Long-term epilepsy surgery outcomes in patients with MRI-negative temporal lobe epilepsy.

PURPOSE: The outcome of surgery in patients with temporal lobe epilepsy (TLE) and normal high-resolution magnetic resonance imaging (MRI) has been significantly worse than in patients with unilateral hippocampal damage upon MRI. The purpose of this study was to determine the long-term outcomes of consecutive true MRI-negative TLE patients who all underwent standardized preoperative evaluation with intracranial electroencephalography (EEG) electrodes. METHODS: In this study we present all adult MRI-negative TLE surgery candidates evaluated between January 1990 and December 2006 at Kuopio Epilepsy Center in Kuopio University Hospital, which provides a national center for epilepsy surgery in Finland. During this period altogether 146 TLE surgery candidates were evaluated with intracranial electrodes, of whom 64 patients with normal high-resolution MRI were included in this study. RESULTS: Among the 38 patients who finally underwent surgery, at the latest follow-up (mean 5.8 years), 15 (40%) were free of disabling seizures (Engel class I) and 6 (16%) were seizure-free (Engel class IA). Twenty-one (55%) of 38 patients had poor outcomes (Engel class III-IV). Outcomes did not change compared to 12-month follow-up. Histopathologic examination failed to reveal any focal pathology in 68% of our MR-negative cases. Only patients with noncongruent positron emission tomography (PET) results had worse outcomes (p = 0.044). DISCUSSION: Our results suggest that epilepsy surgery outcomes in MRI-negative TLE patients are comparable with extratemporal epilepsy surgery in general. Seizure outcomes in the long-term also remain stable. Modern imaging techniques could further improve the postsurgical seizure-free rate. However, these patients usually require chronic intracranial EEG evaluation to define epileptogenic areas.

MR imaging of the brain 1 year after aneurysmal subarachnoid hemorrhage: randomized study comparing surgical with endovascular treatment.

PURPOSE: To prospectively evaluate, with magnetic resonance (MR) imaging, long-term outcome of the brain after endovascular versus neurosurgical treatment for aneurysmal subarachnoid hemorrhage (aSAH). MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. One hundred sixty-eight (77 men, 91 women; mean age +/- standard deviation, 51 years +/- 13) patients were randomly assigned to surgical versus endovascular treatment of the ruptured aneurysm with 138 (67 endovascular, 71 surgical) MR examinations 1 year after aSAH. The presence, localization, volumes, and cause of lesions were analyzed with chi(2), Mann-Whitney U, and Student t tests. Furthermore, correlation between MR-detectable brain parenchymal high-signal intensity (SI) lesions on T2- and intermediate-weighted MR images and neuropsychologic outcome was evaluated by using Spearman correlation coefficient. RESULTS: Only 44 (31.9%) of 138 patients had no lesions associated with aSAH. According to intention to treat, lesions were more frequent after surgical rather than endovascular treatment, predominating in the frontal (surgical: n = 50, [70.4%] vs endovascular: n = 34 [50.7%], P = .018) and temporal (n = 34 [47.9%] vs n = 15 [22.4%], P = .002) lobes. Only endovascular patients had subtentorial lesions (n = 4 [6.0%], P = .037). Ischemic lesions in the parental artery territory were more frequent in surgical (n = 33 [46.5%]) than in endovascular (n = 15 [22.4%], P = .003) patients, with corresponding mean lesion volumes of 20.9 cm(3) +/- 46.5 versus 17.6 cm(3) +/- 35.8 (P = .209). Ischemic lesions in remote vascular territories were equal in frequency and size. Retraction injuries were common in the surgical (n = 40, [56.3%]) treatment group. Ischemic lesion volumes correlated with neuropsychologic test scores. CONCLUSION: Parenchymal high-SI lesions on T2- and intermediate-weighted MR images are more frequent after early surgical rather than endovascular treatment of the ruptured aneurysm, and lesion volumes correlate with the neuropsychologic test performance.

Increased expression of caspase 2 in experimental and human temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is often caused by a neurodegenerative brain insult that triggers epileptogenesis, and eventually results in spontaneous seizures, i.e., epilepsy. Understanding the mechanisms of cell death is a key for designing new drug therapies for preventing the neurodegeneration associated with TLE. Here, we investigated the expression of caspase 2, a protein involved in programmed cell death, during the course of epilepsy. We investigated caspase 2 expression in hippocampal samples derived from patients operated on for drug refractory TLE. To understand the evolution of altered-caspase 2 expression during the epileptic process, we also examined caspase 2 expression and activity in the rat hippocampus after status epilepticus-induced acute damage, during epileptogenesis, and after the onset of epilepsy. Caspase 2 expression was enhanced in the hippocampal neurons in chronic TLE patients. In rats, status epilepticus-induced caspase 2 labeling paralleled the progression of neurodegeneration. Proteolytic activation and cleavage of caspase 2 was also detected in the rat brain undergoing epileptogenesis. Our data suggest that caspase 2-mediated programmed cell death participates in the seizure-induced degenerative process in experimental and human TLE.

Safety profile of plasmid/liposomes and virus vectors in clinical gene therapy.

Despite of more than 500 gene therapy trials worldwide very little systematic safety information is available from gene therapy. Safety information was collected from 146 consecutive patients who participated in three randomized, controlled phase II gene therapy trials in cardiovascular diseases and malignant glioma using adenoviruses, plasmid/liposomes and retrovirus packaging cells. Total follow-up time of the patients was 78794 days which equals 1.5 years per patient. The main outcome measures were serious adverse events, other adverse events and changes in general laboratory parameters. Except fever and increases in CRP values plasmid/liposomes were safe and well tolerated. The incidence of serious adverse events in adenovirus-treated patients was 0.9 and 4.0/10000 patient days in cardiovascular and malignant glioma trials as compared to 0.5 and 2.1 in randomized control patients, respectively. Transient fever, leukopenia and increases in CRP and liver enzymes were detected in virus-treated patients. No deaths from side effects or no new cancers were associated with gene therapy. It is concluded that gene therapy, like any other therapy, is associated with side effects which depend on the administered vector, dose, and route of delivery and properties of the transgene. However, given the limitations of this study and length of the follow-up, the safety profile of gene therapy seems to be acceptable for the treatment of severe human diseases.

Cystatin C expression is associated with granule cell dispersion in epilepsy.

Human temporal lobe epilepsy (TLE) is associated with cellular alterations (eg, hilar cell death, neurogenesis, and granule cell dispersion) in the dentate gyrus but their underlying molecular mechanism are not known. We previously demonstrated increased expression of cystatin C, a protease inhibitor linked to both neurodegeneration and neurogenesis, during epileptogenesis in the rat hippocampus. Here, we investigated cystatin C expression in the dentate gyrus in chronic epilepsy and its association with neuronal loss and neurogenesis. In both rats with epilepsy and human patients with TLE, cystatin C expression was increased in glial cells in the molecular layer of the dentate gyrus, being most prominent in cases with granule cell dispersion. In patients with TLE, high cystatin C expression associated with greater numbers of polysialylated neural cell adhesion molecule-positive newborn cells in the molecular layer, although the overall number was decreased, indicating that the newborn cells migrate to abnormal locations in the epileptic dentate gyrus. These data thus demonstrate that cystatin C expression is altered during the chronic phase of epilepsy and suggest that cystatin C plays a role in network reorganization in the epileptic dentate gyrus, especially in granule cell dispersion and guidance of migrating newborn granule cells.

AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study.

Malignant glioma is a devastating brain tumor with no effective treatment. This randomised, controlled study involved 36 patients with operable primary or recurrent malignant glioma. Seventeen patients were randomized to receive AdvHSV-tk gene therapy (3 x 10(10) pfu) by local injection into the wound bed after tumor resection, followed by intravenous ganciclovir (GCV), 5 mg/kg twice daily for 14 days. The control group of 19 patients received standard care consisting of radical excision followed by radiotherapy in those patients with primary tumors. The primary end-point was survival as defined by death or surgery for recurrence. Secondary end-points were all-cause mortality and tumour progression as determined by MRI. Overall safety and quality of life were also assessed. Findings were also compared with historical controls (n = 36) from the same unit over 2 years preceding the study. AdvHSV-tk treatment produced a clinically and statistically significant increase in mean survival from 39.0 +/- 19.7 (SD) to 70.6 +/- 52.9 weeks (P = 0.0095, log-rank regression vs. randomized controls). The median survival time increased from 37.7 to 62.4 weeks. Six patients had increased anti-adenovirus antibody titers, without adverse effects. The treatment was well tolerated. It is concluded that AdvHSV-tk gene therapy with GCV is a potential new treatment for operable primary or recurrent high-grade glioma.

Retinoblastoma associated with chromosomal 13q14 deletion mosaicism.

PURPOSE: To assess the risk of retinoblastoma developing in children with microscopic chromosomal with mosaic deletions involving 13q14. DESIGN: Case report and systematic literature review. PARTICIPANTS: Data on 29 patients with a mosaic and 107 patients with a nonmosaic somatic deletion of chromosome 13q14 were compared. MAIN OUTCOME MEASURES: Age at diagnosis, frequency, and laterality of retinoblastoma. CASE REPORT: A dysmorphic baby, who carried a chromosomal deletion involving 13q14 in 34% of peripheral blood lymphocytes, had neuroradiologic evidence of retinoblastoma at the age of 2 weeks. She developed trilateral retinoblastoma, a pineal neuroblastic tumor, at the age of 10 months. The diagnosis of her tumor was delayed because of misjudgment of risk of retinoblastoma developing. RESULTS: Meta-analysis revealed no difference between children with mosaic and nonmosaic chromosomal deletion of 13q14 regarding the age at diagnosis, laterality of tumor, and presence of family history for retinoblastoma. A lower percentage of somatic cells with mosaic deletion did not predict a higher age at diagnosis or unilateral tumors. No statistically significant difference was noted regarding the presence of mental retardation, dysmorphic features, and anomalies of internal organs between mosaic and nonmosaic deletions. Only 7% (95% confidence interval, 1-23) of 29 patients who had a mosaic chromosomal deletion including 13q14 were not reported to develop retinoblastoma. CONCLUSIONS: Whenever a 13q14 deletion is diagnosed, immediate ophthalmologic evaluation is recommended to ensure prompt diagnosis of retinoblastoma. Mosaic and nonmosaic chromosomal deletions of 13q14 do not differ regarding the risk and type of retinoblastoma developing.

3-D reconstructed magnetic resonance imaging in localization of subdural EEG electrodes. Case illustration.

We report an illustrative case of presurgical evaluation for epilepsy surgery, where the three-dimensional reconstructed magnetic resonance imaging played a pivotal role in determining the exact location of the subdural strip electrodes in temporomesial area. The tip of one the frontal strip electrodes was actually recording the temporopolar ictal activity. This contributed conclusively to the decision for surgical treatment and to the excellent outcome.

Adenovirus-mediated herpes simplex virus thymidine kinase gene therapy in BT4C rat glioma model.

Adenovirus (Adv)-mediated herpes simplex virus thymidine kinase (adv/tk) gene therapy combined with ganciclovir (GCV) medication is a promising approach for the treatment of malignant glioma. However, optimal administration and the effect of possible adjuvant treatments have not been fully examined. In the present study, we examined the efficacy of adv/tk/GCV gene therapy in a syngeneic BT4C rat malignant glioma model, either as a single administration or given as three injections during three consecutive days. The effect of combined adv-mediated macrophage colony-stimulating factor (MCSF) and adv/tk gene transfer was also studied. BT4C malignant glioma cells were injected into the right corpus callosum of BDIX rats (n=112). Before gene therapy, the presence of tumors was verified by MRI. The rats were divided into eight groups as follows: group I (n=20) received a single adv/tk gene transfer (total dose 4x10(8) pfu) and GCV treatment for 14 days; group II (n=5) received the same gene transfer without GCV; group III (n=28) received three adv/tk injections (total dose 4x10(8) pfu) on three consecutive days and GCV for 14 days; group IV (n=5) received three similar adv/tk injections without GCV medication; group V (n=13) received three adv/MCSF injections (total dose 2x10(8) pfu) on three consecutive days and GCV medication; group VI (n=12) received three adv/tk and adv/MCSF (total dose 6x10(8) pfu) injections on three consecutive days followed by GCV medication; and group VII (n=12) the same treatment without GCV. Group VIII (n=17) consisted of wild-type BT4C malignant glioma tumors without any treatment. Treatment effect and tissue responses were characterized by general histology, immunohistochemistry, MRI, and survival of the study groups. The best treatment effect and survival was found in rats treated with adv/tk gene transfer once a day for three consecutive days (P<.05). No improvement of the treatment effect was seen after the combined adv/tk and adv/MCSF gene transfer compared with the repeated adv/tk gene transfer. The results show that 20% of the rats can be cured (survival >6 months) after optimized adv/tk gene therapy. It is concluded that repeated intratumoral administration of adv/tk is a promising approach for the treatment of malignant glioma tumors in vivo.

Cerebral perfusion before and after endovascular or surgical treatment of acutely ruptured cerebral aneurysms: a 1-year prospective follow-up study.

OBJECTIVE: To prospectively determine temporal changes in regional cerebral perfusion in patients with acutely (<72 h) ruptured cerebral aneurysms treated either endovascularly or surgically. METHODS: Cerebral perfusion was measured both before and 1 week after treatment by use of a (99m)Tc-labeled ethyl-cysteine dimer and single-photon emission computed tomographic (SPECT) studies in 46 of 81 consecutive patients included in a prospective randomized study of early treatment of ruptured aneurysms. In addition to visual analysis of the SPECT images, corticocerebellar perfusion ratios were calculated for seven predefined bilateral regions. Late ischemic deficits were evaluated after 12 months by magnetic resonance imaging of the brain. RESULTS: Acute perfusion deficits were commonly seen before treatment. In the visual comparison between the first and second SPECT studies, the number of new or enlarged deficits (P = 0.006) and deficits that expanded from unilateral to bilateral (P = 0.020) significantly increased in the surgical group but not in the endovascular group. In the second SPECT study, surgical patients had decreased corticocerebellar perfusion ratios in the right frontobasal cortex (P = 0.012) compared with the endovascular patients, and in the ipsilateral frontobasal cortex (P = 0.002) and ipsilateral temporal apex (P = 0.002) compared with the contralateral side of the ruptured aneurysm. The 12-month magnetic resonance imaging of the brain revealed no significant difference in the number of ischemic deficits between the endovascular and surgical groups. CONCLUSION: Disturbances in cerebral perfusion both before and after treatment are common. Although no major differences in the findings were detected between patients treated with either clips or coils, progression of perfusion deficits was more common in the surgical group. However, the 12-month magnetic resonance imaging of the brain revealed equal numbers of ischemic deficits in the treatment groups.