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Somatic mosaicism in the MAPK pathway in sporadic brain arteriovenous malformation and association with phenotype

Gao, Sen; Nelson, Jeffrey; Weinsheimer, Shantel; Winkler, Ethan A; Rutledge, Caleb; Abla, Adib A; Gupta, Nalin; Shieh, Joseph T; Cooke, Daniel L; Hetts, Steven W; Tihan, Tarik; Hess, Christopher P; Ko, Nerissa; Walcott, Brian P; McCulloch, Charles E; Lawton, Michael T; Su, Hua; Pawlikowska, Ludmila; Kim, Helen
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.
PMID: 34214981
ISSN: 1933-0693
CID: 4942542

Delays in presentation and mortality among Black patients with mechanical thrombectomy after large-vessel stroke at a US hospital

Catapano, Joshua S; Rumalla, Kavelin; Srinivasan, Visish M; Nguyen, Candice L; Farhadi, Dara S; Ngo, Brandon; Rutledge, Caleb; Rahmani, Redi; Baranoski, Jacob F; Cole, Tyler S; Jadhav, Ashutosh P; Ducruet, Andrew F; Albuquerque, Felipe C
OBJECTIVE:The incidence and severity of stroke are disproportionately greater among Black patients. In this study, the authors sought to examine clinical outcomes among Black versus White patients after mechanical thrombectomy for stroke at a single US institution. METHODS:All patients who underwent mechanical thrombectomy at a single center from January 1, 2014, through March 31, 2020, were retrospectively analyzed. Patients were grouped based on race, and demographic characteristics, preexisting conditions, clinical presentation, treatment, and stroke outcomes were compared. The association of race with mortality was analyzed in multivariable logistic regression analysis adjusted for potential confounders. RESULTS:In total, 401 patients (233 males) with a reported race of Black (n = 28) or White (n = 373) underwent mechanical thrombectomy during the study period. Tobacco use was more prevalent among Black patients (43% vs 24%, p = 0.04), but there were no significant differences between the groups with respect to insurance, coronary artery disease, diabetes, illicit drug use, hypertension, or hyperlipidemia. The mean time from stroke onset to hospital presentation was significantly greater among Black patients (604.6 vs 333.4 minutes) (p = 0.007). There were no differences in fluoroscopy time, procedural success (Thrombolysis in Cerebral Infarction grade 2b or 3), hospital length of stay, or prevalence of hemicraniectomy. In multivariable analysis, Black race was strongly associated with higher mortality (32.1% vs 14.5%, p = 0.01). The disparity in mortality rates resolved after adjusting for the average time from stroke onset to presentation (p = 0.14). CONCLUSIONS:Black race was associated with an increased risk of death after mechanical thrombectomy for stroke. The increased risk may be associated with access-related factors, including delayed presentation to stroke centers.
PMID: 34198259
ISSN: 1092-0684
CID: 4942582

Letter to the editor: "Is the unruptured intracranial aneurysm treatment score (UIATS) sensitive enough to detect aneurysms at risk of rupture?" [Letter]

Rutledge, Caleb; Raper, Daniel M S; Winkler, Ethan A; Abla, Adib A
PMID: 32783076
ISSN: 1437-2320
CID: 4837352

Propensity-Adjusted Comparative Analysis of Radial Versus Femoral Access for Neurointerventional Treatments

Catapano, Joshua S; Ducruet, Andrew F; Nguyen, Candice L; Majmundar, Neil; Wilkinson, D Andrew; Cole, Tyler S; Baranoski, Jacob F; Cavalcanti, Daniel D; Fredrickson, Vance L; Srinivasan, Visish M; Rutledge, Caleb; Lawton, Michael T; Albuquerque, Felipe C
BACKGROUND:Transradial artery (TRA) catheterization for neuroendovascular procedures is associated with a lower risk of complications than transfemoral artery (TFA) procedures. However, the majority of literature on TRA access pertains to diagnostic procedures rather than interventional treatments. OBJECTIVE:To compare TRA and TFA approaches for cerebrovascular interventions. METHODS:All patients with an endovascular intervention performed at a single center from October 1, 2018 to December 31, 2019 were retrospectively analyzed. Patients were grouped into 2 cohorts on the basis of whether TRA or TFA access was used. Outcomes included complications, fluoroscopy times, and total contrast administered. RESULTS:A total 579 interventional treatments were performed during the 15-mo study period. TFA procedures (n = 417) were associated with a significantly higher complication rate than TRA (n = 162) procedures (43 cases [10%] vs 5 cases [3%]; P = .008). After excluding patients who underwent thrombectomy and performing a propensity adjustment (including age, sex, pathology, procedure, sheath size, and catheter size), TRA catheterization was associated with decreased odds of a complication (odds ratio, 0.25; 95% CI 0.085-0.72; P = .01), but no significant difference in the amount of contrast administered (6.7-mL increase; 95% CI, -7.2 to 20.6; P = .34) or duration of fluoroscopy (2.1-min increase; 95% CI, -2.5 to 6.7; P = .37) compared with TFA catheterization. CONCLUSION/CONCLUSIONS:Neurointerventional procedures and treatments for a variety of pathologies can be performed successfully using the TRA approach, which is associated with a lower risk of complications and no difference in fluoroscopy duration compared with the TFA approach.
PMID: 33582816
ISSN: 1524-4040
CID: 4837432

Endovascular embolization versus surgical clipping in a single surgeon series of basilar artery aneurysms: a complementary approach in the endovascular era

Winkler, Ethan A; Lee, Anthony; Yue, John K; Raygor, Kunal P; Rutledge, W Caleb; Rubio, Roberto R; Josephson, S Andrew; Berger, Mitchel S; Raper, Daniel M S; Abla, Adib A
BACKGROUND:Currently, most basilar artery aneurysms (BAAs) are treated endovascularly. Surgery remains an appropriate therapy for a subset of all intracranial aneurysms. Whether open microsurgery would be required or utilized, and to what extent, for BAAs treated by a surgeon who performs both endovascular and open procedures has not been reported. METHODS:Retrospective analysis of prospectively maintained, single-surgeon series of BAAs treated with endovascular or open surgery from the first 5 years of practice. RESULTS:Forty-two procedures were performed in 34 patients to treat BAAs-including aneurysms arising from basilar artery apex, trunk, and perforators. Unruptured BAAs accounted for 35/42 cases (83.3%), and the mean aneurysm diameter was 8.4 ± 5.4 mm. Endovascular coiling-including stent-assisted coiling-accounted for 26/42 (61.9%) treatments and led to complete obliteration in 76.9% of cases. Four patients in the endovascular cohort required re-treatment. Surgical clip reconstruction accounted for 16/42 (38.1%) treatments and led to complete obliteration in 88.5% of cases. Good neurologic outcome (mRS ≤ 2) was achieved in 88.5% and 75.0% of patients in endovascular and open surgical cohorts, respectively (p = 0.40). Univariate logistic regression analysis demonstrated that advanced age (OR 1.11[95% CI 1.01-1.23]) or peri-procedural adverse event (OR 85.0 [95% CI 6.5-118.9]), but not treatment modality (OR 0.39[95% CI 0.08-2.04]), was the predictor of poor neurologic outcome. CONCLUSIONS:Complementary implementation of both endovascular and open surgery facilitates individualized treatment planning of BAAs. By leveraging strengths of both techniques, equivalent clinical outcomes and technical proficiency may be achieved with both modalities.
PMID: 33694012
ISSN: 0942-0940
CID: 4837452

Resolution of an enlarging subdural haematoma after contralateral middle meningeal artery embolisation

Rutledge, Caleb; Baranoski, Jacob F; Catapano, Joshua S; Jadhav, Ashutosh P; Albuquerque, Felipe C; Ducruet, Andrew F
A man in his 50s presented 1 month after an automobile accident with worsening headaches and an enlarging chronic left subdural haematoma (SDH). He underwent left middle meningeal artery (MMA) embolisation. Due to tortuosity at its origin, we were unable to catheterise the MMA distally. Only proximal coil occlusion at the origin was performed. Follow-up interval head CT showed an increase in the size of the SDH with new haemorrhage, worsening mass effect and midline shift. However, he remained neurologically intact. Contralateral embolisation of the right MMA was performed with a liquid embolic agent. His headaches improved, and a follow-up head CT 3 months later showed near-complete resolution of the SDH.
PMCID:8076938
PMID: 33906882
ISSN: 1757-790x
CID: 5473002

Limited Intradural Anterior Petrosectomy for Upper Basilar Aneurysms: A Technical Note

Rutledge, Caleb; Raper, Daniel M S; Raygor, Kunal P; Budohoski, Karol P; Abla, Adib A
OBJECTIVE:The extradural anterior petrosectomy is a widely used skull base approach to the upper petroclival region, basilar trunk, and ventral pons. However, there is significant procedure-related morbidity and a complete petrosectomy is required, as the intradural structures are not in view at the time of drilling. We describe an intradural anterior petrosectomy for aneurysms of the basilar trunk and anterior inferior cerebellar artery with intraoperative photographs and artwork to illustrate the approach. METHODS:A temporal craniotomy is made at the root of the zygoma and middle fossa floor. After opening dura, the trochlear nerve is identified at the tentorial edge. The tentorium is incised posterior to the trochlear nerve and the incision is carried forward across the cisternal segment of the trigeminal nerve toward V3 and the superior petrosal sinus. The petrous apex is identified and drilled lateral and posterior to V3 with a diamond bur. Intraoperative navigation is useful to confirm its location. Once posterior fossa dura is identified, the superior petrosal sinus may be safely cauterized and divided, connecting the tentorial incision with an incision in the posterior fossa dura, and exposing the upper basilar trunk and its branches. Additional bone is removed only as needed. RESULTS:Two patients underwent successful treatment of a basilar trunk perforator and anterior inferior cerebellar artery aneurysm with a subtemporal approach and tailored intradural petrosectomy. CONCLUSIONS:The intradural anterior petrosectomy allows limited drilling of the petrous apex and provides sufficient exposure of upper basilar artery aneurysms.
PMID: 33640529
ISSN: 1878-8769
CID: 4837442

Supracerebellar Infratentorial Infratrochlear Trans-Quadrangular Lobule Approach to Pontine Cavernous Malformations

Rutledge, Caleb; Raper, Daniel M S; Rodriguez Rubio, Roberto; Winkler, Ethan A; Abla, Adib A
BACKGROUND:Brainstem cavernous malformations with symptomatic hemorrhage have a poor natural history. Those without a pial or ependymal presentation are often observed given the morbidity of resection. Surgical removal is considered only in patients with accessible lesions that have repeated symptomatic hemorrhagic. OBJECTIVE:To describe a novel supracerebellar infratentorial infratrochlear trans-quadrangular lobule approach to safely resect lesions in the upper pons. METHODS:We use a hybrid paramedian/lateral suboccipital craniotomy in the gravity-dependent supine position. Opening the cerebellomesencephalic fissure over the tentorial surface of the cerebellum brings the trochlear nerve, branches of the superior cerebellar artery, and the quadrangular lobule of the cerebellum into view. Removal of small a portion of the quadrangular lobule defines an entry point on the superomedial aspect of the middle cerebellar peduncle, and a surgical trajectory aimed superior to inferior. RESULTS:A total of 6 patients underwent this approach. All presented with symptomatic hemorrhage and all cavernous malformations were completely resected. Five patients were improved or unchanged with modified Rankin scale scores of 1 or 2. CONCLUSION/CONCLUSIONS:The trans-quadrangular lobule approach allows safe resection of upper pontine cavernous malformations along a superior to inferior trajectory.
PMID: 33432968
ISSN: 2332-4260
CID: 4837422

Brain arteriovenous malformations

Rutledge, Caleb; Cooke, Daniel L; Hetts, Steven W; Abla, Adib A
Brain arteriovenous malformations are an important cause of intracerebral hemorrhage in the young. Ruptured AVM's are often treated, as the risk of rebleeding is high. The treatment of incidentally discovered, unruptured AVMs is controversial as the morbidity and mortality of treatment may exceed that of the AVM's natural history. Management is multimodal and includes observation with follow up, as well as microsurgical resection, endovascular embolization, and stereotactic radiosurgery. Multidisciplinary teams are important in evaluating patients for treatment. The goal of treatment is complete AVM obliteration while preserving neurologic function.
PMID: 33272394
ISSN: 0072-9752
CID: 4837412

Controversies and Advances in Adult Intracranial Bypass Surgery in 2020

Raper, Daniel M S; Rutledge, W Caleb; Winkler, Ethan A; Meisel, Karl; Callen, Andrew L; Cooke, Daniel L; Abla, Adib A
Cerebral revascularization utilizing a variety of bypass techniques can provide either flow augmentation or flow replacement in the treatment of a range of intracranial pathologies, including moyamoya disease, intracranial atherosclerotic disease, and complex aneurysms that are not amenable to endovascular or simple surgical techniques. Though once routine, the publication of high-quality prospective evidence, along with the development of flow-diverting stents, has limited the indications for extracranial-to-intracranial (EC-IC) bypass. Nevertheless, advances in imaging, assessment of cerebral hemodynamics, and surgical technique have changed the risk-benefit calculus for EC-IC bypass. New variations of revascularization surgery involving multiple anastomoses, flow preserving solutions, IC-IC constructs, and posterior circulation bypasses have been pioneered for otherwise difficult to treat pathology including giant aneurysms, dolichoectasia, and medically refractory intracranial atherosclerosis. This review provides a practical update on recent advances in adult intracranial bypass surgery.
PMID: 32895706
ISSN: 2332-4260
CID: 4837382