Glutamate quantification in patients with supratentorial gliomas using chemical shift imaging.

This study aimed to evaluate and validate chemical shift imaging (CSI) for in vivo glutamate (Glu) quantification in patients with supratentorial gliomas. If validated, CSI could become an extremely useful tool to investigate metabolic dysfunction of Glu in excitotoxic neuropathologies. Quantitative CSI estimates of Glu concentrations were compared with known concentrations of Glu in aqueous phantom solutions. Forty-one patients with known or likely supratentorial gliomas underwent preoperative CSI. The spectra obtained were analyzed for Glu concentrations and Glu to creatine (Cr) ratios. These in vivo measurements were correlated against ex vivo Glu content quantified by high performance liquid chromatography (HPLC) measured in 65 resected brain tumor and peritumoral brain specimens. For the phantom solutions the CSI estimates of Glu concentration and the Glu/Cr ratios were highly correlated with known Glu concentration (r² = 0.95, p = 0.002, and r² = 0.97, p < 0.0001, respectively). There was a modest, but statistically significant, correlation between the ex vivo measured Glu and in vivo spectroscopic Glu concentration (r² = 0.22, p = 0.04) and ratios of Glu to Cr (r² = 0.30, p = 0.002). Quantitative measurement of Glu content is feasible in patients with supratentorial gliomas using CSI. The in vitro and in vivo results suggest that this has the potential to be a reliable quantitative imaging assay for brain tumor patients. This may have wide clinical research applications in a number of neurological disorders where Glu excitotoxicity and metabolic dysfunction are known to play a role in pathogenesis, including tumor associated epilepsy, epilepsy, stroke and neurotrauma.

Stargazin and AMPA receptor membrane expression is increased in the somatosensory cortex of Genetic Absence Epilepsy Rats from Strasbourg.

Absence-like seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model are believed to arise in hyperexcitable somatosensory cortical neurons, however the cellular basis of this increased excitability remains unknown. We have previously shown that expression of the Transmembrane AMPA receptor Regulatory Protein (TARP), stargazin, is elevated in the somatosensory cortex of GAERS. TARPs are critical regulators of the trafficking and function of AMPA receptors. Here we examine the developmental expression of stargazin and the impact this may have on AMPA receptor trafficking in the GAERS model. We show that elevated stargazin in GAERS is associated with an increase in AMPA receptor proteins, GluA1 and GluA2 in the somatosensory cortex plasma membrane of adult epileptic GAERS. Elevated stargazin expression is not seen in the epileptic WAG/Rij rat, which is a genetically distinct but phenotypically similar rat model also manifesting absence seizures, indicating that the changes seen in GAERS are unlikely to be a secondary consequence of the seizures. In juvenile (6 week old) GAERS, at the age when seizures are just starting to be expressed, there is elevated stargazin mRNA, but not protein expression for stargazin or the AMPA receptor subunits. In neonatal (7 day old) pre-epileptic GAERS there was no alteration in stargazin mRNA expression in any brain region examined. These data demonstrate that stargazin and AMPA receptor membrane targeting is altered in GAERS, potentially contributing to hyperexcitability in somatosensory cortex, with a developmental time course that would suggest a pathophysiological role in the epilepsy phenotype.

Genetic absence epilepsy rats from Strasbourg have increased corticothalamic expression of stargazin.

Stargazin is membrane bound protein involved in trafficking, synapse anchoring and biophysical modulation of AMPA receptors. A quantitative trait locus in chromosome 7 containing the stargazin gene has been identified as controlling the frequency and duration of absence seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Furthermore, mutations in this gene result in the Stargazer mouse that displays an absence epilepsy phenotype. GAERS stargazin mRNA expression is increased 1.8 fold in the somatosensory cortex and by 1.3 fold in the thalamus. The changes were present before and after the onset of absence seizures indicating that increases are not a secondary consequence of the seizures. Stargazin protein expression was also significantly increased in the somatosensory cortex after the onset of spontaneous seizures. The results are of significant importance beyond the GAERS model, as they are the first to show that an increase in stargazin expression may be pro-epileptic.

In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs.

TRAIL/Apo-2L has shown promise as an anti-glioma drug, based on investigations of TRAIL sensitivity in established glioma cell lines, but it is not known how accurately TRAIL signalling pathways of glioma cells in vivo are reproduced in these cell lines in vitro. To replicate as closely as possible the in vivo behaviour of malignant glioma cells, 17 early passage glioma cell lines and 5 freshly resected gliomas were exposed to TRAIL-based agents and/or chemotherapeutic drugs. Normal human hepatocytes and astrocytes and established glioma cell lines were also tested. Cross-linked TRAIL, but not soluble TRAIL, killed both normal cell types and cells from three tumours. Cells from only one glioma were killed by soluble TRAIL, although only inefficiently. High concentrations of cisplatin were lethal to glioma cells, hepatocytes and astrocytes. Isolated combinations of TRAIL and chemotherapy drugs were more toxic to particular gliomas than normal cells, but no combination was generally selective for glioma cells. This study highlights the widespread resistance of glioma cells to TRAIL-based agents, but suggests that a minority of high-grade glioma patients may benefit from particular combinations of TRAIL and chemotherapy drugs. In vitro sensitivity assays may help identify effective drug combinations for individual glioma patients.

Myelin structure is a key difference in the x-ray scattering signature between meningioma, schwannoma and glioblastoma multiforme.

Small angle x-ray scattering (SAXS) patterns of benign and malignant brain tumour tissue were examined. Independent component analysis was used to find a feature set representing the images collected. A set of coefficients was then used to describe each image, which allowed the use of the statistical technique of flexible discriminant analysis to discover a hidden order in the data set. The key difference was found to be in the intensity and spectral content of the second and fourth order myelin scattering peaks. This has clearly demonstrated that significant differences in the structure of myelin exist in the highly malignant glioblastoma multiforme as opposed to the benign: meningioma and schwannoma.

The emergent role of exosomes in glioma.

Extracellular vesicles (EVs) are known mediators of intercellular communication for both normal and tumour cells. With the capability to transfer nucleic acids, proteins and lipids, EVs are able to influence numerous functional and pathological aspects of both donor and recipient cells. The tumour microenvironment possesses a high level of complex heterogeneity, particularly within the most prominent brain malignancy, glioblastoma multiforme (GBM). This complexity relies on a network-based communication between many different components of the local niche, including the various cell types, stroma, blood vessels, secreted factors and surrounding matrix. Exosomes are one type of EV which facilitates this intercellular communication and cross-talk within the tumour microenvironment. Exosomes secreted by tumour cells are increasingly recognized in a number of processes underlying tumour progression including facilitating the transport of receptors, signalling molecules, oncogenic genes and miRNA. They are emerging as a key component in the biogenesis of glioma, in addition to contributing to the modification of the surrounding microenvironment to support tumour progression. In this review we describe advancements in the understanding of the biology of exosomes, as well as their roles in tumour progression, as a tumour biomarker for tracking cancer progression, and as a potential therapeutic target/delivery system, with a contextual emphasis on GBM.

Venous air embolism and the sitting position: a case series.

Venous air embolism is a potentially serious complication of neurosurgery that occurs more commonly when the patient is in the sitting position. In this study, we aimed to quantify the incidence of venous air embolism during neurosurgical procedures performed with the patient in the sitting position in our institution. We performed a prospective audit of venous air embolism in 100 consecutive patients who underwent neurosurgical procedures in the sitting position, as evidenced by a decrease in end-tidal carbon dioxide partial pressure of 5 mmHg or more within 5 min. The incidence of venous air embolism was 9% (95% confidence interval: 3.3-14.7%). These patients did not have a significantly higher rate of hypotension or desaturation. Our results suggest that the sitting position can be safely used in neurosurgery.

Effect of in situ retroviral interleukin-4 transfer on established intracranial tumors.

BACKGROUND: Current therapies for malignant gliomas remain largely ineffective. We have previously demonstrated that interleukin 4 (IL-4) exhibits antitumorigenic activity in athymic nude mice by promoting both eosinophil infiltration and inhibition of tumor angiogenesis (formation of new blood vessels). In this study, we investigated treatment of established rat C6 cell gliomas by retroviral delivery of IL-4 in situ. METHODS: Tumors grown subcutaneously in athymic nude mice or implanted intracranially in immunocompetent Wistar rats were implanted with ecotropic retrovirus (i.e., will replicate only in cells of closely related species) packaging cells (RPCs) that were transfected with a retroviral vector encoding mouse IL-4 (1C5 cells) or a control vector (SV cells). For the demonstration of the long-term effects of such treatment, C6 cells were also implanted into the contralateral hemisphere of the brains of rats previously treated with 1C5 RPCs. Tumor volume measurements and immunohistochemical analyses were performed. RESULTS: Implantation of 1C5 RPCs into subcutaneous C6 cell tumors resulted in tumor growth arrest that was associated with eosinophil infiltration and inhibition of angiogenesis. When 1C5 RPCs were stereotactically implanted into established intracranial tumors in rats, tumor volumes were dramatically smaller than in control animals (approximately 1.8 mm3 versus 70-80 mm3, respectively) 7 days after treatment. All 1C5 RPC-treated rats survived to 106 days after C6 cell implantation (99 days after treatment; an arbitrary end point), whereas control rats had to be killed 14 days after C6 cell implantation because of extensive tumor growth. Histologic analysis demonstrated that treated tumors were completely eradicated, and immunohistochemical analysis revealed an inhibition of tumor angiogenesis and infiltration by CD8+ cells and macrophages. C6 cells implanted contralaterally into the brains of long-term-surviving rats treated with 1C5 RPCs were also rapidly and completely rejected. CONCLUSIONS: Implantation of packaging cells producing IL-4 retrovirus leads to rapid eradication of rat C6 cell gliomas and provides sustained protection against further intracranial challenge.

Development of a xenograft glioma model in mouse brain.

Xenograft intracerebral glioma models have been developed in normal mice by growing the rat C6 glioma in either adult or neonatal mouse brains. Using this tumor line it was possible to grow discrete intracerebral gliomas in either CBA or AKR adult mice or neonatal mice. The size of the tumor mass and length of survival was directly related to the number of tumor cells injected and the time after implantation. To obtain localized intracranial tumor growth cells were suspended in a 1% agarose solution before implantation. Following injection of 10(6) cells into the frontal lobe of adult CBA or AKR mice, discrete tumor masses greater than 4 mm in diameter were obtained in 90% of animals at 14 days, and the largest tumors in adult mice occurred between 21 and 28 days after implantation. The tumor size following implantation of 10(6) cells was significantly greater than with 10(5) cells at 7 days (P less than 0.05) and at 14 and 21 days (P less than 0.01). Less than 60% of mice of BALB/c, RIII, or C57 black strains developed tumors greater than 4 mm diameter at 14 days after intracerebral injection of 10(6) C6 cells. Using neonatal mice it was found that when 10(5) cells were injected intracranially tumors greater than 4 mm in diameter developed in 14 of 15 animals within 2 weeks (CBA mice). Similar results were seen in the RIII, AKR, C57 black, and BALB/c strains. Longer growth periods resulted in larger tumors, up to 8 mm in diameter (6 of 10 animals at 20 days). The tumors in the neonatal animals were not as discrete as in the adult mice, and tumor often spread to the meninges and into the lateral ventricles. The tumor harvested from the brain had a cloning efficiency of 1.2 +/- 0.4% (SD). A panel of monoclonal antibodies was raised to the C6 glioma, and this was used to define clearly the margins of the tumor within the brain. The xenograft mouse models should prove useful for the study of the therapy of gliomas.

Nature of the tumor-localizing components of hematoporphyrin derivative.

Hematoporphyrin derivative linked by ether bonds (HE) was synthesized by unambiguous procedures in order to compare its properties to hematoporphyrin derivative (HpD). Reverse phase high performance liquid and gel filtration chromatography were used to compare the HE derivatives to HpD. The cellular uptake of HE derivatives was compared to HpD using the WEHI 3B (D+) cell line and was shown to be taken up to a degree and in a manner similar to HpD. The efficiency of HE porphyrins as photosensitizers was compared to HpD using the V79 cell line. HE porphyrins were more efficient in sensitizing the V79 cells than was HpD. The in vivo tumor localizing properties of HE porphyrins were compared to HpD in CBA mice bearing the C6 cerebral glioma, and BALB/c mice bearing the EMT6 mammary tumor. HE derivatives localized in both tumor models as effectively as HpD. We conclude that the properties of ether linked hematoporphyrin derivatives are very similar to properties of HpD.

Selective amplification of the cytoplasmic domain of the epidermal growth factor receptor gene in glioblastoma multiforme.

Primary brain tumors of glial origin often overexpress epidermal growth factor receptors (EGF-Rs). This may be associated with amplification of the EGF-R gene. We have examined tissue from 23 glioblastoma multiforme tumors and found amplification and rearrangement of the EGF-R gene in four of these. The cytoplasmic domain of the EGF-R gene was invariably amplified in these four tumors, while the epidermal growth factor binding domain was not uniformly amplified in three of these tumors. Western blot analysis of the EGF-R protein revealed high levels of a truncated EGF-R protein in two of the four tumors with EGF-R gene amplification.

Hyaluronidase-2 overexpression accelerates intracerebral but not subcutaneous tumor formation of murine astrocytoma cells.

Gliomas are highly invasive, invariably fatal intracerebral tumors. It seems that receptors for hyaluronan are required for the invasive process. Hyaluronan is a major component of the extracellular matrix in the brain, and all of the gliomas express CD44, the principal receptor for hyaluronan. To investigate the role of lysosomal hyaluronidases on tumor invasion we overexpressed hyaluronidase-2 (HYAL2) in murine astrocytoma cells. We found that high expression of HYAL2 accelerated intracerebral tumor growth dramatically, whereas the same cells formed s.c. tumors within the same time as the parental cells. The brain tumors were highly vascularized and more invasive than the control tumors. It seems that the interactions of the HYAL2-expressing tumor cells with the hyaluronan-containing extracellular matrix in the brain mediate these effects, whereas the same cells in a s.c. environment, which lacks the high hyaluronan level, behave like the parental cells.

Homozygous deletions of the multiple tumor suppressor gene 1 in the progression of human astrocytomas.

The multiple tumor suppressor gene 1 (MTS1) located on chromosome 9p has recently been implicated as a candidate tumor suppressor gene in many different tumor types. Cytogenetic analysis and deletion mapping studies have revealed that deletion of chromosome 9p occurs in a significant number of primary human astrocytomas. Using multiplex PCR with primers for exon 2 of MTS1 and for D9S196 from chromosome 9q, we have analyzed 78 primary astrocytic tumors for the deletion of MTS1. After controlling for the contamination of tumor samples with normal cells, homozygous loss of MTS1 was found in 13 of 25 anaplastic astrocytomas (WHO grade III) and in 27 of 46 cases of glioblastomas (WHO grade IV) but in none of seven astrocytomas (WHO grade II). These data suggest that MTS1 is an important tumor suppressor gene in the malignant progression of astrocytomas.

Transformation of astrocytes in transgenic mice expressing SV40 T antigen under the transcriptional control of the glial fibrillary acidic protein promoter.

There are many animal models of glioma, but few that represent the biology of low-grade tumors and allow the study of the genetic mechanisms of glial oncogenesis. We report the in vivo transformation of astrocytic cells in transgenic mice by the SV40 T antigen under the control of the 5'-flanking sequence of the murine glial fibrillary acidic protein (GFAP) gene. High levels of T antigen expression were detectable in a tissue distribution that mirrored the normal expression of GFAP. This was associated with a consistent phenotype in the founder mice. Diffuse proliferation occurred in cells of the periventricular subependymal zone with diffuse invasion into the brain parenchyma, leading to death by 19-30 days postnatally. Transformed cells exhibited secondary structuring, a typical histopathological feature of human astrocytomas. Early passage cultures of these cells expressed GFAP in vitro and were transformed on the basis of tumor formation after transplantation into nude mice. These results demonstrate the susceptibility of periventricular astrocytic cells in the immature brain to malignant transformation. Furthermore, this study demonstrates the potential of the transgenic approach for the in vivo determination of genetic events involved in astrocyte transformation and for the development of novel models of astrocytoma.

Use of tissue plasminogen activator in the treatment of shunt blockage secondary to intraventricular haemorrhage.

A 51-year-old woman with a history of idiopathic aqueduct stenosis, treated initially with insertion of a ventriculo peritoneal shunt, presented to our institution with shunt dysfunction. She had previously undergone multiple shunt revisions for shunt infection, shunt blockage and low-pressure symptoms, most recently with conversion to a ventriculo atrial (VA) shunt. Her VA shunt was again revised, with replacement of the ventricular catheter, however surgery was complicated by a large intraventricular haemorrhage (IVH) requiring placement of an external ventricular drain (EVD). Prior to eventual removal of her EVD it was determined that the VA shunt had blocked as a result of the IVH. Subsequently alteplase, a recombinant tissue plasminogen activator (tPA), was administered into the shunt reservoir, resulting in successful return of shunt function, therefore avoiding the need for further shunt revision. This is the first description of the use of tPA to unblock a shunt obstructed by blood.

Phase I and pharmacokinetic study of KRN8602 alone and with filgrastim in patients with advanced cancer.

PURPOSE: To determine the recommended dose, toxicity profile, and pharmacokinetics of KRN8602 (MX2-hydrochloride), a novel morpholino anthracycline with potent cytotoxicity against anthracycline-sensitive and resistant experimental tumors in vitro and in vivo. PATIENTS AND METHODS: KRN8602 was administered alone in increasing doses to patients with advanced cancer or high-grade gliomas until dose-limiting toxicity (DLT) was observed in three or more of five patients treated in a dose level. Because neutropenia was dose limiting, further escalation was investigated with filgrastim support. RESULTS: Fifty-six assessable patients completed at least one cycle of chemotherapy. The recommended dose of KRN8602 alone was 40 mg/m2. Dose escalation was limited by neutropenia. The recommended dose of KRN8602 with filgrastim was 70 mg/m2, and limiting toxicities were neutropenia, diarrhea, and vomiting. The most commonly experienced nonhematologic toxicity was nausea and vomiting. Alopecia and mucositis were infrequent and mild. Pharmacokinetic parameters showed substantial variation, although the area under the plasma concentration-time curve (AUC) and maximum concentration both increased with dose. There was no relationship between pharmacokinetic parameters and toxicity. CONCLUSION: KRN8602 at doses of 40 mg/m2 when administered alone and 70 mg/m2 when administered with filgrastim appeared to be manageable. The major DLTs were neutropenia and, at higher doses, diarrhea and vomiting. The efficacy of this drug is currently being tested in phase II studies.

Phase I and pharmacokinetic study of photodynamic therapy for high-grade gliomas using a novel boronated porphyrin.

PURPOSE: To determine the recommended dose, toxicity profile, and pharmacokinetics of a novel boronated porphyrin (BOPP) for photodynamic therapy (PDT) of intracranial tumors. PATIENTS AND METHODS: BOPP was administered alone in increasing doses (0.25, 0.5, 1.0, 2.0, 4.0, or 8.0 mg/kg) preoperatively in patients with intracranial tumors undergoing postresection PDT until dose-limiting toxicity (DLT) was observed. RESULTS: Twenty-nine assessable patients with intracranial tumors received BOPP intravenously 24 hours before surgery. The recommended dose was 4 mg/kg. Dose escalation was limited by thrombocytopenia. The most common nonhematologic toxicity was skin photosensitivity. Pharmacokinetic parameters showed increased area under the plasma concentration-time curve and maximum concentration with increased dose. Tumor BOPP concentrations also increased with increased dose. CONCLUSION: BOPP at a dose of 4 mg/kg was well tolerated. DLT was thrombocytopenia, and photosensitivity was the only other toxicity of note. The efficacy of PDT using BOPP requires further exploration.

KRN8602 (MX2-hydrochloride): an active new agent for the treatment of recurrent high-grade glioma.

PURPOSE: To assess the efficacy and toxicity of KRN8602 when administered as an intravenous bolus to patients with recurrent high-grade malignant glioma. PATIENTS AND METHODS: Patients with recurrent or persistent anaplastic astrocytoma or glioblastoma multiforme who had not received recent chemotherapy or radiotherapy and were of good performance status (Eastern Cooperative Oncology Group score < or = 2) were treated with an intravenous bolus of 40 mg/m(2) KRN8602 every 28 days. Tumor responses were assessed radiologically and clinically after every second cycle of therapy. Treatment was continued until documented progression or a total of six cycles. RESULTS: A median of three cycles (range, one to six cycles) of KRN8602 was administered to 55 patients, 49 of whom received at least two cycles and were, therefore, assessable for response. The overall response rate (disease stabilization or better) was 43% (95% confidence interval, 29% to 58%). There were three complete responses, one partial response, seven minor responses, and 10 patients with stable disease. The median time to progression was 2 months (range, 1.5 to 37 months) and overall survival was 11 months (range, 1.5 to 40 months). Neutropenia was the most common toxicity, although it was generally of brief duration, and there were only seven episodes of febrile neutropenia in 176 cycles delivered. Nonhematologic toxicity was mostly gastrointestinal (nausea and vomiting, diarrhea) and events were grade 2 or lower except for a single episode of grade 3 vomiting. CONCLUSION: KRN8602 is an active new agent with minimal toxicity in the treatment of relapsed or refractory high-grade glioma. Further studies with KRN8602 in combination with other cytotoxics and in adjuvant treatment of gliomas are warranted.

MRI-negative PET-positive temporal lobe epilepsy: a distinct surgically remediable syndrome.

Most patients with non-lesional temporal lobe epilepsy (NLTLE) will have the findings of hippocampal sclerosis (HS) on a high resolution MRI. However, a significant minority of patients with NLTLE and electroclinically well-lateralized temporal lobe seizures have no evidence of HS on MRI. Many of these patients have concordant hypometabolism on fluorodeoxyglucose-PET ([18F]FDG-PET). The pathophysiological basis of this latter group remains uncertain. We aimed to determine whether NLTLE without HS on MRI represents a variant of or a different clinicopathological syndrome from that of NLTLE with HS on MRI. The clinical, EEG, [18F]FDG-PET, histopathological and surgical outcomes of 30 consecutive NLTLE patients with well-lateralized EEG but without HS on MRI (HS-ve TLE) were compared with 30 consecutive age- and sex-matched NLTLE patients with well-lateralized EEG with HS on MRI (HS+ve TLE). Both the HS+ve TLE group and the HS-ve TLE patients had a high degree of [18F]FDG-PET concordant lateralization (26 out of 30 HS-ve TLE versus 27 out of 27 HS+ve TLE). HS-ve TLE patients had more widespread hypometabolism on [18F]FDG-PET by blinded visual analysis [odds ratio (OR = + infinity (2.51, -), P = 0.001]. The HS-ve TLE group less frequently had a history of febrile convulsions [OR = 0.077 (0.002-0.512), P = 0.002], more commonly had a delta rhythm at ictal onset [OR = 3.67 (0.97-20.47), P = 0.057], and less frequently had histopathological evidence of HS [OR = 0 (0-0.85), P = 0.031]. There was no significant difference in surgical outcome despite half of those without HS having a hippocampal-sparing procedure. Based on the findings outlined, HS-ve PET-positive TLE may be a surgically remediable syndrome distinct from HS+ve TLE, with a pathophysiological basis that primarily involves lateral temporal neocortical rather than mesial temporal structures.

Onset seizures independently predict poor outcome after subarachnoid hemorrhage.

OBJECTIVE: To determine whether onset seizures after subarachnoid hemorrhage (SAH) carry independent prognostic information and to investigate the risk factors for late seizures after SAH. BACKGROUND: Modern management of SAH, including early operation, has substantially reduced mortality. No study has adequately assessed the importance of onset seizures in a contemporary SAH cohort. METHODS: The authors analyzed the records and initial CT scans of 412 consecutive patients with aneurysmal or nonaneurysmal SAH admitted to the Royal Melbourne Hospital from 1990 to 1996. Each patient with an onset seizure (n = 32, 7.8% of cohort) was age and sex matched to two nonseizure patients of the same cohort. Each patient with a late seizure (n = 17, 5.1% of cohort) was matched to five control subjects of the same cohort. RESULTS: With use of logistic regression analysis, onset seizures correlated with the sum score of blood on initial CT scan (OR = 1.1, p = 0.05), but there was no significant correlation with duration of loss of consciousness at onset, Glasgow Coma Score (GCS), presence of aneurysm, or past history of hypertension or epilepsy. Disability 6 weeks after SAH according to the Glasgow Outcome Scale was independently predicted by initial GCS of <6 (OR = 13.7, p < 0.01) and onset seizure (OR = 7.8, p = 0.04). Late seizures within the first 6 weeks were independently related to rebleeding (OR = 94, p < 0.01) and onset seizures (OR = 27, p < 0.01) but not to other onset variables, development of hydrocephalus, or vasospasm. CONCLUSION: In this single-institution cohort of patients with SAH, onset seizures were an independent risk factor for late seizures and a predictor of poor outcome.