Explore the vast range of titles available.

Cerebral cavernous malformations (CCMs) are prone to bleeding but the risk of intracranial haemorrhage and focal neurological deficits, and the factors that might predict their occurrence, are unclear. We aimed to quantify these risks and investigate whether they are affected by sex and CCM location. We undertook a population-based study using multiple overlapping sources of case ascertainment (including a Scotland-wide collaboration of neurologists, neurosurgeons, stroke physicians, radiologists, and pathologists, as well as searches of registers of hospital discharges and death certificates) to identify definite CCM diagnoses first made in Scottish residents between 1999 and 2003, which study neuroradiologists independently validated. We used multiple sources of prospective follow-up both to identify outcome events (which were assessed by use of brain imaging, by investigators masked to potential predictive factors) and to assess adults' dependence. The primary outcome was a composite of intracranial haemorrhage or focal neurological deficits (not including epileptic seizure) that were definitely or possibly related to CCM. 139 adults had at least one definite CCM and 134 were alive at initial presentation. During 1177 person-years of follow-up (completeness 97%), for intracranial haemorrhage alone the 5-year risk of a first haemorrhage was lower than the risk of recurrent haemorrhage (2·4%, 95% CI 0·0–5·7 vs 29·5%, 4·1–55·0; p<0·0001). For the primary outcome, the 5-year risk of a first event was lower than the risk of recurrence (9·3%, 3·1–15·4 vs 42·4%, 26·8–58·0; p<0·0001). The annual risk of recurrence of the primary outcome declined from 19·8% (95% CI 6·1–33·4) in year 1 to 5·0% (0·0–14·8) in year 5 and was higher for women than men (p=0·01) but not for adults with brainstem CCMs versus CCMs in other locations (p=0·17). The risk of recurrent intracranial haemorrhage or focal neurological deficit from a CCM is greater than the risk of a first event, is greater for women than for men, and declines over 5 years. This information can be used in clinical practice, but further work is needed to quantify risks precisely in the long term and to understand why women are at greater risk of recurrence than men. UK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.

Predicting outcomes for people with Parkinson’s (PwP) can enable better information provision, personalised treatments, and enhanced trial design. It is unclear what prognostic models are optimal for use. We systematically reviewed previously published prognostic models for PwP, assessed quality, and made recommendations. We searched MEDLINE and EMBASE for studies developing/validating models predicting clinical outcomes in PwP. We assessed risk of bias and applicability using the PROBAST tool. We screened 1024 references and identified 25 studies (41 prognostic models). The most common outcomes were falls (11 studies), dementia (7) and motor complications (4). Most models made short-term predictions (60% ≤2 years). All studies had concerns about bias, e.g., inadequate population details ( n  = 16), suboptimal methods for missing data ( n  = 21), and no external validation ( n  = 22). 13 models had sufficient information to be used in practice. Further development and validation of prognostic models is needed which follows existing guidelines to reduce risk of bias.

Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true slowing of the neurodegenerative process. A systematic review was undertaken to determine what biomarkers for disease progression in Alzheimer's disease exist and how well they perform. MEDLINE and Embase (1950-2011) were searched using five search strategies. Abstracts were assessed to identify papers meriting review in full. Studies of participants with probable Alzheimer's disease diagnosed by formal criteria were included. We made no restriction on age, disease duration, or drug treatment. We only included studies with a longitudinal design, in which the putative biomarker and clinical measure were both measured at least twice, as this is the only appropriate study design to use when developing a disease progression biomarker. We included studies which attempted to draw associations between the changes over time in the biomarker used to investigate disease progression and a clinical measure of disease progression. Fifty-nine studies were finally included. The commonest biomarker modality examined was brain MRI (17/59, 29% of included studies). Median follow-up in included studies was only 1.0 (IQR 0.8-1.7) year and most studies only measured the putative biomarker and clinical measure twice. Included studies were generally of poor quality with small numbers of participants (median 31 (IQR 17 to 64)), applied excessively restrictive study entry criteria, had flawed methodologies and conducted overly simplistic statistical analyses without adjusting for confounding factors. We found insufficient evidence to recommend the use of any biomarker as an outcome measure for disease progression in Alzheimer's disease trials. However, further investigation into the efficacy of using MRI measurements of ventricular volume and whole brain volume appeared to be merited. A provisional 'roadmap' to improve the quality of future disease progression biomarker studies is presented.

The decision about whether to treat an unruptured brain arteriovenous malformation (AVM) depends on a comparison of the estimated lifetime risk of intracranial haemorrhage with the risks of interventional treatment. We aimed to test whether outcome differs between adults who had interventional AVM treatment and those who did not. All adults in Scotland who were first diagnosed with an unruptured AVM during 1999–2003 (n=114) entered our prospective, population-based study. We compared the baseline characteristics and 3-year outcome of adults who received interventional treatment for their AVM (n=63) with those who did not (n=51). At presentation, adults who were treated were younger (mean 40 vs 55 years of age, 95% CI for difference 9–20; p<0·0001), more likely to present with a seizure (odds ratio 2·4, 95% CI 1·1–5·0), and had fewer comorbidities (median 3 vs 4, p=0·03) than those who were not treated. Despite these baseline imbalances, treated and untreated groups did not differ in progression to Oxford Handicap Scale (OHS) scores of 2–6 (log-rank p=0·12) or 3–6 (log-rank p=0·98) in survival analyses. In a multivariable Cox proportional hazards analysis, the risk of poor outcome (OHS 2–6) was greater in patients who had interventional treatment than in those who did not (hazard ratio 2·5, 95% CI 1·1–6·0) and was greater in patients with a larger AVM nidus (hazard ratio 1·3, 95% CI 1·1–1·7). The treated and untreated groups did not differ in time to an OHS score of 2 or more that was sustained until the end of the third year of follow-up, or in the spectrum of dependence as measured by the OHS at 1, 2, and 3 years of follow-up. Greater AVM size and interventional treatment were associated with worse short-term functional outcome for unruptured AVMs, but the longer-term effects of intervention are unclear.

Beta-adrenoceptor-blockers and agonists have been associated with an increased and decreased risk of Parkinson’s disease (PD), respectively. We aimed to investigate whether these medications are linked to clinical heterogeneity and progression in PD. Longitudinal data from the Parkinson’s Incident Cohorts Collaboration ( n  = 1107) were analysed. Baseline clinical status and progression to Hoehn & Yahr stage 3 (H&Y3) or dementia were compared in beta-blocker or beta-agonist users versus non-users of each drug. Baseline motor and cognitive variables were similar in beta-blocker users ( n  = 195) versus non-users and beta-agonist users ( n  = 68) versus non-users, following adjustment for relevant confounders. Beta-blocker users ( n  = 156) progressed faster to H&Y3 ( p  = 0.002), accounting for relevant confounders (Hazard Ratio (HR) = 1.538; p  = 0.011), while beta-agonist users ( n  = 54) progressed similarly to non-users. Neither drug was associated with progression to dementia. These findings support the possibility that beta-adrenoceptor drugs may have potential in modifying aspects of PD progression. Further investigation is essential to identify any causative component in the relationship.

To define the incidence, predictors and prognosis of the first hospital delirium episode in Parkinson’s disease (PD) and atypical parkinsonism (AP), we identified the first hospital episode of delirium after diagnosis in the Parkinsonism Incidence in North-East Scotland (PINE) study, a prospective community-based incidence cohort of parkinsonism, using chart-based criteria to define delirium. Of 296 patients (189=PD, 107=AP [dementia with Lewy bodies, progressive supranuclear palsy, multiple system atrophy, vascular parkinsonism]), 152 developed delirium (PD = 98, AP = 54). Incidence of first hospital delirium episode per 100 person years was 8.1 (95% confidence interval [CI] 6.6–9.9) in PD and 18.5 (95% CI 13.9–24.7) in AP. Independent predictors of delirium were atypical parkinsonism (Hazard ratio [HR] vs PD = 2.83 [95% CI 1.60–5.03], age in PD but not in AP (HR for 10-year increase 2.29 [95% CI 1.74–3.02]), baseline MMSE (HR = 0.94 [95% CI 0.89–0.99]), APOE ε4 in PD (HR 2.16 [95% CI 1.15–4.08]), and MAPT H1/H1 in PD (HR 2.08 [95% CI 1.08–4.00]). Hazards of dementia and death after delirium vs before delirium were increased (dementia: HR = 6.93 [95% CI 4.18–11.48] in parkinsonism; death: HR = 3.76 [95% CI 2.65–5.35] in PD, 1.59 [95% CI 1.04–2.42] in AP). Delirium is a common non-motor feature of PD and AP and is associated with increased hazards of dementia and mortality. Whether interventions for early identification and treatment improve outcomes requires investigation.

Background Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true disease-modifying effects. A systematic review was undertaken to determine what biomarkers for disease progression in Parkinson’s disease (PD) exist. Methods MEDLINE and EMBASE (1950–2010) were searched using five search strategies. Abstracts were assessed to identify papers meriting review in full. Studies of participants with idiopathic PD diagnosed by formal criteria or clearly described clinical means were included. We made no restriction on age, disease duration, drug treatment, or study design. We included studies which attempted to draw associations between any tests used to investigate disease progression and any clinical measures of disease progression. The electronic search was validated by hand-searching the two journals from which most included articles came. Results 183 studies were included: 163 (89%) cross-sectional, 20 (11%) longitudinal. The electronic search strategy had a sensitivity of 71.4% (95% CI 51.1-86.0) and a specificity of 97.1% (95% CI 96.5-97.7). In longitudinal studies median follow-up was 2.0 years (IQR 1.1-3.5). Included studies were generally poor quality - cross-sectional with small numbers of participants, applying excessive inclusion/exclusion criteria, with flawed methodologies and simplistic statistical analyses. Conclusion We found insufficient evidence to recommend the use of any biomarker for disease progression in PD clinical trials, which may simply reflect the poor quality of research in this area. We therefore present a provisional ‘roadmap’ for conducting future disease progression biomarker studies, and recommend new quality criteria by which future studies may be judged.

Background Misdiagnosis and delayed diagnosis in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are common. Few studies have systematically evaluated the diagnostic process from symptom onset to death in representative cohorts. Methods All PSP/CBD cases ( n  = 28/2) and age-sex matched Parkinson’s disease (PD) cases ( n  = 30) were identified from a UK prospective incident Parkinsonism cohort. Medical and research records were reviewed to compare median times from first index symptom to key diagnostic milestones and the nature/timing of secondary care referral and review. Results Index symptoms were similar apart from more tremor in PD ( p  < 0.001) and more impaired balance ( p  = 0.008) and falls ( p  = 0.004) in PSP/CBD. PD was diagnosed a median 0.96 years after index symptom. In PSP/CBD the median times from index symptom to identifying parkinsonism and then including PSP/CBD in the differential diagnosis and the final diagnosis were 1.88, 3.41 and 4.03 years, respectively (all p  < 0.001). Survival from symptom onset in PSP/CBD and PD was not significantly different (5.98 vs 6.85 years, p  = 0.72). More diagnoses ( p  < 0.001) were considered in PSP/CBD. Prior to diagnosis, PSP/CBD patients had more recurrent emergency attendances (33.3% vs 10.0%, p  = 0.01) and were referred to more specialities than PD (median 5 vs 2). Time to any outpatient referral (0.70 vs 0.03 years, p  = 0.025) and to specialist movement disorder review (1.96 vs 0.57 years, p  = 0.002) was longer in PSP/CBD. Conclusions The duration and complexity of the diagnostic journey were greater in PSP/CBD than age-sex matched PD but can be improved. In this older cohort, there was little difference in survival from symptom onset in PSP/CBD and age-sex matched PD.

Background We conducted a systematic review to identify existing ICD-10 coding validation studies in progressive supranuclear palsy and corticobasal syndrome [PSP/CBS]) and, in a new study, evaluated the accuracy of ICD-10 diagnostic codes for PSP/CBS in Scottish hospital inpatient and death certificate data. Methods Original studies that assessed the accuracy of specific ICD-10 diagnostic codes in PSP/CBS were sought. Separately, we estimated the positive predictive value (PPV) of specific codes for PSP/CBS in inpatient hospital data (SMR01, SMR04) compared to clinical diagnosis in four regions. Sensitivity was assessed in one region due to a concurrent prevalence study. For PSP, the consistency of the G23.1 code in inpatient and death certificate coding was evaluated across Scotland. Results No previous ICD-10 validation studies were identified. 14,767 records (SMR01) and 1497 records (SMR04) were assigned the candidate ICD-10 diagnostic codes between February 2011 and July 2019. The best PPV was achieved with G23.1 (1.00, 95% CI 0.93–1.00) in PSP and G23.9 in CBS (0.20, 95% CI 0.04–0.62). The sensitivity of G23.1 for PSP was 0.52 (95% CI 0.33–0.70) and G31.8 for CBS was 0.17 (95% CI 0.05–0.45). Only 38.1% of deceased G23.1 hospital-coded cases also had this coding on their death certificate: the majority (49.0%) erroneously assigned the G12.2 code. Discussion The high G23.1 PPV in inpatient data shows it is a useful tool for PSP case ascertainment, but death certificate coding is inaccurate. The PPV and sensitivity of existing ICD-10 codes for CBS are poor due to a lack of a specific code.