Faculty Bibliography

BACKGROUND:Hematoma expansion (HE) after intracerebral hemorrhage (ICH) is associated with worse outcome. Lobar ICHs are known to have better outcomes compared to deep ICH; however, it is unclear whether there are HE differences between these locations. We sought to investigate the hypothesis that lobar ICH has less HE compared to deep ICH. METHODS:Primary ICH patients admitted between 2009 and 2016 were included in a prospective single-center ICH cohort study. Patients with preceding anticoagulant use, coagulopathy on admission labs, or presenting after 24 h from symptom onset were excluded. Lobar and deep ICH patients with baseline and follow-up computed tomography (CT) (within 24 h of admission CT) were evaluated. HE was defined primarily as relative growth > 33% given expected baseline hematoma volume differences between locations. Other commonly utilized definitions of HE: > 6 mL, and > 33% or > 6 mL, were additionally assessed. Multivariable logistic regression was used to assess the association of ICH location with HE while adjusting for previously identified covariates of HE. RESULTS:There were 59 lobar and 143 deep ICH patients analyzed. Lobar ICH patients had significantly larger baseline hematoma volumes, lower admission systolic blood pressure, and longer times to admission CT compared to deep ICH. Multivariable logistic regression revealed an association of lobar ICH with lower odds of HE (> 33%) [odds ratio (OR) 0.32; 95% confidence interval (CI) 0.11-0.93; p = 0.04] compared to deep ICH after adjusting for baseline ICH volume, blood pressure, and time to CT. Secondary analysis did not identify an association of lobar ICH with HE defined as > 6 mL (adjusted OR 1.44; 95% CI 0.59-3.50; p = 0.41) or > 33% or > 6 mL (adjusted OR 0.71; 95% CI 0.29-1.70; p = 0.44). CONCLUSION/CONCLUSIONS:We identified less HE in lobar compared to deep ICH. The use of absolute growth thresholds in defining HE may be limited when assessing groups with largely different baseline hematoma sizes. Further study is required to replicate our findings and investigate mechanisms for HE differences between lobar and deep ICH locations.

BACKGROUND:Delirium is a frequent complication of critical illness, but its diagnosis is more difficult in brain-injured patients due to language impairment and disorders of consciousness. We conducted a prospective cohort study to determine whether Richmond Agitation and Sedation Scale (RASS) scores could be used to reliably diagnose delirium in the setting of brain injury. We also examined clinical factors associated with delirium in patients with subdural hematomas (SDH) and assessed its impact on functional outcome at discharge. METHODS:We prospectively enrolled 55 patients with the primary diagnosis of SDH admitted to the neurological intensive care unit (ICU) and screened them for delirium with the Confusion Assessment Method-ICU (CAM-ICU). As our primary outcome, we examined whether the standard deviation of RASS scores (RASS dispersion) could be used to diagnose delirium. We also looked at trends in RASS scores as a way to distinguish different causes of delirium. Then, using logistic regression, we identified factors associated with delirium in patients with SDH and quantified the impact of delirium on the modified Rankin Scale at discharge. RESULTS:Delirium as defined by the CAM-ICU was present in 35% (N = 19) of patients. RASS dispersion correlated well with the CAM-ICU (AUC of the ROC was 0.84). Analyzing the temporal trend of changes in the RASS was helpful in identifying new brain injuries as the underlying etiology of CAM-ICU positivity. Age, APACHE II scores on admission, baseline functional impairment, midline shift on initial imaging, and infections were associated with an increased risk of delirium. Delirium was associated with a worse functional outcome. CONCLUSIONS:RASS dispersion correlates highly with CAM-ICU positivity, and monitoring trends in RASS scores can identify delirium caused by new brain injuries. Delirium as defined by the CAM-ICU is common in patients with SDH and portends worse outcomes.

OBJECTIVE:To test the hypothesis that in patients with spontaneous intracerebral hemorrhage (ICH), perihemorrhagic edema to hematoma ratio (rPHE) on admission CT scan (aCT) is unaffected by home statin use when time from symptom onset to aCT is controlled for. METHODS:In a single-center prospective cohort of 176 consecutive ICH patients, 2 investigators independently determined hematoma and perihemorrhagic edema (PHE) volumes by using semiautomated validated software. rPHE were dichotomized at the median ratio (>0.75 vs ≤0.75). We used binary logistic regression to test for associations with rPHE. RESULTS:= 0.68) associated with rPHE. CONCLUSION/CONCLUSIONS:Use of statins before hospital admission for ICH is not associated with reduced rPHE on admission CT. In future studies, imaging timing relative to ICH onset needs to be controlled for in order to avoid confounding.

Cerebral venous sinus thrombosis (CVST) requires anticoagulation to promote vessel recanalization. Current anticoagulation paradigms utilize plasma tests from peripheral venous/arterial samples for therapeutic monitoring. We describe a medically-refractory case of CVST in a 35-year-old woman later found to have JAK2 mutation and essential thrombocytosis. Despite therapeutic anticoagulation levels, worsening cerebral edema and progression to coma prompted endovascular treatment. Failed endovascular thrombectomy attempts led to placement of 2 separate indwelling microcatheters for continuous infusion of tissue plasminogen activator (tPA). Forty-hours of continuous-tPA in addition to systemic intravenous-heparin led to complete radiographic and clinical resolution of CVST. Whole blood coagulation testing using Rotational Thromboelastometry (ROTEM) from simultaneous samples taken intracranially (via cerebral microcatheters) and peripherally (via antecubital vein) all revealed prolonged intrinsic pathway activation clotting times consistent with heparin anticoagulation use. However, both intracranial ROTEM samples identified faster clotting times compared to the peripheral sample suggesting lower anticoagulation levels intracranially. Our findings were speculative and hypothesis generating as to whether this explained medical treatment failure. If there are coagulopathy differences at local sites of injury not adequately captured by peripheral blood draws, further investigation is required to identify better approaches to avoid under-treatment of similar cases.

Therapeutic hypothermia (TH) is a potent neuroprotectant for experimental ischemic stroke, but studies of TH for intracerebral hemorrhage (ICH) are emerging. We systematically reviewed the experimental literature to assess TH efficacy for ICH. We found 18 suitable papers; quality scores were moderately good. Compared with normothermia, TH reduced measures of edema (mean effect size (95% CI) -1.6873 (-2.3640, -1.0106), p < 0.0001) or blood-brain barrier leakage (p < 0.0001) and improved behavioral outcomes (p < 0.0001). There was no evidence of publication bias. In this meta-analysis of available preclinical studies of ICH, TH is potently effective for reducing perihematomal edema and for improving behavioral outcomes.

BACKGROUND:Non-vitamin K antagonist oral anticoagulant (NOAC) use has significantly reduced intracerebral hemorrhagic (ICH) risk compared with standard anticoagulant treatment. Hematoma expansion (HE) is a known predictor of mortality in warfarin-associated ICH. Little is known about HE in patients using NOACs. METHODS:We conducted a retrospective chart review of patients with ICH admitted to Cedars-Sinai Medical Center from October 2010 to June 2016. We identified patients with concomitant administration of an oral anticoagulant and collected data including evidence of HE on imaging and modified Rankin Scale (mRS) at discharge. We defined HE as relative (≥33% increase) or absolute expansion (≥12 mL). We compared outcomes of patients with and without HE. RESULTS:Out of 814 patients with ICH who were admitted, we identified 9 patients with recent NOAC use and 18 intentionally matched controls on warfarin. We found no significant differences in National Institutes of Health Stroke Scale or ICH score on presentation (median [interquartile range] 15 [5,21] versus 7 [1.25,19.5] [P = .41] and 2 [1,4] versus 1 [1,3] [P = .33]) between patients on NOACs and those on warfarin. Four out of the 9 patients on NOAC and 5 of the 18 patients on warfarin demonstrated HE, with no significant difference (P = .42). There were no significant differences in mRS on discharge between groups (P = .52). CONCLUSIONS:In our coagulopathic NOAC patient population, HE occurs within 6 hours in 44% of patients. This case series did not have sufficient statistical power to detect significant differences between the groups. To our knowledge, this is one of the largest case series reporting on HE with concomitant NOAC use.

OBJECTIVE:To determine a neuro-anatomic cause for central neuropathic pain (CNP) observed in multiple sclerosis (MS) patients. METHODS:Parallel clinical and neuro-anatomical studies were performed. A clinical investigation of consecutively acquired MS patients with and without CNP (i.e. cold allodynia or deep hyperesthesia) within a single MS center was pursued. A multivariate logistic regression model was used to assess the relationship between an upper central thoracic spinal cord focus to central pain complaints. To identify the hypothesized autonomic interneurons with bilateral descending projections to lumbosacral sensory neurons, retrograde single- and double-labeling experiments with CTb and fluorescent tracers were performed in three animal species (i.e. rat, cat, and monkey). RESULTS:Clinical data were available in MS patients with (n = 32; F:23; median age: 34.6 years (interquartile range [IQR]: 27.4-45.5)) and without (n = 30; F:22; median age: 36.6 years [IQR: 31.6-47.1]) CNP. The value of a central focus between T1-T6 in relation to CNP demonstrated a sensitivity of 96.9% (95% confidence interval [CI]: 83.8-99.9) and specificity of 83.3% (95% CI: 65.3-94.4). A significant relationship between CNP and a centrally located focus within the thoracic spine was also observed (odds ratio [OR]: 155.0 [95% CI lower limit: 16.0]; P < 0.0001, two-tailed Fisher exact test). In all animal models, neurons with bilateral descending projections to the lumbosacral superficial dorsal horn were concentrated in the autonomic intermediomedial nucleus surrounding the mid-thoracic central canal. INTERPRETATION/CONCLUSIONS:Our observations provide the first evidence for the etiology of CNP. These data may assist with the development of refined symptomatic therapies and allow for insights into unique pain syndromes observed in other demyelinating subtypes.

We recently observed a reliable phenotypic difference in the inflammatory pain sensitivity of a congenic mouse strain compared to its background strain. By constructing and testing subcongenic strains combined with gene-expression assays, we provide evidence for the candidacy of the Yy1 gene - encoding the ubiquitously expressed and multifunctional Yin Yang 1 transcription factor - as responsible. To confirm this hypothesis, we used a Cre/lox strategy to produce mutant mice in which Yy1 expression was ablated in Nav 1.8-positive neurons of the dorsal root ganglion. These mutants also displayed reduced inflammatory pain sensitivity on the formalin test. Further testing of pain-related phenotypes in these mutants revealed robustly increased sensitivity to systemic and spinal (but not supraspinal) morphine analgesia, and greatly increased endogenous (swim stress-induced) opioid analgesia. None of the known biological roles of Yin Yang 1 were suggestive of such a phenotype, and thus a novel player in pain modulatory systems has been identified.