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 Starling's 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.

Objective Intracerebral hemorrhage (ICH) is a devastating disorder with no current treatment. Whether peri-hematomal edema (PHE) is an independent predictor of neurologic outcome is controversial. We sought to determine whether PHE expansion rate predicts outcome after ICH. Design Retrospective cohort study Setting Tertiary medical center Patients 139 consecutive supratentorial spontaneous ICH patients >18 years admitted between 2000–2013. Interventions None Measurements and Main Results ICH, intraventricular hemorrhage (IVH), and PHE volumes were measured from computed tomography (CT) scans obtained at presentation, 24 hours, and 72 hours post-ICH. PHE expansion rate was the difference between initial and follow-up PHE volumes divided by the time interval. Logistic regression was performed to evaluate the relationship between 1) PHE expansion rate at 24 hours and 90-day mortality and 2) PHE expansion rate at 24 hours and 90-day modified Rankin Scale score (mRS). PHE expansion rate between admission and 24-hours post-ICH was a significant predictor of 90-day mortality (OR 2.97, 95%CI 1.48–5.99, p=0.002). This association persisted after adjusting for all components of the ICH score (OR 2.21, 95% CI 1.05–4.64, p=0.04). Similarly, higher 24-hour PHE expansion rate was associated with poorer mRS in an ordinal shift analysis (OR 2.40, 95% CI 1.37–4.21, p=.002), even after adjustment for all ICH score components (OR 2.07, 95% CI 1.12–3.83, p=0.02). Conclusions Faster PHE expansion rate 24 hours post-ICH is associated with worse outcome. PHE may represent an attractive translational target for secondary injury after ICH.

Background Perihaematomal oedema (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 computerized tomography scan – Time to baseline computerized tomography 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/hr (IQR: 0.12–0.55). The odds of mortality were greater with increasing PHE expansion rate (OR: 2.63, CI: 1.10–6.25), while the odds of poor outcome also increased with greater PHE growth (OR: 1.67, CI: 1.28–2.39). Female sex had an inverse relationship with PHE growth, but baseline hematoma 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 two measures of PHE volume expansion. Conclusions Rate of PHE growth over 72 hours was an independent predictor of mortality and poor functional outcomes following intracerebral haemorrhage. Baseline haematoma volume and gender appear to influence PHE growth.

Background and Purpose Peri-hematomal 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 twenty primary supratentorial ICH subjects. Boundaries were outlined with an edge-detection tool and adjusted after inspection of the three 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 (ICCs) and Bland-Altman plots for interrater consistency. CT-based PHE was also compared using MRI-based PHE detection for eighteen 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 ICCs were 0.98 (0.96–1.00) and 0.98 (0.97–1.00); intrarater ICCs 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 MRI were similar (23.9 ± 16.9 cc vs. 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.

Background and Purpose Perihematomal edema (PHE) expansion rate may predict functional outcome following spontaneous intracerebral hemorrhage (ICH). We hypothesized that the effect of PHE expansion rate on outcome is greater for deep versus lobar ICH. Methods Subjects (n=115) were retrospectively identified from a prospective ICH cohort enrolled from 2000–2013. Inclusion criteria were age ≥18 years, spontaneous supratentorial ICH, and known onset time. Exclusion criteria were primary intraventricular hemorrhage (IVH), trauma, subsequent surgery, or warfarin-related ICH. ICH and PHE volumes were measured from CT scans and used to calculate expansion rates. Logistic regression assessed the association between PHE expansion rates and 90-day mortality or poor functional outcome (modified Rankin Scale >2). Odds ratios are per 0.04 mL/h. Results PHE expansion rate from baseline to 24 hours (PHE24) was associated with mortality for deep (p=0.03, OR 1.13[1.02–1.26]) and lobar ICH (p=0.02, OR 1.03[1.00–1.06]) in unadjusted regression, and in models adjusted for age (deep: p=0.02, OR 1.15[1.02–1.28]; lobar: p=0.03, OR 1.03[1.00–1.06]), Glasgow Coma Scale (deep: p=0.03, OR 1.13[1.01–1.27]; lobar: p=0.02, OR 1.03[1.01–1.06]), or time to baseline CT (deep: p=0.046, OR 1.12[1.00–1.25]; lobar: p=0.047, OR 1.03[1.00–1.06]). PHE expansion rate from baseline to 72 hours (PHE72) was associated with mRS>2 for deep ICH in models that were unadjusted (p=0.02, OR 4.04[1.25–13.04]) or adjusted for ICH volume (p=0.02, OR 4.3[1.25–14.98]), age (p=0.03, OR 5.4[1.21–24.11]), GCS (p=0.02, OR 4.19[1.2–14.55]), or time to first CT (p=0.03, OR 4.02[1.19–13.56]). Conclusions PHE72 was associated with poor functional outcomes after deep ICH, whereas PHE24 was associated with mortality for deep and lobar ICH.

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.

Background and Purpose: For survivors of oral anticoagulation therapy (OAT)–associated intracerebral hemorrhage (OAT-ICH) who are at high risk for thromboembolism, the benefits of OAT resumption must be weighed against increased risk of recurrent hemorrhagic stroke. The ε2/ε4 alleles of the apolipoprotein E ( APOE ) gene, MRI-defined cortical superficial siderosis, and cerebral microbleeds are the most potent risk factors for recurrent ICH. We sought to determine whether combining MRI markers and APOE genotype could have clinical impact by identifying ICH survivors in whom the risks of OAT resumption are highest. Methods: Joint analysis of data from 2 longitudinal cohort studies of OAT-ICH survivors: (1) MGH-ICH study (Massachusetts General Hospital ICH) and (2) longitudinal component of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage). We evaluated whether MRI markers and APOE genotype predict ICH recurrence. We then developed and validated a combined APOE -MRI classification scheme to predict ICH recurrence, using Classification and Regression Tree analysis. Results: Cortical superficial siderosis, cerebral microbleed, and APOE ε2/ε4 variants were independently associated with ICH recurrence after OAT-ICH (all P <0.05). Combining APOE genotype and MRI data resulted in improved prediction of ICH recurrence (Harrell C: 0.79 versus 0.55 for clinical data alone, P =0.033). In the MGH (training) data set, CSS, cerebral microbleed, and APOE ε2/ε4 stratified likelihood of ICH recurrence into high-, medium-, and low-risk categories. In the ERICH (validation) data set, yearly ICH recurrence rates for high-, medium-, and low-risk individuals were 6.6%, 2.5%, and 0.9%, respectively, with overall area under the curve of 0.91 for prediction of recurrent ICH. Conclusions: Combining MRI and APOE genotype stratifies likelihood of ICH recurrence into high, medium, and low risk. If confirmed in prospective studies, this combined APOE -MRI classification scheme may prove useful for selecting individuals for OAT resumption after ICH.

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-MS(E) 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.