Perspectives Commentary on: Racial Associations with Hemorrhagic Presentation in Cerebral Arteriovenous Malformations by Yang et al. World Neurosurg 2015 http://dx.doi.org/10.1016/j.wneu.2015.03.050
Race and Hemorrhage in Cerebral Arteriovenous Malformations Daniel R. Klinger, Jonathan A. White, H. Hunt Batjer
T
he ability to determine the rupture risk of an arteriovenous malformation (AVM) (either initial or subsequent rupture) is a key factor for the clinician who counsels these patients and makes treatment recommendations. The low prevalence of AVMs in the general population, estimated at 0.01%, has made natural history studies of these lesions challenging and limited. The majority of important natural history studies have either evaluated a homogenous, intransient patient population or a patient cohort referred to a regional tertiary referral center with the inherent biases of both these approaches. Despite heterogeneous results when comparing individual studies, what we have gathered from these studies is that the annual rupture risk of most AVMs is likely between 2% and 4%, with previous rupture likely increasing this risk. Further evidence is suggestive, but not conclusive, that deep-seated AVMs, deep venous drainage, and the presence of associated aneurysms may also increase risk of bleed (4). Relatively few studies have elucidated a strong association between AVM hemorrhage and patient demographic factors.
The authors found that of 62 nonwhite patients, nearly 52%, presented with hemorrhage whereas only 34 of 132 (24.6%) white patients presented with hemorrhage. A total of 53.8% of the 39 black patients studied presented with hemorrhage, which was a significantly greater percentage than in the white patient population (P < 0.01). Multivariate analysis revealed nonwhite race (odds ratio [OR] 3.1), AVM size (OR 0.65), nonfrontal lobar (OR 2.61), basal ganglia (OR 6.2), and brainstem/cerebellar AVM locations (OR 4.4) were associated with hemorrhagic presentation of AVMs.
In a paper recently published in WORLD NEUROSURGERY, Yang et al. present a retrospective, single-institution study in which they analyze angiographic features and patient demographics and their association with hemorrhagic presentation in 194 AVM patients. The median age of all patients was 32 years, and 34% of patients presented with AVM hemorrhage. Clinical and angiographic variables such as age, sex, race, hypertension, AVM size, AVM location, venous drainage, and Spetzler-Martin grade were assessed for association with hemorrhage using both univariate and multivariate analysis.
Despite the bevy of literature on the association between race and intracerebral hemorrhage (ICH) in general, there is only one other large clinical study describing an association between race and AVM hemorrhage. Kim et al. (5) evaluated 436 University of California, San Francisco (UCSF) patients with AVM and 1028 Kaiser Permanente patients with AVM longitudinally to assess the risk of hemorrhage. The UCSF patients were followed prospectively for a mean of 2.8 years and the Kaiser patients underwent chart review retrospectively for a mean of 4.7 years. The authors noted an annualized hemorrhage rate of
Key words Arteriovenous malformation - Hemorrhagic presentation - Intracranial hemorrhage - Race -
Abbreviations and Acronyms AVM: Arteriovenous malformation ICH: Intracerebral hemorrhage OR: Odds ratio UCSF: University of California, San Francisco
WORLD NEUROSURGERY - [-]: ---, MONTH 2015
Analyzing the hemorrhagic presentation of AVMs is not a substitute for longitudinal follow-up of patients with known AVMs to assess annual hemorrhage risk. Nevertheless, this study by Yang et al. is unique in that it is the first to describe an association between nonwhite race, particularly black race, and increased rate of hemorrhagic presentation of AVMs compared with white patients at a tertiary referral center. The significance of their finding is harder to define because we can only speculate as to the underlying cause of this racial disparity.
Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA To whom correspondence should be addressed: Daniel R. Klinger, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2015). http://dx.doi.org/10.1016/j.wneu.2015.05.009
www.WORLDNEUROSURGERY.org
1
PERSPECTIVES
2.1% over 5 years, which increased to 3.1% in Hispanic patients. Initial hemorrhagic presentation and Hispanic ethnicity were independent predictors of ICH. They found a trend towards increased risk in black patients who, however, only composed 6% 10% of their patients. In the present study in WORLD NEUROSURGERY, Yang et al. found no association between hemorrhagic presentation and Hispanic ethnicity possibly because of insufficient sample size. Four of 9 Hispanic patients (44%) in the present study compared with 34 of 132 white patients (26%) presented with hemorrhage. The association between race and ICH in general has been well described. The risk of ICH among American black patients may be double that of white patients (1). The annual incidence rate of ICH per 100,000 has been estimated at 48.9 for black and 26.6 for white patients (3). Similarly, Hispanic patients have twice the risk of ICH as non-Hispanic white patients. Much of the disparity in ICH and stroke incidence in black patients may be explained by an increased prevalence of modifiable risk factors such as hypertension, diabetes, and hyperlipidemia. Hypertension in particular is a well-established risk factor for ischemic and hemorrhagic stroke and is more prevalent in black populations. Large population studies in Northern Manhattan and in Kentucky both demonstrated that the greater incidence of ICH in black subjects was largely attributable to deep basal ganglia and brainstem hemorrhages that were likely hypertensive in etiology (6, 7). Perhaps more concerning is that there is some evidence that although the incidence of stroke in white patients may be decreasing in certain U.S. populations, it is stagnant among black patients, leading to growing racial disparities in stroke incidence. Presently, there are large, population-based studies currently attempting to address these issues—the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study is a prospective, multicenter case-control trial attempting to enroll 1000 nonHispanic white, 1000 Hispanic, and 1000 black patients with ICHs with 3000 demographically-matched control subjects from the same population to identify differences in risk factor distribution, ICH characteristics, and outcomes by ethnicity (8). Although deep intracerebral hemorrhages appear to be more common in black patients presumably secondary to an increased incidence of poorly controlled hypertension in this patient population, the explanation for increased hemorrhagic presentation of AVMs and perhaps increased proclivity for AVM hemorrhage in racial/ethnic minorities is, not surprisingly, less clear. Certainly to the extent that uncontrolled hypertension and cardiovascular disease might precipitate AVM hemorrhage, black and non-white Hispanic patients with AVMs may be at a greater risk of early or recurrent hemorrhage. However, an association between hypertension and AVM rupture has not been clearly established in most AVM natural history and patient demographic studies. Perhaps a more palatable theory to explain the potential discrepancy in AVM hemorrhage risk among different racial/ ethnic groups relates to access to care and socioeconomic status. Apart from hemorrhage or seizure, patients with AVM typically present incidentally. Insured patients with economic stability and easy access to care, one may argue, are more likely
2
www.SCIENCEDIRECT.com
to undergo magnetic resonance imaging for the workup of any headache, dizziness, memory problems, or similar complaint. Racial minorities are known to have poorer access to health care. Certain diagnostic evaluations and treatments may be underused in ethnic minorities as well. One example of underuse of neurosurgical care in U.S. ethnic minorities is the case of epilepsy surgery for refractory epilepsy in mesial temporal sclerosis, a practice known to be grossly underused in the United States in general. A recent study in Neurology evaluating U.S. epilepsy treatment trends from 1990 to 2008 found a significant decrease in the use of surgery for temporal lobe epilepsy in racial minorities compared with white patients and a decrease in the use of surgery for patients without private insurance. (Incidentally, white patients in this population were also found to be more likely to have private insurance.) (2). It is reasonable to postulate that the greater rate of hemorrhagic presentation in black patients with AVM in the present study may be explained by the lower likelihood of AVMs being diagnosed in an unruptured state in this patient population secondary to issues regarding access to care and use of care. Commendably, Yang et al. attempted to address this concern by evaluating the patients’ “work-study status” in their work. They noted no significant difference between race and work-study status in their patients. Although this may be a rather crude and imperfect metric for a subpopulation’s access to care, it is notable that in the present study the authors at least attempted to control for this potential source of confounding. One may argue as well that in the UCSF/Kaiser AVM study that demonstrated a greater annual rate of hemorrhage among Hispanic patients, the patient subgroups were, to a certain extent, controlled for socioeconomic status, because 70% of the patients were members of the Northern California Kaiser health care system, a large health-management organization with a network of 30% of the region’s population. Finally, in addition to other already-proposed explanations, genetic variations among racial and ethnic groups may explain an increased hemorrhagic presentation or hemorrhagic risk in patients with AVM. Studies in large ICH and AVM populations based on self-reported racial and ethnic identity clearly only hint at potential genetic variations within patient subgroups, and broad racial classifications cannot capture the degree of admixing within groups of self-identified black and Hispanic subjects, for instance. Regardless of the underlying explanation, the finding of a potential increased propensity for AVM hemorrhage in certain racial minorities may prove significant in the clinical evaluation and counseling of these patients. Knowledge of a greater risk of hemorrhage may prompt closer clinical follow-up and may swing the risk-benefit pendulum in favor of early treatment of unruptured lesions in certain cases. The ability to more accurately counsel our vascular malformation patients on the natural history of their disease process remains a constant endeavor, and continued evaluation through the prism of race and other patient demographic factors may further our progress towards that goal.
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2015.05.009
PERSPECTIVES
REFERENCES 1. Broderick JP, Brott T, Tomsick T, Huster G, Miller R: The risk of subarachnoid and intracerebral hemorrhages in blacks as compared to whites. N Engl J Med 326:733-736, 1992. 2. Englot DJ, Ouyang D, Garcia PA, Barbaro NM, Chang EF: Epilepsy surgery trends in the United States, 1990-2008. Neurology 78:1200-1206, 2012. 3. Flaherty ML, Woo D, Haverbusch M, Sekar P, Khoury J, Moomaw CJ, Schneider A, Kissela B, Kleindorfer D, Broderick JP: Racial variations in location and risk of intracerebral hemorrhage. Stroke 36:934-937, 2005. 4. Gross BA, Du R: Natural history of cerebral arteriovenous malformations: a meta-analysis. J Neurosurg 118:437-443, 2013.
5. Kim H, Sidney S, McCulloch CE, Poon KY, Singh V, Johnston C, Ko NU, Achrol AS, Lawton MT, Higashida RT, Young WL; UCSF BAVM Study Project: Racial/ethnic differences in longitudinal risk of intracranial hemorrhage in brain arteriovenous malformation patients. Stroke 38:2430-2437, 2007. 6. Kleindorfer DO, Khoury J, Moomaw CJ, Alwell K, Woo D, Flaherty ML, Khatri P, Adeoye O, Ferioli S, Broderick JP, Kissela BM: Stroke incidence is decreasing in whites but not in blacks: a population-based estimate of temporal trends in stroke incidence from the Greater Cincinnati/ Northern Kentucky stroke study. Stroke 41: 1326-1331, 2010. 7. Sacco RL, Boden-Albala B, Abel G, Lin IF, Elkind M, Hauser WA, Paik MC, Shea S: Raceethnic disparities in the impact of stroke risk factors: the northern Manhattan stroke study. Stroke 32:1725-1731, 2001.
WORLD NEUROSURGERY - [-]: ---, MONTH 2015
8. Woo D, Rosand J, Kidwell C, McCauley JL, Osborne J, Brown MW, West SE, Rademacher EW, Waddy S, Roberts JN, Koch S, Gonzales NR, Sung G, Kittner SJ, Birnbaum L, Frankel M, Testai FD, Hall CE, Elkind MS, Flaherty M, Coull B, Chong JY, Warwick T, Malkoff M, James ML, Ali LK, Worrall BB, Jones F, Watson T, Leonard A, Martinez R, Sacco RI, Langefeld CD: The ethnic/ racial variations of intracerebral hemorrhages (ERICH) study protocol. Stroke 44:e120-e125, 2013.
Citation: World Neurosurg. (2015). http://dx.doi.org/10.1016/j.wneu.2015.05.009 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
www.WORLDNEUROSURGERY.org
3
Race and Hemorrhage in Cerebral Arteriovenous Malformations Daniel R. Klinger, Jonathan A. White, H. Hunt Batjer
T
he ability to determine the rupture risk of an arteriovenous malformation (AVM) (either initial or subsequent rupture) is a key factor for the clinician who counsels these patients and makes treatment recommendations. The low prevalence of AVMs in the general population, estimated at 0.01%, has made natural history studies of these lesions challenging and limited. The majority of important natural history studies have either evaluated a homogenous, intransient patient population or a patient cohort referred to a regional tertiary referral center with the inherent biases of both these approaches. Despite heterogeneous results when comparing individual studies, what we have gathered from these studies is that the annual rupture risk of most AVMs is likely between 2% and 4%, with previous rupture likely increasing this risk. Further evidence is suggestive, but not conclusive, that deep-seated AVMs, deep venous drainage, and the presence of associated aneurysms may also increase risk of bleed (4). Relatively few studies have elucidated a strong association between AVM hemorrhage and patient demographic factors.
The authors found that of 62 nonwhite patients, nearly 52%, presented with hemorrhage whereas only 34 of 132 (24.6%) white patients presented with hemorrhage. A total of 53.8% of the 39 black patients studied presented with hemorrhage, which was a significantly greater percentage than in the white patient population (P < 0.01). Multivariate analysis revealed nonwhite race (odds ratio [OR] 3.1), AVM size (OR 0.65), nonfrontal lobar (OR 2.61), basal ganglia (OR 6.2), and brainstem/cerebellar AVM locations (OR 4.4) were associated with hemorrhagic presentation of AVMs.
In a paper recently published in WORLD NEUROSURGERY, Yang et al. present a retrospective, single-institution study in which they analyze angiographic features and patient demographics and their association with hemorrhagic presentation in 194 AVM patients. The median age of all patients was 32 years, and 34% of patients presented with AVM hemorrhage. Clinical and angiographic variables such as age, sex, race, hypertension, AVM size, AVM location, venous drainage, and Spetzler-Martin grade were assessed for association with hemorrhage using both univariate and multivariate analysis.
Despite the bevy of literature on the association between race and intracerebral hemorrhage (ICH) in general, there is only one other large clinical study describing an association between race and AVM hemorrhage. Kim et al. (5) evaluated 436 University of California, San Francisco (UCSF) patients with AVM and 1028 Kaiser Permanente patients with AVM longitudinally to assess the risk of hemorrhage. The UCSF patients were followed prospectively for a mean of 2.8 years and the Kaiser patients underwent chart review retrospectively for a mean of 4.7 years. The authors noted an annualized hemorrhage rate of
Key words Arteriovenous malformation - Hemorrhagic presentation - Intracranial hemorrhage - Race -
Abbreviations and Acronyms AVM: Arteriovenous malformation ICH: Intracerebral hemorrhage OR: Odds ratio UCSF: University of California, San Francisco
WORLD NEUROSURGERY - [-]: ---, MONTH 2015
Analyzing the hemorrhagic presentation of AVMs is not a substitute for longitudinal follow-up of patients with known AVMs to assess annual hemorrhage risk. Nevertheless, this study by Yang et al. is unique in that it is the first to describe an association between nonwhite race, particularly black race, and increased rate of hemorrhagic presentation of AVMs compared with white patients at a tertiary referral center. The significance of their finding is harder to define because we can only speculate as to the underlying cause of this racial disparity.
Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA To whom correspondence should be addressed: Daniel R. Klinger, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2015). http://dx.doi.org/10.1016/j.wneu.2015.05.009
www.WORLDNEUROSURGERY.org
1
PERSPECTIVES
2.1% over 5 years, which increased to 3.1% in Hispanic patients. Initial hemorrhagic presentation and Hispanic ethnicity were independent predictors of ICH. They found a trend towards increased risk in black patients who, however, only composed 6% 10% of their patients. In the present study in WORLD NEUROSURGERY, Yang et al. found no association between hemorrhagic presentation and Hispanic ethnicity possibly because of insufficient sample size. Four of 9 Hispanic patients (44%) in the present study compared with 34 of 132 white patients (26%) presented with hemorrhage. The association between race and ICH in general has been well described. The risk of ICH among American black patients may be double that of white patients (1). The annual incidence rate of ICH per 100,000 has been estimated at 48.9 for black and 26.6 for white patients (3). Similarly, Hispanic patients have twice the risk of ICH as non-Hispanic white patients. Much of the disparity in ICH and stroke incidence in black patients may be explained by an increased prevalence of modifiable risk factors such as hypertension, diabetes, and hyperlipidemia. Hypertension in particular is a well-established risk factor for ischemic and hemorrhagic stroke and is more prevalent in black populations. Large population studies in Northern Manhattan and in Kentucky both demonstrated that the greater incidence of ICH in black subjects was largely attributable to deep basal ganglia and brainstem hemorrhages that were likely hypertensive in etiology (6, 7). Perhaps more concerning is that there is some evidence that although the incidence of stroke in white patients may be decreasing in certain U.S. populations, it is stagnant among black patients, leading to growing racial disparities in stroke incidence. Presently, there are large, population-based studies currently attempting to address these issues—the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study is a prospective, multicenter case-control trial attempting to enroll 1000 nonHispanic white, 1000 Hispanic, and 1000 black patients with ICHs with 3000 demographically-matched control subjects from the same population to identify differences in risk factor distribution, ICH characteristics, and outcomes by ethnicity (8). Although deep intracerebral hemorrhages appear to be more common in black patients presumably secondary to an increased incidence of poorly controlled hypertension in this patient population, the explanation for increased hemorrhagic presentation of AVMs and perhaps increased proclivity for AVM hemorrhage in racial/ethnic minorities is, not surprisingly, less clear. Certainly to the extent that uncontrolled hypertension and cardiovascular disease might precipitate AVM hemorrhage, black and non-white Hispanic patients with AVMs may be at a greater risk of early or recurrent hemorrhage. However, an association between hypertension and AVM rupture has not been clearly established in most AVM natural history and patient demographic studies. Perhaps a more palatable theory to explain the potential discrepancy in AVM hemorrhage risk among different racial/ ethnic groups relates to access to care and socioeconomic status. Apart from hemorrhage or seizure, patients with AVM typically present incidentally. Insured patients with economic stability and easy access to care, one may argue, are more likely
2
www.SCIENCEDIRECT.com
to undergo magnetic resonance imaging for the workup of any headache, dizziness, memory problems, or similar complaint. Racial minorities are known to have poorer access to health care. Certain diagnostic evaluations and treatments may be underused in ethnic minorities as well. One example of underuse of neurosurgical care in U.S. ethnic minorities is the case of epilepsy surgery for refractory epilepsy in mesial temporal sclerosis, a practice known to be grossly underused in the United States in general. A recent study in Neurology evaluating U.S. epilepsy treatment trends from 1990 to 2008 found a significant decrease in the use of surgery for temporal lobe epilepsy in racial minorities compared with white patients and a decrease in the use of surgery for patients without private insurance. (Incidentally, white patients in this population were also found to be more likely to have private insurance.) (2). It is reasonable to postulate that the greater rate of hemorrhagic presentation in black patients with AVM in the present study may be explained by the lower likelihood of AVMs being diagnosed in an unruptured state in this patient population secondary to issues regarding access to care and use of care. Commendably, Yang et al. attempted to address this concern by evaluating the patients’ “work-study status” in their work. They noted no significant difference between race and work-study status in their patients. Although this may be a rather crude and imperfect metric for a subpopulation’s access to care, it is notable that in the present study the authors at least attempted to control for this potential source of confounding. One may argue as well that in the UCSF/Kaiser AVM study that demonstrated a greater annual rate of hemorrhage among Hispanic patients, the patient subgroups were, to a certain extent, controlled for socioeconomic status, because 70% of the patients were members of the Northern California Kaiser health care system, a large health-management organization with a network of 30% of the region’s population. Finally, in addition to other already-proposed explanations, genetic variations among racial and ethnic groups may explain an increased hemorrhagic presentation or hemorrhagic risk in patients with AVM. Studies in large ICH and AVM populations based on self-reported racial and ethnic identity clearly only hint at potential genetic variations within patient subgroups, and broad racial classifications cannot capture the degree of admixing within groups of self-identified black and Hispanic subjects, for instance. Regardless of the underlying explanation, the finding of a potential increased propensity for AVM hemorrhage in certain racial minorities may prove significant in the clinical evaluation and counseling of these patients. Knowledge of a greater risk of hemorrhage may prompt closer clinical follow-up and may swing the risk-benefit pendulum in favor of early treatment of unruptured lesions in certain cases. The ability to more accurately counsel our vascular malformation patients on the natural history of their disease process remains a constant endeavor, and continued evaluation through the prism of race and other patient demographic factors may further our progress towards that goal.
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2015.05.009
PERSPECTIVES
REFERENCES 1. Broderick JP, Brott T, Tomsick T, Huster G, Miller R: The risk of subarachnoid and intracerebral hemorrhages in blacks as compared to whites. N Engl J Med 326:733-736, 1992. 2. Englot DJ, Ouyang D, Garcia PA, Barbaro NM, Chang EF: Epilepsy surgery trends in the United States, 1990-2008. Neurology 78:1200-1206, 2012. 3. Flaherty ML, Woo D, Haverbusch M, Sekar P, Khoury J, Moomaw CJ, Schneider A, Kissela B, Kleindorfer D, Broderick JP: Racial variations in location and risk of intracerebral hemorrhage. Stroke 36:934-937, 2005. 4. Gross BA, Du R: Natural history of cerebral arteriovenous malformations: a meta-analysis. J Neurosurg 118:437-443, 2013.
5. Kim H, Sidney S, McCulloch CE, Poon KY, Singh V, Johnston C, Ko NU, Achrol AS, Lawton MT, Higashida RT, Young WL; UCSF BAVM Study Project: Racial/ethnic differences in longitudinal risk of intracranial hemorrhage in brain arteriovenous malformation patients. Stroke 38:2430-2437, 2007. 6. Kleindorfer DO, Khoury J, Moomaw CJ, Alwell K, Woo D, Flaherty ML, Khatri P, Adeoye O, Ferioli S, Broderick JP, Kissela BM: Stroke incidence is decreasing in whites but not in blacks: a population-based estimate of temporal trends in stroke incidence from the Greater Cincinnati/ Northern Kentucky stroke study. Stroke 41: 1326-1331, 2010. 7. Sacco RL, Boden-Albala B, Abel G, Lin IF, Elkind M, Hauser WA, Paik MC, Shea S: Raceethnic disparities in the impact of stroke risk factors: the northern Manhattan stroke study. Stroke 32:1725-1731, 2001.
WORLD NEUROSURGERY - [-]: ---, MONTH 2015
8. Woo D, Rosand J, Kidwell C, McCauley JL, Osborne J, Brown MW, West SE, Rademacher EW, Waddy S, Roberts JN, Koch S, Gonzales NR, Sung G, Kittner SJ, Birnbaum L, Frankel M, Testai FD, Hall CE, Elkind MS, Flaherty M, Coull B, Chong JY, Warwick T, Malkoff M, James ML, Ali LK, Worrall BB, Jones F, Watson T, Leonard A, Martinez R, Sacco RI, Langefeld CD: The ethnic/ racial variations of intracerebral hemorrhages (ERICH) study protocol. Stroke 44:e120-e125, 2013.
Citation: World Neurosurg. (2015). http://dx.doi.org/10.1016/j.wneu.2015.05.009 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.
www.WORLDNEUROSURGERY.org
3
