MMP-9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke: a proof-of-concept study.

BACKGROUND: Matrix metalloproteinases (MMPs) are implied in blood-brain barrier degradation and haemorrhagic transformation following ischaemic stroke, but their local relevance in the hyperacute disease phase is unknown. We aimed to examine ultra-early MMP-9 and MMP-2 release into collateral blood vessels, and to assess its prognostic value before therapeutic recanalisation by endovascular thrombectomy (EVT). METHODS: We report a cross-sectional proof-of-concept study including patients undergoing EVT for large-vessel ischaemic stroke at the University Hospital Würzburg, Germany. We obtained liquid biopsies from the collateral circulation before recanalisation, and systemic control samples. Laboratory workup included quantification of MMP-9 and MMP-2 plasma concentrations by cytometric bead array, immunohistochemical analyses of cellular MMP-9 and MMP-2 expression, and detection of proteolytic activity by gelatine zymography. The clinical impact of MMP concentrations was assessed by stratification according to intracranial haemorrhagic lesions on postinterventional computed tomography (Heidelberg Bleeding Classification, HBC) and early functional outcome (modified Rankin Scale, mRS). We used multivariable logistic regression, receiver-operating-characteristic (ROC) curves, and fixed-level estimates of test accuracy measures to study the prognostic value of MMP-9 concentrations. FINDINGS: Between August 3, 2018, and September 16, 2021, 264 matched samples from 132 patients (86 [65.2%] women, 46 [34.8%] men, aged 40-94 years) were obtained. Median (interquartile range, IQR) MMP-9 (279.7 [IQR 126.4-569.6] vs 441 [IQR 223.4-731.5] ng/ml, p < 0.0001) but not MMP-2 concentrations were increased within collateral blood vessels. The median MMP-9 expression level of invading neutrophils was elevated (fluorescence intensity, arbitrary unit: 2276 [IQR 1007-5086] vs 3078 [IQR 1108-7963], p = 0.0018). Gelatine zymography experiments indicated the locally confined proteolytic activity of MMP-9 but not of MMP-2. Pretherapeutic MMP-9 release into stroke-affected brain regions predicted the degree of intracerebral haemorrhages and clinical stroke severity after recanalisation, and independently increased the odds of space-occupying parenchymal haematomas (HBC1c-3a) by 1.54 times, and the odds of severe disability or death (mRS ≥5 at hospital discharge) by 2.33 times per 1000 ng/ml increase. Excessive concentrations of MMP-9 indicated impending parenchymal haematomas and severe disability or death with high specificity. INTERPRETATION: Measurement of MMP-9 within collateral blood vessels is feasible and identifies patients with stroke at risk of major intracerebral haemorrhages and poor outcome before therapeutic recanalisation by EVT, thereby providing evidence of the concept validity of ultra-early local stroke biomarkers. FUNDING: This work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) and the Interdisciplinary Centre for Clinical Research (IZKF) at the University of Würzburg.

A Retrospective Analysis of Temporal Lobe Gliosis after Middle Fossa Resection of Small Vestibular Schwannomas.

INTRODUCTION: The middle cranial fossa (MCF) approach is a well-established procedure in surgery of the internal auditory canal, as well as with the retrosigmoid and translabyrinthine approaches. It is commonly used in the hearing-preserving microsurgery of small vestibular schwannomas (VS). The debate about the "best" approach for the microsurgery of small VS without contact to the brainstem is controversial. It has been stated that the MCF approach leads to irreversible damage to the temporal lobe, which may be evident in follow-up magnet resonance imaging (MRI) as gliosis in up to 70% of patients. MATERIALS AND METHODS: This study represents a retrospective chart analysis conducted at a tertiary university hospital. Here, 76 postoperative MRIs were re-evaluated by an experienced neuroradiologist and compared with the preoperative images. Temporal lobe gliosis was classified on an ordinal scale as absent, slight, moderate or severe. Occurrence of gliosis was matched to the clinical predictors (tumor stage, tumor volume, sex, age, and side). RESULTS: No case of severe or moderate gliosis was found in the patient group. Slight gliosis of the temporal lobe was rare and was only detected in four patients (5%). There was no relation between clinical predictors and the incidence of gliosis. CONCLUSIONS: In our cohort, postoperative MR imaging did not reveal relevant damage to the temporal lobe parenchyma. This confirms the safe concept of microsurgery of small tumors via the middle fossa approach. The severe glioses described in other studies may be caused by a forced insertion of the retractor or by more extended approaches. However, further prospective neurocognitive studies seem to be necessary in order to assess functional changes in the temporal lobe.

High-resolution Magnetic Resonance Imaging visualizes intracranial large artery involvement in Giant Cell Arteritis.

OBJECTIVE: Giant Cell arteritis (GCA) is a large vessel vasculitis, typically involving the aorta and its branches with predilection for the scalp arteries. Intracranial involvement is still part of ongoing research. We assess inflammation of the intracranial arteries on 3D-black-blood magnetic resonance imaging (3D-CS-BB-MRI) in patients with GCA and age-matched controls. METHODS: 105 patients with 3D-CS-BB-MRI of the brain were included in this retrospective dual-center case-control study; 55 with diagnosed GCA and 50 age-matched controls. High-resolution 3D-CS-BB-MRI was performed on a 3 Tesla MR scanner with a post-contrast 3D-compressed-sensing (CS) MR pulse sequence, specifically a T1-weighted sampling perfection, application-optimized contrasts using different flip angle evolution (SPACE) pulse sequence with whole-brain coverage and isotropic resolution of 0.55 mm3. Two neuroradiologists blinded to clinical data independently scored the cerebral arteries qualitatively for inflammation; circumferential vessel wall thickening and contrast enhancement were scored positive for vasculitis. RESULTS: 8 of 55 GCA patients (14.5%) showed inflammation of at least one intracranial artery. The internal carotid artery (ICA) was affected in 6/55 (10.9%), the vertebral artery in 4/55 (7.3%) and the basilar artery and posterior cerebral artery in 1/55 (1.8%). All patients with inflammatory changes reported headaches and none showed any focal neurological deficit. Besides headache and general weakness, there was no significant correlation between inflammation of the intracranial arteries and clinical symptoms. No age-matched control patient showed inflammatory changes of the intracranial arteries. CONCLUSION: High-resolution 3D-CS-BB-MRI revealed inflammatory changes of intracranial arteries in 14.5% of GCA patients with the intradural ICA as the most frequently affected vessel.

Distinct Alterations in Oxygenation, Ion Composition and Acid-Base Balance in Cerebral Collaterals During Large-Vessel Occlusion Stroke.

PURPOSE: Disturbances of blood gas and ion homeostasis including regional hypoxia and massive sodium (Na+)/potassium (K+) shifts are a hallmark of experimental cerebral ischemia but have not been sufficiently investigated for their relevance in stroke patients. METHODS: We report a prospective observational study on 366 stroke patients who underwent endovascular thrombectomy (EVT) for large-vessel occlusion (LVO) of the anterior circulation (18 December 2018-31 August 2020). Intraprocedural blood gas samples (1 ml) from within cerebral collateral arteries (ischemic) and matched systemic control samples were obtained according to a prespecified protocol in 51 patients. RESULTS: We observed a significant reduction in cerebral oxygen partial pressure (-4.29%, paO2ischemic = 185.3 mm Hg vs. paO2systemic = 193.6 mm Hg; p = 0.035) and K+ concentrations (-5.49%, K+ischemic = 3.44 mmol/L vs. K+systemic = 3.64 mmol/L; p = 0.0083). The cerebral Na+:K+ ratio was significantly increased and negatively correlated with baseline tissue integrity (r = -0.32, p = 0.031). Correspondingly, cerebral Na+ concentrations were most strongly correlated with infarct progression after recanalization (r = 0.42, p = 0.0033). We found more alkaline cerebral pH values (+0.14%, pHischemic = 7.38 vs. pHsystemic = 7.37; p = 0.0019), with a time-dependent shift towards more acidotic conditions (r = -0.36, p = 0.055). CONCLUSION: These findings suggest that stroke-induced changes in oxygen supply, ion composition and acid-base balance occur and dynamically progress within penumbral areas during human cerebral ischemia and are related to acute tissue damage.

Intraorbital findings in giant cell arteritis on black blood MRI.

OBJECTIVE: Blindness is a feared complication of giant cell arteritis (GCA). However, the spectrum of pathologic orbital imaging findings on magnetic resonance imaging (MRI) in GCA is not well understood. In this study, we assess inflammatory changes of intraorbital structures on black blood MRI (BB-MRI) in patients with GCA compared to age-matched controls. METHODS: In this multicenter case-control study, 106 subjects underwent BB-MRI. Fifty-six patients with clinically or histologically diagnosed GCA and 50 age-matched controls without clinical or laboratory evidence of vasculitis were included. All individuals were imaged on a 3-T MR scanner with a post-contrast compressed-sensing (CS) T1-weighted sampling perfection with application-optimized contrasts using different flip angle evolution (SPACE) BB-MRI sequence. Imaging results were correlated with available clinical symptoms. RESULTS: Eighteen of 56 GCA patients (32%) showed inflammatory changes of at least one of the intraorbital structures. The most common finding was enhancement of at least one of the optic nerve sheaths (N = 13, 72%). Vessel wall enhancement of the ophthalmic artery was unilateral in 8 and bilateral in 3 patients. Enhancement of the optic nerve was observed in one patient. There was no significant correlation between imaging features of inflammation and clinically reported orbital symptoms (p = 0.10). None of the age-matched control patients showed any inflammatory changes of intraorbital structures. CONCLUSIONS: BB-MRI revealed inflammatory findings in the orbits in up to 32% of patients with GCA. Optic nerve sheath enhancement was the most common intraorbital inflammatory change on BB-MRI. MRI findings were independent of clinically reported orbital symptoms. KEY POINTS: • Up to 32% of GCA patients shows signs of inflammation of intraorbital structures on BB-MRI. • Enhancement of the optic nerve sheath is the most common intraorbital finding in GCA patients on BB-MRI. • Features of inflammation of intraorbital structures are independent of clinically reported symptoms.

Clinical Utility of C-Reactive Protein and White Blood Cell Count for Scheduling an [18F]FDG PET/CT in Patients with Giant Cell Arteritis.

OBJECTIVES: 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET/CT can be utilized in patients with giant cell arteritis (GCA), but pretest probability of established laboratory marker such as C-reactive protein (CRP) and white blood cell count (WBC) has not been defined yet. We aimed to elucidate the clinical utility of CRP and WBC for scheduling an [18F]FDG scan. METHODS: 18 treatment-naïve GCA patients and 14 GCA subjects with anti-inflammatory treatment (glucocorticoids or comparable drugs), who underwent [18F]FDG PET/CT and who had no other inflammatory disease at time of scan, were identified. A semi-quantitative analysis in 11 vessel segments was conducted, with averaged jugular vein, healthy liver and lung tissue (Target-to-background ratio [TBR]VJ/liver/lung) serving as background. Derived TBR were then correlated with CRP and WBC at time of PET using Spearman's correlation. RESULTS: For all treatment-naïve patients, TBRVJ was 2.3±1.1 (95%CI, 2.2-2.5), TBRliver was 1.0±0.5 (95%CI, 0.9-1.0) and average TBRlung was 6.3±3.6 (95%CI, 5.8-6.8). No significant correlation was noted for either CRP (TBRVJ: R=-0.19; TBRliver: R=-0.03; TBRlung: R=-0.17; each P ≥ 0.44) or for WBC (TBRVJ: R=-0.40; TBRliver: R=-0.32; TBRlung: R=-0.37; each P ≥ 0.10). Similar results were recorded for patients under treatment at time of PET. Again, no significant correlation was reached for either CRP (TBRVJ: R=-0.17; TBRliver: R=-0.28; TBRlung: R=-0.09; each P ≥ 0.32) or WBC (TBRVJ: R=-0.06; TBRliver: R=-0.13; TBRlung: R=0.06; each P ≥ 0.65). CONCLUSIONS: In GCA patients with and without anti-inflammatory treatment, CRP and WBC did not substantially correlate with TBR at time of scan. Given the rather limited pretest probability of those parameters, such laboratory values may have less diagnostic utility to order an [18F]FDG PET/CT.

Safety and Effectiveness of the New Generation APERIO® Hybrid Stent-retriever Device in Large Vessel Occlusion Stroke.

BACKGROUND: It is unknown whether technological advancement of stent-retriever devices influences typical observational indicators of safety or effectiveness. METHODS: Observational retrospective study of APERIO® (AP) vs. new generation APERIO® Hybrid (APH) (Acandis®, Pforzheim, Germany) stent-retriever device (01/2019-09/2020) for mechanical thrombectomy (MT) in large vessel occlusion (LVO) stroke. Primary effectiveness endpoint was successful recanalization eTICI (expanded Thrombolysis In Cerebral Ischemia) ≥ 2b67, primary safety endpoint was occurrence of hemorrhagic complications after MT. Secondary outcome measures were time from groin puncture to first pass and successful reperfusion, and the total number of passes needed to achieve the final recanalization result. RESULTS: A total of 298 patients with LVO stroke who were treated by MT matched the inclusion criteria: 148 patients (49.7%) treated with AP vs. 150 patients (50.3%) treated with new generation APH. Successful recanalization was not statistically different between both groups: 75.7% for AP vs. 79.3% for APH; p = 0.450. Postinterventional hemorrhagic complications and particularly subarachnoid hemorrhage as the entity possibly associated with stent-retriever device type was significantly less frequent in the group treated with the APH: 29.7% for AP and 16.0% for APH; p = 0.005; however, rates of symptomatic hemorrhage with clinical deterioration and in domo mortality were not statistically different. Neither the median number of stent-retriever passages needed to achieve final recanalization, time from groin puncture to first pass, time from groin puncture to final recanalization nor the number of cases in which successful recanalization could only be achieved by using a different stent-retriever as bail-out device differed between both groups. CONCLUSION: In the specific example of the APERIO® stent-retriever device, we observed that further technological developments of the new generation device were not associated with disadvantages with respect to typical observational indicators of safety or effectiveness.

Immune Cells Invade the Collateral Circulation during Human Stroke: Prospective Replication and Extension.

It remains unclear if principal components of the local cerebral stroke immune response can be reliably and reproducibly observed in patients with acute large-vessel-occlusion (LVO) stroke. We prospectively studied a large independent cohort of n = 318 consecutive LVO stroke patients undergoing mechanical thrombectomy during which cerebral blood samples from within the occluded anterior circulation and systemic control samples from the ipsilateral cervical internal carotid artery were obtained. An extensive protocol was applied to homogenize the patient cohort and to standardize the procedural steps of endovascular sample collection, sample processing, and laboratory analyses. N = 58 patients met all inclusion criteria. (1) Mean total leukocyte counts were significantly higher within the occluded ischemic cerebral vasculature (I) vs. intraindividual systemic controls (S): +9.6%, I: 8114/µL ± 529 vs. S: 7406/µL ± 468, p = 0.0125. (2) This increase was driven by neutrophils: +12.1%, I: 7197/µL ± 510 vs. S: 6420/µL ± 438, p = 0.0022. Leukocyte influx was associated with (3) reduced retrograde collateral flow (R2 = 0.09696, p = 0.0373) and (4) greater infarct extent (R2 = 0.08382, p = 0.032). Despite LVO, leukocytes invade the occluded territory via retrograde collateral pathways early during ischemia, likely compromising cerebral hemodynamics and tissue integrity. This inflammatory response can be reliably observed in human stroke by harvesting immune cells from the occluded cerebral vascular compartment.