Clinical manifestations

Presentation and course

Neurologic symptoms are rare in patients with isolated fibromuscular dysplasia. The most common complaints are nonspecific, including headaches (in 90% of reported cases), vertigo, pulsatile tinnitus, sudden hearing loss (42), altered mentation, neck pain, and syncope (51). Transient ischemic attack, stroke, retinal artery occlusion, or subarachnoid hemorrhage may develop (63; 14; 54; 70; 01; 37; 17). Isolated hemianopsia may result from internal carotid artery involvement and distal embolization via posterior communicating artery (65; 46). Isolated posterior cerebral artery involvement has also been reported (86).

Prognosis and complications

Information about the natural history of cephalic fibromuscular dysplasia is scant, although reviews have summarized the condition (36; 82). Transient ischemic attack and stroke are rare complications (37). In a large retrospective study of 79 patients with cerebrovascular fibromuscular dysplasia, only a single untreated patient developed a stroke in the same vascular territory as the fibromuscular dysplasia lesion, at the age of 71 and 216 months after the diagnosis (14). However, in selected studies of fibromuscular dysplasia, transient ischemic attack, stroke, and subarachnoid hemorrhage have been observed in up to one third of persons. Underlying fibromuscular dysplasia-related arterial disease has been reported in up to 20% of cervical carotid dissections (32), and it may account for a large number of "spontaneous" arterial dissections (67). The clinical manifestations of stroke or transient ischemic attack in fibromuscular dysplasia are dependent on the specific arteries involved and the underlying mechanisms. For example, symptoms of ischemic stroke may be related to an occlusion of a major cephalic artery secondary to a dissection or an embolus arising from small intravascular thrombi in the stenosis or saccular aneurysm formed by the fibromuscular dysplasia. Multisite involvement has been associated with relatively higher morbidity and mortality (62). Cerebral infarction may also arise from a compromised distal cerebral blood flow during global hypoperfusion. Recurrent transient ischemic attacks due to hypoperfusion may also occur (24). Distal embolic events may also include retinal artery occlusion (70). Recurrence of cervicocephalic arterial dissection is relatively rare, and the presence of an underlying arteriopathy such as fibromuscular dysplasia may explain recurrent manifestations (05).

Intracranial aneurysms in association with cerebrovascular fibromuscular dysplasia have been reported in 21% to 51% of affected patients (32), although a metaanalysis estimated an incidence of about 7% (11). These aneurysms are in the same vascular locations as those found in patients without fibromuscular dysplasia, and they can lead to subarachnoid hemorrhage (17). Associated basilar aneurysms are exceptionally rare but have been reported (38; 66). Giant aneurysms associated with fibromuscular dysplasia preferentially occur in the extracranial carotid arteries, usually at the high cervical region (C2-C3), and in the same vascular territory as the artery most affected by fibromuscular dysplasia (08). These aneurysms have been shown to cause thromboembolic strokes as well as compressive syndromes (eg, Horner or Collet-Sicard syndromes) (48).

Clinical vignette

A 60-year-old woman presented with history of pulsatile tinnitus in the right ear, vague visual disturbance on the right, and numbness of the left arm. Her examination was remarkable for a loud right carotid bruit. Laboratory data were unremarkable. A carotid duplex scan showed 70% stenosis of the right carotid artery. Cerebral angiogram revealed fibromuscular hyperplasia of both internal carotid arteries at C2 and C3 levels, but worse on the right. The patient underwent graduated intraluminal dilatation of the right carotid artery and did well postoperatively.

Biological basis

Etiology and pathogenesis

The etiology of fibromuscular dysplasia is not known. Several causes have been hypothesized, including congenital or inherited disorder, immunologic or humoral disturbance, ischemic or mechanical injury, or a viral etiology.

The occurrence of families with several members afflicted by fibromuscular dysplasia (22) supports the congenital inherited disorder hypothesis. Only recently has the first genetic locus been linked with fibromuscular dysplasia (16). The phosphatase and actin regulator 1 gene (PHACTR1) may influence transcription activity of the endothelin-1 gene (EDN1) located nearby on chromosome 6. Additionally, the PHACTR1 locus has also been associated with vascular hypertrophy, carotid dissection, migraine, and coronary artery disease (16). A formal pedigree analysis conducted in 20 families revealed vertical transmission of the disease afflicting both sexes. This inheritance pattern was most consistent with an autosomal dominant trait with variable penetrance (68). Cephalic fibromuscular dysplasia has also been observed in a few patients with genetic deficiency of alpha-1 antitrypsin (71). Alpha-1 antitrypsin is an inhibitor of proteolytic enzymes. Its deficiency has been linked to the degradation of connective tissues in various organs, including the arterial wall. Young patients with this condition have been reported to harbor fusiform aneurysms associated with fibromuscular dysplasia of intimal type (72). In addition, the typical anatomic distribution of fibromuscular dysplasia (the cervical internal carotid artery and renal artery) and the frequent coexistence with other somatic malformations (eg, scoliosis and other visceroskeletal abnormalities, cystic medial necrosis, coarctation of aorta, and Ehlers-Danlos syndrome type IV) suggest the possibility of a common mesenchymal disorder (51; 21; 49; 48). Familial fibromuscular dysplasia has been described in association with brachydactyly, syndactyly, cardiac abnormalities, and osteogenesis imperfecta (23; 80).

Fibromuscular dysplasia has a higher incidence in young women, and observational studies have linked it to oral contraceptive use; this suggests a hormonal influence. For example, in a radiologic study of women with a transient ischemic attack or stroke while taking oral contraception, 18% of the patients had radiologic features consistent with fibromuscular dysplasia (26). Other studies have shown similar abnormalities in young women who had ergotamine toxicity or chronic use of methysergide during treatment of migraine headaches (48; 32). An association between migraine and cervicocephalic arterial dissection has been revisited, suggesting that migrainous events may be secondary to abnormalities in the arterial wall and its extracellular matrix (83). Proponents of an ischemic or mechanical injury theory argue that the abnormalities seen in fibromuscular dysplasia may be explained by recurrent mechanical or thrombotic obliteration of the vaso vasorum from repeated microtrauma, leading to mural ischemia and subsequent cell mutation (48). A viral etiology has been postulated because of similar vessel wall abnormalities seen with Rubella syndrome and a disease of viral origin found in domestic turkeys that is similar to fibromuscular dysplasia (47).

The histologic features of fibromuscular dysplasia are well delineated. A pathologic classification of fibromuscular dysplasia first proposed by McCormack and colleagues (50) was subsequently revised by Stanley and colleagues (78). The 3 main types of fibromuscular dysplasia are (1) medial fibromuscular dysplasia, (2) intimal fibroplasia, and (3) periarterial or periadventitial fibroplasia. The most common type is medial fibromuscular dysplasia, seen in over 90% of cases (32). Microscopically, these lesions appear as multifocal thickened fibromuscular ridges alternating with areas of pronounced thinning of vascular wall. Radiographically, these lesions appear as the classic "string-of-beads" stenoses that often affect the internal carotid arteries at levels C1 and C2, usually 2 or more centimeters beyond the bifurcation (59; 76). However, cases of proximal internal carotid artery web may also result from medial fibromuscular dysplasia (54; 41; 10; 29). Choi and colleagues suggest that such carotid webs diagnosed by CT angiography may be ascribed to intimal fibroplasia (10). The latter abnormality may have a higher propensity to cause neurologic complications. The second most common type, intimal fibroplasia, accounts for approximately 1% to 5% of lesions (32). It is characterized by circumferential or eccentric accumulation of fibrous tissue in the intima. In contrast to other vascular diseases involving the intima, there are no inflammatory or lipid components, and necrosis and calcification are absent. The angiographic correlates of intimal fibroplasia are a tubular stenosis or smooth focal stenosis. The least common type of fibromuscular dysplasia is periarterial or periadventitial fibroplasia, present in only 1% to 2% of cases (32). Microscopic observations include collagen encompassing the adventitia and extending into surrounding tissue with or without lymphocytes or plasma cell infiltration.

Epidemiology

The incidence of fibromuscular dysplasia is about 1% in routine autopsies, and cephalic fibromuscular dysplasia makes up about 0.25% to 0.77% (33; 69). In angiographic series, the frequency of fibromuscular dysplasia is similarly low. In a review of 13,955 cerebral angiograms, the incidence of fibromuscular dysplasia was 0.6% (a total of 82 cases); only 14% (13 cases) of those with fibromuscular dysplasia underwent angiography because of transient ischemic attack or stroke symptoms (14). Fibromuscular dysplasia is most common in Caucasian young women, who account for approximately 85% of all cases. The mean age of reported cephalic fibromuscular dysplasia is approximately 50 years. Symptomatic cephalic fibromuscular dysplasia has been observed in children (64; 85; 39), including 1 child who sustained a left thalamic infarct following a judo lesson due to vertebral artery dissection complicating fibromuscular dysplasia (43). Fibromuscular dysplasia of the vertebral arteries leading to stroke in a 3-year-old has also been described (09). Establishment of a registry aids future studies of fibromuscular dysplasia (57; 58; 12). An ongoing registry of fibromuscular dysplasia may provide much data on cerebrovascular manifestations, initially reported to be as common as renovascular disorders (55). Registry data suggest that in patients with fibromuscular dysplasia, male sex, and multisite involvement are associated with cervical artery dissection, in addition to other previously known risk factors (02). These initiatives are important due to the many unknowns regarding fibromuscular dysplasia (56). The Massachusetts General Hospital experience described 81 subjects over a 4-year period, and, interestingly, only 1 patient had a cerebrovascular event of transient ischemic attack as there were no strokes in their series (27).

Prevention

No specific methods of preventing fibromuscular dysplasia are known. Prevention of complications may involve management of known or suspected risk factors for stroke (eg, hypertension, atrial fibrillation, smoking, and use of birth control pills).

Differential diagnosis

The differential diagnosis includes atherosclerosis, arterial dissection, Takayasu arteritis, granulomatous angiitis, segmental mediolytic arteriopathy, stationary arterial waves, and vascular spastic contractions (32). Unlike fibromuscular dysplasia, atherosclerotic lesions usually afflict the aorta and the proximal 1 cm to 2 cm of the internal carotid artery or the origin of the arch vessels. However, atherosclerosis may coexist with fibromuscular dysplasia in up to 35% of the cases, making it difficult to implicate fibromuscular dysplasia as the cause of neurologic complication. Takayasu arteritis has a propensity to affect young women, and typically damages the aortic arch and the origin to proximal segments of its major branches. Granulomatous angitis is seen in medium-sized arteries and precapillary arterioles. Although this disease may have similar "string-of-beads" appearance on angiography, its clinical presentation is more detrimental, with relatively rapid progression leading frequently to death within 1 to 2 years. A similarly poor outcome is seen in segmental mediolytic arteriopathy. This rare disorder is a subacute mucoid degeneration of the arterial media in young adults. Unlike fibromuscular dysplasia, there is less predilection for systemic vessels other than the aorta and cephalic vasculature (45). Stationary arterial waves are short, regular distal arterial constrictions, followed by areas of apparent dilatation seen as a result of elevated intracranial pressure or subarachnoid hemorrhage (69). Circular spastic contractions may cause arterial narrowing not only in the cervical internal carotid artery but also near the origin of the vessel. These contractions usually occur at the site of arterial catheterization; the site of the abnormality changes with each injection of contrast media during angiography (69).

Diagnostic workup

The evaluation of symptomatic subjects should focus on identifying more common causes of cerebrovascular insults, such as atherosclerotic lesions, cardiac abnormalities, or alteration of hematologic or coagulation status. In patients with transient ischemic attack or ischemic stroke, a head CT or MRI and carotid and cardiac noninvasive evaluation (eg, transthoracic echocardiogram, transesophageal echocardiogram, 24-hour Holter monitor, and cardiac stress test) are indicated. The yield of carotid duplex ultrasonography may be limited due to proximity of the typical vascular lesion with the skull base. Color Doppler imaging has been used for lesion detection, yet the sensitivity remains low due to lesion location (03). Angiography remains the standard test in patients with suspected extracranial or intracranial arterial disease, including fibromuscular dysplasia. MRI and MR angiography techniques are now able to differentiate tubular fibromuscular dysplasia from arterial dissection or arterial hypoplasia (20).

Conventional angiography or noninvasive studies (such as CT angiography or MR angiography) of the intracranial circulation should be performed in all patients with cervicocephalic fibromuscular dysplasia to rule out an intracranial aneurysm. MR angiography of the renal vessels may be obtained to support a diagnosis of suspected cervicocephalic fibromuscular dysplasia.

Management

Because the natural history of fibromuscular dysplasia is relatively benign in most patients, treatment is reserved for those who have experienced focal ischemic neurologic deficits, or for those with symptomatic or asymptomatic aneurysms. If fibromuscular dysplasia is the likely cause of the patient's neurologic syndrome, medical therapy with either antiplatelet agents or anticoagulants is warranted. Surgical treatment is usually indicated for intracranial or extracranial aneurysms associated with fibromuscular dysplasia (08). Surgical or endovascular therapy for stenosis secondary to fibromuscular dysplasia includes angioplasty and stenting, endarterectomy, extracranial-intracranial bypass, surgical resection, and graduated intraluminal dilatation. Carotid pseudoaneurysms, or dissecting aneurysms, associated with fibromuscular dysplasia have also been treated with deployment of stent-grafts (40). The efficacy and safety of these surgical treatments remain controversial (81). Moreau and colleagues reported long-term surgical results in 58 subjects who underwent a total of 72 operations for symptomatic cephalic fibromuscular dysplasia; 1 patient had a perioperative stroke, 1 had a transient ischemic attack, and 12 had transient cranial neuropathies (53). Subsequent follow-up revealed 1 death from recurrent stroke and 2 asymptomatic carotid occlusions despite resection-anastomosis procedures. Surgical treatment for fibromuscular dysplasia, therefore, should be reserved for individuals who have failed medical therapy without other known causes for cerebrovascular events.

Special considerations

Pregnancy

Although fibromuscular dysplasia has a higher frequency in young women, its effects in pregnancy and vice versa are not well known. Ezra and colleagues reported a case of cephalic fibromuscular dysplasia complicating pregnancy in a 24-year-old woman (18). The patient suffered a right hemiparesis and paresthesia in the 39th week of gestation despite prophylactic treatment. Following an uncomplicated delivery by cesarean section, the patient had a residual right-hand weakness, but otherwise she had a normal neurologic exam. Although the mechanism of this patient's stroke was not determined, the authors recommended prophylaxis with antiplatelet agents in women with symptomatic fibromuscular dysplasia during pregnancy. There is no reference in the literature regarding maternal versus fetal risk with or without treatment in patients with fibromuscular dysplasia.