In this risk factor-based (age, gender and smoking) screening pilot for an asymptomatic but potentially life-threatening condition, five out of 43 female smokers were identified, each with one suspected UIA (4 diagnosed and one suspected but unconfirmed with DSA). A dural arteriovenous fistula was found in one study participant. The woman with the largest UIA (7 mm) was microsurgically treated without complications, and the patient with the dural arteriovenous fistula is scheduled for treatment. Four patients with small (2–3 mm) UIAs were advised to quit smoking, and all four were scheduled for a 1-year follow-up CTA. Two women with UIAs had hypertension, and one had a family history (≥ 1 first-degree members) of IAs. The proportion of hypertensive participants (n = 9, 21%) was in line with the general Finnish population; about one fifth of the population use antihypertensive medication19.
Previous data suggest that people with autosomal dominant polycystic kidney disease (ADPKD) have a significantly higher prevalence of UIAs2. In the largest study of screened ADPKD patients to date, UIAs (≥ 2 mm in size) were detected in 75 (9.2%) of the 812 ADPKD patients who underwent a magnetic resonance angiography (MRA) screening between 1989 and 2017 at the Mayo Clinic20. Even in ADPKD, selective or widespread screening for UIAs has remained questionable20,21, partly because ADPKD patients have a shortened life-expectancy due to the underlying kidney disease. However, the American Heart Association/American Stroke Association Patients views that ADPKD patients – particularly those with a family history of IAs – should be offered a UIA screening4. In addition to ADPKD, UIAs may be found relatively frequently in families with a history of IAs. In the largest screening study of UIAs in first-degree relatives (parents, siblings or children) of SAH patients to date, UIAs were identified in 4.0% of 626 first-degree relatives (mean age 41 years; 52% women)22. Eighteen out of the 23 screen-positives underwent surgery (11 of which had UIAs smaller than 5 mm), which resulted in complications in 11 (disabling in one)22. In the largest UIA screening study of individuals having two or more first-degree relatives with a history of SAH, UIAs were identified in 11.1% of 458 relatives (median age 38 years; 58% women) in the first screening23. Of the identified UIAs, 25% were smaller than 2 mm and 51% were 3–5 mm in size23. No treatment results were reported23. In a multinational Familial Intracranial Aneurysm (FIA) Study, 548 subjects with a family history of ≥ 2 siblings (first-degree family members) or ≥ 3 any family members with IAs were screened with MRA, if they additionally had a history of ≥ 10 pack-years of smoking (or currently smoking) or hypertension24. The percentage of screen positives was 20.6%, but since 108 (96%) out of 113 found UIAs were small (< 7 mm in size), only 11 patients were treated surgically24. In our study, none of the five screen-positive female smokers reported a family history of IAs in advance. However, earlier patient notes revealed that the one of the five screen-positive women had a family history of aSAH (patient’s mother had suffered from aSAH), and that this woman had also undergone a brain CTA screen 13 years earlier for familial screening (no UIAs were detected). Two of the 38 screen-negatives reported a family history of IAs (≥ 1 first-degree relatives). In comparison to the screening of individuals with ADPKD (a rare disease) and a family history of SAH, the population-wide effect of UIA screening in postmenopausal female smokers might be more significant, particularly since the number of 50 to 60-year-old female smokers is substantial in many countries. For example, in 2018, 16.3% of women aged 45 to 64 years old were current cigarette smokers in the United States25, whereas the estimated prevalence of ADPKD in the Unites States is 0.04%26. Therefore, if the percentage of identified screen positives in high enough, a targeted screening of 50 to 60-year-old female smokers could perhaps lead to a decrease in SAH incidence in women.
Preventive health screenings have the fundamental goal of detecting potential health concerns early, and this should help individuals to stay healthy. In the presented pilot, one major health concern – smoking – was known prior to the targeted CTA screening. Whether the shared information about the high risk of SAH in female smokers has resulted in a long-term smoking cessation among the screened women needs to be followed up and studied. In addition to the possibility of reducing smoking rates in screened individuals, the targeted screening of female smokers should reduce SAH-related morbidity and mortality. Currently, the UIA screening recommendation by the American Heart Association/American Stroke Association views that screening for UIAs is justified in families with two or more affected person with IAs4. In the largest familial SAH study to date, 156 (3.0%) out of 5282 SAH patients had one first-degree family member with a history of SAH27. In one of the largest twin studies conducted to date, study authors identified 6 (1.2%) concordant (5 monozygotic and 1 opposite sex) and 492 discordant twin pairs for SAH out of a total of 504 SAH cases, suggesting that familial SAHs are rare, and that the relative contribution of inherited genes to SAH is moderate at most28. Therefore, even if targeted screening would identify familial UIAs, it is still questionable whether this is an effective way to decrease the incidence of SAH. Contrary to the low familial SAH risk, the risk of SAH is vastly increased in hypertensive smokers. In fact, the incidence of SAH is over 14 times higher (171 per 100,000 person-years) in women with a history of active smoking and high blood pressure (systolic blood pressure ≥ 159mmHg) than in normotensive women without a smoking history29. If it is accurate that close to 50% of smoking women with diagnosed UIAs suffer from SAH at some point in their lives10, and that the incidence of SAH in female smokers is exceptional29, a targeted UIA screening of female smokers (both normotensive and hypertensive) could perhaps be more effective than the familial screening. This might be especially true if the screening identifies women with small UIAs, thus enabling non-invasive, i.e. complication free interventions (smoking cessation and blood pressure control). Smoking cessation decreases the risk of SAH, and five years after quitting, the risk of SAH among former smokers appears to be close to that of people who have never smoked8. Nevertheless, it remains speculative whether screening for UIAs in female smokers is beneficial and cost-effective. In our study, the screening costs were 3 763 EUR (4 524 USD) per screen-positive woman. If estimated that the operated 7 mm UIA had ruptured at some point in life10, and if all screening and treatment-related costs were allocated to the treated screen-positive smoker, the prevention of one aSAH amounted to 48 605 EUR (58 440 USD). Those participants that returned the HRQOL questionnaires before and after the CTA imaging did not deteriorate in the HRQOL. However, one screen-positive woman reported a decline in her HRQOL score after the UIA diagnosis.
Our pilot has a few strengths. Since the overall prevalence of UIAs2 and incidence of SAH7 in Finland do not differ from other countries also reporting reliable prevalence and incidence estimates, UIAs may also be found at a similar frequency in 50 to 60-year-old female smokers in other countries. We chose to screen people with CTA alone, thus decreasing the likelihood of finding false positives and incidental findings, which are more common in MR imaging studies. Most importantly, we tried to diminish the risk of a recruitment bias by inviting only true current smokers. Our study also has limitations. The response rate for the preliminary invitation letters was not high, which may have indeed led to a recruitment bias. Furthermore, the postal strike during 11.-27.11.2019 and the coronavirus pandemic-related restrictions in recruiting research patients between 17.3.-29.7.2020 and 23.11.-13.12.2020 prolonged the study protocol, and may have affected the recruitment protocol. In addition, we cannot be certain that by selecting high-risk individuals for screening, we avoided the most serious harm of screenings, i.e. overdiagnosis. Finally, the number of screened women in our pilot is small. However, without a pilot and a subsequent international peer review, which estimates the scientific justification of the suggested approach, it is challenging to obtain a research permission for larger screening studies from hospital ethics committees, which follow the Declaration of Helsinki as a statement of ethical principles for medical research involving human subjects.