Anti-inflammatory interleukin 1 receptor antagonist concentration in plasma correlates with blood-brain barrier integrity in the primary lesion area in traumatic brain injury patients.

Purpose: Blood-brain barrier (BBB) dysregulation and pro-inflammatory signalling molecules are secondary factors that have been associated with injury severity and long-term clinical outcome following traumatic brain injury (TBI). However, the association between BBB permeability and inflammation is unknown in human TBI patients. In this study, we investigated whether BBI integrity as measured by Dynamic Contrast-Enhanced (DCE) Magnetic Resonance Imaging (MRI) correlates with plasma levels of immunological markers following TBI. Methods: Thirty-two TBI patients recruited from a neurosurgical unit were included in the study. Structural three-dimensional T1-weighted and DCE-MRI images were acquired on a 3T MRI at the earliest opportunity once the participant was sufficiently stable after patient admission to hospital. Blood sampling was performed on the same day as the MRI. The location and extents of the haemorrhagic and contusional lesions were identified. Immunological biomarkers were quantified from the participants' plasma using a multiplex immunoassay. Demographic and clinical information, including age and Glasgow Coma Scale (GCS) were also collected and the immunological biomarker profiles were compared across controls and the TBI severity sub-groups. Contrast agent leakiness through blood-brain barriers (BBB) in the contusional lesions were assessed by fitting DCE-MRI using Patlak model and BBB leakiness characteristics of the participants were correlated with the immunological biomarker profiles. Results: TBI patients showed reduced plasma levels of interleukin (IL)-1ß, IFN-γ, IL-13, and chemokine (C-C motif) ligands (CCL)2 compared to controls and significantly higher levels of platelet-derived growth factor (PDGF-BB), IL-6, and IL-8. BBB leakiness of the contusional lesions did not significantly differ across different TBI severity sub-groups. IL-1ra levels significantly and positively correlated with the contusional lesion's BBB integrity as measured with DCE-MRI via an exponential curve relationship. Discussion: This is the first study to combine DCE-MRI with plasma markers of inflammation in acute TBI patients. Our finding that plasma levels of the anti-inflammatory cytokine IL-1ra correlated negatively with increased leakiness of the BBB.

Blood-brain barrier dysfunction significantly correlates with serum matrix metalloproteinase-7 (MMP-7) following traumatic brain injury.

OBJECTIVES: To determine if radiological evidence of blood brain barrier (BBB) dysfunction, measured using Dynamic Contrast Enhanced MRI (DCE-MRI), correlates with serum matrix metalloproteinase (MMP) levels in traumatic brain injury (TBI) patients, and thereby, identify a potential biomarker for BBB dysfunction. PATIENTS AND METHODS: 20 patients with a mild, moderate, or severe TBI underwent a DCE-MRI scan and BBB dysfunction was interpreted from KTrans. KTrans is a measure of capillary permeability that reflects the efflux of gadolinium contrast into the extra-cellar space. The serum samples were concurrently collected and later analysed for MMP-1, -2, -7, -9, and -10 levels using an ELISA assay. Statistical correlations between MMP levels and the KTrans value were calculated. Multiple testing was corrected using the Benjamin-Hochberg method to control the false-discovery rate (FDR). RESULTS: Serum MMP-1 values ranged from 1.5 to 49.6 ng/ml (12 ± 12.7), MMP-2 values from 58.3 to 174.1 ng/ml (109.5 ± 26.7), MMP-7 from 1.5 to 31.5 ng/mL (10 ± 7.4), MMP-9 from 128.6 to 1917.5 ng/ml (647.7 ± 749.6) and MMP-10 from 0.1 to 0.6 ng/mL (0.3 ± 0.2). Non-parametric Spearman correlation analysis on the data showed significant positive relationship between KTrans and MMP-7 (r = 0.55, p < 0.01). Correlations were also found between KTrans and MMP-1 (r = 0.74, p < 0.0002) and MMP-2 (r = 0.5, p < 0.025) but the actual MMP values were not above reference ranges, limiting the interpretation of results. Statistically significant correlations between KTrans and either MMP-9 or -10 were not found. CONCLUSION: This is the first study to show a correlation between DCE measures and MMP values in patients with a TBI. Our results support the suggestion that serum MMP-7 may be considered as a peripheral biomarker quantifying BBB dysfunction in TBI patients.

Treatment of a middle cerebral artery aneurysm in the setting of Loeys-Dietz syndrome: Case report and review of literature.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder with associated systemic vasculopathies including intracranial arterial aneurysm formation and dissections. LDS is a relatively less well-known entity compared with other connective tissue disorders, such as Ehlers-Danlos or Marfan syndrome, and consequently experience in the management of the associated intracranial aneurysms is suboptimal. We present a case of surgical clipping of a middle cerebral artery aneurysm in a patient with LDS. A 46-year-old female with LDS (type III) was found to have a right middle cerebral artery (MCA) bifurcation aneurysm following vascular screening. The decision was made to surgically clip the aneurysm after consultation in our neurovascular multidisciplinary team meeting. A standard right pterional craniotomy was performed and the aneurysm was secured with 2 straight Sugita clips. The temporal M2 branch was noted to be thin walled and this prompted application of the second tandem clip, rather than risk re-positioning the initial clip. In our case, the MCA aneurysm neck was robust enough to take a clip without any complications, and therefore we suggest that the presence of LDS is not an absolute contra-indication to perform open craniotomy and clipping.

Association between CYP2C9 polymorphisms and ischemic stroke following endovascular neurointervention.

OBJECTIVE: Polymorphisms in the CYP2C9 gene may be associated with adverse vascular events following endovascular procedures independent of antiplatelet therapy. We aimed to investigate the impact of CYP2C9 loss-of-function polymorphisms on adverse vascular events following neurointervention. PATIENTS AND METHODS: Consecutive patients undergoing neurointervention were prospectively recruited between 2010 and 2016. Patients were genotyped for the CYP2C9*2 and *3 loss-of-function polymorphisms. On the basis of possible genetic influence on antiplatelet response, ex vivo clopidogrel response was measured using the VerifyNow® P2Y12 Assay. The primary endpoint was the 90-day incidence of adverse vascular events including ischemic stroke. RESULTS: A total of 229 patients were included. The median age was 57 years (IQR: 49-64), and 158 (69.00%) were female. Eighty-one (35.37%) patients carried at least one CYP2C9 loss-of-function (LOF) allele. After adjustment for stroke risk factors, the 90-day incidence of ischemic stroke was significantly lower in the LOF group compared to the wild type group (1.23% vs 10.14%; ORadj = 0.16, 95% CI: 0.03-0.91; p = 0.04). CONCLUSIONS: Our results suggest protection against ischemic stroke in carriers of CYP2C9*2 or *3 polymorphisms undergoing neurointervention. Our findings warrant further studies to investigate the mechanisms by which CYP2C9 may influence the risk of ischemic stroke.

Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke.

BACKGROUND: Intravenous infusion of alteplase is used for thrombolysis before endovascular thrombectomy for ischemic stroke. Tenecteplase, which is more fibrin-specific and has longer activity than alteplase, is given as a bolus and may increase the incidence of vascular reperfusion. METHODS: We randomly assigned patients with ischemic stroke who had occlusion of the internal carotid, basilar, or middle cerebral artery and who were eligible to undergo thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or alteplase (at a dose of 0.9 mg per kilogram; maximum dose, 90 mg) within 4.5 hours after symptom onset. The primary outcome was reperfusion of greater than 50% of the involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment. Noninferiority of tenecteplase was tested, followed by superiority. Secondary outcomes included the modified Rankin scale score (on a scale from 0 [no neurologic deficit] to 6 [death]) at 90 days. Safety outcomes were death and symptomatic intracerebral hemorrhage. RESULTS: Of 202 patients enrolled, 101 were assigned to receive tenecteplase and 101 to receive alteplase. The primary outcome occurred in 22% of the patients treated with tenecteplase versus 10% of those treated with alteplase (incidence difference, 12 percentage points; 95% confidence interval [CI], 2 to 21; incidence ratio, 2.2; 95% CI, 1.1 to 4.4; P=0.002 for noninferiority; P=0.03 for superiority). Tenecteplase resulted in a better 90-day functional outcome than alteplase (median modified Rankin scale score, 2 vs. 3; common odds ratio, 1.7; 95% CI, 1.0 to 2.8; P=0.04). Symptomatic intracerebral hemorrhage occurred in 1% of the patients in each group. CONCLUSIONS: Tenecteplase before thrombectomy was associated with a higher incidence of reperfusion and better functional outcome than alteplase among patients with ischemic stroke treated within 4.5 hours after symptom onset. (Funded by the National Health and Medical Research Council of Australia and others; EXTEND-IA TNK ClinicalTrials.gov number, NCT02388061 .).

Vascular anomalies of the head and neck in children.

Sixty percent of vascular anomalies in children are found in the head and neck. These lesions can present throughout antenatal, perinatal and childhood development. They broadly fall into two categories: vascular tumours and vascular malformations. Their clinical and, often, psychological impact is determined by both pathological type and location: many lesions follow an uncomplicated natural course and other more complex, extensive or progressive lesions can present a threat to life from mass effect, haemorrhage or large volume arteriovenous shunting. Vascular tumours include infantile haemangioma (IH), congenital haemangioma (CH) and kaposiform hemangioendothelioma (KH); of which IH is the most common. Management options for vascular tumours include conservative approaches, oral medications and surgical intervention as determined by tumour type, location and associated complications. Vascular malformations can be categorised into low flow and high flow lesions. Low flow lesions include capillary, venous and lymphatic malformations (LMs). High flow lesions describe the arteriovenous malformations (AVMs), a highly heterogeneous group of lesions which can present in a variety of ways-the mainstay of treatment for these dynamic lesions is endovascular or surgical obliteration. We provide a practical framework for clinical classification of vascular anomalies of the head and neck in children. We also explore principles of their clinical and radiological assessment along with management, highlighting the importance of a multi-disciplinary approach.

Prediction of stroke thrombolysis outcome using CT brain machine learning.

A critical decision-step in the emergency treatment of ischemic stroke is whether or not to administer thrombolysis - a treatment that can result in good recovery, or deterioration due to symptomatic intracranial haemorrhage (SICH). Certain imaging features based upon early computerized tomography (CT), in combination with clinical variables, have been found to predict SICH, albeit with modest accuracy. In this proof-of-concept study, we determine whether machine learning of CT images can predict which patients receiving tPA will develop SICH as opposed to showing clinical improvement with no haemorrhage. Clinical records and CT brains of 116 acute ischemic stroke patients treated with intravenous thrombolysis were collected retrospectively (including 16 who developed SICH). The sample was split into training (n = 106) and test sets (n = 10), repeatedly for 1760 different combinations. CT brain images acted as inputs into a support vector machine (SVM), along with clinical severity. Performance of the SVM was compared with established prognostication tools (SEDAN and HAT scores; original, or after adaptation to our cohort). Predictive performance, assessed as area under receiver-operating-characteristic curve (AUC), of the SVM (0.744) compared favourably with that of prognostic scores (original and adapted versions: 0.626-0.720; p < 0.01). The SVM also identified 9 out of 16 SICHs, as opposed to 1-5 using prognostic scores, assuming a 10% SICH frequency (p < 0.001). In summary, machine learning methods applied to acute stroke CT images offer automation, and potentially improved performance, for prediction of SICH following thrombolysis. Larger-scale cohorts, and incorporation of advanced imaging, should be tested with such methods.