Contribution of Matrix Metalloproteinase-9 to Cerebral Edema and Functional Outcome following Experimental Subarachnoid Hemorrhage

Background: Cerebral edema is an important risk factor for death and poor outcome following subarachnoid hemorrhage (SAH). However, underlying mechanisms are still poorly understood. Matrix metalloproteinase (MMP)-9 is held responsible for the degradation of microvascular basal lamina proteins leading to blood-brain barrier dysfunction and, thus, formation of vasogenic cerebral edema. The current study was conducted to clarify the role of MMP-9 for the development of cerebral edema and for functional outcome after SAH. Methods: SAH was induced in FVB/N wild-type (WT) or MMP-9 knockout (MMP-9(-/-)) mice by endovascular puncture. Intracranial pressure (ICP), regional cerebral blood flow (rCBF), and mean arterial blood pressure (MABP) were continuously monitored up to 30 min after SAH. Mortality was quantified for 7 days after SAH. In an additional series neurological function and body weight were assessed for 3 days after SAH. Subsequently, ICP and brain water content were quantified. Results: Acute ICP, rCBF, and MABP did not differ between WT and MMP-9(-/-) mice, while 7 days' mortality was lower in MMP-9(-/-) mice (p = 0.03; 20 vs. 60%). MMP-9(-/-) mice also exhibited better neurological recovery, less brain edema formation, and lower chronic ICP. Conclusions: The results of the current study suggest that MMP-9 contributes to the development of early brain damage after SAH by promoting cerebral edema formation. Hence, MMP-9 may represent a novel molecular target for the treatment of SAH. Copyright (C) 2011 S. Karger AG, Base

Molecular diagnostics helps to identify distinct subgroups of spinal astrocytomas

Primary spinal cord astrocytomas are rare, hence few data exist about the prognostic significance of molecular markers. Here we analyze a panel of molecular alterations in association with the clinical course. Histology and genome sequencing was performed in 26 spinal astrocytomas operated upon between 2000 and 2020. Next-generation DNA/RNA sequencing (NGS) and methylome analysis were performed to determine molecular alterations. Histology and NGS allowed the distinction of 5 tumor subgroups: glioblastoma IDH wildtype (GBM); diffuse midline glioma H3 K27M mutated (DMG-H3); high-grade astrocytoma with piloid features (HAP); diffuse astrocytoma IDH mutated (DA), diffuse leptomeningeal glioneural tumors (DGLN) and pilocytic astrocytoma (PA). Within all tumor entities GBM (median OS: 5.5~months), DMG-H3 (median OS: 13~months) and HAP (median OS: 8~months) showed a fatal prognosis. DMG-H3 tend to emerge in adolescence whereas GBM and HAP develop in the elderly. HAP are characterized by CDKN2A/B deletion and ATRX mutation. 50% of PA tumors carried a mutation in the PIK3CA gene which is seemingly associated with better outcome (median OS: PIK3CA mutated 107.5 vs 45.5~months in wildtype PA). This exploratory molecular profiling of spinal cord astrocytomas allows to identify distinct subgroups by combining molecular markers and histomorphology. DMG-H3 tend to develop in adolescence with a similar dismal prognosis like GBM and HAP in the elderly. We here describe spinal HAP with a distinct molecular profile for the first time

Rodent models of focal cerebral ischemia: procedural pitfalls and translational problems

Rodent models of focal cerebral ischemia are essential tools in experimental stroke research. They have added tremendously to our understanding of injury mechanisms in stroke and have helped to identify potential therapeutic targets. A plethora of substances, however, in particular an overwhelming number of putative neuroprotective agents, have been shown to be effective in preclinical stroke research, but have failed in clinical trials. A lot of factors may have contributed to this failure of translation from bench to bedside. Often, deficits in the quality of experimental stroke research seem to be involved. In this article, we review the commonest rodent models of focal cerebral ischemia - middle cerebral artery occlusion, photothrombosis, and embolic stroke models - with their respective advantages and problems, and we address the issue of quality in preclinical stroke modeling as well as potential reasons for translational failure

CT‐Based Classification of Acute Cerebral Edema: Association with Intracranial Pressure and Outcome

Lietke S, Zausinger S, Patzig M, Holtmanspötter M, Kunz M. CT‐Based Classification of Acute Cerebral Edema: Association with Intracranial Pressure and Outcome. Journal of Neuroimaging. 2020;30(5):640-647.**BACKGROUND AND PURPOSE** Brain edema after acute cerebral lesions may lead to raised intracranial pressure (ICP) and worsen outcome. Notwithstanding, no CT‐based scoring system to quantify edema formation exists. This retrospective correlative analysis aimed to establish a valid and definite CT score quantifying brain edema after common acute cerebral lesions. **METHODS** A total of 169 CT investigations in 60 patients were analyzed: traumatic brain injury (TBI;n= 47), subarachnoid hemorrhage (SAH;n= 70), intracerebral hemorrhage (ICH;n= 42), and ischemic stroke (n= 10). Edema formation was classified as 0: no edema, 1: focal edema confined to 1 lobe, 2: unilateral edema > 1 lobe, 3: bilateral edema, 4: global edema with disappearance of sulcal relief, and 5: global edema with basal cisterns effacement. ICP and Glasgow Outcome Score (GOS) were correlated to edema formation. **RESULTS** Median ICP values were 12.0, 14.0, 14.9, 18.2, and 25.9 mm Hg in grades 1‐5, respectively. Edema grading significantly correlated with ICP (r= .51;P r= .5,P r= .5;P r= .6,P r= −.3,P= .046). **CONCLUSION** The proposed CT‐based grading of extent of cerebral edema significantly correlated with ICP and outcome in TBI, SAH, and ICH patients and might be helpful for standardized description of CT‐images and as parameter for clinical studies, for example, measuring effects of antiedematous therapies. </p

Intravenous Magnesium versus Nimodipine in the Treatment of Patients with Aneurysmal Subarachnoid Hemorrhage: A Randomized Study

Abstract OBJECTIVE: The prophylactic use of nimodipine in patients with aneurysmal subarachnoid hemorrhage reduces the risk of ischemic brain damage. However, its efficacy seems to be rather moderate. The question arises whether other types of calcium antagonists offer better protection. Magnesium, nature's physiological calcium antagonist, is neuroprotective in animal models, promotes dilatation of cerebral arteries, and has an established safety profile. The aim of the current pilot study is to evaluate the efficacy of magnesium versus nimodipine to prevent delayed ischemic deficits after aneurysmal subarachnoid hemorrhage. METHODS: One hundred and thirteen patients with aneurysmal subarachnoid hemorrhage were enrolled in the study and were randomized to receive either magnesium sulfate (loading 10 mg/kg followed by 30 mg/kg daily) or nimodipine (48 mg/d) intravenously until at least postoperative Day 7. Primary outcome parameters were incidence of clinical vasospasm and infarction. Secondary outcome measures were the incidence of transcranial Doppler/angiographic vasospasm, the neuronal markers (neuron-specific enolase, S-100), and the patients' Glasgow Outcome Scale scores at discharge and after 1 year. RESULTS: One hundred and four patients met the study requirements. In the magnesium group (n = 53), eight patients (15%) experienced clinical vasospasm and 20 (38%) experienced transcranial Doppler/angiographic vasospasm compared with 14 (27%) and 17 (33%) patients in the nimodipine group (n = 51). If clinical vasospasm occurred, 75% of the magnesium-treated versus 50% of the nimodipine-treated patients experienced cerebral infarction resulting in fatal outcome in 37 and 14%, respectively. Overall, the rate of infarction attributable to vasospasm was virtually the same (19 versus 22%). There was no difference in outcome between groups. CONCLUSION: The efficacy of magnesium in preventing delayed ischemic neurological deficits in patients with aneurysmal subarachnoid hemorrhage seems to be comparable with that of nimodipine. The difference in their pharmacological properties makes studies on the combined administration of magnesium and nimodipine seem promising

Intraoperative ultrasonography in laminectomy for degenerative cervical spondylotic myelopathy: a clinical and radiological evaluation

Background The incidence of cervical myelopathy due to spinal stenosis is constantly growing in an aging population. Especially in multisegmental disease, dorsal laminectomy is the intervention of choice. Intraoperative imaging with ultrasound might provide additional information about extent and sufficiency of spinal cord decompression. Methods In this prospective study, the width of the subarachnoid space was systematically measured by intraoperative ultrasound at predefined sites at the cranial and caudal edge of decompression in axial and sagittal reconstruction. These data were compared with corresponding sites on postoperative T2-weighted MRI imaging. In addition, the functional outcome was assessed by modified Japanese Orthopaedic Association (mJOA) score. A historical patient cohort treated without ultrasound-guided laminectomy served as control group. Results Altogether, 29 patients were included. According to mJOA score at last follow-up, 7/29 patients reported stable symptoms and 21/29 patients showed a substantial benefit with no or minor residual neurological deficits. One patient suffered from a new C5 palsy. Intraoperative ultrasound-guided posterior decompression provided excellent overview in all cases. Measurement of the width of the subarachnoid space acquired by intraoperative ultrasound and postoperative MRI images showed a very high correlation, especially at the cranial level (p < 0.001, r = 0.880). Bland-Altman analysis showed that most patients were within the 1.96 x SD limits of agreement throughout all measurements. No ultrasound procedure-related complications were observed. Compared to a historical cohort of 27 patients, no significant differences were found regarding functional outcome (p = 0.711). Conclusion Intraoperative sonography visualises the surgically achieved restoration of the subarachnoid space in good correlation with postoperative MRI and might serve as a fast, precise and reliable tool for intraoperative imaging in cervical laminectomy. However, we could not demonstrate a clinical benefit with regard to functional outcome