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Dilatative arteriopathy (dolichoectasia) What is known and not known.

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EDITORIAL
Dilatative Arteriopathy (Dolichoectasia):
What Is Known and Not Known
Dolichoectasia describes enlarged, tortuous, and dilated
arteries. Because dilatation seems to be the most important feature, the condition is now often referred to
as dilatative arteriopathy. Dilatation can be severe in
portions of an artery in which the vessels become fusiform aneurysms. Recently, as a part of the French
study of the genetic profile of cerebral infarcts case–
control study (GENIC), the investigators have explored
the associations of intracranial dolichoectasia with
other vascular lesions, stroke mechanisms, and arterial
lesions.1–3 In this issue of the Annals, the GENIC investigators convincingly show an association between
intracranial dolichoectasia and all of the manifestations
of penetrating artery-related infarction and white matter disease.1 Knowledge about dilatative arteriopathy is
growing but there is still much that is not understood.
Location and Clinical Findings
Dilatative arteriopathy involves preferentially the intracranial vertebral and basilar arteries. Carotid and middle cerebral artery ectasia occurs but much less often.
The clinical findings in patients with intracranial arterial dolichoectasia have now been well described. We
know that dilatative arteriopathy can cause strokes.
Elongation and angulation of the intracranial arteries
can stretch and distort the orifices of arterial branches
leading to decreased blood flow especially in penetrating branches of the large arteries, causing, for example,
basilar artery branch territory infarcts in the pons.4,5
Transcranial Doppler studies of dolichoectatic arteries
show reduced mean blood flow velocities, with relatively preserved peak flow velocities.6,7 Blood flow is
often to and fro within the dilated artery causing reduced antegrade flow.6.7 The reduced antegrade flow
may lead to poor opacification on magnetic resonance
angiography, even falsely suggesting occlusion of the
dolichoectatic artery. Reduced flow can lead to stagnation of the blood column and thrombus formation
within the dilated arterial segment.4,8 Extensive atherosclerotic plaques, often with calcification, encroachment on the lumen, and thrombus formation, are often found at necropsy. On microscopic examination,
there are often fibrotic changes in the vessel wall, with
reduced muscularis and attenuated, fragmented, or absent elastica.3,9 Luminal thrombi may obstruct arterial
branches and portions of the clot can embolize distally.4,8 Brain ischemia either transient or persistent results. Occasionally the thin dilated arteries break leading to subarachnoid and brain hemorrhage. 4,8,10
The tortuous elongated arteries can generate pressure
and distortion of brain structures especially in the medulla and pons. Stretching of cranial nerves can lead to
irritative symptoms such as trigeminal pain and hemifacial spasm11 and tinnitus. Lower cranial nerve neuropathies are also common.12 Rarely, the dilated arteries compress the third ventricle contributing to
hydrocephalus.
Occurrence, Pathology, and Associations
Approximately one patient in eight who has brain imaging has some increase in the length and diameter of
intracranial arteries.2,13 Although most often recognized in adults, dilatative arteriopathy does occur in
children and adolescents. Hereditary factors probably
play an important role especially in the young. In one
family, three brothers all had large fusiform basilar artery aneurysms and all had ␣-glucosidase deficiency.14
Necropsy in an 11-year-old girl who died from a ruptured dolichoectatic basilar artery aneurysm showed
that the artery had large gaps in the internal elastic
lamina with only short segments of elastica remaining
in some regions.15 The pathology in other young patients with dolichoectasia has shown deficiencies in the
muscularis and internal elastic lamina with irregular
thickness of the media, multiple gaps in the internal
elastica, and regions of fibrosis. At times, the intima is
thickened, and there is severe elastic tissue degeneration
and an increase in the vasa vasorum.16 Dolichoectasia
occurs in young patients with Marfan’s syndrome17,18
and in Ehlers–Danlos syndrome. Children with AIDS
and Fabry’s disease19 and children and adults with
sickle cell disease also may develop dolichoectatic intracranial arteries. Genetic, infectious, inflammatory, immunological, and degenerative factors all may cause or
contribute to the formation and progression of dolichoectasia.
The GENIC Study
In the GENIC study, 510 patients with strokes and
brain infarcts on magnetic resonance imaging were recruited among 12 French neurological centers.1–3 All
patients were white, and both parents also had to be
white. Characterization of the presence or absence of
intracranial arterial dolichoectasia was made by consensus of two neurologists who reviewed the brain and
vascular imaging examinations. This methodology
highlights the fact that there are no generally accepted
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
469
quantitative criteria for the diagnosis of dilatative arteriopathy. Patients accepted as having dolichoectasia
had to have at least one intracranial artery in the highest quartile of vascular diameter. The GENIC investigators showed that stroke patients with dolichoectasia
had significantly larger diameters of their thoracic aortas than patients without dolichoectasia.2 This finding
suggested that dilatative intracranial arteriopathy was a
systemic problem and not one that was limited to the
brain-supplying arteries.
The GENIC investigators studied the association of
intracranial arterial dolichoectasia with stroke subtypes
and stroke risk factors and found that dilatative arteriopathy was associated with older age, male sex, hypertension, and a history of myocardial infarction.3 Lacunar infarcts but not evidence of carotid artery
atherosclerosis was associated with dolichoectasia.3 In
the investigations reported in this issue of the Annals,
the GENIC investigators showed that not only did patients with dolichoectasia have lacunar infarcts, they
also had significantly more imaging evidence of multiple lacunes, severe leukoaraiosis, and severe etat crible
(dilated Virchow–Robin spaces around penetrating arteries).1 The white matter lesions and lacunar infarcts
are generally attributed to disease of small penetrating
intracranial arteries. Therefore, intracranial dolichoectasia is likely a part of systemic involvement of at least
some systemic large arteries and is also associated with
microsopic-sized arterial disease.
The Arterial Media and Elastica
The bulk of research on arterial diseases that cause
brain ischemia emphasizes the intima and endothelial
portions of large extracranial arteries. The medial and
adventitial coats of arteries have received much less attention. Plaque formation and narrowing of arteries has
received much more attention than arterial dilatation.
Clearly, dolichoectasia relates to abnormal connective
tissue composition and function in large arteries. Two
other conditions, fibromuscular dysplasia and arterial
dissections, also involve the arterial wall.
The Link between Abnormal Connective Tissue
in Penetrating Arteries and White Matter
Abnormalities
Penetrating arterial pathology involves thickening of
the arterial media that contains abnormal amounts of
fibrinoid material and lipids. Dilatative arteriopathy
and penetrating arterial disease have in common the
fact that they are both diseases of the arterial wall
rather than intimal-endothelialopathies. Abnormal connective tissue within the arterial wall affects biochemical constituents such as matrix metalloproteinases. Abnormal composition of matrix metalloproteinases can
alter vascular permeability. Rosenberg and colleagues
have shown that disease of the arterial media is accom-
470
Annals of Neurology
Vol 57
No 4
April 2005
panied by upregulation of matrix metalloproteins.20,21
Increased activity of matrix metalloproteins makes
small arteries more permeable and loosens the blood–
brain barrier. In patients with severe white matter disease, extracellular matrix macromolecules are found in
increased concentrations around lacunar infarcts and
within the abnormal white matter.20 Loosening of the
blood–brain barrier can permit proteins and fluid to
leak from the abnormal walls of the penetrating arteries
and can lead to chronic demyelination, gliosis, and
white matter damage—leukoariosis. 20,22
Clearly, we need to know much more about the
constituents of the arterial wall and their abnormalities.
How do the connective tissue abnormalities cause arterial dilatation? How does abnormal function of the arterial wall lead to dilatation and clinical disease? Further study of arterial dolichoectasia may yield
important clues to many present cerebrovascular mysteries.
Louis R. Caplan, MD
References
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dolichoectasia and small vessel disease in stroke patients. Ann
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Neurology 2004;63:2016 –2021.
3. Pico F, Labreuche J, Touboul P-J, et al. Intracranial arterial
dolichoectasia and its relation with atherosclerosis and stroke
subtype. Neurology 2003;61:1736 –1742.
4. Pessin MS, Chimowitz MI, Levine SR, et al. Stroke in patients
with fusiform vertebrobasilar aneurysms. Neurology 1989;39:
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5. Passero S, Filosomi G. Posterior circulation infarcts in patients
with vertebrobasilar dolichoectasia. Stroke 1998;29:653– 659.
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14. Makos MM, McComb RD, Hart MN, Bennett DR. Alphaglucosidase deficiency and basilar artery aneurysm: report of a
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15. Read D, Esiri MM. Fusiform basilar artery aneurysm in a child.
Neurology 1979;29:1045–1049.
16. Hirsch CS, Roessmann U. Arterial dysplasia with ruptured basilar artery aneurysm: report of a case. Hum Pathol 1975;6:
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17. Silverman IE, Berman DM, Dike GL, et al. Vertebrobasilar
dolichoectasia associated with Marfan syndrome. J Stroke Cerebrovasc Dis 2000;9:196 –198.
18. Zambrino CA, Berardinelli A, Martelli A, et al. Dolichovertebrobasilar abnormality and migraine-like attacks. Eur Neurol 1999;41:10 –14.
19. Mitsias P, Levine SR. Cerebrovascular complications of Fabry’s
disease. Ann Neurol 1996;40:8 –17.
20. Rosenberg GA, Sullivan N, Esiri MM. White matter damage is
associated with matrix metalloproteinases in vascular dementia.
Stroke 2001;32:1162–1168.
21. Pfefferkorn T, Rosenberg GA. Closure of the blood-brain barrier by matrix metalloproteinase inhibition reduces the rtPAmediated mortality in cerebral ischemia with delayed reperfusion. Stroke 2003;34:2025–2030.
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DOI: 10.1002/ana.20447
Caplan: Dilatative Arteriopathy
471
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