Frank C. Tong

Transorbital Puncture for the Treatment of Cavernous Sinus Dural Arteriovenous Fistulas

Summary: This report describes a series of patients for whom dural arteriovenous fistulae (DAVFs) of the cavernous sinus were successfully embolized using a percutaneous, transorbital technique to directly cannulate the cavernous sinus. A vascular access needle and catheter are percutaneously advanced along the inferolateral aspect of the orbit to access the cavernous sinus via the superior orbital fissure. Safe and effective embolization is achieved without the need for a surgical cut-down.

Tissue-Type Plasminogen Activator Regulates the Neuronal Uptake of Glucose in the Ischemic Brain

The ability to sense and adapt to hypoxic conditions plays a pivotal role in neuronal survival. Hypoxia induces the release of tissue-type plasminogen activator (tPA) from cerebral cortical neurons. We found that the release of neuronal tPA or treatment with recombinant tPA promotes cell survival in cerebral cortical neurons previously exposed to hypoxic conditions in vitro or experimental cerebral ischemia in vivo. Our studies using liquid chromatography and tandem mass spectrometry revealed that tPA activates the mammalian target of rapamycin (mTOR) pathway, which adapts cellular processes to the availability of energy and metabolic resources. We found that mTOR activation leads to accumulation of the hypoxia-inducible factor-1α (HIF-1α) and induction and recruitment to the cell membrane of the HIF-1α-regulated neuronal transporter of glucose GLUT3. Accordingly, in vivo positron emission tomography studies with 18-fluorodeoxyglucose in mice overexpressing tPA in neurons show that neuronal tPA induces the uptake of glucose in the ischemic brain and that this effect is associated with a decrease in the volume of the ischemic lesion and improved neurological outcome following the induction of ischemic stroke. Our data indicate that tPA activates a cell signaling pathway that allows neurons to sense and adapt to oxygen and glucose deprivation.

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.

Effect of antiplatelet therapy and platelet function testing on hemorrhagic and thrombotic complications in patients with cerebral aneurysms treated with the pipeline embolization device: a review and meta-analysis.

Purpose The pipeline embolization device (PED) necessitates dual antiplatelet therapy (APT) to decrease thrombotic complications while possibly increasing bleeding risks. The role of APT dose, duration, and response in patients with hemorrhagic and thromboembolic events warrants further analysis. Methods A PubMed and Google Scholar search from 2009 to 2014 was performed using the following search terms individually or in combination: pipeline embolization device, aneurysm(s), and flow diversion, excluding other flow diverters. Review of the bibliographies of the retrieved articles yielded 19 single and multicenter studies. A statistical meta-analysis between aspirin (ASA) dose (low dose ≤160 mg, high dose ≥300 mg), loading doses of APT agents, post-PED APT regimens, and platelet function testing (PFT) with hemorrhagic or thrombotic complications was performed. Results ASA therapy for ≤6 months post-PED was associated with increased hemorrhagic events. High dose ASA ≤6 months post-PED was associated with fewer thrombotic events compared with low dose ASA. Post-PED clopidogrel for ≤6 months demonstrated an increased incidence of symptomatic thrombotic events. Loading doses of ASA plus clopidogrel demonstrated a decreased incidence of permanent symptomatic hemorrhagic events. PFT did not show a statistically significant relationship with symptomatic hemorrhagic or thrombotic complications. Conclusions High dose ASA >6 months is associated with fewer permanent thrombotic and hemorrhagic events. Clopidogrel therapy ≤6 months is associated with higher rates of thrombotic events. Loading doses of ASA and clopidogrel were associated with a decreased incidence of hemorrhagic events. PFT did not have any significant association with symptomatic events.

Angiographic and Clinical Outcomes in 200 Consecutive Patients with Cerebral Aneurysm Treated with Hydrogel-Coated Coils

BACKGROUND AND PURPOSE: Denser coil packing in intracranial aneurysms is believed to result in lower recanalization rates. Hydrogel-coated expandable coils (HydroCoil) improve volumetric packing of aneurysms in animal models and clinical studies, but data from large clinical series are limited. The objective of this retrospective analysis was to analyze immediate and follow-up angiographic results as well as complications in a large consecutive series of patients treated with HydroCoils at a single institution. MATERIALS AND METHODS: Retrospective analysis was performed of periprocedural complications, immediate and follow-up angiograms, and retreatments of the first 200 consecutive intracranial aneurysms treated at Emory University Hospital. RESULTS: One hundred eighty-seven patients with 200 intracranial aneurysms were treated with HydroCoils during a 3-year period. Immediate angiograms showed complete aneurysmal obliteration in 58.4% of small aneurysms and 42.7% of large aneurysms. Periprocedural complications included early rebleeding and thromboembolic events resulting in permanent neurologic morbidity and mortality in 6% of cases. Follow-up angiography during an average of 16.3 months demonstrated recanalization in 17.7% of small aneurysms and 28.6% of large aneurysms, requiring retreatment in 6.3% and 19.0% of cases, respectively. During the same time period, there was delayed angiographic improvement in aneurysm obliteration in 26.6% of small aneurysms and 26.2% of large aneurysms. CONCLUSIONS: First-generation HydroCoil treatment of intracranial aneurysms has a favorable rate of recanalization compared with most large series of pure platinum coils with similar complication rates.

Contrast-enhanced time-resolved MRA for pre-angiographic evaluation of suspected spinal dural arterial venous fistulas

Background Spinal digital subtraction angiography (DSA) is the gold standard for diagnosis of spinal dural arterial venous fistulas (SDAVFs), but can require extensive time, radiation exposure and contrast dose. We hypothesize that contrast-enhanced time-resolved MR angiography (CE-TR MRA) will have utility for the non-invasive diagnosis and pre-angiographic localization of SDAVFs. Methods Eighteen patients underwent both CE-TR MRA and DSA for suspected SDAVFs, with DSA performed a median of 11 days (range 0–41) after MRA. CE-TR MRA was performed on a 1.5 T GE unit using Time Resolved Imaging of Contrast Kinetics (TRICKS). CE-TR MRA and DSA images were evaluated for the presence of SDAVFs and location of the feeding arterial supply, with DSA as the reference standard. DSA was also evaluated for the number of vessels catheterized, contrast volume and fluoroscopic and procedure times. Results Eight of the 18 patients were positive for SDAVF on DSA. Sensitivity, specificity, positive predictive value and negative predictive value for the 18 CE-TR MRAs were 88%, 90%, 88% and 90%, respectively. Localization of the SDAVF arterial supply on CE-TR MRA was within one vertebral level from DSA for 6/7 SDAVFs. Compared with patients with a SDAVF and feeding artery identified on CE-TR MRA, patients with negative or suboptimal CE-TR MRA had a significantly increased number of vessels catheterized (p=0.027) and larger contrast volumes (p=0.022). Conclusions CE-TR MRA is a useful initial examination for the diagnosis and localization of SDAVFs, with a high concordance rate with DSA. When CE-TR MRA demonstrates a SDAVF, the number of catheterized vessels and contrast dose can be decreased during DSA.

Contrast-Enhanced Time-Resolved MRA for Follow-Up of Intracranial Aneurysms Treated with the Pipeline Embolization Device

BACKGROUND AND PURPOSE: Endovascular reconstruction and flow diversion by using the Pipeline Embolization Device is an effective treatment for complex cerebral aneurysms. Accurate noninvasive alternatives to DSA for follow-up after Pipeline Embolization Device treatment are desirable. This study evaluated the accuracy of contrast-enhanced time-resolved MRA for this purpose, hypothesizing that contrast-enhanced time-resolved MRA will be comparable with DSA and superior to 3D-TOF MRA. MATERIALS AND METHODS: During a 24-month period, 37 Pipeline Embolization Device–treated intracranial aneurysms in 26 patients underwent initial follow-up by using 3D-TOF MRA, contrast-enhanced time-resolved MRA, and DSA. MRA was performed on a 1.5T unit by using 3D-TOF and time-resolved imaging of contrast kinetics. All patients underwent DSA a median of 0 days (range, 0–68) after MRA. Studies were evaluated for aneurysm occlusion, quality of visualization of the reconstructed artery, and measurable luminal diameter of the Pipeline Embolization Device, with DSA used as the reference standard. RESULTS: The sensitivity, specificity, and positive and negative predictive values of contrast-enhanced time-resolved MRA relative to DSA for posttreatment aneurysm occlusion were 96%, 85%, 92%, and 92%. Contrast-enhanced time-resolved MRA demonstrated superior quality of visualization (P = .0001) and a higher measurable luminal diameter (P = .0001) of the reconstructed artery compared with 3D-TOF MRA but no significant difference compared with DSA. Contrast-enhanced time-resolved MRA underestimated the luminal diameter of the reconstructed artery by 0.965 ± 0.497 mm (27% ± 13%) relative to DSA. CONCLUSIONS: Contrast-enhanced time-resolved MRA is a reliable noninvasive method for monitoring intracranial aneurysms following flow diversion and vessel reconstruction by using the Pipeline Embolization Device.

Tissue-type plasminogen activator mediates neuronal detection and adaptation to metabolic stress

Adenosine monophosphate-activated protein kinase (AMPK) is an energy sensor that regulates cellular adaptation to metabolic stress. Tissue-type plasminogen activator (tPA) is a serine proteinase found in the intravascular space, where its main role is as thrombolytic enzyme, and in neurons, where its function is less well understood. Here, we report that glucose deprivation induces the mobilization and package of neuronal tPA into presynaptic vesicles. Mass spectrometry and immunohistochemical studies show that the release of this tPA in the synaptic space induces AMPK activation in the postsynaptic terminal, and an AMPK-mediated increase in neuronal uptake of glucose and neuronal adenosine 5′(tetrahydrogen triphosphate; ATP) synthesis. This effect is independent of tPAs proteolytic properties, and instead requires the presence of functional N-methyl-D-aspartate receptors (NMDARs). In agreement with these observations, positron emission tomography (PET) studies and biochemical analysis with synaptoneurosomes indicate that the intravenous administration of recombinant tPA (rtPA) after transient middle cerebral artery occlusion (tMCAO) induces AMPK activation in the synaptic space and NMDAR-mediated glucose uptake in the ischemic brain. These data indicate that the release of neuronal tPA or treatment with rtPA activate a cell signaling pathway in the synaptic space that promotes the detection and adaptation to metabolic stress.

A fast multiparameter MRI approach for acute stroke assessment on a 3T clinical scanner: preliminary results in a non-human primate model with transient ischemic occlusion

Many MRI parameters have been explored and demonstrated the capability or potential to evaluate acute stroke injury, providing anatomical, microstructural, functional, or neurochemical information for diagnostic purposes and therapeutic development. However, the application of multiparameter MRI approach is hindered in clinic due to the very limited time window after stroke insult. Parallel imaging technique can accelerate MRI data acquisition dramatically and has been incorporated in modern clinical scanners and increasingly applied for various diagnostic purposes. In the present study, a fast multiparameter MRI approach including structural T1-weighted imaging (T1W), T2-weighted imaging (T2W), diffusion tensor imaging (DTI), T2-mapping, proton magnetic resonance spectroscopy, cerebral blood flow (CBF), and magnetization transfer (MT) imaging, was implemented and optimized for assessing acute stroke injury on a 3T clinical scanner. A macaque model of transient ischemic stroke induced by a minimal interventional approach was utilized for evaluating the multiparameter MRI approach. The preliminary results indicate the surgical procedure successfully induced ischemic occlusion in the cortex and/or subcortex in adult macaque monkeys (n=4). Application of parallel imaging technique substantially reduced the scanning duration of most MRI data acquisitions, allowing for fast and repeated evaluation of acute stroke injury. Hence, the use of the multiparameter MRI approach with up to five quantitative measures can provide significant advantages in preclinical or clinical studies of stroke disease.

Temporal Evolution of Ischemic Lesions in Nonhuman Primates: A Diffusion and Perfusion MRI Study

Background and Purpose Diffusion-weighted imaging (DWI) and perfusion MRI were used to examine the spatiotemporal evolution of stroke lesions in adult macaques with ischemic occlusion. Methods Permanent MCA occlusion was induced with silk sutures through an interventional approach via the femoral artery in adult rhesus monkeys (n = 8, 10–21 years old). The stroke lesions were examined with high-resolution DWI and perfusion MRI, and T2-weighted imaging (T2W) on a clinical 3T scanner at 1–6, 48, and 96 hours post occlusion and validated with H&E staining. Results The stroke infarct evolved via a natural logarithmic pattern with the mean infarct growth rate = 1.38 ± 1.32 ml per logarithmic time scale (hours) (n = 7) in the hyperacute phase (1–6 hours). The mean infarct volume after 6 hours post occlusion was 3.6±2.8 ml (n = 7, by DWI) and increased to 3.9±2.9 ml (n = 5, by T2W) after 48 hours, and to 4.7±2.2ml (n = 3, by T2W) after 96 hours post occlusion. The infarct volumes predicted by the natural logarithmic function were correlated significantly with the T2W-derived lesion volumes (n = 5, r = 0.92, p = 0.01) at 48 hours post occlusion. The final infarct volumes derived from T2W were correlated significantly with those from H&E staining (r = 0.999, p < 0.0001, n = 4). In addition, the diffusion-perfusion mismatch was visible generally at 6 hours but nearly diminished at 48 hours post occlusion. Conclusion The infarct evolution follows a natural logarithmic pattern in the hyperacute phase of stroke. The logarithmic pattern of evolution could last up to 48 hours after stroke onset and may be used to predict the infarct volume growth during the acute phase of ischemic stroke. The nonhuman primate model, MRI protocols, and post data processing strategy may provide an excellent platform for characterizing the evolution of acute stroke lesion in mechanistic studies and therapeutic interventions of stroke disease.