Robert T. Wicks

Impact of changes in intraoperative somatosensory evoked potentials on stroke rates after clipping of intracranial aneurysms.

BACKGROUND Somatosensory evoked potential (SSEP) monitoring is used during intracranial aneurysm surgery to track the effects of anesthesia, surgical manipulation, and temporary clipping. OBJECTIVE To present the outcomes of 663 consecutive patients (691 cases) treated surgically for intracranial aneurysms who underwent intraoperative SSEP monitoring and to analyze the sensitivity and specificity of significant SSEP changes in predicting postoperative stroke. METHODS Of 691 surgeries analyzed, 403 (391 anterior circulation, 12 posterior circulation) were unruptured aneurysms and 288 (277 anterior, 11 posterior) were ruptured. Postoperatively, symptomatic patients underwent computed tomography imaging. Positive predictive value, negative predictive value, sensitivity, and specificity were calculated with a Fisher exact test (2-tailed P value). RESULTS Changes in SSEP occurred in 45 of 691 cases (6.5%): 16 of 403 (4.0%) in unruptured aneurysms and 29 of 288 (10%) in ruptured aneurysms. In unruptured aneurysms, reversible SSEP changes were associated with a 20% stroke rate, but irreversible changes were associated with an 80% stroke rate. In ruptured aneurysms, however, reversible changes were associated with a 12% stroke rate, and irreversible changes were associated with a 42% stroke rate. The overall accuracy of SSEP changes in predicting postoperative stroke was as follows: positive predictive value, 30%; negative predictive value, 94%; sensitivity, 25%; and specificity, 95%. CONCLUSION Intraoperative SSEP changes are more reliable in unruptured aneurysm cases than in ruptured cases. Whereas irreversible changes in unruptured cases were associated with an 80% stroke rate, such changes in ruptured cases did not have any adverse ischemic sequelae in 58% of patients. This information is helpful during the intraoperative assessment of reported SSEP changes.

Local delivery of cancer-cell glycolytic inhibitors in high-grade glioma

BACKGROUND 3-bromopyruvate (3-BrPA) and dichloroacetate (DCA) are inhibitors of cancer-cell specific aerobic glycolysis. Their application in glioma is limited by 3-BrPAs inability to cross the blood-brain-barrier and DCAs dose-limiting toxicity. The safety and efficacy of intracranial delivery of these compounds were assessed. METHODS Cytotoxicity of 3-BrPA and DCA were analyzed in U87, 9L, and F98 glioma cell lines. 3-BrPA and DCA were incorporated into biodegradable pCPP:SA wafers, and the maximally tolerated dose was determined in F344 rats. Efficacies of the intracranial 3-BrPA wafer and DCA wafer were assessed in a rodent allograft model of high-grade glioma, both as a monotherapy and in combination with temozolomide (TMZ) and radiation therapy (XRT). RESULTS 3-BrPA and DCA were found to have similar IC50 values across the 3 glioma cell lines. 5% 3-BrPA wafer-treated animals had significantly increased survival compared with controls (P = .0027). The median survival of rats with the 50% DCA wafer increased significantly compared with both the oral DCA group (P = .050) and the controls (P = .02). Rats implanted on day 0 with a 5% 3-BrPA wafer in combination with TMZ had significantly increased survival over either therapy alone. No statistical difference in survival was noted when the wafers were added to the combination therapy of TMZ and XRT, but the 5% 3-BrPA wafer given on day 0 in combination with TMZ and XRT resulted in long-term survivorship of 30%. CONCLUSION Intracranial delivery of 3-BrPA and DCA polymer was safe and significantly increased survival in an animal model of glioma, a potential novel therapeutic approach. The combination of intracranial 3-BrPA and TMZ provided a synergistic effect.

Accuracy of computed tomography angiography in the diagnosis of intracranial aneurysms.

OBJECTIVE Although digital subtraction angiography (DSA) remains the standard for intracranial aneurysm diagnosis, computed tomography angiography (CTA) is being increasingly used for this purpose. CTA has sensitivities and specificities reported as high as 97% and 100%, respectively. We analyzed a prospective cohort of 112 patients with 134 unruptured aneurysms who underwent community CTAs and confirmatory DSAs in a tertiary facility. METHODS Patients referred between 2007 and 2010 (mean age 53.2 years) with aneurysms identified by CTA underwent confirmatory DSA. The results were compared to determine accuracy of CTA in diagnosing aneurysms. Aneurysms diagnosed by CTA but ruled out by DSA or aneurysms missed by CTA but diagnosed by DSA were analyzed by size and location. Anatomical variants leading to false CTA positive results were noted. RESULTS CTA identified 132 aneurysms, of which 27 (20.5%) were false positives. Of these 27 aneurysms, 18 were completely negative but 9 had an anatomical structure that explained the CTA finding, 18 were either small (6-10 mm, 4%) or very small (1-5 mm, 63%), and 16 were located either in the anterior communicating artery (ACoA) region (33%) or at the basilar artery bifurcation (26%). Additionally, DSA identified 29 aneurysms (21.6%) missed by CTA. The most common locations for these were the cavernous segment of the internal carotid artery (24%) and the middle cerebral artery (24%), and all but 1 were very small (1-5 mm). CONCLUSION The CTA accuracy rate may be lower than previously reported. CTA is particularly inaccurate in aneurysms 5 mm or smaller and those in the ACoA region.

Local delivery of rapamycin: a toxicity and efficacy study in an experimental malignant glioma model in rats

Rapamycin, an anti-proliferative agent, is effective in the treatment of renal cell carcinoma and recurrent breast cancers. We proposed that this potent mammalian target of rapamycin inhibitor may be useful for the treatment of gliomas as well. We examined the cytotoxicity of rapamycin against a rodent glioma cell line, determined the toxicity of rapamycin when delivered intracranially, and investigated the efficacy of local delivery of rapamycin for the treatment of experimental malignant glioma in vivo. We also examined the dose-dependent efficacy of rapamycin and the effect when locally delivered rapamycin was combined with radiation therapy. Rapamycin was cytotoxic to 9L cells, causing 34% growth inhibition at a concentration of 0.01 µg/mL. No in vivo toxicity was observed when rapamycin was incorporated into biodegradable caprolactone-glycolide (35:65) polymer beads at 0.3%, 3%, and 30% loading doses and implanted intracranially. Three separate efficacy studies were performed to test the reproducibility of the effect of the rapamycin beads as well as the validity of this treatment approach. Animals treated with the highest dose of rapamycin beads tested (30%) consistently demonstrated significantly longer survival durations than the control and placebo groups. All dose-escalating rapamycin bead treatment groups (0.3%, 3% and 30%), treated both concurrently with tumor and in a delayed manner after tumor placement, experienced a significant increase in survival, compared with controls. Radiation therapy in addition to the simultaneous treatment with 30% rapamycin beads led to significantly longer survival duration than either therapy alone. These results suggest that the local delivery of rapamycin for the treatment of gliomas should be further investigated.

Laser Interstitial Thermal Therapy for Mesial Temporal Lobe Epilepsy

Approximately one-third of patients with epilepsy do not achieve adequate seizure control through medical management alone. Mesial temporal lobe epilepsy (MTLE) is one of the most common forms of medically refractory epilepsy referred for surgical management. Stereotactic laser amygdalohippocampotomy using magnetic resonance-guided laser interstitial thermal therapy (MRg-LITT) is an important emerging therapy for MTLE. Initial published reports support MRg-LITT as a less invasive surgical option with a shorter hospital stay and fewer neurocognitive side effects compared with craniotomy for anterior temporal lobectomy with amygdalohippocampectomy and selective amygdalohippocampectomy. We provide a historical overview of laser interstitial thermal therapy development and the technological advancements that led to the currently available commercial systems. Current applications of MRg-LITT for MTLE, reported outcomes, and technical issues of the surgical procedure are reviewed. Although initial reports indicate that stereotactic laser amygdalohippocampotomy may be a safe and effective therapy for medically refractory MTLE, further research is required to establish its long-term effectiveness and its cost/benefit profile. ABBREVIATIONS ATLAH, anterior temporal lobectomy with amygdalohippocampectomyLITT, laser interstitial thermal therapyMRg-LITT, magnetic resonance-guided laser interstitial thermal therapyMTLE, mesial temporal lobe epilepsySAH, selective amygdalohippocampectomySLAH, stereotactic laser amygdalohippocampotomy.

Extravascular optical coherence tomography: evaluation of carotid atherosclerosis and pravastatin therapy.

Background and Purpose— Extravascular optical coherence tomography (OCT), as a noninvasive imaging methodology with micrometer resolution, was evaluated in a murine model of carotid atherosclerosis by way of assessing the efficacy of pravastatin therapy. Methods— An OCT device was engineered for extravascular plaque imaging. Wild-type mice and apolipoprotein E–deficient (ApoE−/−) mice were randomized to 3 treatment groups: (1) wild-type on a diet of standard rodent chow (n=13); (2) ApoE−/− on a high-fat, atherosclerotic diet (HFD; n=13); and (3) ApoE−/− on a HFD given daily pravastatin (n=13). Mice were anesthetized and the left common carotid was surgically exposed. Three-dimensional (3D; 2 spatial dimensions+time) and 4D (3 spatial dimensions+time) OCT images of the vessel lumen patency were evaluated. After perfusion, in situ OCT imaging was performed for statistical comparison with the in vivo results and final histology. Results— Intraoperative OCT imaging positively identified carotid plaque in 100% of ApoE−/− mice on HFD. ApoE−/− mice on HFD had a significantly decreased lumen patency when compared with that in wild-type mice (P<0.001). Pravastatin therapy was found to increase lumen patency significantly in ApoE−/− mice on HFD (P<0.01; compared with ApoE−/− on HFD). The findings were confirmed with OCT imaging after perfusion and histology. Conclusions— OCT imaging offers the potential for real-time, detailed vessel lumen evaluation, potentially improving surgical accuracy and outcomes during cerebrovascular neurosurgical procedures. Pravastatin significantly increases vessel lumen patency in the ApoE−/− mouse on HFD.

Intracranial microcapsule chemotherapy delivery for the localized treatment of rodent metastatic breast adenocarcinoma in the brain

Significance Brain metastases represent the most common intracranial tumors in adults. Adequate chemotherapy delivery to the CNS is hindered by the blood–brain barrier. Efforts in intracranial chemotherapy delivery aim to maximize CNS levels while minimizing systemic toxicity; however, the success has been limited thus far. In this work, intracranial implanted doxorubicin and temozolomide microcapsules are compared with systemic administration in a novel rodent model of breast adenocarcinoma brain metastases. These microcapsules are versatile and efficacious, but that efficacy may depend on the ability of the chemotherapy to diffuse in brain tissue. These insights apply to other non-CNS applications of local drug delivery, and drugs should be evaluated based on their ability to penetrate the targeted tissue as well as their inherent efficacy. Metastases represent the most common brain tumors in adults. Surgical resection alone results in 45% recurrence and is usually accompanied by radiation and chemotherapy. Adequate chemotherapy delivery to the CNS is hindered by the blood–brain barrier. Efforts at delivering chemotherapy locally to gliomas have shown modest increases in survival, likely limited by the infiltrative nature of the tumor. Temozolomide (TMZ) is first-line treatment for gliomas and recurrent brain metastases. Doxorubicin (DOX) is used in treating many types of breast cancer, although its use is limited by severe cardiac toxicity. Intracranially implanted DOX and TMZ microcapsules are compared with systemic administration of the same treatments in a rodent model of breast adenocarcinoma brain metastases. Outcomes were animal survival, quantified drug exposure, and distribution of cleaved caspase 3. Intracranial delivery of TMZ and systemic DOX administration prolong survival more than intracranial DOX or systemic TMZ. Intracranial TMZ generates the more robust induction of apoptotic pathways. We postulate that these differences may be explained by distribution profiles of each drug when administered intracranially: TMZ displays a broader distribution profile than DOX. These microcapsule devices provide a safe, reliable vehicle for intracranial chemotherapy delivery and have the capacity to be efficacious and superior to systemic delivery of chemotherapy. Future work should include strategies to improve the distribution profile. These findings also have broader implications in localized drug delivery to all tissue, because the efficacy of a drug will always be limited by its ability to diffuse into surrounding tissue past its delivery source.

Inhibition of Corneal Neovascularization by Subconjunctival Injection of Fc-Endostatin, a Novel Inhibitor of Angiogenesis.

We assessed the antiangiogenic effects of subconjunctival injection of Fc-endostatin (FcE) using a human vascular endothelial growth factor-induced rabbit corneal neovascularization model. Angiogenesis was induced in rabbit corneas through intrastromal implantations of VEGF polymer implanted 2 mm from the limbus. NZW rabbits were separated into groups receiving twice weekly subconjunctival injections of either saline; 25 mg/mL bevacizumab; 2 mg/mL FcE; or 20 mg/mL FcE. Corneas were digitally imaged at 5 time points. An angiogenesis index (AI) was calculated (vessel length (mm) × vessel number score) for each observation. All treatment groups showed a significant decrease in the vessel length and AI compared to saline on all observation days (P < 0.001). By day 15, FcE 2 inhibited angiogenesis significantly better than FcE 20 (P < 0.01). There was no significant difference between FcE 2 and BV, although the values trended towards significantly increased inhibition by BV. BV was a significantly better inhibitor than FcE 20 by day 8 (P < 0.01). FcE was safe and significantly inhibited new vessel growth in a rabbit corneal neovascularization model. Lower concentration FcE 2 exhibited better inhibition than FcE 20, consistent with previous FcE studies referencing a biphasic dose-response curve. Additional studies are necessary to further elucidate the efficacy and clinical potential of this novel angiogenesis inhibitor.

Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall

OBJECTIVE We demonstrate here the first successful implementation in humans of a proof-of-concept system for restoring and improving memory function via facilitation of memory encoding using the patients own hippocampal spatiotemporal neural codes for memory. Memory in humans is subject to disruption by drugs, disease and brain injury, yet previous attempts to restore or rescue memory function in humans typically involved only nonspecific, modulation of brain areas and neural systems related to memory retrieval. APPROACH We have constructed a model of processes by which the hippocampus encodes memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of short-term memory. A nonlinear multi-input, multi-output (MIMO) model of hippocampal CA3 and CA1 neural firing is computed that predicts activation patterns of CA1 neurons during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task. MAIN RESULTS MIMO model-derived electrical stimulation delivered to the same CA1 locations during the sample phase of DMS trials facilitated short-term/working memory by 37% during the task. Longer term memory retention was also tested in the same human subjects with a delayed recognition (DR) task that utilized images from the DMS task, along with images that were not from the task. Across the subjects, the stimulated trials exhibited significant improvement (35%) in both short-term and long-term retention of visual information. SIGNIFICANCE These results demonstrate the facilitation of memory encoding which is an important feature for the construction of an implantable neural prosthetic to improve human memory.

Radiographic Vasospasm and Clinical (Symptomatic) Vasospasm

Abstract Cerebral vasospasm is a focal or diffuse, temporary narrowing of cerebral arteries as evidenced by digital subtraction angiography, transcranial Doppler, magnetic resonance, or computed tomography angiography. Cerebral vasospasm often results when cerebral vessels are exposed to blood in the subarachnoid space (subarachnoid hemorrhage), but may also occur after traumatic brain injury or secondary to inflammatory conditions such as meningitis and vasculitis. Radiographic spasm may progress to clinical (symptomatic) vasospasm as evidenced by neurologic deterioration and eventual permanent neurologic defect secondary to infarction. Autoregulatory dysfunction, inflammation, microcirculatory failure, and spreading cortical depolarization are multiple facets of the disease process that must be addressed with multimodal treatment to achieve improved neurologic outcomes. Rapid identification of symptomatic vasospasm with urgent treatment is essential to prevent permanent neurologic deficit. Ultimately, symptomatic vasospasm is best managed with hypertension followed by endovascular treatment with intra-arterial spasmolytics and/or balloon angioplasty.