Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory arteriopathy that results in stenosis, aneurysm, dissection and arterial tortuosity.¹ The manifestations beyond pathognomonic multifocal (alternating areas of stenosis and dilation, or "string-of-beads") and focal (single area of stenosis) FMD have been increasingly recognized.^1-6 In the US Registry for FMD, dissection and/or aneurysm was observed in 41.7% of patients, despite a lack of systematic imaging in all patients enrolled in the registry. Overall, the internal carotid and renal arteries were the most common sites for these vascular events.² More recently, studies that obtained routine imaging beyond the initial sites of FMD involvement have identified that multisite disease is common, especially if aneurysm and/or dissection are included as a manifestation of FMD.^3,5,7 These findings have broadened the catchment of patients in whom the FMD diagnosis should be considered and diagnostic testing further pursued.

The clinical manifestations of FMD reflect the arterial bed affected, and the most extreme phenotypes include patients experiencing end-organ ischemia such as myocardial infarction, transient ischemic attack and stroke which most often results from spontaneous arterial dissection or ruptured aneurysm.¹ In the US Registry for FMD, cervical artery dissection (CeAD) occurred in 19% of patients overall.² Historically, FMD is reported in up to 20% of patients presenting with spontaneous CeAD and is associated with multiple CeAD, although no studies to date have imaged patients presenting with CeAD for vascular findings outside of the cerebrovascular circulation.^2,8,9 Thus, these numbers may be an underestimate of true coprevalence of FMD and CeAD. There are a number of similarities between FMD and CeAD across patient demographics and risk factors, associated symptoms, diagnosis and natural history that suggest these conditions may represent a spectrum of the same systemic arteriopathy or at least share common pathophysiology (Table 1). The purpose of this analysis will be to explore commonality between FMD and CeAD.

Table 1: Comparison of Demographics, Risk Factors and Symptoms of CeAD and FMD

	Cervical Artery Dissection	Fibromuscular Dysplasia
Mean Age at Diagnosis	44 years	53.9 ± 14 years Dissection: 48.4 ± 9.6 years
Sex	Men > Women, but women present ~5 years younger	Women >> Men, but men with FMD are more likely to experience dissection, aneurysm
Demographics, Associated Symptoms and Findings	Paucity of traditional CV risk factors, except hypertension Migraine headaches Pulsatile tinnitus (8 – 27%) Tortuosity Cerebral artery aneurysm (8.8% women) Monogenic connective tissue disease – rarely associated	Paucity of traditional CV risk factors, except hypertension Headaches (reported by > 50% patients), esp migraines Pulsatile tinnitus (~30%) Arterial tortuosity, stenosis, aneurysm, dissection Cerebral artery aneurysm (12.9% women) Monogenic connective tissue disease – rarely associated
Genetics	PHACTR1 (rs9349379[A] allele) is associated with increased risk for CeAD, migraine headaches and FMD

The majority of internal carotid and vertebral artery dissections involve the extracranial arterial segments with nearly 80% of all internal carotid artery dissections occurring >2 cm distal to the carotid bifurcation.¹⁰ FMD classically affects the same areas; it is typically seen in the mid-distal artery, which is direct contrast to atherosclerosis observed most often in the origin or proximal vessel.¹¹ Importantly, focal FMD can occur in the proximal or vessel origin and may therefore only be distinguished from atherosclerosis through the use of intravascular ultrasound or optical coherence tomography. Both CeAD and FMD are imaging diagnoses – there are pathognomonic findings that can be seen on cross-sectional imaging (magnetic resonance angiography [MRA], computed tomographic angiography [CTA]) or catheter-based angiography to make the diagnosis (Figure 1). It is important to know that current definitions accept that CeAD can only be attributed to FMD if the typical multifocal or focal FMD stenotic lesions are observed in an arterial bed without dissection.⁵ This is because healing dissection can mimic the imaging findings of multifocal FMD.

Figure 1: Imaging Findings of FMD and CeAD*

Clinically, FMD and CeAD both target young to middle-aged adults without traditional vascular risk factors aside from hypertension.^1,11,12 In the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) international consortium, CeAD affected men slightly more than women overall, however women presented roughly 5 years younger than men on average.^12,13 In the US Registry for FMD, over 94% of patients are women with multifocal disease diagnosed at a mean age of 52 years; however, FMD patients that experience a dissection were identified at a younger age (Table 1), and, although a minority, men with FMD more often experience dissection and/or aneurysm.^2,14,15 Headaches are common in both conditions, particularly migraine headaches.14 Pulsatile tinnitus is reported in 10-27% of patients with acute CeAD,^16,17 whereas nearly one-third of patients in the US Registry for FMD reported this symptom at the time of FMD diagnosis and not necessarily in the setting of CeAD.¹⁴ Thus, while not all patients with CeAD may have FMD (and vice versa) there is a clear subset with shared demographics and likely pathophysiology.

Both CeAD and FMD are associated with broader systemic arterial findings – arterial tortuosity and redundancy (e.g., S-curve, loops, kinks, coils) are commonly observed in both conditions leading many to postulate that patients with these conditions have a systemic arteriopathy.^18,19 Cerebral aneurysms have also been identified in connection with CeAD and FMD at higher rates than observed in the general population (~3.2% of adults, mean age 50 years).²⁰ One study of 164 patients with CeAD identified cerebral aneurysm via medical record and/or imaging review in 8.8% of women.²¹ In the US registry for FMD, cerebral aneurysms were identified in 12.9% of 669 women with available intracranial imaging.²² Genetic investigations for monogenic connective tissue disorders including Ehlers-Danlos type IV vascular type, Loeys-Dietz and Marfan syndrome have been low yield in patients with FMD or CeAD.^23,24 However, a polymorphism (rs9349379[A] allele) of the Phosphatase and Actin Regulator 1 gene (PHACTR1) was identified in association with higher risk of CeAD in patients enrolled in the CADISP international consortium.²⁵ This gene association was replicated for FMD in five independent case-control cohorts supporting shared pathophysiology with CeAD.²⁶ Recently, the same polymorphism was also identified in patients with spontaneous coronary artery dissection,²⁷ which is now recognized to occur in strong association with FMD.²⁸ Together, these data raise the possibility for a common systemic arteriopathy which may manifest heterogeneously as FMD, CeAD and/or spontaneous coronary artery dissection.

There are no data to suggest that CeAD in FMD should be treated differently than subjects without identified FMD and for now general guidelines apply. However, the risk for CeAD after FMD diagnosis has been made appears low, just as it is in patients with a CeAD. Our center investigated the rate of neurovascular events following FMD diagnosis in consecutive patients with more than one cervical imaging exam. Out of 146 patients followed for a mean of 2.9 ± 2 years, cervical artery dissection was the only non-atherosclerotic neurovascular event observed in three patients (2%). All dissections occurred in areas of multifocal FMD on baseline imaging and all patients made a full neurologic recovery.²⁹ In the general CeAD population, the risk for recurrent dissection is estimated to be roughly 1% per year following the first 2 months after acute CeAD, which is in line with our observations in patients with FMD.³⁰

More data to clarify the overlap of CeAD and FMD is needed. However, there is compelling evidence to suggest a systemic arteriopathy with shared manifestations. To date, there is no data to guide practitioners in the diagnostic work up of a patient with CeAD for the presence of FMD. Based on the available data presented, our center currently uses the following approach (Table 2): all patients are evaluated for any signs or symptoms of FMD on history or exam. If any are identified, the patient is referred for cross-sectional imaging of the chest/abdomen/pelvis with CTA, which is preferred over MRA due to improved spatial resolution with CT and the risk for false positive and negative diagnosis of FMD on MR due to motion artifact.^5,6 If no signs or symptoms are readily identified, the patient is referred to our non-invasive diagnostic laboratory for renal artery duplex to screen for findings of FMD, which include elevated velocities, turbulence and tortuosity of the mid-distal renal arteries.¹ If the duplex ultrasound is suspicious, the patient is referred for CTA to confirm the diagnosis and screen for concomitant occult aneurysm or dissection. If the duplex ultrasound is negative, no further testing is pursued in absence of clinical signs and/or symptoms of FMD. In centers without an experienced non-diagnostic vascular laboratory, cross-sectional imaging may be appropriate for all patients with cervical artery dissection however further data clarifying the yield and utility of this approach is needed.

Table 2: One Approach to Evaluating Patients Presenting With CeAD

For all patients, obtain at least a renal artery duplex ultrasound to screen for concomitant FMD

Obtain CTA Chest/Abdomen/Pelvis if: Equivocal or positive renal artery duplex exam Hypertension, age </= 35 years at onset Exam findings: Bruits – cervical, abdominal, flank Systemic signs of heritable connective tissue disease (Beighton score, etc.) Image findings that suggest a generalized arteriopathy (e.g., extreme tortuosity, multiple arterial dissections, aneurysms) Family history of aneurysm, dissection or sudden death

References

1. Olin JW, Gornik HL, Bacharach JM, et al. Fibromuscular dysplasia: state of the science and critical unanswered questions: a scientific statement from the American Heart Association. Circulation 2014;129:1048-78.
2. Kadian-Dodov D, Gornik HL, Gu X, et al. Dissection and aneurysm in patients with fibromuscular dysplasia: findings from the U.S. Registry for FMD. J Am Coll Cardiol 2016;68:176-85.
3. Plouin PF, Baguet JP, Thony F, et al. High prevalence of multiple bed lesions in patients with fibromuscular dysplasia: the ARCADIA registry (Assessment of Renal and Cervical Artery Dysplasia). Hypertension 2017;70:652-8.
4. Savard S, Steichen O, Azarine A, ZAzizi M, Jeunemaitre X, Plouin PF. Association between 2 angiographic subtypes of renal artery fibromuscular dysplasia and clinical characteristics. Circulation 2012;126:3062-9.
5. Olin JW. Expanding clinical phenotype of fibromuscular dysplasia. Hypertension 2017;70:488-9.
6. Olin JW, Kadian-Dodov-D. Fibromuscular dysplasia: looking beyond the "string of beads". JACC Cardiovasc Imaging 2017;10:562-4.
7. Bolen MA, Brinza E, Renapurkar RD, Kim ESH, Gornik HL. Screening CT angiography of the aorta, visceral branch vessels, and pelvic arteries in fibromuscular dysplasia. JACC Cardiovasc Imaging 2017;10:554-61.
8. Dziewas R, Konrad C, Drager B, et al. Cervical artery dissection—clinical features, risk factors, therapy and outcome in 126 patients. J Neurol 2003;250:1179-84.
9. Bejot Y, Aboa-Eboule C, Debette S, et al. Characteristics and outcomes of patients with multiple cervical artery dissection. Stroke 2014;45:37-41.
10. Debette S, Leys D. Cervical-artery dissections: predisposing factors, diagnosis, and outcome. Lancet Neurol 2009;8:668-78.
11. Slovut DP, Olin JW. Fibromuscular dysplasia. N Engl J Med 2004;350:1862-71.
12. Metso TM, Debette S, Grond-Ginsbach C, et al. Age-dependent differences in cervical artery dissection. J Neurol 2012;259:2202-10.
13. Metso AJ, Metso TM, Debette S, et al. Gender and cervical artery dissection. Eur J Neurol 2012;19:594-602.
14. Olin JW, Froehlich J, Gu X, et al. The United States Registry for Fibromuscular Dysplasia: results in the first 447 patients. Circulation 2012;125:3182-90.
15. Kim ESH, Olin JW, Froehlich JB, et al. Clinical manifestations of fibromuscular dysplasia vary by patient sex: a report of the United States registry for fibromuscular dysplasia. J Am Coll Cardiol 2013;62:2026-8.
16. Silbert PL, Mokri B, Schievink WI. Headache and neck pain in spontaneous internal cardotid and vertebral artery dissections. Neurology 1995;45:1517-22.
17. Kellert L, Kloss M, Pezzini A, et al. Prognostic significance of pulsatile tinnitus in cervical artery dissection. Eur J Neurol 2016;23:1183-7.
18. Barbour PJ, Castaldo JE, Rae-Grant AD, et al. Internal carotid artery redundancy is significantly associated with dissection. Stroke 1994;25:1201-6.
19. Sethi SS, Lau JF, Godbold J, Gustavson S, Olin JW. The S curve: a novel morphological finding in the internal carotid artery in patients with fibromuscular dysplasia. Vasc Med 2014;19:356-62.
20. Thompson BJ, Brown RD Jr., Amin-Hanjani S, et al. Guidelines for the management of patients with unruptured intracranial aneurysms: a guideline for the healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2015;46:2368-400.
21. Schievink W, Mokri B, Piepgras DG. Angiographic frequency of saccular intracranial aneurysms in patients with spontaneous cervical artery dissection. J Neurosurg 1992;76:62-6.
22. Lather HD, Gornik HL, Olin JW, et al. Prevalence of intracranial aneurysm in women with fibromuscular dysplasia: a report from the US Registry for Fibromuscular Dysplasia. JAMA Neurol 2017;74:1081-7.
23. Poloskey SL, Kim ESH, Sanghani R, et al. Low yield of genetic testing for known vascular connective tissue disorders in patients with fibromuscular dysplasia. Vasc Med 2012;17:371-8.
24. Debette S, Goeggel Simonetti B, Schilling S, et al. Familial occurrence and heritable connective tissue disorders in cervical artery dissection. Neurology 2014;83:2023-31.
25. Debette S, Kamatani Y, Metso TM, et al. Common variation on PHACTR1 is associated with susceptibility to cervical artery dissection. Nat Genet 2015;47:78-83.
26. Kiando SR, Tucker NR, Castro-Vega LJ, et al. PHACTR1 is a genetic susceptibility locus for fibromuscular dysplasia supporting its complex genetic patter of inheritance. PLoS Genet 2016;12:e1006367.
27. Adlam D, Olson TM, Combaret N, et al. Common genetic variant in PHACTR1/EDN1 locus is associated with spontaneous coronary artery dissection. J Am Coll Cardiol 2018. In press.
28. Hayes SN, Kim ESH, Saw J, et al. Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association. Circulation 2018;137:e523-57.
29. Kadian-Dodov D, Goldfinger JZ, Gustavson S, Olin JW. Natural history of cervical artery fibromuscular dysplasia and associated neurovascular events. Cerebrovasc Dis 2018;46:33-9.
30. Schievink W. Mokri B, O'Fallon WM. Recurrent spontaneous cervical-artery dissection. N Engl J Med 1994;330:393-7.

Keywords: Vertebral Artery Dissection, Carotid Artery, Internal, Dissection, Ischemic Attack, Transient, Intracranial Aneurysm, Renal Artery, Stroke, Fibromuscular Dysplasia, Risk Factors, Magnetic Resonance Angiography, Marfan Syndrome, Constriction, Pathologic, Tomography, Optical Coherence, Brain Ischemia, Dilatation, Coronary Vessels, Skin Diseases, Genetic, Vascular Malformations, Joint Instability, Migraine Disorders, Aneurysm, Ruptured, Hypertension, Atherosclerosis, Registries, Myocardial Infarction, Cerebrovascular Circulation, Tomography, X-Ray Computed, Medical Records, Phosphoric Monoester Hydrolases, Phenotype, Connective Tissue, Cross-Sectional Studies, Case-Control Studies

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