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(Stroke. 1995;26:1935-1940.)
© 1995 American Heart Association, Inc.

Articles

Familial Aorto-Cervicocephalic Arterial Dissections and Congenitally Bicuspid Aortic Valve

Wouter I. Schievink, MD Bahram Mokri, MD

From the Departments of Neurologic Surgery (W.I.S.) and Neurology (B.M.), Mayo Clinic, Rochester, Minn.

	Abstract

Top Abstract Introduction Description of Families Discussion References

 
Background A primary arteriopathy is often implicated in the etiology of spontaneous cervicocephalic arterial dissections, but its exact nature usually remains unknown. We describe the familial occurrence of spontaneous arterial dissections and congenitally bicuspid aortic valve (BAV) and propose a common developmental defect in these families.

Summary of Report In the first family, a 63-year-old man suffered an extracranial internal carotid artery (ICA) dissection, and his 43-year-old cousin with BAV suffered an intracranial vertebral artery (VA) dissection. Two other family members had pathologically proven BAV. In the second family, a 31-year-old woman suffered bilateral extracranial ICA and VA dissections. Her father, at age 46, suffered an aortic dissection associated with cystic medial necrosis and BAV. Her paternal uncle died from an aortic dissection at age 59. In the third family, a 39-year-old woman suffered extracranial ICA and VA dissections, and her brother died at age 48 from an aortic dissection associated with a BAV.

Conclusions The familial occurrence of spontaneous arterial dissections and BAV suggests a common developmental defect. The aortic valvular cusps and the arterial media of the aortic arch and its branches are derived from neural crest cells, suggesting that a neural crest defect may be the underlying abnormality in these families.

Key Words: aorta • carotid arteries • cerebrovascular disorders • dissection • vertebral arteries

	Introduction

Top Abstract Introduction Description of Families Discussion References

 
Dissections of the cervicocephalic arteries are an important cause of ischemic stroke in young and middle-aged people.¹ The annual incidence of spontaneous dissection of the extracranial internal carotid artery (ICA), the most frequently involved vessel, is approximately 2.5 to 3.0 per 100 000 population.^{2 3}

The etiology and pathogenesis of cervicocephalic arterial dissections are poorly understood, but a primary arteriopathy is often implicated, particularly when the arterial dissection is spontaneous and the patient is young. Nevertheless, the nature of the putative underlying arteriopathy remains unknown in the great majority of patients.^{4 5} Several studies have implicated a genetically determined arteriopathy in patients with spontaneous cervical artery dissections.^{6 7 8 9} Among approximately 240 patients with spontaneous cervical artery dissections evaluated at the Mayo Clinic between 1970 and 1992, eight had a family history of arterial dissection. Four of these families have been described previously.^{6 9}

In the present report we describe the familial occurrence of spontaneous arterial dissections and congenitally bicuspid aortic valve (BAV) in three families and propose a common developmental defect in these families. None of these families have been reported previously.

	Description of Families

Top Abstract Introduction Description of Families Discussion References

 
Clinical characteristics of the affected family members are summarized in the Table.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Affected Family Members

Family A (Fig 1)
Subject III₈
A 63-year-old man, the propositus, suffered transient dysphasia, right hemiparesis, and left monocular blindness. He had undergone bilateral inguinal hernia repairs at age 23 and had been known to be hypertensive since age 41. Physical examination was normal. A CT scan of the head was normal. Echocardiography showed aortic valve sclerosis with mild aortic regurgitation, but the exact number of valves could not be determined. Angiography demonstrated a dissection of the left extracranial ICA associated with an intimal flap extending into the petrous portion of the ICA (Fig 2). Multiple luminal irregularities were noted in the distal left common carotid artery.

View larger version (22K): [in this window] [in a new window]   Figure 1. Pedigree of family A.

View larger version (148K): [in this window] [in a new window]   Figure 2. Left carotid angiogram (anteroposterior view) demonstrates a dissection of the internal carotid artery with an intimal flap (arrowheads) extending into the petrous segment of the artery.

At age 77, the patient developed a bifrontal headache followed by gait unsteadiness, vertigo, and hiccups. Neurological examination was significant for truncal ataxia only. A head CT was normal. An MR image of the head showed an area of increased T₂ signal in the right posterior medulla compatible with infarction. Angiography showed a chronic dissection of the left ICA, but the posterior circulation was normal.

Subject V₁
A 43-year-old man, a distant cousin of the propositus, developed an occipital headache associated with abruptly turning his head, followed by gait unsteadiness. His medical history was significant for aortic insufficiency since age 20 years, which was associated with aortic root dilatation and a BAV, as demonstrated on echocardiography. His blood pressure was 140/80 mm Hg, and cardiac auscultation revealed a systolic ejection murmur and a decrescendo diastolic murmur. Neurological examination showed right peripheral seventh and tenth cranial nerve pareses, right Horner's syndrome, and ataxia. A cranial CT scan and examination of cerebrospinal fluid were normal. Angiography revealed a dissection of the intracranial right vertebral artery (VA) just distal to the posterior inferior cerebellar artery, manifested by a high-grade smooth stenosis. The patient recovered slowly from his dysphagia, necessitating a temporary gastrostomy. No new vascular events have developed during 2 years of follow-up.

Subjects IV₃ and III₇
Subjects IV₃ and III₇ suffered ischemic strokes of uncertain etiology at the age of 59 years and 60 years, respectively. Subject IV₃ had severe aortic valve stenosis with moderate insufficiency and was found to have a BAV and aortic root dilatation at surgery. Preoperative echocardiography had failed to demonstrate a BAV. Subject III₇ was found to have a BAV as an incidental finding at postmortem examination.

Family B (Fig 3)
Subject III₁
A 31-year-old woman, the proposita, developed a right-sided headache followed 2 weeks later by vertigo, nausea, left hemifacial numbness, and pulsatile tinnitus. Her medical history was significant for a right inguinal hernia repair at age 3, and she had been hypertensive since age 19. General medical examination was normal. Neurological examination showed absent hearing on the right, bilateral peripheral seventh cranial nerve pareses, a right sixth cranial nerve paresis, bilateral hypesthesia in a V₂ distribution, left-sided dysmetria, and ataxia. Angiography demonstrated bilateral extracranial VA dissections, manifested by occlusion on the right at the C2 level and a high-grade stenosis on the left extending from the C2 level to the origin of the basilar artery. The patient recovered from her strokes with only mild residual ataxia.

View larger version (17K): [in this window] [in a new window]   Figure 3. Pedigree of family B.

Seven years later the patient developed diplopia and right periorbital pain. Neurological examination showed a right third cranial nerve paresis and mild gait ataxia. MRI showed bilateral subacute hematomas in the wall of the extracranial ICAs (Fig 4) and old bilateral posterior fossa infarcts. Angiography showed extensive bilateral extracranial ICA dissections. The appearance of the left VA had normalized, and the right VA showed a moderate degree of residual irregular stenosis. Her third cranial nerve paresis resolved, and no new vascular episodes have developed during 2 years of follow-up.

View larger version (139K): [in this window] [in a new window]   Figure 4. Axial T1-weighted MR image shows crescenteric high signal abnormalities in the wall of both extracranial internal carotid arteries, consistent with intramural hemorrhage (arrows). At this level, the dissection has resulted in marked luminal compromise of the right internal carotid artery.

Analysis of the type III procollagen gene in cultured skin fibroblasts was normal.⁵

Subject II₂
A 46-year-old man, the father of the proposita, experienced an acute onset of chest pain. His medical history was significant for bilateral inguinal hernia repair at age 19 years and hypertension since age 34 years. Cardiac auscultation revealed systolic and diastolic cardiac murmurs consistent with aortic stenosis and insufficiency. Aortography demonstrated aortic root dilatation and an aortic dissection. At surgery, a tear was identified opposite the left subclavian artery, and the dissection was noted to extend into both common iliac arteries. He underwent a bypass graft to both groins but developed right leg ischemia postoperatively, and a femoral saphenous vein bypass graft was successfully performed.

At age 58 years the patient underwent replacement of his dilated ascending aorta and aortic valve replacement for aortic stenosis and insufficiency related to a BAV. Moderately severe cystic medial necrosis of the resected aortic segment was noted (Fig 5). One year later he underwent coronary artery bypass surgery for angina pectoris. He has remained asymptomatic during an additional 7 years of follow-up.

View larger version (166K): [in this window] [in a new window]   Figure 5. Longitudinal section of aorta shows disorganization and fragmentation of elastic fibers (elastic–van Gieson stain; magnification x10).

Analysis of the type III procollagen gene in cultured skin fibroblasts was normal.¹⁰

Subject II₅
A 59-year-old man, a paternal uncle of the proposita, developed severe chest pain. He had been diagnosed with labile hypertension at age 50 years. On admission to the hospital he was hemodynamically stable. A chest film was normal. Several hours later he again developed chest pain. Shortly thereafter he experienced cardiorespiratory arrest. A chest film now showed a markedly widened mediastinum, diagnostic of aortic dissection. Resuscitations were unsuccessful, and the patient died. An autopsy was not performed.

Family C (Fig 6)
Subject II₅
A 39-year-old woman, the proposita, developed a left-sided headache and several episodes of transient right hemiparesis with dysphasia. Neurological examination showed left miosis and ptosis. A head CT was normal. Angiography demonstrated a subcranial dissecting aneurysm of the left ICA associated with irregular stenosis of its proximal extracranial portion.

View larger version (18K): [in this window] [in a new window]   Figure 6. Pedigree of family C.

No further spells occurred until 9 years later, when she developed two episodes of transient right hemiparesis and dysphasia. Her blood pressure was 120/82 mm Hg. Physical examination was normal. Echocardiography showed mild mitral valve prolapse only. Angiography revealed a soft thrombus arising from the known left internal carotid dissecting aneurysm, which had not changed in size, and near complete resolution of the area of stenosis. Luminal irregularities were now noted in the right extracranial ICA. The VAs were normal. She was treated with anticoagulation. On repeat angiography 3 months later, the thrombus had resolved, and the subcranial ICA dissecting aneurysm had not changed in size (Fig 7). However, a new dissecting aneurysm of the left extracranial VA had now developed at the level of C4. No vascular events were noted during 9 years of further follow-up.

View larger version (74K): [in this window] [in a new window]   Figure 7. Left carotid angiogram (anteroposterior view) demonstrates a dissecting aneurysm (arrow) of the distal extracranial internal carotid artery.

Analysis of the type III procollagen gene in cultured skin fibroblasts was normal.⁵

Subject II₁
A 48-year-old man, a brother of the proposita, developed severe chest pain and transient right hemicorporal numbness. On examination his blood pressure was 160/100 mm Hg, the right femoral pulse was absent, and the right leg was cold. Neurological examination was normal. Two days later he had a seizure followed by cardiorespiratory arrest. Postmortem examination revealed an intimal tear of the ascending aorta with hemopericardium and a BAV. The dissection started immediately above the aortic ring and extended into the right innominate, left common carotid, left subclavian, and both common iliac arteries. Microscopic examination confirmed a medial dissection but showed no underlying abnormalities of the arterial wall (Fig 8).

View larger version (179K): [in this window] [in a new window]   Figure 8. Cross section of the left common carotid artery demonstrating an intramural hematoma within the media (asterisk) compressing the true lumen (t) of the artery (elastic–van Gieson stain; magnification x8).

	Discussion

Top Abstract Introduction Description of Families Discussion References

 
Numerous families with arterial dissections have been described,^{6 8 9 11 12 13 14 15 16 17 18 19 20 21 22 23 24} including 10 with at least one member with involvement of the carotid or vertebral arteries.^{6 8 9 14 18 23} Of all these families, the presence of BAV was only noted in a father and son with aortic dissection and cystic medial necrosis reported by McKusick.¹² Several families with BAV but without arterial dissection have also been described,^{25 26 27 28 29} and screening for asymptomatic BAV has been recommended for first-degree relatives.²⁹ A familial aggregation of BAV and spontaneous cervicocephalic arterial dissections has not been previously appreciated.

In the three presently described families, affected members had either spontaneous arterial dissection, BAV, or both. In addition, cystic medial necrosis was found in one of the two patients whose tissue was available for microscopic examination. Although echocardiography showed no evidence for BAV in two of our patients with cervical artery dissections, the sensitivity of echocardiography in identifying BAV is only approximately 78%,³⁰ and the presence of a BAV cannot be excluded with certainty. Autosomal dominant inheritance with variable penetrance and expression appears to be the most likely mode of genetic transmission in two of our families. In the third family only two siblings were known to be affected, and the mode of inheritance is uncertain. There was no evidence in our families for such heritable connective tissue disorders as Marfan's syndrome or Ehlers-Danlos syndrome, which predispose to arterial dissections³¹ and which also have been associated with BAV.^{32 33} Also, there was no evidence for a mutation in the type III procollagen gene (the underlying defect in Ehlers-Danlos syndrome type IV) in the two families that were tested for such a mutation.^{5 10}

Congenitally BAV is one of the most common forms of congenital heart disease in adults and is found in approximately 1% of the population.³⁴ Some patients with BAV remain asymptomatic throughout life, but most eventually develop aortic insufficiency or aortic stenosis.³⁴ Ischemic stroke due to thrombotic or calcific embolization from a BAV has occasionally been reported.^{35 36}

An association of BAV with aortic coarctation, aortic dissection, aortic root dilatation, and cystic medial necrosis has been well established.^{37 38 39 40 41 42 43 44 45 46} Cervicocephalic arterial dissections have also been associated with aortic coarctation^{9 47} and cystic medial necrosis.^{48 49 50} Several studies have shown that BAV is a frequent finding in patients with aortic dissection, particularly in young adults.^{40 41 42} Conversely, among all patients with BAV, aortic dissection is the cause of death in approximately 5%,³⁹ and aortic root dilatation has been reported in more than 50% of affected individuals.^{42 43 45 46} BAV is found in approximately half of patients with coarctation of the aorta, and the association of aortic coarctation with aortic dissection may be mainly a reflection of the presence of BAV.^{37 38 42 44} Cystic medial necrosis of the aorta is commonly identified in patients with BAV as well as in those with aortic coarctation, and this is not related to the presence of arterial hypertension.^{40 41} In addition, aortic root dilatation in patients with BAV has been shown to be unrelated to any hemodynamic changes caused by the abnormal aortic valve,^{43 45} and a common developmental defect is generally implicated in BAV and its associated aortic abnormalities. The possible interrelationship of BAV and its associated arterial abnormalities is presented in Fig 9.

View larger version (21K): [in this window] [in a new window]   Figure 9. Schematic representation of the possible interrelationship of congenitally bicuspid aortic valve and its associated arterial abnormalities.

The left ventricular outflow tract, including the aortic valvular cusps, and the media of the aortic arch and its branches are all derived from cells originating in the neural crest.^{51 52 53} The neural crest is a transient structure in early embryogenesis,⁵¹ and a disorder of neural crest cell migration could possibly explain the findings of arterial dissection, BAV, and cystic medial necrosis in our families. The neural crest has been implicated previously in the development of cervicocephalic arterial dissections.^{9 54}

In conclusion, we describe three families with BAV, cystic medial necrosis, and (or) spontaneous arterial dissections involving the cervicocephalic vessels or the aorta. A common genetically determined developmental defect, possibly involving the neural crest, may be implicated in the familial occurrence of cervicocephalic arterial dissections and BAV.

	Footnotes

 
Reprint requests to Dr Wouter I. Schievink, Department of Neurologic Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

Received April 24, 1995; revision received July 17, 1995; accepted July 17, 1995.

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