Sebastian Urday

Targeting secondary injury in intracerebral haemorrhage—perihaematomal oedema

Perihaematomal oedema (PHO) is an important pathophysiological marker of secondary injury in intracerebral haemorrhage (ICH). In this Review, we describe a novel method to conceptualize PHO formation within the framework of Starlings principle of movement of fluid across a capillary wall. We consider progression of PHO through three stages, characterized by ionic oedema (stage 1) and progressive vasogenic oedema (stages 2 and 3). In this context, possible modifiers of PHO volume and their value in identifying patients who would benefit from therapies that target secondary injury are discussed; the practicalities of using neuroimaging to measure PHO volume are also considered. We examine whether PHO can be used as a predictor of neurological outcome following ICH, and we provide an overview of emerging therapies. Our discussion emphasizes that PHO has clinical relevance both as a therapeutic target, owing to its augmentation of the mass effect of a haemorrhage, and as a surrogate marker for novel interventions that target secondary injury.

Proteomic analysis of the maternal protein restriction rat model for schizophrenia: Identification of translational changes in hormonal signaling pathways and glutamate neurotransmission

Previous studies have found that some first onset schizophrenia patients show signs of impaired insulin signaling. Also, epidemiological studies have shown that periods of suboptimal nutrition including protein deficiencies during pregnancy can lead to increased incidence of metabolic conditions and psychiatric disorders in the offspring. For these reasons, we have carried out a molecular profiling analysis of blood serum and brain tissues from adult offspring produced by the maternal low protein (LP) rat model. The results showed similar changes to those seen in schizophrenia. Multiplex immunoassay profiling identified changes in the levels of insulin, adiponectin, and leptin along with alterations in inflammatory and vascular system‐related proteins such as osteopontin, macrophage colony‐stimulating factor 1, and vascular cell adhesion molecule 1. LC‐MSE proteomic profiling showed that glutamatergic pathways were altered in frontal cortex, while signaling pathways and cytoskeletal proteins involved in hormonal secretion and synaptic remodeling were altered in the hypothalamus. Taken together, these studies indicate that the LP rat model recapitulates several pathophysiological attributes seen in schizophrenia patients. We propose that the LP model may have utility for drug discovery efforts, especially to identify compounds that modulate the metabolic and glutamatergic systems.

Measurement of Perihematomal Edema in Intracerebral Hemorrhage

Background and Purpose— Perihematomal edema (PHE) is a marker of secondary injury in intracerebral hemorrhage (ICH). PHE measurement on computed tomography (CT) is challenging, and the principles used to detect PHE have not been described fully. We developed a systematic approach for CT-based measurement of PHE. Methods— Two independent raters measured PHE volumes on baseline and 24-hour post-ICH CT scans of 20 primary supratentorial ICH subjects. Boundaries were outlined with an edge-detection tool and adjusted after inspection of the 3 orthogonal planes. PHE was delineated with the additional principle that it should be (a) more hypodense than the corresponding area in the contralateral hemisphere and (b) most hypodense immediately surrounding the hemorrhage. We examined intra- and interrater reliability using intraclass correlation coefficients and Bland–Altman plots for interrater consistency. CT-based PHE was also compared using magnetic resonance imaging–based PHE detection for 18 subjects. Results— Median PHE volumes were 22.7 cc at baseline and 20.4 cc at 24 hours post-ICH. There were no statistically significant differences in PHE measurements between raters. Interrater and intrarater reliability for PHE were excellent. At baseline and 24 hours, interrater intraclass correlation coefficients were 0.98 (0.96–1.00) and 0.98 (0.97–1.00); intrarater intraclass correlation coefficients were 0.99 (0.99–1.00) and 0.99 (0.98–1.00). Bland–Altman analysis showed the bias for PHE measurements at baseline and 24 hours, −0.5 cc (SD, 5.4) and −3.2 cc (SD, 5.0), was acceptably small. PHE volumes determined by CT and magnetic resonance imaging were similar (23.9±16.9 cc versus 23.9±16.0 cc, R2 = 0.98, P<0.0001). Conclusions— Our method measures PHE with excellent reliability at baseline and 24 hours post-ICH.

Rate of Perihematomal Edema Expansion Predicts Outcome After Intracerebral Hemorrhage.

Objectives:Intracerebral hemorrhage is a devastating disorder with no current treatment. Whether perihematomal edema is an independent predictor of neurologic outcome is controversial. We sought to determine whether perihematomal edema expansion rate predicts outcome after intracerebral hemorrhage. Design:Retrospective cohort study. Setting:Tertiary medical center. Patients:One hundred thirty-nine consecutive supratentorial spontaneous intracerebral hemorrhage patients 18 years or older admitted between 2000 and 2013. Interventions:None. Measurements and Main Results:Intracerebral hemorrhage, intraventricular hemorrhage, and perihematomal edema volumes were measured from CT scans obtained at presentation, 24-hours, and 72-hours postintracerebral hemorrhage. Perihematomal edema expansion rate was the difference between initial and follow-up perihematomal edema volumes divided by the time interval. Logistic regression was performed to evaluate the relationship between 1) perihematomal edema expansion rate at 24 hours and 90-day mortality and 2) perihematomal edema expansion rate at 24 hours and 90-day modified Rankin Scale score. Perihematomal edema expansion rate between admission and 24-hours postintracerebral hemorrhage was a significant predictor of 90-day mortality (odds ratio, 2.97; 95% CI, 1.48–5.99; p = 0.002). This association persisted after adjusting for all components of the intracerebral hemorrhage score (odds ratio, 2.21; 95% CI, 1.05–4.64; p = 0.04). Similarly, higher 24-hour perihematomal edema expansion rate was associated with poorer modified Rankin Scale score in an ordinal shift analysis (odds ratio, 2.40; 95% CI, 1.37–4.21; p = 0.002). The association persisted after adjustment for all intracerebral hemorrhage score components (odds ratio, 2.07; 95% CI, 1.12–3.83; p = 0.02). Conclusions:Faster perihematomal edema expansion rate 24-hours postintracerebral hemorrhage is associated with worse outcome. Perihematomal edema may represent an attractive translational target for secondary injury after intracerebral hemorrhage.

Analysis of the rat hypothalamus proteome by data-independent label-free LC-MS/MS.

Studies of neuronal, endocrine, and metabolic disorders would be facilitated by characterization of the hypothalamus proteome. Protein extracts prepared from 16 whole rat hypothalami were measured by data‐independent label‐free nano LC‐MS/MS. Peptide features were detected, aligned, and searched against a rat Swiss‐Prot database using ProteinLynx Global Server v.2.5. The final combined dataset comprised 21 455 peptides, corresponding to 622 unique proteins, each identified by a minimum of two distinct peptides. The majority of the proteins (69%) were cytosolic, and 16% were membrane proteins. Important proteins involved in neurological and synaptic function were identified including several members of the Ras‐related protein family and proteins involved in glutamate biosynthesis.

Rate of perihaematomal oedema expansion is associated with poor clinical outcomes in intracerebral haemorrhage

Background Perihaematomal edema (PHE) expansion rate may be a predictor of outcome after intracerebral haemorrhage (ICH). We determined whether PHE expansion rate in the first 72 hours after ICH predicts outcome, and how it compares against other PHE measures. Methods We included patients from the Virtual International Stroke Trials Archive. We calculated PHE expansion rate using the equation: (PHE at 72 hours PHE at baseline)/(time to 72-hour CT scan time to baseline CT scan). Outcomes of interest were mortality and poor 90-day outcome (modified Rankin Scale score of ≥3). Logistic regression was used to assess relationships with outcome. Results A total of 596 patients with ICH were included. At baseline, median haematoma volume was 15.0 mL (IQR 7.9–29.2) with median PHE volume of 8.7 mL (IQR 4.5–15.5). Median PHE expansion rate was 0.31 mL/hour (IQR 0.12–0.55). The odds of mortality were greater with increasing PHE expansion rate (OR 2.63, CI 1.10 to 6.25), while the odds of poor outcome also increased with greater PHE growth (OR 1.67, CI 1.28 to 2.39). Female sex had an inverse relationship with PHE growth, but baseline haematoma volume had a direct correlation. Among other PHE measures, only interval increase in PHE correlated with poor outcome. There was no significant difference between the 2 measures of PHE volume expansion. Conclusions Rate of PHE growth over 72 hours was an independent predictor of mortality and poor functional outcomes following ICH. Baseline haematoma volume and gender appear to influence PHE growth.

Sur1–Trpm4-Promising Target for Brain Edema Treatment in Brain Edema: From Molecular Mechanisms to Clinical Practice

Brain edema after acute neurological injury causes significant morbidity and mortality. In this chapter, we highlight the critical role of the sulfonylurea receptor 1–transient receptor potential M4 (SUR1–TRPM4) channel in the pathogenesis of brain edema across various neurocritical care conditions. We emphasize that SUR1–TRPM4 activation is pivotal at every stage in edema formation. It contributes to every type of edema (cytotoxic, ionic, and vasogenic) and to total microvascular failure, which results in the extravasation of blood and the formation of petechial hemorrhages. We present examples from experimental models that demonstrate that selective blockade of SUR1–TRPM4 with glibenclamide results in improvement in edema, lesion volume, mortality, and neurological function. Clinical studies supporting the role of SUR1–TRPM4 in edema formation in humans are also presented. Although definitive phase III studies are needed, the ability to block SUR1–TRPM4 over a broad time window with a safe medication (glibenclamide) is emerging as a highly promising approach to treat brain edema.