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Nicolas Massager, Jean Régis, Douglas Kondziolka, Théodore Njee, and Marc Levivier

Object. This study was undertaken to assess the efficacy and safety of gamma knife radiosurgery (GKS) for the treatment of arteriovenous malformations (AVMs) located within the brainstem.

Methods. The results of GKS performed in 87 patients with brainstem AVMs at two centers with experienced physicians are reviewed. The mean patient age was 37 years and the population included 19 children. The male/female ratio was 56:31. The malformation was located in the upper brainstem in 52 patients. Seventy-four percent of the patients had suffered a hemorrhage before GKS. For 70% of the patients no other treatment had been proposed before GKS. The mean AVM volume was 1.3 cm3. The lesions were treated with one to eight isocenters, with a margin dose ranging between 11.5 Gy and 30 Gy. The mean clinical follow-up period was 3.2 years. Ninety-five percent of the patients improved or remained neurologically stable. Rebleeding occurred in three patients at 3, 6, and 16 months, respectively, after GKS. Two patients in whom rebleeding occured recovered, and one died. The AVM obliteration rate was 63% at 2 years and 73% at 3 years after GKS. A second GKS was performed in six patients in whom only partial obliteration was demonstrated on angiography 3 years after the first procedure.

Conclusions. Gamma knife radiosurgery may be a valuable first-choice therapy for the treatment of AVMs located within the brainstem.

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Satoshi Maesawa, Douglas Kondziolka, C. Edward Dixon, Jeffrey Balzer, Wendy Fellows, and L. Dade Lunsford

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 µg) 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.

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Satoshi Maesawa, Camille Salame, John C. Flickinger, Stephen Pirris, Douglas Kondziolka, and L. Dade Lunsford

Object. Stereotactic radiosurgery is an increasingly used and the least invasive surgical option for patients with trigeminal neuralgia. In this study, the authors investigate the clinical outcomes in patients treated with this procedure.

Methods. Independently acquired data from 220 patients with idiopathic trigeminal neuralgia who underwent gamma knife radiosurgery were reviewed. The median age was 70 years (range 26–92 years). Most patients had typical features of trigeminal neuralgia, although 16 (7.3%) described additional atypical features. One hundred thirty-five patients (61.4%) had previously undergone surgery and 80 (36.4%) had some degree of sensory disturbance related to the earlier surgery.

Patients were followed for a maximum of 6.5 years (median 2 years). Complete or partial relief was achieved in 85.6% of patients at 1 year. Complete pain relief was achieved in 64.9% of patients at 6 months, 70.3% at 1 year, and 75.4% at 33 months. Patients with an atypical pain component had a lower rate of pain relief (p = 0.025). Because of recurrences, only 55.8% of patients had complete or partial pain relief at 5 years. The absence of preoperative sensory disturbance (p = 0.02) or previous surgery (p = 0.01) correlated with an increased proportion of patients who experienced complete or partial pain relief over time. Thirty patients (13.6%) reported pain recurrence 2 to 58 months after initial relief (median 15.4 months). Only 17 patients (10.2% at 2 years) developed new or increased subjective facial paresthesia or numbness, including one who developed deafferentation pain.

Conclusions. Radiosurgery for idiopathic trigeminal neuralgia was safe and effective, and it provided benefit to a patient population with a high frequency of prior surgical intervention.

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John C. Flickinger, Douglas Kondziolka, Ajay Niranjan, and L. Dade Lunsford

Object. The goal of this study was to define tumor control and complications of radiosurgery encountered using current treatment methods for the initial management of patients with unilateral acoustic neuroma.

Methods. One hundred ninety patients with previously untreated unilateral acoustic neuromas (vestibular schwannomas) underwent gamma knife radiosurgery between 1992 and 1997. The median follow-up period in these patients was 30 months (maximum 85 months). The marginal radiation doses were 11 to 18 Gy (median 13 Gy), the maximum doses were 22 to 36 Gy (median 26 Gy), and the treatment volumes were 0.1 to 33 cm3 (median 2.7 cm3).

The actuarial 5-year clinical tumor-control rate (no requirement for surgical intervention) for the entire series was 97.1 ± 1.9%. Five-year actuarial rates for any new facial weakness, facial numbness, hearing-level preservation, and preservation of testable speech discrimination were 1.1 ± 0.8%, 2.6 ± 1.2%, 71 ± 4.7%, and 91 ± 2.6%, respectively. Facial weakness did not develop in any patient who received a marginal dose of less than 15 Gy (163 patients). Hearing levels improved in 10 (7%) of 141 patients who exhibited decreased hearing (Gardner-Robertson Classes II–V) before undergoing radiosurgery. According to multivariate analysis, increasing marginal dose correlated with increased development of facial weakness (p = 0.0342) and decreased preservation of testable speech discrimination (p = 0.0122).

Conclusions. Radiosurgery for acoustic neuroma performed using current procedures is associated with a continued high rate of tumor control and lower rates of posttreatment morbidity than those published in earlier reports.

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Melvin Field, Timothy F. Witham, John C. Flickinger, Douglas Kondziolka, and L. Dade Lunsford

Object. Stereotactic brain biopsy has played an integral role in the diagnosis and management of brain lesions. At most centers, imaging studies following biopsy are rarely performed. The authors prospectively determined the acute hemorrhage rate after stereotactic biopsy by performing immediate postbiopsy intraoperative computerized tomography (CT) scanning. They then analyzed factors that may influence the risk of hemorrhage and the diagnostic accuracy rate.

Methods. Five hundred consecutive patients undergoing stereotactic brain biopsy underwent immediate postbiopsy intraoperative CT scanning. Before surgery, routine preoperative coagulation studies were performed in all patients. All medical charts, laboratory results, preoperative imaging studies, and postoperative imaging studies were reviewed.

In 40 patients (8%) hemorrhage was detected using immediate postbiopsy intraoperative CT scanning. Neurological deficits developed in six patients (1.2%) and one patient (0.2%) died. Symptomatic delayed neurological deficits developed in two patients (0.4%), despite the fact that the initial postbiopsy CT scans in these cases did not show acute hemorrhage. Both patients had large intracerebral hemorrhages that were confirmed at the time of repeated imaging. The results of a multivariate logistic regression analysis of the risk of postbiopsy hemorrhage of any size showed a significant correlation only with the degree to which the platelet count was below 150,000/mm3 (p = 0.006). The results of a multivariate analysis of a hemorrhage measuring greater than 5 mm in diameter also showed a correlation between the risk of hemorrhage and a lesion location in the pineal region (p = 0.0086). The rate at which a nondiagnostic biopsy specimen was obtained increased as the number of biopsy samples increased (p = 0.0073) and in accordance with younger patient age (p = 0.026).

Conclusions. Stereotactic brain biopsy was associated with a low likelihood of postbiopsy hemorrhage. The risk of hemorrhage increased steadily as the platelet count fell below 150,000/mm3. The authors found a small but definable risk of delayed hemorrhage, despite unremarkable findings on an immediate postbiopsy head CT scan. This risk justifies an overnight hospital observation stay for all patients after having undergone stereotactic brain biopsy.

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Elizabeth Tyler-Kabara, Douglas Kondziolka, John C. Flickinger, and L. Dade Lunsford

✓ The purpose of this report was to review the results of stereotactic radiosurgery in the management of patients with residual neurocytomas after initial resection or biopsy procedures. Four patients underwent stereotactic radiosurgery for histologically proven neurocytoma. Clinical and imaging studies were performed to evaluate the response to treatment.

Radiosurgery was performed to deliver doses to the tumor margin of 14, 15, 16, and 20 Gy, depending on tumor volume and proximity to critical adjacent structures. More than 3 years later, imaging studies revealed significant reductions in tumor size. No new neurological deficits were identified at 53, 50, 42, and 38 months of follow up. The authors' initial experience shows that stereotactic radiosurgery appears to be an effective treatment for neurocytoma.

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Norimoto Nakahara, Hideho Okada, Timothy F. Witham, Jason Attanucci, Wendy K. Fellows, William H. Chambers, Ajay Niranjan, Douglas Kondziolka, and Ian F. Pollack

Object. To determine if the combination of radiosurgery and tumor cell vaccine would enhance the therapy of metastatic lesions of the central nervous system (CNS), the authors examined the antitumoral effects of radiosurgery and cytokine-transduced tumor cell vaccine.

Methods. Fifty-five rats underwent intracranial implantation of 5 × 103 MADB106 cells. On Day 3 after tumor implantation, 34 rats were inoculated in the flank with nonirradiated MADB106 cells that had been retrovirally transduced to express granulocyte-macrophage colony-stimulating factor or interleukin-4. Twenty-seven rats (17 animals that had received the vaccine and 10 that had not) underwent radiosurgery performed using a gamma knife at maximum doses of 32 Gy on Day 5.

No animals in the untreated group or in the vaccine-alone groups survived longer than 21 days. Animals treated by radiosurgery alone displayed prolonged survival in comparison with untreated animals (p < 0.0001), but only one of 10 animals survived longer than 55 days. In contrast, 14 of 17 animals that received the combination therapy of radiosurgery and vaccination survived longer than 55 days (p = 0.0003 compared with animals that underwent radiosurgery alone). On Day 55, the long-term survivors were challenged by parental MADB106 cells, which were implanted in the contralateral hemisphere. All animals from the combination therapy groups survived longer than 50 days after this challenge, but the single survivor from the radiosurgery-alone group died of tumor growth in 27 days.

Conclusions. The combination of radiosurgery and cytokine gene—transduced tumor cell vaccine markedly prolonged animal survival and protected animals from a subsequent challenge by parental tumor cells placed in the CNS. The data provided by this study indicate that this combination therapy represents a strategy that may have clinical applicability for single and/or multiple metastatic brain tumors.