Cerebrovascular fibromuscular dysplasia

Abstract

Background:

Cerebrovascular fibromuscular dysplasia (FMD), that is, involving the cervical or intracranial arteries, is frequently overlooked despite its association with several neurological manifestations.

Objectives:

To describe cerebrovascular FMD.

Design:

Systematic review.

Data sources and methods:

We searched PubMed, Embase, and Medline up to December 2024. We identified additional studies by handsearching the bibliographies of relevant studies. We included articles describing at least one aspect of epidemiology, manifestations, prognosis, and management of cerebrovascular FMD and preferentially focused on studies including ⩾15 patients. The quality of evidence was rated according to the Oxford Centre for Evidence-Based Medicine levels of evidence.

Results:

We included 119 studies. Cerebrovascular FMD predominantly affects women around 50 years of age and most frequently involves the cervical arteries. Cerebrovascular FMD is frequently asymptomatic and incidentally diagnosed. The most common presenting symptoms are headache (8%–52%) and pulsatile tinnitus (17%–23%). Patients with FMD have a higher prevalence of cervical artery dissection (7%–17%) and intracranial saccular aneurysm (7%) compared to the general population. The main complications of cerebrovascular FMD are ischemic stroke (7%–10%), transient ischemic attack (5%–12%), subarachnoid hemorrhage (2%–3%), and intracerebral hemorrhage (0.01%). Webs are the predominant form of FMD in Black populations. Consensus-based recommendations have been summarized in the first international consensus statement on the diagnosis and management of FMD. Imaging of all arteries from brain-to-pelvis is recommended to detect asymptomatic lesions. Antiplatelet therapy is reasonable for patients with cerebrovascular FMD to prevent thromboembolic complications. Endovascular treatment can be considered in patients with risk factors for rupture of an unruptured intracranial aneurysm and in those with recurrent ischemic events despite medical management.

Conclusion:

Existing cross-sectional studies have improved the understanding of the manifestations of cerebrovascular FMD. However, knowledge gaps remain regarding the genetics, pathophysiology, management, and prognosis of cerebrovascular FMD, which should be addressed in future research.

Keywords

cervical arterial dissection fibromuscular dysplasia headache intracranial aneurysm stroke

Introduction

Fibromuscular dysplasia (FMD) is an idiopathic, noninflammatory, nonatherosclerotic vascular disease of small- to medium-sized arteries.¹ Most of the information on patients with FMD comes from the United States (US) and the European/International Fibromuscular Dysplasia Registry, totalizing almost 6000 patients.^2–4 FMD predominantly affects women (80%–85% of patients) and the Caucasian population (80%–90% of patients). FMD can involve any arterial bed but the renal and cervical (extracranial) carotid and vertebral arteries are the most commonly affected in nearly half of the patients.^3,5 Involvement of intracranial arteries is less frequent in adults than in children.^6,7 Cerebrovascular FMD (i.e., involving the cervical or intracranial arteries) is little known to physicians and is often misdiagnosed.

The manifestations and clinical presentations of cerebrovascular FMD are diverse, ranging from incidentally discovered asymptomatic cervical or intracranial arterial lesions to pulsatile tinnitus or migraine, extracranial and intracranial dissection, intracranial aneurysm, ischemic stroke, and intracerebral or subarachnoid hemorrhage.

This systematic review aimed to describe the epidemiologic characteristics, prognosis, and management of cerebrovascular FMD.

Methods

Search strategy

We updated our previous systematic review on cerebrovascular FMD, searching PubMed from January 1, 2018 to December 31, 2024 with (fibromuscular dysplasia (MeSH Terms)) OR (fibromuscular dysplasia (Text Word)) OR (fibromuscular dysplasia).⁸ We also searched Embase from January 1, 1974 to December 31, 2024 and Medline from January 1, 1946 to December 31, 2024 using the same key words. We identified additional studies by handsearching the bibliographies of relevant studies. We included articles describing at least one aspect of epidemiology, clinical characteristics, imaging features, management, or prognosis of cerebrovascular FMD in adults. We preferentially focused on studies including 15 patients or more. However, case reports or small case series describing noteworthy manifestations were eligible for inclusion. If there were multiple publications from one study cohort, we included the publication with the largest amount of data relevant to this review. The quality of evidence was rated according to the Oxford Centre for Evidence-based Medicine levels of evidence.⁹

We reported our study according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.¹⁰

Results

A total of 707 records were identified from the updated PubMed search, 4633 from the Embase search and 1560 from the Medline search, of which 96 were included after screening of full texts. Among the 96 included studies, 23 were also included in our previous systematic review. After handsearching bibliographies, another 23 additional studies were included. Therefore, a total of 119 studies were finally included in this systematic review (Figure 1 and Tables 1 and 2). Studies were mainly case series or retrospective studies and were therefore graded as having a low level of evidence (Table 3).

Figure 1.

PRISMA flow chart.¹⁰

Table 1.

Summary of the largest (⩾15 patients) cohorts of patients with cerebrovascular fibromuscular dysplasia.

Study^Ref	N patients	Mean (range or SD) age, years	Characteristics, %			Race/ethnicity (%)		Clinical presentation, % (non exclusive)							IC FMD, %
Study^Ref	N patients	Mean (range or SD) age, years	Females	Smoking	HTN	Race/ethnicity (%)	TIA	IS^a	ICH	SAH	CeAD^a	Asymptomatic^b	Tinnitus or bruit^c	Headaches^c	UIA	String of beads
Bender et al.¹²⁰	31	62 (46–89)	30	NR	NR	C (77), B (19), H (3)	NR	0	0	13	NR	87	NR	NR	100	90
Bonacina et al.⁸¹	103	46 (±12)	57	53	23	C (98)	7	71	NR	0	100	NR	6	49	14	NR
Boudin et al.⁹⁴	37	47 (NR)	85	NR	NR	NR	70	0	0	NR	14	16	NR	NR	NR	NR
Cloft et al.⁶⁷	117	60 (31–88)	92	NR	NR	NR	NR	NR	NR	16	NR	NR	NR	NR	24	NR
Collins et al.⁷⁷	18	60 (40–80)	100	NR	NR	NR	50	0	0	NR	44	39	NR	5.5	NR	NR
Corrin et al.⁹²	79	58 (18–76)	94	NR	29	NR	8	9	0	13	NR	61	8	NR	NR	0
Effeney et al.⁷³	76	58 (27–83)	97	NR	NR	NR	42	22	0	0	NR	6	23	NR	13	0
Ehrenfield and Wylie⁹⁰	20	52 (NR)	90	NR	NR	NR	35	35	0	9	NR	26	15	NR	NR	NR
Harriott et al.⁹	81	53 (±12)	96	49	68	NR	16	7	NR	4	35	NR	30	52	NR	NR
Houser et al.⁷⁰	52	NR (12–78)	94	NR	NR	NR	8	12	2	17	NR	25	0	NR	6	0
Kadian-Dodov et al.⁸⁵	146	52 (±11)	94	27	60	C (98)	16		NR	NR	17	NR	NR	NR	10	11
Kelly and Morris⁹⁶	40	NR (38–78)	85	NR	NR	NR	30	10	0	0	NR	NR	30	43	NR	NR
Kythreotou et al.¹⁸	86	64 (21–96)	91	NR	31	C (75)	63		NR	10	NR	13	16^d	16^d	10	NR
Liu et al.¹⁶	19	46 (32–64)	53	NR	NR	Asian	5	95	0	0	74	0	NR	16	5	16
Manelfe et al.⁹¹	70	54 (17–75)	74	NR	31	NR	13	41	NR	40	4	13	17	14	NR	83
Mettinger et al.⁷⁵	37	48 (24–70)	81	NR	NR	NR	11	8	8	49	NR	24	38	78	49	2.7
Moreau et al.⁹⁷	58	55 (20–76)	60	NR	25	NR	43		0	0	NR	53	NR	22	NR	NR
Osborn and Anderson⁷²	25	46 (4–71)	80	NR	NR	NR	40	24	0	32	NR	8	4	NR	30	20
Pappaccogli et al.²	171	NR	NR	NR	NR	C (88)	3	8	NR	3	NR	NR	NR	NR	NR	NR
Pasquini et al.⁷⁸	36	57	89	36	39	C	17	47	0	6	25	0	5.6	NR	6	25
Plouin et al.⁵/Arnaud et al.^86,e	165	54 (±12) (NR)	83	44	58	C (88)	22	35	NR	22	45	26	NR	44^f	71	NR
So et al.⁷⁴	32	57 (34–78)	100	NR	NR	NR	28	28	0	16	NR	16	13	NR	22	9
Stewart et al.⁷⁶	49	58 (29–82)	98	NR	NR	NR	35	27	NR	6	NR	42	6	4	8	NR
Talarowsa et al.⁸⁴	17	46 (±7)	82	41	71	NR	12	29	NR	NR	100	NR	18	53	12	NR
Wesen et al.⁹³	30	59 (20–77)	77	47	40	NR	53	10	0	3	NR	26	NR	NR	NR	NR

Patients with IS secondary to CeAD are included in both columns.

Incidental diagnosis of cerebrovascular FMD.

Symptoms reported at any time (where available).

Information not available separately for headache and tinnitus.

The studies by Plouin 2017 and Arnaud 2021 refer to the same population.

Migraine.

B, Black; C, Caucasian; CeAD, cervical artery dissection; H, Hispanic; HTN, hypertension; IC, intracranial; ICH, intracranial hemorrhage; IS, ischemic stroke; NR, not reported; SAH, subarachnoid hemorrhage; TIA, transient ischemic attack; UIA, unruptured intracranial aneurysm.

Table 2.

Summary of the largest (⩾5 patients) cohorts of patients with a symptomatic web, that is, web ipsilateral to the ischemic stroke or TIA.

Study^Ref.	N patients	Mean (range or SD) age, years	Population (%)	Characteristics, %			Race/ethnicity (%)	Location of the web	Secondary prevention treatment (%)	Follow-up
Study^Ref.	N patients	Mean (range or SD) age, years	Population (%)	Female	Smoking	HTN	Race/ethnicity (%)	Location of the web	Secondary prevention treatment (%)	Recurrent IS (%)	Mean (range) follow-up time, months
Brinster et al.¹¹³	52	49 (29–73)	IS (90), TIA (10)	60	40	62	AA (67)	ICA	Stent. (46), Surg. (54)	Stent./Surg.(0)	Stent./Surg.: 38
Choi et al.³⁷	7	50 (41–55)	IS	71	NR	NR		ICA	Surg. if recurrent stroke	71	NR
Compagne et al.⁵⁰	11	59 (46–67)	IS treated with mechanical thrombectomy	91	0	54	C	ICA	NR	NR	NR
Guglielmi et al.¹¹¹	30	57 (46–66)	IS	73	18	33	C	ICA	Antiplat. (77), Anticoag. (17), Surg. (3), Stent. (0)	17	24
Haussen et al.¹¹²/Haussen et al.^114,a	24	46 (41–59)	Undetermined IS (92) and TIA (8)	61	8	41	B (75)	ICA	Med. (34), Stent. (66)	Antiplat. (20),Stent. (0)	12.2 (2.4–12.0), Med.: 0.3, Stent.: 12 (3–19)
Hu et al.⁵¹	12	58	TIA	75	8	0	CH (100)	ICA	NR	Recurrent TIA (75)	3
Joux et al.⁴⁶	25	46 (±6.5)	IS with no other cause than the web	64	NR	NR	AC	ICA	Antiplat. (80),Surg. (20)	Antiplat. (30),Surg. (0)	25.3 (±19.5)
Joux et al.^49,b	10	47 (±7)	Young (<55 y) IS with no other cause than the web	NR	27	37	AC	ICA	NR	NR	NR
Kim et al.⁶³	9	43 (±7.5)	Young (<60 y) IS (95) and TIA (5)	44	22	22	NR	ICA	NR	NR	NR
Landzberg et al.⁵⁵	30	49 (±10)	TIA or IS	73	13	43	C (7), B (87)	ICA	NR	NR	NR
Mathew et al.⁵⁶	10	50(37–71)	IS with carotid web who had a recurrent ipsilateral stroke to the web	70	NR	NR	AA (70), H (20), C (1)	CIA	Stent. (90),Surg. (10)	0	5.5 (0–12)
Multon et al.¹¹⁵	11	42 (39–51)	IS (91) and TIA (9) who had carotid stent. or surg.	46	27	9	AC (82), C (18)	ICA	Stent./Surg. (100)	Stent./Surg. (0)	12
Olindo et al.⁶⁶	92	49 (26–72)	Incident TIA (14) and IS (86)	66	21	21	AC (91), C (9)	ICA	Med. (74)Surg./stent. (26)	Antiplat. (17), Anticoag. (2), Surg./Stent. (0), no treatment (1)	Med.: 36 (11–58),Surg./stent.: 39.8 (27.6–72.4)
Olindo et al.⁴⁸	202	51(±12)	TIA (7), IS (92)	63	63	19	C (48), AC (20)	ICA	Anticoag. (33)Antiplat. (28)Surg. (27)Stent. (73)	Antiplat. (1.5)Anticoag. (1)Stent. (0.5)Surg. (0)	3
Pereira et al.⁴²	19	50 (23–82)	TIA (22), IS (61)	53	NR	NR	C (88)	ICA (87), VA (13)	Surg. (9), Stent. (35), medical (57)	0	NR
Rzepka et al.⁵⁷	27	67 (±14)	IS and TIA who had carotid CTA	59	19	85	C	ICA	NR	NR	NR
Sajedi et al.⁶²	7	38 (30–41)	Cryptogenic IS	86	43	0	AA (86), C (14)	ICA	Med. (71), Surg. (29)	14	NR
Sharashidze et al.⁴⁷	66	51(42–57)	IS	74	20	52	B (83),C (8),H (6)		NR	NR	NR
Turpinat et al.⁵²	21	51 (±9.2)	Young (<65 y) IS	52	43	38	C (76), A (5), ME (14)	ICA	Antiplat. (4.5), Anticoag. (19), Stent. (67)	Med. (20),Stent. (0)	24 (4–55)Med.: NR,Stent.: 10.6 (0–36)
Wang et al.³⁹	41	50	IS who had carotid CTA	24	NR	61	A	ICA (63), CCA (29), VA (2), Subc. (5)	NR	NR	NR
Yu et al.⁵³	33	44(34–53)	IS	64	NR	NR	A	ICA	NR	NR	NR
Zelada-Rios et al.⁵⁸	5	40 (35–43)	IS	60	0	0	H	ICA	Antiplat. (100)	Antiplat. (0)	6

The studies by Haussen 2017 and Haussen 2018 refer to the same population.

The population was included in Joux 2014.

A, Asian; AA, African American; AC, AfroCaribbean; Anticoag., Anticoagulation; Antiplat., Antiplatelet; B, Black; C, Caucasian; CCA, common carotid artery; CH, Chinese; CTA, Computed Tomography Angiography; H, Hispanic; HTN, hypertension; ICA, internal carotid artery; IS, ischemic stroke; ME, Middle East; Med., medical treatment; NR, not reported; Sent., stenting; Subc., subclavian artery; Surg., surgery; TIA, transient ischemic attack; VA, vertebral artery.

Table 3.

Evidence level of studies evaluating the epidemiology, genetics, manifestations, management, and prognosis in of cerebrovascular fibromuscular dysplasia: summary of systematic review according to the Oxford Centre for Evidence-based Medicine.

Manuscript sections	Number of studies included by evidence level
FMD classification	- 3 level 3 studies^2,3,5 - 2 level 5 studies^11,12
Epidemiology	- 6 level 3 studies^{2–5,13,15,18} - 2 level 5 studies^8,7
Genetics	- 1 level 1 study²⁴ - 6 level 3 studies^{19,20,22,25,26,27} - 2 level 4 studies^21,23
Manifestations	- 3 level 1 studies^50,61,83 - 1 level 2 study¹¹¹ - 50 level 3 studies^{2,3,5,6,14,16,17,18,28,29,31,32,37,46,49,51,52,54,55,57,59,60,62,63,66,67,69,71-77,81,82,85,86,90,91,93-97,98,99,103} - 15 level 4 studies^{38,42,43,47,48,56,58,64,65,70,78,79,80,92,104} - 20 level 5 studies^{1,7,8,30,33–36,39,40,41,44,45,68,87–89,101,102,105}
Management	- 1 level 2 study¹¹¹ - 11 level 3 studies^{46,66,81,110,112–116,118,119} - 4 level 4 studies^{56,79,108,120} - 8 level 5 studies^{1,68,106,107,109,117,121,122}
Prognosis	- 4 level 3 studies^2–4,85 - 2 level 4 studies^70,78

Quality Rating Scheme for Studies and Other Evidence according to the Oxford Centre for Evidence-based Medicine.

Levels:

1.Properly powered and conducted randomized clinical trial; systematic review with meta-analysis.

2.Well-designed controlled trial without randomization; prospective comparative cohort trial.

3.Case–control studies; retrospective cohort study.

4.Case series with or without intervention; cross-sectional study.

5.Opinion of respected authorities; case reports.

FMD classification

The European consensus and the American Heart Association scientific statements on FMD have distinguished two forms of FMD: multifocal and focal. This classification is based on the imaging appearance of arterial lesions and replaced the previous histopathologic classification.^11,12 Multifocal FMD is defined as alternating arterial areas of dilatation and constriction (“string of beads” appearance), which are usually located in the middle or distal portion of the artery (Figure 2). Multifocal FMD is the most frequent subtype (90% of cases) and is most commonly due to medial fibroplasia. (2) Focal FMD is characterized by a unifocal (single) smooth concentric (defined as less than 1 cm in length) or tubular (1 cm or more) narrowing affecting any portion of the artery. Focal FMD is rarer (10% of cases) and generally linked to intimal or adventitial fibroplasia (Figure 2). Multifocal and focal lesions may coexist in the same patient. The presence of at least one focal or multifocal arterial lesion is required to establish the diagnosis of FMD. Half of the patients with FMD have multivessel involvement, defined as the presence of FMD lesions in at least two arteries (Figure 3).^2,3,5 FMD is primarily a stenotic disease but can also be associated with other arterial manifestations. However, the isolated presence of an arterial aneurysm, dissection, or tortuosity is insufficient to diagnose FMD if there are no concomitant focal or multifocal FMD lesions in another artery.

Figure 2.

Typical “string of beads” appearance in multifocal fibromuscular dysplasia. (a) Coronal view of a computed tomography angiography of the right internal carotid artery showing alternating arterial areas of dilatation and constriction, these called “string of beads” appearance (arrow) in a patient with fibromuscular dysplasia. (b) Conventional angiography of the left internal carotid artery showing a focal stenosis before the petrous segment (star) with the typical “string of beads” appearance adjacent to the stenosis (arrow) in the same patient.

Figure 3.

Arterial tortuosity in a patient with fibromuscular dysplasia. (a–d) Conventional angiography of the internal carotid artery showing areas of arterial tortuosity in patients with fibromuscular dysplasia.

FMD of extracranial arteries typically involves the medial layer of the vessel wall, while intracranial FMD predominantly affects the intima, and rarely medial fibroplasia, suggesting that the phenotype may vary by anatomical location in the cerebrovascular vasculature.

Epidemiology

The prevalence of cerebrovascular FMD in the general population is unknown. A study from the US using a healthcare system database reported a prevalence of FMD of 12.0 per 100,000 persons.⁴ Autopsic and angiographic case series reported a prevalence of FMD ranging between 0.3% and 3.2%.¹³

Cerebrovascular FMD predominantly affects women and is typically diagnosed around 50 years of age.^2,3,5,14,15 There is usually no family history of FMD, with less than 5% of patients reporting an affected family member.^3,5,7 Cerebrovascular FMD has been more often reported in Caucasian populations but all ethnicities can be affected.^{2,3,5,16–18}

Cerebrovascular FMD most frequently affects the cervical arteries: the carotid artery (often bilaterally) is reported to be involved in 95% and the vertebral artery (usually with co-involvement of the carotid artery) in 60%–85% of FMD patients.⁷ Cerebrovascular FMD typically involves the middle and distal portions of the internal carotid artery and the V3–V4 segment of vertebral arteries at the level of the C1 and C2 vertebrae.^7,18

Multisite involvement is frequent in patients with cerebrovascular FMD. Among the patients with FMD lesions in the cervical arteries in the US FMD registry, 64% had renal artery involvement.³ Similarly, among patients with a cerebrovascular presentation in the ARCADIA (Assessment of Renal and Cervical Artery Dysplasia) Registry, 56% had renal artery involvement.⁵

Genetics

Large-scale studies using low-density exome chip arrays have identified an intronic variant (rs9349379) on chromosome 6 in the phosphatase and actin regulator 1 (PHACTR1) gene (6p24) (GenBank 221692) as a first susceptibility locus for FMD, with an approximately 40% higher risk of FMD in individuals who carry the risk allele.^19,20 This same risk allele has previously been associated with migraine, cervical artery dissection, and spontaneous coronary artery dissection and has also been found to regulate the expression of endothelin-1, which has known physiologic effects on the systemic vasculature.²¹

Exome sequencing has identified loss-of-function variants in the prostaglandin I2 receptor gene (PTGIR) in FMD patients.²² A rare variant in the collagen type V alpha 1 chain (COL5A1) gene, c.1540G>A, p.(Gly514Ser) has also been associated with multifocal FMD, arterial dissections, aneurysms, and tortuosities.²³

More recently, a genome-wide association study meta-analysis of FMD has identified three other independent genetic risk loci: rs11172113 in LRP1, rs7301566 in LIMA1, and rs2681492 in ATP2B1.²⁴ The ATP2B1 variant was also associated with migraine and coronary artery dissection, while the LRP1 variant was also associated with cervical artery dissection, spontaneous coronary artery dissection, and migraine.²⁴

TGF-β signaling pathway has been recognized to play a putative pathophysiological role in FMD, as in other connective tissue disorders, such as Marfan and Loeys–Dietz syndromes.²⁵ Patients with FMD were found to have elevated plasma TGF-β1 and TGF-β2 and increased TGF-β1 and TGF-β2 secretion in dermal fibroblast cell lines compared to age- and sex-matched controls.²⁵ Another study identified a plasma proteomic signature including 37 plasma proteins and 10 lipid subclasses in patients with FMD compared to controls.²⁶ These findings were independently confirmed in a validation cohort, and this offers promising data to potential develop a blood-based test to diagnose FMD.²⁶ A case–control study identified an FMD-associated gene co-expression supernetwork, which brings further insight of the pathophysiology of FMD.²⁷

Manifestations

The epidemiology, clinical characteristics, and management of neurological manifestations of cerebrovascular FMD are summarized in Table 4.

Table 4.

Neurological manifestations, epidemiology, clinical characteristics, and management of cerebrovascular FMD.

Neurological manifestations	Epidemiology	Clinical characteristics	Management
Headache	Common in FMD patients (18%–75%), irrespective of the number of affected arterial bedsCan be preexistent to the diagnosis of FMD.May be more frequent in younger patients.May be the presenting symptom of FMD (8%–52%).	Secondary causes of headache in patients with FMD include cervical or intracranial dissection, TIA or ischemic stroke, ruptured or unruptured intracranial aneurysm, intracranial hemorrhage, and uncontrolled hypertensionFMD patients with headache tend to more frequently experience tinnitus(pulsatile and nonpulsatile), neck pain, cervical or intracranial artery dissection, TIA, stroke, and intracranial aneurysms than FMD patients with no headache.Headache can present with characteristics similar to primary headache disorders. The most commonly described phenotypes resemble migraine, tension-type headache, and trigeminal autonomic cephalgia.	Secondary causes of headache should be assessed, leading to appropriate care.For chronic headache with a migraine phenotype, no specific treatment exists for patients with FMD. A similar approach to the overall migraine population should be proposed, which includes lifestyle modification to avoid triggering factors and medications to abort or prevent migraine. Preventive therapies with antihypertensive medications such as beta-blockers and angiotensin receptor blockers may be particularly interesting in FMD patients that have co-morbid hypertension.
Pulsatile tinnitus	Frequent in FMD patient (22%–27%).May be the presenting symptom of FMD (17%–23%)May be more frequent in younger patients.	Pulsatile tinnitus is more prevalent in women, in cases with involvement of the cervical carotid artery, cervical artery dissection, and in patients with other neurovascular signs including headache, dizziness, and cervical bruit on exam.	Management may include education and sound or cognitive behavioral therapy. One should consider referring to an otolaryngologist to exclude other causes in patients with for severe pulsatile tinnitus.
Cervical (carotid or vertebral) artery dissection	Prevalence ranges between 7% and 17%May be the presenting symptom of FMD (12%)May be more frequent in younger patients with FMD	Male sex, age >50 years, history of migraine or hypertension, and involvement of ⩾3 vascular beds with FMD lesions have been identified as independent risk factors for presentation with cervical artery dissection in FMD.Cervical artery dissection is the main cause of TIA/ischemic stroke.	Symptomatic cervical artery dissection (i.e., TIA or ischemic stroke due to a cervical dissection)-Acute management:Intravenous thrombolysis and mechanical thrombectomy should be offered, unless contraindications are present.-Secondary prevention:Long-term single antiplatelet therapy should be pursued.Endovascular therapy with stenting may be considered in case of recurrent ischemic events despite antithrombotic therapy.Control of hypertension is paramount.Asymptomatic cervical artery dissection:Long-term single antiplatelet therapy should be used.There is no indication for endovascular treatment.Control of hypertension is paramount.
Intracranial aneurysm	Prevalence of 7%		Control of hypertension and smoking cessation are vital.Similar management of unruptured intracranial aneurysm should be offered in FMD patients as in the general population.Noninvasive follow-up imaging should be proposed to monitor the intracranial aneurysm growth. Surgical or endovascular treatment of an unruptured intracranial aneurysm should be discussed in case of risk factors for rupture, with the same indication as in patients without FMD. Endovascular treatment of intracranial aneurysm in FMD patients seems to be safe.There is no evidence to avoid antiplatelet therapy in patients with FMD and an unruptured intracranial aneurysm.
TIA and ischemic stroke	Prevalence of ischemic stroke of 7%–10%Prevalence of TIA of 5%–12%Ischemic stroke or TIA are mainly the presenting symptom of FMD (7%–8% and 3%–9%, respectively)	TIA and ischemic stroke are most frequently due to a cervical artery dissection with artery-to-artery thromboembolism or cerebral hypoperfusion. Other potential causes of TIA and ischemic stroke include cervical or intracranial arterial stenosis or occlusion, thrombosis in an area of stenosis or dilation or less frequently a lacunar stroke via thrombosis of small, perforating arteries, due to chronic hypertension secondary to the coexistence of renal FMD.	Control of hypertension is paramount-Acute management:Should be similar to that of patients without FMD. Acute recanalization therapies with intravenous thrombolysis and mechanical thrombectomy can be used in eligible patients.-Secondary prevention:Secondary prevention management does not differ from non-FMD patients.
Carotid web	Is the predominant form of FMD in Black populationsTypically affects young adults (between the 2nd and 4th decade), predominantly women, of African or Afro-Caribbean ethnicity, and with no atherosclerotic risk factors	The main clinical presentations of webs are ipsilateral TIA or ischemic stroke.The main mechanism of ischemia is embolic secondary to stasis upstream of the web. Webs are frequently related to the presence of an aneurysmal bulb (sometimes called megabulb), which may also contribute to the risk of cerebral thromboembolism	Asymptomatic carotid web:There is no specific follow-up or management to offer.Symptomatic carotid web (i.e., ischemic stroke ipsilateral to the web with no other cause)-Acute management:Should be similar to patients with no web-Secondary prevention:Long-term antiplatelet should be used.Consider carotid endarterectomy or stenting in case of recurrent ischemic events ipsilateral to the web despite medical management.
Intracerebral hemorrhage	Rare, data are scarce (0.01%)	Mainly occurs with rupture of an intracranial aneurysm, an intracranial dissection a spontaneous carotid-cavernous fistula, or in the presence of hypertensive microangiopathy	Acute management and secondary prevention of patients with FMD and intracerebral or subarachnoid hemorrhage should follow international guidelines, as in patients with no FMD.Control of hypertension is paramount to avoid recurrence.
Subarachnoid hemorrhage	Rare (2%–3%)	Primarily related to the rupture of an intracranial aneurysm and rarely to an intracranial dissection involving the vertebral artery	Acute management and secondary prevention of patients with FMD and intracerebral or subarachnoid hemorrhage should follow international guidelines, as in patients with no FMD.Control of hypertension and smoking cessation are paramount to avoid recurrence.

Consensus-based clinical recommendations have been summarized in the first international consensus statement on the diagnosis and management of FMD.¹

FMD, fibromuscular dysplasia; TIA, transient ischemic attack.

Cerebrovascular FMD is frequently asymptomatic and incidentally diagnosed on imaging performed for other indications or in the extension workup of other FMD locations.

The most common presenting symptoms of cerebrovascular FMD are headache (8%–52%) and pulsatile tinnitus (17%–23%).^2,3,7,28 Patients with FMD have a higher prevalence of cervical (carotid or vertebral) artery dissection (7%–17%) and intracranial saccular aneurysm (7%) compared to the general population.²⁹

The main complications of cerebrovascular FMD are, in decreasing order, ischemic stroke (7%–10%), transient ischemic attack (TIA, 5%–12%), subarachnoid hemorrhage (2%–3%), and intracerebral hemorrhage (0.01%).^1,2,8,18,30 The neurological manifestations of FMD may differ by age. In the US FMD registry, patients aged ⩾65 years at the time of FMD diagnosis (17% of all FMD patients) were less likely to have headache, pulsatile tinnitus, or arterial dissection.³¹ Older patients had more frequent extracranial carotid artery involvement than younger patients, while there was no difference in the involvement of intracranial arteries.³¹ The frequency of intracranial aneurysm, ischemic stroke, and subarachnoid hemorrhage did not differ between younger and older adult patients. Whether older patients have a more benign form of FMD than younger patients remains uncertain.

TIA and ischemic stroke

Ischemic stroke and TIA are not uncommon in patients with FMD and are usually the presenting symptoms of FMD.^1–3,5 A total of 7% and 8% of patients presented with ischemic stroke that led to the diagnosis of FMD, in the US and the European/International FMD registries, respectively.^2,3 TIA was the initial presentation in 9% and 3% of the patients in the US and the European/International FMD registries, respectively.^2,3 In all FMD patients, 7%–10% reported a history of ischemic stroke and 5%–12% of TIA.^1,5

TIA and ischemic stroke can be related to various mechanisms. They are most frequently due to a cervical artery dissection with artery-to-artery thromboembolism or cerebral hypoperfusion. Other potential mechanisms include cervical or intracranial arterial stenosis or occlusion (hypoperfusion resulting from hemodynamic mechanism), thrombosis in an area of stenosis or dilation (embolic mechanism), or a lacunar stroke via thrombosis of small, perforating arteries, due to chronic hypertension secondary to the coexistence of renal FMD.

Intracranial FMD most often corresponds to the extension of extracranial cervical FMD. Isolated intracranial FMD with a typical “string of beads” angiographic appearance in the basilar artery, distal internal carotid artery, and middle cerebral artery is less usual and has been suggested to be more common in children than in adults.^6,32

Cases of central retinal artery occlusion^33–35 and central retinal vein occlusion³⁶ in patients with FMD have also been published, with hypertension thought to play a role in the development of these two conditions.

Carotid web

Carotid webs or carotid bulb diaphragms are thin translucent endoluminal lesions that are located in the cervical carotid artery (more frequently on the posterolateral than the anterior side of the carotid bulb) and correspond on arterial imaging (conventional angiography, computed tomography (CT)- or magnetic resonance (MR)-angiography) to a shelf-like linear defect that does not change or disappear after modification of the patient’s head position (Figure 4).^37–39 Since the first description in 1968, an increasing number of cases of carotid web have been published.³⁸ Although less frequent than in the carotid artery, webs have also been described in the vertebral (V3 segment or ostium) and the basilar arteries.^40–45

Figure 4.

Carotid web. (a) Sagittal view of a CTA showing a web in the posterolateral side of the left carotid bulb (arrow) in a patient with an ipsilateral transient ischemic attack. (b) Axial view of a CTA showing the web in the same patient (arrow).

Webs share similar histologic findings with FMD. Intimal fibroplasia without atheromatous or inflammatory changes are described in almost all surgically resected webs.^7,46,47 Some patients with a carotid web have concomitant focal or multifocal FDM lesions in another artery.⁴⁷ Webs typically affect young adults that are between the second and fourth decade, predominantly women, people of African or Afro-Caribbean ethnicity, and with no atherosclerotic risk factors.^42,46,48 This entity is considered to be the predominant form of FMD in Black populations and has been classified as atypical FMD.⁴⁹ Although less frequent, cases have also been described in other populations, such as Caucasians, Asians, and Hispanics.^50–58 No cases of carotid web have been reported in studies of children with ischemic stroke and this suggests that web may not be congenital.⁵⁹

The main clinical presentations of webs are ipsilateral TIA or ischemic stroke. In the presence of ischemic symptoms, webs are classified as symptomatic. Case–control studies report a strong association between cryptogenic anterior circulation ischemic stroke and an ipsilateral carotid bulb web.^49,60–63 The main mechanism of ischemia in patients with symptomatic web is embolic, secondary to stasis upstream of the web. Webs are frequently related to the presence of an aneurysmal bulb (sometimes called megabulb), which may also contribute to the risk of cerebral thromboembolism.^64,65 Carotid webs do not seem to regress over time but their diagnosis may be more challenging at older age because of co-existing atherosclerosis.

The incidence of anterior circulation ischemic stroke with an ipsilateral carotid web and no other cause was 3.8 per 100,000 person-years in the only published population-based study, which involved a predominantly Afro-Caribbean population.⁴⁹ The prevalence of carotid webs in the general population is unknown. Carotid webs account for a low proportion of all ischemic strokes. In a systematic review of patients with a cryptogenic anterior circulation ischemic stroke, the prevalence of an ipsilateral carotid web ranged from 4% to 23%, with a higher prevalence in studies including greater proportions of Black individuals.⁶¹

Most asymptomatic carotid webs (i.e., with no history of ipsilateral carotid ischemic stroke) are identified in patients with a contralateral symptomatic carotid web. The prevalence of asymptomatic carotid webs ranges from 20% to 45% in patients with a contralateral symptomatic web.^48,66 The prognosis of asymptomatic carotid webs is not well understood, and long-term information is scarce. No ischemic events related to an asymptomatic carotid web were described in a study of patients with symptomatic carotid web after a median follow-up of 45 months.⁶⁶

Intracranial aneurysms

In patients with FMD, an intracranial aneurysm is the most common intracranial abnormality, with a prevalence (7%) that is higher than in the general population (<5%).⁶⁷ This justifies the recommendation that FMD patients should have at least one brain-to-pelvis imaging of the main arterial beds (by CT- or MR-angiography), regardless of the initially involved site(s).¹ Intracranial aneurysms in patients with FMD are most often unruptured and incidentally diagnosed rather than discovered after rupture.³⁰

In the US FMD registry, 13% of women with FMD had at least one intracranial aneurysm and 4% had multiple intracranial aneurysms. Interestingly, 29% of these aneurysms were ⩾5 mm, which is the threshold that is usually considered to classify intracranial aneurysms at a higher risk of rupture.⁶⁸ The prevalence of intracranial aneurysms did not vary between patients with renal and cervical FMD.⁶⁹ Other cohorts of cerebrovascular FDM patients reported a prevalence of intracranial aneurysm between 5% and 20%.^{16,18,70–78}

It remains uncertain whether the risk of rupture of intracranial aneurysm is higher in FMD patients than in the general population (estimated to be <1%/year). Data are lacking regarding potential predictors of intracranial aneurysm rupture in FMD patients.⁶⁸

Extracranial and intracranial dissection

In patients with a spontaneous cervical artery dissection, FMD is the most frequent underlying vasculopathy, with a prevalence between 8% and 20%.^79–84 FMD is more often found in the case of multiple or recurrent cervical artery dissections.^{79–81,83,84} Cervical arteries are the main location of arterial dissection in patients with FMD, accounting for up to 65% of all dissections.⁸⁵ The prevalence of cervical artery dissection is estimated to be between 7% and 17% in all patients with FMD.^5,29,85 The carotid arteries (16%) are involved more frequently than the vertebral arteries (5%).⁸⁵ The prevalence of cervical artery dissection is even higher (27%) in the subgroup of patients with a neurological presentation leading to the FMD diagnosis.⁵ Cervical artery dissection was the presenting symptom of FMD in 12% of FMD patients in the US registry.³

Among patients with FMD and a cervical artery dissection, the presence of multiple cervical artery dissections is not uncommon and estimated to be up to 37%.^3,29 Male sex, age >50 years, history of migraine or hypertension, and involvement of ⩾3 vascular beds with FMD lesions have been identified as independent risk factors for presentation with cervical artery dissection in patients with FMD.⁸⁶

Transient or recurrent headache is commonly the presenting symptom of cervical artery dissection in patients with and without FMD.

Intracranial dissection is rarer than cervical dissection in FMD patients and may be more frequent in children than in adults.⁸

Intracranial hemorrhage

Intracerebral hemorrhage remains rare in patients with FMD, and was the presenting manifestation in 0.01% of patients with FMD identified from a national inpatient sample database in the US (n = 2420).¹⁷ In two older cohort studies of patients with cerebrovascular FMD, intracerebral hemorrhage was the presenting manifestation in 2% (n = 52) and 8% (n = 37) of patients, respectively.^71,75 No information on intracerebral hemorrhage was reported in the US and the European/International FMD Registries. No patient presented with an intracerebral hemorrhage in the ARCADIA registry.⁵ Intracerebral hemorrhage mainly occurs due to rupture of an intracranial aneurysm, an intracranial dissection or a spontaneous carotid-cavernous fistula, or in the presence of hypertensive microangiopathy, although rare cases have been reported with no intracranial arterial abnormality.^7,87–89

Subarachnoid hemorrhage is more frequent than intracerebral hemorrhage in FMD and is primarily related to the rupture of an intracranial aneurysm and rarely to an intracranial dissection involving the vertebral artery (Figure 5).⁷ Subarachnoid hemorrhage was the presenting manifestation of FMD in 3% of patients in the European/International FMD Registry while 2% had a history of subarachnoid hemorrhage in the US FMD registry and 5% in the ARCADIA registry.^1,2,5 The prevalence of subarachnoid hemorrhage was between 6% and 8% in smaller contemporary cohorts^18,78 and ranged from 0% to 40% in older cohorts using conventional angiography.^90–97

Figure 5.

Aneurysmal subarachnoid hemorrhage in a patient with fibromuscular dysplasia. (a) Coronal view of a plain CT showing subarachnoid hemorrhage. (b) Coronal view of a CT angiography after contrast enhancement in the same patient harboring an intracranial aneurysm in the left middle cerebral artery. (c) 3D reconstruction of the aneurysm in the left middle cerebral artery (arrow).

Headache

Headache is a commonly described symptom (18%–75%) in patients with FMD, irrespective of the number of affected arterial beds.^{1–3,5,98,99} Headache can preexist the diagnosis of FMD or may be the first presenting symptom leading to the diagnosis of cerebrovascular FMD, as reported in 52% and in 8% of all patients with FMD in the US and the European/International FMD registries, respectively.^2,3

The International Classification of Headache Disorders 3rd edition does not include FMD under “headaches attributed to a cranial or cervical vascular disorder,” although a dissection- or stroke-related headache would fall under this category.¹⁰⁰ Secondary causes of headache in patients with cerebrovascular FMD include cervical or intracranial dissection, TIA or ischemic stroke, ruptured or unruptured intracranial aneurysm, and intracranial hemorrhage.⁸ Headache may also occur in patients with FMD in the absence of cranial or cervical arterial lesions.^2,3,101,102 Another common cause of headache is uncontrolled hypertension, in particular in the presence of FMD lesions in the renal artery.⁸

Headache can present with characteristics similar to primary headache disorders. The most commonly described phenotypes resemble migraine, tension-type headache, and trigeminal autonomic cephalgia.^{3,5,99,103,104}

FMD patients with headache tend to more frequently experience tinnitus (pulsatile and nonpulsatile), neck pain, cervical or intracranial artery dissection, TIA, stroke, and intracranial aneurysms than FMD patients with no headache.⁹⁹ The underlying pathophysiologic mechanisms of headache in FMD are not well established. Various mechanisms have been proposed, including alterations in cerebrovascular flow (e.g., labile hypertension, hyperperfusion, or hypoperfusion), neurovascular dysregulation or dysautonomia, structural injury (e.g., dissection or microtrauma), or heightened sensitivity to pain.^7,12

Tinnitus

Pulsatile tinnitus, defined as a swooshing/whooshing sound timed to the heartbeat, is observed in 22%–27% of patients with FMD.^1,3 Pulsatile tinnitus was reported as the presenting symptom leading to the diagnosis of cerebrovascular FMD in 23% and 17% of all patients with FMD in the US and the European/International FMD registries.^2,28 Pulsatile tinnitus is more prevalent in women, in cases with involvement of the cervical carotid artery or cervical artery dissection and in patients with other neurovascular signs including headache, dizziness, and cervical bruit heard on exam.^3,28,99

Cerebrovascular FMD in children

The epidemiology, clinical presentation, and radiological aspects of cerebrovascular FMD in children differ from adults.¹⁰⁵

The extracranial arteries are less usually involved in children with FMD than in adults while lesions of intracranial arteries are more common in children than in adults.^6,7 Cerebrovascular FMD can affect children, of all ages, from the neonatal period to adolescence, with a predominance in girls.¹⁰⁵ Cases of pediatric cerebrovascular FMD have been reported in children of various ethnicities. Children have a higher proportion of family history of FMD or other genetic arteriopathies compared to adults.

Focal and multifocal FMD have been described, with intima fibroplasia as the typical histopathological appearance. The presence of intracranial aneurysms is also rarer in children than in adults.

The prevalence of stroke in patients with cerebrovascular FMD is lower in children than in adults, ranging from 0% to 3%.

Management of cerebrovascular FMD

In the absence of randomized trials, the management of cerebrovascular FMD mainly relies on observational data and expert opinion. Consensus-based clinical recommendations have been summarized in the first international consensus statement on the diagnosis and management of FMD.¹

General considerations

Regardless of the initial site of arterial involvement, patients with FMD should undergo at least one brain-to-pelvis imaging with CT- or MR-angiography to identify other areas of FMD, as well as occult arterial aneurysm and dissection, especially unruptured intracranial aneurysm. The ideal frequency of follow-up imaging in patients without detected aneurysm remains unknown.

In the absence of contraindication, the initiation of a single antiplatelet therapy is reasonable for patients with symptomatic and asymptomatic cerebrovascular FMD, including unruptured intracranial aneurysm or asymptomatic extracranial dissection, in order to potentially prevent thromboembolic complications. Low-dose aspirin (i.e., 75–100 mg daily) is the most prescribed antiplatelet by FMD practicians, although no trial has assessed the benefit of aspirin to no treatment or compared different antiplatelet agents in FMD patients.

Control of hypertension is paramount in patients with cerebrovascular FMD, especially in those with an intracranial aneurysm, arterial dissection, ischemic stroke, and intracranial hemorrhage.

Tobacco abstinence should be strongly encouraged to reduce the risk of development and rupture of an intracranial aneurysm, among other benefits.

Statins are not routinely recommended in FMD patients, unless patients have other indications such as hyperlipidemia or concomitant atherosclerosis.

There is no evidence to suggest that exogenous hormone therapies (e.g., oral contraceptive pills or hormone replacement therapy) should be avoided in women with FMD in the absence of ischemic stroke or TIA.

Patients with cerebrovascular FMD should be seen in follow-up at least annually for clinical assessment. The modality and frequency of follow-up imaging should be tailored to each patient’s disease.

In view of their increased risk of incident and recurrent cervical artery dissection, patients with FMD should avoid high-risk activities known to be associated with cervical arterial dissection, such as cervical manipulative therapy and roller coaster rides.^81,106

There are no data to guide physical activity in FMD patients. However, as in the general population, reducing sedentary behavior should be promoted and aerobic exercises may be encouraged.¹⁰⁷

A cross-sectional study of patients from the US FMD registry (80% of whom having cerebrovascular FMD) showed that migraine, pulsatile tinnitus, or history of stroke or TIA was associated with lower quality of life, poorer self-rated health, anxiety, and depression. These findings strongly encourage physicians to screen for and take care of comorbid mental health conditions to address these unmet patient needs.¹⁰⁸

Headache

Secondary causes of headache should be assessed, leading to appropriate care.

For chronic headache with a migraine phenotype, there are no treatments that are specific to patients with FMD. A similar approach to the overall migraine population should be proposed, which includes lifestyle modification to avoid triggering factors and medications to abort or prevent migraine. Preventive therapies with antihypertensive medications such as beta-blockers and angiotensin receptor blockers may be particularly interesting in FMD patients that have co-morbid hypertension.

Pulsatile tinnitus

The impact of pulsatile tinnitus on quality of life may vary between patients. Management may include education and sound or cognitive behavioral therapy. For patients with severe pulsatile tinnitus, evaluation by an otolaryngologist is suggested to exclude other causes.¹

TIA or ischemic stroke

In FMD patients with TIA or ischemic stroke, acute management should be similar to that of patients without FMD.¹⁰⁹ Acute recanalization therapies with intravenous thrombolysis and mechanical thrombectomy should be used in eligible patients. Similarly, secondary prevention after TIA or ischemic stroke does not differ from patients without FMD.¹⁰⁶

Cervical artery dissection

In patients with TIA or ischemic stroke due to a cervical (extracranial) carotid or vertebral arterial dissection, intravenous thrombolysis and mechanical thrombectomy should be offered, unless contraindications are present.¹⁰⁹ For the initial weeks after the event, the use of an antiplatelet agent is preferred in most cases; as anticoagulation does not reduce the risk of recurrent ischemic events while increasing the risk of bleeding compared to antiplatelet therapy.^106,110 Endovascular therapy with stenting may be considered in case of recurrent ischemic events despite antithrombotic therapy. The procedure should be done with caution, although it remains unclear whether the risk of iatrogenic arterial injury during endovascular procedures, such as dissection or aneurysm, is increased in patients with FMD. The presence of a dissecting aneurysm or a residual stenosis following a dissection rarely requires endovascular management and should be treated with an antiplatelet agent. For secondary prevention after TIA or ischemic stroke due to a cervical arterial dissection, long-term single antiplatelet therapy should be pursued in patients with FMD.

FMD patients with an asymptomatic cervical carotid or vertebral dissection should be treated with long-term antiplatelet therapy, with no indication for endovascular treatment.

Carotid web

The optimal management of a symptomatic web, that is, ischemic stroke ipsilateral to the web with no other cause, is uncertain. Most of the available observational studies concern carotid web. Acute management (IV thrombolysis, mechanical thrombectomy, antiplatelet agent) of patients with an ischemic stroke or TIA due to an ipsilateral web should be similar to patients with no web.¹⁰⁹ For secondary prevention of stroke in patients with a symptomatic carotid web and no other identified cause despite comprehensive work-up, the American Stroke Association recommends medical treatment with antiplatelet therapy and suggests to consider carotid endarterectomy or stenting in case of recurrent ischemic events ipsilateral to the web despite medical management.¹⁰⁶ Long-term anticoagulation is not recommended because of the increased bleeding risk. The risk of recurrent ischemic stroke in the same territory after a TIA/ischemic stroke ipsilateral to the carotid web appears to be high in the largest published cohorts of patients treated with antiplatelet therapy, reaching approximately 10% at 1 year and 20% at 2 years.^66,111 Male sex and the presence of a covert ipsilateral infarct have been reported to be associated with the risk of recurrent ischemic events.⁶⁶ The largest cohorts of patients with symptomatic carotid web treated with stenting or endarterectomy reported no recurrent stroke, although one cannot exclude the potential for bias in these studies.^{46,56,111–116} For this reason, the European Society for Vascular Surgery stated that carotid endarterectomy or stenting may be considered to prevent recurrent stroke in symptomatic patients with a carotid web in whom no other cause for stroke can be identified after detailed neurovascular work up (class IIb recommendation).¹¹⁷

Unruptured intracranial aneurysm

The annual risk of rupture of an unruptured intracranial aneurysm is considered to be <1% in the general population and it is unknown whether patients with FMD have an increased risk of rupture.⁶⁸ Similar management of unruptured intracranial aneurysm should be offered in FMD patients as in the general population. Practicians should insist on the need to carefully control the risk factors for the development and rupture of an intracranial aneurysm, especially tobacco smoking and hypertension.^79,118,119 As in non-FMD patients, non-invasive follow-up imaging should be proposed to monitor for aneurysmal growth. Surgical or endovascular treatment of an unruptured intracranial aneurysm should be discussed in patients with risk factors for rupture, with the same indication for treatment as in patients without FMD.⁶⁸ Endovascular treatment of intracranial aneurysm in FMD patients seems to be safe. In a cohort of 31 FMD patients with intracranial aneurysm who underwent endovascular embolization, all but one procedure was successful.¹²⁰ Of note, the average aneurysm size was 7 mm, and most aneurysms were incidentally diagnosed.

There is no evidence to suggest that antiplatelet therapy should be avoided in patients with FMD and an unruptured intracranial aneurysm.⁶⁸

Intracranial hemorrhage

Acute management of patients with FMD and intracerebral or subarachnoid hemorrhage should follow the international guidelines, as in patients with no FMD.^121,122

Prognosis

Data on the long-term prognosis of FMD remain sparse. Patients with cerebrovascular FMD do not seem to be at a high risk of FMD progression or of new FMD associated lesions (aneurysm, dissection, etc.).^70,78,85 In the largest prospective cohort study of patients with cerebrovascular FMD (n = 146), imaging findings remained stable after a mean follow-up of nearly 3 years.⁸⁵ None of the patients developed new FMD lesions in a previously uninvolved artery, and none had FMD progression in a previously affected artery over time. Similarly, none of the patients developed a new aneurysm. Three (2%) patients experienced a new cervical artery dissection during follow-up, all of which occurred in areas of previously identified multifocal FMD. Only one patient had a new ischemic stroke during follow-up, which was unrelated to FMD (the cause being intracranial atherosclerosis).⁸⁵

The risk of TIA or ischemic stroke in patients with cerebrovascular FMD ranges from 0.2% to 2.3%/year and the risk of intracerebral hemorrhage is even rarer from 0% to 0.8%/year in the largest cohorts with long-term follow-up (mean duration follow-up between 2.4 and 3.5 years).^70,78,85 The two main causes of TIA or ischemic stroke in FMD patients are cervical artery dissection followed by atherosclerosis.^70,78,85 This highlights the need to better control traditional modifiable vascular risk factors in FMD patients, in particular tobacco smoking and arterial hypertension.^2–4

Conclusion

Although often asymptomatic, cerebrovascular FMD can lead to a wide range of complications including cervical artery dissection, ischemic stroke, intracerebral hemorrhage, and intracranial aneurysm. Adequate diagnosis, management, and follow-up are paramount in FMD patients. This justifies the need to raise awareness and increase knowledge about this condition among the general population, patients, and clinicians.

Limitations

Our study has some limitations. We minimized the potential for selection bias by including studies with a sample size of 15 or more and preferentially reported information from FMD registries. However, we also included case reports or small case series describing interesting or noteworthy manifestations. Most included studies were cohort studies or case series, with a low level of evidence. Nevertheless, FMD remains a relatively rare disease, which is usually diagnosed and managed in tertiary reference centers.

Key recommendations

The implications of this study for clinical practice are that cerebrovascular FMD should be suspected in case of unruptured intracranial aneurysm, recurrent or multiple cervical artery dissection, or ischemic cerebrovascular events, especially in young females with no atherosclerotic risk factors. The consensus-based recommendations summarized in the first international consensus statement on the diagnosis and management of FMD patients are helpful to guide clinicians and harmonize practices. Imaging of all arteries from brain to pelvis should be done at least once in FMD patients, to detect asymptomatic lesions that may require follow-up or intervention. Antiplatelet therapy is reasonable for patients with cerebrovascular FMD to potentially prevent thromboembolic complications. Endovascular treatment should be discussed in patients with risk factors for rupture of an unruptured intracranial aneurysm and in cases with recurrent ischemic events despite medical management.

Existing cross-sectional studies have improved our understanding of the manifestations of cerebrovascular FMD. However, knowledge gaps remain regarding the genetics, pathophysiology, management, and prognosis of cerebrovascular FMD, which should be addressed in future research. Randomized controlled trials would provide the best evidence to determine the optimal preventive and symptomatic management of FMD patients. However, such trials would be challenging given the relatively low prevalence of FMD and the low rate of vascular events in this population. Therefore, international research collaborations with enrolment of patients in the existing FMD registries and implementation of new cohorts in uncovered areas should be promoted to continue to improve our knowledge of this potentially disabling disease. In addition, reference to patient associations should be promoted to better determine the unmet needs of FMD patients and future patient-centered research priorities.

Footnotes

Appendix

Acknowledgements

We are grateful to all the staff and patients involved in the FMD registries.

Declarations

ORCID iDs

Marion Boulanger

Ahmad Nehme

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