A new analysis from the Familial Intracranial Aneurysm (FIA) Study suggests that
small unruptured aneurysms in patients with a family history are more likely to
rupture than similar-sized sporadic aneurysms.

"We have to factor in this increased risk of rupture when we're making decisions
about whether or not we want to coil or clip, even in patients who have small
aneurysms," Joseph P. Broderick, MD, from the University of Cincinnati
Neuroscience Institute at the University of Cincinnati College of Medicine, told
Medscape Neurology & Neurosurgery.

Their findings were presented at the American Stroke Association International
Stroke Conference (ISC) 2009 and published online simultaneously in Stroke.

Familial Risk

The management of unruptured aneurysms must balance the risk for rupture with
the risk associated with intervention, the authors write. A higher risk for
rupture has been associated with larger aneurysms, a history of a prior ruptured
aneurysm, and location of the aneurysm in posterior circulation. In addition,
some studies have suggested an increased risk in older patients, females, those
who smoke, and those with multiple aneurysms.

The aggregation of intracranial aneurysms (IAs) in families suggests genetic and
common environmental factors are at play, they note. "Whether rupture rate
independent of IA formation is higher in these families is an important
unanswered question."

The overall goal of the FIA Study, funded by the National Institute of
Neurological Disorders and Stroke, is to identify gene variants that may flag
susceptibility to the formation and rupture of aneurysms.

For this analysis, first-degree unaffected relatives of subjects with a family
history of IA and a history of smoking or hypertension but no known aneurysm
themselves were offered cerebral magnetic resonance angiography (MRA).

A total of 2874 subjects from 542 FIA study families were enrolled and MRA
performed in 548 family members who had a history of smoking or hypertension.

Of these, 113 subjects, or 20.6%, had 148 IAs on MRA. In 5, these aneurysms were
greater than or equal to 7 mm.

Two patients, 1 with an aneurysm of 3 mm and the other 4 mm, both in an anterior
communicating artery, subsequently had rupture of their aneurysm, for an annual
rate of 1.2 ruptures per 100 subjects (1.2% per year; 95% CI, 0.14%-4.3% per
year). Conversely, none of 435 subjects with a negative MRA had a ruptured
aneurysm.

This rupture rate of 1.2% per year is 17 times higher than the rate of 0.069%
seen in the International Study of Unruptured Intracranial Aneurysm (ISUIA)
among subjects with an unruptured aneurysm less than 6 mm in diameter and no
history of subarrachnoid hemorrhage due to an IA for a matched distribution of
aneurysm size and location, but without a family history.

Survival curves between the groups with and without an MRA positive for IA were
significantly different (P = .0004).

Special Risk Category

"So in essence, these patients are a special risk category," Dr. Broderick said.
Members of families where more than 1 person has already been found to have an
IA should probably undergo some type of brain imaging, particularly if they are
hypertensive or smoke.

"All those people who had rupture in our cohort had either current smoking or
hypertension as a risk factor," he added. "The point is that the risk may be
modifiable; at least some ruptures could have been prevented had the patients
stopped smoking and/or had their hypertension very carefully controlled."

Smoking in particular is a highly modifiable risk factor, with former smokers
having a much lower risk than current smokers. "The relationship between smoking
and brain aneurysm is as strong as smoking and lung cancer," Dr. Broderick said.
Compounding the risk conferred by a family history of aneurysm by smoking, he
adds, "is like putting a loaded gun to your head."

When an unruptured aneurysm is detected, physicians should carefully consider
the patient's family history of aneurysm and screen other family members, Dr.
Broderick said. "If an aneurysm is found, that would probably tilt you more
toward doing some type of intervention to isolate the aneurysm, to clip it or
coil it, than someone with no family history."

Genes for IAs Discovered

In a separate paper presented here at ISC 2009, researchers from Yale University
School of Medicine and the Yale Program on Neurogenetics, in New Haven,
Connecticut, reported 2 novel gene loci that are associated with the development
of IAs.

The genomewide association study, performed in German and Japanese populations,
including more than 10,000 cases (most were ruptured aneurysms) and controls,
turned up common single nucleotide polymorphisms (SNPs) on chromosomes 2 and 8,
as well as confirmed the association of another on chromosome 9, which has
previously been linked to myocardial infarction, diabetes, aging, and brain and
aortic aneurysms, as well as ischemic stroke. The regions on chromosomes 8 and 9
appear to be important in maintenance and repair of the vasculature, the
researchers note.

Subjects with all 3 risk alleles had a 3-fold increase in the risk for aneurysm
over those with none of the risk alleles. However, these SNPs account for less
than 4% of the genetic susceptibility, they note, suggesting other common
variants are likely to play a role in their development.

"This study for the first time provides an opportunity to preclinically identify
at-risk individuals, because the odds ratio of an individual forming an aneurysm
increases more than 3-fold if that individual has all the risk alleles," Murat
Gunel, MD, professor of neurosurgery and neurobiology at Yale, told attendees
here. Further studies in other populations are under way, he added.

The FIA study was funded by a grant from the National Institute of Neurological
Disorders and Stroke. The authors report no disclosures. The study by Gunel et
al was supported by the Yale Center for Human Genetics and Genomics, the Yale
Program on Neurogenetics, the National Institutes of Health, and the Howard
Hughes Medical Institute.

American Stroke Association International Stroke Conference 2009. Abstracts 121
and 141. Presented February 19, 2009.

Stroke. Published online February 19, 2009. Abstract