Introduction

Fibromuscular dysplasia (FMD) is classified as a nonatherosclerotic, noninflammatory vascular disease. Anomalies are frequently seen in the renal, carotid, and vertebral arteries. To a lesser extent, the visceral arteries and arteries of the extremities may be affected [₁₂₃₄₅]. FMD lesions weaken arterial walls and predispose the craniocervical arteries to dissection. This disease is a predisposing factor in 10-20% of carotid artery dissections [₁].

FMD primarily affects women of child-bearing age, and occurs up to four times as often in women than in men [₄]. Clinically, researchers are considering whether hormonal factors are involved [₄₅]. However, current research is limited and samples are small, leading to no conclusive causative links to the disease. Diagnosis to date has typically been made by the classic angiographic finding of the “string of beads”

(Figure 1) [₁₂₃₄]. Although rarely attained, the pathologic specimen is diagnostic [₁₄].

Clinical Manifestations of Cerebrovascular Fibromuscular Dysplasia

Clinical manifestations of symptoms are determined by the arteries affected and the cerebral territory the vessels supply. Hypertension can be attributed to the renal artery (RA), while facial palsies, Horner’s Syndrome, and transient ischemic attacks (TIAs) can be attributed to either the carotid artery (CA) or vertebral artery (VA) [₂]. For a detailed classification of symptoms based on the vascular territories affected after an ischemic or hemorrhagic stroke refer to Table 1 [₆].

Figure 1

Table 1: Cerebral Territories and Stroke Related Symptoms

To further complicate the clinical presentation, 26% of these patients will have the disease diagnosed in more than one vascular bed [₄]. Clinicians must be aware that symptoms alone may not provide adequate guidance in the diagnosis of FMD. Past medical history and unusual symptoms for an age group, accompanied with laboratory and angiographic images, will assist in the diagnosis.

Within the central nervous system (CNS), headaches, vascular dissections, and stroke are the most common clinical presentations [₁₂]. However, symptoms such as vertigo, tinnitus, or syncope may be the primary presenting problem [₄]. In some cases, headache and neck pain may be the only presenting complaints prior to a spontaneous internal carotid artery (ICA) dissection [₇]. Physical examination may reveal a carotid bruit, leading to an incidental finding of FMD [₄₅].

For some time, neurologists have known FMD to be an important cause of stroke in young adults [₈]. The presentation of a carotid or vertebral dissection with an accompanying anterior circulation ischemic stroke affects 10-25% of all ischemic strokes in young adults [₉₁₀]. Ninety-five percent of diagnoses of FMD involve the ICA, followed by the VA 60-85% of the time [₄]. FMD is associated with single or multiple aneurysms found most frequently along the ICA and middle cerebral artery (MCA) [₄]. To gain a better understanding of the angiographic diagnosis of FMD, a description of a classification system will be discussed.

Pathologic Classification

Classification is based on the angiographic appearance of the vessel, which correlates with the dominant arterial wall affected [₁]. Therefore, vessels will either be labeled as medial dysplasia, intimal dysplasia, or adventitial fibroplasia [₁₂₃₄]. Subcategories further assist the practitioner in identifying commonalities in symptoms and the types of patients that FMD affects. The “string of beads” is the most common angiographic finding for FMD in both the RA and ICA, followed by concentric stenosis (Figures1&2) [₁₂₁₁].

Figure 2

Figure 1: String of Beads

Figure 3

Figure 2: Concentric Stenosis

Although this classification was originally developed for use in the RAs, the system has been applied successfully to all vascular beds affected by FMD [₂₄]. Dissection was once a subcategory, but has now been referenced as a cause. Refer to Table 2 for the

Angiographic Classification of FMD [₁₂₄].

Figure 4

Table 2: Angiographic Classification of Fibromuscular Dysplasia

Case Report

History

Physical

On initial physical examination, the blood pressure was documented as 140/84, heart rate 102, respirations 16, and temperature 98.2 F. No audible carotid bruit was heard. However, a grade 2/6 systolic murmur was prominent at the left costal margin.

Cranial nerves II through XII were intact bilaterally. The motor exam noted 5/5 strengths on her left side; however, on her right side, she was noted to have the following strengths: 4/5 in deltoids, biceps, wrist extension, triceps, hip flexor, hip abduction, hip adduction, and quadriceps. Her extensor hallucis longus and her gastrocnemius strength was 4/5 on the right. The deep tendon reflexes were 3/5 in the Achilles, quadriceps biceps, brachial radialis, and triceps tendons bilaterally. The patient was noted to have intact sensation to light touch and sharp/dull discrimination in all extremities. No ataxia was present, and gait was not assessed. Laboratory results are contained in Table 3.

Figure 5

Table 3: Laboratory

Imaging

Treatment

Determining Differential Diagnoses

A thorough history of the patient and first-degree relatives provides invaluable information when attempting to rule out conditions that may be associated with or look similar to FMD. The clinician acts as an investigator, taking note of even the smallest of details. For example, if the patient complained of a “thunder-clap” headache one may suspect a subarachnoid hemorrhage (SAH)” [₁₂]. Despite age or risk factors, unilateral weakness and aphasia require an immediate head CT without contrast to rule out either an ischemic or a hemorrhagic stroke [₁₂]. A diagnosis of an ischemic event in a 15 year-old Caucasian female with no history of recent trauma must cue the provider to think of FMD as a differential diagnosis [₉]. A review of current data will assist in determining appropriate differentials:

1. A 15 year-old Caucasian female with no prior neurologic complications.

2. Recent complaint of a migraine headache and history of herpetic lesions.

3. No history of hypertension, elevated cholesterol, smoking, or diabetes.

4. Maternal and paternal grandparents died at an early age from stroke.

5. Left MCA/ACA infarct, left ICA narrowing, dissection at the bifurcation of the left ICA, and evidence of beading similar to FMD

Atherosclerosis can be considered a reasonable differential in the presence of an ischemic stroke. This condition is known to cause narrowing of the medium-to-large vessels in the brain, heart, or extremities. A blood clot may cause a thrombotic event completely occluding blood flow. Usually developing early in life, atherosclerotic symptoms typically do not occur until the fifth or sixth decade of life [₁₃]. In comparison, this patient was young, with no atherosclerotic risk factors. Laboratory data confirmed the patient having a normal lipid panel and hemoglobin A_1c. Vascular imaging did not observe calcifications or plaque. Atherosclerosis was ruled out.

Vasculitis must be considered in the differential diagnosis. Typically, angiographic findings reveal segmental narrowing and dilatation of vessels similar to FMD. Vasculitis may be considered non-infectious or infectious. Vasculitis may also be confused with a diagnosis of atherosclerosis or FMD. Differentiation from atherosclerosis is that vasculitis tends to affect younger patients with few to no atherosclerotic risk factors. Both vasculitis and atherosclerosis have an inflammatory component that FMD does not share. FMD is a non-inflammatory process, and patients do not usually exhibit anemia or thrombocytopenia upon laboratory work-up. However, when FMD presents in multiple vessels as in intimal fibroplasias, the angiographic findings are similar to necrotizing vasculitis [₁₂₄₅]. Herpes zoster opthalamicus (HZO) can cause a necrotizing vasculitis that affects the proximal segments of anterior and middle cerebral arteries on the same side of the HZO and a contra-lateral hemiparesis [₁₄]. By comparison, this patient did not present with an active herpetic infection, and no evidence was present of an inflammatory response. Other conditions, such as giant cell arteritis and Takayasu’s arteritis, can be differentiated from FMD based on the choice of imaging. In this case, the best imaging technique to differentiate between vasculitis and FMD was an intravascular ultrasound [₂]. The case-study patient exhibited what the radiologist identified as classical features of FMD. The job of the clinician is to further rule out any metabolic or infectious process. Vasculitis was ruled out.

Ehlers-Danlos syndrome type IV (EDS) has been associated with FMD and can be considered as a differential diagnosis. This vascular syndrome produces prominent venous markings and translucent, fragile skin. EDS is a heritable syndrome. A positive family history often reveals a cluster of diagnoses which can be attributed to EDS. Specifically, this syndrome correlates well with a patient who has been diagnosed with medial fibroplasia in the presence of multiple aneurysms or vascular dissections [₁₂₅]. EDS also correlates to the patient with recurrent dissections despite treatment. Angiographic findings and the presence of the COL3A1 gene assist in the diagnosis of this syndrome [₁₂₅]. The patient did present with a medial fibroplasia form of FMD and dissection. However, in the absence of the classic findings of EDS, including multiple aneurysms and dissections, additional work-up was deemed unnecessary. Ehlers-Danlos syndrome type IV was ruled out.

Imaging Studies

FMD can be determined only by angiographic findings or a pathological specimen. Emergent brain and vascular imaging and, specifically, catheter-based angiography remain the gold standard for the determination of cerebrovascular FMD [₂₄₁₀]. A head CT without contrast is the first scan required to differentiate between an ischemic and a hemorrhagic stroke [₁₁₁₂₁₄]. In the absence of a hemorrhagic event, the clinician must consider that an ischemic event has occurred. Magnetic resonance imaging (MRI) of the brain and contrast-enhanced magnetic resonance angiography (CE MRA) of the neck and brain sufficiently detail the “string of beads” pattern seen in most diagnoses of FMD [₂]. A CT angiogram (CTA) of the neck and brain provides an alternative for those individuals who cannot tolerate a MRI. CTA is particularly useful in the identification of stenosis, dissections, and aneurysms that may be associated with FMD [₁₁]. Duplex ultrasonography (DU) is unable to detect FMD in the vertebral and intracranial carotid arteries [₁₀]. However, in patients with carotid dissections, abnormal flow patterns have been identified in more than 90% of patients [₁₀]. DU, used in combination with angiography or magnetic resonance, is almost always confirmatory of dissections and may prove advantageous in the diagnosis of FMD [₂₁₀].

Current Medical Treatment

At this time, no curative treatment exists for the diagnosis of FMD. Treatment is determined by the presenting problem. A carotid artery dissection with no cerebral hemorrhagic event will require intravenous weight-based heparin to be initiated. Once achieving a target international normalized ratio (INR) of 2-3, the patient will be changed to oral warfarin (Coumadin) for a time frame of three to six months [₁₀]. The affected vessel has the highest potential to recanalize during the first three months while on anticoagulation therapy. Therefore, an MRA in three months will re-evaluate the state of the vessel and the need for further treatment. If luminal irregularities persist, the patient will continue antiplatelet therapy. An additional follow-up and MRA study in three months that reveals continued luminal irregularities will likely require the initiation of an anti-platelet agent such as clopidogrel (Plavix) [₁₀]. However, the duration the patient should remain on anti-platelet therapy remains unclear. Current research indicates that, if the patient remains asymptomatic after six months, he or she will likely not experience a repeat event, therefore negating any further medical treatment.

Current Surgical Treatment

Surgical management for cerebrovascular FMD should be reserved for those patients who remain symptomatic despite medical therapy, and have severely stenotic lesions with evidence of cerebral hypoperfusion [₁₀]. Patients who present with a SAH and have angiographic evidence of aneurysms may require emergent surgical intervention. These aneurysms may require coiling or clipping to prevent further bleeding [₁₂].

Currently, percutaneous transluminal angioplasty (PTA) is the first therapeutic option in the symptomatic FMD patient [₃]. PTA is considered to be a safer option than traditional surgical procedures such as an endarectomy [₂]. Stenting may be considered when patients have recurring symptoms and have failed traditional anticoagulation therapy or balloon angioplasty [_24141516]. Clinicians should be aware that very little comparative interventional data exist to support one procedure over another in the patient with cerebrovascular FMD. Although carotid stenting is an alternative, little is known of the long-term results and the possible complications [₁₀]. Stenting should not be considered as a primary therapy [₃].

Conclusion

This case study demonstrates the catastrophic events that occur in a symptomatic patient with FMD. Following current guidelines and research can aid in the prevention and minimization of the complications of FMD. Although cerebrovascular FMD remains a relatively obscure diagnosis, clinicians must become aware of not only the short-term implications but also the long-term outcomes. Increasing funding for researchers is a necessary step for those dedicated to finding answers to this complex disease.

Acknowledgement

Correspondence to

Monique Lambert 10116 Forest Spring Lane Pearland, Texas, 77584 Email: Monique.lambert@uth.tmc.edu