Nima Etminan

Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.

As it is often assumed that delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) is caused by vasospasm, clinical trials often focus on prevention of vasospasm with the aim to improve clinical outcome. However, the role of vasospasm in the pathogenesis of DCI and clinical outcome is possibly smaller than previously assumed. We performed a systematic review and meta-analysis on all randomized, double-blind, placebo-controlled trials that studied the effect of pharmaceutical preventive strategies on vasospasm, DCI, and clinical outcome in SAH patients to further investigate the relationship between vasospasm and clinical outcome. Effect sizes were expressed in pooled risk ratio (RR) estimates with corresponding 95% confidence intervals (CI). A total of 14 studies randomizing 4,235 patients were included. Despite a reduction of vasospasm (RR 0.80 (95% CI 0.70 to 0.92)), no statistically significant effect on poor outcome was observed (RR 0.93 (95% CI 0.85 to 1.03)). The variety of DCI definitions did not justify pooling the DCI data. We conclude that pharmaceutical treatments have significantly decreased the incidence of vasospasm, but not of poor clinical outcome. This dissociation between vasospasm and clinical outcome could result from methodological problems, sample size, insensitivity of clinical outcome measures, or from mechanisms other than vasospasm that also contribute to poor outcome.

Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage

Despite an undisputed association between vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH), there is debate if this association implies causality. It has been suggested that cerebral infarction is a better outcome measure than vasospasm in clinical trials and observational studies. To further investigate the relationship between infarction and outcome, we performed a systematic review and meta-analysis of all randomized, double-blind, placebo-controlled trials that studied the efficacy of pharmaceutical preventive strategies in SAH patients, and had both cerebral infarction and clinical outcome as outcome events. Effect sizes were expressed in (pooled) risk ratio (RR) estimates with corresponding 95% confidence intervals (CIs). Sensitivity analyses were performed for studies with a low risk of bias and for those who reported outcome at 3 months after SAH. Twenty-four studies including 8,552 patients were included. Pharmaceutical treatments decreased the incidence of both cerebral infarction (RR: 0.83; 95% CI: 0.74 to 0.93) and of poor functional outcome (RR: 0.92; 95% CI: 0.86 to 0.98). The sensitivity analyses did not change the results essentially. These data suggest that the previously observed association between cerebral infarction and functional outcome implies causality, and that cerebral infarction is a better outcome measure than vasospasm in clinical trials and observational studies.

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.

The impact of microscope-integrated intraoperative near-infrared indocyanine green videoangiography on surgery of arteriovenous malformations and dural arteriovenous fistulae.

BACKGROUND:Microscope-based intraoperative near-infrared indocyanine green (ICG) videoangiography is useful as an adjunct to intra- or postoperative digital subtraction angiography (DSA) in aneurysm surgery. OBJECTIVE:To evaluate intraoperative ICG videoangiography for surgery of arteriovenous malformations (AVMs) and dural arteriovenous fistulas (dAVFs). METHODS:Seventeen patients undergoing surgical resection of intracranial AVM or AVF were enrolled into this prospective evaluation. ICG videoangiography sequences were analyzed with regard to transit times to differentiate between arterial, early venous, capillary, and venous phase as well as early passage (fistula) and delayed appearance (ischemia). ICG videoangiography was compared with pre- and postoperative angiography. RESULTS:Forty-six ICG videoangiographies were performed in 17 operative procedures. In 41 ICG investigations image quality and spatial resolution were excellent to analyze arterial, early venous, capillary, and venous phase. In 2 cases ICG videoangiography provided additional information to change the surgical strategy. With the exception of one case only, the postoperative angiogram corresponded to the last ICG examination performed after the resection. No side effects related to ICG injection were observed. In one patient with a deep thalamic AVM the final ICG investigation was inconclusive owing to insufficient illumination of the deep surgical field. CONCLUSION:Microscope-integrated repetitive ICG videoangiography during AVM and dAVF surgery is fast, easy to perform, and safe. This simple and safe real-time method is a useful additional tool that can potentially lower the surgical risk in complex AVMs and help avoid missed residuals.

Microscope-integrated quantitative analysis of intraoperative indocyanine green fluorescence angiography for blood flow assessment: first experience in 30 patients.

BACKGROUND: Intraoperative measurements of cerebral blood flow are of interest during vascular neurosurgery. Near-infrared indocyanine green (ICG) fluorescence angiography was introduced for visualizing vessel patency intraoperatively. However, quantitative information has not been available. OBJECTIVE: To report our experience with a microscope with an integrated dynamic ICG fluorescence analysis system supplying semiquantitative information on blood flow. METHODS: We recorded ICG fluorescence curves of cortex and cerebral vessels using software integrated into the surgical microscope (Flow 800 software; Zeiss Pentero) in 30 patients undergoing surgery for different pathologies. The following hemodynamic parameters were assessed: maximum intensity, rise time, time to peak, time to half-maximal fluorescence, cerebral blood flow index, and transit times from arteries to cortex. RESULTS: For patients without obvious perfusion deficit, maximum fluorescence intensity was 177.7 arbitrary intensity units (AIs; 5-mg ICG bolus), mean rise time was 5.2 seconds (range, 2.9-8.2 seconds; SD, 1.3 seconds), mean time to peak was 9.4 seconds (range, 4.9-15.2 seconds; SD, 2.5 seconds), mean cerebral blood flow index was 38.6 AI/s (range, 13.5-180.6 AI/s; SD, 36.9 seconds), and mean transit time was 1.5 seconds (range, 360 milliseconds-3 seconds; SD, 0.73 seconds). For 3 patients with impaired cerebral perfusion, time to peak, rise time, and transit time between arteries and cortex were markedly prolonged (>20, >9 , and >5 seconds). In single patients, the degree of perfusion impairment could be quantified by the cerebral blood flow index ratios between normal and ischemic tissue. Transit times also reflected blood flow perturbations in arteriovenous fistulas. CONCLUSION: Quantification of ICG-based fluorescence angiography appears to be useful for intraoperative monitoring of arterial patency and regional cerebral blood flow.

Multidisciplinary consensus on assessment of unruptured intracranial aneurysms: proposal of an international research group.

Background and Purpose— To address the increasing need to counsel patients about treatment indications for unruptured intracranial aneurysms (UIA), we endeavored to develop a consensus on assessment of UIAs among a group of specialists from diverse fields involved in research and treatment of UIAs. Methods— After composition of the research group, a Delphi consensus was initiated to identify and rate all features, which may be relevant to assess UIAs and their treatment by using ranking scales and analysis of inter-rater agreement (IRA) for each factor. IRA was categorized as very high, high, moderate, or low. Results— Ultimately, 39 specialists from 4 specialties agreed (high or very high IRAs) on the following key factors for or against UIA treatment decisions: (1) patient age, life expectancy, and comorbid diseases; (2) previous subarachnoid hemorrhage from a different aneurysm, family history for UIA or subarachnoid hemorrhage, nicotine use; (3) UIA size, location, and lobulation; (4) UIA growth or de novo formation on serial imaging; (5) clinical symptoms (cranial nerve deficit, mass effect, and thromboembolic events from UIAs); and (6) risk factors for UIA treatment (patient age and life expectancy, UIA size, and estimated risk of treatment). However, IRAs for features rated with low relevance were also generally low, which underlined the existing controversy about the natural history of UIAs. Conclusions— Our results highlight that neurovascular specialists currently consider many features as important when evaluating UIAs but also highlight that the appreciation of natural history of UIAs remains uncertain, even within a group of highly informed individuals.

Subarachnoid Hemorrhage International Trialists Data Repository (SAHIT)

The outcome of patients with aneurysmal subarachnoid hemorrhage (SAH) has improved slowly over the past 25 years. This improvement may be due to early aneurysm repair by endovascular or open means, use of nimodipine, and better critical care management. Despite this improvement, mortality remains at about 40%, and many survivors have permanent neurologic, cognitive, and neuropsychologic deficits. Randomized clinical trials have tested pharmacologic therapies, but few have been successful. There are numerous explanations for the failure of these trials, including ineffective interventions, inadequate sample size, treatment side effects, and insensitive or inappropriate outcome measures. Outcome often is evaluated on a good-bad dichotomous scale that was developed for traumatic brain injury 40 years ago. To address these issues, we established the Subarachnoid Hemorrhage International Trialists (SAHIT) data repository. The primary aim of the SAHIT data repository is to provide a unique resource for prognostic analysis and for studies aimed at optimizing the design and analysis of phase III trials in aneurysmal SAH. With this aim in mind, we convened a multinational investigator meeting to explore merging individual patient data from multiple clinical trials and observational databases of patients with SAH and to create an agreement under which such a group of investigators could submit data and collaborate. We welcome collaboration with other investigators.

Modulation of migratory activity and invasiveness of human glioma spheroids following 5-aminolevulinic acid-based photodynamic treatment. Laboratory investigation.

OBJECT Five-aminolevulinic acid-mediated photodynamic therapy (ALA/PDT) can improve the clinical outcome in patients suffering from glioblastoma. Besides direct phototoxicity, additional mechanisms may contribute. Therefore, the authors studied the influence of ALA/PDT on glioblastomas migratory and invasive behavior in a human glioma cell spheroid model. METHODS Glioma spheroids were grown from human U373 and A172 cell lines. After ALA/PDT of spheroids, the authors assessed the migration of tumor cells and their capacity to invade a collagen matrix, as well as changes in their viability, morphology, and expression of matrix metalloproteinases (MMPs). RESULTS The authors found that ALA/PDT caused long-lasting, nearly complete suppression of glioma cell migration and matrix invasion compared with nontherapeutic controls, including either irradiation or incubation with ALA only. Although ALA/PDT induced tumor cell apoptosis, suppression of migration/invasion was not simply due to phototoxicity because 50% of tumor cells remained vital throughout the observation period. Moreover, the morphology of ALA/PDT-treated cells changed significantly toward a polygonal, epithelial-like appearance, which was associated with alterations in the actin cytoskeleton. Furthermore, downregulation of MMP-7 and -8 was observed after treatment whereas other MMPs remained unchanged. CONCLUSIONS In addition to directly eliminating glioma cells through apoptosis, ALA/PDT alters their invasiveness, possibly due to the effects on the cytoskeletal organization and MMP expression.

Early Perfusion Computerized Tomography Imaging as a Radiographic Surrogate for Delayed Cerebral Ischemia and Functional Outcome After Subarachnoid Hemorrhage

Background and Purpose— To date, there is no immediate radiographic surrogate to quantify primary cerebral injury to identify patients at risk for delayed cerebral ischemia and poor clinical outcome after aneurysmal subarachnoid hemorrhage. Therefore, we investigated the relation of early cerebral perfusion–computerized tomography and clot volume with radiological events of delayed cerebral ischemia and clinical outcome in patients with aneurysmal subarachnoid hemorrhage. Methods— Data from 2 cohorts of patients (51 in main, 28 patients in control cohort) with aneurysmal subarachnoid hemorrhage, receiving computerized tomography and perfusion-computerized tomography scanning <12 hours after ictus, were included. A risk group model for functional outcome was developed on the basis of early mean transit time (MTT) and volumetric blood clot measurements. The relation of the risk group model with subsequent MTT, angiographic vasospasm, new cerebral infarction, and functional outcome was analyzed. Actual and predicted functional outcomes based on the risk group model were compared in the control cohort. Results— The risk group model correlated significantly with subsequent MTT measurements, cerebral infarction, and functional outcome. Odds for poor outcome were significantly higher in case of concomitant increase of early MTT and clot volumes, as opposed to exclusive early MTT or clot volume increase. For patients in the high- or low-risk groups, neurological outcome in the control cohort correlated significantly with predicted outcomes. Conclusions— Assessment of early cerebral perfusion and intracranial blood clot may serve as a radiographic surrogate for delayed cerebral ischemia and functional outcome in patients with aneurysmal subarachnoid hemorrhage using risk group modeling.

Unruptured intracranial aneurysms: development, rupture and preventive management

Saccular unruptured intracranial aneurysms (UIAs) have a prevalence of 3% in the adult population, and are being increasingly detected because of improved quality and higher frequency of cranial imaging. Large amounts of data, providing varying levels of evidence, have been published on aneurysm development, progression and rupture, but less information is available on the risks and efficacy of preventive treatment. When deciding how to best manage UIAs, clinicians must consider the age and life expectancy of the patient, the estimated risk of rupture, the risk of complications attributed to preventive treatment, and the level of anxiety caused by the awareness of having an aneurysm. This Review highlights the latest human data on the formation, progression and rupture of intracranial aneurysms, as well as risks associated with preventive treatment. Considering these we discuss the implication for clinical management. Furthermore, we highlight pivotal questions arising from current data on intracranial aneurysms and the implications the data have for future experimental or clinical research. We also discuss data on novel radiological surrogates for rupture for those aneurysms that do not require preventive occlusion. Finally, we provide guidance for clinicians who are confronted with patients with incidentally detected UIAs.