Baseline factors associated with early and late death in intracerebral haemorrhage survivors.

BACKGROUND AND PURPOSE: The aim of this study was to determine whether early and late death are associated with different baseline factors in intracerebral haemorrhage (ICH) survivors. METHODS: This was a secondary analysis of the multicentre prospective observational CROMIS-2 ICH study. Death was defined as 'early' if occurring within 6 months of study entry and 'late' if occurring after this time point. RESULTS: In our cohort (n = 1094), there were 306 deaths (per 100 patient-years: absolute event rate, 11.7; 95% confidence intervals, 10.5-13.1); 156 were 'early' and 150 'late'. In multivariable analyses, early death was independently associated with age [per year increase; hazard ratio (HR), 1.05, P = 0.003], history of hypertension (HR, 1.89, P = 0.038), pre-event modified Rankin scale score (per point increase; HR, 1.41, P < 0.0001), admission National Institutes of Health Stroke Scale score (per point increase; HR, 1.11, P < 0.0001) and haemorrhage volume >60 mL (HR, 4.08, P < 0.0001). Late death showed independent associations with age (per year increase; HR, 1.04, P = 0.003), pre-event modified Rankin scale score (per point increase; HR, 1.42, P = 0.001), prior anticoagulant use (HR, 2.13, P = 0.028) and the presence of intraventricular extension (HR, 1.73, P = 0.033) in multivariable analyses. In further analyses where time was treated as continuous (rather than dichotomized), the HR of previous cerebral ischaemic events increased with time, whereas HRs for Glasgow Coma Scale score, National Institutes of Health Stroke Scale score and ICH volume decreased over time. CONCLUSIONS: We provide new evidence that not all baseline factors associated with early mortality after ICH are associated with mortality after 6 months and that the effects of baseline variables change over time. Our findings could help design better prognostic scores for later death after ICH.

Discontinuation and non-publication of neurodegenerative disease trials: a cross-sectional analysis.

BACKGROUND AND PURPOSE: Trial discontinuation and non-publication represent major sources of research waste in clinical medicine. No previous studies have investigated non-dissemination bias in clinical trials of neurodegenerative diseases. METHODS: ClinicalTrials.gov was searched for all randomized, interventional, phase II-IV trials that were registered between 1 January 2000 and 31 December 2009 and included adults with Alzheimer's disease, motor neurone disease, multiple sclerosis or Parkinson's disease. Publications from these trials were identified by extensive online searching and contact with authors, and multiple logistic regression analysis was performed to identify characteristics associated with trial discontinuation and non-publication. RESULTS: In all, 362 eligible trials were identified, of which 12% (42/362) were discontinued. 28% (91/320) of completed trials remained unpublished after 5 years. Trial discontinuation was independently associated with number of patients (P = 0.015; more likely in trials with ≤100 patients; odds ratio 2.65, 95% confidence interval 1.21-5.78) and phase of trial (P = 0.009; more likely in phase IV than phase III trials; odds ratio 3.90, 95% confidence interval 1.41-10.83). Trial non-publication was independently associated with blinding status (P = 0.005; more likely in single-blind than double-blind trials; odds ratio 5.63, 95% confidence interval 1.70-18.71), number of centres (P = 0.010; more likely in single-centre than multi-centre trials; odds ratio 2.49, 95% confidence interval 1.25-4.99), phase of trial (P = 0.041; more likely in phase II than phase IV trials; odds ratio 2.88, 95% confidence interval 1.04-7.93) and sponsor category (P = 0.001; more likely in industry-sponsored than university-sponsored trials; odds ratio 5.05, 95% confidence interval 1.87-13.63). CONCLUSIONS: There is evidence of non-dissemination bias in randomized trials of interventions for neurodegenerative diseases. Associations with trial discontinuation and non-publication were similar to findings in other diseases. These biases may distort the therapeutic information available to inform clinical practice.

Early Magnesium Treatment After Aneurysmal Subarachnoid Hemorrhage: Individual Patient Data Meta-Analysis.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Trials of magnesium treatment starting <4 days after symptom onset found no effect on poor outcome or DCI in SAH. Earlier installment of treatment might be more effective, but individual trials had not enough power for such a subanalysis. We performed an individual patient data meta-analysis to study whether magnesium is effective when given within different time frames within 24 hours after the SAH. METHODS: Patients were divided into categories according to the delay between symptom onset and start of the study medication: <6, 6 to 12, 12 to 24, and >24 hours. We calculated adjusted risk ratios with corresponding 95% confidence intervals for magnesium versus placebo treatment for poor outcome and DCI. RESULTS: We included 5 trials totaling 1981 patients; 83 patients started treatment<6 hours. For poor outcome, the adjusted risk ratios of magnesium treatment for start <6 hours were 1.44 (95% confidence interval, 0.83-2.51); for 6 to 12 hours 1.03 (0.65-1.63), for 12 to 24 hours 0.84 (0.65-1.09), and for >24 hours 1.06 (0.87-1.31), and for DCI, <6 hours 1.76 (0.68-4.58), for 6 to 12 hours 2.09 (0.99-4.39), for 12 to 24 hours 0.80 (0.56-1.16), and for >24 hours 1.08 (0.88-1.32). CONCLUSIONS: This meta-analysis suggests no beneficial effect of magnesium treatment on poor outcome or DCI when started early after SAH onset. Although the number of patients was small and a beneficial effect cannot be definitively excluded, we found no justification for a new trial with early magnesium treatment after SAH.

Patient-reported outcome measures in patients with familial cerebral cavernous malformations: results from the Treat_CCM trial.

Background: The Phase 1/2 Treat_CCM randomized controlled trial for people with familial cerebral cavernous malformations (FCCMs) confirmed the safety of propranolol and suggested beneficial effects on intracerebral hemorrhage or new focal neurological deficits, but the effects on patient-reported outcome measures have not been reported. Methods: Participants completed self-reported questionnaires at baseline, 1 and 2 years. Depression was assessed with the Beck Depression Inventory-II (BDI-2); Anxiety with the State-Trait Anxiety Inventory X1 and X2 (STAI X-1 and STAI X-2); and Quality of Life with the Short Form 36 (SF-36), split into the physical and mental component scales (PCS and MCS). Differences between treatment groups and the general population were assessed. Change over time by treatment was assessed by means of mixed models. Results: In total, 71 participants (48 propranolol and 23 standard care) were enrolled, of whom 61 (73%) completed questionnaires at baseline and 2-year FU. At baseline, no differences between treatment groups for any of the questionnaires were present. Twenty (31.7%) patients were considered depressed at baseline, while this proportion was lower in the propranolol group after 2 years (28.6% vs. 55.5%, p = 0.047). The STAI X-1 and X-2 scores were stable over time. PCS was lower in FCCM patients as compared with the general Italian population, while the MCS was similar to the general population. No effect of propranolol was found for both PCS and MCS. Conclusion: Depression is common among patients with FCCM. Patients randomized to propranolol had a lower proportion of participants with depression after 2 years.Clinical trial registration: https://clinicaltrials.gov/, identifier (NCT03589014).

Screening patients with a family history of subarachnoid haemorrhage for intracranial aneurysms: screening uptake, patient characteristics and outcome.

BACKGROUND AND PURPOSE: People with one or more first degree relative affected (FDRA) by aneurysmal subarachnoid haemorrhage (aSAH) are at a higher lifetime risk of an aSAH than those without a family history. Screening may be worthwhile for people with two or more FDRA by aSAH. Little is known about the characteristics of people with a family history of aSAH who undergo screening in clinical practice. METHODS: Observational analysis of consecutive attendances at an intracranial aneurysm screening clinic. RESULTS: Of 96 adults seen, 19 did not have a family history of aSAH and 77 had one or more FDRA by aSAH: 35 had two or more FDRA, 21 had one FDRA plus one or more affected second degree relative and 21 had one FDRA only. In these three respective groups, 29 (83%), 15 (71%) and five (24%) adults underwent screening, of whom six (21%), two (13%) and one (20%) had an aneurysm detected (p=0.5). Of the nine patients with aneurysms, four underwent treatment. Considering other risk factors, adults with two or more FDRA were more likely to be hypertensive (OR 3.3, 95% CI 1.0 to 10.8; p=0.046) but were no more likely to smoke or drink to excess than adults with one FDRA. Adults who underwent screening were more likely to be hypertensive and drink alcohol to excess (both p=0.03), but were no more likely to smoke than those who were not screened. CONCLUSIONS: In clinical practice, people undergoing intracranial aneurysm screening had stronger family histories of aSAH and they were also more likely to have modifiable risk factors for aSAH.

Acute neurological problems: frequency, consultation patterns and the uses of a rapid access neurology clinic.

In secondary care, some patients with acute neurological symptoms are never seen by a neurologist. Rapid access neurology clinics could provide patients with timely access to neurology services. We analysed a retrospective cohort of 12,024 consecutive patients attending the 'immediate care' area of the emergency department or the acute medical admissions unit of the Royal Infirmary of Edinburgh. A total of 1,036 patients (9%) presented with a neurological complaint, of whom 680 (66%) did not have any contact with neurology services. The most common problems were epileptic seizure, cerebrovascular diseases and headache. Of the patients with epileptic seizure or headache who were not seen by a neurologist, about 40% might have benefited from neurological assessment. Following the introduction of a weekly rapid access neurology clinic, the most common problems seen were headache, symptoms that turned out to be medically unexplained and epileptic seizure.

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.

CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) intracranial bleeding study: the effect of tranexamic acid in traumatic brain injury--a nested randomised, placebo-controlled trial.

BACKGROUND: Tranexamic acid (TXA) has been shown to reduce blood loss in surgical patients and the risk of death in patients with traumatic bleeding, with no apparent increase in vascular occlusive events. These findings raise the possibility that it might also be effective in traumatic brain injury (TBI). OBJECTIVE: The Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage Intracranial Bleeding Study (CRASH-2 IBS) was conducted to quantify the effect of an early short course of TXA on intracranial haemorrhage and new focal cerebral ischaemic lesions in patients with TBI. DESIGN: CRASH-2 IBS was a prospective randomised controlled trial nested within the CRASH-2 trial. Randomisation was balanced by centre, with an allocation sequence based on a block size of eight. We used a local pack system that selected the lowest numbered treatment pack from a box containing eight numbered packs. Apart from the pack number, the treatment packs were identical. The pack number was recorded on the entry form, which was sent to the international trial co-ordinating centre in London, UK. Once the treatment pack number was recorded, the patient was included in the trial whether or not the treatment pack was opened or the allocated treatment started. All site investigators and trial co-ordinating centre staff were masked to treatment allocation. SETTING: Ten hospitals: (India) Aditya Neuroscience Centre, Sanjivani Hospital, CARE Hospital, Christian Medical College, Medical Trust Hospital, Jeevan Jyoti Hospital and (Colombia) Hospital Universitario San Vicente de Paul, Hospital Pablo Tobón Uribe, Hospital Universitario San José de Popayán and Fundación Valle del Lili. PARTICIPANTS: The trial was conducted in a subset of 270 CRASH-2 trial participants. Patients eligible for inclusion in the CRASH-2 IBS fulfilled the inclusion criteria for the CRASH-2 trial, and also had TBI [Glasgow Coma Scale score of ≤ 14 and a brain computerised tomography (CT) scan compatible with TBI]. Pregnant women and patients for whom a second brain CT scan was not possible were excluded. INTERVENTIONS: Participants were randomly allocated to receive either a loading dose of 1 g of TXA infused over 10 minutes followed by an intravenous infusion of 1 g over 8 hours or matching placebo. MAIN OUTCOME MEASURE: The primary outcome was the increase in size of intracranial haemorrhage growth between a CT scan at hospital admission and a second scan 24-48 hours later. RESULTS: One hundred and thirty-three patients were allocated to TXA and 137 to placebo, of whom information on the primary (imaging) outcome was available for 123 (92%) and 126 (92%) respectively. The analysis suggested that TXA was likely to be associated with a reduction in haemorrhage growth [adjusted difference -3.8 ml, 95% credibility interval (CrI) -11.5 ml to 3.9 ml], fewer focal ischaemic lesions [adjusted odds ratio (OR) 0.54, 95% CrI 0.20 to 1.46] and fewer deaths (adjusted OR 0.49, 95% CrI 0.22 to 1.06). CONCLUSIONS: This was the first randomised controlled study to evaluate the effect of TXA in TBI patients and it found that neither moderate benefits nor moderate harmful effects can be excluded. However, although uncertainty remains, our analyses suggest that TXA administration might improve outcome in TBI patients and provide grounds for evaluating this hypothesis in future research. TRIAL REGISTRATION: Current Controlled Trials ISRCTN86750102. SOURCE OF FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 13. See the HTA programme website for further project information.

Genetic associations with brain microbleeds: Systematic review and meta-analyses.

OBJECTIVE: We performed a systematic review and meta-analyses to assess the evidence for genetic associations with brain microbleeds (BMBs). METHODS: We sought all published studies of the association between any genetic polymorphism and BMBs studied in a total of >100 people. We critically appraised studies, and calculated pooled odds ratios (ORs) using the generic inverse variance fixed effects method. We used I² and χ² statistics to assess heterogeneity, and fail-safe N estimates to assess the robustness of our results. RESULTS: Only the APOE ε2/3/4 polymorphism had been studied in >100 people (10 studies, 7,351 participants). Compared with people with the ε3/ε3 genotype, carriers of the ε4 allele (ε4+) were statistically significantly more likely to have BMBs in any location (ε4+ vs ε3/ε3: pooled OR 1.22, 95% confidence interval [CI] 1.05-1.41, p = 0.01). For strictly lobar BMBs, this association appeared slightly stronger (ε4+ vs ε3/ε3: pooled OR 1.35, 95% CI 1.10-1.66, p = 0.005). The association of ε4+ genotypes with strictly lobar BMBs was reasonably robust to potential publication and reporting biases. CONCLUSIONS: Given the known associations of APOE alleles with lobar intracerebral hemorrhage and cerebral amyloid angiopathy, these findings support the concept that strictly lobar BMBs may be an imaging biomarker of cerebral amyloid angiopathy.

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.

Emergency department evaluation of sudden, severe headache.

AIM: To assess the clinical management of adults presenting with sudden, severe headache. METHODS: We retrospectively reviewed the medical records of consecutive adults presenting with sudden, severe headache to the emergency department (ED) or medical admissions unit at one teaching hospital. RESULTS: Of 12 025 consecutive attendances over 3 months, 91 adults (0.8%, 95% CI 0.6-0.9%) presented with sudden severe headache. Documentation of time to peak headache intensity and headache duration was complete in only 33% of cases. Brain computed tomography was performed in each of the 29 patients (33%) in whom it appeared indicated for the investigation of headaches peaking within 5 min and lasting more than 1 h, as well as 11 patients (13%) who did not meet these criteria. Lumbar puncture was attempted in every patient for whom it appeared indicated (although it was unsuccessful and abandoned on three of 24 patients), as well as one patient in whom it appeared not to be indicated. When subarachnoid haemorrhage was suspected, 81% of patients had spectrophotometry. Of the patients, 52 (60%) were given a specific diagnosis, 17 (33%) of whom were given a diagnosis despite an apparently insufficient history. A further 12 (14%) could have been diagnosed if the International Headache Society classification had been applied to the documented history. Neurological advice was sought for only 20 patients (23%). CONCLUSION: Patients with sudden, severe headache might benefit if EDs used simple protocols, emphasizing the crucial elements of history and examination, appropriate investigation and targeted consultation with neurologists.

Thyrotoxicosis presenting with headache.

We report three cases of thyrotoxicosis who presented acutely with headache to our neurology service in a 1-year period. In two of these patients there was a pre-existing or subsequent history of migraine. With hindsight, there were other clinical features of thyrotoxicosis but this diagnosis had been missed in primary care. Severe headache can be a striking presenting feature of thyrotoxicosis, but these cases provide reassurance to the clinician that when this does occur, other clinical features of hyperthyroidism are usually present.