Thana Theofanis

Biology of Cerebral Arteriovenous Malformations with a Focus on Inflammation

Cerebral arteriovenous malformations (AVMs) entail a significant risk of intracerebral hemorrhage owing to the direct shunting of arterial blood into the venous vasculature without the dissipation of the arterial blood pressure. The mechanisms involved in the growth, progression and rupture of AVMs are not clearly understood, but a number of studies point to inflammation as a major contributor to their pathogenesis. The upregulation of proinflammatory cytokines induces the overexpression of cell adhesion molecules in AVM endothelial cells, resulting in enhanced recruitment of leukocytes. The increased leukocyte-derived release of metalloproteinase-9 is known to damage AVM walls and lead to rupture. Inflammation is also involved in altering the AVM angioarchitecture via the upregulation of angiogenic factors that affect endothelial cell proliferation, migration and apoptosis. The effects of inflammation on AVM pathogenesis are potentiated by certain single-nucleotide polymorphisms in the genes of proinflammatory cytokines, increasing their protein levels in the AVM tissue. Furthermore, studies on metalloproteinase-9 inhibitors and on the involvement of Notch signaling in AVMs provide promising data for a potential basis for pharmacological treatment of AVMs. Potential therapeutic targets and areas requiring further investigation are highlighted.

Subarachnoid hemorrhage with negative initial catheter angiography: a review of 254 cases evaluating patient clinical outcome and efficacy of short- and long-term repeat angiography.

BACKGROUND Subarachnoid hemorrhage (SAH) is found to have no vascular origin by initial catheter angiography in approximately 15% of cases. The most appropriate course for the type and frequency of additional diagnostic workup remains controversial. OBJECTIVE To retrospectively assess the diagnostic yield of short-term and long-term repeat catheter angiography in the era of advanced imaging. METHODS Between 2003 and 2011, 254 consecutive patients diagnosed with SAH had negative initial angiography. SAH was perimesencephalic (PM) in 46.5% and nonperimesencephalic (NPM) in 53.5%. Angiography was repeated at 1-week (short-term) and 6-week (long-term) intervals from the initial negative angiogram. RESULTS Ten of 254 patients had a vascular source of hemorrhage on short-term follow-up angiography with a diagnostic yield of 3.9%. One hundred seventy-four patients with negative findings on the first 2 angiograms received a third angiogram, and 7 of these patients were found to have a vascular abnormality. The estimated yield of this third angiogram was 4.0%. The overall diagnostic yield of repeat angiography was 0% in the PM group and 12.5% in the NPM group. The diagnostic yield of short-term and long-term follow-up angiography in patients with NPM SAH was 7.3% and 7.8%, respectively. NPM patients were more likely to experience vasospasm and hydrocephalus requiring external ventricular drainage or cerebrospinal fluid diversion than PM patients. CONCLUSION Our results support a protocol of short-term and long-term angiographic follow-up in patients with NPM SAH and negative initial angiography. Aggressive protocols of follow-up angiography may not be necessary in patients with PM SAH.

Safety and efficacy of intraoperative angiography in craniotomies for cerebral aneurysms and arteriovenous malformations: a review of 1093 consecutive cases.

Background In an era of indocyanine angiography, the routine use of intraoperative angiography (IOA) in the surgical treatment of aneurysms and vascular malformations is controversial. Objective To retrospectively assess the safety and efficacy of IOA and to determine predictors of surgical revision. Methods Between 2003 and 2011, IOA was performed during surgical treatment of 976 aneurysms, 101 arteriovenous malformations (AVMs), and 16 arteriovenous fistulas. Results In 80 of 976 aneurysms (8.2%), IOA prompted clip repositioning. The reason for readjustment was residual aneurysm in 54.7%, parent vessel occlusion in 42.9%, and both in 2.4% of cases. In multivariate analysis, increasing aneurysm size (P, .001), ruptured aneurysm (P, .001), and increasing number of vessels injected (P, .001) were strong predictors of clip readjustment. There was a strong trend for posterior circulation aneurysm location to predict clip repositioning (P = .06). IOA revealed residual nidus/ fistula requiring further intervention in 9 of 101 AVMs (8.9%) and 3 of 16 arteriovenous fistulas (18.8%). Of 9 AVMs requiring a surgical revision, 2 (22.2%) were Spetzler-Martin grade II, 5 (55.6%) were grade III, and 2 (22.2%) were grade IV. Mean Spetzler-Martin grade was 3.0 in AVMs requiring surgical revision compared with 2.3 in those not requiring revision (P = .05). IOA-related complications were all transient or minor and occurred in 0.99% of patients; none resulted in permanent morbidity. Conclusion IOA remains a valuable tool in the surgical treatment of brain vascular abnormalities, guiding surgical re-exploration in .8% of cases. Easy access to an angiographer and routine use of IOA are important factors contributing to procedural safety and efficacy.

Endovascular Treatment of Posterior Communicating Artery Aneurysms with Oculomotor Nerve Palsy: Clinical Outcomes and Predictors of Nerve Recovery

BACKGROUND AND PURPOSE: ONP is a well-known presentation of PcomA aneurysms. Reports on recovery of ONP with endovascular coiling have been limited to small case series. We assessed the safety and efficacy of endovascular therapy in a series of PcomA aneurysms with ONP. MATERIALS AND METHODS: We reviewed 37 patients with ONP who underwent endovascular treatment in our institution between 2005 and 2011. Published studies were also reviewed to determine the overall rate of ONP recovery with endovascular therapy. RESULTS: Nineteen patients (51.4%) presented with complete ONP, and 18 (48.6%), with partial ONP. Conventional coiling was performed in 31 (83.8%) patients; stent-assisted coiling, in 4 (10.8%); and balloon remodeling, in 2 (5.4%). There was 1 (2.7%) procedural complication (a transient thromboembolic event). Twenty-seven (73%) patients were treated within 3 days from symptom onset. At the last available clinical follow-up, ONP resolution was complete in 14 (37.8%) patients and partial in 19 (51.4%). Only 4 (10.8%) patients showed no signs of nerve recovery. In multivariate analysis, partial ONP and longer follow-up durations were predictors of complete nerve recovery. Treatment timing, type of endovascular embolization, subarachnoid hemorrhage, and initial degree of aneurysm occlusion were not predictors of nerve recovery. Of 169 patients reported in the literature (including ours), ONP resolved completely in 73 (43.2%) patients and partially in 73 (43.2%). CONCLUSIONS: Endovascular therapy is a safe and highly efficient alternative to surgical clipping for PcomA aneurysms with ONP.

Endovascular management of cerebral vasospasm following aneurysm rupture: Outcomes and predictors in 116 patients

OBJECTIVE To retrospectively assess the safety and efficacy of endovascular treatment of cerebral vasospasm with different modalities and assess predictors of outcome. METHODS Endovascular treatment was indicated in the event of neurological deterioration refractory to medical therapy. Data were collected for 116 patients treated at our institution. RESULTS Vasospasm was treated with balloon angioplasty in 52.6%, intra-arterial nicardipine infusion in 19.8%, or both in 27.6%. Angiographic vasospasm was reversed in all but 4 (96.6%) patients. The complication rate was 0.9%. Twenty patients (17.2%) had incipient pre-procedure hypodensities; 3 (15%) hypodensities were reversed and neurological improvement occurred in 60% of these patients. Retreatment was required in 22 (19%) patients. Higher Hunt and Hess grades and treatment with nicardipine alone predicted retreatment. Neurological improvement was noted in 82%. Male gender, pre-procedure hypodensities, and posterior communicating artery aneurysm location negatively predicted neurological recovery. Favorable outcomes were noted in 73%. Higher Hunt and Hess grades, pre-procedure hypodensities, posterior circulation aneurysms, and no neurological recovery predicted poor outcome. CONCLUSION Endovascular therapy for vasospasm has an excellent safety-efficacy profile. Balloon angioplasty and nicardipine are equally effective but effects of nicardipine are less durable. Patients with incipient pre-procedure hypodensities benefit from endovascular intervention and should probably not be excluded from treatment.

Interferon-Induced Tetherin Restricts Vesicular Stomatitis Virus Release in Neurons

Tetherin, a recently identified interferon (IFN)-inducible, type 2 transmembrane protein, has been shown to be a cellular antiviral restriction factor that retains newly formed virions in infected cells. Thus, tetherin plays an important role in the innate cell-autonomous immune response. The aim of this study was to examine the antiviral activities of tetherin in vesicular stomatitis virus infections of murine neuronal cells. Both IFN-β and IFN-γ induce the expression of tetherin mRNA and protein. Tetherin knockdown experiments were carried out by transfection of tethrin shRNA into murine neuroblastoma cells using a vector containing the pCMV-driven tGFP gene. The efficiency of transfection was monitored through GFP expression by the transfected cells. Selected transfected cells were used for further mRNA and protein analysis, fluorescent immunocytolocalization, and viral infection to study the impact of tetherin knockdown. Our research indicates that tetherin is expressed on the outer face of the plasma membrane of murine neuroblastoma cells, its expression can be induced with both IFN-γ and IFN-β, and tetherin restricts progeny virus release up to 100-fold in mammalian neurons, thus contributing to a potent antiviral state within the host cell.

Treatment of ruptured intracranial aneurysms: comparison of stenting and balloon remodeling.

BACKGROUND Stent-assisted coiling (SAC) and balloon-assisted coiling (BAC) are 2 well-established techniques for the treatment of complex and wide-necked intracranial aneurysms. Most clinicians are reluctant to perform SAC in the setting of subarachnoid hemorrhage because of the need for dual antiplatelet therapy. OBJECTIVE To compare the safety and efficacy of SAC and BAC in acutely ruptured complex and wide-necked aneurysms. METHODS Forty-four patients underwent SAC and 40 underwent BAC. Patients treated with SAC received antiplatelet medications. Perioperative adverse events and outcomes at follow-up (mean, 7.4 months) were retrospectively studied. RESULTS The 2 groups were statistically comparable with respect to all baseline characteristics except for older age in SAC patients (65.6 vs 56.5 years; P = .009). A higher proportion of SAC patients also had poor Hunt and Hess grades (III-V; 70.5% vs 55%; P = .l4). Hemorrhagic, thromboembolic, and overall procedural complications occurred in 6.8%, 11.4%, and 18.2% of the SAC group vs 2.5%, 7.5%, and 10% of the BAC group, respectively (P = .5, P = .6, P = .3, respectively). Favorable outcomes (modified Rankin Scale score 0-2) at follow-up were seen in 61.0% of the SAC group vs 77% of the BAC group (P = .1). In multivariable analysis, after controlling for differences in baseline characteristics, the type of treatment was not a predictor of procedural complications or clinical outcome. CONCLUSION In this study, procedural complications and clinical outcomes did not differ significantly between SAC and BAC in patients with acutely ruptured aneurysms. SAC may be an acceptable alternative to BAC for complex aneurysms in the acute phase of subarachnoid hemorrhage.

Microsurgery for cerebral arteriovenous malformations: postoperative outcomes and predictors of complications in 264 cases

OBJECT The authors conducted a study to assess the safety and efficacy of microsurgical resection of arteriovenous malformations (AVMs) and determine predictors of complications. METHODS A total of 264 patients with cerebral AVMs were treated with microsurgical resection between 1994 and 2010 at the Jefferson Hospital for Neuroscience. A review of patient data was performed, including initial hemorrhage, clinical presentation, Spetzler-Martin (SM) grade, treatment modalities, clinical outcomes, and obliteration rates. Univariate and multivariate analyses were used to determine predictors of operative complications. RESULTS Of the 264 patients treated with microsurgery, 120 (45%) patients initially presented with hemorrhage. There were 27 SM Grade I lesions (10.2%), 101 Grade II lesions (38.3%), 96 Grade III lesions (36.4%), 31 Grade IV lesions (11.7%), and 9 Grade V lesions (3.4%). Among these patients, 102 (38.6%) had undergone prior endovascular embolization. In all patients, resection resulted in complete obliteration of the AVM. Complications occurred in 19 (7.2%) patients and resulted in permanent neurological deficits in 5 (1.9%). In multivariate analysis, predictors of complications were increasing AVM size (OR 3.2, 95% CI 1.5-6.6; p = 0.001), increasing number of embolizations (OR 1.6, 95% CI 1.1-2.2; p = 0.01), and unruptured AVMs (OR 2.7, 95% CI 1-7.2; p = 0.05). CONCLUSIONS Microsurgical resection of AVMs is highly efficient and can be undertaken with low rates of morbidity at high-volume neurovascular centers. Unruptured and larger AVMs were associated with higher complication rates.

Comparison of neurologic and radiographic outcomes with Solitaire versus Merci/Penumbra systems for acute stroke intervention.

Background and Purpose. The Solitaire Flow Restoration was approved by the FDA in 2012 for mechanical thrombolysis of proximal occlusion of intracranial arteries. To compare the Solitaire FR device and the Merci/Penumbra (previously FDA approved) systems in terms of safety, clinical outcomes, and efficacy including radiographic brain parenchymal salvage. Methods. Thirty-one consecutive patients treated with the Solitaire and 20 patients with comparable baseline characteristics treated with Merci or Penumbra systems were included in the study. Primary outcome measures included recanalization rate and modified Rankin Scale score at followup. Secondary outcomes included length of procedure, incidence of symptomatic intracranial hemorrhage, 90-day mortality, and radiographic analysis of percentage area salvage. Results. Compared with the Merci/Penumbra group, the Solitaire group showed a statistically significant improvement in favorable outcomes (mRS ≤ 2) (69% versus 35%, P = 0.03) and symptomatic ICH rate (0 versus 15%, P = 0.05) with a trend towards higher recanalization rates (93.5% versus 75%, P = 0.096) and shorter length of procedure (58.5 min versus 70.8 min, P = 0.08). Radiographic comparison also showed a significantly larger area of salvage in the Solitaire group (81.9% versus 71.9%, P = 0.05). Conclusion. Our study suggests that the Solitaire system allows faster, safer, and more efficient thrombectomy than Merci or Penumbra systems.

Stereotactic Radiosurgery with Neoadjuvant Embolization of Larger Arteriovenous Malformations: An Institutional Experience

Objective. This study investigates the safety and efficacy of a multimodality approach combining staged endovascular embolizations with subsequent SRS for the management of larger AVMs. Methods. Ninety-five patients with larger AVMs were treated with staged endovascular embolization followed by SRS between 1996 and 2011. Results. The median volume of AVM in this series was 28 cm3 and 47 patients (48%) were Spetzler-Martin grade IV or V. Twenty-seven patients initially presented with hemorrhage. Sixty-one patients underwent multiple embolizations while a single SRS session was performed in 64 patients. The median follow-up after SRS session was 32 months (range 9–136 months). Overall procedural complications occurred in 14 patients. There were 13 minor neurologic complications and 1 major complication (due to embolization) while four patients had posttreatment hemorrhage. Thirty-eight patients (40%) were cured radiographically. The postradiosurgery actuarial rate of obliteration was 45% at 5 years, 56% at 7 years, and 63% at 10 years. In multivariate analysis, larger AVM size, deep venous drainage, and the increasing number of embolization/SRS sessions were negative predictors of obliteration. The number of embolizations correlated positively with the number of stereotactic radiosurgeries (P < 0.005). Conclusions. Multimodality endovascular and radiosurgical approach is an efficacious treatment strategy for large AVM.