Clinical Context

Acute subarachnoid hemorrhage is frequently devastating, resulting in early mortality rates of approximately 50%. Comparatively, the authors of the current study surmised that treatment for UIA can result in permanent neurologic deficit in as few as 1% to 3% of patients treated.

Therefore, UIA may be a good screening target, but who is at risk for UIA? Women appear to have a higher rate of UIA compared with men, and other risk factors include a family history of UIA, previously diagnosed UIA, polycystic kidney disease, and connective tissue disorders. Current guidelines recommend screening for UIA among patients with 2 or more first-degree family members with a history of intracranial aneurysm and among patients with autosomal dominant polycystic kidney disease.

Hypertension and cigarette smoking are possible risk factors for intracranial aneurysms as well. The current study by Oglivy and colleagues uses a retrospective analysis to evaluate their role in UIA among women between the ages of 30 and 60 years.

Study Synopsis and Perspective

Women who smoke cigarettes are at increased risk for intracranial aneurysms, new research suggests.

In a case-control study of more than 500 women between the ages of 30 and 60 years, women with a history of smoking had an approximately 4-fold increased risk of having an UIA compared with women without a history of smoking.

In addition, chronic hypertension compared with normotension was associated with a 3-fold increase in risk for UIA.

The findings suggest that screening for UIAs among women in this age range who smoke might be beneficial, the researchers noted.

"Prior to our study, risk factor assessments showed a relationship between cigarettes and intracranial aneurysms," coinvestigators Christopher S. Ogilvy, MD, director of endovascular and operative neurovascular surgery, and Santiago Gomez-Paz, MD, postdoctoral research fellow, both at Beth Israel Deaconess Medical Center in Boston, Massachusetts, told Medscape Medical News via email.

Those studies, however, failed to account for crucial confounding factors, such as a family history of UIA or aneurysmal subarachnoid hemorrhage, they noted.

"Our findings provide conclusive evidence that cigarette smoking is an independent risk factor for harboring an incidentally found intracranial aneurysm in middle-aged women," Ogilvy and Gomez-Paz said.

The study was published online July 28 in the Journal of Neurology, Neurosurgery and Psychiatry.

AHA/ASA Recommendations

The American Heart Association (AHA) and the American Stroke Association (ASA) recommend UIA screening for patients with 2 or more first-degree family members who have a history of these aneurysms and for patients with autosomal-dominant polycystic kidney disease.

Past research has shown an association between smoking and aneurysmal growth and rupture. In a previous single-center study by Ogilvy and colleagues, the prevalence of UIAs among women who smoked was 19%. They said they studied women because most patients with UIA are women.

"Cigarettes contain many toxic components, such as nicotine and reactive oxygen species, that play a role in inflammation and modulation of macrophages, ultimately resulting in phenotypic changes of smooth muscle cells into a proinflammatory phenotype within the aneurysm wall," said Ogilvy and Gomez-Paz.

Another indirect component thought to play a critical role is the hemodynamic changes induced by cigarette consumption, such as changes in blood viscosity, velocity, and shear wall stress, they added.

The investigators conducted a multicenter case-control study to evaluate this association further.

They searched the neuroradiology databases of 5 large academic hospitals in the United States and Canada from 2016 through 2018. Eligible patients were women between the ages of 30 and 60 years -- the age range in which the prevalence of smoking is highest -- who had received an incidental diagnosis of UIA on magnetic resonance angiography (MRA).

Researchers excluded patients with a history of UIA and patients with a family history of UIA, subarachnoid hemorrhage related to such an aneurysm, connective tissue disorder, or cerebrovascular anomaly.

The control group comprised patients who had an MRA for any reason and whose imaging results were normal. These patients were matched by age and race to patients who had an aneurysm in a ratio of 3:1.

The investigators gathered baseline demographic information, as well as the reason for imaging, the date of aneurysm diagnosis, aneurysm characteristics, and treatment. Smoking and chronic hypertension were the exposures of interest.

The researchers performed a conditional logistic regression analysis, matching on the confounders of age and race, to examine the relationship among smoking, hypertension, and UIA.

Smoking Plus Hypertension

The investigators identified 152 patients with aneurysms and 393 participants for the control group. After they matched patients and control persons in a 1:1 ratio with regard to age and race, the sample included 113 in the patient group and 113 in the control group.

Hypertension was more common among the patient group (46%) than among the control group (31%). Smoking history, too, was more common (57.5% vs 37.2%). In both groups, the most common reason for undergoing MRA was as workup for chronic headaches.

Most aneurysms (95.3%) had a saccular morphology, and most (91.4%) were in the anterior circulation. The internal carotid artery was the most common location within the anterior circulation (53.9%). The median aneurysm size was 4 mm, and approximately 34% of aneurysms were treated.

Among participants with a history of smoking, the odds ratio (OR) of UIA was 3.69 compared with participants with no smoking history. Among individuals with chronic hypertension, the OR of UIA was 3.16 compared with participants without chronic hypertension.

Among participants who had a history of smoking and chronic hypertension, the OR of UIA was 6.92.

A sensitivity analysis showed that smoking duration was correlated with incidental UIA. The median duration of cigarette smoking was 29 years in patients with UIA and 20 years in the control group.

"Considerations such as a screening recommendation should be made on a patient-by-patient basis until conclusive recommendations are made assessing the cost-effectiveness of a secondary prevention strategy," said Ogilvy and Gomez-Paz.

The investigators are currently working on a cost-benefit analysis of screening for intracranial aneurysms in middle-aged women who smoke cigarettes, they reported.

"This research will consolidate aneurysm-related findings, such as the rupture and the treatment risks, as well as the prevalence of intracranial aneurysms in women, to determine whether a specific strategy proves to be cost beneficial," they added.

Further Confirmation

Commenting for Medscape Medical News, Judy Huang, MD, professor of neurosurgery at Johns Hopkins University School of Medicine in Baltimore, Maryland, said the matched case-control design of the study "is well suited" for detecting prevalence.

In addition, "the findings further confirm the previously established, strong association between cigarette smoking and UIA," said Huang, who was not involved with the research.

She noted that because the study's detailed data on smoking history enabled analysis of the effect of duration and intensity of smoking exposure on the risk for incidental detection of a UIA, the investigators were able to establish that the risk for UIA increases with duration of smoking history.

"This is useful in patient counseling for smoking cessation," Huang said.

Nonetheless, the cohort was relatively homogeneous, so the study results may not be generalizable to nonwhite populations, she noted. In addition, the researchers did not explain how clinicians decided to treat certain UIAs or how they chose the type of procedure performed.

The study also raises several questions for further research, Huang added. For example, it is unclear how often women who smoke have hypertension or have both should be screened for UIAs. Likewise, the effect on a patient of knowing about an untreated UIA is unknown.

Also, the researchers did not report whether any of the conservatively managed aneurysms eventually required treatment because of growth or rupture during the follow-up period, Huang noted.

"In women aged 30 to 60 years who undergo imaging for evaluation of headaches, MRA screening will lead to higher rates of detection of incidental small UIAs in those with a positive smoking history, hypertension, or both, of which the majority do not require treatment," she said.

"Appropriate patient selection for prophylactic treatment of incidentally discovered UIA still requires understanding of the natural history of UIA," she added.

The study was funded by a research grant from the Brain Aneurysm Foundation. Ogilvy, Gomez-Paz, and Huang report no relevant financial relationships.

J Neurol Neurosurg Psychiatry. Published online July 28, 2020.^[1]

Clinical Implications

• Women appear to have a higher rate of UIA compared with men, and other risk factors include a family history of UIA, previously diagnosed UIA, polycystic kidney disease, and connective tissue disorders.
• The current study by Oglivy and colleagues finds that both hypertension and smoking are associated with a higher risk for UIA among women between 30 and 60 years of age, and the presence of hypertension and smoking together appeared synergistic in raising the risk for UIA.
• Implications for the Healthcare Team: The healthcare team should emphasize smoking cessation for young women and carefully monitor blood pressure as potential means to reduce the consequences of intracranial aneurysms. Meeting in patient care rounds and discussing methods of reducing these risk factors with individual patients is key.

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