Dynamic Intracranial Pressure Waveform Morphology Predicts Ventriculitis.

BACKGROUND: Intracranial pressure waveform morphology reflects compliance, which can be decreased by ventriculitis. We investigated whether morphologic analysis of intracranial pressure dynamics predicts the onset of ventriculitis. METHODS: Ventriculitis was defined as culture or Gram stain positive cerebrospinal fluid, warranting treatment. We developed a pipeline to automatically isolate segments of intracranial pressure waveforms from extraventricular catheters, extract dominant pulses, and obtain morphologically similar groupings. We used a previously validated clinician-supervised active learning paradigm to identify metaclusters of triphasic, single-peak, or artifactual peaks. Metacluster distributions were concatenated with temperature and routine blood laboratory values to create feature vectors. A L2-regularized logistic regression classifier was trained to distinguish patients with ventriculitis from matched controls, and the discriminative performance using area under receiver operating characteristic curve with bootstrapping cross-validation was reported. RESULTS: Fifty-eight patients were included for analysis. Twenty-seven patients with ventriculitis from two centers were identified. Thirty-one patients with catheters but without ventriculitis were selected as matched controls based on age, sex, and primary diagnosis. There were 1590 h of segmented data, including 396,130 dominant pulses in patients with ventriculitis and 557,435 pulses in patients without ventriculitis. There were significant differences in metacluster distribution comparing before culture-positivity versus during culture-positivity (p < 0.001) and after culture-positivity (p < 0.001). The classifier demonstrated good discrimination with median area under receiver operating characteristic 0.70 (interquartile range 0.55-0.80). There were 1.5 true alerts (ventriculitis detected) for every false alert. CONCLUSIONS: Intracranial pressure waveform morphology analysis can classify ventriculitis without cerebrospinal fluid sampling.

Revised and updated recommendations for the establishment of primary stroke centers: a summary statement from the brain attack coalition.

BACKGROUND AND PURPOSE: The formation and certification of Primary Stroke Centers has progressed rapidly since the Brain Attack Coalition's original recommendations in 2000. The purpose of this article is to revise and update our recommendations for Primary Stroke Centers to reflect the latest data and experience. METHODS: We conducted a literature review using MEDLINE and PubMed from March 2000 to January 2011. The review focused on studies that were relevant for acute stroke diagnosis, treatment, and care. Original references as well as meta-analyses and other care guidelines were also reviewed and included if found to be valid and relevant. Levels of evidence were added to reflect current guideline development practices. RESULTS: Based on the literature review and experience at Primary Stroke Centers, the importance of some elements has been further strengthened, and several new areas have been added. These include (1) the importance of acute stroke teams; (2) the importance of Stroke Units with telemetry monitoring; (3) performance of brain imaging with MRI and diffusion-weighted sequences; (4) assessment of cerebral vasculature with MR angiography or CT angiography; (5) cardiac imaging; (6) early initiation of rehabilitation therapies; and (7) certification by an independent body, including a site visit and disease performance measures. CONCLUSIONS: Based on the evidence, several elements of Primary Stroke Centers are particularly important for improving the care of patients with an acute stroke. Additional elements focus on imaging of the brain, the cerebral vasculature, and the heart. These new elements may improve the care and outcomes for patients with stroke cared for at a Primary Stroke Center.

Rebleeding after aneurysmal subarachnoid hemorrhage.

Rebleeding after initial aneurysmal subarachnoid hemorrhage (SAH) can have substantial impact on overall patient outcome. While older studies have suggested rebleeding occurs in about 4% of patients during the first day after initial aneurysmal bleed, these studies may have failed to capture very early rebleeds and, consequently, underestimated the impact of rebleeding. An electronic literature search was performed to identify English-language articles published or available for review from February 1975 through October 2010. A total of 43 articles (40 original research and 3 review articles) focused on rebleeding after initial aneurysmal SAH in humans were selected for review. Although most studies supported an incidence of rebleeding ≤4%, studies investigating ultra-early rebleeding reported bleeding within the first 24 h following aneurysmal SAH in as many as 9-17% of patients, with most cases occurring within 6 h of initial hemorrhage. Overall, studies investigating antifibrinolytic therapy to reduce rebleeding have failed to clearly demonstrate overall therapeutic benefit. Short-course antifibrinolytic therapy may have a role prior to initial aneurysm repair, although insufficient data are currently available.

Targeted inhibition of intrinsic coagulation limits cerebral injury in stroke without increasing intracerebral hemorrhage.

Agents that restore vascular patency in stroke also increase the risk of intracerebral hemorrhage (ICH). As Factor IXa is a key intermediary in the intrinsic pathway of coagulation, targeted inhibition of Factor IXa-dependent coagulation might inhibit microvascular thrombosis in stroke without impairing extrinsic hemostatic mechanisms that limit ICH. A competitive inhibitor of native Factor IXa for assembly into the intrinsic Factor X activation complex, Factor IXai, was prepared by covalent modification of the Factor IXa active site. In a modified cephalin clotting time assay, in vivo administration of Factor IXai caused a dose-dependent increase in time to clot formation (3.6-fold increase at the 300 micrograms/kg dose compared with vehicle-treated control animals, P < 0.05). Mice given Factor IXai and subjected to middle cerebral artery occlusion and reperfusion demonstrated reduced microvascular fibrin accumulation by immunoblotting and immunostaining, reduced 111In-labeled platelet deposition (42% decrease, P < 0.05), increased cerebral perfusion (2.6-fold increase in ipsilateral blood flow by laser doppler, P < 0.05), and smaller cerebral infarcts than vehicle-treated controls (70% reduction, P < 0.05) based on triphenyl tetrazolium chloride staining of serial cerebral sections. At therapeutically effective doses, Factor IXai was not associated with increased ICH, as opposed to tissue plasminogen activator (tPA) or heparin, both of which significantly increased ICH. Factor IXai was cerebroprotective even when given after the onset of stroke, indicating that microvascular thrombosis continues to evolve (and may be inhibited) even after primary occlusion of a major cerebrovascular tributary.

Neuronal protection in stroke by an sLex-glycosylated complement inhibitory protein.

Glycoprotein adhesion receptors such as selectins contribute to tissue injury in stroke. Ischemic neurons strongly expressed C1q, which may target them for complement-mediated attack or C1qRp-mediated clearance. A hybrid molecule was used to simultaneously inhibit both complement activation and selectin-mediated adhesion. The extracellular domain of soluble complement receptor-1 (sCR1) was sialyl Lewis x glycosylated (sCR1sLex) to inhibit complement activation and endothelial-platelet-leukocyte interactions. sCR1 and sCR1sLex colocalized to ischemic cerebral microvessels and C1q-expressing neurons, inhibited neutrophil and platelet accumulation, and reduced cerebral infarct volumes. Additional benefit was conferred by sialyl Lewis x glycosylation of the unmodified parent sCR1 molecule.

Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke.

Acute neutrophil (PMN) recruitment to postischemic cardiac or pulmonary tissue has deleterious effects in the early reperfusion period, but the mechanisms and effects of neutrophil influx in the pathogenesis of evolving stroke remain controversial. To investigate whether PMNs contribute to adverse neurologic sequelae and mortality after stroke, and to study the potential role of the leukocyte adhesion molecule intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of stroke, we used a murine model of transient focal cerebral ischemia consisting of intraluminal middle cerebral artery occlusion for 45 min followed by 22 h of reperfusion. PMN accumulation, monitored by deposition of 111In-labeled PMNs in postischemic cerebral tissue, was increased 2.5-fold in the ipsilateral (infarcted) hemisphere compared with the contralateral (noninfarcted) hemisphere (P < 0.01). Mice immunodepleted of neutrophils before surgery demonstrated a 3.0-fold reduction in infarct volumes (P < 0.001), based on triphenyltetrazolium chloride staining of serial cerebral sections, improved ipsilateral cortical cerebral blood flow (measured by laser Doppler), and reduced neurological deficit compared with controls. In wild-type mice subjected to 45 min of ischemia followed by 22 h of reperfusion, ICAM-1 mRNA was increased in the ipsilateral hemisphere, with immunohistochemistry localizing increased ICAM-1 expression on cerebral microvascular endothelium. The role of ICAM-1 expression in stroke was investigated in homozygous null ICAM-1 mice (ICAM-1 -/-) in comparison with wild-type controls (ICAM-1 +/+). ICAM-1 -/- mice demonstrated a 3.7-fold reduction in infarct volume (P < 0.005), a 35% increase in survival (P < 0.05), and reduced neurologic deficit compared with ICAM-1 +/+ controls. Cerebral blood flow to the infarcted hemisphere was 3.1-fold greater in ICAM-1 -/- mice compared with ICAM-1 +/+ controls (P < 0.01), suggesting an important role for ICAM-1 in the genesis of postischemic cerebral no-reflow. Because PMN-depleted and ICAM-1-deficient mice are relatively resistant to cerebral ischemia-reperfusion injury, these studies suggest an important role for ICAM-1-mediated PMN adhesion in the pathophysiology of evolving stroke.

Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor-mediated platelet aggregation.

Treatment options in acute stroke are limited by a dearth of safe and effective regimens for recanalization of an occluded cerebrovascular tributary, as well as by the fact that patients present only after the occlusive event is established. We hypothesized that even if the site of major arterial occlusion is recanalized after stroke, microvascular thrombosis continues to occur at distal sites, reducing postischemic flow and contributing to ongoing neuronal death. To test this hypothesis, and to show that microvascular thrombosis occurs as an ongoing, dynamic process after the onset of stroke, we tested the effects of a potent antiplatelet agent given both before and after the onset of middle cerebral arterial (MCA) occlusion in a murine model of stroke. After 45 min of MCA occlusion and 23 h of reperfusion, fibrin accumulates in the ipsilateral cerebral hemisphere, based upon immunoblotting, and localizes to microvascular lumena, based upon immunostaining. In concordance with these data, there is a nearly threefold increase in the ipsilateral accumulation of 111In-labeled platelets in mice subjected to stroke compared with mice not subjected to stroke. When a novel inhibitor of the glycoprotein IIb/IIIa receptor (SDZ GPI 562) was administered immediately before MCA occlusion, platelet accumulation was reduced 48%, and fibrin accumulation was reduced by 47% by immunoblot densitometry. GPI 562 exhibited a dose-dependent reduction of cerebral infarct volumes measured by triphenyltetrazolium chloride staining, as well as improvement in postischemic cerebral blood flow, measured by laser doppler. GPI 562 caused a dose-dependent increase in tail vein bleeding time, but intracerebral hemorrhage (ICH) was not significantly increased at therapeutic doses; however, there was an increase in ICH at the highest doses tested. When given immediately after withdrawal of the MCA occluding suture, GPI 562 was shown to reduce cerebral infarct volumes by 70%. These data support the hypothesis that in ischemic regions of brain, microvascular thrombi continue to accumulate even after recanalization of the MCA, contributing to postischemic hypoperfusion and ongoing neuronal damage.

Correlation of cerebral metabolites with functional outcome in experimental primate stroke using in vivo 1H-magnetic resonance spectroscopy.

BACKGROUND AND PURPOSE: Ensuring the translatability of primate stroke models is critical for preclinical testing of cerebroprotective strategies, and such models would benefit from further characterization of the experimental ischemic tissue. Our purpose was to examine the cerebral metabolic response to stroke in baboons with MR spectroscopy and to correlate metabolite levels with functional neurologic outcomes. METHODS: Seven baboons underwent 1 hour of middle cerebral artery occlusion. At 3 and 10 days, each animal was imaged with traditional MR imaging and multivoxel proton (1)H-MR spectroscopy, and a neurologic examination was performed. Spectra obtained from the infarcted hemisphere of each animal were compared with the contralateral hemisphere, and metabolite levels were correlated with neurologic outcome scores. RESULTS: Spectra obtained at 3 days postischemia revealed prominent lactate (LAC) resonances and attenuated N-acetylaspartate (NAA) peaks in infarcted hemispheres. Ten-day spectra showed persistence of these findings in animals with large strokes (>30% of the hemisphere), with partial normalization of the spectra in animals with small strokes (<30% of the hemisphere). Mean area under the curve from LAC spectra had a negative correlation with functional outcome by 2 different scoring systems (r(2) = 0.72 and 0.73), whereas NAA showed a positive correlation (r(2) = 0.79 and 0.62). CONCLUSIONS: The metabolic alterations observed in our primate model of reperfused ischemia by (1)H-MR spectroscopy recapitulate those seen in clinical stroke. Furthermore, correlations between LAC and NAA peaks with functional outcome further suggest that MR spectroscopy may play a role in outcome prediction following cerebral infarction in higher primates.

Shunt failure in idiopathic intracranial hypertension presenting with spontaneous cerebrospinal fluid leak.

A case of spontaneous cerebrospinal (CSF) fluid leak after ventriculoperitoneal shunt (VPS) failure in a patient with idiopathic intracranial hypertension (IIH) is reported. This is the first report of spontaneous CSF leak in an IIH patient without a history of trauma, sinus surgery, or intracranial surgery. The diagnosis was confirmed using thin-sliced post-contrast computed tomography, which revealed a micro-dehiscence of the cribiform plate at the superior aspect of the ethmoid sinus. The patient underwent VPS revision without complication, resulting in complete amelioration of symptoms and cessation of CSF rhinorrhoea at 1 year follow up.

Dysplastic vessels after surgery for brain arteriovenous malformations.

BACKGROUND AND PURPOSE: The cause and clinical significance of residual dysplastic vessels after surgery for brain arteriovenous malformations (AVM) are unclear. We studied predictors and frequency of residual dysplastic vessels on cerebral angiography after AVM surgery. METHODS: The 240 prospectively enrolled surgical patients from the New York AVM Databank underwent 269 AVM-related surgical procedures. Reported postoperative brain angiographic findings were classified post hoc as showing (1) persistent dysplastic vessels, (2) a residual AVM, (3) focal hyperemia in the surgical bed, (4) other changes, or (5) a normal angiogram. Univariate and multivariate models were applied to test for an association between residual dysplastic vessels and patient age, sex, preoperative AVM size, anatomic AVM location, number of embolization procedures before surgery, and the time interval between AVM surgery and the postoperative angiogram. RESULTS: Of the 224 documented postoperative angiograms, 78 (35%) showed dysplastic vessels, 24 (11%) had evidence for a residual AVM, 16 (7%) showed focal hyperemia, 6 (2%) revealed other findings, and 100 (45%) were normal. The number of cases showing angiographic evidence for dysplastic vessels was significantly associated with increasing size of the AVM (in millimeter increments; P=0.0001); the mean diameter of AVMs in patients showing dysplastic vessels after surgery was significantly larger (41 mm, SD +/-14) than in those without residual dysplastic vessels (27 mm, SD +/-13; P<0.001). Symptomatic postoperative intracerebral hemorrhage occurred in 4 patients (1%), in 2 of whom dysplastic vessels were seen on the postoperative angiogram. CONCLUSIONS: The findings suggest that persistent dysplastic vessels may be found in approximately one third of angiograms after AVM surgery. Preoperative AVM size was found to be an independent predictor for the occurrence of dysplastic vessels on the postoperative angiogram.

A modified transorbital baboon model of reperfused stroke.

BACKGROUND AND PURPOSE: Although pathophysiological studies of focal cerebral ischemia in nonhuman primates can provide important information not obtainable in rodent models, primate experimentation is limited by considerations of cost, availability, effort, and ethics. A reproducible and quantitative model that minimizes the number of animals necessary to detect differences between treatment groups is therefore crucial. METHODS: Eight male baboons (weight, 22+/-2 kg) underwent left transorbital craniectomy followed by 1 hour of temporary ipsilateral internal carotid artery occlusion at the level of the anterior choroidal artery together with bilateral temporary occlusion of both anterior cerebral arteries (A1) proximal to the anterior communicating artery. A tightly controlled nitrous oxide-narcotic anesthetic allowed for intraoperative motor evoked potential confirmation of middle cerebral artery (MCA) territory ischemia. Animals survived to 72 hours or 10 days if successfully self-caring. Outcomes were assessed with a 100-point neurological grading system, and infarct volume was quantified by planimetric analysis of both MRI and triphenyltetrazolium chloride-stained sections. RESULTS: Infarction volumes (on T2-weighted images) were 32+/-7% (mean+/-SEM) of the ipsilateral hemisphere, and neurological scores averaged 29+/-9. All animals demonstrated evidence of hemispheric infarction, with damage evident in both cortical and subcortical regions in the MCA vascular territory. Histologically determined infarction volumes differed by <3% and correlated with absolute neurological scores (r=0.9, P:=0.003). CONCLUSIONS: Transorbital temporary occlusion of the entire anterior cerebral circulation with strict control of physiological parameters can reliably produce reperfused MCA territory infarction. The magnitude of the resultant infarct with little interanimal variability diminishes the potential number of animals required to distinguish between 2 treatment regimens. The anatomic distribution of the infarct and associated functional deficits offer comparability to human hemispheric strokes.

Effect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: the Fisher scale revisited.

BACKGROUND AND PURPOSE: Thick cisternal clot on CT is a well-recognized risk factor for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH). Whether intraventricular hemorrhage (IVH) or intracerebral hemorrhage (ICH) predisposes to DCI is unclear. The Fisher CT grading scale identifies thick SAH but does not separately account for IVH or ICH. METHODS: We studied 276 consecutively admitted patients with an available admission CT scan performed within 72 hours of onset. Demographic, clinical, laboratory, and neuroimaging data were recorded, and the amount and location of SAH, IVH, and ICH on admission CT scans were quantified. The relationship between these variables and DCI was analyzed separately and in combination with multiple logistic regression. RESULTS: DCI developed in 20% of patients (54 of 276). Among SAH variables, thick clot completely filling any cistern or fissure was the best predictor of DCI (P=0.008), and among IVH variables, blood in both lateral ventricles was most predictive (P=0.001). These variables had independent predictive value for DCI in a multivariate analysis of CT findings, and both were included in a final multivariate model when evaluated in conjunction with other clinical risk factors: IVH (OR 4.1, 95% CI 1.7 to 9.8), SAH (OR 2.3, 95% CI 1.5 to 9.5), mean arterial pressure >112 mm Hg (OR 4.9, 95% CI 2.1 to 11.4), and transcranial Doppler mean velocity >140 cm/s within 5 days of hemorrhage (OR 3.8, 95% CI 1.5 to 9.5). Similar results were obtained in a repeat analysis with infarction due to vasospasm as the dependent variable. CONCLUSIONS: SAH completely filling any cistern or fissure and IVH in the lateral ventricles are both risk factors for DCI, and their risk is additive. We propose a new SAH rating scale that accounts for the independent predictive value of subarachnoid and ventricular blood for DCI.

Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke.

BACKGROUND AND PURPOSE: Although the deleterious role of several proinflammatory mediators, including P-selectin, in reperfused stroke is well established, the role of E-selectin has not been fully characterized. METHODS: E-selectin mRNA expression was studied at 4, 10, and 24 hours after reperfusion with reverse transcription and polymerase chain reaction in mice (n=18) subjected to transient intraluminal middle cerebral artery occlusion (MCAO). Mice received intravenous injection with anti-E-selectin monoclonal antibody (10, 35, or 50 microg), nonimmune IgG, or vehicle immediately before MCAO and 90 minutes later (n=85). Others received anti-E-selectin antibody 3 or 6 hours after MCAO (n=32). Myeloperoxidase activity was measured in sham-operated mice and after 10 hours of reperfusion in saline-, nonimmune IgG-, or anti-E-selectin IgG-treated cohorts (n=17). Serial cerebral blood flow was measured with laser-Doppler flowmetry, and outcomes were assessed by neurological deficits and infarct volumes with the use of planimetric analysis of triphenyltetrazolium chloride-stained sections. RESULTS: Upregulated E-selectin expression occurred in the ischemic cerebral vasculature within 4 hours of reperfusion and persisted for 24 hours. Anti-E-selectin antibody increased ischemic cortical cerebral blood flow up to 2.6-fold (P:<0.05). In addition to dose-dependent reductions in neurological deficits (P:<0.05), mortality, and infarct volumes (P:<0.01 for 35 and 50 microg), anti-E-selectin treatment reduced cerebral neutrophil accumulation (P:<0.05) and was neuroprotective even if delayed until 3 hours after ischemia (P:<0. 05). CONCLUSIONS: These findings establish a functional role for E-selectin in the pathogenesis of tissue injury after cerebral ischemia and reperfusion and suggest that E-selectin blockade may be clinically useful in the treatment of reperfused stroke.

Comparison of radionuclide scans with computer-assisted tomography in diagnosis of intracranial disease.

Radionuclide brain scans were compared with computer-assisted tomography (CAT) for the diagnosis of intracranial disorders in 297 patients. The diagnosis was confirmed in 281 patients who formed the population for the study. The radionuclide scan was false positive for 12 patients (3.9 percent) and false negative for eight (2.6 percent). The CAT was false positive for three patients (1 percent) and false negative for one (0.3 percent). In the 133 patients in whom both tests were negative, no evidence of central nervous system pathology has been found during the 6 to 18 month follow-up. Brain tumors and intracerebral hemorrhage are more readily detectable with CAT.

Global and domain-specific cognitive impairment and outcome after subarachnoid hemorrhage.

BACKGROUND: Cognitive dysfunction is the most common form of neurologic impairment after subarachnoid hemorrhage (SAH). OBJECTIVE: To evaluate the impact of global and domain-specific cognitive impairment on functional recovery and quality of life (QOL) after SAH. METHODS: One hundred thirteen patients (mean age 49 years; 68% women) were evaluated 3 months after SAH. Three simple tests of global mental status and neuropsychological tests to assess seven specific cognitive domains were administered. Four aspects of outcome (global handicap, disability, emotional status, and QOL) were compared between cognitively impaired and unimpaired patients with analysis-of-covariance models controlling for age, race/ethnicity, and education. Multiple linear regression was used to evaluate the relative contribution of global and domain-specific cognitive status for predicting concurrent modified Rankin Scale (mRS) and Sickness Impact Profile (SIP) scores. RESULTS: Impairment of global mental status on the Telephone Interview of Cognitive Status (TICS) was associated with poor performance in all seven cognitive domains (all p < 0.0005) and was the only cognitive measure associated with poor recovery in all four aspects of outcome (all p < or = 0.005). Cognitive impairment in four specific domains was also associated with functional disability or reduced QOL. After accounting for global cognitive impairment with the TICS, however, neuropsychological testing did not contribute additional predictive value for concurrent mRS or SIP total scores. CONCLUSIONS: Cognitive impairment impacts broadly on functional status, emotional health, and QOL after SAH. The TICS may be a useful alternative to more detailed neuropsychological testing for detecting clinically relevant global cognitive impairment after SAH.

Radiographic evidence and surgical confirmation of a saccular aneurysm on a hypoplastic duplicated A1 segment of the anterior cerebral artery: case report.

OBJECTIVE AND IMPORTANCE: True duplication of the A1 segment of the anterior cerebral artery is extremely rare, as is finding a true A1 segment saccular aneurysm. We report the angiographic and surgical findings of such a case with the additional association of a hypoplastic ipsilateral M1 segment of the middle cerebral artery. CLINICAL PRESENTATION: A 68-year-old man presented with a Hunt and Hess Grade II subarachnoid hemorrhage and symptoms of headache, nuchal rigidity, and facial paresis. INTERVENTION: Angiographic evaluation with superselective exploration revealed a small ruptured aneurysm located on a duplicated hypoplastic A1 segment of the left anterior cerebral artery with associated middle cerebral artery stenosis and secondary early moyamoya changes. Surgical clipping of the aneurysm was performed successfully while sparing the hypoplastic A1 segment. CONCLUSION: A1 aneurysms occurring on a duplicated anterior cerebral artery segment probably develop from a congenital weakness of the parent vessel and increased local shear stress. Superselective angiography was helpful in the preoperative planning and facilitated the decision to treat with surgical clipping instead of embolization.

Immunohistochemical detection of intracranial vasa vasorum: a human autopsy study.

The existence of intracranial vasa vasorum supplying the larger vessels of the circle of Willis has long been debated. Much of this debate results from contradictory findings of microanatomic studies in a variety of nonprimate species. Recently, however, a growing body of evidence seems to suggest that in certain pathological situations, such as human intracranial atherosclerosis, vasa vasorum are present. In an effort to determine whether intracranial vasa vasorum are present in humans without clinical evidence of intracranial vascular disease, we studied the circle of Willis in five autopsy specimens using immunohistochemistry. Antiserum to the endothelial-specific antigen, Factor VIII, revealed staining of 10- to 20-microns vascular channels in the outer media and adventitial layers. Staining was present in the proximal carotid, middle cerebral (M1), and anterior cerebral (A1) arteries but could not be detected in M2 or A2 segments. Hematoxylin and eosin staining was additionally helpful in identifying the nuclear morphology of the endothelial cells lining these channels, as well as the presence of erythrocytes within them. We conclude that in nonpathological settings, endothelial-lined channels exist in the proximal intracranial vessels of humans. These vessels might represent intracranial vasa vasorum, which in turn might play a role in pathological conditions, such as atheroma formation, intracranial dissection, and vasospasm.

Serum elastase and alpha-1-antitrypsin levels in patients with ruptured and unruptured cerebral aneurysms.

Despite advances in surgical treatment and postoperative care, subarachnoid hemorrhage from ruptured cerebral aneurysms remains a devastating event. Excellent surgical results in treating unruptured aneurysms suggest the utility of screening tests to identify high-risk individuals. Unfortunately, none of the known risk factors for subarachnoid hemorrhage correlates strongly enough with the illness to warrant widespread screening for occult aneurysms. Other disease entities suggest that protease-antiprotease imbalances contribute to somatic vessel wall degradation and aneurysm formation. Detection of similar imbalances in selected patients may identify a predisposition to cerebral aneurysm formation. Serum concentrations of elastase and alpha-1-antitrypsin (AAT), important proteolytic and antiproteolytic enzymes, were measured in a series of 19 patients with unruptured aneurysms, 41 patients with ruptured aneurysms, and 27 age-matched operative and nonoperative controls. The elastase:AAT ratio was nearly twice as high in patients with unruptured aneurysms as in operative controls (0.527 +/- 0.1 versus 0.285 +/- 0.06; P < 0.04). Elastase:AAT ratios in patients with ruptured aneurysms (subarachnoid hemorrhage < 48 h) were roughly twice those of controls (0.582 +/- 0.095; P < 0.01). There was no statistical difference between elastase:AAT ratios for patients with ruptured and unruptured aneurysms. Likewise, elastase-AAT values for operative controls and nonoperative volunteers were not significantly different. Differences in serum elastase:AAT ratios between patients with aneurysms and controls reflected differences in elastase concentration (99 +/- 56 micrograms/ml versus 67 +/- 56 micrograms/ml; P < 0.03), not in AAT levels (147 +/- 56 micrograms/ml versus 141 +/- 56 micrograms/ml; P < 0.72).(ABSTRACT TRUNCATED AT 250 WORDS)

Procedural and strain-related variables significantly affect outcome in a murine model of focal cerebral ischemia.

The recent availability of transgenic mice has led to a burgeoning number of reports describing the effects of specific gene products on the pathophysiology of stroke. Although focal cerebral ischemia models in rats have been well described, descriptions of a murine model of middle cerebral artery occlusion are scant and sources of potential experimental variability remain undefined. We hypothesized that slight technical modifications would produce widely discrepant results in a murine model of stroke and that controlling surgical and procedural conditions could lead to reproducible physiological and anatomic stroke outcomes. To test this hypothesis, we established a murine model that would permit either permanent or transient focal cerebral ischemia by intraluminal occlusion of the middle cerebral artery. This study provides a detailed description of the surgical technique and reveals important differences among strains commonly used in the production of transgenic mice. In addition to strain-related differences, infarct volume, neurological outcome, and cerebral blood flow appear to be importantly affected by temperature during the ischemic and postischemic periods, mouse size, and the size of the suture that obstructs the vascular lumen. When these variables were kept constant, there was remarkable uniformity of stroke outcome. These data emphasize the protective effects of hypothermia in stroke and might help to standardize techniques among different laboratories to provide a cohesive framework for evaluating the results of future studies in transgenic animals.