Faculty Bibliography

Because limited histological information is available from clinical radiosurgical experience, animal investigations are needed to answer questions regarding the biological response of both normal and pathological tissues. To determine the radiosurgical dose-response relationship of normal brain, we irradiated the right frontal lobe of 18 rats with a single 4-mm isocenter of stereotactic irradiation using the 201-source 60Co gamma unit. Maximal single-fraction doses varied from 30 to 200 Gy (2 rats per dose). All animals were observed for 90 days, killed, and histologically examined. No animal developed neurological dysfunction during that interval, regardless of dose. Animals that received 30, 40, 50, or 60 Gy had no pathological changes. In those given 70 Gy, we found occasional shrunken neurons, and at 80 Gy, rare arteriolar wall thickening. One animal that received 100 Gy had marked capillary endothelial cell degeneration and protein extravasation in the target volume, and the other had a 4-mm diameter necrotic region. Circumscribed cerebral necrosis also was identified in all 4 rats treated with either 150 or 200 Gy; astrocytosis, edema, and microhemorrhage were noted within the surrounding 1 to 2 mm of adjacent brain, and tissue outside that volume had a more normal appearance. We constructed a dose-response relationship based on the cellular, spatial, and temporal effects of focused single-fraction irradiation of the rat brain. To determine the temporal evolution of a known necrotic lesion (200 Gy), 12 other animals were killed (2 each) 1, 7, 14, 21, 30, or 60 days after radiosurgery.(ABSTRACT TRUNCATED AT 250 WORDS)

We developed an experimental animal model to evaluate the potential role of stereotactic radiosurgery for glial neoplasms. Rats were randomized to control or treatment groups after implantation of C6 glioma cells into the right frontal region; 14 days later, 19 rats underwent stereotactic radiosurgical treatment of the induced tumor, using the 4-mm collimator of the gamma unit. Both groups were observed for up to 65 days after implantation. Treated animals had a mean survival of 39.2 days; the 22 control animals lived a mean of 29.4 days before death from tumor growth (P = 0.07). Six treated animals (32%), but only one control animal, survived the full observation period (P = 0.07). The mean tumor diameter in the control group was 9.64 mm; in the radiosurgery group, it was 6.47 mm (P = 0.001). Compared with tumors in control animals, treated tumors had a hypocellular appearance (P less than 0.001) and demonstrated cellular edema (P less than 0.005) under light microscopy, indicating a direct cytotoxic response to treatment. No difference was identified in the amount of tumor necrosis, intratumor hemorrhage, or degree of brain invasion between the two groups. Variations in the maximum treatment dose (30, 40, 50, 70, or 100 Gy) did not result in observed differences in tumor response. This in vivo rat malignant glioma model is a valuable tool to evaluate the tumoricidal effects of single-fraction, focused irradiation. Additional studies are warranted to evaluate dose-response relationships, radiation sensitizers, and use of radiosurgery with other adjuvant treatments.

Every neurosurgeon can appreciate Dandy's recognition that the drainage of brain abscesses causes trauma to the delicate parenchyma. Over the years, brain surgery has evolved toward management of problems by using less and less invasive techniques and thus gaining ever lower morbidity. Clearly, the advent of better imaging techniques has improved the outcome in patients afflicted with intracerebral infections. The combination of stereotaxy with these imaging techniques is contributing a "zero mortality" in the treatment of these infections. In our series of 29 consecutive patients with non-AIDS-related infections, no patient died as a direct result of a stereotactic surgical procedure. Two patients (7%) had new neurologic deficits after surgery. The only patient left with a permanent disability had a kidney allograft and subacute bacterial endocarditis. His condition deteriorated 6 hours after aspiration of a sterile abscess, when an intra-abscess hematoma was diagnosed and evacuated. In retrospect, this complication may have been avoided by less vigorous aspiration. Three of the four patients with nonviral infections who died were iatrogenically immunosuppressed for their organ transplants. These patients are difficult to treat, and given the current popularity of transplantation procedures, neurosurgeons will face more and more opportunistic infections. In general, the patients with abscesses did well. On the other hand, nonoperative mortality was extremely high for patients with viral encephalitides. This high mortality may have resulted from a delay in diagnosis and treatment or from the unavailability of highly effective antiviral agents at the time the biopsies were performed. The importance of early diagnosis and treatment of infection cannot be overemphasized. T.H. Flewett's warning about the management of HSE applies to the management of all cerebral infections: "It seems clear from everybody's published results [in the papers already given] if we wait to do biopsy until the clinical indications are unmistakable, we have waited so long that the patient, if he survives, will be left a severe neurological cripple." Because it is relatively noninvasive, stereotactic neurosurgery has been used increasingly to diagnose brain masses in patients with AIDS. We recommend its use for establishing diagnoses in all suspected cases of cerebral infection. We agree with Rosenblum et al: Empiric treatment of brain infections should be regarded as "radical." Such treatment should be reserved for patients who have an identifiable source of infection and causative organism or for patients who are clinically too unstable to undergo surgery.(ABSTRACT TRUNCATED AT 400 WORDS)

The spatial accuracy of magnetic resonance imaging (MRI) has not been established for stereotactic surgery. Magnetic susceptibility artifacts may lead to anatomical distortion and inaccurate stereotactic MRI coordinates, especially when targets are in regions of the brain out of the center of the magnetic field. MRI-guided stereotactic localization, however, provides better multiplanar target resolution than is available with computed tomographic (CT) scanning. Therefore, we compared the accuracy of stereotactic coordinates determined by MRI and CT studies in 41 patients (53 targets). Coordinates were measured in each plane and as vector distances between the target and the center of the stereotactic frame on axial or coronal MRI studies. Absolute axial plane MRI and CT distances varied an average of 2.13 +/- 1.59 mm. The mean difference in measurements in the X (left-right) dimension was 1.19 mm and 1.55 mm in the Y (anterior-posterior) dimension. Central targets (located less than 2 cm from the frame center) had a mean MRI-CT difference of 2.09 +/- 1.79 mm; peripheral targets (greater than 2 cm from the frame center) differed by 2.17 +/- 1.3 mm. The voxel volumes were calculated for all compared images. Although differences between the physical properties of data acquisition with each imaging modality could explain the observed CT-MRI discrepancies, a 1-pixel difference in target selection could account totally for all the variance observed. MRI field strength (0.5 vs. 1.5 T) did not correlate with coordinate determination accuracy. We conclude that MRI-guided stereotactic localization can be used with confidence for most diagnostic, functional, and therapeutic stereotactic procedures.

Despite the great capacity for the pediatric brain to recover from stroke, the morbidity and mortality in children who harbor an arteriovenous malformation (AVM) remains high. This study examines the clinical data and management experience with 132 patients with brain AVM from 1949 to 1989. Although the high tendency for a childhood AVM to present with hemorrhage (79%) remained constant for the forty year study period, the associated morbidity and mortality of hemorrhage changed. The mortality rate from hemorrhage for the entire series was 25%, which was reduced from 39% to 16% after the introduction of computed tomography. The mortality from AVM hemorrhage since 1975 was dependent on location; 8 of 14 patients (57%) with a cerebellar AVM died from hemorrhage while only 2 of 44 patients (4.5%) with a cerebral hemisphere AVM died (p less than 0.0001). Sixteen children (12%) presented with a chronic seizure disorder. Surgical excision of the malformation resulted in complete seizure control off anti-convulsant medication in 73% of patients. Although 21% of patients were treated non-operatively (many with terminal poor-grade hemorrhage), 79% had a surgical procedure with total AVM excision achieved in 70 patients (53.1%). Complete AVM resection was followed by a normal neurological outcome in 47 children (67%). Most partial excisions (n = 9) and clipping of feeding arteries (n = 7) were performed in the early years of this study, and did not provide protection from rehemorrhage. Although conservative management has been advocated for selected non-hemorrhagic AVMs, we conclude that essentially all children with an AVM should be treated in order to eliminate the risk of hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)

Stereotactic radiosurgery using the gamma unit was performed in 251 patients with brain vascular malformations in a 3-year interval. Our efforts include the identification of factors related to both success and complications, including analysis of the malformation location, volume, and dose used. Radiosurgery is a valuable alternative treatment for many patients with brain vascular malformations, including those currently believed to be poor surgical candidates.

A series of initial radiobiologic investigations have been performed using three animal models. The baboon model proved to be a valuable technique to assess the in vivo radiobiologic response of single-fraction irradiation doses delivered to the primate brain stem. Multimodality neurodiagnostic testing, including CT, MR imaging, xenon-enhanced CT, evoked potential studies, and analysis of CSF myelin basic protein levels, all of which eventually were correlated with neuropathologic examination, enabled detection of lesions produced with high-dose (150 Gy) radiosurgery as early as 6 weeks. Within the first 6 months after radiosurgery, lower doses (20 Gy, 50 Gy) did not result in clinically or neurodiagnostically detectable lesions. The rat arteriovenous fistula model permits analysis of the delayed histopathologic effects of radiosurgery on an experimentally created fistula designed to mimic an AVM. The rat C6 glioma model is designed to evaluate the effect of radiosurgery in an infiltrative tumor that simulates a human malignant brain tumor. These studies are intended eventually to increase our knowledge about the safety and efficacy of radiosurgery in both the normal and tumor-implanted brains. We believe that such fundamental studies ultimately will improve our ability to reach the goals of radiosurgery: to destroy the target and spare the surrounding brain. Eventually, it may become feasible to achieve these goals by combining radiosurgical technique with both radiation sensitizers (for the treated volume) and brain protectors.

The optimal use of radiosurgery as a treatment technique requires thorough planning, including careful fitting of the high-dose treatment volume to the target volume, and an understanding of the effects of high-dose single-fraction irradiation on both the target volume and the surrounding normal brain. The integrated logistic formula appears to be useful as an aid for predicting the risks of complications from radiosurgery, but greater understanding of the radiation tolerance for all the different areas of the brain (particularly the cranial nerves) is needed. The risk of developing MR imaging-defined changes after radiosurgery for AVMs was significantly related to predictions from the integrated logistic formula. The obliteration rate of AVMs after radiosurgery was volume dependent. Our assessment of the integrated logistic formula to date also indicates that it provides a reasonable guide for predicting complications in the radiosurgical treatment of meningiomas and in the treatment of solitary brain metastases using a combination of fractionated whole-brain irradiation and radiosurgery. The formula did not adequately predict complications in the treatment of AOVMs, however. In the treatment of acoustic tumors, the risks of injury to cranial nerves V, VII, and VIII clearly varied with treatment volume. Further data are needed to fully understand the therapeutic dose-response functions and volume effects for the obliteration of AVMs, the prevention of rebleeding from AOVMs, and growth arrest of meningiomas and acoustic neuromas.