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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.

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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.

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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.

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Thomas L. Beaumont, David D. Limbrick Jr., Keith M. Rich, Franz J. Wippold II and Ralph G. Dacey Jr.

OBJECTIVE

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.

METHODS

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.

RESULTS

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).

CONCLUSIONS

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.

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Terrence F. Holekamp, Matthew E. Mollman, Rory K. J. Murphy, Grant R. Kolar, Neha M. Kramer, Colin P. Derdeyn, Christopher J. Moran, Richard J. Perrin, Keith M. Rich, Giuseppe Lanzino and Gregory J. Zipfel

Nonhemorrhagic neurological deficits are underrecognized symptoms of intracranial dural arteriovenous fistulas (dAVFs) having cortical venous drainage. These symptoms are the consequence of cortical venous hypertension and portend a clinical course with increased risk of neurological morbidity and mortality. One rarely documented and easily misinterpreted type of nonhemorrhagic neurological deficit is progressive dementia, which can result from venous hypertension in the cortex or in bilateral thalami. The latter, which is due to dAVF drainage into the deep venous system, is the less common of these 2 dementia syndromes. Herein, the authors report 4 cases of dAVF with venous drainage into the vein of Galen causing bithalamic edema and rapidly progressive dementia. Two patients were treated successfully with endovascular embolization, and the other 2 patients were treated successfully with endovascular embolization followed by surgery. The radiographic abnormalities and presenting symptoms rapidly resolved after dAVF obliteration in all 4 cases. Detailed descriptions of these 4 cases are presented along with a critical review of 15 previously reported cases. In our analysis of these 19 published cases, the following were emphasized: 1) the clinical and radiographic differences between dAVF-induced thalamic versus cortical dementia syndromes; 2) the differential diagnosis and necessary radiographic workup for patients presenting with a rapidly progressive thalamic dementia syndrome; 3) the frequency at which delays in diagnosis occurred and potentially dangerous and avoidable diagnostic procedures were used; and 4) the rapidity and completeness of symptom resolution following dAVF treatment.

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Chad W. Washington, Colin P. Derdeyn, Rajat Dhar, Eric J. Arias, Michael R. Chicoine, DeWitte T. Cross, Ralph G. Dacey Jr., Byung Hee Han, Christopher J. Moran, Keith M. Rich, Ananth K. Vellimana and Gregory J. Zipfel

OBJECT

Studies show that phosphodiesterase-V (PDE-V) inhibition reduces cerebral vasospasm (CVS) and improves outcomes after experimental subarachnoid hemorrhage (SAH). This study was performed to investigate the safety and effect of sildenafil (an FDA-approved PDE-V inhibitor) on angiographic CVS in SAH patients.

METHODS

A2-phase, prospective, nonrandomized, human trial was implemented. Subarachnoid hemorrhage patients underwent angiography on Day 7 to assess for CVS. Those with CVS were given 10 mg of intravenous sildenafil in the first phase of the study and 30 mg in the second phase. In both, angiography was repeated 30 minutes after infusion. Safety was assessed by monitoring neurological examination findings and vital signs and for the development of adverse reactions. For angiographic assessment, in a blinded fashion, pre- and post-sildenafil images were graded as “improvement” or “no improvement” in CVS. Unblinded measurements were made between pre- and post-sildenafil angiograms.

RESULTS

Twelve patients received sildenafil; 5 patients received 10 mg and 7 received 30 mg. There were no adverse reactions. There was no adverse effect on heart rate or intracranial pressure. Sildenafil resulted in a transient decline in mean arterial pressure, an average of 17% with a return to baseline in an average of 18 minutes. Eight patients (67%) were found to have a positive angiographic response to sildenafil, 3 (60%) in the low-dose group and 5 (71%) in the high-dose group. The largest degree of vessel dilation was an average of 0.8 mm (range 0–2.1 mm). This corresponded to an average percentage increase in vessel diameter of 62% (range 0%–200%).

CONCLUSIONS

The results from this Phase I safety and proof-of-concept trial assessing the use of intravenous sildenafil in patients with CVS show that sildenafil is safe and well tolerated in the setting of SAH. Furthermore, the angiographic data suggest that sildenafil has a positive impact on human CVS.