Faculty Bibliography

LARS LEKSELL BEGAN radiobiological investigations to study the effect of high-dose focused radiation on the central nervous system more than 5 decades ago. Although the effects of radiosurgery on the brain tumor microenvironment are still under investigation, radiosurgery has become a preferred management modality for many intracranial tumors and vascular malformations. The effects and the pathogenesis of biological effects after radiosurgery may be unique. The need for basic research concerning the radiobiological effects of high-dose, single-fraction, ionizing radiation on nervous system tissue is crucial. Information from those studies would be useful in devising strategies to avoid, prevent, or ameliorate damage to normal tissue without compromising treatment efficacy. The development of future applications of radiosurgery will depend on an increase in our understanding of the radiobiology of radiosurgery, which in turn will affect the efficacy of treatment. This article analyzes the current state of radiosurgery research with regard to the nature of central nervous system effects, the techniques developed to increase therapeutic efficacy, investigations into the use of radiosurgery for functional disorders, radiosurgery as a tool for investigations into basic central nervous system biology, and the additional areas that require further investigation.

Malignant glioma is a fatal human cancer in which surgery, chemo- and radiation therapies are ineffective. Therapeutic gene transfer used in combination with current treatment methods may augment their effectiveness with improved clinical outcome. We have shown that NUREL-C2, a replication-defective multigene HSV-based vector, is effective in treating animal models of glioma. Here, we report safety and biodistribution studies of NUREL-C2 using rhesus macaques as a model host. Increasing total doses (1 x 10(7) to 1 x 10(9) plaque forming units (PFU)) of NUREL-C2 were delivered into the cortex with concomitant delivery of ganciclovir (GCV). The animals were evaluated for changes in behavior, alterations in blood cell counts and chemistry. The results showed that animal behavior was generally unchanged, although the chronic intermediate dose animal became slightly ataxic on day 12 postinjection, a condition resolved by treatment with aspirin. The blood chemistries were unremarkable for all doses. At 4 days following vector injections, magnetic resonance imaging showed inflammatory changes at sites of vector injections concomitant with HSV-TK and TNFalpha expression. The inflammatory response was reduced at 14 days, resolving by 1 month postinjection, a time point when transgene expression also became undetectable. Immunohistochemical staining following animal killing showed the presence of a diffuse low-grade gliosis with infiltrating macrophages localized to the injection site, which also resolved by 1 month postinoculation. Viral antigens were not detected and injected animals did not develop HSV-neutralizing antibodies. Biodistribution studies revealed that vector genomes remained at the site of injection and were not detected in other tissues including contralateral brain. We concluded that intracranial delivery of 1 x 10(9) PFU NUREL-C2, the highest anticipated patient dose, was well tolerated and should be suitable for safety testing in humans.

Essential tremor can be surgically treated by thalamotomy or deep brain stimulation. During the surgical procedure for both of these procedures, a transient microthalamotomy effect has been observed. This benefit is usually short-lived and appears to be predictive of patient outcome. This report describes a patient who underwent a temporary placement of a stimulating electrode within the ventral intermediate nucleus of the motor thalamus. The procedure was aborted intraoperatively and the patient demonstrated a microthalamotomy effect. This microthalamotomy effect has remained persistent for 24 months, and the patient remains tremor free. This case report lends evidence to the idea that the volume of motor thalamus responsible for tremor may be small and precise. By recognizing the benefit obtained from small lesions with minimal tissue manipulation, surgeons can continue to refine the target for movement disorder surgery.

BACKGROUND: Brain metastases are the most common type of intracranial tumor. Until recently, whole brain fractionated radiation therapy (WBRT) was the mainstay of treatment, thereby confining the role of neurosurgeons to resection of an occasional solitary, accessible, and symptomatic brain metastasis. Median survival after surgery and radiation typically ranged from 5 to 11 months. METHODS: We analyzed various demographic incidence reports and our series of brain metastasis patients treated with radiosurgery. During a 15-year interval (1987-2002), radiosurgery was performed on 5,032 patients of whom 1,088 (21.6%) had metastatic brain tumors. RESULTS: In the United States, 266,820 to 533,640 new cases of brain metastases will be diagnosed in the year 2003. Evidence to date demonstrates that radiosurgery provides effective local tumor control for brain metastases. Important prognostic factors affecting patient survival include the absence of active systemic disease, the patient's preoperative performance status, age, and the number of metastases. Survival and local tumor control rates attained with radiosurgery are superior to those of either conventional surgery or WBRT. The morbidity associated with radiosurgery of brain metastasis is very low, and the mortality rate approaches zero. CONCLUSIONS: Compelling evidence indicates that radiosurgery is an effective neurosurgical management strategy for intracranial brain metastases. Quite often, favorable tumor control and survival can be achieved without WBRT. With radiosurgery as a therapeutic option, neurosurgeons now have a vastly expanded armamentarium for treatment of patients with brain metastases. The large number of patients with brain metastases who require care by a neurosurgeon for optimal treatment has significant implications for both the patterns of neurosurgical training and practice in the United States.

OBJECTIVE: Neurotransplantation has focused on disorders that involve subcortical brain targets. We evaluated the concepts of epileptic focus repair and changes in animal behavior through replacement of lost hippocampal neurons. The safety of hippocampal neurotransplantation was assessed in the rat kainic acid (KA) epilepsy model. METHODS: Sixty-three rats were studied and classified into six groups: KA plus 40,000 LBS-Neurons (Layton BioScience, Sunnyvale, CA; n = 13); KA plus 80,000 cells (n = 12); KA plus media (n = 9); no-KA plus 40,000 cells (n = 12); no-KA plus 80,000 cells (n = 12); and no-KA plus media (n = 5). Clinical observation (2 h daily) and electroencephalogram recording (3 h every other week) were performed to check for seizures until Week 11 after KA injection. On Week 12, the Morris water maze test was performed to assess spatial learning and memory. RESULTS: Four rats were excluded because of intracranial hematoma or abscess. In the clinical observation of seizures, the no-KA plus media group had significantly fewer seizures than rats that received KA followed by injection of 40,000 cells, 80,000 cells, or media (P = 0.001, 0.0004, and 0.004, respectively). On electroencephalographic analysis, there was no significant difference between any of the groups. Transplanted rats with KA-induced epilepsy did not have an increased number of seizures. In the Morris water maze test, the hidden platform task showed that the KA plus 80,000 cell group had significantly longer swim latencies than groups with no-KA plus 40,000 cells (P = 0.035) or no-KA plus 80,000 cells (P = 0.015), demonstrating the behavioral deficits caused by KA injection. The probe trial showed no significant difference for the percentage of time in the target quadrant between any of the groups. Histological studies showed that 26 (59%) of 44 transplanted rats had evidence of graft survival. CONCLUSION: The safety of cortical neurotransplantation was demonstrated, even in an animal model predisposed to epilepsy. We did not find evidence for cessation of seizures or improvement in behavior using this model.

Patients who have an acoustic neuroma (vestibular schwannoma) can be managed with observation, open surgical resection, stereotactic radiosurgery, or fractionated radiotherapy. Increasing numbers of patients are choosing radiosurgery over resection for their tumor. In this report we discuss the history of stereotactic radiosurgery, and the evolution in technique that has led to current results with this approach. We discuss the indications for and expectations with the different treatments. The literature on radiosurgery and radiotherapy is reviewed. It is expected that clinical and basic studies will further improve results.

Stereotactic fractionated radiotherapy has been proposed as a strategy to improve upon the results of single-fraction radiosurgery. The rationale for the strategy is that fractionation will allow complciations to be reduced while maintaining the same degree of long-term tumor control. This paper reviews the radiobiological arguements for fractionating radiation treatment of acoustic neuromas and examines claims for improvement in outcome.

OBJECTIVE: The efficacy of stereotactic intracavitary irradiation with phosphorus-32 ((32)P) for patients with cystic craniopharyngiomas was assessed on the basis of patient survival, tumor control, and visual and endocrinological function before and after treatment. Limited data are available regarding long-term outcomes. METHODS: Forty-nine patients were treated with stereotactic (32)P intracavitary irradiation. Of these, 25 had had no prior treatment as the primary treatment, and 24 were treated for residual or recurrent tumor cysts. At the time of (32)P intracavitary irradiation, 34 of the patients were adults, and 15 were children younger than 16 years of age. The mean cyst volume was 13 ml. The radiation dose varied from 189 to 250 Gy to the cyst wall during five half-lives of the isotope (mean, 224 Gy). The mean follow-up periods were 7 years after diagnosis and 4 years after (32)P treatment. RESULTS: The actuarial survival rates were 90% at 5 years after the diagnosis and 80% at 10 years. The actuarial tumor cyst control rates were 76% at 5 years and 70% at 10 years after the diagnosis. After treatment, 9 (23%) of 40 patients who underwent preoperative and postoperative visual testing were found to have delayed worsening in visual function, 6 as a result of tumor progression and 3 attributed to irradiation. Nineteen patients (48%) had improved visual function. Of 17 patients who had normal preoperative pituitary function or stalk effect, 12 (71%) had preserved and 5 (29%) had worsened visual function. No complications other than visual or endocrinological deterioration occurred in these patients. CONCLUSION: For patients with cystic craniopharyngiomas, (32)P intracavitary irradiation proved effective, with a low risk of complications, for the control of tumor cysts but not of solid tumor components.

OBJECT: Management options for arteriovenous malformations (AVMs) of the brainstem are limited. The long-term results of stereotactic radiosurgery for these disease entities are poorly understood. In this report the authors reviewed both neurological and radiological outcomes following stereotactic radiosurgery for brainstem AVMs over 15 years of experience. METHODS: Fifty patients with brainstem AVMs underwent gamma knife surgery between 1987 and 2002. There were 29 male and 21 female patients with an age range of 7 to 79 years (median 35 years). Anatomical locations of these AVMs included the midbrain (39 lesions), pons (20 lesions), and medulla oblongata (three lesions). The radiation dose applied to the margin of the AVM varied from 12 to 26 Gy (median 20 Gy). Forty-five patients were followed up from 5 to 176 months (mean 72 months). The angiographically confirmed actuarial obliteration rate was 66% at the final follow-up examination. Two patients experienced a hemorrhage before obliteration. The annual hemorrhage rate was 1.7% for the first 3 years after radiosurgery and 0% thereafter. Patients who had received irradiation at two or fewer isocenters had higher obliteration rates (80% compared with 44% for > two isocenters, p = 0.006), and this was related to a more spherical nidus shape. The rate of persistent neurological complications in patients treated using magnetic resonance imaging-based dose planning after 1993 was 7%, compared with 20% in patients treated before 1993. An older patient age, a lesion located in the tectum, and a higher radiosurgery-based score were significantly associated with greater neurological complications. CONCLUSIONS: Stereotactic radiosurgery provided complete obliteration of AVMs in two thirds of the patients with a low risk of latency-interval hemorrhage. Better three-dimensional imaging studies and conformal dose planning reduced the risk of adverse radiation effects. Younger patients harboring more spherical AVMs that did not involve the tectal plate had the best outcomes.

Glial tumors occur as intraaxial masses in the brain and are uniformly fatal due to lack of effective therapy. Resection combined with radiation and chemotherapy fails to eradicate malignant cells infiltrating into normal brain, and recurrence at the original site is ultimately fatal. Gene transfer offers the potential to enhance tumor cell killing while sparing surrounding normal brain. Several approaches have been developed to deliver genes to tumor cells in order to kill these cells. The first strategy involves the use of viral vectors that are replication-competent, but depend on attributes unique to the tumor cell to support viral growth. Both replication-competent adenovirus and herpes simplex virus (HSV) vectors have been employed in pre-clinical studies and most recently in human clinical trials. For this purpose, HSV vectors have been engineered that replicate in dividing cells, such as tumor cells, but not in normal neurons. The use of conditional replication competent viruses could allow for their spread in tumor tissue while minimizing damage to normal brain, thus increasing the specificity and effectiveness. Such mutants include those lacking the viral thymidine kinase (tk) gene (4-7), ribonucleotide reductase gene (8,9), a protein kinase gene, or a gene (gamma34.5) required for growth specifically in neurons (11-13).