Albert J. Schuette

EGFRvIII Antibody–Conjugated Iron Oxide Nanoparticles for Magnetic Resonance Imaging–Guided Convection-Enhanced Delivery and Targeted Therapy of Glioblastoma

The magnetic nanoparticle has emerged as a potential multifunctional clinical tool that can provide cancer cell detection by magnetic resonance imaging (MRI) contrast enhancement as well as targeted cancer cell therapy. A major barrier in the use of nanotechnology for brain tumor applications is the difficulty in delivering nanoparticles to intracranial tumors. Iron oxide nanoparticles (IONP; 10 nm in core size) conjugated to a purified antibody that selectively binds to the epidermal growth factor receptor (EGFR) deletion mutant (EGFRvIII) present on human glioblastoma multiforme (GBM) cells were used for therapeutic targeting and MRI contrast enhancement of experimental glioblastoma, both in vitro and in vivo, after convection-enhanced delivery (CED). A significant decrease in glioblastoma cell survival was observed after nanoparticle treatment and no toxicity was observed with treatment of human astrocytes (P < 0.001). Lower EGFR phosphorylation was found in glioblastoma cells after EGFRvIIIAb-IONP treatment. Apoptosis was determined to be the mode of cell death after treatment of GBM cells and glioblastoma stem cell-containing neurospheres with EGFRvIIIAb-IONPs. MRI-guided CED of EGFRvIIIAb-IONPs allowed for the initial distribution of magnetic nanoparticles within or adjacent to intracranial human xenograft tumors and continued dispersion days later. A significant increase in animal survival was found after CED of magnetic nanoparticles (P < 0.01) in mice implanted with highly tumorigenic glioblastoma xenografts (U87DeltaEGFRvIII). IONPs conjugated to an antibody specific to the EGFRvIII deletion mutant constitutively expressed by human glioblastoma tumors can provide selective MRI contrast enhancement of tumor cells and targeted therapy of infiltrative glioblastoma cells after CED.

Indocyanine green videoangiography in the management of dural arteriovenous fistulae.

OBJECTIVETo evaluate the usefulness of indocyanine green (ICG) videoangiography in the operative management of dural arteriovenous fistulae (dAVFs). METHODSIntraoperative ICG videoangiography was used as a surgical adjunct in 25 patients with cranial and spinal dural arteriovenous fistulae to identify the fistula and verify its complete obliteration. The findings on ICG videoangiography were compared with intraoperative and/or postoperative imaging. RESULTSAll dural arteriovenous fistulae were clearly identified by intraoperative ICG videoangiography and obliteration was documented in each case. Findings on ICG videoangiography correlated with intraoperative and/or postoperative imaging. CONCLUSIONICG videoangiography is a useful adjunct to the surgical management of dural arteriovenous fistulae for localization and confirmation of complete obliteration. The safety and ease of use make it an attractive modality. The surgeon can only evaluate what is visualized under the operating microscope and must therefore fully expose the venous drainage of the fistula to confirm obliteration.

Endovascular therapy of very small aneurysms of the anterior communicating artery: five-fold increased incidence of rupture.

BACKGROUND:Intraprocedural rupture is a dangerous complication of endovascular treatment. Small ruptured anterior communicating artery (ACoA) aneurysms and microaneurysms present a challenge for both surgical and endovascular therapies to achieve obliteration. An understanding of the complication rates of treating ruptured ACoA microaneurysms may help guide therapeutic options. OBJECTIVE:To report the largest cohort of ACoA microaneurysms treated with endovascular therapy over the course of the past 10 years. METHODS:We performed a retrospective review of 347 ACoA aneurysms treated in 347 patients at Cleveland Clinic and Emory University over a 10-year period. Patient demographics, aneurysmal rupture, size, use of balloon remodeling, patient outcomes, intraprocedural rupture, and rerupture were reviewed. RESULTS:Rupture rates were examined by size for all patients and subgroups and dichotomized to evaluate for size ranges associated with increased rupture rates. The highest risk of rupture was noted in aneurysms less than 4 mm. Of 347 aneurysms, 74 (21%) were less than 4 mm. The intraprocedural rupture rate was 5% (18/347) for ACoA aneurysms of any size. There was an intraprocedural rupture rate of 2.9% (8/273) among ACoA aneurysms greater than 4 mm compared with 13.5% (10/74) in less than 4-mm aneurysms. Procedural rupture was a statistically significant predictor of modified Rankin score after adjusting for Hunt and Hess grades (HH). CONCLUSION:ACoA aneurysms less than 4 mm have a 5-fold higher incidence of intraprocedural rerupture during coil embolization. Outcome is negatively affected by intraprocedural rerupture after adjusting for HH grade.

Microsurgical and endovascular management of pericallosal aneurysms.

Background Pericallosal, or A2 bifurcation, aneurysms are an infrequently encountered cause of subarachnoid hemorrhage (SAH). While the International Subarachnoid Aneurysm Trial showed improved outcomes for patients with any ruptured anterior circulation aneurysm treated with embolization, there was also a higher recurrence rate for embolized aneurysms. Notably, there were relatively few pericallosal aneurysms. Objective Specific analysis of pericallosal aneurysms may help guide therapeutic decisions. Methods Retrospective analysis of patients who presented with proven saccular pericallosal aneurysms was performed at two institutions from 1999 to 2009. Patients were stratified according to presentation Hunt and Hess grades and modified Fisher scores, treatment modality and outcomes as well as development of vasospasm, hydrocephalus and required treatment. Results Eighty-eight patients with pericallosal aneurysms were identified. Sixty-two presented with SAH and 26 in elective fashion, 2 of whom had a prior history of SAH. Fifty-four patients underwent microsurgical repair and 32 endovascular repair. Patients presenting with SAH due to pericallosal aneurysm treated with an endovascular approach were more likely to have a good modified Rankin scale (mRS) (mRS 0–2 vs 3–6) (p=0.028), to make a complete recovery (mRS=0) (p=0.017) and were less likely to die (mRS=6) (p=0.026). Patients with electively treated pericallosal aneurysms did not have statistically significant differences in outcome between surgical and endovascular cohorts. Differences in secondary endpoints did not reach significance. Conclusion Patients with ruptured pericallosal aneurysms fare better with endovascular therapy, with better chance of complete recovery. Surgical and endovascular treatments of unruptured pericallosal aneurysms have similar results and outcome.

Advances in Surgical Approaches to Dural Fistulas

Dural arteriovenous fistulas are abnormal connections of dural arteries to dural veins or venous sinuses originating from within the dural leaflets. They are usually located near or within the wall of a dural venous sinus that is frequently obstructed or stenosed. The dural fistula sac is contained within the dural leaflets, and drainage can be via a dural sinus or retrograde through cortical veins (leptomeningeal drainage). Dural arteriovenous fistulas can occur at any dural sinus but are found most frequently at the cavernous or transverse sinus. Leptomeningeal venous drainage can lead to venous hypertension and intracranial hemorrhage. The various treatment options include transarterial and transvenous embolization, stereotactic radiosurgery, and open surgery. Although many of the advances in dural arteriovenous fistula treatment have occurred in the endovascular arena, open microsurgical advances in the past decade have primarily been in the tools available to the surgeon. Improvements in microsurgical and skull base approaches have allowed surgeons to approach and obliterate fistulas with little or no retraction of the brain. Image-guided systems have also allowed better localization and more efficient approaches. A better understanding of the need to simply obliterate the venous drainage at the site of the fistula has eliminated the riskier resections of the past. Finally, the use of intraoperative angiography or indocyanine green videoangiography confirms the complete disconnection of fistula while the patient is still on the operating room table, preventing reoperation for residual fistulas.Dural arteriovenous fistulas are abnormal connections of dural arteries to dural veins or venous sinuses originating from within the dural leaflets. They are usually located near or within the wall of a dural venous sinus that is frequently obstructed or stenosed. The dural fistula sac is contained within the dural leaflets, and drainage can be via a dural sinus or retrograde through cortical veins (leptomeningeal drainage). Dural arteriovenous fistulas can occur at any dural sinus but are found most frequently at the cavernous or transverse sinus. Leptomeningeal venous drainage can lead to venous hypertension and intracranial hemorrhage. The various treatment options include transarterial and transvenous embolization, stereotactic radiosurgery, and open surgery. Although many of the advances in dural arteriovenous fistula treatment have occurred in the endovascular arena, open microsurgical advances in the past decade have primarily been in the tools available to the surgeon. Improvements in microsurgical and skull base approaches have allowed surgeons to approach and obliterate fistulas with little or no retraction of the brain. Image-guided systems have also allowed better localization and more efficient approaches. A better understanding of the need to simply obliterate the venous drainage at the site of the fistula has eliminated the riskier resections of the past. Finally, the use of intraoperative angiography or indocyanine green videoangiography confirms the complete disconnection of fistula while the patient is still on the operating room table, preventing reoperation for residual fistulas.

Antithrombotic states and outcomes in patients with angiographically negative subarachnoid hemorrhage.

BACKGROUND:Antithrombotic states are encountered frequently, either because of medical therapy or by preexistent pathological states, and may affect the severity of hemorrhagic strokes such as angiographically negative subarachnoid hemorrhages. OBJECTIVE:To determine the effects of antithrombotic states on the outcomes of patients with angiographically negative subarachnoid hemorrhage by examining data pooled from 2 institutions. METHODS:This is a retrospective review of patients who experienced angiographically negative subarachnoid hemorrhage at 2 institutions over the past 5 years. The patients were grouped into those with and those without an antithrombotic state at time of hemorrhage and were stratified according to presentation, clinical grades, outcomes, need for cerebrospinal fluid diversion, and development of vasospasm. Computed tomography of the head was assessed for bleed pattern and modified Fisher grade. Patients were excluded if a causative lesion was subsequently discovered. RESULTS:There is a statistically significant association between antithrombotic states and poorer presentation, higher Hunt and Hess score, increased amount of subarachnoid hemorrhage, higher modified Fisher grade, increased incidence of vasospasm, hydrocephalus, and poor outcomes as assessed by modified Rankin scale (P < .001). Patients with an antithrombotic state experience worse outcomes even with adjustment for the amount of hemorrhage as assessed by modified Fisher grade (P < .001). CONCLUSION:Patients in an antithrombotic state presenting with angiographically negative subarachnoid hemorrhage present with inferior clinical scores, diffuse hemorrhage patterns, and worse modified Fisher grades and have worse outcomes.

Pial Arteriovenous Fistula Resulting from Ventriculostomy

OBJECTIVE Ventriculostomy complications are well documented in the literature. We report the first known example of an arteriovenous fistula created during passage of a ventriculostomy catheter for the treatment of hydrocephalus. METHODS A 47-year-old female patient initially presented with a subarachnoid hemorrhage and an anterior communicating artery aneurysm. The patient underwent coil embolization followed by a ventriculostomy catheter for hydrocephalus. After recovery, a follow-up angiogram demonstrated a new arteriovenous fistula at the site of the ventriculostomy. A craniotomy was performed at the site of the ventriculostomy burr-hole site. Indocyanine green videoangiography confirmed the site of the fistula. RESULTS The fistulous point was coagulated and divided and confirmed with both indocyanine green videoangiography and intraoperative diagnostic angiography. The patient recovered without deficit. CONCLUSION This is the first reported case of a pial arteriovenous fistula from a ventriculostomy catheter. The formation of a fistula can occur from trauma to cortical arteries and veins at the pial entry site. Although rare, vascular injury and subsequent fistula formation may form in patients in whom catheter tract hemorrhages occur after catheter placement.

Indocyanine Green Videoangiography for Confirmation of Bypass Graft Patency

OBJECTIVE The aim of the study is to determine the efficacy of indocyanine green (ICG) videoangiography for confirmation of vascular anastomosis patency in both extracranial-intracranial and intracranial-intracranial bypasses. METHODS Intraoperative ICG videoangiography was used as a surgical adjunct for 56 bypasses in 47 patients to assay the patency of intracranial vascular anastomosis. These patients underwent a bypass for cerebral ischemia in 31 instances and as an adjunct to intracranial aneurysm surgery in 25. After completion of the bypass, ICG was administered to assess the patency of the graft. The findings on ICG videoangiography were then compared to intraoperative and/or postoperative imaging. RESULTS ICG provided an excellent visualization of all cerebral arteries and grafts at the time of surgery. Four grafts were determined to be suboptimal and were revised at the time of surgery. Findings on ICG videoangiography correlated with intraoperative and/or postoperative imaging. CONCLUSION ICG videoangiography is rapid, effective, and reliable in determining the intraoperative patency of bypass grafts. It provides intraoperative information allowing revision to reduce the incidence of technical errors that may lead to early graft thrombosis.

ε-Aminocaproic acid in angiographically negative subarachnoid hemorrhage patients is safe: a retrospective review of 83 consecutive patients.

BACKGROUND ε-Aminocaproic acid (EACA) has been used to reduce the rate of cerebral aneurysm rerupture before definitive treatment. In centers administering EACA to patients with a subarachnoid hemorrhage (SAH), patients eventually diagnosed with angiographically negative subarachnoid hemorrhage (ANSAH) may also initially receive EACA, perhaps placing them at increased risk for ischemic complications. OBJECTIVE To evaluate the effect of short-term EACA on outcomes and secondary measures in patients with ANSAH. METHODS We conducted a retrospective study of 454 consecutive SAH patients over a 2-year period under a current protocol for EACA use. Patients were excluded if a source for the SAH was discovered, yielding a total of 83 ANSAH patients. The patients were assigned to groups that did or did not receive EACA. The primary end points of the study were ischemic complications, pulmonary emboli, vasospasm, ventriculoperitoneal shunting rates, and outcomes. RESULTS Statistical analysis yielded no significant difference between the 2 arms with respect to any of the end points: vasospasm (P = .65), deep vein thrombosis (P = .51), pulmonary embolism (P = 1.0), stroke (P = 1.0), myocardial infarction (P = 1.0), and ventriculoperitoneal shunt (P = .57). There was no statistically significant outcome difference using the modified Rankin Scale (P = .30). CONCLUSION Short-term (<72 hour) application of EACA does not result in an increase in adverse events in patients with ANSAH.

Experience with coil embolization of previously clipped aneurysms presenting with rupture.

Introduction Endovascular coil embolization has an established role alongside microsurgical clipping in the treatment of aneurysms. We studied previously clipped aneurysms that presented as subarachnoid hemorrhage and were treated by coil embolization. Methods A retrospective review was performed of two prospectively maintained databases from two institutions (Cleveland Clinic, Emory University) that spanned 12 years. Results Seven patients were identified (mean age 56.9 years) who had previously undergone surgical clipping for aneurysm obliteration; six (86%) were previously ruptured. Patients presented with aneurysm rupture with a mean time of 11.5 years (range 4 months to 20 years) following surgical treatment. Aneurysm location included anterior communicating artery (n=4), posterior communicating artery (n=1), internal carotid artery terminus (n=1) and anterior choroidal (n=1). Three patients presented in Hunt and Hess (HH) grade 1, one in HH2, two in HH3 and one in HH4. Four of the patients underwent unassisted coil embolization while balloon assistance was employed in three. Angiographic results were as follows: complete occlusion (n=3; 42.9%) and residual neck (n=4; 57.1%). There were no intraprocedural complications. Conclusion Aneurysm rupture following surgical obliteration is a rare event and may occur remote from the initial treatment. Endovascular embolization with or without balloon assistance can be safely employed in cases of aneurysm recurrence rupture following surgical treatment with satisfactory angiographic treatment.