Dataset Information

Periventricular Location as a Risk Factor for Hemorrhage and Severe Clinical Presentation in Pediatric Patients with Untreated Brain Arteriovenous Malformations.

ABSTRACT:

Background and purpose

The morphologic features of brain arteriovenous malformations differ between children and adults; therefore, our aim was to analyze various features of brain arteriovenous malformations to assess the risk of hemorrhage in children.

Materials and methods

We identified all consecutive children admitted to Beijing Tiantan Hospital for brain arteriovenous malformations between July 2009 and April 2014. The effects of demographic characteristics and brain arteriovenous malformation morphology on hemorrhage presentation, annual bleeding rates, postnatal hemorrhage, and immediate posthemorrhagic neurologic outcomes were studied by using univariate and multivariable regression analyses.

Results

A total of 108 pediatric brain arteriovenous malformation cases were identified, 66 (61.1%) of which presented with hemorrhage. Of these, 69.7% of ruptured brain arteriovenous malformations were in a periventricular location. Periventricular nidus location (OR, 3.443; 95% CI, 1.328-8.926; P = .011) and nidus size (OR, 0.965; 95% CI, 0.941-0.989; P = .005) were independent predictors of hemorrhagic presentation. The annual hemorrhage rates in children with periventricular brain arteriovenous malformations were higher at 6.88% (OR, 1.965; 95% CI, 1.155-3.341; P < .05). The hemorrhage-free survival rates were also lower for children with periventricular brain arteriovenous malformations (log-rank, P = .01). Periventricular location (hazard ratio, 1.917; 95% CI, 1.131-3.250; P = .016) and nidus size (hazard ratio, 0.983; 95% CI, 0.969-0.997; P = .015) were associated with hemorrhage after birth in pediatric brain arteriovenous malformations. An ordinal analysis showed lower immediate posthemorrhage mRS in patients with periventricular brain arteriovenous malformations (OR for greater disability, 2.71; 95% CI, 1.03-7.11; P = .043).

Conclusions

Small periventricular brain arteriovenous malformations were associated with increased hemorrhage risk in pediatric patients. Cautious follow-up of children with untreated periventricular brain arteriovenous malformations is recommended because of a higher hemorrhage risk and potentially more severe neurologic outcomes.

SUBMITTER: Ma L

PROVIDER: S-EPMC7964676 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND AND PURPOSE:Brain arteriovenous malformation (bAVM) is an important risk factor for intracranial hemorrhage. Current treatments for bAVM are all associated with considerable risks. There is no safe method to prevent bAVM hemorrhage. Thalidomide reduces nose bleeding in patients with hereditary hemorrhagic telangiectasia, an inherited disorder characterized by vascular malformations. In this study, we tested whether thalidomide and its less toxic analog, lenalidomide, reduce bAVM hemorrhage using a mouse model. METHODS:bAVMs were induced through induction of brain focal activin-like kinase 1 (Alk1, an AVM causative gene) gene deletion and angiogenesis in adult Alk1-floxed mice. Thalidomide was injected intraperitoneally twice per week for 6 weeks, starting either 2 or 8 weeks after AVM induction. Lenalidomide was injected intraperitoneally daily starting 8 weeks after AVM induction for 6 weeks. Brain samples were collected at the end of the treatments for morphology, mRNA, and protein analyses. The influence of Alk1 downregulation on PDGFB (platelet-derived growth factor B) expression was also studied on cultured human brain microvascular endothelial cells. The effect of PDGFB in mural cell recruitment in bAVM was explored by injection of a PDGFB overexpressing lentiviral vector to the mouse brain. RESULTS:Thalidomide or lenalidomide treatment reduced the number of dysplastic vessels and hemorrhage and increased mural cell (vascular smooth muscle cells and pericytes) coverage in the bAVM lesion. Thalidomide reduced the burden of CD68+ cells and the expression of inflammatory cytokines in the bAVM lesions. PDGFB expression was reduced in ALK1-knockdown human brain microvascular endothelial cells and in mouse bAVM lesion. Thalidomide increased Pdgfb expression in bAVM lesion. Overexpression of PDGFB mimicked the effect of thalidomide. CONCLUSIONS:Thalidomide and lenalidomide improve mural cell coverage of bAVM vessels and reduce bAVM hemorrhage, which is likely through upregulation of Pdgfb expression.

Project description:Children with untreated brain arteriovenous malformations (bAVM) are at risk of encountering life-threatening hemorrhage very early in their lives. The primary aim of invasive treatment is to reduce unfavorable outcome associated with a bAVM rupture. A better understanding of the morbidity of bAVM hemorrhage might be helpful for weighing the risks of untreated bAVM and invasive treatment. Our aim was to assess the clinical outcome after bAVM rupture and identify features to predict severe hemorrhage in children.We identified all consecutive children admitted to our institution for bAVMs between July 2009 and December 2014. Clinical outcome after hemorrhagic presentation and subsequent hemorrhage was evaluated using the modified Rankin Scale (mRS) for children. The association of demographic characteristics and bAVM morphology with severe hemorrhage (mRS >3 or requiring emergency hematoma evacuation) was studied using univariate and multivariable regression analyses. A nomogram based on multivariable analysis was formulated to predict severe hemorrhage risk for individual patients.A total of 134 patients were identified with a mean treatment-free follow-up period of 2.1 years. bAVM ruptured in 83 (62%) children: 82 had a hemorrhage at presentation and 6 of them experienced a recurrent hemorrhage during follow-up; 1 patient had other diagnostic symptoms but bled during follow-up. Among them, 49% (41/83) had a severe hemorrhage; emergency hematoma evacuation was required in 28% of them (23/83), and 24% (20/83) remained as disabled (mRS ?3) at last follow-up. Forty-six percent (38/82) of children with hemorrhagic presentation were severely disabled (mRS >3). Forty-three percent (3/7) were severely disabled after subsequent hemorrhage. The annual rate of severe subsequent hemorrhage was 1% in the overall cohort and 3.3% in children with ruptured presentation. All the subsequent severe hemorrhage events occurred in children with severe hemorrhage history (7%, 3/41). Periventricular location, non-temporal lobe location, and long draining vein were predictors for severe hemorrhage in pediatric untreated bAVMs. A nomogram based on bAVM morphology was contracted to predict severe hemorrhage risk for individual patients, which was well calibrated and had a good discriminative ability (adjusted C-statistic, 0.72).Evaluating bAVM morbidity and morphology might be helpful for weighing the risks of untreated bAVM in pediatric patients.

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