Research

JAMA Neurology | Original Investigation Prevalence of Intracranial in Women With Fibromuscular Dysplasia A Report From the US Registry for Fibromuscular Dysplasia

Henry D. Lather, BS; Heather L. Gornik, MD, MHS; Jeffrey W. Olin, DO; Xiaokui Gu, MA; Steven T. Heidt, BA; Esther S. H. Kim, MD, MPH; Daniella Kadian-Dodov, MD; Aditya Sharma, MBBS; Bruce Gray, DO; Michael R. Jaff, DO; Yung-Wei Chi, DO; Pamela Mace, RN; Eva Kline-Rogers, MS, RN, NP; James B. Froehlich, MD, MPH

IMPORTANCE The prevalence of in patients with fibromuscular dysplasia (FMD) is uncertain.

OBJECTIVE To examine the prevalence of intracranial aneurysm in women diagnosed with FMD.

DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study included 669 women with intracranial imaging registered in the US Registry for Fibromuscular Dysplasia, an observational disease-based registry of patients with FMD confirmed by vascular imaging and currently enrolling at 14 participating US academic centers. Registry enrollment began in 2008, and data were abstracted in September 2015. Patients younger than 18 years at the time of FMD diagnosis were excluded. Imaging reports of all patients with reported internal carotid, vertebral, or suspected intracranial were reviewed. Only saccular or broad-based aneurysms 2 mm or larger in greatest dimension were included. Extradural aneurysms in the were included; fusiform aneurysms, infundibulae, and vascular segments with uncertainty were excluded.

MAIN OUTCOMES AND MEASURES Percentage of women with FMD with intracranial imaging who had an intracranial aneurysm.

RESULTS Of 1112 female patients in the registry, 669 (60.2%) had undergone intracranial imaging at the time of enrollment (mean [SD] age at enrollment, 55.6 [10.9] years). Of the 669 patients included in the analysis, 86 (12.9%; 95% CI, 10.3%-15.9%) had at least 1 intracranial aneurysm. Of these 86 patients, 25 (53.8%) had more than 1 intracranial aneurysm. Intracranial aneurysms 5 mm or larger occurred in 32 of 74 patients (43.2%), and 24 of 128 intracranial aneurysms (18.8%) were in the posterior communicating or posterior . The presence of intracranial aneurysm did not vary with location of extracranial FMD involvement. A history of smoking was significantly associated with intracranial aneurysm: 42 of 78 patients with intracranial aneurysm (53.8%) had a smoking history vs 163 of 564 patients without intracranial aneurysm (28.9%; P < .001).

CONCLUSIONS AND RELEVANCE The prevalence of intracranial aneurysm in women diagnosed with FMD is significantly higher than reported in the general population. Although the clinical benefit of screening for intracranial aneurysm in patients with FMD has yet to be proven, these data lend support to the recommendation that all patients with FMD undergo intracranial imaging if not already performed.

Author Affiliations: Author affiliations are listed at the end of this article. Corresponding Author: James B. Froehlich, MD, MPH, Cardiovascular Center, University of Michigan Medical School, 1500 E Medical JAMA Neurol. 2017;74(9):1081-1087. doi:10.1001/jamaneurol.2017.1333 Center Dr, SPC 5853, Ann Arbor, MI Published online July 17, 2017. Corrected on January 2, 2018. 48109 ([email protected]).

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ibromuscular dysplasia (FMD) is an uncommon, non- inflammatory, nonatherosclerotic disease of the me- Key Points dium and large arteries.1,2 Its cause is not known; how- F Question What is the prevalence of intracranial aneurysm in 3 ever, it is far more common in women. It can occur in any women with fibromuscular dysplasia? arterial bed, although it is most commonly found in the renal Findings In this cross-sectional registry study that included 669 and cervical arteries.3 The clinical presentation of FMD var- women with a diagnosis of fibromuscular dysplasia and intracranial ies, depending on the location of the arterial lesions. Often FMD imaging, the prevalence of intracranial aneurysm was 12.9%. is asymptomatic and therefore frequently found inciden- tally. In addition, FMD is associated with a substantial risk of Meaning The prevalence of intracranial aneurysm in women with fibromuscular dysplasia is high enough to warrant consideration of aneurysm formation and rupture, as well as arterial dissec- screening patients with fibromuscular dysplasia for intracranial tion and occlusion.3,4 aneurysm with noninvasive imaging. Previously published data suggest an increased risk of in- tracranial aneurysm (IA) in patients with carotid artery (CA) and vertebral artery (VA) FMD.2 Intracranial aneurysms may confirmed by vascular imaging and currently enrolling at 14 rupture, leading to (SAH) and sig- participating centers. Registry enrollment began in 2008, and nificant morbidity and mortality. The mortality among pa- data were abstracted in September 2015. Registry details and tients who experience SAH is approximately 50%,5 with 12% standardization of data collection have been described dying immediately.6 The most commonly identified cause of previously.3 Written informed consent was obtained from all SAH is IA rupture (85%).7 It is not known whether the natural participants, and all sites had institutional review board ap- history of IA in patients with FMD is similar to that in patients proval (Institutional Review Boards of the University of Michi- without FMD. Although outcomes in patients with SAH are gan Medical School, Cleveland Clinic Foundation Institu- poor,6 sizable IAs identified before rupture can be repaired or tional Review Board, Program for the Protection of Human excluded with endovascular or surgical techniques.8 How- Subjects at Icahn School of Medicine at Mount Sinai, Univer- ever, the risk of treatment must be balanced with the risk of sity of Virginia Institutional Review Board for Health Sci- rupture9; therefore, the clinical benefit of screening for IA, even ences Research, Greenville Health System Institutional Re- in populations with known increased risk, is uncertain.10,11 view Board, Partners Institutional Review Boards, and Previous estimates of IA prevalence among patients with University of California, Davis, Institutional Review Board). All CA and/or VA FMD come from neurosurgery and radiology case data were deidentified. series, which suffer from selection bias in patient inclusion.12 Patients enrolled from all sites in the US Registry for Fibro- Previous studies12 estimated the prevalence of IA to be 21% to muscular Dysplasia who had undergone intracranial imaging at 51%. The most recent estimate was published in a 1998 meta- or before enrollment, as documented on the initial registry data analysis and case series by Cloft and colleagues12 in which IA form, were included. For the purposes of this report, intracra- prevalence was calculated with and without IA symptoms (eg, nial imaging was defined as catheter-based , com- SAH) among patients with CA and/or VA FMD who underwent puted tomographic angiography, or magnetic resonance angi- cerebral angiography.In most patients with IA in that series, SAH ography (MRA). Patients were also included in this study if they was the indication for angiography; FMD was often inciden- had a known repaired IA. Patients younger than 18 years at the tally found. Among asymptomatic patients with FMD, there was time of FMD diagnosis were excluded because of concern that a mean (SD) prevalence of IA of 7.3% (2.2%; 38 of 517 patients). FMD and IAs in children may be different from those in adults.8,13 In the 2014 American Heart Association (AHA) Scientific Because male sex may affect the pathophysiologic mechanism Statement on FMD, the writing committee identified the deter- of FMD14 and aneurysms,15 male patients were also excluded. mination of the prevalence of IA among patients with FMD as In addition, male patients constituted only 5.7% of individuals a top research priority.2 Although there have been several esti- in the registry. Although positive family history of IA or SAH in- mates of IA prevalence among patients with FMD in the CAs creases the likelihood of IA by 3.4-fold,15 this information was and/or VAs, to our knowledge, there are no published reports not available in the database. of the prevalence of IA among patients with FMD in the renal Intracranial aneurysm was defined as a saccular or broad- arteries. Because of the life-threatening consequences of rup- based aneurysm greater than or equal to 2 mm in greatest di- tured IAs and the possible association with FMD, the writing mension occurring at or above the level of the skull base. Ex- committee recommended IA screening for all patients with FMD tradural (but intracranial) aneurysms in the petrous segment found in any arterial bed. The current study uses the largest da- of the internal CA (C2 in the Bouthillier classification16) and tabase of patients with FMD, the US Registry for Fibromuscu- above were included. To ensure that the definition of IA was met, lar Dysplasia, to estimate the prevalence of IA and characterize all available imaging reports from each patient with a CA aneu- IAs in FMD. rysm, VA aneurysm, and/or IA were reviewed and assessed using these criteria. If patients had multiple imaging reports, the larg- est recorded dimension of each IA was used. Any registry site Methods that was unable to provide deidentified imaging reports to the coordinating center was excluded from the analysis. The US Registry for Fibromuscular Dysplasia is an observa- To address the question of whether IA is more prevalent in tional disease-based registry of patients with diagnosis of FMD patients with cervical FMD vs noncervical FMD, we analyzed

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Table 1. Characteristics of Women With Fibromuscular Dysplasia With and Without Intracranial Imaging at the Time of Registry Enrollmenta

Intracranial Imaging No Intracranial Imaging Characteristic (n = 669)b (n = 460)b P Value Age at enrollment, mean (SD), y 55.6 (10.9) 57.4 (13.9) .02 Body mass index, mean (SD)c 25.0 (5.0) 25.2 (4.9) .54 408/655 (62.3) 355/441 (80.5) <.001 Headache 501/658 (76.1) 229/412 (55.6) <.001 History of smoking 205/642 (31.9) 154/413 (37.3) .07 a Data are presented as proportion 81/646 (12.5) 23/417 (5.5) <.001 (percentage) of women unless otherwise indicated. Intracranial Atherosclerotic coronary artery disease 37/616 (6.0) 40/402 (10.0) .02 imaging was performed by Myocardial infarction 40/635 (6.3) 16/404 (4.0) .10 angiography, computed Horner syndrome 52/599 (8.7) 11/402 (2.7) <.001 tomographic angiography, or magnetic resonance angiography. Subarachnoid hemorrhage 22/615 (3.6) 3/403 (0.7) .003 b Denominators are different because Arterial 215/644 (33.4) 46/413 (11.1) <.001 not all information was available for 191/447 (42.7) 102/258 (39.5) .41 each patient. History of contraceptive or hormone use 325/434 (74.9) 186/306 (60.8) <.001 c Calculated as weight in kilograms divided by height in meters Menopause 331/506 (65.4) 214/346 (61.8) .29 squared.

the prevalence of IA in patients with renal and/or cervical FMD. (86 of 669 women; 95% CI, 10.3%-15.9%). The prevalence of Renal FMD was defined by imaging consistent with FMD in one IA was 11.9% (41 of 344; 95% CI, 8.6%-16.2%) among patients or both renal arteries. Cervical FMD was defined as imaging con- with renal FMD and 13.7% (77 of 563; 95% CI, 10.8%-17.1%) sistent with FMD in extracranial CAs and/or VAs. Noncervical among patients with cervical FMD. A total of 242 patients were and nonrenal subgroups were defined by the absence of FMD identified with renal and cervical FMD, and 32 (13.2%) of these in those vascular beds only if both renal and cervical imaging patients had IA. The prevalence of IA among patients with in- were performed. Patients with noncervical FMD were defined tracranial FMD was not assessed because many centers con- as having no FMD in the extracranial CAs and/or VAs. Most of sider IA to be a manifestation of intracranial FMD and thus rec- these patients had renal FMD but could have had FMD in other ord it as intracranial FMD even if traditional beading was not vascular beds (eg, external iliac). Nonrenal FMD was defined present in intracranial arteries. similarly, and likewise, patients in this group had predomi- The IA prevalence was not significantly different when nantly cervical FMD. stratified by arterial location of FMD. No significant differ- Comparisons of differences between groups were per- ence was found between the prevalence of IA among patients formed with 2-tailed, unpaired t tests or Wilcoxon rank sum with noncervical FMD (primarily renal FMD) (7.7% [8 of 104]; tests for continuous variables and with χ2 or Fisher exact tests 95% CI, 3.3%-15.2%) and patients with nonrenal FMD (12.3% for categorical variables. A 2-sided P < .05 was considered to [31 of 252]; 95% CI, 8.4%-17.5%). Conversely, the prevalence be statistically significant for all comparisons. All analyses were of cervical FMD with IA (90.6% [77 of 85]) was not signifi- performed with SAS statistical software, version 9.3 (SAS In- cantly different (P = .14) from that of cervical FMD without IA stitute Inc). (83.9% [486 of 579]), and the percentage of patients with IA and renal FMD (56.9% [41 of 72]) was not significantly differ- ent from that of patients without IA with renal FMD (57.4% [303 Results of 528]; P =.94). To account for the possible selection bias in imaging raised At the time of data extraction (September 2015), there were 1145 by Cloft and colleagues,12 unruptured IA (UIA) prevalence was female patients and 71 male patients across 11 sites. Of the fe- also calculated by subtracting patients with a history of SAH male patients, 685 (59.8%) had undergone intracranial imaging (11.1% [66 of 593 women in the registry with no history of SAH before enrollment. Two of these female patients were younger had IA]; 95% CI, 8.6%-14.2%). Patient characteristics of those than 18 years at the time of FMD diagnosis and thus were ex- with and without intracranial imaging are presented in Table 1. cluded. Fourteen patients (2.0%) with intracranial imaging A total of 12 women with intracranial imaging had a po- were excluded because the 2 enrolling sites for those patients tential IA that did not meet our criteria: 2 had saccular aneu- were unable to provide imaging reports. The final cohort for rysms smaller than 2 mm, 3 had fusiform aneurysms, and 7 this study consisted of 669 women, all with intracranial had aneurysms that were not definitively saccular aneu- imaging (mean [SD] age at enrollment, 55.6 [10.9] years). Demo- rysms. Many patients had multiple IAs; 128 saccular or broad- graphic and clinical characteristics of these women are pre- based IAs were found in 86 women with FMD. The number of sented in Table 1. IAs in each patient ranged from 1 to 8, with a median of 1 and The overall prevalence of saccular or broad-based IA of at a mean (SD) of 1.5 (1.0). A total of 26 of 86 women (30.2%) least 2 mm in greatest dimension among women with FMD had more than 1 IA. Aneurysm locations are reported in Table 2. with intracranial imaging and enrolled in the registry was 12.9% Of the 2 patients with unknown IA location, 1 patient had 2

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Table 2. Location of the IAs Table 3. Size of the IAs

No. (%) of IAs No. (%) of IAs Vascular Territory (n = 128a) Size in Largest Dimension, mm (n = 128a) Anterior arteriesb 15 (12) 2.0-2.9 36 (28) Middle cerebral artery 19 (15) 3.0-3.9 23 (18) Unspecified ICA 5 (4) 4.0-4.9 17 (13) Extradural ICAc 11 (9) 5.0-6.9 19 (15) Intradural ICAd 52 (41) 7.0-9.9 11 (9) Posterior communicating 12 (9) 10.0-12.9 6 (5) Posterior arteriese 12 (9) 13.0-24.9 1 (1) Unknownf 2 (2) Unknown size but repaired 15 (12)

Abbreviations: IA, intracranial aneurysm; ICA, internal carotid artery. Abbreviation: IA, intracranial aneurysm. a More than 86 of the IAs were attributable to more than 1 IA in some patients. a More than 86 of the IAs were attributable to more than 1 IA in some patients. b Anterior arteries include anterior cerebral arteries and anterior communicating artery. and colleagues12 tried to correct for the bias inherent in select- c Extradural ICA includes segments C2 (petrous) and C4 (cavernous) of ing patients with FMD who were undergoing catheter-based Bouthillier classification.16 intracranial angiography by excluding patients with signs and d Intradural ICA includes segments C5 (clinoidal), C6 (ophthalmic), and C7 (communicating) and aneurysms in the ophthalmic, hypophyseal, and anterior symptoms of IA (namely, SAH and cranial nerve defects). Ad- choroidal arteries. justing for symptomatic IAs in that series decreased reported e Posterior arteries include posterior cerebral artery, posterior inferior cerebellar IA prevalence in cervical FMD from 23.9% to 6.3%.12 In con- artery, and basilar artery. trast, the IA prevalence found in the current report from the f Both unknown IAs were surgically repaired. registry was minimally different, excluding patients with SAH (decreasing from 12.9% to 11.1%), suggesting that intracranial aneurysms, and the IA location and repair status of that pa- imaging in the registry is not nearly as biased toward those with tient were unknown from the available medical records. The symptomatic aneurysms as in previous reports. Aside from IA, other patient had a remote history of aneurysm repair but no few clinical characteristics are specific for SAH; therefore, specific documentation of the site. Eleven IAs in the intracra- imaging performed to investigate symptoms, such as nial portion of the internal CA were extradural. The exact lo- and headaches without SAH, is less likely to bias toward IA cation of 5 additional IAs in the internal CA, although intra- prevalence. Estimates of the prevalence of UIAs in the gen- cranial, could not be discerned from imaging reports. The IA eral population have improved greatly since Cloft and sizes are reported in Table 3. Size was unavailable in some pa- colleagues12 estimated the IA prevalence among patients with tients who had a record of IA repair but lacked original imaging FMD in 1998. Vlak and colleagues15 performed a systematic re- reports. Of the 74 patients with all IAs of known size, the larg- view and meta-analysis of UIAs in the general population in est IA per patient was 5 mm or larger in 32 (43.2%). 2011 that identified 1450 UIAs in 94 912 patients, for an over- Demographic characteristics and medical history were all prevalence of 3.2% (95% CI, 1.9%-5.2%) in a population with- compared between patients with and without IA (Table 4). Only out comorbidity, with a mean age of 50 years, and consisting history of smoking, increased age at smoking cessation, num- of 50% men. Smoking and hypertension were not evaluated ber of tobacco pack-years, and SAH were significantly associ- as comorbidities. The prevalence ratios in populations of ated with IA. The presence of a nonintracranial aneurysm was women were 1.61 (95% CI, 1.02-2.54) for a mean age of 50 years not associated with IA: 9 of 86 patients with IA (10.5%) had a and 2.2 (95% CI, 1.3-3.6) for a mean age older than 50 years. nonintracranial aneurysm, whereas 60 of 583 patients with- The overall prevalence of UIA among women of all ages was out IA (10.3%) had a nonintracranial aneurysm. 6.0% (95% CI, 4.5%-8.0%). This meta-analysis included a notable study17 in which 7345 healthy Japanese volunteers (mean age, 55.5 years) were screened with MRA for intracra- Discussion nial abnormalities, including aneurysm. The UIA prevalence among female patients was 2.7%, and overall (male and fe- We found a 12.9% prevalence of IAs among women with FMD male) mean (SD) diameter was 3.9 (1.6) mm. In a subsequent with intracranial imaging at the time of enrollment in the US cross-sectional study,18 4813 Chinese adults aged 35 to 75 years Registry for Fibromuscular Dysplasia. The prevalence of IA was were screened with MRA for UIA. The prevalence was 7.0% not significantly different when stratified by location of FMD. (95% CI, 6.3%-7.7%) overall and 8.4% (7.3%-9.5%) among Unlike previous reports of IA prevalence among patients women. Among women aged 55 to 64 years, the prevalence with FMD, the women currently described in this study are not was 11.0% (95% CI, 8.4%-13.6%), and among women aged 65 from a neurosurgical case series. Furthermore, a prior report12 to 75 years, the prevalence was 9.9% (95% CI, 6.9%-13.0%). The performed before noninvasive imaging was widely used to prevalence of UIA (ie, no SAH) in the US Registry of Fibromus- evaluate less serious presentations, such as headache and/or cular Dysplasia (11.1%) is significantly greater than the 6.0%15 pulsatile . Other investigators have reported esti- (P < .001) and 8.4%18 (P = .03) reported in the other aforemen- mates of IA prevalence as high as 50% in cervical FMD.12 Cloft tioned studies.

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Table 4. Characteristics of Women With Fibromuscular Dysplasia With and Without IAa

IA No IA (With Intracranial Imaging) Characteristic (n=86b) (n = 583b) P Value Age at enrollment, mean (SD) 57.4 (12.4) [57.8] 55.5 (10.6) [55] .10 [median], y Hypertension 59/84 (70.2) 349/571 (61.1) .11 Headache 66/85 (77.6) 435/573 (75.9) .73 History of smoking 42/78 (53.8) 163/564 (28.9) <.001 Age at smoking onset, mean (SD) 21.3 (7.4) [18] 20.6 (7.0) [18] .79 [median], y Age at stopping smoking, mean (SD) 42.3 (12.1) [42] 35.5 (13.5) [34] .01 [median], y No. of pack-years, mean (SD), 20.2 (13.0), 17 16.8 (20.2), 10 .03 median, y Stroke 15/84 (17.9) 66/562 (11.7) .11 Atherosclerotic coronary 3/78 (3.8) 34/538 (6.3) .61 artery disease Horner syndrome 3/79 (3.8) 49/520 (9.4) .13 Abbreviations: HRT, hormone Subarachnoid hemorrhage 14/80 (18.0) 8/535 (1.5) <.001 replacement therapy; IA, intracranial Any arterial dissection 21/84 (25.0) 194/560 (34.6) .08 aneurysm. a Hyperlipidemia 25/61 (41.0) 166/386 (43.0) .77 Data are presented as proportion (percentage) of women unless History of contraceptive 43/65 (66.1) 282/369 (76.4) .08 or hormone use otherwise indicated. b Systematic HRT or estrogen use 22/62 (35.5) 127/319 (39.8) .52 Denominators are different because not all information was available for Menopause 48/68 (70.6) 283/438 (64.6) .34 each patient.

Of interest, the UIAs that we report from the registry have FMD.21 Perhaps smoking similarly worsens the underlying higher-risk features for rupture (ie, they are larger and more of- FMD disease state that leads to IA formation. In addition, ten in the posterior circulation) than do those in screening stud- smoking is thought to be a risk factor for rupture of IA in ies of healthy volunteers. In an MRI screening study19 in the patients without FMD.22 Although it has long been recom- Netherlands with 2000 participants (mean age, 63.3 years; 52% mended that patients with FMD do not smoke,23 the asso- women), UIA was found in 35 individuals (1.8%), but only 3 UIAs ciation with IA and particularly age of cessation and number (8.6%) were 7 mm or larger, and the largest was only 12 mm. In of pack-years provides more compelling evidence in favor of the Chinese study,18 90.2% of UIAs had a maximum diameter smoking cessation. less than 5 mm, with a mean diameter of 3.7 mm in women. Only The benefits of screening for IA must be balanced with the 0.9% of UIAs were 10 mm or larger. The authors noted that the risks of intervention, among other considerations. Although one increased prevalence and preponderance of small aneurysms mathematical model found that the clinical benefit of screen- might be in part attributable to the high-quality 3.0-T 3-dimen- ing depended not on the prevalence of IA but the risk of sional time-of-flight MRA used in the study. In contrast, the rupture,10 the AHA/American Stroke Association guideline on mean size of UIAs in the current study of women with FMD was the management of patients with UIA still recommends screen- at least 5.0 mm, and the largest UIA in 22.0% of patients was ing in selected populations based on increased prevalence.11 7 mm or larger (although 10.6% of patients had at least 1 UIA of unknown size owing to repair and thus were excluded Limitations from this calculation). Rupture risk also depends on location; This study has a number of limitations. Not all patients en- UIAs in the posterior communicating (relative risk, 2.4) and rolled in the registry had undergone intracranial imaging at the posterior circulation (relative risk, 2.5) have the greatest risk time of initial enrollment in the registry, and there were no stan- of rupture, compared with middle cerebral arteries.9 In the dard protocols to recommend it; thus, potential for bias in pa- current report, 18.3% of UIAs were in these higher-risk arter- tient selection for imaging exists. Differences were found in ies, compared with 5.7%19 and 2.2%18 in other studies. In demographic and clinical characteristics between those pa- addition, only 8.0% of patients in the study by Li et al18 had tients with FMD with and without intracranial imaging (Table 1), multiple aneurysms compared with 24.2% of patients with although patients without intracranial imaging were older and FMD. However, even after correcting for sex and age, signifi- had a higher prevalence of hypertension and smoking history, cant differences were found in the patient populations; established risk factors for IA. Furthermore, imaging protocols therefore, direct comparison is difficult. for IA were not standardized across centers; thus, choice of mo- Finally, smoking was strongly associated with IA in dality and quality of images may have varied significantly. This patients in the registry, consistent with related registry likely underestimates IA prevalence because 1.5-T MRA and findings.20 Smoking is considered a risk factor for the devel- lower-quality computed tomographic angiography likely miss opment of IA in patients without FMD,11 although it was not rather than falsely report IAs. All registry research introduces associated with IA prevalence in the Chinese study.18 Smok- selection bias and has other inherent limitations, including ing has also been associated with onset and severity of renal potential issues with data quality and completeness, re-

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cruitment and enrollment strategies, and confounding vari- ables, both known and unknown. Specifically, the US Registry Conclusions for Fibromuscular Dysplasia has unique limitations because of the nature of FMD, including its underdiagnosis, heteroge- The prevalence of IA among women with FMD at enrollment neity of presentation, and poorly understood mechanism and in the US Registry for Fibromuscular Dysplasia was 12.9%, sig- natural history. Data derived from the registry are also likely to nificantly greater than that estimated for the general popula- be enriched with patients with symptomatic and complicated tion of women with a mean age older than 50 years. There was FMD who seek care at the referral centers that comprise regis- no difference in IA prevalence among patients in the registry try centers. with FMD in the renal or cervical arteries, suggesting that lo- Reports of imaging studies were reviewed according to cation of FMD does not affect the prevalence of IA. Many reg- standardized criteria by 2 of us (H.D.L. and J.B.F.), but the ex- istry patients with FMD had multiple IAs, IAs of significant size, isting resources of the US Registry of Fibromuscular Dyspla- and IAs in rupture-prone locations. These data support a strong sia did not allow for centralized review of imaging studies in association of IAs with FMD. In light of the AHA/American a core laboratory. Some imaging reports were not available for Stroke Association guidelines on treating patients with un- review, such as those performed at nonparticipating hospi- ruptured IA,11 the current data support the recommendation tals. These factors make comparison of these findings with for screening intracranial imaging in patients with FMD.2 These those of several large, high-quality studies17-19 in patients with- data also suggest that a prospective intracranial imaging study out FMD less definitive. of consecutive patients with FMD should be performed.

ARTICLE INFORMATION Obtained funding: Froehlich, Olin. System, Greenville Health System, Massachusetts Accepted for Publication: April 19, 2017. Administrative, technical, or material support: General Hospital, and Michigan Medicine provided Froehlich, Olin, Heidt, Sharma, Gray, Chi, data and responded to imaging queries. Published Online: July 17, 2017. Kline-Rogers. doi:10.1001/jamaneurol.2017.1333 Study supervision: Froehlich, Gornik, Olin, Heidt, REFERENCES Correction: This article was corrected on January 2, Kim, Sharma, Kline-Rogers. 2017, to change “dystrophy” to “dysplasia” 1. Slovut DP, Olin JW. Fibromuscular dysplasia. throughout the article. Conflict of Interest Disclosures: Dr Gornik reports N Engl J Med. 2004;350(18):1862-1871. being a noncompensated board member and Author Affiliations: Department of Medicine, 2. Olin JW, Gornik HL, Bacharach JM, et al; medical advisory committee member of the American Heart Association Council on Peripheral Cardiovascular Center, University of Michigan Fibromuscular Dysplasia Society of America Medical School, Ann Arbor (Lather, Gu, Heidt, ; American Heart Association (FMDSA). Dr Olin reports being a noncompensated Council on Clinical ; American Heart Kline-Rogers, Froehlich); Department of board member and medical advisory committee Cardiovascular Medicine, Miller Family Heart and Association Council on Cardiopulmonary, Critical chair of the FMDSA, a steering committee member Care, Perioperative and Resuscitation; American Vascular Institute, Cleveland Clinic Foundation, for the AstraZeneca EUCLID (Effects of Ticagrelor Cleveland, Ohio (Gornik); Zena and Michael A. Heart Association Council on Cardiovascular and Clopidogrel in Patients with Peripheral Artery Disease in the Young; American Heart Association Wiener Cardiovascular Institute, Icahn School of Disease) Trial, and a member of the AstraZeneca Medicine at Mount Sinai, New York, New York (Olin, Council on Cardiovascular Radiology and medical advisory board. Dr Kim is a consultant for Intervention; American Heart Association Council Kadian-Dodov); Department of Cardiovascular Philips Ultrasound. Dr Gray is a consultant for Medicine Miller Family Heart and Vascular Institute, on Epidemiology and Prevention; American Heart Medtronic and Gore. Dr Jaff reports being a Association Council on Functional Genomics and Vanderbilt University Medical Center, Nashville, compensated VIVA Physicians board member. Ms Tennessee (Kim); Department of Medicine Translational Biology; American Heart Association Mace reports being the Executive Director of the Council for High Blood Pressure Research; (Cardiovascular Medicine) and Emergency FMDSA. Dr Froehlich reports being a consultant for Medicine, University of Virginia Health System, American Heart Association Council on the Kidney Janssen Pharmaceuticals, Merck, and Novartis and in ; American Heart Charlottesville (Sharma); Department of Surgery/ an advisory committee member of Vascular Medicine, Greenville Health System, Association Stroke Council. Fibromuscular Boehringer-Ingelheim and Pfizer and receiving dysplasia: state of the science and critical Greenville, South Carolina (Gray); Fireman Vascular grant/research support from Blue Cross Blue Shield Center, Massachusetts General Hospital, Harvard unanswered questions: a scientific statement from of Michigan and the FMDSA. No other disclosures the American Heart Association. Circulation. 2014; Medical School, Boston, Massachusetts (Jaff); were reported. Division of Cardiovascular Medicine, University of 129(9):1048-1078. doi:10.1161/01.cir.0000442577 California Davis Health System, Sacramento (Chi); Funding/Support: This work was supported by the .96802.8c Fibromuscular Dysplasia Society of America, Rocky FMDSA, a nonprofit organization, and the 3. Olin JW, Froehlich J, Gu X, et al. The United River, Ohio (Mace). University of Michigan Medical School through the States Registry for Fibromuscular Dysplasia: results Summer Biomedical Research Program (Mr Lather). Author Contributions: Ms Gu and Dr Froehlich had in the first 447 patients. Circulation. 2012;125(25): full access to all the data in the study and take Role of the Funder/Sponsor: The funding source 3182-3190. doi:10.1161/CIRCULATIONAHA.112.091223 responsibility for the integrity of the data and the had no role in the design and conduct of the study; 4. Kadian-Dodov D, Gornik HL, Gu X, et al. accuracy of the data analysis. collection, management, analysis, and Dissection and aneurysm in patients with Study concept and design: Froehlich, Lather, Gornik, interpretation of the data; preparation, review, or fibromuscular dysplasia: findings from the United Olin, Heidt, Sharma, Kline-Rogers. approval of the manuscript; and the decision to States Registry for FMD. J Am Coll Cardiol. 2016;68 Acquisition, analysis, or interpretation of data: submit the manuscript for publication. (2):176-185. Froehlich, Lather, Gornik, Olin, Gu, Heidt, Kim, Additional Contributions: Ellen Brinza, BS, 5. van Gijn J, Kerr RS, Rinkel GJE. Subarachnoid Kadian-Dodov, Gray, Jaff, Chi, Mace, Kline-Rogers. Cleveland Clinic, Cleveland, Ohio, assisted in haemorrhage. Lancet. 2007;369(9558):306-318. Drafting of the manuscript: Lather, Gornik, Chi, abstracting and preparing imaging reports and doi:10.1016/S0140-6736(07)60153-6 Mace. Rachel Krallman, BS, Michigan Medicine, University Critical revision of the manuscript for important of Michigan, Ann Arbor, assisted in preparing the 6. Rinkel GJE, Algra A. Long-term outcomes of intellectual content: Froehlich, Lather, Gornik, Olin, manuscript; they were not compensated for their patients with aneurysmal subarachnoid Gu, Heidt, Kim, Kadian-Dodov, Sharma, Gray, Jaff, work on this article. Cleveland Clinic, Mount Sinai haemorrhage. Lancet Neurol. 2011;10(4):349-356. Kline-Rogers. Health System, University of Virginia Health doi:10.1016/S1474-4422(11)70017-5 Statistical analysis: Lather, Gu. System, University of California Davis Health

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