A Prospective Safety Trial of Atorvastatin Treatment to Assess Rebleeding after Spontaneous Intracerebral Hemorrhage: A Serial MRI Investigation.

AIM: This study was designed to determine any rebleeding after atorvastatin treatment following spontaneous intracerebral hemorrhage (ICH) in a prospective safety trial. PATIENTS: Atorvastatin (80 mg/day) therapy was initiated in 6 patients with primary ICH with admission Glasgow Coma Score (GCS) >5 within 24 hours of ictus and continued for 7 days, with the dose tapered and treatment terminated over the next 5 days. Patients were studied longitudinally by multiparametric magnetic resonance imaging (MRI) at three time points: acute (3 to 5 days), subacute (4 to 6 weeks) and chronic (3 to 4 months). Imaging sequences included T1, T2-weighted imaging (T2WI), diffusion tensor imaging (DTI) and contrast-enhanced MRI measures of cerebral perfusion, blood volume and blood-brain barrier (BBB) permeability. Susceptibility weighted imaging (SWI) was used to identify primary ICH and to check for secondary rebleeding. Final outcome was assessed using Glasgow Outcome Score (GOS) at 3-4 months. RESULTS: Mean admission GCS was 13.2±4.0 and mean GOS at 3 months was 4.5±0.6. Hemorrhagic lesions were segmented into core and rim areas. Mean lesion volumes decreased significantly between the acute and chronic study time points (p=0.008). Average ipsilateral hemispheric tissue loss at 3 to 4 months was 11.4±4.6 cm3. MRI showed acutely reduced CBF (p=0.004) and CBV (p=0.002) in the rim, followed by steady normalization. Apparent diffusion coefficient of water (ADC) in the rim demonstrated no alterations at any of the time points (p>0.2). The T2 values were significantly elevated in the rim acutely (p=0.02), but later returned to baseline. The ICH core showed sustained low CBF and CBV values concurrent with a small reduction in ADC acutely, but significant ADC elevation at the end suggestive of irreversible injury. CONCLUSION: Despite the presence of a small, probably permanent, cerebral lesion in the ICH core, no patients exhibited post-treatment rebleeding. These data suggest that larger, Phase 2 trials are warranted to establish long term clinical safety of atorvastatin in spontaneous ICH.

Erythropoietin promotes neurological recovery after intracerebral haemorrhage in rats.

BACKGROUND: Attention has turned to neurorestorative therapies, including erythropoietin, for experimental ischaemic stroke and head injury. Treatments for intracerebral haemorrhage need to be developed, as this represents a particularly devastating and common form of neurological injury. Aim The aim of this study is to investigate the therapeutic potential of erythropoietin after intracerebral haemorrhage in rats and to measure its effects on mechanisms of recovery and neurogenesis. METHODS: Intracerebral haemorrhage was induced in 24 Wistar male rats by intrastriatal infusion of autologous blood. Recombinant human erythropoietin (5000 or 10,000 U/kg BW/day) or saline was administered starting 1 day after intracerebral haemorrhage and continued daily for 1 week (n=8 for each group). To label proliferating cells, 5'-bromo-2' deoxyuridine was injected daily for 13 days after intracerebral haemorrhage. All animals survived for 2 weeks after intracerebral haemorrhage. Functional outcome, area of tissue loss and immunohistochemical staining were measured at 14 days after intracerebral haemorrhage. Global test or anova was used to test the erythropoietin dose effect. RESULTS: Rats receiving recombinant human erythropoietin after intracerebral haemorrhage exhibited significant improvement in modified neurological severity score and corner test at 14 days (P<0.05). Increased expression of phenotypes of synaptogenesis and proliferating immature neurons were shown by immunohistochemical staining. Only the group receiving a lower dose of recombinant human erythropoietin had significantly less tissue loss compared with the control group (P<0.05). In rats treated with recombinant human erythropoietin, double staining for 5'-bromo-2' deoxyuridine and TUJ1 revealed a subpopulation of cells that express an immature neuronal marker while still dividing. CONCLUSIONS: Erythropoietin improves neurological outcome and increases histochemical parameters of neurogenesis when given after intracerebral haemorrhage in rats. Intriguingly, only the lower dose of recombinant human erythropoietin was effective in reducing tissue loss in the region of intracerebral haemorrhage.

A selective cysteine protease inhibitor is non-toxic and cerebroprotective in rats undergoing transient middle cerebral artery ischemia.

Ischemic neuronal injury mediated by cysteine proteases such as calpains and caspases has been demonstrated in various experimental models. Cathepsins B and L are also cysteine proteases which may contribute to neuronal death after ischemia. The authors measured in vitro and in vivo toxicity and post-ischemic cytoprotective effects of a cysteine protease inhibitor which does not block calpain or caspase but, rather, is relatively selective for cathepsins B and L. The compound belongs to the peptidyl-diazomethane family (cysteine protease inhibitor 1, termed CP-1). In vitro toxicity was measured using an assay of cell viability, and in vivo toxicity was measured by histological tissue analysis after infusion of CP-1 in rats. Two hours of middle cerebral artery (MCA) occlusion in rats was performed by the intravascular suture method. Immediately following reperfusion, intravenous infusion of CP-1 or vehicle was performed for 4 h at 0.9 ml/h. After a 7-day survival, the infarct volumes were measured. CP-1 was non-toxic to cultured glial cells to a local concentration of 200 microM, and relatively non-toxic to cultured endothelial cells at concentrations of 100-200 microM. No animal exhibited toxic effects at any of the doses used. Histologic comparisons revealed no signs of tissue toxicity. CP-1 significantly reduced hemispheric infarct volume compared to control (37+/-8.2%) at concentrations of 10, 50, and 250 microM [22+/-15%, P=0.008; 20+/-13%, P=0.002; 23+/-15%, P=0.022, respectively (mean+/-standard deviation; N=7-10 per group)]. CP-1, at the concentration of 50 microM, improved the functional score of the animals, but did not significantly alter cerebral blood flow. This study supports the hypothesis that the lysosomal cathepsins B and/or L contribute to cerebral injury after focal ischemia with reperfusion. Cysteine protease inhibitors which are relatively selective for cathepsins B and L, but not the calpains or caspases, are effective at reducing infarct volume after intravenous post-ischemic administration.

Temporal lobe arteriovenous malformations: surgical management and outcome.

BACKGROUND: Temporal lobe arteriovenous malformations (AVMs) represent a subgroup of intracranial AVMs with particular characteristics and management issues. METHODS: We performed a retrospective analysis of 24 consecutive patients with temporal lobe AVMs treated with surgical excision. Factors such as location, size, arterial feeders, venous drainage, and clinical follow-up were recorded for each. Results were compared with those of 132 patients with nontemporal lobe AVMs surgically treated over the same time period. RESULTS: Sixteen of the temporal AVMs were located in the convexity, six in the mesotemporal region, and two were predominantly intraventricular. The mode of presentation was seizure in 11 patients, hemorrhage in 7, headache in 4, and 2 were asymptomatic. Patients with convexity AVMs more commonly presented with seizures, whereas patients with mesotemporal or intraventricular AVMs were more likely to present with hemorrhage. One patient with subarachnoid hemorrhage from a basilar artery aneurysm died. Postoperatively, 2 patients (8.3%) had a new hemiparesis and dysphasia, 1 (4%) had a new dysphasia and hemianopsia, and 3 others (13%) were left with an isolated superior quadrant field deficit. Lasting surgical morbidity other than isolated field deficit was 13% for patients with temporal AVMs and 15% for those with nontemporal AVMs. CONCLUSIONS: Temporal lobe AVMs may be successfully resected using a direct microsurgical approach with limited morbidity and excellent prognosis for recovery. Most of the deficits relating to AVM hemorrhage and those of the immediate postoperative period improved significantly over the subsequent few months.

The transcondylar approach to the jugular foramen: a comparative anatomic study.

The standard neurosurgical approach to the jugular foramen involves suboccipital craniectomy with access along the petrous bone. However, even after wide removal of the foramen magnum, only limited access into the infratemporal fossa can be obtained. The neurootologic exposures provide excellent infratemporal access but limited exposure to the posterior fossa, resulting in hearing loss and facial paresis or paralysis. Using cadaver specimens, we exposed the jugular foramen region by the transcondylar approach. A retromastoid incision is extended into the neck. The transverse foramen of the atlas is opened and the vertebral artery transposed medially, thereby providing exposure into the infratemporal fossa. A suboccipital craniectomy extending anterior to the sigmoid sinus is performed, and the posterolateral occipital condyle is resected. After resection of the sigmoid sinus, cranial nerves 9 through 12 are easily identified extracranially in the infratemporal fossa and can be followed proximally through their foramina to the brain stem. We compared the transcondylar approach to three standard approaches, morphometrically and anatomically, and found that the transcondylar approach not only compares favorably but also offers advantages in that it preserves auditory and facial nerve function and is useful for one-stage tumor resection.

Selective protection from the inhibition by EEDQ of D1 and D2 dopamine agonist-induced rotational behavior in mice.

Mice with unilateral lesions of dopamine nigrostriatal neurons produced by injecting 6-hydroxydopamine into the striatum exhibited contralateral rotational behavior to the non-selective dopamine agonist apomorphine, the D1 dopamine agonist SKF 38393, and the D2 agonist quinpirole. The non-specific dopamine antagonist EEDQ blocked the circling responses to the three agonists. Pretreatment with specific, reversible dopamine antagonists before the EEDQ injection selectively prevented this blockade. Thus, if mice were pretreated with the D1 receptor antagonist SCH 23390 before EEDQ and the animals challenged with the D1 and D2 agonists 24 hours later, the rotational response to quinpirole was still inhibited, but the response to SKF 38393 was now evident. Similarly, in mice pretreated with the D2 receptor antagonist sulpiride before EEDQ and again challenged with the D1 and D2 agonists 24 hours later, the rotational response to SKF 38393 was still inhibited but the response to quinpirole was no longer inhibited. These results indicate that in vivo blockade of either D1 or D2 subpopulations of dopamine receptors may be achieved by selective protection with a reversible dopamine antagonist given prior to the administration of an irreversibly acting dopamine antagonist such as EEDQ.