Response by Juvela to Letter Regarding Article, "Treatment Scoring of Unruptured Intracranial Aneurysms".

In Response: I thank 2 young Finnish neurosurgeons for their interest in our long-term, well-known prospective follow-up study. Contrary to well-known international and Finnish senior aneurysm researchers, you unlikely are not very familiar to this cohort and its previous results as well as to basic epidemiological guidelines and correct statistical methods. You perhaps are neither familiar with significance of careful planning of study designs and sources of bias in proving cause and effect. Risk factors of rupture of unruptured intracranial aneurysm (UIAs) can be studied reliably only with prospective follow-up studies, of which this cohort has had least sources of selection bias in 6 prospective ones, which was noted by the authors of the meta-analysis. In other cohorts, >50% of patients with proved high rupture risk aneurysms (smokers, younger patients, and those with larger UIAs) were not at all followed and were treated at baseline. This causes serious selection bias. In our Helsinki study from era when these were not treated and of course not screened, selection occurred only by prior subarachnoid hemorrhage and multiple aneurysms. These have not been shown to be independent risk factors for aneurysm rupture in larger cohort studies. Helsinki cohort results represent much closer to natural history of UIAs than others. Aneurysms are biologically similar independent of the periods of history. Only the risk factor profiles of populations change with elapsed time. Our previous reports have also shown this when decreasing of smoking prevalence also decreased UIA rupture rate during the follow-up. You try to prove that cross-sectional retrospective studies (end point, ie, ruptured aneurysms have diagnosed after rupture) are more valuable in estimating risk of rupture of UIAs than prospective cohort studies without treatment selection bias. I recommend you to consult epidemiologists and statisticians for this. You have reported several studies where you have compared populationbased subarachnoid hemorrhage population with patients with UIAs. You have erroneously considered subarachnoid hemorrhage population to be population-based although patients dying without any hospital admission or in emergency rooms of other hospitals without referral to your university hospital and thus not included in your studies. Your hospital-based patients are principally those of tertiary care center and have different risk factor profiles compared with those without hospital admission, for example, for age, aneurysm size and location, hypertension, and smoking. Similarly, patients with UIAs have been selected with different study indications (principally incidental UIAs found in older patients with different brain diseases or in screening of family members of aneurysm patients), which do not well represent true UIA population of the background general population. When these selected 2 aneurysm populations are compared with each other, the results are subject to a considerable study bias and are difficult to be generalized to aneurysms of the general population (Berkson bias). This also explains conflicts between the results of prospective and retrospective studies. You have fundamental misconception when you use this score for already ruptured aneurysms. The purpose of scoring is to predict lifelong rupture risk of only UIAs of patients of working age. Most rupturing small aneurysms rupture soon after their appearance because of a high relative growth rate of aneurysm for which there is recent evidence. UIAs have already existed before diagnosis for different times. Another misconception is that use of some laboratory markers for evaluation of rupture risk in low-risk UIAs could define treatment indications is incorrect when highrisk patients are yet treated at baseline. This may lead even to a more increased overtreatment of UIAs because current practice is difficult to change so that all patients remain untreated because of laboratory marker studies. It is not ethical. I strongly recommend that you should consult epidemiologists before planning such studies.