SummaryBackgroundCerebral 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.MethodsWe 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.Findings139 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).InterpretationThe 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.FundingUK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.
SummaryBackgroundCerebral cavernous malformations (CCMs) can cause symptomatic intracranial haemorrhage (ICH), but the estimated risks are imprecise and predictors remain uncertain. We aimed to obtain precise estimates and predictors of the risk of ICH during untreated follow-up in an individual patient data meta-analysis.MethodsWe invited investigators of published cohorts of people aged at least 16 years, identified by a systematic review of Ovid MEDLINE and Embase from inception to April 30, 2015, to provide individual patient data on clinical course from CCM diagnosis until first CCM treatment or last available follow-up. We used survival analysis to estimate the 5-year risk of symptomatic ICH due to CCMs (primary outcome), multivariable Cox regression to identify baseline predictors of outcome, and random-effects models to pool estimates in a meta-analysis.FindingsAmong 1620 people in seven cohorts from six studies, 204 experienced ICH during 5197 person-years of follow-up (Kaplan-Meier estimated 5-year risk 15·8%, 95% CI 13·7–17·9). The primary outcome of ICH within 5 years of CCM diagnosis was associated with clinical presentation with ICH or new focal neurological deficit (FND) without brain imaging evidence of recent haemorrhage versus other modes of presentation (hazard ratio 5·6, 95% CI 3·2–9·7) and with brainstem CCM location versus other locations (4·4, 2·3–8·6), but age, sex, and CCM multiplicity did not add independent prognostic information. The 5-year estimated risk of ICH during untreated follow-up was 3·8% (95% CI 2·1–5·5) for 718 people with non-brainstem CCM presenting without ICH or FND, 8·0% (0·1–15·9) for 80 people with brainstem CCM presenting without ICH or FND, 18·4% (13·3–23·5) for 327 people with non-brainstem CCM presenting with ICH or FND, and 30·8% (26·3–35·2) for 495 people with brainstem CCM presenting with ICH or FND.InterpretationMode of clinical presentation and CCM location are independently associated with ICH within 5 years of CCM diagnosis. These findings can inform decisions about CCM treatment.FundingUK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.
Objective: There have been few comparative studies of microsurgical excision vs conservative management of cerebral cavernous malformations (CCM) and none of them has reliably demonstrated a statistically and clinically significant difference. Methods:We conducted a prospective, population-based study to identify and independently validate definite CCM diagnoses first made in 1999-2003 in Scottish adult residents. We used multiple sources of prospective follow-up to assess adults' dependence and to identify and independently validate outcome events. We used univariate and multivariable survival analyses to test the influence of CCM excision on outcome, adjusted for prognostic factors and baseline imbalances.Results: Of 134 adults, 25 underwent CCM excision; these adults were younger (34 vs 43 years at diagnosis, p 5 0.004) and more likely to present with symptomatic intracranial hemorrhage or focal neurologic deficit than adults managed conservatively (48% vs 26%; odds ratio 2.7, 95% confidence interval [CI] 1.1-6.5). During 5 years of follow-up, CCM excision was associated with a deterioration to an Oxford Handicap Scale score 2-6 sustained over at least 2 successive years (adjusted hazard ratio [HR] 2.2, 95% CI 1.1-4.3) and the occurrence of symptomatic intracranial hemorrhage or new focal neurologic deficit (adjusted HR 3.6, 95% CI 1.3-10.0).Conclusions: CCM excision was associated with worse outcomes over 5 years compared to conservative management. Long-term follow-up will determine whether this difference is sustained over patients' lifetimes. Meanwhile, a randomized controlled trial appears justified. Classification of evidence:This study provides Class III evidence that CCM excision worsens shortterm disability scores and increases the risk of symptomatic intracranial hemorrhage and new focal neurologic deficits.
Background Understanding the risk factors for poor outcomes among COVID-19 patients could help identify vulnerable populations who would need prioritisation in prevention and treatment for COVID-19. We aimed to critically appraise and synthesise published evidence on the risk factors for poor outcomes in hospitalised COVID-19 patients. Methods We searched PubMed, medRxiv and the WHO COVID-19 literature database for studies that reported characteristics of COVID-19 patients who required hospitalisation. We included studies published between January and May 2020 that reported adjusted effect size of any demographic and/or clinical factors for any of the three poor outcomes: mortality, intensive care unit (ICU) admission, and invasive mechanical ventilation. We appraised the quality of the included studies using Joanna Briggs Institute appraisal tools and quantitatively synthesised the evidence through a series of random-effect meta-analyses. To aid data interpretation, we further developed an interpretation framework that indicated strength of the evidence, informed by both quantity and quality of the evidence. Results We included a total of 40 studies in our review. Most of the included studies (29/40, 73%) were assessed as “good quality”, with assessment scores of 80 or more. We found that male sex (pooled odds ratio (OR) = 1.32 (95% confidence interval (CI) = 1.18-1.48; 20 studies), older age (OR = 1.05, 95% CI = 1.04-1.07, per one year of age increase; 10 studies), obesity (OR = 1.59, 95% CI = 1.02-2.48; 4 studies), diabetes (OR = 1.25, 95% CI = 1.11-1.40; 11 studies) and chronic kidney diseases (6 studies; OR = 1.57, 95% CI = 1.27-1.93) were associated with increased risks for mortality with the greatest strength of evidence based on our interpretation framework. We did not find increased risk of mortality for several factors including chronic obstructive pulmonary diseases (5 studies), cancer (4 studies), or current smoker (5 studies); however, this does not indicate absence of risk due to limited data on each of these factors. Conclusion Male sex, older age, obesity, diabetes and chronic kidney diseases are important risk factors of COVID-19 poor outcomes. Our review provides not only an appraisal and synthesis of evidence on the risk factors of COVID-19 poor outcomes, but also a data interpretation framework that could be adopted by relevant future research.
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