Enoxaparin in neurosurgical patients.
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Anticoagulants↗
Biomedical subjects
E S Connolly
Publications and source records attributed to E S Connolly.
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.
Animals↗
The epidemiology of urban pediatric neurological trauma: evaluation of, and implications for, injury prevention programs.
OBJECTIVE: To describe the incidence and causes of pediatric head, spinal cord, and peripheral nerve injuries in an urban setting and to assess the implications of these data for injury prevention programs. METHODS: Pediatric deaths and hospital admissions secondary to neurological trauma included in the Northern Manhattan Injury Surveillance System from 1983 to 1992 were linked to census counts to compute incidence rates. Rates before the implementation of a nonspecific injury prevention program were compared with rates after the implementation, and rates for the target population were compared to rates for the control population. Rates were analyzed on the basis of the cause of injury as well as the age, gender, and neighborhood income level of the injured. RESULTS: The incidence of neurological injuries resulting in hospitalization or death was 155 incidents per 100,000 population per year; the mortality rate was 6 people per 100,000 population per year. Neurological injuries represented 18% of all pediatric injuries and accounted for 23% of all traumatic deaths. Spinal cord and peripheral nerve injuries were relatively rare (5%) compared to head injuries (95%). Minor head injuries, including isolated cranial fractures, minor concussions (<1 h loss of consciousness), and unspecified minor head injuries, accounted for the majority of neurological injuries (76%), whereas severe head injuries, including severe concussion (>1 h loss of consciousness), cerebral laceration/contusion, intracerebral hemorrhage, and unspecified major injuries, were less common (18% of all neurological injuries). Boys were more often affected than girls at every age, and this preference increased with age. Children younger than 1 year showed the highest incidence of both major and minor injuries. One- to 4-year olds showed the lowest rates, with steady increases thereafter. Traffic accidents and falls were the leading causes (38 and 34%, respectively), and assaults were the next leading causes (12%). Among children admitted to surveillance system hospitals, falls were most common in children younger than 4 years, pedestrian motor vehicle accidents were most common in late childhood, and assaults were most common in early adolescence. CASE: fatality rates were 5 to 7% for all age groups except 5- to 12-year-olds, for whom the case:fatality rate was 1.9%. Residence in a low-income neighborhood was associated with an increased risk of injury (rate ratio, 1.71; confidence interval, 95%, 1.54, 1.89). The average hospitalization cost per injury was $8502. Medicaid (54%) and other government sources (5%) covered the majority of expenses, including indirect reimbursement of usually uncollected self-pay billing (19%). Although injury incidence rates fell in both the control and intervention cohorts during implementation of a nonspecific injury prevention program, targeted age and population groups demonstrated greater relative reductions in injuries than nontargeted ones, suggesting a positive effect. CONCLUSIONS: Deaths and hospital admissions secondary to pediatric neurological trauma represent a significant public health problem, with the majority of the direct cost being born by government agencies. Future efforts to prevent neurological trauma in children who live in inner cities should focus on families with low incomes and provide novel education programs regarding infant abuse, infant neglect, and infant injury avoidance. Age-appropriate school-based programs should also be developed to address traffic safety and conflict resolution.
Adolescent↗
The posterior approach to a series of glomus (Type II) intramedullary spinal cord arteriovenous malformations.
OBJECTIVE: Intramedullary spinal cord arteriovenous malformations (AVMs) are comprised of those AVMs which in either glomus or nidal form are found partially or entirely within the substance of the spinal cord. An effort to subdivide these lesions into either glomus Type II or juvenile Type III spinal cord AVMs has underscored the diffuse, unresectable nature of the latter but has done little to suggest a logical management paradigm for the more well-defined, low-flow glomus lesion. METHODS: To address this shortcoming, 15 cases of glomus Type II spinal AVMs were identified from a larger series of a variety of spinal AVMs. Computed tomography, magnetic resonance imaging, and superselective angiography rendered the anatomic diagnosis of these lesions accurate in all cases. All lesions were approached posteriorly via a standard laminectomy, with the goal of total extirpation, and all patients underwent immediate postoperative angiography to verify cure. In the vast majority of cases, patients underwent follow-up imaging to confirm the durability of this cure, and long-term outcome was determined using both a subjective quality of life assay and a functional grading scale. Age, sex, mode of presentation, and radiographic features were subsequently analyzed with respect to functional outcome. RESULTS: Most glomus spinal AVMs presented with a rapid cascade of signs and symptoms (73%), often caused by subarachnoid hemorrhage (60%) and often leading to significant neurological deficits (47%). Initially, 14 of 15 patients (94%) were angiographically cured of their malformations. The remaining patient was neurologically improved after a 90% resection, and follow-up angiography demonstrated that the residual was thrombosed. However, not uncommonly, follow-up angiography and magnetic resonance imaging revealed recurrences, with three of the patients who underwent delayed imaging (23%) demonstrating new draining veins. Fortunately, in each case, the recurrence was asymptomatic. Therefore, the long-term cure rate (mean follow-up, 8.5 yr; range, 1-17 yr) was 80%, with no subsequent bleeding or progression of symptoms. Outcomes were generally good, with six patients (40%) demonstrating objective improvement, eight (53%) being neurologically stable, and one (7%) being worse. Sixty-six percent were independent, 20% required moderate assistance, and 14% remained entirely dependent. There were no deaths. Patients possessing lesions with large direct feeders off the anterior spinal artery and occupying a primarily anterior position in the cord fared somewhat worse, as did those with rapidly progressing symptomatology in the absence of subarachnoid hemorrhage. However, even in those with preserved or improved function, chronic pain was a significant problem, affecting one-third of all patients. Chronic pain was especially common in young women who had presented with significant preoperative pain that responded poorly to all subsequent therapeutic manipulations. CONCLUSION: With careful evaluation of high-quality superselective angiography and the judicious use of preoperative embolization, posterior surgical approaches can deliver results comparable with those achieved for other benign intramedullary lesions in terms of long-term cure (80%), control of symptom progression (100%), and good functional outcome (86%). Despite these results, chronic dysesthetic pain syndromes are not uncommon and continue to present a significant management problem.
Adult↗
Surgical management of high-grade intracranial dural arteriovenous fistulas: leptomeningeal venous disruption without nidus excision.
OBJECTIVE: Of intracranial dural arteriovenous malformations (AVMs), those with cortical venous drainage pose the greatest risk of hemorrhaging. Given recent advances in endovascular, surgical, and radiosurgical techniques, the optimal management of these dural AVMs is controversial. For surgical candidates, the choice of intraoperative techniques remains unclear. Several authors have suggested that surgical clipping of the draining vein close to the nidus of dural AVMs can provide adequate treatment for some lesions. However, recent reports have also promoted partial or complete surgical resection of these lesions. METHODS: We present five cases of dural AVMs with cortical venous drainage that were surgically treated by the senior author between 1993 and 1996, and we review their management. Our series includes two frontal, one temporal, and two occipital lesions. Three patients presented with intracerebral hemorrhages, one with headache and eye pain, and one without symptoms. All five patients demonstrated venous aneurysms associated with the AVMs. Two patients underwent incomplete endovascular embolization before surgery. Operative management in all cases involved clipping of the draining vein as close as possible to the AVMs, together with extensive cautery of the surrounding dura. RESULTS: Postoperative angiography demonstrated complete angiographic obliteration in all cases. The four symptomatic patients all experienced clinical improvement postoperatively. The asymptomatic patient remained asymptomatic. With a mean follow-up period of 29 months, no patient has developed recurrent symptoms. CONCLUSION: Surgical clipping of the draining vein close to dural AVMs has proven safe and effective in our experience. Given the highly vascular nature of dural AVMs, often near major dural sinuses, surgical resection of these lesions may not be indicated.
Adult↗
Complex intracranial aneurysms: combined operative and endovascular approaches.
OBJECTIVE: Endovascular management of complex intracranial aneurysms is increasingly being considered as an alternative to standard surgical clipping. However, little attention has been paid to the complementary nature of surgery and endovascular therapy. METHODS: Between September 1992 and May 1997, 12 patients with complex intracranial aneurysms were treated with combined operative and endovascular methods. Seven patients demonstrated subarachnoid hemorrhage (two of Grade II, two of Grade III, and three of Grade IV). Five patients demonstrated unruptured aneurysms, i.e., three giant aneurysms (one vertebrobasilar junction aneurysm, one middle cerebral artery bifurcation aneurysm, and one internal carotid artery-ophthalmic artery aneurysm), one large internal carotid artery-ophthalmic artery aneurysm, and one middle cerebral artery serpentine aneurysm. Management strategies involved either surgery followed by endovascular therapy (S-E; n = 5) or endovascular therapy followed by surgery (E-S; n = 7). S-E paradigms included aneurysm exploration followed by endovascular treatment (S-E1; n = 3), partial aneurysm clipping followed by endovascular aneurysm packing (S-E2; n = 1), and extracranial-to-intracranial bypass followed by endovascular parent vessel occlusion (S-E3; n = 1). E-S paradigms included superselective angiography followed by surgical clipping (E-S1; n = 2), Guglielmi detachable coil partial dome packing followed by delayed surgical clipping (E-S2; n = 2), proximal temporary vessel balloon occlusion followed by aneurysm clipping (E-S3; n = 2), and proximal permanent vessel occlusion followed by surgical aneurysm decompression for mass effect treatment (E-S4; n = 1). RESULTS: Eleven aneurysms (92%) were completely eliminated. The remaining aneurysm was 90% obliterated and remained quiescent at the 34-month follow-up examination, despite presenting with subarachnoid hemorrhage. No patient experienced repeat bleeding (follow-up period, 23+/-28 mo). There were no deaths. One patient achieved a fair outcome (Glasgow Outcome Scale score of III); all other patients experienced excellent outcomes (Glasgow Outcome Scale score of I). In all cases, the aneurysm management paradigm chosen had a positive effect on definitive therapy. CONCLUSION: Several factors can contribute to the complexity of intracranial aneurysms. Management strategies that combine operative and endovascular techniques in a complementary way, for the best possible outcomes for these patients, can be designed accordingly.
Adult↗
Neuropsychometric changes in patients after carotid endarterectomy.
BACKGROUND AND PURPOSE: One hundred twelve patients undergoing elective carotid endarterectomy for symptomatic and asymptomatic carotid artery stenosis were enrolled in a prospective study to evaluate the incidence of change in postoperative cerebral function. METHODS: Patients were evaluated preoperatively and postoperatively before hospital discharge and at follow-up 1 and 5 months later with a battery of neuropsychometric tests. The results were analyzed by both event-rate and group-rate analyses. For event-rate analysis, change was defined as either a decline or improvement in postoperative neuropsychometric performance by 25% or more compared with a preoperative baseline. RESULTS: Approximately 80% of patients showed decline in one or more test scores, and 60% had one or more improved test scores at the first follow-up examination. The percentage of declined test scores decreased and the percentage of improved test scores increased with subsequent follow-up examinations. Group-rate analysis was similar for group performance on individual tests. However, a decline in performance was seen most commonly on verbal memory tests, and improved performance was seen most commonly on executive and motor tests. CONCLUSIONS: Neuropsychometric evaluation of patients undergoing carotid endarterectomy for significant carotid artery stenosis demonstrates both declines and improvements in neuropsychometric performance. The test changes that showed decreased performance may be associated with ischemia from global hypoperfusion or embolic phenomena, and the improvement seen may be related to increased cerebral blood flow from removal of stenosis.
Aged↗
Management of symptomatic and asymptomatic unruptured aneurysms.
Intradural unruptured saccular aneurysms are being diagnosed with increasing frequency. Left untreated, these lesions usually progress, and the cumulative risk from bleeding usually outweighs the risk of treatment. Exceptions include patients with limited life expectancy and patients over the age of 70 with small asymptomatic or giant posterior circulation lesions associated with few symptoms. Therapeutic intervention offers little over the natural history for these patients, and therapy should be considered only if symptoms progress or growth is documented. Treatment options should be coordinated by an experienced cerebrovascular surgeon with access to interventional adjuncts; EC-IC bypass, and circulatory arrest. GDC coiling should be reserved for non-surgical cases, as the durability of this treatment is still being evaluated.
Aneurysm, Ruptured↗
Hypothermic cardiac standstill for cerebral aneurysm surgery.
Surgical management of giant cerebral aneurysms remains a major technical challenge for modern neurosurgeons. Endovascular approaches for giant aneurysms does not provide an acceptable alternative to direct surgical approaches. The use of deep hypothermic circulatory arrest as an adjunct during clipping of complex giant aneurysms shows promise as a treatment for otherwise incurable lesions. Patient selection and techniques of circulatory arrest surgery are discussed.
Brain↗
Giant posterior fossa cystic craniopharyngiomas presenting with hearing loss. Report of three cases and review of the literature.
BACKGROUND: Autopsy studies and recent reviews report that 4% of craniopharyngiomas have posterior fossa extension at initial operation, and 12% subsequently develop this extension during their course. However, only two patients in the literature have been shown to present with deafness, which preceded the more typical suprasellar signs and symptoms of increased intracranial pressure, endocrine disturbance, altered mentation, and visual deterioration. METHODS: The authors report three cases of giant cystic posterior fossa craniopharyngioma initially presenting in childhood with either unilateral or bilateral deafness. These cases are presented, the literature on posterior fossa craniopharyngioma is reviewed, and staged operative management is discussed. RESULTS: Despite being rarely reported, 10% to 20% of giant cystic craniopharyngiomas with posterior fossa extension at presentation may have unilateral or bilateral deafness as their first symptom. Deafness as a presenting symptom is much less common in patients presenting with recurrent tumors in this location than with primary tumors. Pterional or bifrontal craniotomy is appropriate for management of the parasellar component and should be undertaken first when visual symptoms are present. Suboccipital craniectomy is appropriate for management of the posterior fossa component and should be undertaken first when brain stem compressive symptoms make it necessary. Skull-base techniques may have value in certain settings, but patient's morbidity when using these techniques must be carefully considered. CONCLUSIONS: Our results indicate that staged operations with the goal of achieving gross total resection can yield excellent results. Adjuvant radiation is indicated for those with residual tumor seen on magnetic resonance imaging (MRI), but in young children without residual tumors by MRI, we prefer to follow carefully with serial scans. Since the loss of hearing in children can compromise language development, we suggest referral of these children to a specialist in language rehabilitation.
Child↗
The safety of intraoperative lumbar subarachnoid drainage for acutely ruptured intracranial aneurysm: technical note.
Recently, some concern has arisen regarding the safety of intraoperative spinal drainage for brain relaxation in aneurysm surgery, due to anecdotal association with both aneurysmal rebleeding and increases in symptomatic vasospasm. To address these concerns, we reviewed our experience with frequent spinal drainage and early surgery in 432 consecutive cases of surgically treated aneurysmal subarachnoid hemorrhage. Unless contraindicated by mass effect or associated pathology, all grade I-III patients referred within 14 days were treated with spinal drainage at surgery. In this cohort (n = 314), there were no cases of meningitis or nerve root injury. Only one case of intraoperative rebleeding could be associated with spinal drain placement (0.3%). In grade IV-V patients, 47% required preoperative ventriculostomy, and 11% were ineligible for spinal drainage due to mass effect. There were, however, no complications related to spinal drainage in the remaining 23 patients. Permanently-shunted hydrocephalus (8%) and symptomatic vasospasm (19%) were infrequent overall. When analyzed by grade, spinal drains were generally associated with equal or reduced incidence of these developments when compared to patients without spinal drainage. We conclude that brain relaxation can be safely and effectively obtained using intraoperative spinal drains during early aneurysm surgery.
Acute Disease↗
Elastin degradation in the superficial temporal arteries of patients with intracranial aneurysms reflects changes in plasma elastase.
OBJECTIVE: alpha 1-Antitrypsin (AAT) and alpha 2-macroglobulin (AMG) are elastase inhibitors that bind the enzyme and reduce measured levels of free elastase. It was recently demonstrated that some patients with intracranial aneurysms have significantly elevated plasma elastase (PE) levels. Although this elevation is unrelated to plasma AAT, it is unknown whether abnormal AAT phenotypes or reduced AMG levels play a role. Moreover, the pathological significance of this elevation is not understood. METHODS: Plasma from 24 patients with aneurysms (ruptured, n = 15; unruptured, n = 9) and 10 age-matched patients who comprised a control group was analyzed for PE and AMG levels by enzyme-linked immunosorbent assay and for AAT phenotype by isoelectric focusing. Sections of superficial temporal temporal artery obtained from these patients at the time of surgery were examined for evidence of elastin degradation by using a van Gieson stain, with scoring on a nine-point quantitative scale. RESULTS: Patients with aneurysms showed significantly elevated PE levels (119 +/- 28 versus 17 +/- 7 micrograms/ml, P < 0.05), but AMG levels were not decreased. AAT phenotypic abnormalities were observed in 10% (2 of 20) of the patients with aneurysms, but this was not different from the expected population incidence (7%). Elastin degradation scores were significantly higher in patients with aneurysms than in patients control group (4.26 +/- 0.54 versus 1.21 +/- 0.43, P < 0.05). In addition, patients with higher elastase levels (> 80 micrograms/ml) demonstrated 55% higher degradation scores than did those with lower elastase levels (< 80 micrograms/ml). CONCLUSION: These data suggest that high PE levels may play a role in systemic arterial elastin degradation seen in patients with intracranial aneurysms. These data also support the contention that elevated elastase levels are not the result of decreased protease inhibitor levels. Although PE levels were significantly higher for the entire group of patients with aneurysms, this assay has relatively low sensitivity for predicting the presence of unruptured aneurysms. Additional study is necessary to determine whether serum elastase levels greater than 80 micrograms/ml, in the setting of other risk factors, are useful in identifying asymptomatic patients for additional screening.
Adult↗
Matrix metalloproteinase-9 in cerebral aneurysms.
OBJECTIVE: Generalized disruption of arterial wall morphological changes in patients harboring cerebral aneurysms has been documented; however, little is known regarding the pathogenesis of these changes. To explore the role of the elastolytic gelatinase, matrix metalloproteinase-9 (MMP-9), levels of this enzyme in the wall of intracranial aneurysms were compared with those in both intracranial and extracranial arteries. The tissue levels of its major inhibitor, tissue inhibitor of metalloproteinase (TIMP), were measured in these tissues as well. The activity of MMP-9 in plasma was also evaluated. METHODS: The aneurysm wall was excised from three of six patients undergoing craniotomies for aneurysm clipping. A 1-cm segment of superficial temporal artery (STA) was obtained from each of six patients. Additional STAs were obtained from six patients in the control group who were undergoing craniotomies for nonvascular disease. An intracranial artery was also obtained from the anterior temporal neocortical resection of a patient undergoing a craniotomy for mesial temporal sclerosis. MMP-9 and TIMP levels were determined via Western blot analysis. Using substrate gel Zymography, MMP-9 plasma activity was determined for a separate cohort of patients with aneurysms (n = 6) and patients in the control group (n = 6). RESULTS: MMP-9 and TIMP levels in the aneurysm wall were markedly increased beyond levels in both extracranial arteries (STAs from patients with aneurysms and patients in the control group) and the intracranial artery. There were no differences in the levels of MMP-9 in the STAs of patients harboring aneurysms when compared with patients in the control group. Also, no differences were noted in plasma MMP-9 activity. CONCLUSION: Local rather than systemic perturbations in MMP-9 levels may contribute to the matrix disruption associated with cerebral aneurysms. This local up-regulation is not the result of TIMP down-regulation. The lack of increased systemic metalloproteinase activity precludes the use of plasma MMP-9 activity as a screening tool for presymptomatic aneurysms. However, local therapeutic modulation of MMP-9 activity may help arrest aneurysm progression.
Aneurysm, Ruptured↗
Treatment of inoperable carotid aneurysms with endovascular carotid occlusion after extracranial-intracranial bypass surgery.
OBJECTIVE: Hunterian ligation of the internal carotid artery (ICA) is an accepted treatment for inoperable carotid aneurysms. Preliminary extracranial-intracranial (EC-IC) bypass surgery is required in some patients. The reported incidence of thromboembolic and ischemic complications remains significant for these patients, despite a variety of advocated management strategies. We present our treatment paradigm. METHODS: Between April 1992 and March 1997, nine patients with inoperable ICA aneurysms were treated using EC-IC bypass surgery and then permanent endovascular ICA occlusion. All of the patients except one had been selected for bypass surgery on the basis of failing results of the ICA test occlusion with hypotensive challenge. ICA occlusion was performed by endovascular means and was delayed after bypass surgery was performed by a mean of 6 days (range, 2-20 d). All patients were managed in the intensive care unit after ICA occlusion. RESULTS: Clinical improvement was noted in all patients (mean follow-up, 21 mo; range, 3-42 mo). There were no major complications. Aneurysmal thrombosis was confirmed in all patients. Although ICA occlusion was delayed after bypass surgery, only one bypass was noted to be occluded. The occluded bypass occurred in a patient who subsequently underwent successful ICA occlusion. This patient was thought to have been improperly selected for bypass surgery. CONCLUSION: Certain carotid aneurysms can be effectively managed with hunterian ICA ligation. After preliminary identification of patients with borderline cerebrovascular reserve as candidates for EC-IC bypass surgery, close attention to the following points may help enhance clinical outcome: 1) excellence in surgical technique for EC-IC bypass surgery, 2) occlusion of the parent vessel as close to the aneurysm neck as possible by endovascular means, and 3) judicious postoperative combination of anticoagulation, fluid, and pressure management.
Adult↗
Exacerbation of cerebral injury in mice that express the P-selectin gene: identification of P-selectin blockade as a new target for the treatment of stroke.
There is currently a stark therapeutic void in the treatment of evolving stroke. Although P-selectin is rapidly expressed by hypoxic endothelial cells in vitro, the functional significance of P-selectin expression in stroke remains unexplored. In order to identify the pathophysiological consequences of P-selectin expression and to identify P-selectin blockade as a potential new approach for the treatment of stroke, experiments were performed using a murine model of focal cerebral ischemia and reperfusion. Early P-selectin expression in the postischemic cerebral cortex was demonstrated by the specific accumulation of radiolabeled anti-murine P-selectin IgG, with the increased P-selectin expression localized to the ipsilateral cerebral microvascular endothelial cells by immunohistochemistry. In experiments designed to test the functional significance of increased P-selectin expression in stroke, neutrophil accumulation in the ischemic cortex of mice expressing the P-selectin gene (PS +/+) was demonstrated to be significantly greater than that in homozygous P-selectin-null mice (PS -/-). Reduced neutrophil influx was accompanied by greater postischemic cerebral reflow (measured by laser Doppler) in the PS -/- mice. In addition, PS -/- mice demonstrated smaller infarct volumes (5-fold reduction, P<.05) and improved survival compared with PS +/+ mice (88% versus 44%, P<.05). Functional blockade of P-selectin in PS +/+ mice using a monoclonal antibody directed against murine P-selectin also improved early reflow and stroke outcome compared with control mice, with reduced cerebral infarction volumes noted even when the blocking antibody was administered after occlusion of the middle cerebral artery. These data are the first to demonstrate a pathophysiological role for P-selectin in stroke and suggest that P-selectin blockade may represent a new therapeutic target in the treatment of stroke.
Animals↗
Use of a spectrophotometric hemoglobin assay to objectively quantify intracerebral hemorrhage in mice.
BACKGROUND AND PURPOSE: There is great interest in developing novel anticoagulant or thrombolytic strategies to treat ischemic stroke. However, at present there are limited means to accurately assess the hemorrhagic potential of these agents. The present studies were designed to develop and validate a method to accurately quantify the degree of intracerebral hemorrhage (ICH) in murine models. METHODS: In a murine model, ICH was induced by stereotaxic intraparenchymal infusion of collagenase B alone (6 x 10(-6) U; n = 5) or collagenase B followed by intravenous recombinant tissue plasminogen activator (rt-PA) (0.1 mg/kg; n = 6). Controls consisted of either sham surgery with stereotaxic infusion of saline (n = 5) or untreated animals (n = 5). ICH was (1) graded by a scale based on maximal hemorrhage diameter on coronal sections and (2) quantified by a spectrophotometric assay measuring cyanomethemoglobin in chemically reduced extracts of homogenized murine brain. This spectrophotometric assay was validated with the use of known quantities of hemoglobin or autologous blood added to a separate cohort of homogenized brains. With this assay, the degree of hemorrhage after focal middle cerebral artery occlusion/reperfusion was quantified in mice treated with postocclusion high-dose intravenous rt-PA (10 mg/kg; n = 11) and control mice subjected to stroke but treated with physiological saline solution (n = 9). RESULTS: Known quantities of hemoglobin or autologous blood added to fresh whole brain tissue homogenates showed a linear relationship between the amount added and optical density (OD) at the absorbance peak of cyanomethemoglobin (r = 1.00 and .98, respectively). When in vivo studies were performed to quantify experimentally induced ICH, animals receiving intracerebral infusion of collagenase B had significantly higher ODs than saline-infused controls (2.1-fold, increase; P = .05). In a middle cerebral artery occlusion and reperfusion model of stroke, administration of rt-PA after reperfusion increased the OD by 1.8-fold compared with animals that received physiological saline solution (P < .001). When the two methods of measuring ICH (visual score and OD) were compared, there was a linear correlation (r = .88). Additional experiments demonstrated that triphenyltetrazolium staining, which is commonly used to stain viable brain tissue, does not interfere with the spectrophotometric quantification of ICH. CONCLUSIONS: These data demonstrate that the spectrophotometric assay accurately and reliably quantifies murine ICH. This new method should aid objective assessment of the hemorrhagic risks of novel anticoagulant or thrombolytic strategies to treat stroke and can facilitate quantification of other forms of ICH.
Animals↗
Management of spinal epidural hematoma after tissue plasminogen activator. A case report.
STUDY DESIGN: This case report illustrates a patient with a spontaneous epidural hematoma after tissue plasminogen activator therapy who presented 10 days after the incident with a resolving Brown-Sèquard syndrome. OBJECTIVES: The treatment of this patient involves the principles of conservative follow-up directed by an improving examination and an understanding of the pathophysiology of coagulopathy-induced spontaneous epidural bleeds. SUMMARY OF BACKGROUND DATA: The use of tissue plasminogen activator therapy for thrombolysis in patients with early acute myocardial infarction is becoming increasingly routine. Use is limited most significantly by bleeding complications. Recently, several groups have drawn attention to the neurologic complications associated with intracranial hemorrhage after tissue plasminogen activator therapy. Spontaneous spinal epidural hemorrhage has, by comparison, received little attention. The authors report the second case in the literature and the first without a history of antecedent trauma. METHODS: The onset of the painful myelopathy in this patient was missed in the acute setting because of low suspicion. When the diagnosis was made, coadministered heparin had already been discontinued without reversal, and the patient's examination had already improved. Careful follow-up by neurologic examination and magnetic resonance imaging was obtained without spinal angiography being performed. RESULTS: The patient regained his prehemorrhage neurologic status, experienced no further bleeding, and his coronary ischemia remained subclinical. CONCLUSIONS: Spinal epidural hemorrhage secondary to thrombolytic therapy is becoming increasingly common. Urgent surgical decompression is generally warranted to preserve neurologic function. In cases where the deficit is minimal or resolving, a conservative approach may be warranted with magnetic resonance imaging but not angiographic follow-up.
Aged↗
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.
Animals↗