Dennis J. Nieuwkamp

Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis.

BACKGROUND In a systematic review, published in 1997, we found that the case fatality of aneurysmal subarachnoid haemorrhage (SAH) decreased during the period 1960-95. Because diagnostic and treatment strategies have improved and new studies from previously non-studied regions have been published since 1995, we did an updated meta-analysis to assess changes in case fatality and morbidity and differences according to age, sex, and region. METHODS A new search of PubMed with predefined inclusion criteria for case finding and diagnosis identified reports on prospective population-based studies published between January, 1995, and July, 2007. The studies included in the previous systematic review were reassessed with the new inclusion criteria. Changes in case fatality over time and the effect of age and sex were quantified with weighted linear regression. Regional differences were analysed with linear regression analysis, and the regions of interest were subsequently defined as reference regions and compared with the other regions. FINDINGS 33 studies (23 of which were published in 1995 or later) were included that described 39 study periods. These studies reported on 8739 patients, of whom 7659 [88%] were reported on after 1995. 11 of the studies that were included in the previous review did not meet the current, more stringent, inclusion criteria. The mean age of patients had increased in the period 1973 to 2002 from 52 to 62 years. Case fatality varied from 8.3% to 66.7% between studies and decreased 0.8% per year (95% CI 0.2 to 1.3). The decrease was unchanged after adjustment for sex, but the decrease per year was 0.4% (-0.5 to 1.2) after adjustment for age. Case fatality was 11.8% (3.8 to 19.9) lower in Japan than it was in Europe, the USA, Australia, and New Zealand. The unadjusted decrease in case fatality excluding the data for Japan was 0.6% per year (0.0 to 1.1), a 17% decrease over the three decades. Six studies reported data on case morbidity, but these were insufficient to assess changes over time. INTERPRETATION Despite an increase in the mean age of patients with SAH, case-fatality rates have decreased by 17% between 1973 and 2002 and show potentially important regional differences. This decrease coincides with the introduction of improved management strategies. FUNDING Netherlands Organisation for Scientific Research; ZonMw.

Treatment and outcome of severe intraventricular extension in patients with subarachnoid or intracerebral hemorrhage: a systematic review of the literature

Abstract Severe intraventricular hemorrhage caused by extension from subarachnoid hemorrhage or intracerebral hemorrhage leads to hydrocephalus and often to poor outcome. We conducted a systematic review to compare conservative treatment, extraventricular drainage, and extraventricular drainage combined with fibrinolysis. We carried out a search in Medline of the literature between January 1966 and December 1998 and an additional hand-search from January 1990 to December 1998. Pharmaceutical companies were contacted to gather unpublished data. We reviewed the reference lists of all relevant articles. Two authors independently assessed eligibility of the studies and extracted data on characteristics of study design, patients, and treatment. Patients with primary intraventricular hemorrhage were excluded. Main outcome measures were death and poor outcome (defined as death or dependency) at the end of follow-up. No randomized clinical trial has yet been conducted so far, and we therefore reviewed only observational studies. The case fatality rate for conservative treatment (ten studies) was 78%. For extraventricular drainage (seven studies) it was 58% [relative risk versus conservative treatment (RR) 0.74; 95% confidence interval (CI) 0.55–0.99]. For extraventricular drainage with fibrinolytic agents (five studies) the case fatality rate was 6% (RR 0.08; 95% CI 0.02–¶0.24). The poor outcome rate for conservative treatment was 90%, that for extraventricular drainage 89% (RR 0.98; 95% CI 0.75–1.30) and that for extraventricular drainage with fibrinolytic agents 34% (RR 0.38; 95% CI 0.21–0.68). All RR values remained essentially the same after adjusting for age, sex, World Federation of Neurological Surgeons scale, study design, and year of publication for the studies that provided these data. Outcome is thus poor in patients with intraventricular extension of subarachnoid or intracerebral hemorrhage. This meta-analysis suggests that treatment with ventricular drainage combined with fibrinolytics may improve outcome for such patients, although this impression is derived only from an indirect comparison between observational studies. ¶A randomized clinical trial is warranted.

Subarachnoid haemorrhage in patients ⩾75 years: clinical course, treatment and outcome

Background: The number of elderly patients being admitted with aneurysmal subarachnoid haemorrhage (SAH) has been increasing. Treatment of the aneurysm may be offset by the higher rate of surgical or endovascular complications. Aim: To study the clinical condition at onset, complications during clinical course, treatment and outcome in a consecutive series of elderly patients. Methods: Patients who were ⩾75 years at the onset of SAH were selected from the databases of two hospitals. Data on clinical condition at onset (poor condition defined as World Federation of Neurological Surgeons (WFNS) Scale IV and V), clinical course, treatment and outcome were extracted. Univariate and multivariate regression analyses were carried out to identify predictors for in-hospital death and poor outcome, defined as death or dependency. Results: The data of 170 patients were retrieved, of whom 25 (15%) patients were independent at discharge; none of these patients had been admitted in a poor condition. Poor clinical condition on admission (odds ratio (OR) 7.9; 95% confidence interval (CI) 3.7 to 17) and recurrent haemorrhage (OR 7.5; 95% CI 2.5 to 23) were the strongest predictors for in-hospital death. Recurrent haemorrhage was the strongest predictor for poor outcome in the subset of patients who were admitted in good clinical condition. In all, 10 of 47 (21%) patients were independent at discharge after neurosurgical clipping (n = 34) or endovascular coiling (n = 13). Conclusion: Elderly patients with SAH have a poor prognosis. The effect of the initial haemorrhage is the most common reason for poor outcome. For patients who are admitted in good clinical condition, the most important complication leading to poor outcome is recurrent haemorrhage. Treatment of the aneurysm in patients ⩾75 years is feasible, may improve the outcome and should be strongly considered in patients who are admitted in a good condition.

Excess Mortality and Cardiovascular Events in Patients Surviving Subarachnoid Hemorrhage A Nationwide Study in Sweden

Background and Purpose— Survivors of aneurysmal subarachnoid hemorrhage (SAH) may have an increased risk of cardiovascular events because of shared risk factors. We compared incidences of vascular diseases, vascular death, and all-cause death after SAH with those in the general population. Methods— From the Swedish Hospital Discharge and Cause of Death registries, we identified patients with SAH between January 1987 and January 2003. Conditional on survival of 3 months after SAH, we calculated standardized mortality and incidence ratios with corresponding 95% CIs for vascular death, all-cause death, and fatal or nonfatal vascular diseases. Cumulative risks were estimated with survival analysis. Results— Of 17 705 patients with SAH (mean age, 59.7 years; 59.5% women), 11 374 survived at least 3 months after SAH. During follow-up (mean, 6.8 years), 2152 (18.9%) died. The risk of death was 12.9% within 5 years, 23.6% within 10 years, and 35.4% within 15 years after SAH. The overall standardized mortality ratio was 1.57 (95% CI, 1.44 to 1.70) for vascular death and 1.61 (95% CI, 1.52 to 1.70) for all-cause death. The standardized mortality ratios were particularly high in younger individuals, ranging from 2.1 to 3.7 for vascular death and from 2.1 to 2.6 for all-cause death for patients between 50 and 65 years of age. The standardized incidence ratio for fatal or nonfatal vascular diseases was 1.51 (95% CI, 1.45 to 1.56). Conclusions— Mortality and risk of vascular diseases are increased in survivors of SAH. Prevention of new vascular diseases after SAH by management of risk factors seems important.

Timing of aneurysm surgery in subarachnoid haemorrhage--an observational study in The Netherlands.

SummaryBackground. There is still lack of evidence on the optimal timing of surgery in patients with aneurysmal subarachnoid haemorrhage. Only one randomised clinical trial has been done, which showed no difference between early and late surgery. Other studies were observational in nature and most had methodological drawbacks that preclude clinically meaningful conclusions. We performed a retrospective observational study on the timing of aneurysm surgery in The Netherlands over a two-year period.Method. In eight hospitals we identified 1500 patients with an aneurysmal subarachnoid haemorrhage. They were subjected to predefined inclusion criteria. We included all patients who were admitted and were conscious at any one time between admission and the end of the third day after the haemorrhage. We categorised the clinical condition on admission according the World Federation of Neurological Surgeons (WFNS) grading scale. Early aneurysm surgery was defined as operation performed within three days after onset of subarachnoid haemorrhage; intermediate surgery as performed on days four to seven, and late surgery as performed after day seven. Outcome was classified as the proportion of patients with poor outcome (death or dependent) two to four months after onset of subarachnoid haemorrhage. We calculated crude odds ratios with late surgery as reference. We distinguished between management results (reconstructed intention to treat analysis) and surgical results (on treatment analysis). The results were adjusted for the major prognosticators for outcome after subarachnoid haemorrhage.Findings. We included 411 patients. There were 276 patients in the early surgery group, 36 in the intermediate surgery group and 99 in the late surgery group. On admission 78% were in good neurological condition (WFNS I–III).Management results. Overall, 93 patients (34%) operated on early had a poor outcome, 13 (36%) of those with intermediate surgery and 37 (37%) in the late surgery group had a poor outcome. For patients in good clinical condition on admission and planned for early surgery the adjusted odds ratio (OR) was 1.3 (95% CI 0.5 to 3.0). The adjusted OR for patients admitted in poor neurologicalcondition (WFNS IV–V) and planned for early surgery was 0.1 (95% CI 0.0 to 0.6).Surgical results. For patients in good clinical condition on admission who underwent early operation the adjusted OR was 1.1 (95% CI 0.4 to 3.2); it was 0.2 (95% CI 0.0 to 0.9) for patients admitted in poor clinical condition.Conclusions. In this observational study we found no significant difference in outcome between early and late operation for patients in good clinical condition on admission. For patients in poor clinical condition on admission outcome was significantly better after early surgery. The optimal timing of surgery is not yet settled. Ideally, evidence on this issue should come from a randomised clinical trial. However, such a trial or even a prospective study are unlikely to be ever performed because of the rapid development of endovascular coiling.

Age‐ and gender‐specific time trend in risk of death of patients admitted with aneurysmal subarachnoid hemorrhage in the Netherlands

Background and aim In a meta-analysis of population-based studies, case-fatality rates of subarachnoid hemorrhage have decreased worldwide by 17% between 1973 and 2002. However, age- and gender-specific decreases could not be determined. Because >10% of patients with subarachnoid hemorrhage die before reaching the hospital, this suggests that the prognosis for hospitalized subarachnoid hemorrhage patients has improved even more. We assessed age- and gender-specific time trends of the risk of death for hospitalized subarachnoid hemorrhage patients. Methods From the Dutch hospital discharge register (nationwide coverage), we identified 9403 patients admitted with subarachnoid hemorrhage in the Netherlands between 1997 and 2006. Changes in risk of death within this time frame and influence of age and gender were quantified with Poisson regression. Results The overall 30-day risk of death was 34·0% (95% confidence interval 33·1↔35·0%). After adjustment for age and gender, the annual decrease was 1·6% (95% confidence interval 0·5↔2·6%), which confers to a decrease of 13·4% (95% confidence interval4·8↔21·2%) in the study period. The one-year risk of death decreased 2·0% per year (95% confidence interval1·1↔2·9%). The decrease in risk of death was mainly found in the period 2003–2005, was not found for patients ≥65 years and was statistically significant for men, but not for women. Conclusions The decrease in risk of death for patients admitted in the Netherlands with subarachnoid hemorrhage is overall considerable, but unevenly distributed over age and gender. Further research should focus on reasons for improved survival (improved diagnostics, improved treatment) and reasons why improvement has not occurred for women and for patients in older age categories.

Risk of cardiovascular events and death in the life after aneurysmal subarachnoid haemorrhage: a nationwide study

Background and aim The increased mortality rates of survivors of aneurysmal subarachnoid haemorrhage have been attributed to an increased risk of cardiovascular events in a registry study in Sweden. Swedish registries have however not been validated for subarachnoid haemorrhage and Scandinavian incidences of cardiovascular disease differ from that in Western European countries. We assessed risks of vascular disease and death in subarachnoid haemorrhage survivors in the Netherlands. Methods From the Dutch hospital discharge register, we identified all patients with subarachnoid haemorrhage admission between 1997 and 2008. We determined the accuracy of coding of the diagnosis subarachnoid haemorrhage for patients admitted to our centre. Conditional on survival of three-months after the subarachnoid haemorrhage, we calculated standardized incidence and mortality ratios for fatal or nonfatal vascular diseases, vascular death, and all-cause death. Cumulative risks were estimated with survival analysis. Results The diagnosis of nontraumatic subarachnoid haemorrhage was correct in 95·4% of 1472 patients. Of 11 263 admitted subarachnoid haemorrhage patients, 6999 survived more than three-months. During follow-up (mean 5·1 years), 874 (12·5%) died. The risks of death were 3·3% within one-year, 11·3% within five-years, and 21·5% within 10 years. The standardized mortality ratio was 3·4 (95% confidence interval: 3·1 to 3·7) for vascular death and 2·2 (95% confidence interval: 2·1 to 2·3) for all-cause death. The standardized incidence ratio for fatal or nonfatal vascular diseases was 2·7 (95% confidence interval: 2·6 to 2·8). Conclusions Dutch hospital discharge and cause of death registries are a valid source of data for subarachnoid haemorrhage, and show that the increased mortality rate in subarachnoid haemorrhage survivors is explained by increased risks for vascular diseases and death.

Additional risk of hypertension and smoking for aneurysms in people with a family history of subarachnoid haemorrhage

Background Smoking and hypertension increase the risk of aneurismal subarachnoid haemorrhage (SAH) two to threefold whereas a familial predisposition increases the risk sixfold. We assessed the additional risk of smoking and hypertension for the presence of an intracranial aneurysm (IA) in first-degree relatives of patients with familial SAH. Methods We studied first-degree relatives of patients with familial SAH who were screened for the presence of aneurysms. RRs with corresponding 95% CIs for the risk of IA were calculated for smoking and hypertension. Results The RRs were 1.5 (95% CI 0.7 to 3.2) for smoking, 1.9 (95% CI 1.0 to 3.7) for hypertension and 2.7 (95% CI 1.4 to 5.3) for smoking plus hypertension. The increased RR for hypertension was found in both women and men, but the increased RR for smoking was found in women only. Conclusion The extent of the increased risk of smoking and hypertension for the presence of IA in first-degree relatives of patients with familial SAH is similar to that in patients without familial predisposition. Risk factor profiles should be included in future genetic studies.

Clinical and radiological heterogeneity in aneurysmal sub-arachnoid haemorrhage according to risk-factor profile.

Background and Aim Risk factors for aneurysmal sub-arachnoid haemorrhage can be divided into environmental and inherited factors; the latter being presumed more important in young patients. We explored in young sub-arachnoid haemorrhage patients whether risk-factor profiles influence clinical and radiological characteristics of aneurysms and sub-arachnoid haemorrhage. Methods From the 2139 aneurysmal sub-arachnoid haemorrhage patients who had been entered in our prospectively collected database between January 1997 and August 2012, we retrieved data on young (18–40 years) aneurysmal sub-arachnoid haemorrhage patients and compared those with smoking or hypertension (atherogenic risk factors) with those without. Clinical and radiological characteristics were compared with risk ratios and corresponding 95% confidence intervals. Possible confounding by age and gender was adjusted with multivariable Poisson regression analysis. Results Patients with atherogenic risk factors (n = 113) were less often female (risk ratio: 0·7; 95% confidence interval: 0·6↔0·9), had less often a small aneurysm (risk ratio: 0·4; 95% confidence interval: 0·2↔0·7), and tended to have less often middle cerebral artery aneurysms (risk ratio: 0·5; 95% confidence interval: 0·3↔1·1) than the 29 patients without these risk factors. After adjustment for gender and age, patients with atherogenic risk factors had more often multiple aneurysms (risk ratio: 7·5; 95% confidence interval: 1·1↔52·9). There were no overt differences in the amount of cisternal and intraventricular blood, the shape of the aneurysm, and configuration of the circle of Willis between the patient groups. After adjustment for gender and age, patients with atherogenic risk factors had more often poor outcome (risk ratio: 3·8; 95% confidence interval: 1·0↔14·5). Conclusions Young sub-arachnoid haemorrhage patients without atherogenic risk factors are rare. Clinical and radiological characteristics vary between sub-arachnoid haemorrhage patients with different risk-factor profiles. This clinical heterogeneity should be taken into account in future genetic and other etiological studies.

Multiple intracerebral haematomas during normal intensity anticoagulation

A 57-year-old man suddenly developed a ‘stinging’ headache and paresis of his left arm. He was transferred immediately to our hospital. Seven months earlier he had suffered an ascending aorta dissection (Standford type A—originating in but not confined to the ascending aorta) which necessitated implanting a prosthetic valve conduit and resulted in paraparesis that made him a wheelchair user. He had started oral anticoagulation following the surgery. On examination the patient was alert and well oriented. He had a temperature of 39°C. Apart from the pre-existing paraparesis, he now had a left-sided facial droop, a new paresis of his left arm and denser paresis of his left leg. #### Question 1 What is the differential diagnosis? The abnormalities on neurological examination indicate a structural lesion in the right cerebral hemisphere. The sudden onset suggests a vascular cause, such as an ischaemic stroke or intracerebral haemorrhage (ICH), the latter especially because the patient was receiving anticoagulation. If this was a haemorrhage, the combination with fever and a prosthetic heart valve should raise the suspicion of a ruptured infective aneurysm. #### Question 2 What investigations would you perform now? Laboratory investigation demonstrated anaemia (haemoglobin 5.6 mmol/litre), elevated leucocytes (12.3×109/litre), increased erythrocyte sedimentation rate (>140 mm after 1 h) and C reactive protein (97 mg/litre). The international normalised ratio (INR) was 2.2. He had a CT scan of the head to rule out haemorrhagic stroke. It showed a recent ICH in the right parietal lobe (figure 1). We stopped …