Metamorphosis of Subarachnoid Hemorrhage Research: from Delayed Vasospasm to Early Brain Injury

Delayed vasospasm that develops 3–7 days after aneurysmal subarachnoid hemorrhage (SAH) has traditionally been considered the most important determinant of delayed ischemic injury and poor outcome. Consequently, most therapies against delayed ischemic injury are directed towards reducing the incidence of vasospasm. The clinical trials based on this strategy, however, have so far claimed limited success; the incidence of vasospasm is reduced without reduction in delayed ischemic injury or improvement in the long-term outcome. This fact has shifted research interest to the early brain injury (first 72 h) evoked by SAH. In recent years, several pathological mechanisms that activate within minutes after the initial bleed and lead to early brain injury are identified. In addition, it is found that many of these mechanisms evolve with time and participate in the pathogenesis of delayed ischemic injury and poor outcome. Therefore, a therapy or therapies focused on these early mechanisms may not only prevent the early brain injury but may also help reduce the intensity of later developing neurological complications. This manuscript reviews the pathological mechanisms of early brain injury after SAH and summarizes the status of current therapies

To Look Beyond Vasospasm in Aneurysmal Subarachnoid Haemorrhage.

Delayed cerebral vasospasm has classically been considered the most important and treatable cause of mortality and morbidity in patients with aneurysmal subarachnoid hemorrhage (aSAH). Secondary ischemia (or delayed ischemic neurological deficit, DIND) has been shown to be the leading determinant of poor clinical outcome in patients with aSAH surviving the early phase and cerebral vasospasm has been attributed to being primarily responsible. Recently, various clinical trials aimed at treating vasospasm have produced disappointing results. DIND seems to have a multifactorial etiology and vasospasm may simply represent one contributing factor and not the major determinant. Increasing evidence shows that a series of early secondary cerebral insults may occur following aneurysm rupture (the so-called early brain injury). This further aggravates the initial insult and actually determines the functional outcome. A better understanding of these mechanisms and their prevention in the very early phase is needed to improve the prognosis. The aim of this review is to summarize the existing literature on this topic and so to illustrate how the presence of cerebral vasospasm may not necessarily be a prerequisite for DIND development. The various factors determining DIND that worsen functional outcome and prognosis are then discussed

White matter T2 hyperintensities and blood‐brain barrier disruption in the hyperacute stage of subarachnoid hemorrhage in male mice: The role of lipocalin‐2

AimsThe current study examined whether white matter injury occurs in the hyperacute (4 hours) phase after subarachnoid hemorrhage (SAH) and the potential role of blood‐brain barrier (BBB) disruption and an acute phase protein, lipocalin 2 (LCN2), in that injury.MethodsSubarachnoid hemorrhage was induced by endovascular perforation in adult mice. First, wild‐type (WT) mice underwent MRI 4 hours after SAH to detect white matter T2 hyperintensities. Second, changes in LCN2 expression and BBB disruption associated with the MRI findings were examined. Third, SAH‐induced white matter injury at 4 hours was compared in WT and LCN2 knockout (LCN2 KO) mice.ResultsAt 4 hours, most animals had uni‐ or bilateral white matter T2 hyperintensities after SAH in WT mice that were associated with BBB disruption and LCN2 upregulation. However, some disruption and LCN2 upregulation was also found in mice with no T2‐hyperintensity lesion. In contrast, there were no white matter T2 hyperintensities in LCN2 KO mice after SAH. LCN2 deficiency also attenuated BBB disruption, myelin damage, and oligodendrocyte loss.ConclusionsSubarachnoid hemorrhage causes very early BBB disruption and LCN2 expression in white matter that is associated with and may precede T2 hyperintensities. LCN2 deletion attenuates MRI changes and pathological changes in white matter after SAH.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151855/1/cns13221.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151855/2/cns13221_am.pd

On The Development of a Dynamic Contrast-Enhanced Near-Infrared Technique to Measure Cerebral Blood Flow in the Neurocritical Care Unit

A dynamic contrast-enhanced (DCE) near-infrared (NIR) method to measure cerebral blood flow (CBF) in the neurocritical care unit (NCU) is described. A primary concern in managing patients with acquired brain injury (ABI) is onset of delayed ischemic injury (DII) caused by complications during the days to weeks following the initial insult, resulting in reduced CBF and impaired oxygen delivery. The development of a safe, portable, and quantitative DCE-NIR method for measuring CBF in NCU patients is addressed by focusing on four main areas: designing a clinically compatible instrument, developing an appropriate analytical framework, creating a relevant ABI animal model, and validating the method against CT perfusion. In Chapter 2, depth-resolved continuous-wave NIR recovered values of CBF in a juvenile pig show strong correlation with CT perfusion CBF during mild ischemia and hyperemia (r=0.84, p\u3c0.001). In particular, subject-specific light propagation modeling reduces the variability caused by extracerebral layer contamination. In Chapter 3, time-resolved (TR) NIR improves the signal sensitivity to brain tissue, and a relative CBF index is be both sensitive and specific to flow changes in the brain. In particular, when compared with the change in CBF measured with CT perfusion during hypocapnia, the deconvolution-based index has an error of 0.8%, compared to 21.8% with the time-to-peak method. To enable measurement of absolute CBF, a method for characterizing the AIF is described in Chapter 4, and the theoretical basis for an advanced analytical framework—the kinetic deconvolution optical reconstruction (KDOR)—is provided in Chapter 5. Finally, a multichannel TR-NIR system is combined with KDOR to quantify CBF in an adult pig model of ischemia (Chapter 6). In this final study, measurements of CBF obtained with the DCE-NIR technique show strong agreement with CT perfusion measurements of CBF in mild and moderate ischemia (r=0.86, p\u3c0.001). The principle conclusion of this thesis is that the DCE-NIR method, combining multidistance TR instrumentation with the KDOR analytical framework, can recover CBF values that are in strong agreement with CT perfusion values of CBF. Ultimately, bedside CBF measurements could improve clinical management of ABI by detecting delayed ischemia before permanent brain damage occurs

Regional Differences in Cerebral Glucose Metabolism After Cardiac Arrest and Resuscitation in Rats Using [(18)F]FDG Positron Emission Tomography and Autoradiography.

BACKGROUND Cardiac arrest is an important cause of morbidity and mortality. Brain injury severity and prognosis of cardiac arrest patients are related to the cerebral areas affected. To this aim, we evaluated the variability and the distribution of brain glucose metabolism after cardiac arrest and resuscitation in an adult rat model. METHODS Ten rats underwent 8-min cardiac arrest, induced with a mixture of potassium and esmolol, and resuscitation, performed with chest compressions and epinephrine. Eight sham animals received anesthesia and experimental procedures identical to the ischemic group except cardiac arrest induction. Brain metabolism was assessed using [(18)F]FDG autoradiography and small animal-dedicated positron emission tomography. RESULTS The absolute glucose metabolism measured with [(18)F]FDG autoradiography 2 h after cardiac arrest and resuscitation was lower in the frontal, parietal, occipital, and temporal cortices of cardiac arrest animals, showing, respectively, a 36% (p = 0.006), 32% (p = 0.016), 36% (p = 0.009), and 32% (p = 0.013) decrease compared to sham group. Striatum, hippocampus, thalamus, brainstem, and cerebellum showed no significant changes. Relative regional metabolism indicated a redistribution of metabolism from cortical area to brainstem and cerebellum. CONCLUSIONS Our data suggest that cerebral regions have different susceptibility to moderate global ischemia in terms of glucose metabolism. The neocortex showed a higher sensibility to hypoxia-ischemia than other regions. Other subcortical regions, in particular brainstem and cerebellum, showed no significant change compared to non-ischemic rats

Malignant astrocyte swelling and impaired glutamate clearance drive the expansion of injurious spreading depolarization foci

Spreading depolarizations (SDs) indicate injury progression and predict worse clinical outcome in acute brain injury. We demonstrate in rodents that acute brain swelling upon cerebral ischemia impairs astroglial glutamate clearance and increases the tissue area invaded by SD. The cytotoxic extracellular glutamate accumulation (>15 mu M) predisposes an extensive bulk of tissue (4-5 mm(2)) for a yet undescribed simultaneous depolarization (SiD). We confirm in rat brain slices exposed to osmotic stress that SiD is the pathological expansion of prior punctual SD foci (0.5-1 mm(2)), is associated with astrocyte swelling, and triggers oncotic neuron death. The blockade of astrocytic aquaporin-4 channels and Na+/K+/Cl- co-transporters, or volume-regulated anion channels mitigated slice edema, extracellular glutamate accumulation (<10 mu M) and SiD occurrence. Reversal of slice swelling by hyperosmotic mannitol counteracted glutamate accumulation and prevented SiD. In contrast, inhibition of glial metabolism or inhibition of astrocyte glutamate transporters reproduced the SiD phenotype. Finally, we show in the rodent water intoxication model of cytotoxic edema that astrocyte swelling and altered astrocyte calcium waves are central in the evolution of SiD. We discuss our results in the light of evidence for SiD in the human cortex. Our results emphasize the need of preventive osmotherapy in acute brain injury

Adhesion of Leukocytes to Cerebral Venules Precedes Neuronal Cell Death and Is Sufficient to Trigger Tissue Damage After Cerebral Ischemia

BackgroundLeukocytes contribute to tissue damage after cerebral ischemia;however, the mechanisms underlying this process are still unclear. This study investigates the temporal and spatial relationship between vascular leukocyte recruitment and tissue damage and aims to uncover which step of the leukocyte recruitment cascade is involved in ischemic brain injury. MethodsMale wild-type, ICAM-1-deficient, anti-CD18 antibody treated, or selectin-deficient [fucusyltransferase (FucT IV/VII-/-)] mice were subjected to 60 min of middle cerebral artery occlusion (MCAo). The interaction between leukocytes and the cerebrovascular endothelium was quantified by in vivo fluorescence microscopy up to 15 h thereafter. Temporal dynamics of neuronal cell death and leukocyte migration were assessed at the same time points and in the same tissue volume by histology. ResultsIn wild-type mice, leukocytes started to firmly adhere to the wall of pial postcapillary venules two hours after reperfusion. Three hours later, neuronal loss started and 13 h later, leukocytes transmigrated into brain tissue. Loss of selectin function did not influence this process. Application of an anti-CD18 antibody or genetic deletion of ICAM-1, however, significantly reduced tight adhesion of leukocytes to the cerebrovascular endothelium (-60%;p < 0.01) and increased the number of viable neurons in the ischemic penumbra by 5-fold (p < 0.01);the number of intraparenchymal leukocytes was not affected. ConclusionsOur findings suggest that ischemia triggers only a transient adhesion of leukocytes to the venous endothelium and that inhibition of this process is sufficient to partly prevent ischemic tissue damage