Intracranial Hemorrhage Rate and Lesion Burden in Patients With Familial Cerebral Cavernous Malformation.

Background Familial cerebral cavernous alformation (CCM) is an autosomal dominant disease caused by mutations in KRIT1, CCM2, or PDCD10. Cases typically present with multiple lesions, strong family history, and neurological symptoms, including seizures, headaches, or other deficits. Intracranial hemorrhage (ICH) is a severe manifestation of CCM, which can lead to death or long-term neurological deficits. Few studies have reported ICH rates and risk factors in familial CCM. We report ICH rates and assess whether CCM lesion burden, a disease severity marker, is associated with risk of symptomatic ICH during follow-up in a well-characterized cohort of familial CCM cases. Methods and Results We studied 386 patients with familial CCM with follow-up data enrolled in the Brain Vascular Malformation Consortium CCM Project. We estimated symptomatic ICH rates overall and stratified by history of ICH before enrollment. CCM lesion burden (total lesion count and large lesion size) assessed at baseline enrollment was tested for association with increased risk of subsequent ICH during follow-up using Cox regression models adjusted for history of ICH before enrollment, age, sex, and family structure and stratified on recruitment site. The symptomatic ICH rate for familial CCM cases was 2.8 per 100 patient-years (95% CI, 1.9-4.1). Those with ICH before enrollment had a follow-up ICH rate of 4.5 per 100 patient-years (95% CI, 2.6-8.1) compared with 2.0 per 100 patient-years (95% CI, 1.3-3.5) in those without (P=0.042). Total lesion count was associated with increased risk of ICH during follow-up (hazard ratio [HR], 1.37 per doubling of total lesion count [95% CI, 1.10-1.71], P=0.006). The symptomatic ICH rate for familial CCM cases was 2.8 per 100 patient-years (95% CI, 1.9-4.1). Those with ICH before enrollment had a follow-up ICH rate of 4.5 per 100 patient-years (95% CI, 2.6-8.1) compared with 2.0 per 100 patient-years (95% CI, 1.3-3.5) in those without (P=0.042). Total lesion count was associated with increased risk of ICH during follow-up (hazard ratio [HR], 1.37 per doubling of total lesion count [95% CI, 1.10-1.71], P=0.006). Conclusions Patients with familial CCM with prior history of an ICH event are at higher risk for rehemorrhage during follow-up. In addition, total CCM lesion burden is significantly associated with increased risk of subsequent symptomatic ICH; hence lesion burden may be an important predictor of patient outcome and aid patient risk stratification.

Decompressive Craniectomy and Risk of Wound Infection After Microsurgical Treatment of Ruptured Aneurysms.

BACKGROUND: Owing to prolonged hospitalization and the complexity of care required for patients with aneurysmal subarachnoid hemorrhage (aSAH), these patients have a high risk of complications. The risk for wound infection after microsurgical treatment for aSAH was analyzed. METHODS: All patients who underwent microsurgical treatment for aSAH between August 1, 2007, and July 31, 2019, and were recorded in the Post-Barrow Ruptured Aneurysm Trial database were retrospectively reviewed. The patients were analyzed for risk factors for wound infection after treatment. RESULTS: Of 594 patients who underwent microsurgical treatment for aSAH, 23 (3.9%) had wound infections. There was no significant difference in age between patients with wound infection and patients without infection (mean, 52.6 ± 12.2 years vs. 54.2 ± 4.0 years; P = 0.45). The presence of multiple comorbidities (including diabetes, tobacco use, and obesity), external ventricular drain, ventriculoperitoneal shunt, pneumonia, or urinary tract infection was not associated with an increased risk for wound infection. Furthermore, there was no significant difference in mean operative time between patients with wound infection and those without infection (280 ± 112 minutes vs. 260 ± 92 minutes; P = 0.38). Patients who required decompressive craniectomy (DC) were at increased risk of wound infection (odds ratio, 5.0; 95% confidence interval, 1.8-14.1; P = 0.002). Among the 23 total infections, 9 were diagnosed following cranioplasty after DC. CONCLUSIONS: Microsurgical treatment for aSAH is associated with a relatively low risk of wound infection. However, patients undergoing DC may be at an increased risk for infection. Additional attention and comprehensive wound care are warranted for these patients.

Propranolol inhibits cavernous vascular malformations by ß1 adrenergic receptor antagonism in animal models.

Propranolol, a pleiotropic ß-adrenergic blocker, has been anecdotally reported to reduce cerebral cavernous malformations (CCMs) in humans. However, propranolol has not been rigorously evaluated in animal models, nor has its mechanism of action in CCM been defined. We report that propranolol or its S(-) enantiomer dramatically reduced embryonic venous cavernomas in ccm2 mosaic zebrafish, whereas R-(+)-propranolol, lacking ß antagonism, had no effect. Silencing of the ß1, but not ß2, adrenergic receptor mimicked the beneficial effects of propranolol in a zebrafish CCM model, as did the ß1-selective antagonist metoprolol. Thus, propranolol ameliorated cavernous malformations by ß1 adrenergic antagonism in zebrafish. Oral propranolol significantly reduced lesion burden in 2 chronic murine models of the exceptionally aggressive Pdcd10/Ccm3 form of CCM. Propranolol or other ß1-selective antagonists may be beneficial in CCM disease.

Re-Irradiation Using Brachytherapy for Recurrent Intracranial Tumors: A Systematic Review and Meta-Analysis of the Literature.

Introduction We aim to compare the efficacy and toxicity of re-irradiation using brachytherapy for patients with locally recurrent brain tumors after previous radiation therapy.  Methods We performed a systematic review of the major biomedical databases from 2005 to 2020 for eligible studies where patients were treated with re-irradiation for recurrent same site tumors using brachytherapy. Tumor types included high-grade gliomas (HGG) (World Health Organization (WHO) Grades 3 and 4), meningiomas, and metastases. The outcomes of interest were median overall survival (OS) and progression-free survival (PFS) after re-irradiation, the incidence of radiation necrosis (RN), and other relevant radiation-related adverse events (AE). We used a fixed-effect meta-analysis regression moderation model to compared results of interstitial versus intracavitary therapy, treatment with low-dose-rate (LDR) versus high-dose-rate (HDR) techniques, and outcomes by tumor type. Results The search resulted in a total of 194 articles. A total of 16 articles with 695 patients fulfilled the inclusion criteria and were selected for analysis. For high-grade glioma, meningioma, and brain metastasis the pooled meta-analysis showed mean symptomatic RN rates of 3.3% (standard error (SE) = 0.8%), 17.3% (SE = 5.0%), and 22.4% (SE = 7.0%), respectively, and mean rates of RN requiring surgical intervention of 3.0% (SE = 1.0%), 11.9% (SE = 5.3%), and 10.0% (SE = 7.3%), respectively. The mean symptomatic RN rates in the meta-analysis comparing interstitial versus intracavitary therapy were 3.4% and 4.9%, respectively (p = 0.36), and for the comparison of LDR versus HDR, the rates were 2.6% and 5.7%, respectively (p = 0.046). In comparing the symptomatic RN rates in comparison to HGG versus meningioma, the means were 3.3% and 17.3%, respectively (p = 0.006), and in HGG versus metastatic tumors, the means were 3.3% and 22.4%, respectively (p = 0.007). There was no significant difference in rates of RN requiring surgery in any of these groups. Due to the small number of studies and inconsistent recording of OS and PFS, statistical analysis of these parameters could not be performed. Conclusion Published literature on the same site re-irradiation using brachytherapy for recurrent brain tumors is highly limited, with inconsistent reporting of safety and efficacy outcomes. To overcome these shortcomings, we utilized a structured meta-analysis approach to show that re-irradiation with modern brachytherapy is generally safe in terms of the risks of symptomatic RN. We also found that symptomatic RN rates for brachytherapy are significantly lower in recurrent HGG compared to recurrent meningiomas (p = 0.006) and metastatic tumors (p = 0.007). Re-irradiation with brachytherapy is a feasible option for appropriately selected patients. The availability of Cesium-131 (Cs-131) shows promise in reducing toxicity while achieving excellent local control due to its physical properties, and the recent introduction of a novel surgically targeted radiation therapy device, that makes brachytherapy less technically demanding, may allow for more widespread adoption. Prospective trials with consistent reporting of endpoints are needed to explore whether these advances improve safety and efficacy in patients with recurrent, previously irradiated tumors.

Laparoscopic-Assisted Ventriculoperitoneal Shunt Placement and Reduction in Operative Time and Total Hospital Charges.

OBJECTIVE: In ventriculoperitoneal shunt (VPS) placement, distal placement of the peritoneal catheter will typically be performed by a neurosurgeon. More recently, laparoscopic-assisted (LA) placement of the distal peritoneal catheter by general surgeons has become common. The present study examined whether LA placement of a VPS (LAVPS) is associated with a reduced operative time, lower hospital costs, and fewer distal revisions. METHODS: A retrospective review was performed of the data from all patients who had received a new VPS at our institution from 2013 to 2016. Age, sex, diagnosis, previous abdominal surgery, operative time, anesthesia grade, incidence of 30-day shunt failure, and total hospital charges were analyzed. RESULTS: A total of 680 patients had undergone first-time VPS placement, including 199 with LAVPS and 481 with non-LAVPS placement (non-LAVPS). The mean age of the LAVPS patients was significantly older than that of the non-LAVPS patients (64.1 vs. 59.3 years; P = 0.002). The mean operative time was shorter in the LAVPS group than in the non-LAVPS group (55 vs. 75 minutes; P < 0.001). Distal shunt revision within 30 days occurred more often for the non-LAVPS patients (6 of 481 [1.2%]) than for the LAVPS patients (0 of 199 [0%]). A subset analysis of patients with normal-pressure hydrocephalus found decreased total hospital charges in the LAVPS group ($67,124 vs. $80,890; P = 0.009). CONCLUSIONS: Compared with non-LAVPS, LAVPS was associated with significantly shorter operative times and fewer distal shunt revisions within 30 days. The findings from a subset analysis supported a decrease in total hospital charges. Additional studies are needed; however, these data suggest that LAVPS is a safer, less-expensive alternative to non-LAVPS.

Superficial Femoral Artery Interposition Graft for Repair of a Ruptured Mycotic Common Carotid Artery Pseudoaneurysm: Case Report and Review of the Literature.

BACKGROUND: Indications for reconstruction of the common carotid artery (CCA) include trauma, iatrogenic injury, neoplastic growth (such as invasive neck carcinomas), postoperative infection, and cervical carotid aneurysm. Although various techniques and conduits have been described, the clinical scenario may preclude the use of the most commonly used grafts. We describe a case using a superficial femoral artery (SFA) interposition graft to repair the CCA and review the available literature, highlighting the feasibility of this technique for carotid artery reconstruction. CASE DESCRIPTION: A patient aged 51 years presented with a ruptured mycotic CCA pseudoaneurysm that developed in the setting of a pharyngeal-carotid fistula. Because of the presence of a pharyngeal-carotid fistula and active infection within the vessel wall, endovascular treatment of the pseudoaneurysm was not feasible, and open surgical correction was required to repair the fistulous connection. Furthermore, owing to the extensive soft tissue infection, the use of a synthetic or venous autograft conduit for repair of the artery was contraindicated. Therefore, we harvested a segment of the SFA and used it as an interposition graft to reconstruct the diseased CCA, achieving an excellent anatomic and clinical result. CONCLUSIONS: This case highlights the feasibility of using an SFA interposition graft for short-segment CCA reconstruction, which can provide significant utility in the setting of a hostile operative field due to prior infection or radiation.

Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation.

Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.

Resection and permanent intracranial brachytherapy using modular, biocompatible cesium-131 implants: results in 20 recurrent, previously irradiated meningiomas.

OBJECTIVE: Effective treatments for recurrent, previously irradiated intracranial meningiomas are limited, and resection alone is not usually curative. Thus, the authors studied the combination of maximum safe resection and adjuvant radiation using permanent intracranial brachytherapy (R+BT) in patients with recurrent, previously irradiated aggressive meningiomas. METHODS: Patients with recurrent, previously irradiated meningiomas were treated between June 2013 and October 2016 in a prospective single-arm trial of R+BT. Cesium-131 (Cs-131) radiation sources were embedded in modular collagen carriers positioned in the operative bed on completion of resection. The Cox proportional hazards model with this treatment as a predictive term was used to model its effect on time to local tumor progression. RESULTS: Nineteen patients (median age 64.5 years, range 50-78 years) with 20 recurrent, previously irradiated tumors were treated. The WHO grade at R+BT was I in 4 (20%), II in 14 (70%), and III in 2 (10%) cases. The median number of prior same-site radiation courses and same-site surgeries were 1 (range 1-3) and 2 (range 1-4), respectively; the median preoperative tumor volume was 11.3 cm3 (range 0.9-92.0 cm3). The median radiation dose from BT was 63 Gy (range 54-80 Gy). At a median radiographic follow-up of 15.4 months (range 0.03-47.5 months), local failure (within 1.5 cm of the implant bed) occurred in 2 cases (10%). The median treatment-site time to progression after R+BT has not been reached; that after the most recent prior therapy was 18.3 months (range 3.9-321.9 months; HR 0.17, p = 0.02, log-rank test). The median overall survival after R+BT was 26 months, with 9 patient deaths (47% of patients). Treatment was well tolerated; 2 patients required surgery for complications, and 2 experienced radiation necrosis, which was managed medically. CONCLUSIONS: R+BT utilizing Cs-131 sources in modular carriers represents a potentially safe and effective treatment option for recurrent, previously irradiated aggressive meningiomas.

Analysis of saccular aneurysms in the Barrow Ruptured Aneurysm Trial.

OBJECTIVE The Barrow Ruptured Aneurysm Trial (BRAT) is a prospective, randomized trial in which treatment with clipping was compared to treatment with coil embolization. Patients were randomized to treatment on presentation with any nontraumatic subarachnoid hemorrhage (SAH). Because all other randomized trials comparing these 2 types of treatments have been limited to saccular aneurysms, the authors analyzed the current BRAT data for this subgroup of lesions. METHODS The primary BRAT analysis included all sources of SAH: nonaneurysmal lesions; saccular, blister, fusiform, and dissecting aneurysms; and SAHs from an aneurysm associated with either an arteriovenous malformation or a fistula. In this post hoc review, the outcomes for the subgroup of patients with saccular aneurysms were further analyzed by type of treatment. The extent of aneurysm obliteration was adjudicated by an independent neuroradiologist not involved in treatment. RESULTS Of the 471 patients enrolled in the BRAT, 362 (77%) had an SAH from a saccular aneurysm. Patients with saccular aneurysms were assigned equally to the clipping and the coiling cohorts (181 each). In each cohort, 3 patients died before treatment and 178 were treated. Of the 178 clip-assigned patients with saccular aneurysms, 1 (1%) was crossed over to coiling, and 64 (36%) of the 178 coil-assigned patients were crossed over to clipping. There was no statistically significant difference in poor outcome (modified Rankin Scale score > 2) between these 2 treatment arms at any recorded time point during 6 years of follow-up. After the initial hospitalization, 1 of 241 (0.4%) clipped saccular aneurysms and 21 of 115 (18%) coiled saccular aneurysms required retreatment (p < 0.001). At the 6-year follow-up, 95% (95/100) of the clipped aneurysms were completely obliterated, compared with 40% (16/40) of the coiled aneurysms (p < 0.001). There was no difference in morbidity between the 2 treatment groups (p = 0.10). CONCLUSIONS In the subgroup of patients with saccular aneurysms enrolled in the BRAT, there was no significant difference between modified Rankin Scale outcomes at any follow-up time in patients with saccular aneurysms assigned to clipping compared with those assigned to coiling (intent-to-treat analysis). At the 6-year follow-up evaluation, rates of retreatment and complete aneurysm obliteration significantly favored patients who underwent clipping compared with those who underwent coiling. Clinical trial registration no.: NCT01593267 (clinicaltrials.gov).

A morphometric and analytical cadaver dissection study of a tumor-simulation balloon model.

We quantified the effects on anatomical cadaver dissection of a balloon-inflation tumor model positioned in the parasellar region and approached through an orbitozygomatic (OZ) craniotomy. A modified supraorbital OZ was performed bilaterally on 5 silicon-injected cadaver heads. Ten predetermined anatomical points assigned using a frameless stereotactic device were used to measure the working area of exposure, degree of surgical freedom, and horizontal and vertical angles of attack to specific target points before and after inflation of a balloon catheter mimicking a parasellar tumor. Balloon inflation displaced the central anatomical structures (pituitary stalk, lamina terminalis, anterior chiasm, and internal carotid artery [ICA]-posterior communicating artery and ICA-A1 junctions) by 14-51% (p ≤ .05). With tumor simulation, the vertical angle of attack increased by 67% (p < .01), while the area of exposure increased by 83% (p < .01) and surgical freedom increased by 58% (p < .01). This tumor model also significantly displaced central anatomical sella-associated structures. Compared to a normal anatomical configuration, the tumor simulation (balloon) opened surgical corridors (especially vertical) and acted as a natural retractor, widening the angle of access to the infundibular apex-hypothalamic junction. Although this model cannot exactly mimic a tumor mass in a patient, the effects of tumor compression and sequential displacement of important structures can be combined into and then assessed in a cadaveric neurosurgical anatomical scenario for training and research.

Corrigendum: Cerebral Cavernous Malformations: Review of the Genetic and Protein-Protein Interactions Resulting in Disease Pathogenesis.

[This corrects the article on p. 60 in vol. 3, PMID: 27896269.].

Developmental venous anomalies.

Developmental venous anomalies (DVAs) are relatively common lesions, present in up to 3% of the population. The defining characteristic of these lesions is the confluence of radially oriented veins into a single dilated venous channel. DVAs are also known as cerebral venous angiomas, cerebral venous malformations, and cerebral venous medullary malformations. They are the most common type of cerebral vascular malformation found on autopsy studies, and they are often encountered as incidental findings on neuroimaging studies. DVAs are congenital lesions thought to arise from aberrations that occur during venous development, but continue to provide the normal venous drainage to the cerebral territory in which they reside. Although the natural history of DVAs is benign, they may be associated with cavernous malformations or other vascular abnormalities, which can lead to hemorrhage in the vicinity of the DVA. Surgical or endovascular obliteration of DVAs carries a significant risk of venous infarction; thus, conservative management is the treatment of choice for patients with these lesions.

Far-Lateral Approach Without Drilling the Occipital Condyle for Vertebral Artery-Posterior Inferior Cerebellar Artery Aneurysms.

BACKGROUND: The far-lateral transcondylar surgical approach is often used to clip vertebral artery (VA) and posterior inferior cerebellar artery (PICA) aneurysms. The role of condyle resection during this approach is controversial. OBJECTIVE: To evaluate patient outcomes in patients with VA-PICA aneurysms in whom drilling the occipital condyle was not necessary. METHODS: Between May 2005 and December 2012, a total of 56 consecutive patients with incidental or ruptured VA-PICA aneurysms underwent surgery with a far-lateral approach without condylar resection. Clinical presentation, surgical reports, presurgery and postsurgery radiological examinations, and clinical follow-up reports were assessed. Anatomic aneurysm location was analyzed through angiography or computed tomography angiography. We compared postsurgical Glasgow Outcome Scale scores, modified Rankin Scale scores, and morbidity in 2 groups: those with aneurysms in the anterior medullary segment and those with aneurysms in the lateral medullary segment. RESULTS: The predominant presentation was subarachnoid hemorrhage in 34 patients (60.7%). Most aneurysms (n = 27 [48.2%]) were located in the lateral medullary segment of the PICA, followed by the anterior medullary segment (n = 25 [44.6%]). Total aneurysm occlusion was achieved in 100% of patients, and bypass techniques were necessary in 3 patients (5.4%). Fifty-two patients (92.8%) had Glasgow Outcome Scale scores of 4 or 5 postsurgery. CONCLUSIONS: A far-lateral approach that leaves the occipital condyle intact is adequate for treating most patients with VA-PICA aneurysms.

Maxillary Artery to Middle Cerebral Artery Bypass: A Novel Technique for Exposure of the Maxillary Artery.

OBJECTIVE: To define the maxillary artery (MaxA) anatomy and present a novel technique for exposing and preparing this vessel as a bypass donor. METHODS: Cadaveric and radiologic studies were used to define the MaxA anatomy and show a novel method for harvesting and preparing it for extracranial to intracranial bypass. RESULTS: The MaxA runs parallel to the frontal branch of the superficial temporal artery and is located on average 24.8 ± 3.8 mm inferior to the midpoint of the zygomatic arch. The pterygoid segment of the MaxA is most appropriate for bypass with a maximal diameter of 2.5 ± 0.4 mm. The pterygoid segment can be divided into a main trunk and terminal part based on anatomic features and use in the bypass procedure. The main trunk of the pterygoid segment can be reached extracranially, either by following the deep temporal arteries downward toward their origin from the MaxA or by following the sphenoid groove downward to the terminal part of the pterygoid segment, which can be followed proximally to expose the entire MaxA. In comparison, the prebifurcation diameter of the superficial temporal artery is 1.9 ± 0.5 mm. The average lengths of the mandibular and pterygoid MaxA segments are 6.3 ± 2.4 and 6.7 ± 3.3 mm, respectively. CONCLUSIONS: The MaxA can be exposed without zygomatic osteotomies or resection of the middle fossa floor. Anatomic landmarks for exposing the MaxA include the anterior and posterior deep temporal arteries and the pterygomaxillary fissure.

Revascularization of Moyamoya Angiopathy in Older Adults.

BACKGROUND: Moyamoya angiopathy most often manifests in patients in the second and third decades of life. Although uncommon, it can also manifest later in life. We present our results in patients >50 years old with moyamoya angiopathy who were treated with surgical revascularization via either direct bypass or indirect bypass (encephaloduroarteriosynangiosis). METHODS: A retrospective review was conducted to identify patients with moyamoya disease who were treated with surgical revascularization at our institution between 2002 and 2015. Outcomes and complications were analyzed. RESULTS: We identified 33 patients with moyamoya angiopathy >50 years old (mean age 59.0 years ± 7.6) who were treated with surgical revascularization of 45 affected hemispheres. Of the affected hemispheres, 27 (60%) were treated with indirect bypasses and 18 (40%) were treated with direct bypasses. Neurologic complications occurred in 4 (12%) patients. The mean length of follow-up was 18.7 months ± 18.6; 4 patients were lost to follow-up. At last follow-up, 11 of 18 (61%) direct bypasses were patent. Treatment failed in 5 of 45 (11%) treated hemispheres (stroke in 2 and persistent transient ischemic attacks in 3). In terms of functional outcome at last follow-up, 16 of 29 (55%) patients were the same as before surgery, 10 (35%) were better, and 3 (10%) were worse (including 1 death). CONCLUSIONS: Although uncommon, moyamoya angiopathy can manifest in older adults. Surgical revascularization is a reasonable treatment option with good functional outcomes and an acceptable complication rate.