Case of the Week
Section Editors: Matylda Machnowska1 and Anvita Pauranik2
1University of Toronto, Toronto, Ontario, Canada
2BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
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June 16, 2022
ACTA2-related Cerebrovascular Disease
- Background:
- ACTA2-related cerebrovascular disease (ARCD) is a newly defined disorder resulting from a mutation in the ACTA2 gene, which leads to diffuse vascular smooth muscle dysfunction and a unique cerebral arteriopathy. This characteristic cerebral arteriopathy leads to ischemic events in younger individuals.
- The ACTA2 gene encodes for alpha-smooth-muscle-actin, a significant component of the contractile units of vascular smooth muscle cells. However, it is not expressed in the brain parenchyma itself.
- ACTA2 mutations have a gain of function effect, leading to vascular smooth muscle cell proliferation with medial fibrosis and, consequently, occlusion of arteries.
- There is no conclusive reasoning for the exact mechanism that leads to the neuroradiologic findings, but the general hypothesis is that the increased rigidity likely results in the characteristic straight appearance of the vessels. These vessels are thought to produce a local mechanical effect on the brain parenchyma during embryologic development, which leads to the morphologic brain abnormalities seen.
- To our knowledge and based on a review of the literature, this is the oldest patient with an initial presentation of an acute ischemic event stemming from ARCD.
- Clinical Presentation:
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The multisystem smooth muscle dysfunction seen with ACTA2 mutations predisposes patients to early ischemic cerebrovascular events, usually initially presenting in the pediatric population. Nevertheless, the brain malformations seen do not appear to have any other specific clinical associations.
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Epilepsy is rare aside from that due to cerebral ischemia.
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There is also no current evidence that these malformations directly lead to intellectual abnormalities other than those seen following brain injury from hypoperfusion.
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- Key Diagnostic Features:
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Common neuroradiologic findings seen in individuals with ARCD include:
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Dilation of the proximal internal carotid arteries with stenosis of the distal aspect; straight, “broomsticklike” arteries of the circle of Willis; and an absence of basal lenticulostriate collaterals
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A characteristic V-shaped anterior corpus callosum with excessive inferior bending and hypoplasia, along with an apparent absence of the anterior cingulate gyrus
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Atypical radial gyration of the frontal lobes
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A “twin peaks” pons, which describes flattening of the pons on the midline with an impression of the basilar artery on the anterior surface
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Colpocephaly-like dilatation of the trigone and occipital horns of the lateral ventricles (this has been linked to white matter dysfunction and is suggestive of chronic periventricular white matter damage from ischemia in ARCD patients)
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- The diagnosis of ARCD is highly suggested by these characteristic imaging findings, with confirmation achieved through genetic testing.
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- Differential Diagnoses:
- ARCD was previously considered a variant of Moyamoya disease but is now classified as a novel, separate cerebrovascular disorder. While the straight arterial course can be seen in both, a key distinguishing feature is the absence of the “puff of smoke” basal lenticulostriate collateral vessels characteristically seen in Moyamoya disease. Other differences from Moyamoya disease include a more diffuse cerebrovascular arteriopathy, dilation of the internal carotid artery, and arterial ectasia. Furthermore, white matter disease is a distinctive feature of ARCD and is rarely seen in Moyamoya disease.
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Cortical malformations such as focal cortical dysplasia, polymicrogyria, agyria, or pachygyria have not been observed in patients with ARCD.
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Treatment:
- There are currently no standard indications for neurosurgical revascularization in these patients. This may be due in part to the high risk of postoperative stroke as well as the scarcity of reported cases.
- While direct and indirect revascularization techniques are the primary treatment options for Moyamoya disease and exhibit a significant protective effect in preventing stroke recurrence, a similar effect has not been observed in patients with ACTA2 cerebral arteriopathy. Some studies have reported a successful revascularization strategy following an encephaloduroarteriomyosynangiosis (EDAMS) procedure for preventing future ischemic infarcts. However, surgical interventions in these patients must be undertaken with extreme caution, as the vascular fragility can lead to rupture and death.
- Proposed screening and surveillance recommendations include a baseline brain MRI along with magnetic resonance angiography of the head and neck at the time of diagnosis. This can help elucidate the degree of cerebrovascular stenosis along with screening for current or past ischemic insults. Furthermore, transcranial Doppler ultrasonography can be utilized to monitor cerebrovascular disease progression, but optimal surveillance techniques and intervals are yet to be established.
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