Impact of flow and angioarchitecture on brain arteriovenous malformation outcome after gamma knife radiosurgery: the role of hemodynamics and morphology in obliteration.

BACKGROUND: Few studies have evaluated the relationship between brain arteriovenous malformations (bAVMs) angioarchitecture and the response to Gamma Knife Stereotactic Radiosurgery (GKSR). METHODS: A prospectively enrolled single-center cohort of patients with bAVMs treated by GKSR has been studied to define independent predictors of obliteration with particular attention to angioarchitectural variables. Only patients older than 18 years old (y.o.), who underwent baseline digital subtraction angiography (DSA) and clinico-radiological follow-up of at least 36 months, were included in the study. RESULTS: Data of 191 patients were evaluated. After a mean follow-up of 80 months (range 37-173), total obliteration rate after first GKSR treatment was 66%. Mean dose higher than 22 Gy (P = .019, OR = 2.39, 95% CI 1.15-4.97) and flow rate dichotomized into high vs non-high (P < .001, OR = 0.23, 95% CI 0.11-0.51) resulted to be independent predictors of obliteration. Flow-surrogate angioarchitectural features did not emerge as independent outcome predictors. CONCLUSIONS: Flow rate seems to be associated in predicting outcome after GKSR conferring high-flow AVM a lower occlusion rate. Its role should be considered when planning radiosurgical treatment of bAVM, and it could be added to other parameters used in GKRS outcome predicting scales.

Radiosurgical treatment of arteriovenous malformations in a retrospective study group of 33 children: the importance of radiobiological scores.

PURPOSE: Arteriovenous malformations' (AVMs) obliteration depends on several factors; among the many factors that must be considered to obtain a high rate of obliteration and a low rate of complications, Flickinger-Pollock Score (FPS) seems to have an important role but still have to be validated in the pediatric population while Paddick-Conformity Index (PCI) still has no demonstration of its utility on the outcome and is considered only as a treatment quality marker. METHODS: We retrospectively analyzed 33 consecutive children (2-18 years) with an AVM, treated with stereotactic radiosurgery Gamma Knife (SRS-GK) from 2001 to 2014 in our institution. We assess angiographic (DSA) Obliteration Rate (OR) as well FPS and PCI to draw conclusions. RESULTS: DSA-OR was 60.6% with a rate of hemorrhage of 0%. median target volume (TV) was 3.60 cc (mean 4.32 ± 3.63; range 0.15-14.2), median PD was 22 Gy (mean 21.4 ± 2.6; range 16.5-25). Median percentage of coverage was 98% (mean 97 ± 3; range 84-100). The median modified FPS was 0.78 (mean 0.89 ± 0.52; range 0.21-2.1) and highly correlate with OR (p = 0.01). The median PCI was 0.65 (mean 0.65 ± 0.14; range 0.34-0.95) A PCI lower than 0.57 highly correlates with final OR (p = 0.02). CONCLUSION: SRS-GK was safe and gradually effective in children. A prescription dose-like that used in adult population (i.e. > 18 and between 20 and 25 Gy) is essential to achieve obliteration. A PD of 23 Gy and 22 Gy did impact OR, respectively (p = 0.02) and (p = 0.05). FPS and PCI are valuable scores that seem to correlate with the OR also in the pediatric population although further prospective studies are needed to confirm these observations.

Hemorrhagic burden in poor-grade aneurysmal subarachnoid hemorrhage: a volumetric analysis of different bleeding distributions.

BACKGROUND: Volumetric assessment of aneurysmal bleeding has been evaluated in few studies and emerged as a promising outcome predictor. There is a lack of studies evaluating its impact in the poor-grade population. METHODS: Retrospective review of 63 consecutive poor-grade aneurysmal subarachnoid hemorrhage (aSAH) patients, defined as grade IV and V according to the World Federation of Neurological Surgeons (WFNS) classifications. Global intracranial bleeding volume was calculated with its subarachnoid, intracerebral (ICH), and intraventricular (IVH) portions by means of analytical software. Univariate and multivariate analyses were performed in order to identify independent predictors of outcome. Good outcome was defined as modified Rankin Scale (mRS) 0-2 and mortality as mRS 6. The cutoff values of bleeding volumes were derived by receiver operating curve (ROC) analysis. RESULTS: Mean follow-up was of 12.5 (± 1.5) months. Thirty (47.7%) patients achieved good outcome, whereas 19 (30.2) patients out of 63 died. Global intracranial bleeding resulted as an independent predictor of good outcome (cutoff 24 mL). Furthermore, ICH relative percentage of global volume (10% of total) and pure SAH (64% of total) emerged respectively as independent predictors of worsened and improved outcome. Global bleeding volume (cutoff 51 mL) along with global cerebral edema showed to independently predict mortality in the examined poor-grade aSAH population. CONCLUSIONS: Volumetric assessment of aneurysmal bleeding has the potential for identifying cutoff values that independently predict outcome. Further insights into the relative importance of different bleeding volumes may be implicated in better tailoring the management of this dismal aSAH population.

Evaluation of prognostic factors as predictor of AVMS obliteration after Gamma Knife radiosurgery.

BACKGROUND: The reported AVMs obliteration rate after Gamma Knife radiosurgery (GKS) ranges from 70 to 94 %. The objective of the present study was to assess prognostic factors predictive for cerebral AVMs obliteration in 127 patients who underwent GKS. METHODS: The AVMs were classified according to the Spetzler-Martin classification. Twenty-one cases (16.5 %) were classified as grade I, 46 cases (36.2 %) as grade II, 51 cases (40.1 %) as grade III, and nine cases (7.1 %) as grade IV-V. The AVMs were deeply located in 16.5 % of patients. The peripheral prescription dose ranged from 16 to 30 Gy (mean 22.3 Gy). The AVMs volume ranged from 0.1 to 13 cc (mean 2.7 cc). RESULTS: In 72 patients out of the 104 (69.2 %) with a radiological follow-up, MRI showed the AVM obliteration; in 54 cases (60 %) out of the 90 that performed a DSA, a complete AVM obliteration was achieved (average closure time 48.5 months). The volume of the nidus (p = 0.001), the prescription dose (p = 0.004), the 2002 Pollock-Flickinger classification (p = 0.031), and their 2008 revised classification (p = 0.025) were found to be statistically significant in predicting the probability of AVM closure. In the multivariate analysis, only the prescription dose was found to be an independent prognostic factor (p = 0.009) for AVM obliteration. CONCLUSIONS: The volume of the nidus and the prescription dose significantly influence the outcome of radiosurgical treatment. The Pollock-Flickinger classification was found to be a reliable scoring system in predicting the AVM closure and an important tool for selection of patients candidate for GKS.

Neutrophils predominate the immune signature of cerebral thrombi in COVID-19 stroke patients.

Coronavirus disease 2019 (COVID-19) is associated with an increased risk of thrombotic events. Ischemic stroke in COVID-19 patients entails high severity and mortality rates. Here we aimed to analyze cerebral thrombi of COVID-19 patients with large vessel occlusion (LVO) acute ischemic stroke to expose molecular evidence for SARS-CoV-2 in the thrombus and to unravel any peculiar immune-thrombotic features. We conducted a systematic pathological analysis of cerebral thrombi retrieved by endovascular thrombectomy in patients with LVO stroke infected with COVID-19 (n = 7 patients) and non-covid LVO controls (n = 23). In thrombi of COVID-19 patients, the SARS-CoV-2 docking receptor ACE2 was mainly expressed in monocytes/macrophages and showed higher expression levels compared to controls. Using polymerase chain reaction and sequencing, we detected SARS-CoV-2 Clade20A, in the thrombus of one COVID-19 patient. Comparing thrombus composition of COVID-19 and control patients, we noted no overt differences in terms of red blood cells, fibrin, neutrophil extracellular traps (NETs), von Willebrand Factor (vWF), platelets and complement complex C5b-9. However, thrombi of COVID-19 patients showed increased neutrophil density (MPO+ cells) and a three-fold higher Neutrophil-to-Lymphocyte Ratio (tNLR). In the ROC analysis both neutrophils and tNLR had a good discriminative ability to differentiate thrombi of COVID-19 patients from controls. In summary, cerebral thrombi of COVID-19 patients can harbor SARS-CoV2 and are characterized by an increased neutrophil number and tNLR and higher ACE2 expression. These findings suggest neutrophils as the possible culprit in COVID-19-related thrombosis.

Cerebral thrombi of cardioembolic etiology have an increased content of neutrophil extracellular traps.

BACKGROUND: Inflammation is emerging as an essential trigger for thrombosis. In the interplay between innate immunity and coagulation cascade, neutrophils and neutrophil extracellular traps (NETs) can promote thrombus formation and stabilization. In ischemic stroke, it is uncertain whether the involvement of the inflammatory component may differ in thrombi of diverse etiology. We here aimed to evaluate the presence of neutrophils and NETs in cerebral thrombi of diverse etiology retrieved by endovascular thrombectomy (EVT). METHODS: We performed a systematic histological analysis on 80 human cerebral thrombi retrieved through EVT in acute ischemic stroke patients. Thrombus composition was investigated in terms of neutrophils (MPO+ cells) and NET content (citH3+ area), employing specific immunostainings. NET plasma content was determined and compared to NET density in the thrombus. RESULTS: Neutrophils and NETs were heterogeneously represented within all cerebral thrombi. Thrombi of diverse etiology did not display a statistically significant difference in the number of neutrophils (p = 0.51). However, NET content was significantly increased in cardioembolic compared to large artery atherosclerosis thrombi (p = 0.04), and the association between NET content and stroke etiology remained significant after adjusted analysis (beta coefficient = -6.19, 95%CI = -11.69 to -1.34, p = 0.01). Moreover, NET content in the thrombus was found to correlate with NET content in the plasma (p ≤ 0.001, r = 0.62). CONCLUSION: Our study highlights how the analysis of the immune component within the cerebral thrombus, and specifically the NET burden, might provide additional insight for differentiating stroke from diverse etiologies.

Safety and feasibility of lumbar drainage in the management of poor grade aneurysmal subarachnoid hemorrhage.

The use of lumbar drain (LD) in the aneurysmal subarachnoid hemorrhage (aSAH) has been described to reduce cerebral vasospasm and delayed cerebral ischemia (DCI), with a lack of studies referring to high grade population. The purpose of our study is to assess safety and feasibility of LD in the poor grade aSAH population subjected to endovascular aneurysm occlusion. Twenty-four consecutive poor grade aSAH patients, defined as grade IV and V according to World Federation of Neurological Surgeons (WFNS) classification, subjected to endovascular aneurysm occlusion, were retrospectively reviewed. Details of CSF drainage via LD and related complications were analyzed. Ventriculo-lumbar pressure gradient (VLPG) lower than 6 mmHg was considered in order to start LD use. Good outcome was defined as modified Rankin Scale (mRS) 0-2. LD was started within 72 h since aSAH in 17 cases (70.8%), and in 7 cases (29.2%) it was delayed due to contraindications. The mean LD length was of 13.8 days. The median VLPG during drainage was 2 mmHg (IQR: 0-4). No cases of brain or spinal hemorrhage, permanent neurological worsening due to brain herniation were noted. Three cases (12.5%) of CSF infection and a related death (4.2%) were reported. The use of LD, in association with external ventricular drain (EVD), seems to be safe and feasible in the poor grade aSAH population. VLPG monitoring seems to play a key role in avoiding potentially severe complications.

Debunking 7 myths that hamper the realization of randomized controlled trials on intra-arterial thrombolysis for acute ischemic stroke.

BACKGROUND AND PURPOSE: Although intravenous (IV) thrombolysis is the standard treatment for patients with ischemic stroke occurring within 3 hours from symptom onset, a few interventional neuroradiologists have been treating this category of patients by an intra-arterial (IA) route for >25 years. However, evidence is still required to support the clinical feeling that IA treatment, which needs longer time and greater complexity, leads to a better outcome. Therefore, the objective of the present review was to analyze beliefs and myths underlying the selection of patients for IA thrombolysis. METHODS: We identified and debunked the following myths on IA thrombolysis: (1) IA thrombolysis works better than IV because it achieves higher recanalization rates; (2) IA thrombolysis works better than IV after the 3-hour window; (3) IA thrombolysis works better than IV in vertebrobasilar stroke; (4) carotid duplex, transcranial doppler, CT angiography, or MRA should be used to screen for major vessel occlusion treatable with IA thrombolysis; (5) to be treated with IA thrombolysis, patients should be selected with diffusion/perfusion MRI; (6) IA thrombolysis should be used as a "rescue" therapy for IV thrombolysis; and (7) the efficacy of IA thrombolysis depends on the thrombolytic agent or the device used. CONCLUSIONS: Evidence on acute stroke management with IA thrombolysis is scant. Therefore, neither clinicians nor patients have enough information to make truly informed decisions about the most appropriate treatment. Only randomized controlled trials can clear uncertainties about the possible superiority of IA over IV thrombolysis. Regretfully, case series on IA treatment have limited the organization of such trials and have only favored the spread of myths.

Cerebrospinal Fluid Amyloid-ß 42, Total Tau and Phosphorylated Tau are Low in Patients with Normal Pressure Hydrocephalus: Analogies and Differences with Alzheimer's Disease.

Co-existence of Alzheimer's disease (AD) in normal pressure hydrocephalus (NPH) is a frequent finding, thus a common pathophysiological basis between AD and NPH has been postulated. We measured CSF amyloid-ß 42 (Aß42), total tau (t-tau), and phosphorylated tau (p-tau) concentrations in a sample of 294 patients with different types of dementia and 32 subjects without dementia. We then compared scores on neuropsychological tests of NPH patients with pathological and normal CSF Aß42 values. Aß42 levels were significantly lower in NPH than in control patients, with no significant differences between AD and NPH. On the contrary, t-tau and p-tau levels were significantly lower in NPH than in AD, with no differences between NPH and controls. NPH patients with pathological Aß42 levels did not perform worse than NPH patients with normal Aß42 levels in any cognitive domains. Our data seem to support the hypothesis of amyloid accumulation in brains of NPH patients. Nevertheless, amyloid does not seem to play a pathogenetic role in the development of cognitive deficits in NPH.

Tirofiban as treatment for acute retinal artery occlusion following internal carotid artery flow diverter implantation.

PURPOSE: To report a favorable outcome of branch retinal artery occlusion (BRAO) treated by means of early administration of tirofiban, a glycoprotein IIb-IIIa platelet receptor inhibitor. METHODS: Case report. RESULTS: A 65-year-old woman developed dramatic visual impairment in her left eye secondary to BRAO after left internal carotid artery endovascular reconstruction with flow diverter stent implant; visual acuity was hand motion. A dose of intravenous tirofiban was injected 10 minutes after symptoms onset. Fourteen hours after drug infusion, retinal fluorescein angiography revealed a well-perfused macula with a partial reperfusion of the inferior temporal branch of the central retinal artery; visual acuity was 20/20 in both eyes. CONCLUSIONS: This case supports the effectiveness of tirofiban in secondary BRAO in neurosurgery and may open its usage to further research.

Comparison of 3D TOF-MRA and 3D CE-MRA at 3T for imaging of intracranial aneurysms.

PURPOSE: To compare 3T elliptical-centric CE MRA with 3T TOF MRA for the detection and characterization of unruptured intracranial aneurysms (UIAs), by using digital subtracted angiography (DSA) as reference. MATERIALS AND METHODS: Twenty-nine patients (12 male, 17 female; mean age: 62 years) with 41 aneurysms (34 saccular, 7 fusiform; mean diameter: 8.85 mm [range 2.0-26.4mm]) were evaluated with MRA at 3T each underwent 3D TOF-MRA examination without contrast and then a 3D contrast-enhanced (CE-MRA) examination with 0.1mmol/kg bodyweight gadobenate dimeglumine and k-space elliptic mapping (Contrast ENhanced Timing Robust Angiography [CENTRA]). Both TOF and CE-MRA images were used to evaluate morphologic features that impact the risk of rupture and the selection of a treatment. Almost half (20/41) of UIAs were located in the internal carotid artery, 7 in the anterior communicating artery, 9 in the middle cerebral artery and 4 in the vertebro-basilar arterial system. All patients also underwent DSA before or after the MR examination. RESULTS: The CE-MRA results were in all cases consistent with the DSA dataset. No differences were noted between 3D TOF-MRA and CE-MRA concerning the detection and location of the 41 aneurysms or visualization of the parental artery. Differences were apparent concerning the visualization of morphologic features, especially for large aneurysms (>13 mm). An irregular sac shape was demonstrated for 21 aneurysms on CE-MRA but only 13/21 aneurysms on 3D TOF-MRA. Likewise, CE-MRA permitted visualization of an aneurismal neck and calculation of the sac/neck ratio for all 34 aneurysms with a neck demonstrated at DSA. Conversely, a neck was visible for only 24/34 aneurysms at 3D TOF-MRA. 3D CE-MRA detected 15 aneurysms with branches originating from the sac and/or neck, whereas branches were recognized in only 12/15 aneurysms at 3D TOF-MRA. CONCLUSION: For evaluation of intracranial aneurysms at 3T, 3D CE-MRA is superior to 3D TOF-MRA for assessment of sac shape, detection of aneurysmal neck, and visualization of branches originating from the sac or neck itself, if the size of the aneurysm is greater than 13 mm. 3T 3D CE-MRA is as accurate and effective as DSA for the evaluation of UIAs.

Follow-up of coiled cerebral aneurysms: comparison of three-dimensional time-of-flight magnetic resonance angiography at 3 tesla with three-dimensional time-of-flight magnetic resonance angiography and contrast-enhanced magnetic resonance angiography at 1.5 Tesla.

OBJECTIVES: To compare three-dimensional (3D) time-of-flight (TOF)-magnetic resonance angiography (MRA) at 3 T with 3D TOF-MRA and ultrafast contrast-enhanced (CE)-MRA at 1.5 T and to determine the optimum MRA sequence for follow-up of cerebral aneurysms treated with Guglielmi detachable coils (GDCs). MATERIAL AND METHODS: Twenty-eight patients treated with GDCs for 29 cerebral aneurysms underwent MRA at 3 T and 1.5 T within 24 hours (during the same session for outpatients). All imaging was performed using a sensitivity-encoding head coil (SENSE factor = 2). Unenhanced axial 3D TOF-MRA at 3 T was performed with repetition time (TR)/echo time (TE) = 16/2.9. At 1.5 T, axial 3D TOF-MRA (TR/TE = 23/4) was performed first, followed by axial 3D ultrafast gradient echo MRA (TR/TE = 6/2) enhanced with 0.1 mmol/kg gadobenate dimeglumine (MultiHance). Source images and maximum intensity projection and shaded surface display reconstructions for each acquisition sequence were evaluated for quality of visualization of residual aneurysm patency and scored for visualization preference. RESULTS: Residual aneurysm was detected in 15/29 cases on CE-MRA at 1.5 T and TOF-MRA at 3 T but in only 11/29 cases on TOF-MRA at 1.5 T. CE-MRA at 1.5 T was preferred to TOF-MRA at 1.5 T in 13 cases (P = 0.004) and to TOF-MRA at 3 T in 3 cases. TOF-MRA at 3 T was preferred to TOF-MRA at 1.5 T in 11 cases (P = 0.04) but was not preferred to CE-MRA at 1.5 T in any case. The parent artery was identifiable in all 29 cases after TOF-MRA at 3 T and CE-MRA at 1.5 T but in only 27 cases after 3D TOF-MRA at 1.5 T. CONCLUSIONS: TOF-MRA follow-up of coiled aneurysms is better at 3 T than at 1.5 T; nevertheless, greater definition of residual patency is achieved with ultrafast CE-MRA at 1.5 T.

Carotid artery stenosis: intraindividual correlations of 3D time-of-flight MR angiography, contrast-enhanced MR angiography, conventional DSA, and rotational angiography for detection and grading.

PURPOSE: To compare three-dimensional (3D) time-of-flight (TOF) MR angiography, contrast-enhanced MR angiography, digital subtraction angiography (DSA), and rotational angiography for depiction of stenosis. MATERIALS AND METHODS: The study had Ethics Committee approval, and each patient gave written informed consent. Forty-nine patients (18 women, mean age, 67.2 years +/- 9.1 [+/- standard deviation], and 31 men, mean age, 63.1 years +/- 8.0) with symptomatic stenosis of internal carotid artery (ICA) diagnosed at duplex ultrasonography underwent transverse 3D TOF MR angiography with sliding interleaved kY acquisition and coronal contrast-enhanced MR angiography, followed by DSA and rotational angiography within 48 hours. MR angiography was performed at 1.5-T with a cervical coil. Contrast-enhanced MR angiograms were obtained after a bolus injection of 20 mL of gadobenate dimeglumine. Maximum ICA stenosis on maximum intensity projection and source images was quantified according to NASCET criteria. Correlations for 3D TOF MR angiography, contrast-enhanced MR angiography, DSA, and rotational angiography were determined by means of cross tabulation, and accuracy for detection and grading of stenoses were calculated. Data were evaluated with analysis of variance, Wilcoxon signed rank test, and McNemar test, all at significance of P < .05. RESULTS: Ninety-eight ICAs were evaluated at contrast-enhanced MR angiography, DSA, and rotational angiography, and 97 were evaluated at 3D TOF MR angiography. Correlations for contrast-enhanced MR angiography, 3D TOF MR angiography, and DSA relative to rotational angiography were r2 = 0.9332, r2 = 0.9048, and r2 = 0.9255, respectively. Lower correlation (r2 = 0.8593) was noted for contrast-enhanced MR angiography and DSA. Respective sensitivity and specificity for detection of hemodynamically relevant stenosis relative to rotational angiography were 100% and 90% for contrast-enhanced MR angiography, 95.5% and 87.2% for 3D TOF MR angiography, and 88.6% and 100% for DSA. Four of 31 severe stenoses were underestimated at DSA, and three were underestimated at contrast-enhanced MR angiography. Three severe stenoses were underestimated at 3D TOF MR angiography, and one was misclassified as occluded. Of 13 moderate (50%-69%) stenoses, one was overestimated at contrast-enhanced MR angiography, two were underestimated and three overestimated at 3D TOF MR angiography, and two were underestimated at DSA. CONCLUSION: DSA results in an underestimation of ICA stenosis compared with rotational angiography. Contrast-enhanced MR angiography correlates best with rotational angiography.