Isabel Wanke

The Pipeline Embolization Device for the Intracranial Treatment of Aneurysms Trial

BACKGROUND AND PURPOSE: Endoluminal reconstruction with flow diverting devices represents a novel constructive technique for the treatment of cerebral aneurysms. We present the results of the first prospective multicenter trial of a flow-diverting construct for the treatment of intracranial aneurysms. MATERIALS AND METHODS: Patients with unruptured aneurysms that were wide-necked (>4 mm), had unfavorable dome/neck ratios (<1.5), or had failed previous therapy were enrolled in the PITA trial between January and May 2007 at 4 (3 European and 1 South American) centers. Aneurysms were treated with the PED with or without adjunctive coil embolization. All patients underwent clinical evaluation at 30 and 180 days and conventional angiography 180 days after treatment. Angiographic results were adjudicated by an experienced neuroradiologist at a nonparticipating site. RESULTS: Thirty-one patients with 31 intracranial aneurysms (6 men; 42–76 years of age; average age, 54.6 years) were treated during the study period. Twenty-eight aneurysms arose from the ICA (5 cavernous, 15 parophthalmic, 4 superior hypophyseal, and 4 posterior communicating segments), 1 from the MCA, 1 from the vertebral artery, and 1 from the vertebrobasilar junction. Mean aneurysm size was 11.5 mm, and mean neck size was 5.8 mm. Twelve (38.7%) aneurysms had failed (or recurred after) a previous endovascular treatment. PED placement was technically successful in 30 of 31 patients (96.8%). Most aneurysms were treated with either 1 (n = 18) or 2 (n = 11) PEDs. Fifteen aneurysms (48.4%) were treated with a PED alone, while 16 were treated with both PED and embolization coils. Two patients experienced major periprocedural stroke. Follow-up angiography demonstrated complete aneurysm occlusion in 28 (93.3%) of the 30 patients who underwent angiographic follow-up. No significant in-construct stenosis (≥50%) was identified at follow-up angiography. CONCLUSIONS: Intracranial aneurysm treatment with the PED is technically feasible and can be achieved with a safety profile analogous to that reported for stent-supported coil embolization. PED treatment elicited a very high rate (93%) of complete angiographic occlusion at 6 months in a population of the most challenging anatomic subtypes of cerebral aneurysms.

Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2)

BACKGROUND Clazosentan, an endothelin receptor antagonist, significantly and dose-dependently reduced angiographic vasospasm after aneurysmal subarachnoid haemorrhage (aSAH). We investigated whether clazosentan reduced vasospasm-related morbidity and all-cause mortality. METHODS In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with aSAH secured by surgical clipping to clazosentan (5 mg/h, n=768) or placebo (n=389) for up to 14 days (27 countries, 102 sites, inpatient and outpatient settings) using an interactive web response system. The primary composite endpoint (week 6) included all-cause mortality, vasospasm-related new cerebral infarcts, delayed ischaemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was dichotomised extended Glasgow outcome scale (GOSE; week 12). This trial is registered with ClinicalTrials.gov, number NCT00558311. FINDINGS In the all-treated dataset, the primary endpoint was met in 161 (21%) of 764 clazosentan-treated patients and 97 (25%) of 383 placebo-treated patients (relative risk reduction 17%, 95% CI -4 to 33; p=0·10). Poor functional outcome (GOSE score ≤4) occurred in 224 (29%) clazosentan-treated patients and 95 (25%) placebo-treated patients (-18%, -45 to 4; p=0·10). Lung complications, anaemia, and hypotension were more common with clazosentan. Mortality (week 12) was 6% in both groups. INTERPRETATION Clazosentan at 5 mg/h had no significant effect on mortality and vasospasm-related morbidity or functional outcome. Further investigation of patients undergoing endovascular coiling of ruptured aneurysms is needed to fully understand the potential usefulness of clazosentan in patients with aSAH. FUNDING Actelion Pharmaceuticals.

Embolization of Intracranial Arteriovenous Malformations with Ethylene-Vinyl Alcohol Copolymer (Onyx)

BACKGROUND AND PURPOSE: Endovascular therapy of intracranial arteriovenous malformations (AVMs) is increasingly used. However, it is still under discussion which embolic material is optimal. We report our experience in the treatment of AVMs with ethylene-vinyl alcohol copolymer (Onyx). MATERIALS AND METHODS: Between July 2002 and January 2008, brain AVMs were embolized with Onyx in 82 consecutive patients in our department. There were 41 females and 41 males with a mean age of 44.2 years (range, 15–85 years). Clinical presentation included symptoms due to intracerebral hemorrhage (n = 37), seizures (n = 18), nonhemorrhagic neurologic deficits (n = 8), headaches (n = 9), or incidental symptoms (n = 10). According to the Spetzler-Martin scale, 59 AVMs were grades I–II, 16 were grade III, and 7 were grades IV–V. RESULTS: Complete obliteration at the end of all endovascular procedures was achieved in 20/82 patients (24.4%), with an average of 75% (range, 30%–100%) volume reduction. A mean of 2.9 (range, 1–10) feeding pedicles was embolized per patient, whereas an average of 2.6-mL Onyx was used per patient. Procedure-related permanent disabling morbidity was 3.8%, whereas mortality was 2.4%. CONCLUSIONS: The overall initial complete obliteration rate of intracranial AVMs with Onyx embolization is relatively high, compared with other embolic agents, with evidence of stability with time. Morbidomortality rates due to AVM embolization as a single treatment method or as a part of a multimodality treatment should be further assessed regarding the natural course of the disease.

High-Profile Flow Diverter (Silk) Implantation in the Basilar Artery: Efficacy in the Treatment of Aneurysms and the Role of the Perforators

Background and Purpose— The introduction of flow diverters (FDs) has expanded the possibilities for reconstructive treatment of difficult intracranial aneurysms. Concern remains as to the long-term patency of the perforating arteries and side branches covered during stent placement. Our purpose was to evaluate the performance of and early effect on covered branches after implantation of the Silk FD in the treatment of basilar artery aneurysms. Methods— Twelve patients with an aneurysm of the basilar artery that was treated by implantation of the Silk FD were included in our retrospective study. Both unruptured and previously ruptured, formerly untreated, and recurrent aneurysms were treated. During follow-up, patients were monitored for clinical evolution, patency of the covered vessels, and aneurysmal obliteration. Results— Of the 2 ruptured aneurysms, 1 was initially treated by FD implantation. The FD covered the basilar bifurcation and the origin of a P1 segment of the posterior cerebral artery in 9 cases, the origin of the superior cerebellar artery in 9, and of the anterior inferior cerebellar artery in 3. There was 1 acute basilar artery occlusion a few hours after FD implantation. During a mean follow-up of 16 weeks, 3 patients experienced a symptomatic neurologic event. Conclusions— Implantation of the Silk FD in the basilar artery was feasible and well tolerated in most cases to date. However, late ischemic events affecting perforating arteries may occur after FD implantation, suggesting that the indication should be restricted to otherwise untreatable aneurysms in this location.

First clinical study on ultra-high-field MR imaging in patients with multiple sclerosis: comparison of 1.5T and 7T.

BACKGROUND AND PURPOSE: Higher magnetic field strengths and continuous improvement of high-resolution imaging in multiple sclerosis (MS) are expected to provide unique in-vivo and non-invasive insights in pathogenesis and clinical monitoring. The purpose of this study was to investigate the potential of high-resolution imaging of MS lesions in vivo comparing 7T with conventional 1.5T. MATERIALS AND METHODS: Twelve consecutive patients with clinically definite MS were scanned on a 7T whole-body scanner and on a 1.5T Avanto. The 1.5T and 7T imaging protocol consisted of high-resolution axial proton density (PD) + T2-weighted turbo spin-echo and T2*-weighted gradient-echo (GRE), and sagittal T1-weighted 3D magnetization-prepared rapid acquisition of gradient echo. RESULTS: The sequence parameters at 7T had to be modified because of specific absorption rate (SAR) restrictions while keeping contrast parameters equivalent to 1.5T. White matter lesions were better detected and delineated from adjacent structures at 7T compared with 1.5T. There were 42% of the patients who showed additional lesions at 7T: there were 97 white matter lesions detected on 1.5T versus 126 lesions at 7T, an increase of 23%. The perivascular migration of MS lesions was well visualized on T2*-weighted GRE sequences. In larger lesions (10 mm), a multilayer structure was revealed on T2*-weighted GRE not seen at 1.5T. Because of the higher resolution, it was possible to differentiate between juxtacortical white matter lesions and cortical lesions. There were 44% of the subcortical lesions depicted at 7T that showed cortical involvement. CONCLUSIONS: Ultra-high-field imaging of patients with MS at 7T was well tolerated and provided better visualization of MS lesions in the gray matter and demonstrated structural abnormalities within the MS lesions themselves more effectively.

Neuroimaging of infections

SummaryNeuroimaging plays a crucial role in the diagnosis and therapeutic decision making in infectious diseases of the nervous system. The review summarizes imaging findings and recent advances in the diagnosis of pyogenic brain abscess, ventriculitis, viral disease including exotic and emergent viruses, and opportunistic disease. For each condition, the ensuing therapeutic steps are presented. In cases of uncomplicated meningitis, cranial computed tomography (CT) appears to be sufficient for clinical management to exclude acute brain edema, hydrocephalus, and pathology of the base of skull. Magnetic resonance imaging (MRI) is superior in depicting complications like sub-/epidural empyema and vasculitic complications notably on FLAIR (fluid-attenuated inversion recovery)-weighted images. The newer technique of diffusion-weighted imaging (DWI) shows early parenchymal complications of meningitis earlier and with more clarity and is of help in differentiation of pyogenic abscess (PA) from ring enhancing lesions of other etiology. Proton magnetic resonance spectroscopy (PMRS) seems to produce specific peak patterns in cases of abscess. The presence of lactate cytosolic amino acids and absence of choline seems to indicate PA. Also in cases of suspected opportunistic infection due to toxoplasma DWI may be of help in the differentiation from lymphoma, showing no restriction of water diffusion. In patients with herpes simplex and more exotic viruses like West Nile and Murray Valley virus DWI allows earlier lesion detection and therapeutic intervention with virustatic drugs.

Randomized Trial of Clazosentan in Patients With Aneurysmal Subarachnoid Hemorrhage Undergoing Endovascular Coiling

Background and Purpose— Clazosentan, an endothelin receptor antagonist, has been shown to reduce vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). CONSCIOUS-3 assessed whether clazosentan reduced vasospasm-related morbidity and all-cause mortality postaSAH secured by endovascular coiling. Methods— This double-blind, placebo-controlled, phase III trial randomized patients with aSAH secured by endovascular coiling to ⩽14 days intravenous clazosentan (5 or 15 mg/h) or placebo. The primary composite end point (all-cause mortality; vasospasm-related new cerebral infarcts or delayed ischemic neurological deficits; rescue therapy for vasospasm) was evaluated 6 weeks postaSAH. The main secondary end point was dichotomized extended Glasgow Outcome Scale (week 12). Results— CONSCIOUS-3 was halted prematurely following completion of CONSCIOUS-2; 577/1500 of planned patients (38%) were enrolled and 571 were treated (placebo, n=189; clazosentan 5 mg/h, n=194; clazosentan 15 mg/h, n=188). The primary end point occurred in 50/189 of placebo-treated patients (27%), compared with 47/194 patients (24%) treated with clazosentan 5 mg/h (odds ratio [OR], 0.786; 95% CI, 0.479–1.289; P=0.340), and 28/188 patients (15%) treated with clazosentan 15 mg/h (OR, 0.474; 95% CI, 0.275–0.818; P=0.007). Poor outcome (extended Glasgow Outcome Scale score ⩽4) occurred in 24% of patients with placebo, 25% of patients with clazosentan 5 mg/h (OR, 0.918; 95% CI, 0.546–1.544; P=0.748), and 28% of patients with clazosentan 15 mg/h (OR, 1.337; 95% CI, 0.802–2.227; P=0.266). Pulmonary complications, anemia, and hypotension were more common in patients who received clazosentan than in those who received placebo. At week 12, mortality was 6%, 4%, and 6% with placebo, clazosentan 5 mg/h, and clazosentan 15 mg/h, respectively. Conclusions— Clazosentan 15 mg/h significantly reduced postaSAH vasospasm-related morbidity/all-cause mortality; however, neither dose improved outcome (extended Glasgow Outcome Scale). Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique identifier: NCT00940095.

Stents for intracranial wide-necked aneurysms: more than mechanical protection

Treatment of wide-necked aneurysms by endovascular coil embolization usually requires mechanical aids in order to protect the parent artery from occlusion due to extension of coils or thrombosis. Endovascular stents are one tool that can be deployed to solve this essentially mechanical problem. The effect of a stent placed in the situation may also act as a hemodynamically active flow diverter. Endovascular stents used in other circumstances are prone to the unwanted side effect of neoinitmal proliferation, but this phenomenon should be seen as a potential asset for “aneurysmal stents” because it may lead to a reaction that contributes to vessel wall healing.

The unruptured intracranial aneurysm treatment score A multidisciplinary consensus

Objective: We endeavored to develop an unruptured intracranial aneurysm (UIA) treatment score (UIATS) model that includes and quantifies key factors involved in clinical decision-making in the management of UIAs and to assess agreement for this model among specialists in UIA management and research. Methods: An international multidisciplinary (neurosurgery, neuroradiology, neurology, clinical epidemiology) group of 69 specialists was convened to develop and validate the UIATS model using a Delphi consensus. For internal (39 panel members involved in identification of relevant features) and external validation (30 independent external reviewers), 30 selected UIA cases were used to analyze agreement with UIATS management recommendations based on a 5-point Likert scale (5 indicating strong agreement). Interrater agreement (IRA) was assessed with standardized coefficients of dispersion (vr*) (vr* = 0 indicating excellent agreement and vr* = 1 indicating poor agreement). Results: The UIATS accounts for 29 key factors in UIA management. Agreement with UIATS (mean Likert scores) was 4.2 (95% confidence interval [CI] 4.1–4.3) per reviewer for both reviewer cohorts; agreement per case was 4.3 (95% CI 4.1–4.4) for panel members and 4.5 (95% CI 4.3–4.6) for external reviewers (p = 0.017). Mean Likert scores were 4.2 (95% CI 4.1–4.3) for interventional reviewers (n = 56) and 4.1 (95% CI 3.9–4.4) for noninterventional reviewers (n = 12) (p = 0.290). Overall IRA (vr*) for both cohorts was 0.026 (95% CI 0.019–0.033). Conclusions: This novel UIA decision guidance study captures an excellent consensus among highly informed individuals on UIA management, irrespective of their underlying specialty. Clinicians can use the UIATS as a comprehensive mechanism for indicating how a large group of specialists might manage an individual patient with a UIA.

Effect of flow diversion treatment on very small ruptured aneurysms

BACKGROUNDRuptured aneurysms of < 2 mm are not amenable to endovascular coiling and therefore pose a significant treatment challenge. OBJECTIVETo test recently introduced flow diverters that allow endovascular reconstruction via another method and may represent a new treatment option for such lesions. PATIENTS AND METHODSThree female patients presented with acute subarachnoid hemorrhage. An aneurysm of < 2 mm was identified in all patients as the cause of bleeding. The aneurysms were located at the C2 segment of the internal carotid in 2 patients and on the basilar bifurcation in the other. All patients had failed early endovascular treatment attempts. Flow diversion with the SILK flow diverter was offered as an alternative in each patient. RESULTSSILK deployment successfully eliminated the aneurysms in all 3 instances. One of the aneurysms was excluded from contrast material visualization immediately after stent deployment. Transient thrombotic complication was observed in the case of the basilar artery aneurysm. It resolved with the administration of intraarterial tirofiban. There was no treatment-related morbidity, and none of the aneurysms reruptured after SILK implantation during a clinical follow-up of at least 4 months (range, 4–10 months). Imaging follow-up showed complete vessel remodeling in all cases. CONCLUSIONFlow diversion treatment prevented rebleeding during the follow-up period. Reverse remodeling of the concerned vascular segment with delayed disappearance of the aneurysm was observed in each case.