Matti Vapalahti

BACKGROUND AND PURPOSE: This prospective study was conducted to compare the outcomes of surgical clipping and endovascular treatment in acute (<72 hours) aneurysmal subarachnoid hemorrhage (SAH). METHODS: One hundred nine consecutive patients were randomly assigned to either surgical (n=57) or endovascular (n=52) treatment. Clinical and neuropsychological outcome was assessed at 3 and 12 months after treatment; MRI of the brain was performed at 12 months. Follow-up angiography was scheduled after clipping and 3 and 12 months after endovascular treatment. RESULTS: One year postoperatively, 43/41 (surgical/endovascular) patients had good or moderate recovery, 5/4 had severe disability or were in a vegetative state, and 9/7 had died (NS) according to intention to treat. Patients with good clinical recovery did not differ in their neuropsychological test scores. Symptomatic vasospasm (OR 2.47; 95% CI 1.45 to 4.19; P<0.001), poorer Hunt and Hess grade (OR 2.50; 95% CI 1.31 to 4.75; P=0.005), need for permanent shunt (OR 8.90; 95% CI 1.80 to 44.15; P=0.008), and larger size of the aneurysm (OR 1. 22; 95% CI 1.02 to 1.45; P=0.032) independently predicted worsened clinical outcome regardless of the treatment modality. In MRI, superficial brain retraction deficits (P<0.001) and ischemic lesions in the territory of the ruptured aneurysm (P=0.025) were more frequent in the surgical group. Kaplan-Meier analysis (mean+/-SD follow-up 39+/-18 months) revealed equal survival in both treatment groups. No late rebleedings have occurred. CONCLUSIONS: One-year clinical and neuropsychological outcomes seem comparable after early surgical and endovascular treatment of ruptured intracranial aneurysms. The long-term efficacy of endovascular treatment in preventing rebleeding remains open.

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.

✓ Cerebral blood flow (CBF), intracranial pressure (ICP), brain metabolism (CMRO 2 ), systemic arterial pressure (SAP), and arterial blood gases were measured in comatose patients, most of whom had suffered a head injury. The patients were divided into two groups according to whether a mass lesion was or was not demonstrated by bilateral carotid angiography. In the majority of patients a control run measuring regional cerebral blood flow (rCBF) was followed by a test of cerebral autoregulation; hypertonic mannitol was then administered. During the control period there was marked and unpredictable variability in all of the parameters recorded. There was no correlation between ICP or CBF and neurological status or CMRO 2 except at very high levels of ICP. Autoregulation was intact in some patients and defective in others, and there was no correlation between the status of autoregulation on the one hand and CBF or survival on the other. Mannitol increased CBF in nearly all patients, to twice the control value in a few, and CMRO 2 increased with CBF in several patients. The change in CBF was independent of the initial ICP or the response of ICP to mannitol. Thus, the relationship of these parameters was unpredictable in acutely brain-damaged patients; the status of autoregulation was also unpredictable.

Herpes simplex virus thymidine kinase (HSV tk) gene therapy combined with ganciclovir (GCV) medication is a potential new method for the treatment of malignant glioma. We have used both retrovirus-packaging cells (PA317/tk) and adenoviruses (Adv/tk) for gene therapy for malignant glioma. Retrovirus-packaging cells were used for eight tumors in seven patients and adenoviruses were used for seven tumors in seven patients. As a control group, seven tumors in seven patients were transduced with lacZ marker gene 4-5 days before tumor resection. Safety and efficacy of the gene therapy were studied with clinical evaluation, blood and urine samples, MRI follow-up, and survival of the patients. Four patients with adenovirus injections had a significant increase in anti-adenovirus antibodies and two of them had a short-term fever reaction. Frequency of epileptic seizures increased in two patients. No other adverse events possibly related to gene therapy were detected. In the retrovirus group, all treated gliomas showed progression by MRI at the 3-month time point, whereas three of the seven patients treated with Adv/tk remained stable (p < 0.05). Mean survival times for retrovirus, adenovirus, and control groups were 7.4, 15.0, and 8. 3 months, respectively. The difference in the survival times between the adenovirus and retrovirus groups was significant (p < 0.012). It is concluded that HSV tk gene therapy is safe and well tolerated. On the basis of these results further trials are justified, especially with adenovirus vectors.

BACKGROUND AND PURPOSE: Population-based patient materials have not been used earlier in assessing the effects of neurosurgical treatment on survival and functional outcome of subarachnoid hemorrhage. Moreover, the proportion of all subarachnoid hemorrhage patients who might be candidates for neurosurgical treatment has not been estimated. METHODS: We compared the survival and functional outcome of two population-based patient materials from Central Finland in 1976 through 1978 (n = 146) and 1980 through 1987 (n = 351). The most important basic characteristics of both materials were similar. In the 1970s, only patients aged < 60 years with carotid territory aneurysms were operated on after an interval of 2 weeks from the bleeding. In the 1980s, early surgery was attempted, and the other exclusion criteria were abandoned. Allocation to medical or surgical treatment was not randomized. RESULTS: During the 1970s, only 14% of the patients had surgical treatment, with a median delay of 15 days after the bleeding; in the 1980s, the corresponding figures were 46% and 4 days. Despite these fundamental changes in the treatment policy, the survival up to 3 years in the 1980s was only marginally improved compared with the 1970s. Conversely, the functional outcome at 4 years after the bleeding was significantly better in the 1980s than the 1970s, with 82% and 64% of the survivors, respectively, being independent in the activities of daily living (P = .002). We estimated that 60% of all patients with subarachnoid hemorrhage might be candidates for neurosurgical treatment, provided that there are no delays in admission or evaluation. CONCLUSIONS: An active treatment policy of subarachnoid hemorrhage including early surgery only marginally improves survival, but the quality of life of the survivors is significantly better. Only 60% of all patients in the population with subarachnoid hemorrhage can, at least theoretically, benefit from surgical treatment.