Systemic and CNS manifestations of inherited cerebrovascular malformations

Blaine L Hart, Marc C Mabray, Leslie Morrison, Kevin J Whitehead, Helen Kim, Blaine L Hart, Marc C Mabray, Leslie Morrison, Kevin J Whitehead, Helen Kim

Abstract

Cerebrovascular malformations occur in both sporadic and inherited patterns. This paper reviews imaging and clinical features of cerebrovascular malformations with a genetic basis. Genetic diseases such as familial cerebral cavernous malformations and hereditary hemorrhagic telangiectasia often have manifestations in bone, skin, eyes, and visceral organs, which should be recognized. Genetic and molecular mechanisms underlying the inherited disorders are becoming better understood, and treatments are likely to follow. An interaction between the intestinal microbiome and formation of cerebral cavernous malformations has emerged, with possible treatment implications. Two-hit mechanisms are involved in these disorders, and additional triggering mechanisms are part of the development of malformations. Hereditary hemorrhagic telangiectasia encompasses a variety of vascular malformations, with widely varying risks, and a more recently recognized association with cortical malformations. Somatic mutations are implicated in the genesis of some sporadic malformations, which means that discoveries related to inherited disorders may aid treatment of sporadic cases. This paper summarizes the current state of knowledge of these conditions, salient features regarding mechanisms of development, and treatment prospects.

Keywords: Arteriovenous malformation; Capillary malformation-arteriovenous malformation; Cerebral cavernous malformation; Cerebrovascular malformations; Neurocutaneous syndrome.

Copyright © 2021 Elsevier Inc. All rights reserved.

Figures

Fig. 1—
Fig. 1—
Familial cerebral cavernous malformations (CCMs). 63-year-old woman with hemiplegia and gait difficulties. Axial MRI, FSE T2 (A), T2 GR (B), and SWI (C), show numerous CCMs, ranging from a large, reticulated type right occipital CCM to multiple small, mixed-signal-intensity CCMs to a large number of smaller lesions, including one in the splenium of the corpus callosum, with progressively more seen on GR and SWI.
Fig. 2--
Fig. 2--
Sporadic cerebral cavernous malformation and developmental venous anomaly. 65-year-old man with acute mental status change. A. Nonenhanced CT revealed irregular left frontal lobe calcification. B. MRI, axial TSE T2 performed soon after showed no acute hemorrhage but typical reticulated appearance of CCM with hemosiderin rim. C. MRI, coronal post gadolinium T1 shows that the CCM (arrow) lies at the inferior margin of a DVA with superficially draining collector vein.
Fig. 3—
Fig. 3—
Spinal cord cavernous malformations. 17-year-old male with left shoulder and arm pain. Sagittal T1 (A) and TSE T2 (B) MRI shows complex region of hemorrhage including fluid-fluid layer, swelling, and edema, originally suspected to be neoplasm. Brain MRI showed several small cavernous malformations. Spinal cord cavernous malformation was resected, with good outcome. CCM1 mutation confirmed after initial presentation. Compare with cavernous malformation without acute hemorrhage in the ventral spinal cord (arrow) at C7 in a 58 year-old-woman with right upper extremity weakness and numbness (C, sagittal T2). Brain MRI revealed multiple cavernous malformations.
Fig. 4—
Fig. 4—
Skin vascular malformation in familial CCM. 29-year-old woman with familial cerebral cavernous malformations and lobulated vascular lesion in dorsal soft tissues of right hand had MRI. Coronal T1 (A) and T2 STIR (B), demonstrate lobulated lesion in the soft tissue. Multiple CCMs were present on brain MRI and there was a family history of CCMs.
Fig. 5--
Fig. 5--
Adrenal calcifications in familial cerebral cavernous malformations. 59-year-old man with documented CCM1 mutation, multiple brain CCMs, and unrelated cirrhosis. CT abdomen without intravenous contrast administration. There were 2 right (not pictured on this slice) and 5 left adrenal calcifications, incidental findings. A vertebral vascular malformation is visible in the right side of the T12 vertebral body (see below regarding osseous vascular malformations).
Fig. 6.
Fig. 6.
MRI-atypical vertebral osseous vascular malformations in FCCM. 50-year-old woman with documented CCM1 mutation and numerous cavernous malformations in the brain, MRI cervical spine done for unsteadiness. MRI, sagittal T1 (A), sagittal TSE T2 (B) and axial TSE T2 (C) of the cervical spine shows low T1/high T2 lesions in C5 and T1, stippled appearance on axial T2 through the C5 lesion. They remained stable for years.
Fig. 7—
Fig. 7—
Cerebral AVMs in HHT. 10-year-old girl with hereditary hemorrhagic telangiectasia. A. Axial source image from MRA shows right occipital and left temporal lobe small AVMs, as well as resection site of previous posterior right temporal AVM. B. At age 17, acute left temporal hemorrhage is visible on nonenhanced CT. C. Angiogram, lateral view of left ICA injection shows anterior left temporal AVM with enlarged feeding arteries, tangle of vessels, and early shunting into venous system.
Fig. 8—
Fig. 8—
Pial AVF in HHT. 9-year-old boy with HHT, screening MRI of brain performed. A. MRI axial TSE T2 shows left parietal malformation. B. Angiogram, AP view LICA injection, shows left parietal enlarged arteries and veins with a venous varix but no discernable nidus, consistent with pial arteriovenous fistula.
Fig. 9—
Fig. 9—
Capillary vascular malformation in hereditary hemorrhagic telangiectasia. 24-year-old woman with hereditary hemorrhagic telangiectasia. A. Contrast-enhanced axial T1 MRI of a 24 year old woman shows focus of enhancement <1 cm in the medial right thalamus. Subsequent angiogram, right vertebral injection, lateral view (B) and AP view (C), shows a blush without enlarged feeding or draining vessels (arrows). Location in the thalamus is unusual; subcortical location is much more common.
Fig. 10—
Fig. 10—
Spinal arteriovenous fistula in HHT. 8-year-old boy with hereditary hemorrhagic telangiectasia had spinal vascular malformation detected incidentally, when partially visualized on MRI brain. A. MRI, sagittal TSE T2 shows numerous dilated, tortuous vessels seen in the thoracic spine. B. AP view of spinal angiogram, injection at T7, shows tortuous vessels of spinal arteriovenous fistula. Treated with embolization.
Fig. 11—
Fig. 11—
Lung AVMs in HHT. 45-year-old woman with hypoxia and family history of hereditary hemorrhagic telangiectasia. Basilar lung AVMs demonstrated on both CT (A, coronal reformat) and pulmonary angiography (B). These and others not illustrated were embolized.
Fig. 12—
Fig. 12—
Capillary telangiectasia. 31-year-old woman with hemianopsia, incidental finding of capillary telangiectasia. Left pontine capillary telangiectasia (black arrow) visible on MRI TSE T2 (A), SWI (B), and post gadolinium T1 (C). Slightly increased T2 signal intensity (A) and draining vein (white arrow) are not uncommon.

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