Justin M. Caplan

Immediate procedural outcomes in 44 consecutive Pipeline Flex cases: the first North American single-center series

Background Flow diversion is an established technique for treatment of cerebral aneurysms. The Pipeline embolization device (PED) is the only FDA-approved flow diverting stent in the USA. A second-generation device, PED Flex, has recently been released with modifications to the delivery system. Published reports of experience with this new device are limited. Objective To describe the initial outcomes from the first North American series using the PED Flex—a single-center experience of 44 cases. Methods All patients consecutively treated with the PED Flex embolization device from February 2015 through April 2015 were included in the study. Data were collected for patient demographics, aneurysm characteristics, technical procedural details, and early outcomes. Results PED Flex treatment was attempted in 42 patients (mean 56.6±2.0 years) with 44 aneurysms (mean size 6.5±0.6 mm), 41/44 (93%) of which were anterior circulation and 3/44 (7%) were posterior circulation. PED Flex was successfully implanted in 43/44 cases (98%). A single device was used in 41/43 cases (95%), with a mean of 1.07±0.05 devices implanted per case. Resheathing was performed in 4/44 cases (9%). Mean postprocedure hospital length of stay was 1.3±0.2 days. One significant neurological complication (2.3%) occurred, which was a stroke in a patient non-compliant with the prescribed antiplatelet regimen. Conclusions Pipeline Flex is a second-generation flow diverter with enhanced features compared with the first-generation PED. These modifications allow for more reliable deployment with continued improvements in procedural safety.

A thermal gel depot for local delivery of paclitaxel to treat experimental brain tumors in rats: Laboratory investigation

OBJECT Paclitaxel, a cellular proliferation inhibitor/radiation sensitizer, while effective against gliomas in vitro, has poor CNS penetration and dose-limiting toxicities when administered systemically. OncoGel (paclitaxel in Re-Gel) provides controlled local paclitaxel release when placed into the CNS. The authors evaluated the safety and efficacy of OncoGel in rats with intracranial 9L gliosarcoma. METHODS Safety studies included intracranial delivery of increasing volumes of ReGel and OncoGel containing 1.5 (OncoGel 1.5) or 6.3 (OncoGel 6.3) mg/ml paclitaxel. An in vivo radiolabeled biodistribution study was performed in 18 Fischer-344 rats to determine intracerebral distribution. Efficacy studies compared overall survival for controls, ReGel only, radiation therapy only, OncoGel 6.3, or OncoGel 6.3 in combination with radiation therapy. ReGel and OncoGel 6.3 were delivered either simultaneously with tumor implantation (Day 0) or 5 days later (Day 5). Radiation therapy was given on Day 5. RESULTS Control and ReGel animals died of tumor within 17 days. Survival significantly increased in the Onco-Gel 6.3 group on Day 0 (median 31 days; p = 0.0001), in the OncoGel 6.3 group on Day 5 (median 17 days; p = 0.02), and in the radiation therapy-only group (median 26 days; p = 0.0001) compared with controls. Animals receiving both OncoGel and radiation therapy had the longest median survival: 83 days in the group with radiation therapy combined with OncoGel 6.3 on Day 0, and 32 days in the group combined with OncoGel 6.3 on Day 5 (p = 0.0001 vs controls). After 120 days, 37.5% of the animals in the OncoGel Day 0 group, 37.5% of animals in the OncoGel 6.3 Day 0 in combination with radiation therapy group, and 12.5% of the animals in the OncoGel 6.3 on Day 5 in combination with radiation therapy group were alive. In the biodistribution study, measurable radioactivity was observed throughout the ipsilateral hemisphere up to 3 weeks after the OncoGel injection, with the most radioactivity detected 3 hours after injection. The highest dose of radioactivity observed in the contralateral hemisphere was at the Day 3 time point. CONCLUSIONS OncoGel containing 6.3 mg/ml of paclitaxel is safe for intracranial injection in rats and effective when administered on Day 0. When combined with radiation therapy, the combination was more effective than either therapy alone and should be studied clinically for the treatment of malignant glioma.

Flow diversion of large internal carotid artery aneurysms with the surpass device: impressions and technical nuance from the initial North American experience

Background Flow diversion is an important tool for treatment of cerebral aneurysms, particularly large and giant aneurysms. The Surpass flow diverter is a new system under evaluation in the USA. Objective To report our initial experience of 20 cases with the Surpass flow diverter to demonstrate its basic properties, the required triaxial delivery platform, and the methodologies used to deploy it during treatment of large internal carotid artery (ICA) aneurysms Methods Twenty patients with ICA aneurysms ≥10 mm with ≥4 mm neck treated as part of the Surpass IntraCranial Aneurysm Embolization System Pivotal Trial (the SCENT trial; Stryker) were included. Details of patient demographics, aneurysm characteristics, and technical procedures were collected. Results Twenty patients (mean age 63.3±1.3 years; range 51–72) with 20 unruptured aneurysms (mean size 13.4±0.9 mm; range 10–21 mm) were treated. For proximal access, 60% of cases had aortic arch ≥grade II, 55% had significant cervical ICA tortuosity, and 60% had cavernous ICA ≥grade II. The Surpass device was implanted in 19/20 (95%) cases. Of 19 cases, a single device was used in 18 cases (95%) and 2 devices in only 1 case (5%). Balloon angioplasty was performed in 8/19 cases (42%). Complete aneurysm neck coverage and adequate vessel wall apposition was obtained in all 19 cases. Conclusions Surpass is a next-generation flow diverter with unique device-specific and delivery-specific features compared with clinically available endoluminal flow diverters. Our initial experience demonstrates a favorable technical profile in treatment of large and giant ICA aneurysms. Trial registration number NCT01716117.

The Minipterional Craniotomy for Anterior Circulation Aneurysms: Initial Experience With 72 Patients

BACKGROUND: The pterional craniotomy is well established for microsurgical clipping of most anterior circulation aneurysms. The incision and temporalis muscle dissection impacts postoperative recovery and cosmetic outcomes. The minipterional (MPT) craniotomy offers similar microsurgical corridors, with a substantially shorter incision, less muscle dissection, and a smaller craniotomy flap. OBJECTIVE: To report our experience with the MPT craniotomy in select unruptured anterior circulation aneurysms. METHODS: From January 2009 to July 2013, 82 unruptured aneurysms were treated in 72 patients, with 74 MPT craniotomies. Seven patients had multiple aneurysms treated with a single MPT craniotomy. The average patient age was 56 years (range: 24-87). Aneurysms were located along the middle cerebral artery (n = 36), posterior communicating (n = 22), paraophthalmic (n = 22), choroidal (n = 1), and dorsal ICA segments (n = 1). The MPT craniotomy utilized an incision just posterior to the hairline and a single myocutaneous flap. RESULTS: The average aneurysm size was 5.45 mm (range: 1-14). There were no instances of compromised operative corridors requiring craniotomy extension. Three significant early postoperative complications included epidural and subdural hematomas requiring evacuation, and a middle cerebral artery infarction. Average length of hospitalization was 3.96 days (range: 2-20). Two patients required reoperation for wound infections. Average follow-up was 421 days (range: 5-1618). Minimal to no temporalis muscle wasting was noted in 96% of patients. CONCLUSION: The MPT craniotomy is a worthwhile alternative to the standard pterional craniotomy. There were no instances of suboptimal operative corridors and clip applications when the MPT craniotomy was utilized in the treatment of unruptured middle cerebral artery and supraclinoid internal carotid artery aneurysms proximal to the terminal internal carotid artery bifurcation. ABBREVIATIONS: Acomm, anterior communicating MPT, minipterional Pcomm, posterior communicating SAH, subarachnoid hemorrhage

Delayed onset of paresis in rats with experimental intramedullary spinal cord gliosarcoma following intratumoral administration of the paclitaxel delivery system OncoGel: Laboratory investigation

OBJECT Treatment options for anaplastic or malignant intramedullary spinal cord tumors (IMSCTs) remain limited. Paclitaxel has potent cytotoxicity against experimental intracranial gliomas and could be beneficial in the treatment of IMSCTs, but poor CNS penetration and significant toxicity limit its use. Such limitations could be overcome with local intratumoral delivery. Paclitaxel has been previously incorporated into a biodegradable gel depot delivery system (OncoGel) and in this study the authors evaluated the safety of intramedullary injections of OncoGel in rats and its efficacy against an intramedullary rat gliosarcoma. METHODS Safety of intramedullary OncoGel was tested in 12 Fischer-344 rats using OncoGel concentrations of 1.5 and 6.0 mg/ml (5 μl); median survival and functional motor scores (Basso-Beattie-Bresnahan [BBB] scale) were compared with those obtained with placebo (ReGel) and medium-only injections. Efficacy of OncoGel was tested in 61 Fischer-344 rats implanted with an intramedullary injection of 9L gliosarcoma containing 100,000 cells in 5 μl of medium, and randomized to receive OncoGel administered on the same day (in 32 rats) or 5 days after tumor implantation (in 29 rats) using either 1.5 mg/ml or 3.0 mg/ml doses of paclitaxel. Median survival and BBB scores were compared with those of ReGel-treated and tumor-only rats. Animals were killed after the onset of deficits for histopathological analysis. RESULTS OncoGel was safe for intramedullary injection in rats in doses up to 5 μl of 3.0 mg/ml of paclitaxel; a dose of 5 μl of 6.0 mg/ml caused rapid deterioration in BBB scores. OncoGel at concentrations of 1.5 mg/ml and 3.0 mg/ml paclitaxel given on both Day 0 and Day 5 prolonged median survival and preserved BBB scores compared with controls. OncoGel 1.5 mg/ml produced 62.5% long-term survivors when delivered on Day 0. A comparison between the 1.5 mg/ml and the 3.0 mg/ml doses showed higher median survival with the 1.5 mg/ml dose on Day 0, and no differences in median survival or BBB scores after treatment on Day 5. CONCLUSIONS OncoGel is safe for intramedullary injection in rats in doses up to 5 μl of 3.0 mg/ml, prolongs median survival, and increases functional motor scores in rats challenged with an intramedullary gliosarcoma at the doses tested. This study suggests that locally delivered chemotherapeutic agents could be of temporary benefit in the treatment of malignant IMSCTs under experimental settings.

A novel model of intramedullary spinal cord tumors in rats: functional progression and histopathological characterization.

OBJECTIVE Intramedullary spinal cord tumors are difficult lesions to treat given their recurrence rate and limited treatment options. The absence of an adequate animal model, however, has hindered the development of new treatment paradigms. In this study, we describe the technique for intramedullary injection of two experimental rodent gliomas (9L and F98) and present the methodology for functional and histopathological analysis of tumor progression. METHODS F344 rats (n = 24) were randomized into three groups. Group 1 (n = 8) received a 5 microl intramedullary injection of Dulbeccos modified Eagle medium, Group 2 received a 5 microl intramedullary injection of 9L gliosarcoma (100,000) cells, and Group 3 received a 5 microl intramedullary injection of F98 glioma (100,000) cells. The animals were anesthetized, a 2 cm incision was made in the dorsal mid-thoracic region, and the spinous process of the T5 vertebrae was removed to expose the intervertebral space. The ligamentum flavum was removed, and an intramedullary injection was made into the spinal cord. The animals were evaluated daily for signs of paralysis using the Basso, Beattie, and Bresnahan scale and sacrificed after the onset of deficits for histopathological analysis. RESULTS Animals injected with 9L-gliosarcoma had a median onset of hind limb paresis at 12 +/- 2.9 days. Animals injected with F98 glioma had a median onset of hind limb paresis at 19 +/- 3 days. Animals injected with Dulbeccos modified Eagle medium did not show neurological deficits. Hematoxylin-eosin cross sections confirmed the presence of intramedullary 9L and F98 tumor invading the spinal cord. Control animals had no significant histopathological findings. CONCLUSION Animals injected with 9L or F98 consistently developed hind limb paresis in a reliable and reproducible manner. The progression of neurological deficits is similar to that seen in patients with intramedullary spinal cord tumors. These findings suggest that this model mimics the behavior of intramedullary spinal cord tumors in humans and may be used to examine the efficacy of new treatment options for both low- and high-grade intramedullary tumors.

Impact of indocyanine green videoangiography on rate of clip adjustments following intraoperative angiography.

BACKGROUND Intraoperative angiography (IA) is used to evaluate the adequacy of clip reconstruction of intracranial aneurysms. Alternative imaging such as indocyanine green videoangiography (ICG-VA) has been proposed. The additional benefit of ICG-VA when IA is routinely used has not been previously determined. OBJECTIVE To report our experience with the use of ICG-VA in combination with IA vs IA alone. METHODS We retrospectively reviewed cases of aneurysm clipping during a 21-month period by a single surgeon in which ICG-VA was performed after clip reconstruction prior to IA, or IA alone was performed to verify optimal clipping. Records were reviewed for age, sex, race, length of stay, rupture status, Hunt and Hess grade, aneurysm size, location, and temporary clipping. Intraoperative decision making was determined for each group. RESULTS Ninety-four patients who underwent 97 craniotomies for 128 aneurysms met inclusion criteria for this study. ICG-VA+IA was performed in 37 craniotomies; IA alone was performed for 60 craniotomies. Baseline characteristics were similar with the exception that median aneurysm size was slightly larger in the ICG-VA group (5.6 mm vs 4.3 mm, P = .04). ICG-VA produced 4 false negatives, which required clip adjustments following IA (10.8%), vs 7 patients (11.7%) in the IA-alone group requiring clip adjustments (P = .897). CONCLUSION When IA is routinely performed, the additional use of ICG-VA does not eliminate the need for post-IA clip adjustments owing to the possibility of false negatives. When ICG-VA suggests optimal clipping, but is followed by IA, the rate of post-IA modifications in this study did not differ significantly than if ICG-VA had not been performed.

Racial Associations with Hemorrhagic Presentation in Cerebral Arteriovenous Malformations.

BACKGROUND Studies focusing on hemorrhagic presentation of brain arteriovenous malformations (AVMs) have largely limited their analysis to angiographic features. We report the importance of race/ethnicity as a clinical factor associated with hemorrhagic AVM presentation in addition to previously reported angiographic features. METHODS Data were prospectively and retrospectively collected on patients (N = 194) during the period 1993-2010 who presented with a single intracranial AVM, and baseline characteristics were compared for hemorrhagic presentation versus nonhemorrhagic presentation. Features that were statistically significant in univariate analysis or clinically significant were included in a multivariate analysis. RESULTS The median age at presentation was 32 years; 37.2% of patients were male. Spetzler-Martin grades were I in 17.5%, II in 37.1%, III in 28.9%, IV in 14.9%, and V in 1.5%. Baseline characteristics that differed significantly between patients presenting with hemorrhage compared with patients without hemorrhage were the following: race (P < 0.01), AVM size (P < 0.01), <3 feeding arteries (P = 0.01), absence of middle cerebral artery supply to AVM (P < 0.01), and AVM location (P < 0.01). Multivariate analysis revealed nonwhite race (odds ratio [OR] = 3.09 [95% confidence interval (CI) = 1.52, 6.44], P < 0.01); smaller AVM size (OR = 0.65 [95% CI = 0.19, 0.86], P < 0.01); and nonfrontal lobar (OR = 2.61 [95% CI = 1.2, 5.59], P = 0.02), basal ganglia (OR = 6.20 [95% CI = 1.52, 26.26], P = 0.01), or brainstem locations (OR = 4.41 [95% CI = 1.38, 14.92], P = 0.01) as factors associated with hemorrhagic presentation of brain AVMs. CONCLUSIONS To our knowledge, this is the first study demonstrating that race/ethnicity is significantly associated with hemorrhagic presentation of AVMs. We also confirmed previous observations that AVM size and location are associated with hemorrhagic presentation.

Predictors of functional outcome following treatment of posterior fossa arteriovenous malformations

Posterior fossa arteriovenous malformations (AVM) present particular therapeutic challenges. Studies aimed at clarifying risk of hemorrhage focus on obliteration rates, but few have addressed functional outcomes in these patients. In this study, we aim to explore the predictors of good functional outcome for posterior fossa AVM after treatment. A retrospective review of patients diagnosed with posterior fossa AVM at our institution from 1990 to 2013 was performed, and 61 patients met the inclusion criteria. Functional outcomes were assessed using the modified Rankin Scale (mRS), and mRS ⩽ 1 was defined as good outcome. Within our cohort, 39 patients presented with hemorrhage (64.0%). Spetzler-Martin grades were I (n = 9, 14.8%), II (n = 20, 32.8%), III (n = 22, 36.1%), IV (n = 8, 13.1%), and V (n = 2, 3.3%). Patients were treated with surgery (n = 8), radiosurgery (n = 34), embolization (n = 2) or multimodal therapies (n = 8). Nine patients did not undergo treatment. Average follow-up was 41.9 months. Obliteration of AVM was confirmed in 44.3% of patients (n = 27). Forty-three patients (70.5%) achieved good functional outcomes (mRS ⩽ 1). The absence of pre-treatment symptoms (p < 0.01) and AVM obliteration (p = 0.04) were predictive of good functional outcomes. In contrast, non-hemorrhagic presentation was not a significant predictor (p = 0.60). Asymptomatic presentation and AVM obliteration are associated with good functional outcomes in patients with posterior fossa AVM. Non-hemorrhagic presentation does not necessarily predict good functional outcome. Therefore treatment should not be considered only for those who present with hemorrhage. Posterior fossa AVM should be considered for definitive treatment in order to prevent future hemorrhages and subsequent poor functional outcomes.

Lower Risk of Intracranial Arteriovenous Malformation Hemorrhage in Patients With Hereditary Hemorrhagic Telangiectasia

BACKGROUND Patients diagnosed with hereditary hemorrhagic telangiectasia (HHT) are at risk of developing intracranial arteriovenous malformations (AVM). However, the clinical manifestations and natural history of HHT-related AVMs remain unclear due to the rarity of these lesions. OBJECTIVE To clarify the clinical characteristics and hemorrhagic risk in HHT-related AVMs. METHODS We performed a retrospective review of all patients diagnosed with both HHT and intracranial AVMs who were evaluated at our institution from 1990 to 2013. Patients with missing data or lost to follow-up were excluded. Baseline characteristics and subsequent hemorrhagic risk were evaluated. RESULTS In an AVM database of 531 patients with 542 AVMs, a total of 12 HHT patients (2.3%) with 23 AVMs were found. Mean age at diagnosis was 36.5 years, with 41.7% male. Compared to patients with sporadic AVMs, patients with HHT were less likely to present with ruptured AVM (P = .04), headaches (P = .02), and seizures (P = .02), and presented with better modified Rankin scores (P < .01). HHT-related AVMs were smaller in size (P < .01), of lower Spetzler-Martin grade (P = .01), and had less temporal lobe involvement (P = .02) compared to sporadic AVMs. Six HHT patients (50.0%) were found with multiple intracranial AVMs. One hemorrhage was found during an observation period of 149.6 patient-years and 297.5 lesion-years, translating to 1.3% per patient per year or 0.7% per AVM per year. CONCLUSION HHT-related AVMs are smaller in size with lower Spetzler-Martin grade and less temporal lobe involvement than sporadic AVMs. Patients with HHT frequently present with multiple intracranial AVMs. Conservative management is generally recommended due to lesion multiplicity and relatively low hemorrhagic risk.