Benjamin Zusman

Sulfonylurea Receptor-1: A Novel Biomarker for Cerebral Edema in Severe Traumatic Brain Injury

Objectives: Cerebral edema is a key poor prognosticator in traumatic brain injury. There are no biomarkers identifying patients at-risk, or guiding mechanistically-precise therapies. Sulfonylurea receptor-1–transient receptor potential cation channel M4 is upregulated only after brain injury, causing edema in animal studies. We hypothesized that sulfonylurea receptor-1 is measurable in human cerebrospinal fluid after severe traumatic brain injury and is an informative biomarker of edema and outcome. Design: A total of 119 cerebrospinal fluid samples were collected from 28 severe traumatic brain injury patients. Samples were retrieved at 12, 24, 48, 72 hours and before external ventricular drain removal. Fifteen control samples were obtained from patients with normal pressure hydrocephalus. Sulfonylurea receptor- 1 was quantified by enzyme-linked immunosorbent assay. Outcomes included CT edema, intracranial pressure measurements, therapies targeting edema, and 3-month Glasgow Outcome Scale score. Main Results: Sulfonylurea receptor-1 was present in all severe traumatic brain injury patients (mean = 3.54 ± 3.39 ng/mL, peak = 7.13 ± 6.09 ng/mL) but undetectable in all controls (p < 0.001). Mean and peak sulfonylurea receptor-1 was higher in patients with CT edema (4.96 ± 1.13 ng/mL vs 2.10 ± 0.34 ng/mL; p = 0.023). There was a temporal delay between peak sulfonylurea receptor-1 and peak intracranial pressure in 91.7% of patients with intracranial hypertension. There was no association between mean/peak sulfonylurea receptor-1 and mean/peak intracranial pressure, proportion of intracranial pressure greater than 20 mm Hg, use of edema-directed therapies, decompressive craniotomy, or 3-month Glasgow Outcome Scale. However, decreasing sulfonylurea receptor-1 trajectories between 48 and 72 hours were significantly associated with improved cerebral edema and clinical outcome. Area under the multivariate model receiver operating characteristic curve was 0.881. Conclusions: This is the first report quantifying human cerebrospinal fluid sulfonylurea receptor-1. Sulfonylurea receptor-1 was detected in severe traumatic brain injury, absent in controls, correlated with CT-edema and preceded peak intracranial pressure. Sulfonylurea receptor-1 trajectories between 48 and 72 hours were associated with outcome. Because a therapy inhibiting sulfonylurea receptor-1 is available, assessing cerebrospinal fluid sulfonylurea receptor-1 in larger studies is warranted to evaluate our exploratory findings regarding its diagnostic, and monitoring utility, as well as its potential to guide targeted therapies in traumatic brain injury and other diseases involving cerebral edema.

Regionally clustered ABCC8 polymorphisms in a prospective cohort predict cerebral oedema and outcome in severe traumatic brain injury

Objective ABCC8 encodes sulfonylurea receptor 1, a key regulatory protein of cerebral oedema in many neurological disorders including traumatic brain injury (TBI). Sulfonylurea-receptor-1 inhibition has been promising in ameliorating cerebral oedema in clinical trials. We evaluated whether ABCC8 tag single-nucleotide polymorphisms predicted oedema and outcome in TBI. Methods DNA was extracted from 485 prospectively enrolled patients with severe TBI. 410 were analysed after quality control. ABCC8 tag single-nucleotide polymorphisms (SNPs) were identified (Hapmap, r2>0.8, minor-allele frequency >0.20) and sequenced (iPlex-Gold, MassArray). Outcomes included radiographic oedema, intracranial pressure (ICP) and 3-month Glasgow Outcome Scale (GOS) score. Proxy SNPs, spatial modelling, amino acid topology and functional predictions were determined using established software programs. Results Wild-type rs7105832 and rs2237982 alleles and genotypes were associated with lower average ICP (β=−2.91, p=0.001; β=−2.28, p=0.003) and decreased radiographic oedema (OR 0.42, p=0.012; OR 0.52, p=0.017). Wild-type rs2237982 also increased favourable 3-month GOS (OR 2.45, p=0.006); this was partially mediated by oedema (p=0.03). Different polymorphisms predicted 3-month outcome: variant rs11024286 increased (OR 1.84, p=0.006) and wild-type rs4148622 decreased (OR 0.40, p=0.01) the odds of favourable outcome. Significant tag and concordant proxy SNPs regionally span introns/exons 2–15 of the 39-exon gene. Conclusions This study identifies four ABCC8 tag SNPs associated with cerebral oedema and/or outcome in TBI, tagging a region including 33 polymorphisms. In polymorphisms predictive of oedema, variant alleles/genotypes confer increased risk. Different variant polymorphisms were associated with favourable outcome, potentially suggesting distinct mechanisms. Significant polymorphisms spatially clustered flanking exons encoding the sulfonylurea receptor site and transmembrane domain 0/loop 0 (juxtaposing the channel pore/binding site). This, if validated, may help build a foundation for developing future strategies that may guide individualised care, treatment response, prognosis and patient selection for clinical trials.

Seizures After Intracerebral Hemorrhage: Incidence, Risk Factors, and Impact on Mortality and Morbidity

OBJECTIVE Spontaneous intracerebral hemorrhage (ICH) is one of the most frequent causes of epilepsy in the United States. However, reported risk factors for seizure after are inconsistent, and their impact on inpatient morbidity and mortality is unclear. We aimed to study the incidence, risk factors, and impact of seizures after ICH in a nationwide patient sample. METHODS We queried the Nationwide Inpatient Sample for patients admitted to the hospital with a primary diagnosis of ICH between the years 1999 and 2011. Patients were subsequently dichotomized into groups of those with a diagnosis consistent with seizure and those without. Multivariate logistic regression was used to assess risk factors for seizure in this patient sample, and the association between seizures and mortality and morbidity. Logistic regression was then used for trend analysis of incidence of seizure diagnoses over time. RESULTS We identified 220,075 patients admitted with a primary diagnosis of ICH. Of these, 11.87% had a diagnosis consistent with seizure. Factors associated with increased risk of seizure after ICH included higher categorical van Walraven score, encephalopathy, alcohol abuse, solid tumor, and prior stroke. Seizure was independently associated with decreased odds of morbidity (odds ratio [OR], 0.89; 95% confidence interval [CI], 0.86-0.92) and mortality (OR, 0.75; 95% CI, 0.72-0.77) in multivariate models controlling for existing comorbidities. CONCLUSIONS Seizures after were associated with decreased mortality and morbidity despite attempts to correct for existing comorbidities. Continuous monitoring of these patients for seizures may not be necessary in all circumstances, despite their frequency.