BE-FAST: A Sensitive Screening Tool to Identify In-Hospital Acute Ischemic Stroke.

BACKGROUND: Development of acute ischemic stroke in hospitalized patients represents a significant proportion of all cerebral ischemia. Several prehospital stroke scales were developed to screen for acute ischemic stroke in the community. Despite the advent of inpatient stroke alert systems, there is a lack of validated screening tools for the inpatient population. This study aims to assess the validity of BE-FAST (Balance, Eyes, Face, Arm, Speech, Time) as a screening tool for acute ischemic stroke among inpatients. METHODS: We retrospectively analyzed all stroke alert activations at a single academic medical center between 2012 and 2016. We classified the triggering symptom as: focal neurologic deficit, aphasia, dysarthria, ataxia/vertigo/dizziness, alteration of consciousness, acute confusion, or headache. BE-FAST was applied retrospectively, and patients were classified as BE-FAST positive or negative. The final diagnosis was classified as acute ischemic stroke, transient ischemic attack , intracranial hemorrhage or noncerebrovascular diagnosis. RESULTS: Of 1965 stroke alerts, 489 were among inpatients. The mean age was 63 ± 16.1 years; 57% of patients were women (n = 1121). Acute ischemic stroke was diagnosed in 29% of all the activations (n = 567), transient ischemic attack in 12% (n = 232), intracranial hemorrhage in 8 % (n = 160) and noncerebrovascular in 51% (n = 1006). When comparing inpatient with community-onset stroke alerts, the sensitivity of BE-FAST for diagnosing acute ischemic stroke was 85% versus 94% (P = .005), with a specificity of 43% versus 23% (P < .001), respectively. However, when evaluating in-patients with an intact level of consciousness separately, BE-FAST sensitivity for diagnosing acute ischemic stroke was 92% compared to 94% in the community (P = .579). Among in-patients with acute ischemic stroke who were (1) candidates for reperfusion therapy and (2) diagnosed with acute large vessel occlusion, the sensitivity of BE-FAST was 83% and 94%, respectively. CONCLUSIONS: This is the first study to analyze the performance of BE-FAST among hospitalized patients evaluated through the inpatient stroke alert system. We found BE-FAST to be a very sensitive tool for screening for all in-hospital acute ischemic strokes, including inpatients that were candidates for acute reperfusion therapy.

Intracranial Hemorrhage in Hospitalized Patients: An Infrequently Studied Condition with High Mortality.

BACKGROUND: Intracranial hemorrhage (ICH) may occur in patients admitted to the hospital for unrelated medical conditions, resulting in prolonged hospitalization and worse prognosis. We aim to assess the clinical presentation and outcomes of in-hospital ICH compared to patients with ICH presenting from the community. METHODS: We conducted a retrospective analysis of all acute stroke alerts diagnosed with ICH in an urban academic hospital over a 4-year period. Demographics, clinical presentation, use of antithrombotic therapy, and presence of coagulopathy were recorded. ICH score and a sequential organ failure assessment score were calculated during the initial assessment. Initial head computed tomography was reviewed to determine ICH subtype, location, and volume of the hematoma. In-hospital mortality and discharge disposition were used as surrogate of clinical outcome. RESULTS: From the 1965 stroke alert cases analyzed over the studied years, 145 (7.4%) were diagnosed with ICH. Overall, the mean age was 62.9 ± 13.9 and 53.7% were women. Thirty-two patients (22%) developed ICH in the inpatient setting and 113 (78%) presented from the community. Systolic blood pressure at presentation was lower in the in-hospital group (p < 0.01). Inpatients who developed ICH were more likely than community ICH patients to be on combination of antiplatelet agents (21.9% vs. 5.3%, p < 0.05) or therapeutic heparinoids (21.9% vs. 0.9%, p < 0.01). Also, In-hospital ICH patients had a higher rate of spontaneous or iatrogenic coagulopathy (65.6% vs. 10.6%, p < 0.01) and thrombocytopenia (31.3% vs. 1.8%, p < 0.01). Lobar hemorrhages were more prevalent in the in-hospital group (82.6% vs. 39.1%, p < 0.01) and the mean hematoma volume was higher (40.9 ± 43.1 mL vs. 24.1 ± 30.4 mL; p < 0.02). Median ICH score in the in-hospital group was not statistically different from the emergency department group: 2 (IQR: 0-3) versus 1 (IQR: 0-3). When comparing patients with in-hospital ICH and those from the community, the short-term mortality was higher in the former group (81% vs. 31%, p < 0.01). The incidence of withdrawal of life-sustaining therapies as a proximate mechanism of death was higher, but not statistically significant, in the in-hospital group (86% vs. 61%). CONCLUSION: ICH is a critical complication in the inpatient setting, predominantly occurring in already ill patients with underlying spontaneous or iatrogenic coagulopathy. Large volume lobar intraparenchymal hemorrhage is a common radiographic finding. ICH is frequently a catastrophic event and powerfully weighs in with end-of-life discussion, resulting in high short-term mortality rate.

Mechanical Thrombectomy for Patients with In-Hospital Ischemic Stroke: A Case-Control Study.

BACKGROUND AND AIM: Patients with in-hospital acute ischemic stroke (AIS) have, in general, worse outcomes compared to those presenting from the community, partly attributed to the numerous contraindications to intravenous thrombolysis. We aimed to identify and analyze a group of patients with in-hospital AIS who remain suitable candidates for acute endovascular therapies. METHODS: A retrospective 6-year data analysis was conducted in patients evaluated through the in-hospital stroke alert protocol in a single tertiary care university hospital to identify those with in-hospital AIS due to acute intracranial large vessel occlusion (ILVO). Feasibility and safety of mechanical thrombectomy for in-hospital AIS was assessed in a case-control study comparing inpatients to those presenting from the community. RESULTS: From 1460 in-hospital stroke alert activations, 11% had a final diagnosis of AIS (n = 167). One hundred and two patients with in-hospital AIS had emergent intracranial vessel imaging and were included in our cohort. Acute ILVO was identified in 27 patients within this cohort. Patients were younger in the ILVO group and had more severe neurologic deficit on presentation. Compared to a matched (1:2) control group of patients presenting from the community, inpatients who underwent mechanical thrombectomy achieved equivalent technical success, safety, and clinical outcomes. CONCLUSIONS: The incidence of acute ILVO in patients with in-hospital AIS who underwent emergent vessel imaging is similar to the reported incidence of ILVO in patients presenting with community-onset AIS. Among patients with in-hospital AIS secondary to ILVO, mechanical thrombectomy is a feasible and safe therapy associated with favorable outcomes.

Clinical Characteristics and Emergent Therapeutic Interventions in Patients Evaluated through the In-hospital Stroke Alert Protocol.

BACKGROUND AND PURPOSE: Emergent evaluation of inpatients with suspected acute ischemic stroke faces difficulty of symptoms recognition, false alarms, and high rate of contraindications to reperfusion therapies. We aim to assess the clinical characteristics and therapeutic interventions implemented in patients evaluated though the in-hospital Stroke Alert Protocol. METHODS: We analyzed 4 years-worth of Stroke Alert cases at a university hospital. Demographics, clinical presentation, final diagnosis, and acute interventions were compared between inpatients and those presenting to the emergency department. FINDINGS: A total of 1965 Stroke Alert cases were included: 959 (48.8%) were acute cerebrovascular events and 1006 (51.2%) were noncerebrovascular. Hospitalized patients accounted for 489 (24.9%) of Stroke Alerts and patients in the emergency department for 1476 (75.1%). Inpatients were more likely to present with nonfocal neurological deficits (46.2% versus 32.4%, P < .0001) and be diagnosed with noncerebrovascular disorders (62.4% versus 47.5%, P < .0001). Acute interventions other than thrombolysis were delivered in 77.1% of in-hospital cases. Compared to the emergency department, inpatients were more commonly managed with rectification of metabolic abnormalities (21.5% versus 13.7%, P < .001), suspension or pharmacological reversal of drugs (11% versus 3.7%, P < .001), and initiation of respiratory support (13.5% versus 9.3%, P = .01). Inpatients with acute ischemic stroke received intravenous thrombolysis less frequently (4.9% versus 23.9%, P < .001), but the endovascular treatment rate was comparable (9.8% versus 10.3%) to the emergency department. CONCLUSION: Nonfocal neurological deficits and noncerebrovascular disorders are commonly encountered during in-hospital Stroke Alerts. In the inpatient setting, intravenous thrombolysis is rarely delivered while other time-sensitive therapeutic interventions are frequently implemented.

Somatosensory Evoked Potentials as a Tool to Evaluate Brainstem Herniation in the Neuroscience Intensive Care Unit.

Somatosensory evoked potentials (SSEPs) are a sensitive, minimally invasive technique used to localize dysfunction of myelinated peripheral and central axons in the nervous system. The utility of SSEPs in acutely assessing central nervous system function in brainstem herniation in the neuroscience intensive care unit (NICU) has not been well established. We discuss a case of an 18-year-old, postpartum female who presented with intermittent headache, diplopia, nausea/vomiting and cachexia following delivery two months prior. Shortly after arrival to the emergency department, she developed flaccid quadriparesis and complete ophthalmoplegia. Computed tomography (CT) of the head showed effacement of the basal cisterns along with 2 cm cerebellar tonsillar herniation into the foramen magnum concerning for intracranial hypotension. Raising the head of bed caused hemodynamic instability necessitating prolonged Trendelenburg positioning. The patient was evaluated with serial SSEPs which initially showed a bilateral low amplitude N20 response and normal N13 response. Subsequent SSEP testing showed increased N20 amplitude which correlated with clinical improvement in the patient. SSEP is a minimally invasive and sensitive method used to assess the integrity of the somatosensory nervous system pathway; SSEPs may be a useful monitoring adjunct to assess the evolution of posterior fossa lesions leading to brainstem compression.

Frequency of Inverted Electrocardiographic T Waves (Cerebral T Waves) in Patients With Acute Strokes and Their Relation to Left Ventricular Wall Motion Abnormalities.

Transient, symmetric, and deep inverted electrocardiogram (ECG) T waves in the setting of stroke, commonly referred to as cerebral T waves, are rare, and the underlying mechanism is unclear. Our study aimed to test the hypothesis that cerebral T waves are associated with transient cardiac dysfunction. This retrospective study included 800 patients admitted with the primary diagnosis of hemorrhagic or ischemic stroke. ECGs were examined for cerebral T waves, defined as T-wave inversion of ≥5 mm depth in ≥4 contiguous precordial leads. Echocardiograms of those meeting these criteria were examined for the presence of left ventricular (LV) wall motion abnormalities. Follow-up evaluation included both ECG and echocardiogram. Of the 800 patients, 17 had cerebral T waves on ECG (2.1%). All 17 patients had ischemic strokes, of which 11 were in the middle cerebral artery distribution (65%), and 2 were cerebellar (12%), whereas the remaining 4 involved other locations. Follow-up ECG showed resolution of the T-wave changes in all 17 patients. Of these patients, 14 (82%) had normal wall motion, and 3 had transient wall motion abnormalities (18%). Two of these patients had Takotsubo-like cardiomyopathy with apical ballooning, and the third had globally reduced LV function. Coronary angiography showed no significant disease to explain the LV dysfunction. In summary, in our cohort of patients with acute stroke, cerebral T waves were rare and occurred only in ischemic stroke. Eighteen percent of patients with cerebral T waves had significant transient wall motion abnormalities. Patients with stroke with cerebral T waves, especially in those with ischemic strokes, should be assessed for cardiac dysfunction.

The State of Neurocritical Care Fellowship Training and Attitudes toward Accreditation and Certification: A Survey of Neurocritical Care Fellowship Program Directors.

Neurocritical care as a recognized and distinct subspecialty of critical care has grown remarkably since its inception in the 1980s. As of 2016, there were 61 fellowship training programs accredited by the United Council for Neurologic Subspecialties (UCNS) in the United States and more than 1,000 UCNS-certified neurointensivists from diverse medical backgrounds. In late 2015, the Program Accreditation, Physician Certification, and Fellowship Training (PACT) Committee of the Neurocritical Care Society (NCS) was convened to promote and support excellence in the training and certification of neurointensivists. One of the first tasks of the committee was to survey neurocritical care fellowship training program directors to ascertain the current state of fellowship training and attitudes regarding transition to Accreditation Council for Graduate Medical Education (ACGME) accreditation of training programs and American Board of Medical Specialties (ABMS) certification of physicians. First, the survey revealed significant heterogeneities in the manner of neurocritical care training and a lack of consistency in requirements for fellow procedural competency. Second, although a majority of the 33 respondents indicated that a move toward ACGME accreditation/ABMS certification would facilitate further growth and mainstreaming of training in neurocritical care, many programs do not currently meet administrative requirements and do not receive the level of institutional support that would be needed for such a transition. In summary, the results revealed that there is an opportunity for future harmonization of training standards and that a transition to ACGME accreditation/ABMS certification is preferred. While the results reflect the opinions of more than half of the survey respondents, they represent only a small sample of neurointensivists.

Transgenic expression of HuR increases vasogenic edema and impedes functional recovery in rodent ischemic stroke.

BACKGROUND AND PURPOSE: Ischemic stroke produces significant morbidity and mortality, and acute interventions are limited by short therapeutic windows. Novel approaches to neuroprotection and neurorepair are necessary. HuR is an RNA-binding protein (RBP) which modulates RNA stability and translational efficiency of genes linked to ischemic stroke injury. METHODS: Using a transgenic (Tg) mouse model, we examined the impact of ectopic HuR expression in astrocytes on acute injury evolution after transient middle cerebral artery occlusion (tMCAO). RESULTS: HuR transgene expression was detected in astrocytes in perilesional regions and contralaterally. HuR Tg mice did not improve neurologically 72h after injury, whereas littermate controls did. In Tg mice, increased cerebral vascular permeability and edema were observed. Infarct volume was not affected by the presence of the transgene. CONCLUSIONS: Ectopic expression of HuR in astrocytes worsens outcome after transient ischemic stroke in mice in part by increasing vasogenic cerebral edema. These findings suggest that HuR could be a therapeutic target in cerebral ischemia/reperfusion.

Monitoring Pressure Augmentation in Patients With Ischemic Penumbra Using Continuous Electroencephalogram: Three Cases and a Review of the Literature.

BACKGROUND: Continuous electroencephalography (CEEG) is a sensitive, noninvasive surrogate monitor of cerebral blood flow (CBF). Changes in CBF can be seen as changes in the frequencies on the CEEG. This case series suggests that increase in CEEG frequencies may be used to detect improved CBF following pressure augmentation such as with treatment of vasospasm from subarachnoid hemorrhage (SAH) or acute thrombosis from ischemic stroke. The application of this observation to clinical decision-making has not been clearly defined and requires further study. METHODS: Case series and imaging. RESULTS: We present 3 patients with ischemic penumbras either from vasospasm from SAH or thrombosis from acute ischemic stroke. All patients were monitored on CEEG and found to have lateralized slowing. During pressure augmentation, the lateralized slowing improved in frequency, which corresponded with improvement in the patients' neurological examinations. CONCLUSION: Continuous electroencephalography may be used as a noninvasive monitor to allow for individualization of pressure augmentation in cases of vasospasm from SAH or in cases of acute ischemic strokes. This customized approach may allow for less morbidity associated with pressure augmentation in patients who otherwise may have dysfunction of their intracerebral autoregulation.

Hyperglycemia in acute ischemic stroke: Is it time to re-evaluate our understanding?

Among 700,000 new and recurrent ischemic stroke patients per year, forty percent are hyperglycemic on admission. In-vitro, hyperglycemia is toxic to neurons. Acute ischemic stroke patients who are hyperglycemic on admission experience higher morbidity and mortality. Results of multiple trials have provided no evidence supporting benefit in achieving normoglycemia. On the contrary, there is some evidence that tight glycemic control in acute brain injury is associated with poor outcome. Current consensus derived guidelines from the American Heart Association/American Stroke Association recommend an upper limit of blood glucose of 140-180mg/dl, as there is no evidence to support strict control. The lack of improved outcomes with normoglycemia in this population dictates reconsideration of assumptions regarding the underlying pathophysiology of hyperglycemia. Review of the current data suggests there are two distinct pathophysiologic entities of hyperglycemia in acute ischemic stroke patients: diabetic and non-diabetic. We propose that the lack of positive results from well-designed intention-to-treat trials in hyperglycemic acute ischemic stroke patients could be attributed to treating these distinct groups as one.

The Benefit of Neuromuscular Blockade in Patients with Postanoxic Myoclonus Otherwise Obscuring Continuous Electroencephalography (CEEG).

Introduction. Myoclonus status epilepticus is independently associated with poor outcome in coma patients after cardiac arrest. Determining if myoclonus is of cortical origin on continuous electroencephalography (CEEG) can be difficult secondary to the muscle artifact obscuring the underlying CEEG. The use of a neuromuscular blocker can be useful in these cases. Methods. Retrospective review of CEEG in patients with postanoxic myoclonus who received cisatracurium while being monitored. Results. Twelve patients (mean age: 53.3 years; 58.3% male) met inclusion criteria of clinical postanoxic myoclonus. The initial CEEG patterns immediately prior to neuromuscular blockade showed myoclonic artifact with continuous slowing (50%), burst suppression with myoclonic artifact (41.7%), and continuous myogenic artifact obscuring CEEG (8.3%). After intravenous administration of cisatracurium (0.1 mg-2 mg), reduction in artifact improved quality of CEEG recordings in 9/12 (75%), revealing previously unrecognized patterns: continuous EEG seizures (33.3%), lateralizing slowing (16.7%), burst suppression (16.7%), generalized periodic discharges (8.3%), and, in the patient who had an initially uninterpretable CEEG from myogenic artifact, continuous slowing. Conclusion. Short-acting neuromuscular blockade is useful in determining background cerebral activity on CEEG otherwise partially or completely obscured by muscle artifact in patients with postanoxic myoclonus. Fully understanding background cerebral activity is important in prognostication and treatment, particularly when there are underlying EEG seizures.

High-dose estrogen treatment at reperfusion reduces lesion volume and accelerates recovery of sensorimotor function after experimental ischemic stroke.

Estrogens have previously been shown to protect the brain against acute ischemic insults, by potentially augmenting cerebrovascular function after ischemic stroke. The current study hypothesized that treatment with sustained release of high-dose 17ß-estradiol (E2) at the time of reperfusion from middle cerebral artery occlusion (MCAO) in rats would attenuate reperfusion injury, augment post-stroke angiogenesis and cerebral blood flow, and attenuate lesion volume. Female Wistar rats underwent ovariectomy, followed two weeks later by transient, two-hour right MCAO (tMCAO) and treatment with E2 (n=13) or placebo (P; n=12) pellets starting at reperfusion. E2 treatment resulted in significantly smaller total lesion volume, smaller lesions within striatal and cortical brain regions, and less atrophy of the ipsilateral hemisphere after six weeks of recovery. E2-treated animals exhibited accelerated recovery of contralateral forelimb sensorimotor function in the cylinder test. Magnetic resonance imaging (MRI) showed that E2 treatment reduced the formation of lesion cysts, decreased lesion volume, and increased lesional cerebral blood flow (CBF). K(trans), a measure of vascular permeability, was increased in the lesions. This finding, which represents lesion neovascularization, was not altered by E2 treatment. Ischemic stroke-related angiogenesis and vessel formation was confirmed with immunolabeling of brain tissue and was not altered with E2 treatment. In summary, E2 treatment administered immediately following reperfusion significantly reduced lesion size, cyst formation, and brain atrophy while improving lesional CBF and accelerating recovery of functional deficits in a rat model of ischemic stroke.

Pupillometry in brain death: differences in pupillary diameter between paediatric and adult subjects.

OBJECTIVES: The determination of brain death in neonates, infants, children and adults relies on a clinical diagnosis based on the absence of neurological function with a known irreversible cause of brain injury. Evaluation of pupil size and non-reactivity is a requisite for determination of brain death. There are no studies in the literature that quantitatively assess pupil size in brain dead children and adults. METHODS: Infants, children and adults diagnosed with brain death were included in the study. Pupils were measured with a quantitative pupillometer (Forsite; Neuroptics, Irvine, CA, USA). Median, minimum and maximum pupil sizes were documented and the results were adjudicated for age, vasopressor use and temperature. RESULTS: Median right and left pupil sizes were 5.01 ± 0.85 mm and 5.12 ± 0.87 mm, respectively, with a range between 3.69 and 7.34 mm. Paediatric pupils were larger than adult pupils (right pupil 5.53 vs 4.73 mm p: 0.018; left pupil 5.87 vs 4.77 mm P: 0.03), and there was no correlation of pupil size with temperature or increasing number of vasopressors. CONCLUSION: This is the first study in the literature objectively evaluating pupil sizes in infants, children and adults diagnosed with brain death. We observed variation between observed pupil size and that expected based on brain death determination guidelines.

Macroglossia associated with brainstem injury.

BACKGROUND: Macroglossia has been reported in patients undergoing posterior fossa neurosurgical procedures and is thought to be as a result of venous engorgement from intubation or mechanical positioning during these prolonged procedures. METHODS: We report three patients who developed macroglossia and dysautonomia of central neurogenic origin following brainstem injury. RESULTS: The three patients developed macroglossia and dysautonomia with wide hemodynamic fluctuations in the setting of posterior fossa injury of the lower brainstem structures, necessitating tracheostomy placement. Macroglossia was managed with dexamethasone and there was complete resolution of dysautonomia while treated with beta-blockers and gabapentin. CONCLUSIONS: Neurointensivists should be aware of macroglossia with dysautonomia complicating brainstem injury, which may have perilous consequences in the setting of cerebral edema or intracranial hypertension.

Unusual case of bilateral caudate infarcts following pituitary apoplexy.

IMPORTANCE: Cerebral ischemia due to pituitary apoplexy is very rare. It may be caused by vasospasm or direct compression of cerebral vessels by the expanding mass. Bilateral caudate infarcts also are very rare. To our knowledge, this is the first case report that presents pituitary apoplexy causing compression of bilateral anterior cerebral artery branches and leading to bilateral caudate infarcts. OBSERVATIONS: An 81-year-old woman with a pituitary macroadenoma presented with circulatory shock due to pituitary apoplexy. Neurological examination revealed new asymmetric quadriparesis with chronic bilateral visual disturbance. On brain magnetic resonance imaging, she was found to have watershed infarcts in the anterior cerebral artery-middle cerebral artery and middle cerebral artery-posterior cerebral artery watershed zones in addition to bilateral caudate infarcts. CONCLUSIONS AND RELEVANCE: Pituitary apoplexy can cause compression of bilateral anterior cerebral arteries from the expanding mass and lead to bilateral caudate infarcts. It is important to understand the pathophysiology of cerebral ischemia in pituitary apoplexy to improve management.

Practice variability in brain death determination: a call to action.

OBJECTIVE: To characterize the present state of brain death (BD) determination in actual practice relative to contemporary American Academy of Neurology (AAN) guidelines. METHODS: We reviewed the charts of all adult (16 years and older) BD organ donors during 2011 from 68 heterogeneous hospitals in the Midwest United States. Data were collected across 5 categories: guideline performance, preclinical testing, clinical examination, apnea testing, and use of ancillary tests. Practice within categories and overall adherence to AAN guidelines were assessed. RESULTS: Two hundred twenty-six BD organ donors were included. Practice exceeded recommendations in guideline performance but varied widely and deviated from AAN guidelines in all other categories. One hundred two (45.1%) had complete documentation of brainstem areflexia and absent motor response. One hundred sixty-six (73.5%) had completed apnea testing. Of the 60 without completed apnea testing, 56 (93.3%) had ancillary tests consistent with BD. Overall, 101 (44.7%) strictly and 84 (37.2%) loosely adhered to contemporary AAN guidelines. CONCLUSIONS: There is wide variability in the documentation of BD determination, likely reflecting similar variability in practice. This is a call for improved documentation, better uniformity of policies, and comprehensive and strategically targeted educational initiatives to ensure consistently contemporary approaches to BD determination in every patient.

Stromal derived growth factor-1 (CXCL12) modulates synaptic transmission to immature neurons during post-ischemic cerebral repair.

In response to ischemic injury, the brain mounts a repair process involving the development of new neurons, oligodendrocytes, and astrocytes. However, the manner in which new neurons integrate into existing brain circuitry is not well understood. Here we observed that during the four weeks after transient middle cerebral artery occlusion (MCAO), doublecortin (DCX)-expressing neural progenitors originating in the subventricular zone (SVZ) were present in the ischemic lesion borderzone, where they received γ-aminobutyric acid (GABA) inputs, a feature that is common to newly developing neurons. The chemokine stromal derived factor-1 (SDF-1 or CXCL12) was enriched in lesional endothelial and microglial cells for up to four weeks after transient MCAO, and application of SDF-1 to acute brain slices enhanced GABAergic inputs to the new neurons. These observations suggest that SDF-1 is in a position to coordinate neovascularization and neurogenesis during the repair process after cerebral ischemia-reperfusion.

Estradiol modulates post-ischemic cerebral vascular remodeling and improves long-term functional outcome in a rat model of stroke.

We previously observed that 17ß-estradiol (E2) augments ischemic borderzone vascular density 10 days after focal cerebral ischemia-reperfusion in rats. We now evaluated the effect of E2 on vascular remodeling, lesional characteristics, and motor recovery up to 30 days after injury. Peri-lesional vascular density in tissue sections from rats treated with 0.72 mg E2 pellets was higher compared to 0.18 mg E2 pellets or placebo (P) pellets: vascular density index, 1.9 ± 0.2 (0.72 mg E2) vs. 1.4 ± 0.2 (0.18 mg E2) vs. 1.5 ± 0.4 (P), p=0.01. This was consistent with perfusion magnetic resonance imaging (MRI) measurements of lesional relative cerebral blood flow (rCBF): 1.89 ± 0.32 (0.72 mg E2) vs. 1.32 ± 0.19 (P), p=0.04. Post-ischemic angiogenesis occurred in P-treated as well as E2-treated rats. There was no treatment-related effect on lesional size, but lesional tissue was better preserved in E2-treated rats: cystic component as a % of total lesion, 30 ± 12 (0.72 mg E2) vs. 29 ± 17 (0.18 mg E2) vs. 61 ± 29 (P), p=0.008. Three weeks after right middle cerebral artery territory injury, rats treated with 0.72 mg E2 pellets used the left forelimb more than P-treated or 0.18 mg E2-treated rats: limb use asymmetry score, 0.09 ± 0.43 (0.72 mg E2) vs. 0.54 ± 0.12 (0.18 mg E2) vs. 0.54 ± 0.40 (P), p=0.05. We conclude that treatment with 0.72 mg E2 pellets beginning one week prior to ischemia/reperfusion and continuing through the one-month recovery period results in augmentation of lesional vascularity and perfusion, as well as improved motor recovery.

Sex hormone-dependent attenuation of EAE in a transgenic mouse with astrocytic expression of the RNA regulator HuR.

In experimental autoimmune encephalomyelitis (EAE) and other neurodegenerative diseases, astrocytes play an important role in promoting or attenuating the inflammatory response through induction of different cytokines and growth factors. HuR plays a major role in regulating many of these factors by modulating RNA stability and translational efficiency. Here, we engineered transgenic mice to express HuR in astrocytes using the human glial fibrillary acidic protein promoter and found that female transgenic mice had significantly less clinical disability and histopathological changes in the spinal cord. Ovariectomy prior to EAE induction abrogated the protective effect. Our findings support a role for the astrocyte and posttranscriptional regulation in hormonally-mediated attenuation of EAE.