Early brain injury linearly correlates with reduction in cerebral perfusion pressure during the hyperacute phase of subarachnoid hemorrhage

BACKGROUND It is unclear how complex pathophysiological mechanisms that result in early brain injury (EBI) after subarachnoid hemorrhage (SAH) are triggered. We investigate how peak intracranial pressure (ICP), amount of subarachnoid blood, and hyperacute depletion of cerebral perfusion pressure (CPP) correlate to the onset of EBI following experimental SAH. METHODS An entire spectrum of various degrees of SAH severities measured as peak ICP was generated and controlled using the blood shunt SAH model in rabbits. Standard cardiovascular monitoring, ICP, CPP, and bilateral regional cerebral blood flow (rCBF) were continuously measured. Cells with DNA damage and neurodegeneration were detected using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Fluoro-jade B (FJB). RESULTS rCBF was significantly correlated to reduction in CPP during the initial 15 min after SAH in a linear regression pattern (r (2) = 0.68, p < 0.001). FJB- and TUNEL-labeled cells were linearly correlated to reduction in CPP during the first 3 min of hemorrhage in the hippocampal regions (FJB: r (2) = 0.50, p < 0.01; TUNEL: r (2) = 0.35, p < 0.05), as well as in the basal cortex (TUNEL: r (2) = 0.58, p < 0.01). EBI occurred in animals with severe (relative CPP depletion >0.4) and moderate (relative CPP depletion >0.25 but <0.4) SAH. Neuronal cell death was equally detected in vulnerable and more resistant brain regions. CONCLUSIONS The degree of EBI in terms of neuronal cell degeneration in both the hippocampal regions and the basal cortex linearly correlates with reduced CPP during hyperacute SAH. Temporary CPP reduction, however, is not solely responsible for EBI but potentially triggers processes that eventually result in early brain damage.

Nitric oxide inhalation reduces brain damage, prevents mortality, and improves neurological outcome after subarachnoid hemorrhage by resolving early pial microvasospasms.

Subarachnoid hemorrhage is a stroke subtype with particularly bad outcome. Recent findings suggest that constrictions of pial arterioles occurring early after hemorrhage may be responsible for cerebral ischemia and - subsequently - unfavorable outcome after subarachnoid hemorrhage. Since we recently hypothesized that the lack of nitric oxide may cause post-hemorrhagic microvasospasms, our aim was to investigate whether inhaled nitric oxide, a treatment paradigm selectively delivering nitric oxide to ischemic microvessels, is able to dilate post-hemorrhagic microvasospasms; thereby improving outcome after experimental subarachnoid hemorrhage. C57BL/6 mice were subjected to experimental SAH. Three hours after subarachnoid hemorrhage pial artery spasms were quantified by intravital microscopy, then mice received inhaled nitric oxide or vehicle. For induction of large artery spasms mice received an intracisternal injection of autologous blood. Inhaled nitric oxide significantly reduced number and severity of subarachnoid hemorrhage-induced post-hemorrhage microvasospasms while only having limited effect on large artery spasms. This resulted in less brain-edema-formation, less hippocampal neuronal loss, lack of mortality, and significantly improved neurological outcome after subarachnoid hemorrhage. This suggests that spasms of pial arterioles play a major role for the outcome after subarachnoid hemorrhage and that lack of nitric oxide is an important mechanism of post-hemorrhagic microvascular dysfunction. Reversing microvascular dysfunction by inhaled nitric oxide might be a promising treatment strategy for subarachnoid hemorrhage.

Clinical outcome after first and recurrent hemorrhage in patients with untreated brain arteriovenous malformation

Background and Purpose: The morbidity from spontaneous hemorrhage of untreated brain arteriovenous malformations (AVM) is not well described. Methods: The 241 consecutive AVM patients (mean age 3716 years, 52% women) from the prospective Columbia AVM Databank initially presenting with hemorrhage were evaluated using the Rankin Scale (RS) and the National Institute of Health Stroke Scale (NIHSS). From the 241 AVM patients, 29 (12%) had subsequent intracranial hemorrhage during follow-up. For further comparisons, 84 non-AVM patients with intracerebral hemorrhage from the Northern Manhattan Study (NOMAS) served as a control group. Results: In 241 AVM patients presenting with hemorrhage the median RS was 2 and the median NIHSS was 1 (49% RS 0 to 1, 61% NIHSS 2). The median time between hemorrhage and clinical evaluation was 11 days (mean 219 days). Recurrent AVM hemorrhage during follow-up resulted in no significant increase in morbidity (median RS 2, P0.004; median NIHSS 3, P0.322; time between hemorrhage and study evaluation: median 55 days, mean 657 days). Among AVM-hemorrhage subtypes, parenchymatous AVM hemorrhage was associated with higher stroke morbidity (odds ratio, 2.9; 95% CI, 1.5 to 5.8 for NIHSS 2) than nonparenchymatous hemorrhages. Parenchymatous AVM hemorrhage had a significantly better outcome (median NIHSS 1) than non-AVM related hemorrhage (median NIHSS 12; P0.0001). Conclusions: Hemorrhage, either at initial presentation or during follow-up of untreated AVM patients appears to carry

The role of mast cells in ischemic and hemorrhagic brain injury

Stroke, ischemic or hemorrhagic, belongs among the foremost causes of death and disability worldwide. Massive brain swelling is the leading cause of death in large hemispheric strokes and is only modestly alleviated by available treatment. Thrombolysis with tissue plasminogen activator (TPA) is the only approved therapy in acute ischemic stroke, but fear of TPA-mediated hemorrhage is often a reason for withholding this otherwise beneficial treatment. In addition, recanalization of the occluded artery (spontaneously or with thrombolysis) may cause reperfusion injury by promoting brain edema, hemorrhage, and inflammatory cell infiltration. A dominant event underlying these phenomena seems to be disruption of the blood-brain barrier (BBB). In contrast to ischemic stroke, no widely approved clinical therapy exists for intracerebral hemorrhage (ICH), which is associated with poor outcome mainly due to the mass effect of enlarging hematoma and associated brain swelling. Mast cells (MCs) are perivascularly located resident inflammatory cells which contain potent vasoactive, proteolytic, and fibrinolytic substances in their cytoplasmic granules. Experiments from our laboratory showed MC density and their state of granulation to be altered early following focal transient cerebral ischemia, and degranulating MCs were associated with perivascular edema and hemorrhage. (I) Pharmacological MC stabilization led to significantly reduced ischemic brain swelling (40%) and BBB leakage (50%), whereas pharmacological MC degranulation raised these by 90% and 50%, respectively. Pharmacological MC stabilization also revealed a 40% reduction in neutrophil infiltration. Moreover, genetic MC deficiency was associated with an almost 60% reduction in brain swelling, 50% reduction in BBB leakage, and 50% less neutrophil infiltration, compared with controls. (II) TPA induced MC degranulation in vitro. In vivo experiments with post-ischemic TPA administration demonstrated 70- to 100-fold increases in hemorrhage formation (HF) compared with controls HF. HF was significantly reduced by pharmacological MC stabilization at 3 (95%), 6 (75%), and 24 hours (95%) of follow-up. Genetic MC deficiency again supported the role of MCs, leading to 90% reduction in HF at 6 and 24 hours. Pharmacological MC stabilization and genetic MC deficiency were also associated with significant reduction in brain swelling and in neutrophil infiltration. Importantly, these effects translated into a significantly better neurological outcome and lower mortality after 24 hours. (III) Finally, in ICH experiments, pharmacological MC stabilization resulted in significantly less brain swelling, diminished growth in hematoma volume, better neurological scores, and decreased mortality. Pharmacological MC degranulation produced the opposite effects. Genetic MC deficiency revealed a beneficial effect similar to that found with pharmacological MC stabilization. In sum, the role of MCs in these clinically relevant scenarios is supported by a series of experiments performed both in vitro and in vivo. That not only genetic MC deficiency but also drugs targeting MCs could modulate these parameters (translated into better outcome and decreased mortality), suggests a potential therapeutic approach in a number of highly prevalent cerebral insults in which extensive tissue injury is followed by dangerous brain swelling and inflammatory cell infiltration. Furthermore, these experiments could hint at a novel therapy to improve the safety of thrombolytics, and a potential cellular target for those seeking novel forms of treatment for ICH.

Brain and Spinal Cavernomas : Helsinki Experience

Cavernomas are rare neurovascular lesions, encountered in up to 10% of patients harboring vascular abnormalities of the CNS. Cavernomas consist of dilated thin-walled sinusoids or caverns covered by a single layer of endothelium. Due to advancements in neuroradiology, the number of cavernoma patients coming to be evaluated in neurosurgical practice is increasing. In the present work, we summarized our results on the treatment of cavernomas. Particular attention was paid to uncommon locations or insufficiently investigated cavernomas, including 1. Intraventricular cavernomas; 2. Multiple cavernomas; 3. Spinal cavernomas; and 4. Temporal lobe cavernomas. After analyzing the patient series with these lesions, we concluded that: 1. IVCs are characterized by a high tendency to cause repetitive hemorrhages in a short period of time after the first event. In most patients, hemorrhages were not life-threatening. Surgery is indicated when re-bleedings are frequent and the mass-effect causes progressive neurological deterioration. Modern microsurgical techniques allow safe removal of the IVC, but surgery on fourth ventricle cavernomas carries increased risk of postoperative cranial nerve deficits. 2. In MC cases, when the cavernoma bleeds or generates drug-resistant epilepsy, microsurgical removal of the symptomatic lesion is beneficial to patients. In our series, surgical removal of the most active cavernoma usually the biggest lesion with signs of recent hemorrhage - was safe and prevented further bleedings. Epilepsy outcome showed the effectiveness of active treatment of MCs. However, due to the remaining cavernomas, epileptogenic activity can persist postoperatively, frequently necessitating long-term use of antiepileptic drugs. 3. Spinal cavernomas can cause severe neurological deterioration due to low tolerance of the spinal cord to mass-effect with progressive myelopathy. When aggravated by extralesional massive hemorrhage, neurological decline is usually acute and requires immediate treatment. Microsurgical removal of a cavernoma is effective and safe, improving neurological deficits. Sensorimotor deficits and pain improved postoperatively at a high rate, whereas bladder dysfunction remained essentially unchanged, causing social discomfort to patients. 4. Microsurgical removal of temporal lobe cavernomas is beneficial for patents suffering from drug-resistant epilepsy. In our series, 69% of patients with this condition became seizure-free postoperatively. Duration of epilepsy did not correlate with seizure prognosis. The most frequent disabling symptom at follow-up was memory disorder, considered to be the result of a complex interplay between chronic epilepsy and possible damage to the temporal lobe during surgery.

Role of surgery in the management of brain arteriovenous malformations: prospective cohort study.

BACKGROUND AND PURPOSE: Management of brain arteriovenous malformation (bAVM) is controversial. We have analyzed the largest surgical bAVM cohort for outcome. METHODS: Both operated and nonoperated cases were included for analysis. A total of 779 patients with bAVMs were consecutively enrolled between 1989 and 2014. Initial management recommendations were recorded before commencement of treatment. Surgical outcome was prospectively recorded and outcomes assigned at the last follow-up visit using modified Rankin Scale. First, a sensitivity analyses was performed to select a subset of the entire cohort for which the results of surgery could be generalized. Second, from this subset, variables were analyzed for risk of deficit or near miss (intraoperative hemorrhage requiring blood transfusion of ≥2.5 L, hemorrhage in resection bed requiring reoperation, and hemorrhage associated with either digital subtraction angiography or embolization). RESULTS: A total of 7.7% of patients with Spetzler-Ponce classes A and B bAVM had an adverse outcome from surgery leading to a modified Rankin Scale >1. Sensitivity analyses that demonstrated outcome results were not subject to selection bias for Spetzler-Ponce classes A and B bAVMs. Risk factors for adverse outcomes from surgery for these bAVMs include size, presence of deep venous drainage, and eloquent location. Preoperative embolization did not affect the risk of perioperative hemorrhage. CONCLUSIONS: Most of the ruptured and unruptured low and middle-grade bAVMs (Spetzler-Ponce A and B) can be surgically treated with a low risk of permanent morbidity and a high likelihood of preventing future hemorrhage. Our results do not apply to Spetzler-Ponce C bAVMs.

Brain herniation in a patient with apparently normal intracranial pressure: a case report

Introduction Intracranial pressure monitoring is commonly implemented in patients with neurologic injury and at high risk of developing intracranial hypertension, to detect changes in intracranial pressure in a timely manner. This enables early and potentially life-saving treatment of intracranial hypertension. Case presentation An intraparenchymal pressure probe was placed in the hemisphere contralateral to a large basal ganglia hemorrhage in a 75-year-old Caucasian man who was mechanically ventilated and sedated because of depressed consciousness. Intracranial pressures were continuously recorded and never exceeded 17 mmHg. After sedation had been stopped, our patient showed clinical signs of transtentorial brain herniation, despite apparently normal intracranial pressures (less than 10 mmHg). Computed tomography revealed that the size of the intracerebral hematoma had increased together with significant unilateral brain edema and transtentorial herniation. The contralateral hemisphere where the intraparenchymal pressure probe was placed appeared normal. Our patient underwent emergency decompressive craniotomy and was tracheotomized early, but did not completely recover. Conclusions Intraparenchymal pressure probes placed in the hemisphere contralateral to an intracerebral hematoma may dramatically underestimate intracranial pressure despite apparently normal values, even in the case of transtentorial brain herniation.

Preliminary results of an ICP-controlled subarachnoid hemorrhage rabbit model for the study of delayed cerebral vasospasm

INTRODUCTION: Intracisternal blood injection is the most common applied experimental subarachnoid bleeding technique in rabbits. The model comprises examiner-dependent variables and does not closely represent the human pathophysiological sequelae of ruptured cerebral aneurysm. The degree of achieved delayed cerebral vasospasm (DCVS) in this model is often mild. The aim of this study was to characterize and evaluate the feasibility of a clinically more relevant experimental SAH in vivo model. SAH was performed by arterial blood shunting from the subclavian artery into the great cerebral cistern. A total of five experiments were performed. Intracranial pressure (ICP), arterial blood pressure, heart rate, arterial blood gas analysis, and neurological status were monitored throughout the experiments. SAH induced vasoconstriction of the basilar artery was 52.1±3.4% on day 3 compared to baseline (P<0.05). Post-mortem gross examination of the brain showed massive blood clot accumulation around the brainstem and ventral surface of the brain. The novel technique offers an examiner independent SAH induction and triggers high degrees of delayed cerebral vasospasm. The severity of vasospasm attained offers a unique opportunity to evaluate future therapeutic treatment options.

Traumatic subarachnoid hemorrhage, basal ganglia hematoma and ischemic stroke caused by a torn lenticulostriate artery

Subarachnoid hemorrhage (SAH), basal ganglia hematoma (BGH) and ischemic stroke are common diseases with diverging therapies. The simultaneous occurrence of these diseases is rare and complicates the therapy. We report the case of a 30-year-old man with a ruptured lenticulostriate artery after traumatic brain injury that caused the combination of SAH, BGH and ischemic stroke and subsequent cerebral vasospasm. This rupture mimicked the pathophysiology and imaging appearance of aneurysmal SAH. The site of rupture was not secured by any treatment; however, hyperdynamic therapy and percutaneous transluminal angioplasty were feasible in this setting to prevent additional delayed neurological deficit.

Experimental subarachnoid hemorrhage causes early and long-lasting microarterial constriction and microthrombosis: an in-vivo microscopy study

Early brain injury (EBI) after subarachnoid hemorrhage (SAH) is characterized by a severe, cerebral perfusion pressure (CPP)-independent reduction in cerebral blood flow suggesting alterations on the level of cerebral microvessels. Therefore, we aimed to use in-vivo imaging to investigate the cerebral microcirculation after experimental SAH. Subarachnoid hemorrhage was induced in C57/BL6 mice by endovascular perforation. Pial arterioles and venules (10 to 80 μm diameter) were examined using in-vivo fluorescence microscopy, 3, 6, and 72 hours after SAH. Venular diameter or flow was not affected by SAH, while >70% of arterioles constricted by 22% to 33% up to 3 days after hemorrhage (P<0.05 versus sham). The smaller the investigated arterioles, the more pronounced the constriction (r(2)=0.92, P<0.04). Approximately 30% of constricted arterioles were occluded by microthrombi and the frequency of arteriolar microthrombosis correlated with the degree of constriction (r(2)=0.93, P<0.03). The current study demonstrates that SAH induces microarterial constrictions and microthrombosis in vivo. These findings may explain the early CPP-independent decrease in cerebral blood flow after SAH and may therefore serve as novel targets for the treatment of early perfusion deficits after SAH.

Long-term pallidal deep brain stimulation in patients with advanced Parkinson disease: 1-year follow-up study

OBJECT: The goal of this study was to investigate the efficacy of long-term deep brain stimulation (DBS) of the posteroventral lateral globus pallidus internus (GPi) accomplished using a single-contact monopolar electrode in patients with advanced Parkinson disease (PD). METHODS: Sixteen patients suffering from severe PD and levodopa-induced side effects such as dyskinesias and on-off fluctuations were enrolled in a prospective study protocol. There were six women and 10 men and their mean age at surgery was 65 years. All patients underwent implantation of a monopolar electrode in the posteroventral lateral GPi. Initially, nine patients received unilateral stimulation. Three of these patients underwent contralateral surgery at a later time. Ten patients received bilateral stimulation (contemporaneous bilateral surgery was performed in seven patients and staged bilateral surgery in the three patients who had received unilateral stimulation initially). Formal assessments were performed during both off-medication and on-medication (levodopa) periods preoperatively, and at 3 and 12 months postoperatively. There were no serious complications related to surgery or to DBS. Two transient adverse events occurred: in one patient a small pallidal hematoma developed, resulting in a prolonged micropallidotomy effect, and in another patient a subcutaneous hemorrhage occurred at the site of the pacemaker. In patients who received unilateral DBS, the Unified Parkinson's Disease Rating Scale activities of daily living (ADL) score during the off-levodopa period decreased from 30.8 at baseline to 20.4 at 3 months (34% improvement) and 20.6 at 12 months (33% improvement) postoperatively. The motor score during the off period improved from 57.2 at baseline to 35.2 at 3 months (38% improvement) and 35.3 at 12 months (38% improvement) postoperatively. Bilateral DBS resulted in a reduction in the ADL score during the off period from 34.9 at baseline to 22.3 at 3 months (36% improvement) and 22.9 at 12 months (34% improvement). The motor score for the off period changed from 63.4 at baseline to 40.3 at 3 months (36% improvement) and 37.5 at 12 months (41% improvement). In addition, there were significant improvements in patients' symptoms during the on period and in on-off motor fluctuations. CONCLUSIONS: Pallidal DBS accomplished using a monopolar electrode is a safe and effective procedure for treatment of advanced PD. Compared with pallidotomy, the advantages of pallidal DBS lie in its reversibility and the option to perform bilateral surgery in one session. Comparative studies in which DBS is applied to other targets are needed.

Decompressive craniectomy in subarachnoid hemorrhage

OBJECT: The aim of this study was to analyze decompressive craniectomy (DC) in the setting of subarachnoid hemorrhage (SAH) with bleeding, infarction, or brain swelling as the underlying pathology in a large cohort of consecutive patients. METHODS: Decompressive craniectomy was performed in 79 of 939 patients with SAH. Patients were stratified according to the indication for DC: 1) primary brain swelling without or 2) with additional intracerebral hematoma, 3) secondary brain swelling without rebleeding or infarcts, and 4) secondary brain swelling with infarcts or 5) with rebleeding. Outcome was assessed according to the modified Rankin Scale (mRS) at 6 months (mRS Score 0-3 favorable vs 4-6 unfavorable). RESULTS: Overall, 61 (77.2%) of 79 patients who did and 292 (34%) of the 860 patients who did not undergo DC had a poor clinical grade on admission (World Federation of Neurosurgical Societies Grade IV-V, p < 0.0001). A favorable outcome was attained in 21 (26.6%) of 79 patients who had undergone DC. In a comparison of favorable outcomes in patients with primary (28.0%) or secondary DC (25.5%), no difference could be found (p = 0.8). Subgroup analysis with respect to the underlying indication for DC (brain swelling vs bleeding vs infarction) revealed no difference in the rate of favorable outcomes. On multivariate analysis, acute hydrocephalus (p = 0.009) and clinical signs of herniation (p = 0.02) were significantly associated with an unfavorable outcome. CONCLUSIONS: Based on the data in this study the authors concluded that primary as well as secondary craniectomy might be warranted, regardless of the underlying etiology (hemorrhage, infarction, or brain swelling) and admission clinical grade of the patient. The time from the onset of intractable intracranial pressure to DC seems to be crucial for a favorable outcome, even when a DC is performed late in the disease course after SAH.

THE EXPRESSION AND CELLULAR LOCALIZATION OF CC-CHEMOKINE RECEPTOR 5 (CCR5) AFTER TRAUMATIC BRAIN INJURY

Traumatic brain injury results from a primary insult and secondary events that together result in tissue injury. This primary injury occurs at the moment of impact and damage can include scalp laceration, skull fraction, cerebral contusions and lacerations as well as intracranial hemorrhage. Following the initial insult, a delayed response occurs and is characterized by hypoxia, ischemia, cerebral edema, and infection. During secondary brain injury, a series of neuroinflammatory events are triggered that can produce additional damage but may also help to protect nervous tissue from invading pathogens and help to repair the damaged tissue. Brain microglia and astrocytes become activated and migrate to the site of injury where these cells secrete immune mediators such as cytokines and chemokines. CC-chemokine receptor 5 (CCR5) is a member of the CC chemokine receptor family of seven transmembrane G protein coupled receptors. CCR5 is expressed in the immune system and is found in monocytes, leukoctyes, memory T cells, and immature dendritic cells. Upon binding to its ligands, CCR5 functions in the chemotaxis of these immune cells to the site of inflammation. In the CNS, CCR5 and its ligands are expressed in multiple cell types. In this study, I investigated whether CCR5 expression is altered in brain after traumatic brain injury. I examined the time course of CCR5 protein expression in cortex and hippocampus using quantitative western analysis of tissues from injured rat brain after mild impact injury. In addition, I also investigated the cellular localization of CCR5 before and after brain injury using confocal microscopy. I have observed that after brain injury CCR5 is upregulated in a time dependent manner in neurons of the parietal cortex and hippocampus. The absence of CCR5 expression in microglia and its delayed expression in neurons after injury suggests a role for CCR5 in neuronal survival after injury.

THE EXPRESSION AND CELLULAR LOCALIZATION OF CC-CHEMOKINE RECEPTOR 5 (CCR5) AFTER TRAUMATIC BRAIN INJURY

Traumatic brain injury results from a primary insult and secondary events that together result in tissue injury. This primary injury occurs at the moment of impact and damage can include scalp laceration, skull fraction, cerebral contusions and lacerations as well as intracranial hemorrhage. Following the initial insult, a delayed response occurs and is characterized by hypoxia, ischemia, cerebral edema, and infection. During secondary brain injury, a series of neuroinflammatory events are triggered that can produce additional damage but may also help to protect nervous tissue from invading pathogens and help to repair the damaged tissue. Brain microglia and astrocytes become activated and migrate to the site of injury where these cells secrete immune mediators such as cytokines and chemokines. CC-chemokine receptor 5 (CCR5) is a member of the CC chemokine receptor family of seven transmembrane G protein coupled receptors. CCR5 is expressed in the immune system and is found in monocytes, leukoctyes, memory T cells, and immature dendritic cells. Upon binding to its ligands, CCR5 functions in the chemotaxis of these immune cells to the site of inflammation. In the CNS, CCR5 and its ligands are expressed in multiple cell types. In this study, I investigated whether CCR5 expression is altered in brain after traumatic brain injury. I examined the time course of CCR5 protein expression in cortex and hippocampus using quantitative western analysis of tissues from injured rat brain after mild impact injury. In addition, I also investigated the cellular localization of CCR5 before and after brain injury using confocal microscopy. I have observed that after brain injury CCR5 is upregulated in a time dependent manner in neurons of the parietal cortex and hippocampus. The absence of CCR5 expression in microglia and its delayed expression in neurons after injury suggests a role for CCR5 in neuronal survival after injury.