The R18 Polyarginine Peptide Is More Effective Than the TAT-NR2B9c (NA-1) Peptide When Administered 60 Minutes after Permanent Middle Cerebral Artery Occlusion in the Rat.

We examined the dose responsiveness of polyarginine R18 (100, 300, and 1000 nmol/kg) when administered 60 minutes after permanent middle cerebral artery occlusion (MCAO). The TAT-NR2B9c peptide, which is known to be neuroprotective in rodent and nonhuman primate stroke models, served as a positive control. At 24 hours after MCAO, there was reduced total infarct volume in R18 treated animals at all doses, but this reduction only reached statistical significance at doses of 100 and 1000 nmol/kg. The TAT-NR2B9c peptide reduced infarct volume at doses of 300 and 1000 nmol/kg, but not to a statistically significant extent, while the 100 nmol/kg dose was ineffective. The reduction in infarct volume with R18 and TAT-NR2B9c peptide treatments was mirrored by improvements in one or more functional outcomes (namely, neurological score, adhesive tape removal, and rota-rod), but not to a statistically significant extent. These findings further confirm the neuroprotective properties of polyarginine peptides and for R18 extend its therapeutic time window and dose range, as well as demonstrating its greater efficacy compared to TAT-NR2B9c in a severe stroke model. The superior neuroprotective efficacy of R18 over TAT-NR2B9c highlights the potential of this polyarginine peptide as a lead candidate for studies in human stroke.

A prospective study of surgical patterns of care for high grade glioma in the current era of multimodality therapy.

Previous surgical patterns of care reports in high grade glioma (HGG) antedated the use of chemo-radiotherapy. This study, from an elective neurosurgical centre serving an isolated population of over 2 million, identified adult patients with HGG from a prospective multidisciplinary database. Of 328 patients in Western Australia who were diagnosed with HGG between 1 June 2006 and 30 June 2008, 283 patients (86%) received care at the study site. A total of 4% were diagnosed on imaging and clinical factors alone; 12% had surgery outside the study site. The remaining 231 patients had 264 surgical procedures; 78% resection and 22% biopsy. Median survival (grade IV) was 9.4 months. Resection predicted improved survival (hazard ratio 0.64; 95% confidence interval 0.4-0.89); however, in multivariable analysis, only age and grade predicted outcome. The proportion of patients having no tissue diagnosis, or biopsy alone, compares favourably with data before the use of chemo-radiotherapy, as does survival. The therapeutic nihilism surrounding HGG may have decreased since the introduction of temozolomide.

Modes of Neuronal Calcium Entry and Homeostasis following Cerebral Ischemia.

One of the major instigators leading to neuronal cell death and brain damage following cerebral ischemia is calcium dysregulation. The neuron's inability to maintain calcium homeostasis is believed to be a result of increased calcium influx and impaired calcium extrusion across the plasma membrane. The need to better understand the cellular and biochemical mechanisms of calcium dysregulation contributing to neuronal loss following stroke/cerebral ischemia is essential for the development of new treatments in order to reduce ischemic brain injury. The aim of this paper is to provide a concise overview of the various calcium influx pathways in response to ischemia and how neuronal cells attempts to overcome this calcium overload.

P-POSSUM scoring system for mortality prediction in general neurosurgery.

The Physiological and Operative Severity Score for enUmeration of Mortality and morbidity (POSSUM) scoring systems have been designed for comparative audit and have been well validated in general and vascular surgery. The Portsmouth predictor equation (P-POSSUM) was highly predictive of mortality in a study of elective craniotomies for neurosurgery but has yet to be validated in spinal, peripheral nerve or acute cranial neurosurgery. The West Australian Categorisation of Operative Severity (WA classification) was created for all neurosurgical procedures. Case notes and laboratory results of 531 consecutive patients undergoing neurosurgery were reviewed retrospectively. All POSSUM variables were collected and the POSSUM and P-POSSUM mortality equations were applied. The observed mortality rate was 4.52% and the WA P-POSSUM predicted mortality rate was 4.58% (p>0.951). The WA P-POSSUM rate was more predictive than either the WA POSSUM rate (10.9%, p<0.0001) or the previously proposed elective craniotomy P-POSSUM classification (5.8%, p<0.198). We concluded that the P-POSSUM model with WA classification has the potential to be used in mortality audits for general neurosurgery. By quantifying preoperative risk, P-POSSUM might provide a useful denominator to observed death rates for meaningful comparison of individual neurosurgeons and between departments.

Is magnesium neuroprotective following global and focal cerebral ischaemia? A review of published studies.

Neuroprotective activity with magnesium associated with animal models of cerebral ischaemia, seizure, perinatal hypoxia/ischaemia, subarachnoid haemorrhage and traumatic brain injury has provided the justification for clinical stroke trials. However, the recent IMAGES stroke clinical trial found magnesium to be largely ineffective. Hence, due to the negative stroke trial outcome, current FAST-MAG trial and our own experience with magnesium in cerebral ischaemia animal models, we thought it prudent to review these preclinical and clinical studies. We reviewed nine studies describing the use of magnesium following global cerebral ischaemia and fourteen following focal cerebral ischaemia. Four global ischaemia and six focal ischaemia studies did not show a significant neuroprotective effect with magnesium. In the majority of positive magnesium studies animal body temperature was not monitored post-ischaemia. Thus the effects of post-ischaemic hypothermia cannot be ruled out as a confounding factor in positive magnesium cerebral ischaemia studies. Moreover, data from our own laboratory indicates that magnesium is only neuroprotective when combined with post-ischaemic hypothermia. These data provide a possible explanation of why the IMAGES trial was largely unsuccessful, as current stroke patient management does not involve hypothermia induction. Future preclinical and clinical cerebral ischaemia trials with magnesium should consider combining treatment with mild hypothermia.

Cerebral amyloid angiopathy presenting with vasculitic pathology.

We present an elderly patient with an unusual extensive multifocal central nervous system mass lesion, with dramatic imaging changes but only minor disturbance of cerebral function. Cerebral biopsy revealed an unexpected finding of severe cerebral amyloid angiopathy with secondary florid vasculitic appearances, which is a very rare but recognised association. Immunosuppression has produced significant sustained clinical and radiological remission.

The protective effect of hypoxic preconditioning on cortical neuronal cultures is associated with increases in the activity of several antioxidant enzymes.

Preconditioning describes a variety of treatments that induce neurons to become more resistant to a subsequent ischemic insult. How preconditioned neurons adapt to subsequent ischemic stress is not fully understood, but is likely to involve multiple protective mechanisms. We hypothesized hypoxic preconditioning induces protection by a coordinated up-regulation of antioxidant enzyme activity. To test this hypothesis, we developed two in vitro models of ischemia/reperfusion, involving oxygen-glucose deprivation (OGD) where neuronal cell death was predominantly by necrosis (necrotic model) or programmed cell death (PCD model). Hypoxic preconditioning 24 h prior to OGD significantly reduced cell death from 83% to 22% in the necrotic model and 68% to 11% in the PCD model. Consistent with the hypothesis, the activity of the antioxidant enzymes glutathione peroxidase, glutathione reductase, and Mn superoxide dismutase were significantly increased by 54%, 73% and 32%, respectively, in neuronal cultures subjected to hypoxic preconditioning. Furthermore, superoxide and hydrogen peroxide concentrations following OGD were significantly lower in the PCD model that had been subjected to hypoxic preconditioning.

Longitudinal clivus fracture associated with trapped basilar artery: unusual survival with good neurological recovery.

A 46-year-old motorcyclist sustained severe cranio-facial fractures from a fall at 60 km/h. He gradually developed a left hemiparesis and diplopia but retained a GCS of 15. CT head scan revealed a longitudinal clivus fracture. MRA of intracranial vessels identified a trapped basilar artery. The patient made an excellent recovery with residual left abducens palsy on follow-up at 10 weeks. Such recovery with minimal residual deficit in the context of this injury has not previously been reported. Reported cases to date are reviewed and causative mechanisms discussed.

Ossification of the ligamentum flavum.

We report the case of a 32-year-old South Korean male who presented with bilateral leg weakness, spastic gait and associated sensory loss from below the T5 dermatome. MRI and CT scans of the spine confirmed the presence of calcified ligamentum flavum from T1-T6. A thoracic laminectomy resulted in an excellent post-operative recovery with full return of all functions. This case review will discuss the differences that exist between ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF), but also the similarities at a molecular and possibly at a genetic level. We have reviewed the reported literature of patients presenting with progressive lower limb spacity due to OLF, and an excellent outcome is achieved using decompressive laminectomy.

Establishment of neuronal in vitro models of ischemia in 96-well microtiter strip-plates that result in acute, progressive and delayed neuronal death.

Using 96-well microtiter strip-plates we established in vitro ischemia models with acute, progressive and delayed neuronal death onset. In vitro ischemia was induced by washing neuronal cultures with a balanced salt solution with (acute/delayed models) or without (progressive model) 25 mM 2-deoxy-D-glucose and incubating in an anaerobic chamber. Reperfusion was performed by removing cultures from the anaerobic chamber and washing and/or adding Dulbecco's modified Eagle medium containing N2 supplement. Acute neuronal death resulted in cell swelling during in vitro ischemic incubation with the majority of neurons appearing swollen and necrotic within 3 h post-insult. Progressive neuronal death was characterized by cell shrinkage during and immediately following in vitro ischemia with increasing neuronal degeneration resembling both necrosis and apoptosis over a 24-h period post-in vitro ischemia. Delayed neuronal death was induced by glutamate-receptor blockade during in vitro ischemia. Neurons appeared morphologically normal immediately following and up to 6 h after in vitro ischemia and then started to degenerate over the next 42 h by a process resembling apoptosis. We monitored oxygen consumption during in vitro ischemia and found it to be similar for the three models and have shown that plastic culture wells store oxygen. The establishment of acute, progressive and delayed in vitro models of ischemia using 96-well microtiter strip-plates will provide useful tools to further investigate ischemic neuronal death/survival mechanisms and provide a high-throughput system to evaluate potential neuroprotective agents. Oxygen storage in plastic culture wells is likely to contribute to the extended oxygen- and oxygen-glucose-deprivation times required to induce significant neuronal injury in vitro.

Corticotroph pituitary carcinoma: case report and literature review.

Pituitary carcinomas, currently defined as primary adenohypophyseal neoplasms with evidence of either brain invasion or metastatic spread, are exceptionally rare. A case of corticotroph pituitary carcinoma is reported. A 17-year-old female first presented with an invasive and clinically non-functioning pituitary macroadenoma. The primary pituitary lesion lacked atypical histological features and retrospective immunohistochemical studies confirmed its corticotrophic nature. Repeated episodes of local recurrence followed together with the acquisition of severe Cushing's disease. Local disease control was not obtained despite repeated surgical decompression and courses of radiation therapy. Systemic dissemination with multiple bone metastases became manifest eleven years after the first presentation. Atypical histological features and Crooke's hyaline change were evident in both the recurrent and metastatic disease. She remains alive at last follow-up with severe complications relating to persisting sellar and metastatic disease and ongoing endocrine dysfunction. A further 32 cases of pituitary corticotroph carcinoma reported in English are reviewed to highlight the clinicopathological features of this rare form of pituitary neoplasm. Difficulties associated with the diagnosis and management of pituitary carcinoma are also discussed.

Suppression subtraction hybridization and northern analysis reveal upregulation of heat shock, trkB, and sodium calcium exchanger genes following global cerebral ischemia in the rat.

Driver (sham-operated) and tester (ischemic) hippocampal cDNAs were subtracted, and the resulting ischemia-induced upregulated gene expression was verified by northern analysis. cDNAs isolated corresponded to (1) genes known to be upregulated following ischemia, (hsc70, hsp90, hsp105 and trkB) and (2) a gene not previously implicated with cerebral ischemia, sodium calcium exchanger (ncx). Furthermore, upregulation of these genes was demonstrated following preconditioning transient global ischemia.

Endovascular management of acute subarachnoid haemorrhage in the elderly.

The objective of this study was to analyse the technical and clinical outcome in elderly patients receiving endovascular treatment for acutely ruptured intracranial aneurysms. The case notes and angiograms of 14 patients over the age of 69 years undergoing endovascular treatment for subarachnoid haemorrhage within the Interventional Neuroradiology Unit, Royal Perth Hospital over a period of 6 years were retrospectively reviewed. The degree of angiographic occlusion achieved, and periprocedural, short-term and long-term clinical outcome were retrospectively assessed. Greater than 90% occlusion was obtained in 92% of cases. 82% of patients with Hunt and Hess grade I and II had an excellent clinical outcome. We conclude that endovascular coiling is an effective means of treating acute subarachnoid haemorrhage in grade I and II elderly patients.

Endovascular treatment of posterior circulation aneurysms.

The objective of this paper was to analyse the technical and clinical outcome in patients receiving endovascular treatment for posterior circulation intracranial aneurysms at Royal Perth Hospital. The case notes and angiograms of 35 patients with ruptured and unruptured posterior circulation aneurysms treated by endovascular coil occlusion between 1992 and 1998 were included in the study. The degree of angiographic occlusion achieved, and periprocedural, short and long-term clinical outcome were retrospectively analysed. Total aneurysm occlusion was achieved at initial treatment in 46% of cases, with 90% or greater occlusion achieved in 97% of cases. For aneurysms 12 mm or less in diameter, 100% of patients treated electively, and 100% of patients with grade I or II subarachnoid haemorrhage treated in the acute postictal phase had a good clinical outcome (Rankin Disability Score 1 and 2), with no serious morbidity or associated mortality. Excluding patients with grade V subarachnoid haemorrhage, the treatment-related serious morbidity rate was 3.4% and procedure-related mortality rate was 0%. We conclude that endovascular management provides an effective means of treatment for selected cases of posterior circulation aneurysms.

Extradural spinal cavernous haemangioma: case report and review of the literature.

Cavernous haemangiomas (cavernomas) are uncommon vascular malformations of the central nervous system (CNS). They occur in both sporadic and familial forms and may involve any site in the CNS. Spinal cavernomas are less common than intracerebral lesion s, and examples in the spinal epidural space are rare. A case of a solitary sporadic spinal extradural cavernoma in a 41 year old male which presented as progressive lower limb numbness and weakness is reported. The literature regarding spinal cavernomas is reviewed and the symptomatology, diagnostic evaluation, pathology, management and prognosis of these lesions are discussed.

Postischemic intravenous administration of magnesium sulfate inhibits hippocampal CA1 neuronal death after transient global ischemia in rats.

OBJECTIVE: We aimed to determine an effective dose schedule for intravenously administered magnesium, to establish its neuroprotective efficacy in both pre- and postischemic treatment paradigms, and to compare the neuroprotective properties of MgSO(4) and MgCl(2). METHODS: Rats that had been subjected to the bilateral carotid artery occlusion plus hypotension model of transient forebrain cerebral ischemia received either an intravenously administered loading dose (LD) of 360 micromol/kg MgSO(4) only or an intravenously administered LD of 360 micromol/kg followed by a 48-hour intravenous infusion of MgSO(4) at either 60, 120, 240, or 480 micromol/kg/h. For evaluation of the efficacy of MgSO(4) after ischemia, the dose (LD, 360 micromol/kg; infusion, 120 micromol/kg/h) that provided maximal neuroprotection before ischemia was administered 4, 8, 12, or 24 hours after ischemia. MgCl(2) (LD, 360 micromol/kg; infusion, 120 micromol/kg/h) was administered before and 8 hours after ischemia. At 7 days after ischemia, hippocampal CA1 neurons were histologically examined for protection. RESULTS: Animals that received the LD only demonstrated 33% hippocampal CA1 neuronal survival. Animals that received the LD followed by continuous infusion of MgSO(4) at either 60, 120, 240, or 480 micromol/kg/h demonstrated 30, 80, 16, and less than 5% CA1 neuronal survival, respectively. MgSO(4) treatment commencing at 4, 8, 12, or 24 hours resulted in 82, 71, 52, and 33% CA1 neuronal survival, respectively. Preischemic and 8-hour postischemic administration of MgCl(2) resulted in 50% and less than 5% CA1 neuronal survival, respectively. CONCLUSION: These results demonstrate a neuroprotective intravenous dose of MgSO(4), which is effective when administered before or late after ischemia, and a previously uncharacterized dose-response curve for MgSO(4).

Arachnoiditis ossificans and syringomyelia: a unique case report.

A 62-year-old male presented with progressive quadriparesis. Magnetic resonance imaging of the spine revealed a spinal cord syrinx but failed to detect extensive arachnoiditis ossificans noted on insertion of a syringopleural shunt. A postoperative computed tomography scan clearly demonstrated the abnormality and its extent. We present a rare case of syringomyelia resulting from spinal arachnoiditis ossificans and review the relevant literature.

Choroid plexus recovery after transient forebrain ischemia: role of growth factors and other repair mechanisms.

1. Transient forebrain ischemia in adult rats, induced by 10 min of bilateral carotid occlusion and an arterial hypotension of 40 mmHg, caused substantial damage not only to CA-1 neurons in hippocampus but also to epithelial cells in lateral ventricle choroid plexus. 2. When transient forebrain ischemia was followed by reperfusion (recovery) intervals of 0 to 12 hr, there was moderate to severe damage to many frond regions of the choroidal epithelium. In some areas, epithelial debris was sloughed into cerebrospinal fluid (CSF). Although some epithelial cells were disrupted and necrotic, their neighbors exhibited normal morphology. This patchy response to ischemia was probably due to regional differences in reperfusion or cellular metabolism. 3. Between 12 and 24 hr postischemia, there was marked restoration of the Na+, K+, water content, and ultrastructure of the choroid plexus epithelium. Since there was no microscopical evidence for mitosis, we postulate that healthy epithelial cells either were compressed together on the villus or migrated from the choroid plexus stalk to more distal regions, in order to "fill in gaps" along the basal lamina caused by necrotic epithelial cell disintegration. 4. Epithelial cells of mammalian choroid plexus synthesize and secrete many growth factors and other peptides that are of trophic benefit following injury to regions of the cerebroventricular system. For example, several growth factors are upregulated in choroid plexus after ischemic and traumatic insults to the central nervous system. 5. The presence of numerous types of growth factor receptors in choroid plexus allows growth factor mediation of recovery processes by autocrine and paracrine mechanisms. 6. The capability of choroid plexus after acute ischemia to recover its barrier and CSF formation functions is an important factor in stabilizing brain fluid balance. 7. Moreover, growth factors secreted by choroid plexus into CSF are distributed by diffusion and convection into brain tissue near the ventricular system, e.g., hippocampus. By this endocrine-like mechanism, growth factors are conveyed throughout the choroid plexus-CSF-brain nexus and can consequently promote repair of ischemia-damaged tissue in the ventricular wall and underlying brain.

Pituitary abscess.

A 28-year-old Caucasian woman presented with a 12 month history of secondary amenorrhoea, polyuria and polydipsia with fatigue and weight loss. Investigations revealed panhypopituitarism, diabetes insipidus, an intrasellar mass and papilloedema, thought to be due to benign intracranial hypertension. She was treated conservatively. However, a repeat magnetic resonance image showed enlargement of the pituitary mass with compression of the optic nerves. The pituitary abscess was drained by a transsphenoidal approach. Postoperatively the patient received antibiotics with no recurrence of the pituitary abscess. Copyright 1999 Harcourt Publishers Ltd.