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Joseph H. Garcia, Ethan A. Winkler, Ramin A. Morshed, Alex Lu, Simon G. Ammanuel, Satvir Saggi, Elaina J. Wang, Steve Braunstein, Christine K. Fox, Heather J. Fullerton, Helen Kim, Daniel L. Cooke, Steven W. Hetts, Michael T. Lawton, Adib A. Abla, and Nalin Gupta

OBJECTIVE

Children with cerebral arteriovenous malformations (AVMs) can present with seizures, potentially increasing morbidity and impacting clinical management. However, the factors that lead to seizures as a presenting sign are not well defined. While AVM-related seizures have been described in case series, most studies have focused on adults and have included patients who developed seizures after an AVM rupture. To address this, the authors sought to analyze demographic and morphological characteristics of AVMs in a large cohort of children.

METHODS

The demographic, clinical, and AVM morphological characteristics of 189 pediatric patients from a single-center database were studied. Univariate and multivariate logistic regression models were used to test the effect of these characteristics on seizures as an initial presenting symptom in patients with unruptured brain AVMs.

RESULTS

Overall, 28 of 189 patients initially presented with seizures (14.8%). By univariate comparison, frontal lobe location (p = 0.02), larger AVM size (p = 0.003), older patient age (p = 0.04), and the Supplemented Spetzler-Martin (Supp-SM) grade (0.0006) were associated with seizure presentation. Multivariate analysis confirmed an independent effect of frontal lobe AVM location and higher Supp-SM grade. All patients presenting with seizures had AVMs in the cortex or subcortical white matter.

CONCLUSIONS

While children and adults share some risk factors for seizure presentation, their risk factor profiles do not entirely overlap. Pediatric patients with cortical AVMs in the frontal lobe were more likely to present with seizures. Additionally, the Supp-SM grade was highly associated with seizure presentation. Future clinical research should focus on the effect of therapeutic interventions targeting AVMs on seizure control in these patients.

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Sen Gao, Jeffrey Nelson, Shantel Weinsheimer, Ethan A. Winkler, Caleb Rutledge, Adib A. Abla, Nalin Gupta, Joseph T. Shieh, Daniel L. Cooke, Steven W. Hetts, Tarik Tihan, Christopher P. Hess, Nerissa Ko, Brian P. Walcott, Charles E. McCulloch, Michael T. Lawton, Hua Su, Ludmila Pawlikowska, and Helen Kim

OBJECTIVE

Sporadic brain arteriovenous malformation (BAVM) is a tangled vascular lesion characterized by direct artery-to-vein connections that can cause life-threatening intracerebral hemorrhage (ICH). Recently, somatic mutations in KRAS have been reported in sporadic BAVM, and mutations in other mitogen-activated protein kinase (MAPK) signaling pathway genes have been identified in other vascular malformations. The objectives of this study were to systematically evaluate somatic mutations in MAPK pathway genes in patients with sporadic BAVM lesions and to evaluate the association of somatic mutations with phenotypes of sporadic BAVM severity.

METHODS

The authors performed whole-exome sequencing on paired lesion and blood DNA samples from 14 patients with sporadic BAVM, and 295 genes in the MAPK signaling pathway were evaluated to identify genes with somatic mutations in multiple patients with BAVM. Digital droplet polymerase chain reaction was used to validate KRAS G12V and G12D mutations and to assay an additional 56 BAVM samples.

RESULTS

The authors identified a total of 24 candidate BAVM-associated somatic variants in 11 MAPK pathway genes. The previously identified KRAS G12V and G12D mutations were the only recurrent mutations. Overall, somatic KRAS G12V was present in 14.5% of BAVM lesions and G12D was present in 31.9%. The authors did not detect a significant association between the presence or allelic burden of KRAS mutation and three BAVM phenotypes: lesion size (maximum diameter), age at diagnosis, and age at ICH.

CONCLUSIONS

The authors confirmed the high prevalence of somatic KRAS mutations in sporadic BAVM lesions and identified several candidate somatic variants in other MAPK pathway genes. These somatic variants may contribute to understanding of the etiology of sporadic BAVM and the clinical characteristics of patients with this condition.

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Grace F. Donzelli, Jeffrey Nelson, David McCoy, Charles E. McCulloch, Steven W. Hetts, Matthew R. Amans, Christopher F. Dowd, Van V. Halbach, Randall T. Higashida, Michael T. Lawton, Helen Kim, and Daniel L. Cooke

OBJECTIVE

Preoperative embolization of brain arteriovenous malformations (AVMs) is performed to facilitate resection, although its impact on surgical performance has not been clearly defined. The authors tested for associations between embolization and surgical performance metrics.

METHODS

The authors analyzed AVM cases resected by one neurosurgeon from 2006 to 2017. They tested whether cases with and without embolization differed from one another with respect to patient and AVM characteristics using t-tests for continuous variables and Fisher’s exact tests for categorical variables. They used simple and multivariable regression models to test whether surgical outcomes (blood loss, resection time, surgical clip usage, and modified Rankin Scale [mRS] score) were associated with embolization. Additional regression analyses integrated the peak arterial afferent contrast normalized for the size of the region of interest (Cmax/ROI) into models as an additional predictor.

RESULTS

The authors included 319 patients, of whom 151 (47%) had preoperative embolization. Embolized AVMs tended to be larger (38% with diameter > 3 cm vs 19%, p = 0.001), less likely to have hemorrhaged (48% vs 63%, p = 0.013), or be diffuse (19% vs 29%, p = 0.045). Embolized AVMs were more likely to have both superficial and deep venous drainage and less likely to have exclusively deep drainage (32% vs 17% and 12% vs 23%, respectively; p = 0.002). In multivariable analysis, embolization was not a significant predictor of blood loss or mRS score changes, but did predict longer operating times (+29 minutes, 95% CI 2–56 minutes; p = 0.034) and increased clip usage (OR 2.61, 95% CI 1.45–4.71; p = 0.001). Cmax/ROI was not a significant predictor, although cases with large Cmax/ROI tended to have longer procedure times (+25 minutes per doubling of Cmax/ROI, 95% CI 0–50 minutes; p = 0.051).

CONCLUSIONS

In this series, preoperative embolization was associated with longer median resection times and had no association with intraoperative blood loss or mRS score changes.