Insight into the prevalence of unruptured intracranial aneurysms in a targeted risk-factor population: towards targeted screening

An intracranial aneurysms (IA) is an abnormal bulging of an intracranial artery
that is present in around 2-3% of the general population. Rupture of an IA
results in a subarachnoid hemorrhage (aSAH) and often occurs unexpectedly,
hampering timely management. This type of stroke ranks 18th in the most common
causes of death in middle-aged people, surpassing ischemic stroke deaths and
disproportionately affects women. Besides the clear patient- and
disease-related burden, the occurrence of aSAH also leads to enormous direct
and indirect costs for society, due to high costs of care and loss of
productivity. Risk factors for the development of IAs include female sex,
smoking, age above 50 years old, and hypertension. It is estimated that the
incidence of aSAH in smoking women aged 45-65 years with hypertension ranges
from 56 to 80 per 100,000 person/year. In comparison, the incidence of colon
cancer in the general population in 2008 was 74 per 100,000 person/year.
Females have a 1.24 higher chance (95% confidence interval, 1.09-1.42) of
getting an aSAH compared to men. Besides this, there is evidence of an additive
interaction between sex, smoking and hypertension. Indeed, in a study on the
long-term risk of SAH, the incidence of SAH was twenty times higher in smoking
and hypertensive women in comparison to never smoking, non-hypertensive men.
The most effective strategy to reduce the burden of disease related to SAH
could be screening of populations most at risk of harbouring an UIA for early
detection and mitigation of adverse events. Moreover, UIA are rarely
symptomatic, and therefore, screening is the only method to detect UIAs before
rupture. Detecting an IA through screening enables timely management by
counseling patients for smoking cessation and by treating other modifiable risk
factors like hypertension. Moreover, occlusive treatment of the aneurysm could
be considered in those IAs most at risk of rupture, reducing the risks of aSAH,
and thus potentially decreasing associated morbidity and mortality rates. Early
treatment of UIAs is associated with less complications compared to patients
who have suffered from an aSAH.
A study from Huhtakangas et al. recently showed that IAs were present in 12 %
of Finnish smoking women between 50-60 years, which is around 4 times more
frequently than in the general population. In collaboration with Huhtakangas et
al, we aim to apply a similar study among 50- to 60-year-old smoking females in
the Dutch population to determine the prevalence of UIAs in a targeted
population at risk. This is a first step to identify a subgroup of patients
potentially at increased risk of harboring an IA, in whom early screening could
result in health benefits.

Primary objective:
- Determine the number of unruptured IAs in smoking women aged 50-60 years in
the Dutch population in a cohort of 55 participants.

Secondary objectives:
- Evaluate the possible changes in quality of life associated with a screening
program for UIAs in a group of 55 smoking women aged 50-60 years.
- Determine possible differences in the prevalence of UIAs in smoking women
aged 50-60 years in a Dutch cohort versus a Finnish cohort.
- Determine the direct and indirect costs associated with the screening and
potential treatment of UIAs in a targeted group of 55 smoking women aged 50-60
years.

This study is a single-center prospective observational pilot study with a
single-arm interventional study, which will last about two years.
Recruitment of women will take place at the smoking cessation clinic. The
specialized nurse in charge of advising patients for smoking cessation will
identify women that could potentially be eligible for participation in the
study (based on age). If the patients agree and consents, a patientfolder will
be given and contact information will be shared with the researcher. The
researcher, a doctor with ample experience within the field of neurovascular
pathology, contacts the patient shortly thereafter by phone or during a consult
at the hospital, at the patient's discretion. During this conversation, any
questions or doubts can be addressed. If the patient agrees to participate in
the study and if she is eligible, she will be able to send the signed informed
consent form after 7 days (bedenktijd). Moreover, the participant will be asked
to fill in a general questionnaire about her health status (Risk factors and
Demographic Data Questionnaire) and quality of life (the 5-level EQ-5D
(EQ-5D-5L), HRQoL).

Scanning
An MRA of the brain will be scheduled. Blood pressure will also be measured on
that day. Patient scanning protocol will be a 3D-Time-of Flight MRA. Scanning
will be performed on Philips Achieva 3T or Ingenia CX 3T MRI Scanner.
3-dimensional-time-of-flight (3D-TOF) MRA imaging is the most widely used
non-contrast enhancement MRA technique. We have chosen 3D-TOF-MRA instead of
computed tomography angiography (CTA) for several reasons: unlike CTA imaging,
patients are not exposed to radiation and are not given any contrast agent,
thereby limiting the risks of kidney injury and other contrast related
side-effects like allergic reactions or skin reactions. Moreover, current
screening protocols for patients with one or more first degree relatives with
aSAH are screened using MRA. A recent review by Rinkel et al exploring groups
at high risks of aSAH who may benefit from preventive screening for UIAs also
recommend the use of MRAs to this end. A meta-analysis from HaiFeng et al
including 18 studies with 3463 patients revealed that 3D-TOF-MRA had an
excellent diagnostic performance for the assessment of IAs (sensitivity 89%,
specificity 94%). Besides this, a large-cohort comparison between 3D-TOF MRA
and DSA (the gold standard for detection of IAs), found a sensitivity of 100%
and accuracy of 95.1% to 97% per aneurysm, and an excellent correlation with
DSA17.
An experienced (neuro)intervention radiologist will critically assess the
obtained MRA images. In case of doubts about the radiological findings, second
reading will be performed by another neuro-radiologist. If the observers
disagree, additional imaging could be performed in consultation with the
patient, eg CTA, CE-MRA or DSA.

MRA protocol:
A TOF protocol will be applied for the detection of IAs. This kind of MRA will
be performed using a Philips Ingenia CX 3T or Philips Achieva 3T. The TOF-MRA
is obtained using 3D-T1-fast field echo sequences TR/TE 23/6.9; flip angle, 20
degrees, with a total scan duration of 06:53.8 minutes.

The observational study ends after the MRA, and this is the primary endpoint of
the study.

Follow-up
Negative MRA findings
Screened women with a negative MRA will receive a letter describing the
radiological findings, which are also discussed during a telephone
consultation. Additional information and advice can be discussed during the
consult for smoking cessation and blood pressure regulation. The participants
are asked to fill in the quality-of-life questionnaire directly and six months
after the telephone consultation. Smoking status is also recorded at 6 months
after the MRA and potential ((S)AE's related to the screening.

Positive MRA findings
Similar to the participants with negative MRA findings, participants will be
asked to fill in the quality-of-life questionnaire directly after the MRA
results and 6 months after diagnosis of the IA. From the moment of diagnosis of
the IA onwards, patients* treatment and follow-up will fall beyond the scope of
this study and the participants will fall under the responsibility of their
treating physicians.Participants will be invited to the neurology outpatient
clinic to discuss the findings and their implications with a consultant
neurologists or neurosurgeon specialized in neurovascular diseases. Depending
on the characteristics of the IA and presence of risk factors for rupture,
patients are counselled for a wait and scan policy (including the treatment of
modifiable risk factors for rupture) or intervention (microsurgical clipping or
endovascular treatment). Prior to the outpatient clinic visit, the management
options are considered in the local multidisciplinary team consisting of
interventional radiologists, neurosurgeons and neurologists. Smoking status
will be recorded at 6 months, but also outcomes of the management of the IA and
potential complications thereof ((S)AE's).

The single-arm interventional study ends after 6 months for the measurements of
quality of life, regardless of MRA outcomes.

Coincidental findings
There is a chance that the MRA reveals another finding like for example another
vascular malformation. Depending on whether the finding has clinical
consequences for the participant, she will be informed by the researcher and
will be referred to the required specialist if needed.

The burden of this study is related to possible side effects from the MRA
including muscle twitching, feeling warmth, dizziness or nausea. All these side
effects are however temporary and do not significantly affect the participants'
health. Moreover, possible burdens of this study could be related to having to
visit the hospital for an MRA and having to fill in questionnaires. Finally,
some studies have suggested that screening can cause a decrease in quality of
life due to anxiety caused by the possibility of discovering an aneurysm.
However, a recent screening study including more than 461 participants did not
show significant decrease in quality of life in the participants compared to
the general population. Overall, however, the risks of this study are very
limited. We believe that the possible positive effects of this study, eg.
identifying an intracranial aneurysm before it ruptures (thereby opening
avenues for therapeutic interventions) weighs against the burden of
participating in the study.