A 58 year-old woman applied for life insurance. She reported being in good health. Six months prior to the application she saw her doctor and complained of a “swishing sound in her ears.” They performed a computed tomographic angiogram (CTA) of the head and neck and found changes in the left vertebral and both internal carotid arteries consistent with Fibromuscular Dysplasia. The CTA report also indicated no presence of aneurysm or stenosis and was otherwise normal. The records provided no documentation about follow-up action.
What is Fibromuscular Dysplasia (FMD), and how does it affect morbidity or mortality?
FMD was first described in 1938. Making the diagnosis during life initially required invasive arteriography, which was typically done in symptomatic patients when the index of suspicion was high. With the relatively recent advent of CTA and Magnetic Resonance Arteriography (MRA) the disorder can be studied more easily and is more often discovered in asymptomatic individuals. There has been increased study of the disorder, but there is still much to be discovered.
FMD is described as a nonatherosclerotic, non-inflammatory disease of the vessels that may lead to arterial stenosis, dissection, occlusion or aneurysm. Its prevalence among the population is unknown.
Studies of potential kidney donors found that 3.8%-6.6% had angiographic evidence of renal artery FMD. However, since many potential donors have close relatives with renal failure, this is not considered representative of the general population. A small autopsy study from 1970 reportedly found FMD pathology in about 1% of 819 consecutive autopsies.
We do know that FMD is more common in women than men at an approximate 9:1 ratio. Carotid, vertebral and intracranial FMD has not been studied as much as renal FMD. Studies of these cerebral arteries by reviewing consecutive angiograms showed a prevalence of FMD of .3%-3.2%. Again, the clinical threshold for performing cerebral angiograms would make this population much different from the general population. A study of more than 20,000 consecutive autopsies at the Mayo Clinic detected only four cases with carotid FMD.
Cause of Disease
The cause of FMD is not known. It has been observed in identical twins and is more common in first degree relatives, so there is likely a genetic component. Studies using renal angiograms to diagnose FMD estimate that familial cases make up 7%-11% of FMD patients. Similarly, in the US Registry of FMD patients only 7.3% report a confirmed diagnosis of FMD in a family member. However, 23.5% of the Registry patients reported a family history of aneurysm.
FMD is often classified by histological pathology or angiographic location and appearance. Histologically, one of 3 layers of the artery wall is predominately involved. Starting from the lumen, intimal fibroplasia occurs in 1-2% of FMD cases. This is usually focal and can cause tubular narrowing of the artery.
The medial arterial layer is most often affected, and can follow 3 patterns: the most common is medial fibroplasia (60%-70%); perimedial fibroplasia (15%-25%) and medial hyperplasia (5%-15%) make up the other possibilities. All of the medial lesions tend to be more multifocal. The rarest form is adventitial FMD (<1%).
The diagnosis of FMD has become a radiologic one, and tissue is rarely obtained. The American Heart Association has proposed two classes of the disease: Multifocal disease consisting of the classic “string of beads” which is almost always caused by medial fibroplasia in adults (Figure 1), and focal disease consisting of one narrow point that can be of any length.
Focal disease can be seen with intimal fibroplasia, medial hyperplasia or adventitial FMD. A single patient can have focal disease in one vascular territory and multifocal disease in another territory. Specifically for renal FMD, focal disease tends to be diagnosed at a younger age, has more males (female to male ratio 2:1) and had a higher rate of cure of hypertension after revascularization (54% versus 26% in multifocal disease).
Presenting clinical manifestations of FMD vary considerably. Only 5.6% of patients in the US Registry were truly asymptomatic. The top 10 presentations in the Registry are listed in Figure 2.
Prior history of headaches||
Chest pain/shortness of breath||
Figure 2 - Most Prevalent Presentations of FMD
Neurologic events are some of the most debilitating complications of FMD and can be caused by stenosis, embolization, thrombosis, arterial dissection or rupture of an aneurysm. In reviewing the presentation data of the FMD Registry, 13.4% of patients had suffered a hemispheric TIA, 5.2% had experienced amaurosis fugax, 12.1% had experienced cervical artery dissection, and 9.8% had suffered a stroke at presentation. The frequency of subarachnoid hemorrhage was 1.1%, and the frequency of cerebrovascular aneurysms (includes carotid and vertebral) was about 7%.
FMD lesions of the coronary arteries have been reported. Coronary artery dissection has occurred in some patients, resulting in myocardial infarction. The US Registry reported coronary artery disease in 6.5% of patients, but its cause (atherosclerosis or FMD) is unclear. We should also note that among patients in the US FMD Registry, 20% reported sudden death in first- and second-degree relatives.
Aneurysms are a well-documented complication of FMD. Asymptomatic brain aneurysms may occur in up to 7.3% of FMD patients, and in the US Registry 17% of patients reported an aneurysm of any artery (3.4% of the cohort had an aortic aneurysm, a higher percent than one would anticipate in predominantly middle-aged females).
Disorders in the differential diagnosis of FMD would include atherosclerotic vascular disease (ASCVD) and vasculitis. ASCVD is favored in older individuals with vascular risk factors like smoking, diabetes and hyperlipidemia. ASCVD also tends to occur in the opening (ostial) or proximal portion of vessels, while FMD is more commonly in the mid-portion or distal arterial location. Vasculitis can be recognized by elevation of acute reactants like Erythrocyte Sedimentation Rate (ESR) and C-reactive protein (CRP). The vessel’s “string of beads” appearance on imaging is characteristic of FMD.
Treatment of FMD includes control of hypertension and the opening or bypassing of symptomatic narrowing in affected arteries. Balloon angioplasty with or without stenting is often used to restore blood flow. Most experts suggest aspirin therapy to prevent platelet deposition in the irregular arterial sections. Stronger anticoagulants are often used in symptomatic or post-procedure patients. 72% of the original 447 patients in the FMD Registry had hypertension (as of 2012).
Angiographic studies of potential kidney donors noted that over a 2.5-7.5 year follow-up of those with FMD, 26%-29% developed hypertension. Therefore, those diagnosed with FMD should have blood pressure and serum creatinine monitored every 6-12 months. Additionally, all patients with FMD of any arterial distribution should be screened for intracranical aneurysms with CTA or MRA.
Following and treating those with cerebral aneurysms are the same as in the general population: those with aneurysms should be monitored with MRA to follow the size of the aneurysm. Those with FMD of the renal artery can also be followed with duplex ultrasound and by ultrasound measurement of the renal cortex. Atrophic changes in the renal parenchyma may result from chronic ischemic damage.
Returning to the Case
The US Registry for FMD was started in 2008, so long term follow-up is lacking for this condition. One of the stated goals of the American Heart Association study group is to determine the natural history of FMD and to develop tools for risk stratification of FMD patients.
Some studies of small numbers of patients with extracranial FMD (carotid and vertebral) from the 1980s reported the risk of stroke and TIA at 0-5% per year. However, the patients were heterogeneous and lacked uniform treatment and follow-up.
Some case reports have documented progression of cervical FMD lesions over time, and there is clearly an association of FMD and arterial dissection, although no prospective data controlled for hypertension. It would be reasonable to expect an evaluation of the renal arteries and aorta by ultrasound or another modality in this case given the association of FMD with aneurysms. If studies are normal and proper treatment and follow-up is started, we might anticipate a moderate extra mortality risk.
Olin JW, et al. “The United States Registry for Fibromuscular Dysplasia: Results in the First 447 Patients.” Circulation. 2012;125:3182-3190.
Olin JW, et al. “Fibromuscular Dysplasia: State of the Science and Critical Unanswered Questions: A Scientific Statement From the American Heart Association.” Circulation. 2014;129:1048-1078.
Touze, E, et al. “Fibromuscular dysplasia of cervical and intracranial arteries.” Int J of Stroke. 2010;5:296-305.
http://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-fibromuscular-dysplasia?source=machineLearning&search=fibromuscular+dysplasia&selectedTitle=1%7E39§ionRank=3&anchor=H18#H18. Last accessed 11/17/14. ∞