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Rheumatology Grand Rounds Monger and Collier April 23, 1996
Fibromuscular Dysplasia
Introduction:
Fibromuscular dysplasia (FMD) is a nonatherosclerotic and noninflammatory vascular disease that primarily affects the medium-sized and small arteries, most commonly the renal and carotid arteries. Typical clinical manifestations are renovascular hypertension, stroke, subarachnoid hemorrhage, and claudication of the extremities. Caucasian women are predominantly affected.
A. History:
-The first description of FMD is attributed to Leadbetter and Burkland who in 1938 described a five year old boy with hypertension and an ectopic right kidney, whose blood pressure returned to normal following nephrectomy. Histologically, the renal artery appeared to be obstructed by "an intraluminal mass of smooth muscle."
-In 1958, McCormack et al introduced the term "fibromuscular hyperplasia" when describing three young patients with renovascular hypertension and an unusual type of renal artery stenosis.
- It soon became apparent that arteries other than the renal arteries could be affected:
B. Prevalence:
- Information about the true prevalence of FMD is incomplete. There are over 1500 case reports of FMD in the literature, but no studies to determine prevalence.
- In the hypertensive population, renovascular FMD is found in less than 1% of patients.
-A pathologic classification was proposed by Harrison and McCormack in 1971, and revised by Stanley et al in 1975, based histologically on the predominant site of dysplasia in the arterial wall. From this classification three main types of FMD have been identified; initial fibroplasia, medial FMD, and periarterial fibroplasia.
-Medial FMD is the most frequent type among the three main FMD types, and can be further subdivided into medial fibroplasia, perimedial fibroplasia, and medial hyperplasia. Medial fibroplasia is by far the most common, accounting for 75-95% of all FMD, and causing the typical "string of beads" sign on angiograms.
- Typically the "beads" exceed the diameter of the proximal unaffected part of the artery. Multifocal thickened fibromuscular ridges alternating with areas of thinned vascular wall give rise to this phenomenon.
- In the renal artery the distal 2/3s is typically involved, and often the lesion extends into the branch arteries.
- In the cerebrovascular circulation, medial FMD characteristically affects the internal carotid artery at the level of the C1 and C2 vertebrae, sparing the origins and proximal segments of the major extracranial arteries.
-In the subtype perimedial fibroplasia, the "beads" are smaller and less numerous. Histologically, it is characterized by extensive fibroplasia of the outer half of the media, and the external elastic membrane is often effaced or disrupted. It is found almost exclusively in women younger than 30 years who have right sided renal artery stenosis and hypertension.
- In the subtype medial hyperplasia, excessive medial smooth muscle causes focal concentric stenosis, which is often tubular and smooth. This subtype accounts for less than 5% of FMD.
- Initial fibroplasia is angiographically indistinguishable from medial hyperplasia, histologically it is characterized by a circumferential or eccentric accumulations of fibrous tissue in the intima. Both sexes are affected equally. Periarterial fibroplasia is the rarest subtype of FMD; fibroplasia with collagen encompasses the adventia and extends into the surrounding tissue. Slight focal infiltration with lymphocytes and plasma cells may be present.
C. Pathogenesis
The cause of FMD is unknown. Several hypotheses have been proposed including the following:
1. Hormonal Factors: in most series of patients with FMD women have been affected much more commonly than men. Oral contraceptives have been shown to realer induce initial hyperplasia, and alteratin of the vascular media may occur during pregnancy. However, gravity and parity rates do not differ in patients with FMD compared to the general populatino, and pregnancy does not seem to alter the natural course of FMD.
2. Genetics: There are many case reports of familial occurrence of FMD, and in an analysis of 20 families in which at least one member had confirmed FMD, Rushton found evidence of an autosomal dominant pattern of involvement with variable penetrance. An analysis by Mettinger of 37 patients with FMD discovered an associated occurrence of FMD, in about 35% of families of stroke, especially among young and middle aged females, and indicated that FMD in the majority of cases is inherited as an autosomal dominant trait with reduced penetrance in males.
3. Mechanical Factors: It has been suggested that repeated stretching of the internal carotid artery during hyperextension of the vertebral column, and stretching of the renal artery during changes in posture/breathing may partially explain the prevalence of FMD in those arteries. Experimental studies, however, have revealed only minor histologic changes in response to stretching.
4. Ischemia: Experimental occlusion of arterial vasa vasorum causes distinct morphologic changes of the vascular wall, including an increase in the extracellular connective tissue. Some authors have concluded that a decrease
in the blood supply to the vascular wall might be the primary event in the pathogenesis of FMD.
5. Other:
-Some patients with pheochromocytoma have vascular stenosis which resemble FMD, and in some patients stenotic lesion of the renal artery have resolved after removal of the tumor, suggesting that catecholamines may be associated with the pathogenesis.
- The incidence of smoking amongst patients with FMD is high, possibly implicating smoking in the pathogenesis of FMD.
-Vascular changes similar to FMD can be found following rubella syndrome.
D. Clinical Manifestations:
1. In a review by Mettinger of 1100 reported cases of FMD:
- Most patients were Caucasian (only 30 patients were black)
- Female male about 2:1
- The mean age of reported aortocranial FMD is about 50 years; renovascular FMD is reported at an average of 39 years.
- About 300 out of 1100 patients had cerebrovascular FMD.
- Age range: 1-90 years old.
2. An association between FMD, especially cerebrovascular FMD, and intracranial aneurysm disease is well established. In a review of 321 cases of cerebrovascular FMD, 61 had intracranial aneurysms (21%), and 20 patiens had two or more aneurysms:
Table 3 - Review of 321 Cases of Aortocranial Arterial FMD From Literature
Female 246
Male 75
Age Mean 50
Range 0-90
Carotid 302
Vertebral 55
Ischemic stroke 141
Hemorrhagic stroke 87
Intracranial aneurysm
Internal carotid a. 34
Middle cerebral a 18
Anterior cerebral a. 25
(missing last data )
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In a review by Mettinger of 37 patients with cerebrovascular FMD, selected from 4000 previously performed angiograms, 51% (19/37) had a total of 25 intracranial aneurysms. Only 9 out of 19 patients had hypertension implying that hypertension secondary to FMD was not the etiology of the aneurysms. The aneurysms had no pathognomonic appearance, and were most commonly seen on the same side as the most affected extracranial carotid artery.
3. Renovascular FMD:
- Compared to patients with atherosclerotic renal artery stenosis, patients with renovascular FMD are younger, more often female, and have a shorter duration of hypertension.
- the right renal artery is more often affected than the left.
- Family history of hypertension is variable, as is family history of stroke, aneurysm, myocardial infarction, or other vascular disease.
- Renal artery aneurysms are commonly associated with renal FMD.
-Symptomatic or asymptomatic extrarenal FMD may be present.Renovascular FMD causes hypertension if the stenosis is severe enough to cause renal ischemia, which in turn activates the renin-angiotensin system. Renovascular hypertension is distinguished from renovascular disease without hypertension by the presence of several stenosis (>75%), a decrease in kidney size, and lateralization of secretion of renin toward the involved side:
. Other Associations: in the review by Mettinger of 1100 reported FMD cases, numerous associated findings were noted:
E. Natural History:
Progression of FMD has been confirmed on repeat angiograms in many patients with renovascular disease:
- Meany et al reported that 16% of patients had progression of renovascular FMD after a follow-up period ranging 6 months to 10 years (compared to 36% of patients with atherosclerotic renovascular disease)
- In a Mayo clinic series, FMD of the renal arteries progressed in 35% of patients after a mean observation period of 3 years.
- No patient has been noted to have progression of the disease to the point of occlusion of the vessels.
-Spontaneous reversal of FMD with reversal of hypertension has been reported in rare cases.
- Progression of cerebrovascular FMD is thought to be less pronounced than renovascular FMD, possible because hypertension is less common in cerebrovascular FMD than renovascular disease.
F. Diagnosis:
FMD is a histology diagnosis, however, the diagnosis can be made with a high degree of accuracy based on angiography.
1. Atherosclerotic plaques can be sometimes confused with FMD: atherosclerotic stenosis are usually located within 1cm of the orifice of the main renal or internal carotid artery and are typically eccentric. Also, atherosclerotic renal artery stenoses are often associated with atherosclerotic changes in the abdominal aorta. FMD almost always involves the middle or distal segment of the renal or carotid artery, and the focal stenoses are concentric and typically have a smooth appearance.
2. Because FMD is noninflammatory, laboratory evidence of inflammation is absent, helping to differentiate it from most inflammatory vasculopathies, IE Giant Cell arteritis. Takayasu's arteritis has a different pattern of involvement than FMD; the aorta is almost always involved in Takayasu's, and the large arteries are stenotic at or near their origin.
3. Patients with hereditary connective tissue diseases may have aneurysms of the major arteries similar to FMD, IE Ehlers-Danlos Syndrome. These patients will generally have other characteristic clinical signs (joint laxity, skin elasticity, etc.) Suggesting the diagnosis.
4. Neurofibromatosis may be associated with stenosis at the orifices of the renal, celiac, and superior masenteric arteries; the proximal site of the arterial involvement, along with the stigmas of neurofibromatosis of the skin helps distinguish this disease from FMD.
G. Management of FMD:
1. Renovascular hypertension; Treatment may be indicated to normalize BP; in contrast to atherosclerotic renovascular disease, preservation of renal function is rarely a primary decision for treatment.
-Surgical vascular reconstruction and nephrectomy were the mainstays of treatment 10-15 years ago, and surgery may still be indicated in whom angioplasty fails or is technically impossible. Cure rates for surgical intervention range from 35-85%, with surgical mortality estimated at 1-2% (probably lower now). Surgical options include revascularization with an autologous graft, operative dilation, and autotransplantation.
- Angioplasty of involved vessels, possible with stent placement, is the generally accepted intervention at this time. Complication rates are most closely related to experience of the center performing the procedure. The technology is rapidly changing, and there are no head to head trials of surgery vs. Angioplasty.
- Medical therapy with ACE inhibitors is an option, especially in patients who are poor surgical risks. Potential side effects of medical therapy include drug side effects, patient noncompliance, and risk of disease progression.
2. Cerebrovascular FMD: Management of FMD involving the cerebral vasculature of the disease should be kept in mind in asymptomatic patients; antiplatelet agents are commonly used. Patients with headaches or other neurologic symptoms may be candidates for angioplasty or stent placement.
H. Screening;
Because the prevalence of disease is unknown, it is difficult to make screening recommendations. It may be reasonable to screen first degree relatives of patients with known FMD, especially if the relatives have headache or other neurological symptoms.
-A continuous bruit may be heard in about 2/3s of patients with significant renovascular FMD. Renal artery dissection is an uncommon complication of renovascular FMD.
- Renal infarction is a potential complication, and clinically can present with abdominal of flank pain with nausea and fever. Not all patients with renal infarcts from renovacular FMD have hypertension.
Bibliography availble upon request
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