Hemispheric Swelling Research Articles

The Formation of Microthrombi in Parenchymal Microvessels after Traumatic Brain Injury Is Independent of Coagulation Factor XI

Microthrombus formation and bleeding worsen the outcome after traumatic brain injury (TBI). The aim of the current study was to characterize these processes in the brain parenchyma after experimental TBI and to determine the involvement of coagulation factor XI (FXI). C57BL/6 mice (n = 101) and FXI-deficient mice (n = 15) were subjected to controlled cortical impact (CCI). Wild-type mice received an inhibitory antibody against FXI (14E11) or control immunoglobulin G 24 h before or 30 or 120 min after CCI. Cerebral microcirculation was visualized in vivo by 2-photon microscopy 2-3 h post-trauma and histopathological outcome was assessed after 24 h. TBI induced hemorrhage and microthrombus formation in the brain parenchyma (p < 0.001). Inhibition of FXI activation or FXI deficiency did not reduce cerebral thrombogenesis, lesion volume, or hemispheric swelling. However, it also did not increase intracranial hemorrhage. Formation of microthrombosis in the brain parenchyma after TBI is independent of the intrinsic coagulation cascade since it was not reduced by inhibition of FXI. However, since targeting FXI has well-established antithrombotic effects in humans and experimental animals, inhibition of FXI could represent a reasonable strategy for the prevention of deep venous thrombosis in immobilized patients with TBI.

Acute Hyperglycemia Does Not Affect Brain Swelling or Infarction Volume After Middle Cerebral Artery Occlusion in Rats.

Stroke disproportionally affects diabetic and hyperglycemic patients with increased incidence and is associated with higher morbidity and mortality due to brain swelling. In this study, the intraluminal suture middle cerebral artery occlusion (MCAO) model was used to examine the effects of blood glucose on brain swelling and infarct volume in acutely hyperglycemic rats and normo-glycemic controls. Fifty-four rats were distributed into normo-glycemic sham surgery, hyperglycemic sham surgery, normo-glycemic MCAO, and hyperglycemic MCAO. To induce hyperglycemia, 15 min before MCAO surgery, animals were injected with 50 % dextrose. Animals were subjected to 90 min of MCAO and sacrificed 24 h after reperfusion for hemispheric brain swelling and infarct volume calculations using standard equations. While normo-glycemic and hyperglycemic animals after MCAO presented with significantly higher brain swelling and larger infarcts than their respective controls, no statistical difference was observed for either brain swelling or infarct volume between normo-glycemic shams and hyperglycemic shams or normo-glycemic MCAO animals and hyperglycemic MCAO animals. The findings of this study suggest that blood glucose does not have any significant effect on hemispheric brain swelling or infarct volume after MCAO in rats.

Effect of Gender on Iron-induced Brain Injury in Low Aerobic Capacity Rats.

Brain iron overload has a key role in brain injury after intracerebral hemorrhage (ICH). Low aerobic capacity is a risk factor for cardiovascular disease and our previous study demonstrated that ICH-induced brain injury is enhanced in rats with low aerobic capacity (low capacity runners; LCRs). We have found that ICH-induced injury is less in female rats compared with that in males. In the present study, we examined the effects of gender on iron-induced brain injury in rats with low aerobic capacity. Adult male and female LCR rats had an intracaudate injection of FeCl2 (50 μl 0.5 mM). T2 Magnetic resonance imaging was carried out at 24 h to determine brain swelling and T2 brain lesion volume. Albumin leakage, an indicator of blood-brain barrier (BBB) disruption, and heme oxygenase-1 (HO-1, a stress marker) levels were determined. Male LCR rats had more severe hemisphere swelling (difference of ipsilateral to contralateral hemisphere volume: 16.6 ± 4.1 vs 11.1 ± 2.6 % in females, p < 0.05) and larger T2 lesion volumes (120 ± 28 vs 87 ± 27 mm(3) in females, p < 0.05) after iron injection. Iron also resulted in more severe BBB disruption in the ipsilateral hemisphere of males (albumin levels: 7,717 ± 1,502 pixels in males vs 5,287 ± 1,342 pixels in females; p < 0.05). The immunoreactivity of HO-1 was also significantly higher in males than females (HO-1/β-actin: 1.31 ± 0.44 vs 1.03 ± 0.05, p < 0.05). Female LCR rats had less iron-induced brain swelling, smaller lesion volumes, and reduced BBB disruption and HO-1 upregulation compared with male LCR rats. This may contribute to the reduced ICH-induced brain injury found in females.

Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke.

There have been recurring translational failures in treatment strategies for stroke. One underlying issue is the disparity in outcome analysis between animal and clinical studies. The former mainly depends on acute infarct size, whereas long-term functional recovery is an important outcome in patients. In an attempt to identify agents that promote functional recovery, we discovered that an FDA-approved soy isoflavone, daidzein, improved stroke-induced behavioral deficits via enhancing cholesterol homeostasis in chronic stroke, and this occurs without causing adverse effects in the acute phase. With its known safety in humans, the study suggests that the early and chronic use of daidzein serves as a potential strategy to promote functional recovery in stroke patients.

Management of Hemispheric Infarction and Ischemic Swelling.

This article provides an overview of large territory hemispheric infarction, with an emphasis on recent developments and practical issues related to its evaluation, diagnosis, monitoring, and treatment. Swelling after large infarction results in severe morbidity and often death. Early vigilance for the development of swelling is critical to optimize patient outcome. Comprehensive management is highly dependent on a strong multidisciplinary, collaborative approach. Several advances in the last decade have led to an increasingly standardized approach to the patient with significant brain swelling after stroke. In particular, early identification of patients with large stroke at high risk for deterioration, and decompressive craniectomy as an important treatment option, are two significant advances. Effective management of hemispheric ischemic stroke and swelling requires a team skilled in the neurologic examination of critically ill patients and a broad understanding of the natural history of brain swelling after stroke.

Analysis of Long-Term Prognosis and Prognostic Predictors in Severe Brain Injury Patients Undergoing Decompressive Craniectomy and Standard Care.

Decompressive craniectomy (DC) is widely used to treat acute subdural haematoma and hemispheric swelling following traumatic brain injury (TBI). The therapeutic effect of DC on severe TBI treatment is still controversial. The aim of our study was to evaluate effectiveness of DC treatment and seek some prognostic predictors. According to the therapy method, we divided the patients into 2 groups: DC group and standard care group. Between 2010 and 2014, a total number of 223 severe TBI patients, containing 112 patients undergoing DC and 111 patients undergoing standard care, were enrolled into the study according to Glasgow Coma Scale (GCS). The long-term prognosis was evaluated by Extended Glasgow Outcome Scale 12 months after discharging from hospital. We used univariate analysis and receiver operating characteristic curves to explore prognostic predictors. The results showed that patients in the DC group had a lower mortality, but there was no statistical significance in long-term prognosis between these 2 groups. It seemed that admission GCS, platelet, neutrophile granulocyte, total protein, and albumin were associated with long-term prognosis in DC group and reactivity of pupils in standard care group. Simultaneously, using the multivariable logistic regression model, we confirmed that admission GCS and albumin were independent prognostic predictors for patients undergoing DC, and reactivity of pupils for those undergoing standard care. Our data suggested that DC was an effective therapy for severe TBI patients in reducing mortality, but it failed to improve long-term prognosis. Through our study, we could comprehend the characteristics of the 2 treatments and provide more scientific individuation therapy for severe TBI patients.

Technique of Stepwise Intracranial Decompression Combined with External Ventricular Drainage Catheters Improves the Prognosis of Acute Post-Traumatic Cerebral Hemispheric Brain Swelling Patients.

Acute post-traumatic cerebral hemispheric brain swelling (ACHS) is a serious disorder that occurs after traumatic brain injury, and it often requires immediate treatment. The aim of our clinical study was to assess the effects of stepwise intracranial decompression combined with external ventricular drainage (EVD) catheters on the prognosis of ACHS patients. A retrospective study was performed on 172 cases of severe craniocerebral trauma patients with ACHS. The patients were divided into two groups: unilateral stepwise standard large trauma craniectomy (S-SLTC) combined with EVD catheter implants (n = 86) and unilateral routine frontal temporal parietal SLTC (control group, n = 86). No significant differences in age, sex, or pre-operative Glasgow Coma Scale score were observed between groups (P < 0.05). There were no significant differences in the ipsilateral subdural effusion incidence rates between the S-SLTC + EVD treatment group and the routine SLTC group. However, the incidence rates of intraoperative acute encephalocele and contralateral epidural and subdural hematoma in the S-SLTC + EVD group were significantly lower than those in the SLTC group (17.4 and 3.5 vs. 37.2 and 23.3%, respectively). The mean intracranial pressure (ICP) values of patients in the S-SLTC + EVD group were also lower than those in the SLTC group at days 1 through 7 (P < 0.05). A positive neurological outcome [Glasgow Outcome Scale (GOS) score 4-5, 50.0%] and decreased mortality (15.1%) was observed in the S-SLTC + EVD group compared to the neurological outcome (GOS score 4-5, 33.8%; 36.0%) in the SLTC group (P < 0.05). Our data suggest that S-SLTC + EVD is more effective for controlling ICP, improving neurological outcome, and decreasing mortality rate compared with routine SLTC.

Bryostatin extends tPA time window to 6 h following middle cerebral artery occlusion in aged female rats

Blood–brain barrier (BBB) disruption and hemorrhagic transformation (HT) following ischemic/reperfusion injury contributes to post-stroke morbidity and mortality. Bryostatin, a potent protein kinase C (PKC) modulator, has shown promise in treating neurological injury. In the present study, we tested the hypothesis that administration of bryostatin would reduce BBB disruption and HT following acute ischemic stroke; thus, prolonging the time window for administering recombinant tissue plasminogen activator (r-tPA). Acute cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery (MCAO) in 18–20-month-old female rats using an autologous blood clot with delayed r-tPA reperfusion. Bryostatin (or vehicle) was administered at 2h post-MCAO and r-tPA was administered at 6h post-MCAO. Functional assessment, lesion volume, and hemispheric swelling measurements were performed at 24h post-MCAO. Assessment of BBB permeability, measurement of hemoglobin, assessment of matrix metalloproteinase (MMP) levels by gel zymography, and measurement of PKCε, PKCα, PKCδ expression by western blot were conducted at 24h post-MCAO. Rats treated with bryostatin prior to r-tPA administration had decreased mortality and hemispheric swelling when compared with rats treated with r-tPA alone. Administration of bryostatin also limited BBB disruption and HT and down-regulated MMP-9 expression while up-regulating PKCε expression at 24h post-MCAO. Bryostatin administration ameliorates BBB disruption and reduces the risk of HT by down-regulating MMP-9 activation and up-regulating PKCε. In this proof-of-concept study, bryostatin treatment lengthened the time-to-treatment window and enhanced the efficacy and safety of thrombolytic therapy.

Iron-induced necrotic brain cell death in rats with different aerobic capacity.

Brain iron overload has a key role in brain injury after intracerebral hemorrhage (ICH). Our recent study demonstrated that ICH-induced brain injury was greater in low capacity runner (LCR) than in high capacity runner (HCR) rats. The present study examines whether iron-induced brain injury differs between LCRs and HCRs. Adult male LCR and HCR rats had an intracaudate injection of iron or saline. Rats were euthanized at 2 and at 24 h after T2 magnetic resonance imaging, and the brains were used for immunostaining and Western blotting. LCRs had more hemispheric swelling, T2 lesion volumes, blood-brain barrier disruption, and neuronal death at 24 h after iron injection (p < 0.05). Many propidium iodide (PI)-positive cells, indicative of necrotic cell death, were observed in the ipsilateral basal ganglia of both HCRs and LCRs at 2 h after iron injection. PI fluorescence intensity was higher in LCRs than in HCRs. In addition, membrane attack complex (MAC) expression was increased at 2 h after iron injection and was higher in LCRs than in HCRs. The PI-positive cells co-localized with MAC-positive cells in the ipsilateral basal ganglia. Iron induces more severe necrotic brain cell death, brain swelling, and blood-brain barrier disruption in LCR rats, which may be related with complement activation and MAC formation.

Abstract T P223: Post-stroke Body Weight Loss Predicts Acute Stroke Outcome In Mice

Background and Purpose: Longitudinal imaging studies in stroke demonstrated that infarct development is a dynamic process and it matures over several days, even weeks depending on the severity of stroke. However, due to high cost and multiple exposure of anesthesia associated with repeated imaging, infarct volume has been typically measured at a fixed time point in preclinical studies, which prevent further assessment of behaviors during stroke recovery. In identifying a non-invasive physiological parameter that predicts the extent of stroke-induced brain injury, the study investigated whether acute body weight loss predicts the extent of brain injury and swelling. Methods: C57 male mice (10-12 wk old, 25-30 gr) were subjected to the proximal middle cerebral artery (MCA) occlusion for 30 min. Body weight was recorded daily. Infarct volume corrected with swelling (IVInd) and percent hemispheric swelling (%SW) were determined at 1, 3 and 7d after MCAO. In a retrospective study, we analyzed correlations between 3d %body weight reduction (%BWred) and stroke outcomes (IVInd &amp; %SW) in C57 male animals that were subjected to MCAO by 3 different individuals over 8 years (n=91-96). Results: Stroke induced acute BW loss (%BWred; 1d, 88.9±3.3; 3d, 84.5±8.6; 5d, 86.8±10.6; 7d, 88.9±8.9). Correlation analyses in the post-ischemic time points showed IVind and %SW were significantly correlated with only at 3d BW reduction, but not 1d and 7d (Fig.1). A retrospective analysis in C57 mice also showed a significant correlation between 3d %BWred and IVInd &amp; %SW (Fig.2). Conclusions: The study showed that acute post-stroke BWred is a simple and suitable index to predict the extent of stroke injury in C57 mice. Whether the prediction can be generalized across different strains and in comorbid conditions warrant further investigation.

Novel modified surgical treatment of auricular pseudocyst using plastic sheet compression.

To introduce a novel modified surgical procedure of excision of anterior cartilage of the pseudocyst along with plastic sheet compression for the treatment of auricular pseudocyst and ascertain the effect of the surgical modality of this disease. A retrospective study. Medical college hospital. Eighty-seven auricular pseudocyst patients were subjected to excision of the anterior cartilage of the pseudocyst followed by plastic sheet compression from July 2006 to September 2013. The effects of the operation were evaluated. Eighty patients were males and 7 were females. The median age was 52 years old. The lesions of 86 patients were unilateral and only 1 was bilateral. The clinical features presented a hemispheric painless swelling, which was seen on the ventral side of the auricle, usually the scaphoid and triangular fossa. The average major axis of the pseudocyst was 1.7 ± 0.6 cm. The patients underwent excision of anterior cartilage of the pseudocyst along with plastic sheet compression. The average follow-up period was 51.9 ± 19.1 months. No recurrence was observed with this technique, and the appearance of the auricle was cosmetically acceptable. Our novel modified surgical procedure of excision of anterior cartilage of pseudocyst along with plastic sheet compression is an effective surgical management for the auricular pseudocyst. The advantages of a simple technique, a short-term therapeutic period, and no recurrence made the surgical procedure worth recommending as the definitive treatment of auricular pseudocysts.

Targeting CD36-mediated inflammation reduces acute brain injury in transient, but not permanent, ischemic stroke.

The pathology of stroke consists of multiple pro-death processes, and CD36 has been suggested as a multimodal target to reduce oxidative stress and inflammation in ischemic stroke. Using CD36-deficient mice and SS-31, a cell permeable tetrapeptide known to down-regulate CD36 pathways, the current study investigated whether targeting CD36 is effective in transient and permanent ischemic stroke. Wild-type or CD36-deficient mice were subjected to either 30-min transient or permanent focal ischemic stroke. In parallel, a cohort of mice subjected to either transient or permanent stroke received either vehicle or 5 mg/kg of SS-31. Monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2, mRNA levels, and infarct volume and percent hemispheric swelling were measured in the postischemic brain. CD36 deficiency or SS-31 treatment significantly attenuated MCP-1 or CCR2 mRNA up-regulation and injury size in the transient ischemic stroke. However, the approaches failed to show the protective effect in permanent ischemic stroke. The study revealed that targeting CD36 has a beneficial effect on transient but not permanent focal ischemic stroke. The study thus precludes a generalized strategy targeting CD36 in ischemic stroke and suggests careful consideration of types of stroke and associated pathology in developing stroke therapies.

Congenital ataxia and hemiplegic migraine with cerebral edema associated with a novel gain of function mutation in the calcium channel CACNA1A

Mutations in the CACNA1A gene, encoding the α1 subunit of the voltage-gated calcium channel CaV2.1 (P/Q-type), have been associated with three neurological phenotypes: familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6). We report a child with congenital ataxia, abnormal eye movements and developmental delay who presented severe attacks of hemiplegic migraine triggered by minor head traumas and associated with hemispheric swelling and seizures. Progressive cerebellar atrophy was also observed. Remission of the attacks was obtained with acetazolamide. A de novo 3bp deletion was found in heterozygosity causing loss of a phenylalanine residue at position 1502, in one of the critical transmembrane domains of the protein contributing to the inner part of the pore. We characterized the electrophysiology of this mutant in a Xenopus oocyte in vitro system and showed that it causes gain of function of the channel. The mutant CaV2.1 activates at lower voltage threshold than the wild type. These findings provide further evidence of this molecular mechanism as causative of FHM1 and expand the phenotypic spectrum of CACNA1A mutations with a child exhibiting severe SHM1 and non-episodic ataxia of congenital onset.

Ischemic stroke‐induced increases in circulating microparticles promote leukocyte adhesion in intact microvessels (672.3)

Studies in both stroke patients and experimental animals indicate an association between ischemic stroke and post stroke peripheral inflammation, but the mechanisms are poorly understood. Our ongoing study indicated that circulating microparticles (MPs), the small vesicles released from the cell membrane upon activation, were significantly elevated in both patients and animals with diabetes, and increased circulating MPs with phosphatidylserine (PS) exposure on their outer membrane played important roles in the development of diabetes‐associated microvascular complications. The objective of this study was to investigate whether local ischemic stroke produced increased circulating MPs and determine their impact on post stroke‐associated peripheral vascular inflammation. Acute cerebral ischemia was induced by occlusion of the right middle cerebral artery (MCAO) in 3‐4 month old rats using an autologous blood clot. Functional assessment, lesion volume, and hemispheric swelling were evaluated at 24h after MCAO. Plasma MPs 24h after stroke induction were quantified and characterized using flow cytometry. The number of PS exposed MPs in stroke plasma, identified by Annexin V binding, significantly increased from 5.0 x 103 (normal rats) to 30 x 103 per µl. Antibodies directly against cell specific antigens were used to differentiate the MP cell origin. Results showed that 67% of the increased stroke plasma MPs were derived from platelets. Perfusion of individually cannulated normal rat mesenteric microvessels with isolated stroke MPs for 30 min followed by 10 min of resumed blood flow induced a 4‐fold increase in leukocyte adhesion compared to baseline. These results indicate that stroke‐induced increased circulating MPs serve as mediators capable of disseminating local inflammation to remote vasculatures, and therefore, promoting post stroke systemic complications.Grant Funding Source: Supported by HL56237, DK097391, NS061954

Gray Mold Caused by Botryotinia fuckeliana on Edible Pods of Pea in Brazil.

Gray mold on edible pods of snow pea (Pisum sativum Lam. [Fabaceae]) was observed in greenhouse-cultivated pea (cvs. Luana Gigante and Gigante Flor Roxa) in the city of Pelotas (Rio Grande do Sul, Brazil) in September and October 2012. The incidence of diseased pods was high (∼25% of immature pods) after up to 3 cloudy and rainy days that hindered the ventilation inside the greenhouse resulting in high relative humidity. Infection occurred first on senescing petals adhered to the forming pods, leading to pod abortion or rotting that began at the contact site with the infected petal. The first symptoms on pods included water soaked tissue that quickly turned light brown and progressed to necrosis. Conidia and conidiophores produced on profuse gray mycelium could be easily seen on infected tissue 2 to 3 days after the appearance of symptoms. Conidiophores were smooth-walled, 400 μm to over 1.5 mm long, hyaline to pale brown, and branched in their upper part; each branch ended with a hemispherical or spherical swelling, 5 to 9 μm in diameter with minute sterigmata. Macroconidia were globose, ellipsoidal, smooth, hyaline to pale brown, usually with protuberant hila, 7 to 15 × 5 to 9 μm. Microconidia were not observed. On potato dextrose agar (PDA), colonies were fast-growing, white, low, covering entire 10 cm petri plates in 4 to 5 days when they turned gray to brownish-gray. Conidiophores and conidia were often formed in sectors. Shield-like, elliptical, lenticular to irregular, black, 1.5 to 6.0 × 1.0 to 4.0 mm sclerotia developed in 10-day-old colonies incubated at room temperature. Genomic DNA was extracted from conidia, conidiophores, and mycelium and used to amplify both the internal transcribed spacer (ITS) (ITS1-5.8s-ITS2) region and the β-tubulin gene using the ITS1/4 and Bt2a/b primers, respectively (1,4). The ITS (541 bp) and β-tubulin (467 bp) sequences were deposited in GenBank under accessions KC683713 and KC683712, respectively. BLASTn searches revealed similarity of 100% (EF207415) and 99% (FQ790278) with Botryotinia fuckeliana (De Bary) Whetzel for the ITS and β- tubulin sequences, respectively. Based on morphological characteristics and sequence analysis, the pathogen causing pod rot of peas was identified as B. fuckeliana. To fulfill Koch's postulates, 10 unwounded pods of P. sativum 'Luana Gigante' were inoculated by depositing PDA plugs (5 mm) colonized with fungal mycelium on their surface. Non-inoculated and mock-inoculated pods with sterile PDA plugs served as control. Inoculated and control pods were incubated inside a clear plastic box (11 × 11 × 3.5 cm) and over moistened filter paper under 12-h photoperiod at 25 ± 1°C. A surrounding water-soaked halo was visible only on pods inoculated with the fungus 48 h after inoculation (hai). Intense sporulation and necrosis were visible 96 hai. Botrytis spp. was previously detected, through standard blotter test, on seeds of P. sativum in Brazil, but without pathogenicity test nor its transmission through seeds (2,3). To our knowledge, this is the first report of B. fuckeliana causing epidemics on pea pods in Brazil. The high incidence of the disease in a protected environment has the potential to cause significant economic impact due to its damage to the pods, rendering them unmarketable.

Recommendations for the Management of Cerebral and Cerebellar Infarction With Swelling

There are uncertainties surrounding the optimal management of patients with brain swelling after an ischemic stroke. Guidelines are needed on how to manage this major complication, how to provide the best comprehensive neurological and medical care, and how to best inform families facing complex decisions on surgical intervention in deteriorating patients. This scientific statement addresses the early approach to the patient with a swollen ischemic stroke in a cerebral or cerebellar hemisphere. The writing group used systematic literature reviews, references to published clinical and epidemiology studies, morbidity and mortality reports, clinical and public health guidelines, authoritative statements, personal files, and expert opinion to summarize existing evidence and to indicate gaps in current knowledge. The panel reviewed the most relevant articles on adults through computerized searches of the medical literature using MEDLINE, EMBASE, and Web of Science through March 2013. The evidence is organized within the context of the American Heart Association framework and is classified according to the joint American Heart Association/American College of Cardiology Foundation and supplementary American Heart Association Stroke Council methods of classifying the level of certainty and the class and level of evidence. The document underwent extensive American Heart Association internal peer review. Clinical criteria are available for hemispheric (involving the entire middle cerebral artery territory or more) and cerebellar (involving the posterior inferior cerebellar artery or superior cerebellar artery) swelling caused by ischemic infarction. Clinical signs that signify deterioration in swollen supratentorial hemispheric ischemic stroke include new or further impairment of consciousness, cerebral ptosis, and changes in pupillary size. In swollen cerebellar infarction, a decrease in level of consciousness occurs as a result of brainstem compression and therefore may include early loss of corneal reflexes and the development of miosis. Standardized definitions should be established to facilitate multicenter and population-based studies of incidence, prevalence, risk factors, and outcomes. Identification of patients at high risk for brain swelling should include clinical and neuroimaging data. If a full resuscitative status is warranted in a patient with a large territorial stroke, admission to a unit with neurological monitoring capabilities is needed. These patients are best admitted to intensive care or stroke units attended by skilled and experienced physicians such as neurointensivists or vascular neurologists. Complex medical care includes airway management and mechanical ventilation, blood pressure control, fluid management, and glucose and temperature control. In swollen supratentorial hemispheric ischemic stroke, routine intracranial pressure monitoring or cerebrospinal fluid diversion is not indicated, but decompressive craniectomy with dural expansion should be considered in patients who continue to deteriorate neurologically. There is uncertainty about the efficacy of decompressive craniectomy in patients ≥60 years of age. In swollen cerebellar stroke, suboccipital craniectomy with dural expansion should be performed in patients who deteriorate neurologically. Ventriculostomy to relieve obstructive hydrocephalus after a cerebellar infarct should be accompanied by decompressive suboccipital craniectomy to avoid deterioration from upward cerebellar displacement. In swollen hemispheric supratentorial infarcts, outcome can be satisfactory, but one should anticipate that one third of patients will be severely disabled and fully dependent on care even after decompressive craniectomy. Surgery after a cerebellar infarct leads to acceptable functional outcome in most patients. Swollen cerebral and cerebellar infarcts are critical conditions that warrant immediate, specialized neurointensive care and often neurosurgical intervention. Decompressive craniectomy is a necessary option in many patients. Selected patients may benefit greatly from such an approach, and although disabled, they may be functionally independent.

Clot Injection Technique Affects Thrombolytic Efficacy in a Rat Embolic Stroke Model: Implications for Translaboratory Collaborations

Current recommendations encourage the use of embolic stroke (ES) models and replication of results across laboratories in preclinical research. Since such endeavors employ different surgeons, we sought to ascertain the impact of injection technique on outcome and response to thrombolysis in an ES model. Embolic stroke was induced in Male Wistar Kyoto rats (n=166) by a fast or a slow clot injection (CI) technique. Saline or recombinant tissue plasminogen activator (rtPA) was given at 1 hour after stroke. Flow rate curves were assessed in 24 animals. Cerebral perfusion was assessed using laser Doppler flowmetry. Edema corrected infarct volume, hemispheric swelling, hemorrhagic transformation, and neurologic outcome were assessed at 24 hours after stroke. Clot burden was estimated in a subset of animals (n=40). Slow CI resulted in significantly smaller infarct volumes (P=0.024) and better neurologic outcomes (P=0.01) compared with fast CI at 24 hours. Unexpectedly, rtPA treatment attenuated infarct size in fast (P<0.001) but not in slow CI experiments (P=0.382), possibly related to reperfusion injury as indicated by greater hemorrhagic transformation (P<0.001) and hemispheric swelling (P<0.05). Outcome and response to thrombolysis after ES are operator dependent, which needs to be considered when comparing results obtained from different laboratories.

Progesterone Attenuates Hemorrhagic Transformation after Delayed tPA Treatment in an Experimental Model of Stroke in Rats: Involvement of the VEGF–MMP Pathway

Tissue plasminogen activator (tPA) is the only FDA-approved treatment for acute stroke, but its use remains limited. Progesterone (PROG) has shown neuroprotection in ischemia, but before clinical testing, we must determine how it affects hemorrhagic transformation in tPA-treated ischemic rats. Male Sprague-Dawley rats underwent middle cerebral artery occlusion with reperfusion at 4.5 hours and tPA treatment at 4.5 hours, or PROG treatment intraperitoneally at 2 hours followed by subcutaneous injection at 6 hours post occlusion. Rats were killed at 24 hours and brains evaluated for cerebral hemorrhage, swelling, blood-brain barrier (BBB) permeability, and levels of matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor level (VEGF), and tight junction (TJ) proteins. We also evaluated PROG's efficacy in preventing tPA-induced impairment of transendothelial electrical resistance (TEER) and TJ proteins under hypoxia/reoxygenation in the endothelial cells. Delayed tPA treatment induced significant hemorrhagic conversion and brain swelling. Treatment with PROG plus tPA ameliorated hemorrhage, hemispheric swelling, BBB permeability, MMP-9 induction, and VEGF levels compared with controls. Progesterone treatment significantly prevented tPA-induced decrease in TEER and expression of occludin and claudin-5, and attenuated VEGF levels in culture media subjected to hypoxia. The study concluded that PROG may extend the time window for tPA administration in ischemic stroke and reduce hemorrhagic conversion.

The protective role of Tongxinluo on blood–brain barrier after ischemia–reperfusion brain injury

Ethnopharmacological relevanceTongxinluo (TXL), a renowned traditional Chinese medicine, consists of several different kinds of ingredients and has been widely used to treat myocardial infarction and ischemic stroke. However, the underlying neuroprotective mechanisms are not fully understood. Aim of the studyWe focus on the effect of TXL on blood–brain barrier (BBB) including edema formation and tight junction (TJ) protein rearrangement, and inflammatory response after transient middle cerebral artery occlusion (tMCAO). We further explore the protective mechanism of TXL on ischemia-induced BBB damage. Materials and methodsAdult CD1 male mice (n=168) were randomly divided into TXL pre-treatment group, TXL pre-post treatment group, TXL post-treatment group, control group and sham group. Mice in TXL pre-treatment group were given TXL solution by 1g/kg/day orally for 7 days before tMCAO. Mice in pre-post treatment group were continuously given TXL 7 days before and 14 days after tMCAO. Mice in TXL post-treatment group were given TXL solution immediately after tMCAO. Rotarod test and neurological severity scores were evaluated at 1–14 days following tMCAO. Brains were harvested for examining infarct volume, edema formation, and immunofluorescent staining at 1 and 3 days after tMCAO. Cytokines IL-6, IL-1β and TNF-α mRNA expression, and BBB permeability were further examined by RT-PCR and immunostaining. ResultsTXL pre-post treatment improved neurobehavioral outcomes and reduced infarct volume compared to the control (p<0.05). Meanwhile, hemispheric swelling, Evans blue and IgG protein extravasation reduced, while TJ protein expression up-regulated in pre-post treatment group (p<0.05). Further study indicated that infarct volume was smaller and BBB damage was less severe in TXL pre-post treatment group compared to TXL pre-treatment alone. It was noted that fewer myeloperoxidase (MPO) positive cells and less cytokines IL-6, IL-1β and TNF-α expression in pre-post treatment group compared to the control group (p<0.05). ConclusionsTXL pre-treatment and pre-post treatment effectively protected the brain from BBB disruption via alleviating inflammatory response. Moreover, pre-post treatment has better outcomes, suggesting that continuous administration of TXL before and throughout ischemia period is necessary because of multiple functions of TXL.

Clinical values of ICP monitoring for patients with traumatic acute bilateral hemisphere diffuse brain swelling

Objective To explore the guiding role of invasive intracranial pressure (ICP) monitoring in the treatment of posttraumatic acute bilateral hemispheric diffuse brain swelling,and to analyze the relationship between ICP and the prognosis.Methods A total of 59 patients with acute posttranmatic bilateral hemisphere diffuse brain swelling,treated under the monitoring of invasive intracranial pressure between Feb.2010 and Oct.2011,in our department were chosen for the study.ICP values at admission,before,and after decompressive craniectomy of all 59 patients were collected.The 59 patients were divided into a group of good recovery (GOS 4 ～ 5) and a group of bad recovery (GOS 1 ～ 3) based on the Glasgow outcome scale (COS) 6 months after craniocerebral trauma.The relationship between prognosis and ICP at admission,ICP before and after decompressive craniectomy was analyzed.Results The good recovery rate was 69％ (41/59) and the bad recovery rate was 31％ (18/59),while the death rate was 15％ (9/59).No mortality or plant survival occurred in patients whose GCS ≥ 9 at admission,and all patients,whose GCS were between 13 ～ 14,came back to work or study (GOS =5).Twenty-nine patients accepted decompressive cranieetomy under continuous invasive ICP monitoring; for those with good recoveries,ICP at admission,ICP before and after decompressive craniectomy were respectively (22.2 ± 7.9)mmHg,(31.9±9.5) mm Hg,and (123 ±2.9) mm Hg; for those with bad recoveries,these indexes were respectively (33.4 ±18.9) mm Hg,(43.7 ± 14.6) mm Hg,and (13.0 ±5.6)mm Hg.There were significant statistic differences between the two groups for the indexes of patients' ICP at admission and ICP before decompressive craniectomy (P＜ 0.05).However,there were no significant statistical differences of ICP after decompressive craniectomy (P＞ 0.05).Conclusion Continuous invasive ICP monitoring has an important role in guiding the treatments for patients of posttraumatic bilateral hemispheric acute diffuse brain swelling,whose prognosis were related to ICP at admission and ICP before decompressive craniectomy. Key words: Craniocerebral trauma; Diffuse brain swelling; ICP monitoring; Prognosis