✓ The clinical usefulness of intraoperative electroencephalographic (EEG) monitoring of cerebral perfusion during aneurysm surgery has received little attention, primarily due to problems with electrode placement over the operative site, which is the area of maximal risk. In this report, 27 patients undergoing surgery for anterior circulation aneurysms were monitored intraoperatively with a two-channel computerized EEG complex using a bilateral frontal-occipital montage. In 16 patients, a normal EEG pattern was observed throughout surgery; all 16 awoke neurologically intact and their postoperative angiograms did not reveal cerebral vasospasm. In the other 11 patients, one of two patterns of persistent EEG abnormalities was identified. 1) In six of these patients a marked attenuation of EEG activity was observed ipsilaterally which coincided with various intraoperative events including brain retraction, hypotension, and aneurysm dissection/clipping. Five of these six patients awoke with new neurological deficits which persisted beyond 12 hours in two, both of whom had angiographically proven vasospasm 24 hours after surgery. 2) In the remaining five patients, a distinct abnormal EEG pattern consisting of marked hyperactivity in the delta, theta, and alpha frequency ranges was observed ipsilaterally. Four of these five patients had a poor neurological outcome and vasospasm on their angiogram 24 hours after surgery. Thus, EEG monitoring which spans the operative area during aneurysm surgery is practicable and appears to be of value in the detection of compromised cerebral perfusion during aneurysm surgery. The possible significance of the two abnormal EEG patterns identified in this report is discussed.
Rene Tempelhoff, Paul A. Modica, Keith M. Rich and Robert L. Grubb Jr.
Dysembryoplastic neuroepithelial tumor and oligodendroglioma: the diagnostic value of magnetic resonance spectroscopy
Case report and review of the literature
Eric W. Sherburn, Mark M. Bahn, Murat Gokden, Daniel L. Silbergeld and Keith M. Rich
Preoperative differentiation between dysembryoplastic neuroepithelial tumor (DNT) and low-grade glioma is often not possible. Dysembryoplastic neuroepithelial tumor is a recently described entity of uncertain origin; however, the diagnosis has important clinical implications. Clinical and radiological findings of DNT and low-grade glioma, especially oligodendroglioma, may be similar. Treatment options and prognosis differ significantly between these two lesions; consequently, accurate diagnosis is imperative. The authors describe two individuals who presented simultaneously at their institution: one patient with an oligodendroglioma and a second patient with DNT. The natural history, neurodiagnostic, and pathological features of each are reviewed with special emphasis on the potential utility of magnetic resonance spectroscopy in differentiating these lesions.
Michael A. Vogelbaum, Jianxin X. Tong, Rajashri Perugu, David H. Gutmann and Keith M. Rich
Object. Cells that lose their ability to undergo apoptosis may promote the development of neoplasms and result in resistance to clinical treatment with DNA-damaging modalities such as radio- and chemotherapy. Four established human glioma cell lines that are resistant to apoptosis were transfected with the proapoptotic gene bax and assessed for their sensitivity to a proapoptotic stimulus.
Methods. Two cell lines had a wild-type p53 genotype (U87 and D247MG) and two had mutant p53 genotypes (U138 and U373). Constitutive overexpression of murine bax was achieved in U138 and U373 only, which resulted in an increased sensitivity of these lines to the apoptosis-inducing effect of cytosine arabinoside (ara-C). Multiple attempts to produce constitutive overexpression of bax in U87 and D247MG cells resulted in spontaneous, near-complete cell loss. Vector-only control transfections were successful in all four cell lines. Inducible overexpression of bax was achieved in the U87 cells and elevated levels of BAX were observed as early as 6 hours after gene induction. This overexpression of BAX resulted in the spontaneous induction of apoptosis in these cells.
Conclusions. Overexpression of BAX in four human glioma cell lines resulted in increased sensitivity to apoptosis. In the two lines that had a wild-type p53 genotype, overexpression of BAX produced spontaneous apoptosis. In contrast, the lines that had mutant, nonfunctional P53 did not undergo spontaneous apoptosis, but they were rendered more sensitive to the apoptosis-inducing effect of ara-C. Modulation of BAX expression may be a useful therapeutic modality for gliomas, regardless of p53 genotype.
Michael A. Vogelbaum, Jianxin X. Tong, Ryuji Higashikubo, David H. Gutmann and Keith M. Rich
Object. Genes known to be involved in the regulation of apoptosis include members of the bcl-2 gene family, such as inhibitors of apoptosis (bcl-2 and bcl-xl) and promoters of apoptosis (bax). The authors investigated a potential approach for the treatment of malignant gliomas by using a gene transfection technique to manipulate the level of an intracellular protein involved in the control of apoptosis.
Methods. The authors transfected the murine bax gene, which had been cloned into a mammalian expression vector, into the C6 rat glioma cell line. Overexpression of the bax gene resulted in a decreased growth rate (average doubling time of 32.96 hours compared with 22.49 hours for untransfected C6, and 23.11 hours for clones transfected with pcDNA3 only), which may be caused, in part, by an increased rate of spontaneous apoptosis (0.77 ± 0.15% compared with 0.42 ± 0.08% for the vector-only transfected C6 cell line; p = 0.038, two-tailed Student's t-test). Treatment with 1 µM cytosine arabinoside (ara-C) resulted in significantly more cells undergoing apoptosis in the cell line overexpressing bax than in the vector-only control cell line (23.57 ± 2.6% compared with 5.3 ± 0.7% terminal deoxynucleotidyl transferase—mediated biotinylated—deoxyuridine triphosphate nick-end labeling technique—positive cells; p = 0.007). Furthermore, measurements of growth curves obtained immediately after treatment with 0.5 µM ara-C demonstrated a prolonged growth arrest of at least 6 days in the cell line overexpressing bax.
Conclusions. These results can be used collectively to argue that overexpression of bax results in increased sensitivity of C6 cells to ara-C and that increasing bax expression may be a useful strategy, in general, for increasing the sensitivity of gliomas to antineoplastic treatments.
Dennis J. Rivet, James K. Goddard III, Keith M. Rich and Colin P. Derdeyn
✓ Definitive endovascular treatment of dural arteriovenous fistulas (DAVFs) requires obliteration of the site of the fistula: either the diseased dural sinus or the pial vein. Access to this site is often limited by occlusion of the sinus proximal and distal to the segment containing the fistula. The authors describe a technique in which the mastoid emissary vein is used to gain access to a Borden–Shucart Type II DAVF in the transverse–sigmoid sinus. Recognition of this route of access, if present, may facilitate endovascular treatment of these lesions. Access to the transverse sinus via this approach can be straightforward and may be underused.
Michael A. Vogelbaum, Jianxin X. Tong, Ryuji Higashikubo, David H. Gutmann and Keith M. Rich
Genes known to be involved in the regulation of apoptosis include members of the bcl-2 gene family, such as inhibitors of apoptosis (bcl-2 and bcl-xl) and promotors of apoptosis (bax). The authors investigated a potential approach for the treatment of malignant gliomas by using a gene transfection technique to manipulate the level of an intracellular protein involved in the control of apoptosis.
The authors transfected the murine bax gene, which had been cloned into a mammalian expression vector, into the C6 rat glioma cell line. Overexpression of the bax gene resulted in a decreased growth rate (average doubling time of 32.96 hours compared with 22.49 hours for untransfected C6, and 23.11 hours for clones transfected with pcDNA3 only), which may be caused, in part, by an increased rate of spontaneous apoptosis (0.77 ± 0.15% compared with 0.42 ± 0.08% for the vector-only transfected C6 cell line; p = 0.038, two-tailed Student's t-test). Treatment with 1 μM of cytosine arabinoside (ara-C) resulted in significantly more cells undergoing apoptosis in the cell line overexpressing bax than in the vector-only control cell line (23.57 ± 2.6% compared with 5.3 ± 0.7% terminal deoxynucleotidyl transferase-mediated biotinylated-deoxyuridine triphosphate nick-end labeling technique-positive cells; p = 0.007). Furthermore, measurements of growth curves obtained immediately after treatment with 0.5 μM ara-C demonstrated a prolonged growth arrest of at least 6 days in the cell line overexpressing bax.
These results can be used collectively to argue that overexpression of bax results in increased sensitivity of C6 cells to ara-C and that increasing bax expression may be a useful strategy, in general, for increasing the sensitivity of gliomas to antineoplastic treatments.
David N. Loy, Keith M. Rich, Joseph Simpson, Ian Dorward, Lakshmi Santanam and Colin P. Derdeyn
This report demonstrates that time-of-flight (TOF) MR angiography is a useful adjunct for planning stereotactic radiosurgery (SRS) of large arteriovenous malformations (AVMs) after staged embolization with Onyx.
Onyx (ethylene vinyl copolymer), a recently approved liquid embolic agent, has been increasingly used to exclude portions of large AVMs from the parent circulation prior to SRS. Limiting SRS to regions of persistent arteriovenous shunting and excluding regions eliminated by embolization may reduce unnecessary radiation doses to eloquent brain structures. However, SRS dosimetry planning presents unique challenges after Onyx embolization because it creates extensive artifacts on CT scans, and it cannot be delineated from untreated nidus on standard MR sequences.
During the radiosurgery procedure, MR images were obtained using a GE Signa 1.5-T unit. Standard axial T2 fast spin echo high-resolution images (TR 3000 msec, TE 108 msec, slice thickness 2.5 mm) were generated for optimal visualization of brain tissue and AVM flow voids. The 3D TOF MR angiography images of the circle of Willis and vertebral arteries were subsequently obtained to visualize AVM regions embolized with Onyx (TR 37 msec, TE 6.9 msec, flip angle 20°).
Adjunct TOF MR angiography images demonstrated excellent contrast between nidus embolized with Onyx and regions of persistent arteriovenous shunting within a large AVM prior to SRS. Additional information derived from these sequences resulted in substantial adjustments to the treatment plan and an overall reduction in the treated tissue volume.
Maria Mamalui-Hunter, Thomas Jiang, Keith M. Rich, Colin P. Derdeyn and Robert E. Drzymala
The effectiveness of Gamma Knife stereotactic surgery to obliterate brain arteriovenous malformations (AVMs) may be diminished by the preoperative adjunctive use of endovascular liquid embolic agents. The purpose of the present investigation was to determine if commercially available liquid embolic agents reduce the radiation dose to the target because of attenuation of the 60Co beam.
The apparent linear attenuation coefficients for 120- to 140-keV radiographs in embolized regions were retrieved from CT scans for several patients with AVMs who had undergone embolization procedures with liquid embolic agents to reduce nidal volumes. Based on these coefficients and a virtual model of Gamma Knife surgery (GKS) with basic ray tracing, the authors obtained the path lengths and densities of the embolized regions. The attenuation of 60Co beams was then calculated for various sizes and positions of embolized AVM regions and for the number of beams used for treatment. Published experiments for several high-atomic-number materials were used to estimate the effective 60Co beam attenuation coefficients for the N-butyl cyanoacrylate (NBCA, suspended in ethiodized oil) and ethylene vinyl alcohol copolymer (EVOH, with suspended micronized tantalum powder, Onyx) used in the AVM embolizations. Dose reductions during GKS were calculated for a theoretical model based on the CT-documented apparent linear attenuation coefficients and for the 60Co energy attenuation coefficient. Dose measurements were obtained in a phantom study with EVOH for comparison with the estimates generated from the two attenuation coefficients.
Based on CT (keV) apparent attenuation coefficients, the authors' theoretical model predicted that the cumulative effect of either of the embolic agents decreased the number of kilovoltage photons in an embolized nidus by −8% to −15% because of the increased atomic number and density of NBCA and Onyx. However, in using the effective attenuation coefficient for the 60Co energies as is used in GKS, the authors' theoretical model yielded only a 0.2% dose reduction per beam and a < 0.01%–0.2% dose reduction in total. These theoretical results were validated by measurements in a head phantom containing Onyx.
Dose reduction due to attenuation of the 60Co beam by the AVM embolization material was negligible for both NBCA and EVOH because of the high-energy 60Co beam.
Thomas L. Beaumont, David D. Limbrick Jr., Keith M. Rich, Franz J. Wippold II and Ralph G. Dacey Jr.
Colloid cysts are rare, histologically benign lesions that may result in obstructive hydrocephalus and death. Understanding the natural history of colloid cysts has been challenging given their low incidence and the small number of cases in most reported series. This has complicated efforts to establish reliable prognostic factors and surgical indications, particularly for asymptomatic patients with incidental lesions. Risk factors for obstructive hydrocephalus in the setting of colloid cysts remain poorly defined, and there are no grading scales on which to develop standard management strategies.
The authors performed a single-center retrospective review of all cases of colloid cysts of the third ventricle treated over nearly 2 decades at Washington University. Univariate analysis was used to identify clinical, imaging, and anatomical factors associated with 2 outcome variables: symptomatic clinical status and presentation with obstructive hydrocephalus. A risk-prediction model was defined using bootstrapped logistic regression. Predictive factors were then combined into a simple 5-point clinical scale referred to as the Colloid Cyst Risk Score (CCRS), and this was evaluated with receiver-operator characteristics.
The study included 163 colloid cysts, more than half of which were discovered incidentally. More than half of the incidental cysts (58%) were followed with surveillance neuroimaging (mean follow-up 5.1 years). Five patients with incidental cysts (8.8%) progressed and underwent resection. No patient with an incidental, asymptomatic colloid cyst experienced acute obstructive hydrocephalus or sudden neurological deterioration in the absence of antecedent trauma. Nearly half (46.2%) of symptomatic patients presented with hydrocephalus. Eight patients (12.3%) presented acutely, and there were 2 deaths due to obstructive hydrocephalus and herniation. The authors identified several factors that were strongly correlated with the 2 outcome variables and defined third ventricle risk zones where colloid cysts can cause obstructive hydrocephalus. No patient with a lesion outside these risk zones presented with obstructive hydrocephalus. The CCRS had significant predictive capacity for symptomatic clinical status (area under the curve [AUC] 0.917) and obstructive hydrocephalus (AUC 0.845). A CCRS ≥ 4 was significantly associated with obstructive hydrocephalus (p < 0.0001, RR 19.4).
Patients with incidentally discovered colloid cysts can experience both lesion enlargement and symptom progression or less commonly, contraction and symptom regression. Incidental lesions rarely cause acute obstructive hydrocephalus or sudden neurological deterioration in the absence of antecedent trauma. Nearly one-half of patients with symptomatic colloid cysts present with obstructive hydrocephalus, which has an associated 3.1% risk of death. The CCRS is a simple 5-point clinical tool that can be used to identify symptomatic lesions and stratify the risk of obstructive hydrocephalus. External validation of the CCRS will be necessary before objective surgical indications can be established. Surgical intervention should be considered for all patients with CCRS ≥ 4, as they represent the high-risk subgroup.
Ananth K. Vellimana, Yasha Kadkhodayan, Keith M. Rich, DeWitte T. Cross III, Christopher J. Moran, Allyson R. Zazulia, Jin-Moo Lee, Michael R. Chicoine, Ralph G. Dacey Jr., Colin P. Derdeyn and Gregory J. Zipfel
The aim of this study was to define the optimal treatment for patients with symptomatic intraluminal carotid artery thrombus (ICAT).
The authors performed a retrospective chart review of patients who had presented with symptomatic ICAT at their institution between 2001 and 2011.
Twenty-four patients (16 males and 8 females) with ICAT presented with ischemic stroke (18 patients) or transient ischemic attack ([TIA], 6 patients). All were initially treated using anticoagulation with or without antiplatelet drugs. Eight of these patients had no or only mild carotid artery stenosis on initial angiography and were treated with medical management alone. The remaining 16 patients had moderate or severe carotid stenosis on initial angiography; of these, 10 underwent delayed revascularization (8 patients, carotid endarterectomy [CEA]; 2 patients, angioplasty and stenting), 2 refused revascularization, and 4 were treated with medical therapy alone. One patient had multiple TIAs despite medical therapy and eventually underwent CEA; the remaining 23 patients had no TIAs after treatment. No patient suffered ischemic or hemorrhagic stroke while on anticoagulation therapy, either during the perioperative period or in the long-term follow-up; 1 patient died of an unrelated condition. The mean follow-up was 16.4 months.
Results of this study suggest that initial anticoagulation for symptomatic ICAT leads to a low rate of recurrent ischemic events and that carotid revascularization, if indicated, can be safely performed in a delayed manner.