Faculty Bibliography

OBJECT: Any analysis of the potential role of stereotactic radiosurgery for epilepsy requires the experimental study of its potential antiepileptogenic, behavioral, and histological effects. The authors hypothesized that radiosurgery performed using subnecrotic tissue doses would reduce or abolish epilepsy without causing demonstrable behavioral side effects. The kainic acid model in rats was chosen to test this hypothesis. METHODS: Chronic epilepsy was successfully created by stereotactic injection of kainic acid (8 microg) into the rat hippocampus. Epileptic rats were divided into three groups: high-dose radiosurgery (60 Gy, 16 animals), low-dose (30 Gy, 15 animals), and controls. After chronic epilepsy was confirmed by observation of the seizure pattern and by using electroencephalography (EEG), radiosurgery was performed on Day 10 postinjection. Serial seizure and behavior observation was supplemented by weekly EEG sessions performed for the next 11 weeks. To detect behavioral deficits, the Morris water maze test was performed during Week 12 to study spatial learning and memory. Tasks involved a hidden platform, a visible platform, and a probe trial. After radiosurgery, the incidence of observed and EEG-defined seizures was markedly reduced in rats from either radiosurgically treated group. A significant reduction was noted after high-dose (60 Gy) radiosurgery in Weeks 5 to 9 (p < 0.003). After low-dose (30 Gy) radiosurgery, a significant reduction was found after 7 to 9 weeks (p < 0.04). During the task involving the hidden platform, kainic acid-injected rats displayed significantly prolonged latencies compared with those of control animals (p < 0.05). Hippocampal radiosurgery did not worsen this performance. The probe trial showed that kainic acid-injected rats that did not undergo radiosurgery spent significantly less time than control rats in the target quadrant (p = 0.03). Rats that had undergone radiosurgery displayed no difference compared with control rats and demonstrated better performance than rats that received kainic acid alone (p = 0.04). Radiosurgery caused no adverse histological effects. CONCLUSIONS: In a rat model, radiosurgery performed with subnecrotic tissue doses controlled epilepsy without causing subsequent behavioral impairment.

Radiosurgery is a surgical procedure associated with minimal functional morbidity and allows patients to return rapidly to their previous level of activity. Most tumors regress in volume with extended follow-up, and the rare occurrence of tumor growth after radiosurgery seems to occur early. Similarly, cranial neuropathy or other neurologic symptoms after irradiation occur within the first few years and are usually mild and transient. Current results indicate a low rate of cranial neuropathy (lower than with any other technique). Useful hearing preservation in patients with NF2 seems to be an attainable goal with more sophisticated radiosurgery techniques. We anticipate the increased use of stereotactic radiosurgery for patients with vestibular schwannomas as more and more smaller sized tumors are identified.

OBJECTIVE: The optimal management of intracranial arteriovenous malformations (AVMs) in children remains controversial. Children with intracranial AVMs present a special challenge in therapeutic decision-making because of the early recognition of their future life-long risks of hemorrhage if they are treated conservatively. The goals of radiosurgery are to achieve complete AVM obliteration and to preserve neurological function. We present long-term outcomes for a series of children treated using radiosurgery. METHODS: The findings for 53 consecutive children who underwent at least 36 months of imaging follow-up monitoring after radiosurgery were reviewed. The median age at the time of treatment was 12 years (range, 2-17 yr). Thirty-one children (58%) presented after their first intracranial hemorrhaging episodes, two (4%) after their second hemorrhaging episodes, and one (2%) after five hemorrhaging episodes. Nineteen children (36%) presented with unruptured AVMs, and a total of 25 children (47%) exhibited neurological deficits. AVMs were graded as Spetzler-Martin Grade I (2%), Grade II (23%), Grade III (36%), Grade IV (9%), or Grade VI (30%). The median AVM volume was 1.7 ml (range, 0.11-10.2 ml). The median marginal dose was 20 Gy (range, 15-25 Gy). RESULTS: Results were stratified according to AVM volumes (Group 1, < or =3 ml; Group 2, >3 ml to < or =10 ml; Group 3, >10 ml). Twenty-eight patients (80%) in Group 1 and 11 (64.7%) in Group 2 achieved complete obliteration. The only patient in Group 3 did not achieve obliteration. Complications included brainstem edema (n = 1) and transient pulmonary edema (n = 1). Four patients experienced hemorrhaging episodes, 30, 40, 84, and 96 months after radiosurgery. Multivariate logistic regression analysis demonstrated that only volume was significantly correlated with obliteration rates (P = 0.0109). CONCLUSION: Radiosurgery is safe and efficacious for selected children with AVMs. The obliteration rates and the attendant low morbidity rates suggest a primary role for stereotactic radiosurgery for pediatric AVMs.

BACKGROUND: The care of patients with a brain metastasis from unknown primary site is controversial. The authors reviewed the results of stereotactic radiosurgery in this group of patients to better define clinical expectations. METHODS: During an 11-year interval, radiosurgery was performed in 421 patients with brain metastases at the University of Pittsburgh. Fifteen patients had solitary or multiple (< or = 5) brain metastases without a detectable primary site at the time of initial presentation. In five patients, a histologic diagnosis of cancer was obtained from extracranial metastatic sites. In 10 patients, a diagnosis was obtained from the brain. A total of 31 tumors with a mean volume of 4.3 mL (range, 0. 05-18.6 mL) underwent radiosurgery with a mean marginal dose of 16.2 Gray (Gy) (range, 12-20 Gy). Fourteen patients (93.3%) also received whole brain fractionated radiation therapy. RESULTS: The median survival was 15 months after radiosurgery (range, 1-48 months) and 27 months after their initial diagnosis of cancer. In 4 patients (26. 7%), the primary tumor was discovered later (lung in 3 patients and liver in 1). Three of these four patients died due to progression of their primary tumor. Of the remaining 11 patients, 4 died of progression of extracranial metastases, 2 died of other systemic diseases, and 3 patients died because of progression of brain metastasis. Three patients (20%) were still living between 21-48 months after radiosurgery. The presence of active systemic disease and brain stem location both were associated with a poor outcome (P = 0.004 and 0.04). The actuarial imaging-defined local tumor control rate was 91.3 +/- 5.9% at 4 years. CONCLUSIONS: Radiosurgery was an effective strategy for patients with brain metastases from an unknown primary site. Disease progression outside of the brain was the usual cause for patient death.

Transplantation of cultured neuronal cells is safe in animal models and improves motor and cognitive deficits in rats with stroke. The authors studied the safety and feasibility of human neuronal cellular transplantation in patients with basal ganglia stroke and fixed motor deficits, including 12 patients (aged 44 to 75 years) with an infarct 6 months to 6 years previously (stable for at least 2 months). Serial evaluations (12 to 18 months) showed no adverse cell-related serologic or imaging-defined effects. The total European Stroke Scale score improved in six patients (3 to 10 points), with a mean improvement 2.9 points in all patients (p = 0. 046). Six of 11 PET scans at 6 months showed improved fluorodeoxyglucose uptake at the implant site. Neuronal transplantation is feasible in patients with motor infarction.

OBJECT: Multiple brain metastases are a common health problem, frequently found in patients with cancer. The prognosis, even after treatment with whole-brain radiation therapy (WBRT), is poor, with an average expected survival time of less than 6 months. Investigators at numerous centers have evaluated the role of stereotactic radiosurgery in retrospective case series of patients harboring solitary or multiple tumors. Tumor resection is used mainly for patients with large tumors that cause acute neurological syndromes. The authors conducted a randomized trial in which they compared radiosurgery combined with WBRT with WBRT alone. METHODS: Twenty-seven patients were randomized (14 to recieve WBRT alone and 13 to receive WBRT combined with radiosurgery). The rate of local failure at 1 year was 100% after WBRT alone but only 8% in patients in whom boost radiosurgery was performed. The median time to local failure was 6 months after WBRT alone (95% confidence interval (CI) 3.5-8.5) in comparison to 36 months (95% CI 15.6-57) after WBRT and radiosurgery (p = 0.0005). The median time to the development of any brain failure was improved in the combined modality group (p = 0.002). Survival was shown to be related to the extent of extracranial disease (p = 0.02). CONCLUSIONS: Combined WBRT and radiosurgery for the treatment of patients with two to four brain metastases significantly improves control of brain disease. Whole-brain radiation therapy alone does not provide lasting and effective care when treating most patients. Surgical resection remains important for patients with large symptomatic tumors and in whom limited extracranial disease has been demonstrated.