7 to 42.0) and DAVF (14.1 cm3, IQR 4.9 to 21.5) were similar, but CM haematoma volumes were smaller (median 1.8 cm3, IQR 1.3 to 4.3). These findings were robust in sensitivity analyses. Small haematoma volumes occurred among all IVM types; the largest haematoma volume due to CM was 12 cm3, and volumes of >34 cm3 were only due to BAVM. CONCLUSIONS: Intracranial haemorrhages found to be due to IVMs differ in adults' age of presentation and clinical severity, as well as the volume and distribution of the haematoma within the brain compartments.

Screening for undiagnosed parkinsonism in people aged 65 years and over in the community.

We screened a random sample of 2449 people aged 65 years and over for undiagnosed parkinsonism, using a postal screening questionnaire followed by clinical neurological assessment. Amongst the 1556 (63.5%) patients who responded, four patients with previously undiagnosed parkinsonism were identified, suggesting a prevalence of 257 per 100,000 (95% CI 70, 658) in this age-group. Although only small, the numbers were sufficient to significantly increase the incidence of parkinsonism in an incidence study. Two simple screening questions achieved a high sensitivity for newly diagnosed parkinsonism of 95%, but a low specificity of 28%.

Monoamine oxidase B inhibitors for early Parkinson's disease.

BACKGROUND: It has been postulated that monoamine oxidase B (MAO-B) inhibitors alter disease progression in Parkinson's disease (PD). Clinical trials have produced conflicting results. OBJECTIVES: To assess the evidence from randomized controlled trials for the effectiveness and safety of long-term use of MAO-B inhibitors in early PD. SEARCH STRATEGY: We searched the following electronic databases: Cochrane Central Register of Controlled trials (CENTRAL) (The Cochrane Library Issue 2, 2004), MEDLINE (last searched 18th August 2004) and EMBASE (last searched 18th August 2004). We also handsearched neurology and movement disorders conference proceedings, checked reference lists of relevant studies and contacted other researchers. SELECTION CRITERIA: We sought to include all unconfounded randomized controlled trials that compared a MAO-B inhibitor with control, in the presence or absence of levodopa or dopamine agonists, in patients with early PD and where treatment and follow up lasted at least one year. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion, assessed the methodological quality, and extracted the data. A small amount of additional data was provided by the original authors. Random-effects models were used to analyse results, where appropriate. MAIN RESULTS: Ten trials were included (a total of 2422 patients), nine using selegiline, one using lazabemide. The methodological quality was reasonable although concealment of allocation was definitely adequate in only four trials. The mean follow up was for 5.8 years. MAO-B inhibitors were not associated with a significant increase in deaths (odds ratio (OR) 1.15; 95% confidence interval (CI) 0.92 to 1.44). They provided small benefits over control in impairment (weighted mean difference (WMD) for change in motor UPDRS score was 3.81 points less with MAO-B inhibitors; 95% CI 2.27 to 5.36) and disability (WMD for change in UPDRS ADL score was 1.50 less; 95% CI 0.48 to 2.53) at one year which, although statistically significant, were not clinically significant. There was a marked levodopa-sparing effect with MAO-B inhibitors which was associated with a significant reduction in motor fluctuations (OR 0.75; 95% CI 0.59 to 0.94) but not dyskinesia (OR 0.97; 95% CI 0.76 to 1.25). The reduction in motor fluctuations was, however, not robust in sensitivity analyses. Although adverse events were generally mild and infrequent, withdrawals due to side-effects were higher (OR 2.36; 95% CI 1.32 to 4.20) with MAO-B inhibitors. AUTHORS' CONCLUSIONS: MAO-B inhibitors do not appear to delay disease progression but may have a beneficial effect on motor fluctuations. There was no statistically significant effect on deaths although the confidence interval does not exclude a small increase with MAO-B inhibitors. At present we do not feel these drugs can be recommended for routine use in the treatment of early Parkinson's disease but further randomized controlled trials should be carried out to clarify, in particular, their effect on deaths and motor complications.

Reliability of the variables in a new set of models that predict outcome after stroke.

OBJECTIVES: To provide valid predictions of outcome, the variables included in a prognostic model must be capable of reliable collection. The authors have recently reported a set of simple but rigorously developed models that predict outcome after stroke. The aim of this study was to establish the inter-rater reliability of the variables included in the models. METHODS: Inter-rater agreement was measured prospectively (between two clinicians; 92 patients) and retrospectively (between two auditors; 200 patients) and the validity of the data collected retrospectively was estimated by comparing them with data collected prospectively (195 patients). In the prospective study inter-rater agreement for urinary incontinence and for the variables of three other previously published models was also measured. The median difference (md) between ages and kappa statistics for other variables was calculated. RESULTS: For the model variables, prospective agreement ranged from good to excellent (age: md 0 years; living alone before the stroke kappa 0.84; pre-stroke functional independence kappa 0.67; normal verbal Glasgow Coma Scale score kappa 0.79; ability to lift both arms against gravity kappa 0.97; ability to walk unaided kappa 0.91) while retrospective agreement (age: md 0 years; kappa 0.55-0.92) and agreement between prospective and retrospective observers (age: md 0 years; kappa 0.49-0.78) was acceptable but less good. Prospective agreement was excellent for urinary incontinence (kappa 0.87) and variable for the other models (kappa 0.23-0.81) CONCLUSION: The variables included in these new simple models of outcome after stroke are capable of reliable collection, comparable to or better than that of the other predictive variables considered. When collected retrospectively, the model variables are likely to remain reliable and reasonably valid.

Incidence studies of primary and secondary intracranial tumors: a systematic review of their methodology and results.

We reviewed the incidence studies of intracranial tumors to compare their methodology and identify whether there was evidence of true differences in incidence by time, place, age, or sex. Studies were identified from Medline (1966-95), bibliographies of relevant articles, and personal knowledge. For each study, various methodological details were recorded, along with the age-standardized incidence of all primary tumors and the crude and age/sex-specific incidences of different types of intracranial tumor. Methodological factors which significantly influenced the reported incidence were identified and the results of different studies were compared and combined in a meta-analysis if appropriate. Twenty studies (over 20,000 primary tumors) were included. Higher incidences of primary tumors were found in studies that: used many methods to identify cases (odds ratio [OR] 1.92); included a high percentage of asymptomatic patients (OR 2.03); did not require histologic confirmation of the diagnosis (OR 1.69). Studies from the 1980's reported higher incidences than in previous decades (OR 1.51), probably because of improved methodology. Comparable studies from the 1980's gave widely different incidence rates for all primary tumors (7.1-18.6 per 100,000 per year). In all studies, the incidence of neuroepithelial and meningeal tumors increased dramatically with age. Neuroepithelial tumors were 40% more common in men, whilst meningeal and cranial nerve tumors were about 80% and 40% more common in women, respectively. Further incidence studies are required to establish geographical and secular variations in the incidence of primary intracranial tumors but these must use comparable methodologies. Provisional guidelines for future studies are given.

Limitations of using a cancer registry to identify incident primary intracranial tumours.

The completeness and accuracy of registration of primary intracranial tumours in the Scottish Cancer Registry was compared with a detailed incidence study performed over a two year period (1989-90). Of 228 patients with any primary intracranial tumour in the incidence study, 124 (54%) were identified as intracranial tumours in the cancer registry. The registry excluded benign tumours (although this was not consistent) and so the sensitivity of the registry varied with tumour type (84% for neuroepithelial tumours, 22% meningeal, 29% sellar, 0% cranial nerve). Of the 31 malignant tumours not found in the registry on our initial search, nine were found to have been included between 1989-90 but using different International Classification of Diseases-9th revision (ICD-9) codes or postcodes, and seven were found registered after 1990. Eleven per cent of cases (18/170) identified in the cancer registry were excluded from the incidence study: 11 had evidence of an intracranial tumour before 1989 whereas four definitely did not have an intracranial tumour. The cancer registry therefore significantly underestimated the incidence of all primary intracranial tumours, and of malignant intracranial tumours. Incidence studies must use additional methods to identify all primary tumours. Cancer registries should consider registering all primary intracranial tumours and may improve case ascertainment by screening neuroradiology data.

Local versus general anaesthesia in carotid endarterectomy: a systematic review of the evidence.

OBJECTIVE: To determine whether carotid endarterectomy under local anaesthesia is safer and as effective as under general anaesthesia. DESIGN: Systematic review of the randomised and non-randomised studies. MATERIALS: Studies were identified from the Cochrane Stroke Group's database plus additional handsearching and electronic searching. METHODS: Two authors independently selected studies for inclusion and extracted details of trial quality and data on death, any stroke, myocardial infarction and other operative complications. Meta-analysis was performed using the Peto method. RESULTS: There were 17 non-randomised studies (about 5970 patients) and only three randomised studies (143 patients). The non-randomised studies suggested that the use of local anaesthesia may be associated with clinically important reductions (approximately 50%) in the odds of stroke, stroke or death, myocardial infarction and pulmonary complications during the perioperative period, and with reductions in hospital stay. There were far too little data from the randomised trials to confirm or refute these findings: only one death and seven strokes were reported. CONCLUSIONS: Non-randomised studies suggest potentially important benefits from performing carotid endarterectomy under local anaesthesia. However, these studies were seriously flawed and can only be hypothesis generating. The results must be confirmed in large well-designed randomised trials before any recommendations on the use of local anaesthetic can be made.

A systematic review of the randomised trials of carotid patch angioplasty in carotid endarterectomy.

OBJECTIVES: To determine whether patch angioplasty is more effective than primary closure in carotid endarterectomy, and whether one type of patch is better than another. DESIGN: Systematic review of the randomised trials. MATERIALS: Trials were identified from the Cochrane Stroke Review Group database plus additional handsearching, electronic searching, and personal contact. METHODS: Two authors independently selected studies for inclusion and extracted details of trial quality and data on the following outcomes: any stroke; stroke ipsilateral to the operated artery; death; occlusion or restenosis, and other significant arterial complications. Meta-analysis of odds ratios (OR) was performed using the Peto method. RESULTS: Six trials (882 operations) compared routine patching with primary closure. Routine patching was associated with significant reductions in the risks of ipsilateral stroke during the perioperative period (OR 0.34, 95% CI 0.15-0.76) and during long-term follow-up (OR 0.38, 95% CI 0.16-0.88). Significant reductions in the odds of any stroke, stroke or death, acute arterial occlusion and long-term restenosis were also found. However, these results were based on very small numbers of outcome events and may be biased by losses to follow-up and publication bias. Three trials (326 operations) compared the use of polytetrafluoroethylene patches with venous patches. There were too few events (strokes, deaths, arterial complications) to determine whether there were significant differences between the patch materials. Fewer pseudoaneurysms occurred in those who received synthetic patches but the clinical consequence of this was unclear. CONCLUSIONS: Routine carotid patch angioplasty was associated with promising reductions in the risks of ipsilateral stroke and death, but the results should be interpreted cautiously because of the small number of outcome events, significant losses to follow-up, and poor trial methodology. Ideally, a large definitive trial should be performed. There is insufficient evidence to support the preferential use of one particular type of patch versus another.

Incidence of intracranial tumours in the Lothian region of Scotland, 1989-90.

OBJECTIVE: To determine the incidence of primary and secondary intracranial tumours in the Lothian region of south east Scotland. METHODS: A population based study was performed. Patients from Lothian with incident intracranial tumours diagnosed in 1989 and 1990 (by CT or histology) were identified retrospectively using multiple sources. Differences in incidence by tumour type, age, sex, and socioeconomic status were examined. RESULTS: Four hundred and forty two patients with incident intracranial tumours were identified (228 primary tumours and 214 secondary tumours). The crude yearly incidences of primary and secondary tumours were 15.3 and 14.3 per 100,000 respectively. The commonest primary tumours were neuroepithelial tumours (53.5%), meningeal tumours (19.5%), and sellar tumours (16.5%). About 50% of patients with secondary tumours had an underlying lung cancer. The incidence of primary and secondary tumours increased markedly with age. Meningeal tumours were more common in women, and neuroepithelial tumours were more common in those who lived in more affluent areas. CONCLUSIONS: The incidence rates of primary and secondary intracranial tumours in Lothian were more than twice those previously reported in the United Kingdom. Intracranial tumours are a significant cause of morbidity and mortality in the United Kingdom, and further research into their aetiology and treatment is urgently required.