Fibromuscular Dysplasia (FMD)

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Table of Contents

•Fibromuscular Dysplasia Overview–Histology–Components of Vascular System–Pathology–Etiology–Clinical Presentation–Associated Diseases

•FMD Discussion by Arterial Involvement–Renal Arterial Involvement•Mechanisms of Hypertension•Natural History•Diagnosis•Treatment

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Table of Contents (Continued)

•FMD Discussion by Arterial Involvement (cont.)–Carotid Arterial Involvement•Natural History•Diagnosis•Treatment•Associated Conditions

–Non-Renal Abdominal Viscera Presentation and Treatment–Peripheral Artery Disease

•Case Studies

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Fibromuscular Dysplasia (FMD)

• Nonatherosclerotic, noninflammatory disease• More common in women and younger individuals– The incidence of FMD in children is unknown.

• Described in almost every vascular bed1

– Renal arteries (60-75%)– Cervicocranial arteries (25-30%)– Non-renal visceral arteries (9%)– Arteries in the extremities (5%)– Others including pulmonary and coronary arteries

• Multiple vascular beds in 28% of patients2

1Gray BH et al In Peripheral Vascular Diseases 1996, 2Lüscher TF et al Nephron 1986

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FMD - Histology of Arteries

•Lumen•Endothelium (basal lamina)• Intima• Internal elastic lamina•Media•External elastic lamina•Adventitia

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Components of the Vascular System

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Elastic Laminae in a Large Artery

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FMD - Pathologic Classification

• Intimal fibroplasia (less than 10%)•Medial dysplasia–Medial fibroplasia (80%)–Perimedial fibroplasia (10-15%)–Medial hyperplasia (1-2%)

•Adventitial (periarterial) fibroplasia

Harrison EG Jr and McCormack LJ Mayo Clinic Proc 1971

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FMD Pathology - Intimal Fibroplasia

•Children and young adults•Circumferential deposition of collagen in the intima, often

projecting into lumina• Internal elastic lamina may be duplicated or disrupted

but can be identified•Long, irregular (tubular) or focal, smooth (concentric

band) stenoses1

1Stanley JC et al Arch Surg 1975

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FMD Pathology - Intimal Fibroplasia

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FMD Pathology - Medial Fibroplasia

• 25-50 year old women• Thickened media alternating with thinned media aneurysmal

dilatation–“String of beads”

• Thickened media is replaced by collagen• Internal elastic lamina may be thinned or fragmented– May lead to macroaneurysm formation1

• Frequently affects the renal arteries bilaterally

1Stanley JC Arch Surg 1975

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FMD Pathology- Perimedial Fibroplasia

•15- 30year old women•Collagen deposition in the outer half of the media

replacing the external elastic lamina; intact adventitialconnective tissue–“String of beads”–Can result in severe stenosis

•Often associated with collateral circulation•Preferentially affects the renal artery (mid portion)

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FMD Pathology - Adventitial (periarterial) Fibroplasia

• Adventitial (periarterial) fibroplasia– Very rare– Collagen replaces the fibrous adventitia– May extend beyond artery

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FMD - Etiology

•Genetic–Autosomal dominant with variable penetrance in 60% of cases

based on“clinical symptoms”1

–11% prevalence angiographically2

•Hormonal–No difference in gravidity or parity rates, effect on disease

progression3

–Oral contraceptive pill use?4,5,

1Rushton AR Arch Intern Med 1980, 2Pannier-Moreau I et al J of Hypertens 1997, 3Stanley JC et alArch Surg 1975, 4Sang CH et al Hypertension 1989, 5Hardy-Godon S et al J of Neuroradiol 1979

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FMD - Etiology

•Mechanical–Ptosis of the right kidney1

–Repetitive trauma such as hyperextension and rotation of theneck1

•Mural ischemia–Occlusion of the vasa vasorum2

–Vasospasm (ergotamines, methysergide)3

–Tobacco use4

1Lüscher TF et al Mayo Clin Proc 1987, 2Sottiurai V et al J of Surg Res 1978,3Fievez ML Med Hypotheses 1984, 4Sang CN et al Hypertension1989

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FMD - Clinical Presentation

•Asymptomatic•Nonspecific symptoms–Headaches, altered mentation, tinnitus, vertigo, carotidynia

•Neurologic symptoms–Transient ischemic attacks, cerebral infarctions, subarachnoidhemorrhages, syncope, Horner’s syndrome, cranial nerve palsies

Mettinger KL and Ericson K Stroke 1982, Houser OW et al Radiology 1971

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FMD - Associated Diseases

• Turner’s syndrome• Alport’ssyndrome• Neurofibromatosis• Coarctation of the aorta• Moyamoya disease

• Cystic medial necrosis• Hypertrophic cardiomyopathy• Heterozygous α1- antitrypsin

deficiency• Pheochromocytoma

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Arterial Involvement

Slovut DP et al N Engl J Med 2004;350:1862

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Renal Arteries

• Leadbetter and Burkland (1938) reported the first case of FMD1

• 40% of all patients with renovascular disease have FMD2

• Symptomatic patients present with hypertension– Onset of hypertension before age 30– Epigastric bruit (systolic/diastolic)3

• Less frequently develop ischemic renal atrophy and chronic renalfailure

1Leadbetter WF and Burkland CE J Urol 1938, 2 Olin JW and Novick ACIn Peripheral Vascular Diseases 1996, 3Eipper DF et al Am J of Cardiol 1976

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Renal Arteries

Panel A shows string of beads. Panel B shows gadolinium-enhancedMRA revealing bilateral medial fibroplasiaof the renal arteries.

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Renal Arteries - Mechanism of Hypertension

Ischemia

Renin

Angiotensinogen Angiotensin I Angiotensin II

Direct Vasoconstriction & Aldosterone Secretion

Salt & Water Retention

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Upper Percentiles ofBlood Pressure forGirls

The Fourth Report on the Diagnosis, Evaluation, andTreatment of High Blood Pressure in Children andAdolescents Pediatrics 114(2) Part 3 of 3 August 2004.

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The Fourth Report on the Diagnosis, Evaluation, andTreatment of High Blood Pressure in Children andAdolescents Pediatrics 114(2) Part 3 of 3 August 2004.

Upper Percentiles ofBlood Pressure forBoys

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Renal Arteries - Natural History

•Angiographically- proven progression–Goncharenko (1981) 42/42 patients•Follow-up 1–136 months•75% bilateral, 29% medial FMD, 62% change in kidney size

0.5 cm

–Schreiber (1984) 66 patients with medial FMD•Follow-up 45 months angio, 104 months clinical•33% progression–9% increase in creatinine, 27% atrophy of

ipsilateral kidney (1.5 cm)

Goncharenko V et al Radiology 1981, Schreiber MJ et al Urol Clin of North Am 1984

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Renal Arteries - Natural History

• Clinically-proven progression– Cragg (1989)–71 potential kidney donors (f/up 49)

•26.6% developed hypertension at 7.5 years (30 w/o nephrectomy)•26.3% developed hypertension at 4.4 years (19 with nephrectomy)•6.1% age and sex-matched controls developed hypertension at 7.1

years

• Clinical progression may reflect the development of concomitantdevelopment of essential hypertension or atherosclerosis

Cragg AH et al Radiology 1989

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Renal Arteries - Diagnosis

•Captopril renography (functional)•Spiral CT angiography1

–Transverse sections and maximum-intensity projections

•MR angiography2

•Duplex Ultrasonography–Color power angio

•Angiography

1Beregi J-P et al AJR 1999, 2Leung DA et al Hypertension 1999

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Renal Arteries Diagnosis - Duplex Ultrasonography

No flow signal from artery ORLow amplitude parenchymal signal

small kidney

Occlusion

RAR 3.5(EDV 150 cm/sec)

60-99%(EDV suggests > 80% stenosis)

RAR < 3.5< 60%

DUPLEX CRITERIASTENOSIS

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Renal Arteries - Treatment

•Stop smoking•Antiplatelet therapy•Medical therapy following JNC- VI guidelines1 and The

Fourth Task Force Report2

–Unilateral diseaseangiotensin-converting enzyme inhibitor,angiotensin II antagonist

–Bilateral diseasediuretic/calcium channel blocker

1JNC-VI Guidelines Arch Intern Med 1997 2The Fourth Report Pediatrics 114(2) Part 3 of 3 August 2004

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Renal Arteries - Indications for Intervention

•Blood pressure cannot be controlled despite threeantihypertensive medications at maximal doses

•The individual is intolerant to the medications•Compliance is an issue•An alternative to lifelong dependency on a medication in

a relatively young individual

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Renal Arteries - Endovascular Therapy:BP

11.3

42.7

15.7

11-26

F/UP MOS

25%43%98%Kløw (1998) 49

22%63%88.6%Bonelli (1995) 105

39%59%100%Tegtmeyer (1991)66

50%42%90.7%Ramsey (1990)193

CUREIMPROVEPRIMARYPATENCY

STUDY pts

Ramsey LE and Waller PC BMJ 1990, Tegtmeyer CJ et al Circulation 1991,Bonelli FS et al Mayo Clin Proc 1995, Kløw N-E et al Acta Radiol 1998

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Renal Arteries - Endovascular Therapy: CRI

(2) 14†PTS NOTIMPROVE

(12) 86*PTS IMPROVE

291.72.4CREATININE

3924.640.4BUN

IMPROVE (%)POST-PTA(mg/dl)

PRE-PTA(mg/dl)

Tegtmeyer CJ et al Circulation 1991

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Renal Arteries - Endovascular Therapy:Branch Lesions

•Segmental renal arteries are affected in 30- 56% ofpatients with FMD

•Cluzel (1994)–20 patients with 25 arteries–Technical success rate 84%–91% patency rate at 6 months–Hypertension cure•Post-PTRA 70%, 6-month 76%, long-term 68%

–Hypertension improved•Post-PTRA 25%, 6-month 24%, long-term 16%

Cluzel P et al Radiology 1994

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Renal Arteries –Intervention Complications

• Puncture site– AVF, pseudoaneurysm, bleeding/hematoma, femoral nerve injury,

infection

• Catheter-related– Dissection, perforation/rupture, AED, balloon rupture, thrombosis, renal

artery spasm

• Contrast Media– ARF, anaphylaxis

• Medical

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Renal Arteries –Predictors of Cure ofHypertension in FMD

• Younger patients with milder hypertension of a shorter duration weremost likely to be cured.

• Some patients with an extremely low chance of cure might bemanaged with a trial of medical therapy

• FMD is unlikely to progress to renal failure

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Renal Arteries - Surgery

• Indications– Lack of endovascular expertise, recurrent disease, inaccessible branch

lesions• Approaches– Aortorenal bypass, extracorporeal revascularization &

autotransplantation, spleno- or hepato-renal• Blood pressure– 36-63% cure, 30-50% improvement

• Outcomes– Low morbidity and mortality

Hansen KJ et al J Vasc Surg 1992, Novick AC et al JAMA 1987, Reiher L et al Eur J Endovasc Surg 2000

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Renal Arteries - Surgery

• 45 children with renovascular FMD, 17 with aortic involvement• Average age at diagnosis was 9 years• Three with renal failure• Twenty-three of the 45 had bilateral vessel involvement• A variety of surgical approaches were used depending on the

pathology encountered• Thirty-eight patients underwent revascularization, seven underwent

primary nephrectomy, five underwent primary partial nephrectomy,and 12 had aortoaortic bypass performed

• Seventy percent were cured, 26% improved; and 4% did notrespond to treatment with up to 16 years of follow-up

• There was no mortality.

O'Neill JA Jr.Long-term outcome with surgical treatment of renovascular hypertension. Pediatr Surg 1998;33(1):106-11

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Carotid Arteries

•Palubinskas and Ripley (1964) described a case of FMDinvolving the extracranial internal carotid artery1

•Carotid arteries (95%) frequently bilaterally2

•Vertebral involvement is rare and usually associated withcarotid involvement3

•Predominately affects extracranial segments

1Palubinskas AJ and Ripley HR Radiology 1964, 2Healton EB In Stroke:Pathophysiology,Diagnosis, and Management 1986, 3Osborn AG and Anderson RE Stroke 1977

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Carotid Arteries

Panel C, a 16 row multidetector of the ICA Panel D, duplex ultrasonography of the ICA.

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Carotid Arteries

See Examples of FMD:

Panel A–severe concentric stenosisin the ICA.

Panel B–ICA after percutaneousangioplasty.

Panel C–shows sever redundancy &a kink in the distal ICA.

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Carotid Arteries - Natural History

•Look at clinical outcome, not angiographic progression–Corrin (1981) 79 patients, 3 strokes (3.8%)•13 TIA/CVA, 10 SAH, TX [4 OR, 11 med]

–Wells (1982) 17 patients, 2 strokes* (13%)•9 TIA, TX [1 OR, 3 med]

–Stewart (1986) 45 patients, 0 strokes (0%) in the 35 who did nothave an operation•10 OR <3mos, 23/35 TIA/CVA only 1 symptomatic

Corrin LS et al Arch Neurol 1981, Wells RP and Smith RRNeurosurgery 1982, Stewart MT et al J Vasc Surg 1986

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Carotid Arteries - Diagnosis

• Angiography remains the gold standard– “String of beads”, smooth tubular stenoses, diverticula, well-

defined webs or septations1

– FMD has been associated with carotid kinks2

• Carotid duplex ultrasonography3

• Magnetic resonance angiography4

1Osborn AG and Anderson RE Stroke 1977, 2Schneider PA and Rutherford RB In Vascular Surgery 2000,3Boespflug OJM Neuroradiology 1985, 4Heiserman JE et al AJNR 1992

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Carotid Arteries - Treatment

• Stop smoking• Antiplatelet therapy• Intervention– Surgery including a resection with end-to-side anastomosis (or

interposition graft), endarterectomy, carotid-middle cerebral arterybypass

– Graduated intraluminal dilatation– Percutaneous transluminal angioplasty

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Carotid Arteries - Treatment

1.3%0%2.9%2.6%7.7%70(78)

Chiche(1997)

0%2.9%1.2%1.7%6.0%115(168)

Schneider(1994)

0%2.8%3.8%1.4%1.4%58(72)

Moreau(1993)

0%N/A4.6%2.3%6.2%86(130)

Effeney(1980)

PeriopDeath

Late OccStenosis

Late CVAOpCVAOpTIA#Pts(#op)

Study

Effeney DJ et al Arch Surg 1980, Moreau P et al J Cardiovasc Surg 1993, Schneider PAet al In Vascular Surgery:Principles and Practice 1994, Chiche L et al Ann Vasc Surg 1997

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Carotid Arteries - Associated Conditions

•Intracranial “berry” aneurysms– Incidence 21% to 51%1

–Multiple, found predominately in the internal carotid and middlecerebral arteries2

–Obtain a MRA for screening

•Dissections3

•Arteriovenous fistulas4

1Healton EB In Stroke:Pathophysiology, Diagnosis, and Management 1986, 2Mettinger KL Stroke1982, 3Müller BT et al J Vasc Surg 2000, 4Hieshima GB et al Neurosurgery 1986

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Non-Renal Abdominal Viscera

•Celiac, superior mesenteric, inferior mesenteric, hepatic,and splenic arteries

•More typically appear as long tubular stenoses1

•Component of a systemic process mimicking vasculitis(intimal FMD)

1Lüscher TF et al Mayo Clin Proc 1987

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Non-Renal Abdominal VisceraPresentation & Treatment

• Asymptomatic• Mesenteric ischemia1

– postprandial pain, weight loss, epigastric bruit

• Abdominal pain due to ruptured aneurysm2

• Bowel infarction is rare3

• Treatment with percutaneous transluminal angioplastyor surgical revascularization

1Yamaguchi R et al Am J Gastro 1996, 2Jones HJ et al J Rheumatol 1998,3Hamed RMA and Ghandour K J Pediatr Surg 1997

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Peripheral Arterial Disease

•Lower extremities–External iliac, femoral popliteal, tibial, peroneal–Digital ischemia, intermittent claudication, acute limb ischemia1

•Upper extremities–Subclavian, axillary, brachial, radial, ulnar–Arm claudication, paresthesias, subclavian steal syndrome,

weakness, ischemic digits (hypothenar hammer syndrome)

1Sauer L et al J Vasc Surg 1990

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Summary

•FMD can occur in almost any arterial bed•Angiography remains the diagnostic test of choice but

other, less invasive techniques may be useful•All patients must stop smoking and be treated with an

antiplatelet agent• Intervention should be reserved for symptomatic patients

FMD Case Studies

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• MF a 14 year old male• Routine physical examination

found to have hypertension• No symptoms or signs by

history or on examination

• BP 170/105 mmHg on repeatmeasurements

• EKG/ECHO–LV+• Metabolic panel normal

Case Study 1

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DMSA showsno scarring withequal uptake byboth kidneys

Case Study 1

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Case Study 1

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Case Study 1

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•Management–Antihypertensives–Right nephrectomy after failed repair to a large thin walled extra-

parenchymal aneurysm

•Follow- up–No further hypertension, off all medications. No indication of any

further vessel involvement after 36 months follow up.

Case Study 1

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Case Study 2

• GB 13 year male• Presented with severe hypertension• Found by routine school screening• Poorly functional right kidney, small size , severe right renal artery

stenosis• Normal left kidney and normal vessels• Right nephrectomy–off blood pressure medications

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Case Study 2

• GB now 15 years old• Severe hypertension recurred• Left kidney now with stenosis• Repeated balloon dilatation• Ongoing need for blood pressure medication

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Gerard Burns

Left kidney withtrident renal arterysub-branchinvolvement

Case Study 2

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• Patient JB• Found to have HTN on routinePediatrician’s visit

• Past history of trauma to the rightflank and back related tobaseball

• BP elevated to 160/100 mmHg

• LVH• Non-functional right kidney with

severe right renal arterynarrowing

• Unilateral Nephrectomy• No HTN after 3 years of follow up

Case Study 3

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For more information

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P.O. Box 999, Hudson, OH 44236-0999

(330) 653-8416

www.fmdsa.org admin@fmdsa.org