Shuhan He

Emerging experimental therapies for intracerebral hemorrhage: targeting mechanisms of secondary brain injury

Intracerebral hemorrhage (ICH) is associated with a higher degree of morbidity and mortality than other stroke subtypes. Despite this burden, currently approved treatments have demonstrated limited efficacy. To date, therapeutic strategies have principally targeted hematoma expansion and resultant mass effect. However, secondary mechanisms of brain injury are believed to be critical effectors of cell death and neurological outcome following ICH. This article reviews the pathophysiology of secondary brain injury relevant to ICH, examines pertinent experimental models, and highlights emerging therapeutic strategies. Treatment paradigms discussed include thrombin inhibitors, deferoxamine, minocycline, statins, granulocyte-colony stimulating factors, and therapeutic hypothermia. Despite promising experimental and preliminary human data, further studies are warranted prior to effective clinical translation.

Trends in Acute Ischemic Stroke Hospitalizations in the United States

Background Population‐based studies have revealed declining acute ischemic stroke (AIS) hospitalization rates in the United States, but no study has assessed recent temporal trends in race/ethnic‐, age‐, and sex‐specific AIS hospitalization rates. Methods and Results Temporal trends in hospitalization for AIS from 2000 to 2010 were assessed among adults ≥25 years using the Nationwide Inpatient Sample. Age‐, sex‐, and race/ethnic‐specific and age‐adjusted stroke hospitalization rates were calculated using the weighted number of hospitalizations and US census data. From 2000 to 2010, age‐adjusted stroke hospitalization rates decreased from 250 to 204 per 100 000 (overall rate reduction 18.4%). Age‐specific AIS hospitalization rates decreased for individuals aged 65 to 84 years (846 to 605 per 100 000) and ≥85 years (2077 to 1618 per 100 000), but increased for individuals aged 25 to 44 years (16 to 23 per 100 000) and 45 to 64 years (149 to 156 per 100 000). Blacks had the highest age‐adjusted yearly hospitalization rates, followed by Hispanics and whites (358, 170, and 155 per 100 000 in 2010). Age‐adjusted AIS hospitalization rates increased for blacks but decreased for Hispanics and whites. Age‐adjusted AIS hospitalization rates were lower in women and declined more steeply compared to men (272 to 212 per 100 000 in women versus 298 to 245 per 100 000 in men). Conclusions Although overall stroke hospitalizations declined in the United States, the reduction was more pronounced among older individuals, women, Hispanics, and whites. Renewed efforts at targeting risk factor control among vulnerable individuals may be warranted.

DNA Methylation in the Malignant Transformation of Meningiomas

Meningiomas are central nervous system tumors that originate from the meningeal coverings of the brain and spinal cord. Most meningiomas are pathologically benign or atypical, but 3–5% display malignant features. Despite previous studies on benign and atypical meningiomas, the key molecular pathways involved in malignant transformation remain to be determined, as does the extent of epigenetic alteration in malignant meningiomas. In this study, we explored the landscape of DNA methylation in ten benign, five atypical and four malignant meningiomas. Compared to the benign tumors, the atypical and malignant meningiomas demonstrate increased global DNA hypomethylation. Clustering analysis readily separates malignant from atypical and benign tumors, implicating that DNA methylation patterns may serve as diagnostic biomarkers for malignancy. Genes with hypermethylated CpG islands in malignant meningiomas (such as HOXA6 and HOXA9) tend to coincide with the binding sites of polycomb repressive complexes (PRC) in early developmental stages. Most genes with hypermethylated CpG islands at promoters are suppressed in malignant and benign meningiomas, suggesting the switching of gene silencing machinery from PRC binding to DNA methylation in malignant meningiomas. One exception is the MAL2 gene that is highly expressed in benign group and silenced in malignant group, representing de novo gene silencing induced by DNA methylation. In summary, our results suggest that malignant meningiomas have distinct DNA methylation patterns compared to their benign and atypical counterparts, and that the differentially methylated genes may serve as diagnostic biomarkers or candidate causal genes for malignant transformation.

Medical Management of Cerebral Vasospasm following Aneurysmal Subarachnoid Hemorrhage: A Review of Current and Emerging Therapeutic Interventions.

Cerebral vasospasm is a major source of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). Evidence suggests a multifactorial etiology and this concept remains supported by the assortment of therapeutic modalities under investigation. The authors provide an updated review of the literature for previous and recent clinical trials evaluating medical treatments in patients with cerebral vasospasm secondary to aSAH. Currently, the strongest evidence supports use of prophylactic oral nimodipine and initiation of triple-H therapy for patients in cerebral vasospasm. Other agents presented in this report include magnesium, statins, endothelin receptor antagonists, nitric oxide promoters, free radical scavengers, thromboxane inhibitors, thrombolysis, anti-inflammatory agents and neuroprotectants. Although promising data is beginning to emerge for several treatments, few prospective randomized clinical trials are presently available. Additionally, future investigational efforts will need to resolve discrepant definitions and outcome measures for cerebral vasospasm in order to permit adequate study comparisons. Until then, definitive recommendations cannot be made regarding the safety and efficacy for each of these therapeutic strategies and medical management practices will continue to be implemented in a wide-ranging manner.

Conservative management of ossification of the posterior longitudinal ligament. A review

OBJECT Ossification of the posterior longitudinal ligament (OPLL) can result in significant myelopathy. Surgical treatment for OPLL has been extensively documented in the literature, but less data exist on conservative management of this condition. METHODS The authors conducted a systematic review to identify all reported cases of OPLL that were conservatively managed without surgery. RESULTS The review yielded 11 published studies reporting on a total of 480 patients (range per study 1-359 patients) over a mean follow-up period of 14.6 years (range 0.4-26 years). Of these 480 patients, 348 (72.5%) were without myelopathy on initial presentation, whereas 76 patients (15.8%) had signs of myelopathy; in 56 cases (15.8%), the presence of myelopathy was not specified. The mean aggregate Japanese Orthopaedic Association score on presentation for 111 patients was 15.3. Data available for 330 patients who initially presented without myelopathy showed progression to myelopathy in 55 (16.7%), whereas the other 275 (83.3%) remained progression free. In the 76 patients presenting with myelopathy, 37 (48.7%) showed clinical progression, whereas 39 (51.5%) remained clinically unchanged or improved. CONCLUSIONS Patients who present without myelopathy have a high chance of remaining progression free. Those who already have signs of myelopathy at presentation may benefit from surgery due to a higher rate of progression over continued follow-up.

A review of epigenetic and gene expression alterations associated with intracranial meningiomas

OBJECT A more comprehensive understanding of the epigenetic abnormalities associated with meningioma tumorigenesis, growth, and invasion may provide useful targets for molecular classification and development of targeted therapies for meningiomas. METHODS The authors performed a review of the current literature to identify the epigenetic modifications associated with the formation and/or progression of meningiomas. RESULTS Several epigenomic alterations, mainly pertaining to DNA methylation, have been associated with meningiomas. Hypermethylation of TIMP3 inactivates its tumor suppression activity while CDKN2 (p14[ARF]) and TP73 gene hypermethylation and HIST1H1c upregulation interact with the p53 regulation of cell cycle control. Other factors such as HOX, IGF, WNK2, and TGF-β epigenetic modifications allow either upregulation or downregulation of critical pathways for meningioma development, progression, and recurrence. CONCLUSIONS Genome-wide methylation profiling demonstrated that global hypomethylation correlates with tumor grades and severity. Identification of additional epigenetic changes, such as histone modification and higher-order chromosomal structure, may allow for a more thorough understanding of tumorigenesis and enable future individualized treatment strategies for meningiomas.

Mechanical Thrombectomy in Acute Stroke: Utilization Variances and Impact of Procedural Volume on Inpatient Mortality

BACKGROUND An increasing number of endovascular mechanical thrombectomy procedures are being performed for the treatment of acute ischemic stroke. This study examines variances in the allocation of these procedures in the United States at the hospital level. We investigate operative volume across centers performing mechanical revascularization and establish that procedural volume is independently associated with inpatient mortality. METHODS Data was collected using the Nationwide Inpatient Sample database in the United States for 2008. Medical centers performing mechanical thrombectomy were identified using International Classification of Diseases, 9th revision codes, and procedural volumes were evaluated according to hospital size, location, control/ownership, geographic characteristics, and teaching status. Inpatient mortality was compared for hospitals performing ≥10 mechanical thrombectomy procedures versus those performing<10 procedures annually. After univariate analysis identified the factors that were significantly related to mortality, multivariable logistic regression was performed to compare mortality outcome by hospital procedure volume independent of covariates. RESULTS Significant allocation differences existed for mechanical thrombectomy procedures according to hospital size (P<.001), location (P<.0001), control/ownership (P<.0001), geography (P<.05), and teaching status (P<.0001). Substantial procedural volume was independently associated with decreased mortality (P=.0002; odds ratio 0.49) when adjusting for demographic covariates. CONCLUSIONS The number of mechanical thrombectomy procedures performed nationally remains relatively low, with a disproportionate distribution of neurointerventional centers in high-volume, urban teaching hospitals. Procedural volume is associated with mortality in facilities performing mechanical thrombectomy for acute ischemic stroke patients. These results suggest a potential benefit for treatment centralization to facilities with substantial operative volume.

Expansion of U.S. Emergency Medical Service Routing for Stroke Care: 2000–2010

Introduction Organized stroke systems of care include preferential emergency medical services (EMS) routing to deliver suspected stroke patients to designated hospitals. To characterize the growth and implementation of EMS routing of stroke nationwide, we describe the proportion of stroke hospitalizations in the United States (U.S.) occurring within regions having adopted these protocols. Methods We collected data on ischemic stroke using International Classification of Diseases-9 (ICD-9) coding from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample (NIS) database from the years 2000–2010. The NIS contains all discharge data from 1,051 hospitals located in 45 states, approximating a 20% stratified sample. We obtained data on EMS systems of care from a review of archives, reports, and interviews with state emergency medical services (EMS) officials. A county or state was considered to be in transition if the protocol was adopted in the calendar year, with establishment in the year following transition. Results Nationwide, stroke hospitalizations remained constant over the course of the study period: 583,000 in 2000 and 573,000 in 2010. From 2000–2003 there were no states or counties participating in the NIS with EMS systems of care. The proportion of U.S. stroke hospitalizations occurring in jurisdictions with established EMS regional systems of acute stroke care increased steadily from 2004 to 2010 (1%, 13%, 28%, 30%, 30%, 34%, 49%). In 2010, 278,538 stroke hospitalizations, 49% of all U.S. stroke hospitalizations, occurred in areas with established EMS routing, with an additional 18,979 (3%) patients in regions undergoing a transition to EMS routing. Conclusion In 2010, a majority of stroke patients in the U.S. were hospitalized in states with established or transitioning to organized stroke systems of care. This milestone coverage of half the U.S. population is a major advance in systematic stroke care and emphasizes the need for novel approaches to further extend access to stroke center care to all patients.

Stroke Damage Is Exacerbated by Nano-Size Particulate Matter in a Mouse Model

This study examines the effects of nano-size particulate matter (nPM) exposure in the setting of murine reperfused stroke. Particulate matter is a potent source of inflammation and oxidative stress. These processes are known to influence stroke progression through recruitment of marginally viable penumbral tissue into the ischemic core. nPM was collected in an urban area in central Los Angeles, impacted primarily by traffic emissions. Re-aerosolized nPM or filtered air was then administered to mice through whole body exposure chambers for forty-five cumulative hours. Exposed mice then underwent middle cerebral artery occlusion/ reperfusion. Following cerebral ischemia/ reperfusion, mice exposed to nPM exhibited significantly larger infarct volumes and less favorable neurological deficit scores when compared to mice exposed to filtered air. Mice exposed to nPM also demonstrated increases in markers of inflammation and oxidative stress in the region of the ischemic core. The findings suggest a detrimental effect of urban airborne particulate matter exposure in the setting of acute ischemic stroke.

White Matter Injury Due to Experimental Chronic Cerebral Hypoperfusion Is Associated with C5 Deposition

The C5 complement protein is a potent inflammatory mediator that has been implicated in the pathogenesis of both stroke and neurodegenerative disease. Microvascular failure is proposed as a potential mechanism of injury. Along these lines, this investigation examines the role of C5 in the setting of chronic cerebral hypoperfusion. Following experimental bilateral carotid artery stenosis, C5 protein deposition increases in the corpus callosum over thirty days (p<0.05). The time course is temporally consistent with the appearance of white matter injury. Concurrently, systemic serum C5 levels do not appear to differ between bilateral carotid artery stenosis and sham-operated mice, implicating a local cerebral process. Following bilateral carotid artery stenosis, C5 deficient mice demonstrate decreased white matter ischemia in the corpus callosum when compared to C5 sufficient controls (p<0.05). Further, the C5 deficient mice exhibit fewer reactive astrocytes and microglia (p<0.01). This study reveals that the C5 complement protein may play a critical role in mediating white matter injury through inflammation in the setting of chronic cerebral hypoperfusion.