Brain Hemorrhage Lands Bret Michaels of Poison in the ICU - Can Risk for Subarachnoid Hemorrhage Be Genetic?

Rocker Bret Michaels, of Poison fame, has unfortunately reportedly suffered a subarachnoid hemorrhage (a type of brain hemorrhage) and is apparently in an intensive care unit in critical condition (according to People magazine).

It's sort of surreal as I was just thinking last weekend, when I saw Hot Tub Time Machine (which features a Poison cover band), that I probably hadn't thought about the band in over a decade (obviously I am not a Celebrity Apprentice fan). 

It's terribly sad to hear when someone has suffered a subarachnoid hemorrhage as it is often a pretty grim diagnosis (as KevinMD has carefully explained here).  Hopefully, Bret Michaels will have a better outcome than most.  As a physician, subarachnoid hemorrhage is one of those adversaries that you hope you don't see again for a long time.  When I was training in Internal Medicine in Seattle at the University of Washington, I remember seeing quite a few at Harborview Medical Center.  One of my very first admissions as an intern was a subarachnoid hemorrhage, and at times as a 2nd year resident in the ER at Harborview, it seemed like far too many were being helicoptered in from Alaska and rural areas all over the Pacific Northwest.

Later, in my Clinical Genetics training in Seattle, I learned that for some subarachnoid hemorrhages, there can be a genetic connection.  So, in light of the fact that tomorrow is DNA Day, I thought it might be worth touching on the genetics of subarachnoid hemorrhage, particularly those caused by rupture of an intracranial aneurysm.   

Subarachnoid Hemorrhage and Intracranial Aneurysms

Subarachnoid hemorrhage (SAH) affects about 30,000 people each year in the United States and accounts for somewhere between 1 in 20 to 1 in 50 of all new strokes.  Subarachnoid hemorrhages are very serious; about one-half of the time they result in death.  Almost 50% of survivors have some long-term cognitive impairment and a significant fraction require lifelong care.

There are several causes of subarachnoid hemorrhage, including trauma.  Often they are due to rupture of an intracranial aneurysm - an abnormal outpouching of the arterial system in the brain that can be prone to rupture.  About 3/4 of nontraumatic subarachnoid hemorrhages are due to rupture of so-called "berry aneurysms" that are often found in the arterial system around the base of the brain.

With respect to risk for SAH, there are likely factors that affect both the risk of developing an intracranial aneurysm in the first place, and also factors that impact risk of rupture of an existing aneurysm leading to the SAH.  Interestingly, there are several major known risk factors for SAH that are potentially modifiable.  Among them:

• cigarette smoking
• high blood pressure
• cocaine use
• heavy alcohol use

Thus, to some extent, lifestyle clearly can impact risk for SAH. 

However, it is also clear that risk is elevated in first-degree relatives (parents, brothers, sisters, and children) of individuals who have had a subarachnoid hemorrhage.  Overall, first-degree relatives may have somewhere between 2- and 6-fold elevated risk.  In some cases this is due to rare Mendelian conditions that are associated with a significantly elevated risk; however, there is also evidence supporting a heritable genetic influence on intracranial aneurysms and SAH that occurs outside of the context of rare syndromes.  In this case, risk is complex and associated with weaker genetic influences and environmental risk factors.

Rare Mendelian Conditions Associated With Intracranial Aneurysms

Among the rare conditions with Mendelian inheritance in which intracranial aneurysms and subarachnoid hemorrhage may be seen with increased frequency are the following:

• Autosomal Dominant Polycystic Kidney Disease
• Ehlers-Danlos Syndrome Type IV (aka the vascular type)
• Loeys-Deitz Syndrome

Complex Genetics of Sporadic Intracranial Aneurysm Development

Although risks for development of intracranial aneurysms (which can lead to subarachnoid hemorrhages) are substantially elevated in the above Mendelian conditions, with the exception of ADPKD they are all rare (ADPKD is the most common potentially lethal single gene disorder and affects approximately 600,000 people in the United States). 

However, physicians and scientists have recently begun to make headway in discovering regions of the genome that are (modestly) associated with risk for intracranial aneurysm and subarachnoid hemorrhage by studying large numbers of individuals with these conditions and unaffected controls in studies called genome-wide association studies (GWAS).  Some of the chromosomal regions and single nucleotide polymorphisms (SNPs) that have been associated in well-done peer reviewed studies are the following:

• Chromosome 9p21.3, rs10757278 - G (near the CDKN2A and CDKN2B genes)
• Chromosome 8q11.23, rs10958409 - A (near the SOX17 gene)
• Chromosome 10q24.32, rs12413409 - G
• Chromosome 13q13.1, rs9315204 - T (near the STARD13 and KL genes)
• Chromosome 18q11.2, rs11661542 - C (near the RBBP8 gene)

All of these are subject to a number of caveats related to genome-wide association-implicated SNPs that we will be discussing here at DNA and You soon.

If one makes the assumption that genes nearby these single nucleotide polymorphisms are actually involved in the process of aneurysm development, an emerging hypothesis is that some of the risk loci may affect cell cycle progression in cells involved in the formation and repair of blood vessels.  However, the underlying science is not well understood.  There is far more that we don't know than that which we know about the underlying science and the impact on risk at this time. 

It's also important to note that while these SNP associations are important initial clues toward underlying biology that may ultimately result in improved treatments, they are not helpful clinically at this time.  Future studies will address whether they can impact risk assessment and/or treatment strategies in a clinically meaningful way; however, given that the baseline risk for intracranial aneurysms is at most 5 percent and that these SNPs only explain about 4 percent of the familial component of risk for intracranial aneurysms, it seems unlikely that they will play a significant role in the clinic in the near future.

What You Can Do

The sad news about Bret Michaels and his hospitalization is an opportunity to reflect on those things that you can do if you are at risk for subarachnoid hemorrhage (either because of your family history or for other reasons).  If you or a family member has had a subarachnoid hemorrhage or are known to have intracranial aneurysm, talk with your doctor about how you can best do the following things:

• Stop smoking
• Control your blood pressure if it is high
• Do not use cocaine
• Do not drink alcohol heavily

Further Information and Support

• The Brain Aneurysm Foundation

 

Key References

Suarez JI, Tarr RW, Selman WR.  Aneurysmal subarachnoid hemorrhage.  New England Journal of Medicine 2006; 354:387-96.

Brisman JL, Song JK, Newell DW.  Cerebral aneurysms.  New England Journal of Medicine 2006; 355:928-39.

Yasuno K, Bilguvar K, Bijlenga P, et al.  Genome-wide association study of intracranial aneurysm identifies three new risk loci.  Nature Genetics 2010; Published online 4 April 2010, doi:10.1038/ng.563.

Bilguvar K, Yasuno K, Niemela M, et al.  Susceptibility loci for intracranial aneurysm in European and Japanese populations.  Nature Genetics 2008; 40:1472-77.

Helgadottir A, Thorleifsson G, Magnusson KP, et al.  The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm.  Nature Genetics 2008; 40:217-24.

Comments

[Margie Pesante]

Hello, I suffered a subrachnoid bleed in 2005, fortunatley I was rushed to the hospital, and although intially the diagnosis was grim, thank god I pulled through...While in ICU, I suffered a massive pulmonary embolism, and was rushed to the operating room, where I underwent an emblectomy..after two months of rehab....I am almost okay. I am grateful that I am able to walk, and had to impairments with speech or movement. I am of course very interested in this subject. A younger sister, had suffered a aneurysm in 2001, and also survived. We are five sisters that have a strong genetic bond, four of us are breast cancer survivors, two have long term sarcoidois disease, and two of us have had bleeding in the brain. I had a MRA in 2001, following my sister's aneurysm, which was negative. Currently, I take coumadin everyday, necessary because I have a blood clotting disorder, which causes ongoing concern of a repeat bleed.

[Matt Mealiffe, M.D.]

Margie - Thanks so much for your comment...wow, quite a story! I'm glad to hear that you made it through and that things are looking up for you health-wise... Thanks for reading DNAandYou! Sincerely, Matt Mealiffe