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Mark P. Piedra, Paul D. Brown, Paul C. Carpenter and Michael J. Link

✓ The authors present the case of a 58-year-old woman who presented with symptoms of diabetes insipidus (DI) 1 year after she was found to have a Stage 3 (of 4) estrogen receptor—positive infiltrating ductal adenocarcinoma of the left breast with pulmonary and bone metastases. Magnetic resonance images demonstrated a solitary site of metastasis in the patient's pituitary stalk, and gamma knife surgery (GKS) was performed to treat the lesion. Three months after GKS the patient was able to reduce the medication she required for the DI. There was no evidence of pituitary failure and no negative effect on her vision.

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Bruce E. Pollock, Deborah A. Gorman and Paul D. Brown

Object

Although stereotactic radiosurgery is frequently performed for arteriovenous malformations (AVMs) in deep locations, outcomes after radiosurgery for these patients have not been well studied. The goal of this paper was to study these outcomes.

Methods

Between 1990 and 2000, 56 patients underwent radiosurgery for AVMs located in the basal ganglia (10 patients), thalamus (30 patients), or brainstem (16 patients). The median age of these patients was 34.2 years. Thirty-five patients (62%) had experienced previous bleeding. The AVMs were classified Grade IIIB in 62% of patients and Grade IV in 38% according to the modified Spetzler—Martin Scale; the median radiosurgery-based AVM score was 1.83. The median volume of the lesion was 3.8 cm3 and the median radiation dose delivered to its margin was 18 Gy. The median duration of follow-up review after radiosurgery was 45 months (range 3–121 months).

In seven patients (12%) hemorrhage occurred at a median of 12 months after radiosurgery; five patients (9%) died and two recovered without any deficit. Permanent radiation-related complications occurred in six (12%) of 51 patients (excluding the five patients who died of hemorrhage) after one procedure and in three (18%) of 17 patients after repeated radiosurgery. Obliteration of the AVM was noted in 24 patients (43%; obliteration was confirmed by angiography in 18 patients and by magnetic resonance [MR] imaging in six patients) after a single procedure and in 32 patients (57%; confirmed by angiography in 25 patients and by MR imaging in seven patients) after one or more procedures. Excellent outcomes (obliteration of the lesion without any new deficit) were obtained in 39% of patients after one radiosurgical procedure and in 48% after one or more procedures. Twelve (67%) of 18 patients with AVM scores lower than 1.5 had excellent outcomes compared with 15 (39%) of 38 patients with AVM scores greater than 1.5 (p = 0.053).

Conclusions

Less than half of the patients with deeply located AVMs were cured of the future risk of hemorrhage without new neurological deficits. This experience emphasizes the difficulty in treating patients with deeply located AVMs; the majority of whom are also poor candidates for resection or embolization.

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Spencer S. Kellis, Paul A. House, Kyle E. Thomson, Richard Brown and Bradley Greger

Object

The goal of this study was to determine whether a nonpenetrating, high-density microwire array could provide sufficient information to serve as the interface for decoding motor cortical signals.

Methods

Arrays of nonpenetrating microwires were implanted over the human motor cortex in 2 patients. The patients performed directed stereotypical reaching movements in 2 directions. The resulting data were used to determine whether the reach direction could be distinguished through a frequency power analysis.

Results

Correlation analysis revealed decreasing signal correlation with distance. The gamma-band power during motor planning allowed binary classification of gross directionality in the reaching movements. The degree of power change was correlated to the underlying gyral pattern.

Conclusions

The nonpenetrating microwire platform showed good potential for allowing differentiated signals to be recorded with high spatial fidelity without cortical penetration.

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Bruce E. Pollock, Jeffrey T. Jacob, Paul D. Brown and Todd B. Nippoldt

Object

The authors reviewed outcomes after stereotactic radiosurgery for patients with acromegaly and analyzed factors associated with biochemical remission.

Methods

Retrospective analysis was performed for 46 consecutive cases of growth hormone (GH)–producing pituitary adenomas treated by radiosurgery between 1991 and 2004. Biochemical remission was defined as a fasting GH less than 2 ng/ml and a normal age- and sex-adjusted insulin-like growth factor–I (IGF-I) level while patients were not receiving any pituitary suppressive medications. The median follow up after radiosurgery was 63 months (range 22–168 months).

Twenty-three patients (50%) had biochemical remission documented at a median of 36 months (range 6–63 months) after one radiosurgical procedure. The actuarial rates of biochemical remission at 2 and 5 years after radiosurgery were 11 and 60%, respectively. Multivariate analysis showed that IGF-I levels less than 2.25 times the upper limit of normal (hazard ratio [HR] 2.9, 95% confidence interval [CI] 1.2–6.9, p = 0.02) and the absence of pituitary suppressive medications at the time of radiosurgery (HR 4.2, 95% CI 1.4–13.2, p = 0.01) correlated with biochemical remission. The incidence of new anterior pituitary deficits was 10% at 2 years and 33% at 5 years.

Conclusions

Discontinuation of pituitary suppressive medications at least 1 month before radiosurgery significantly improved endocrine outcomes for patients with acromegaly. Patients with GH–producing pituitary adenomas should not undergo further radiation therapy or surgery for at least 5 years after radiosurgery because GH and IGF-I levels continue to normalize over that interval.

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Atom Sarkar, Bruce E. Pollock, Paul D. Brown and Deborah A. Gorman

Object. Radiosurgery is commonly used for the treatment of patients with glioma. The goal of this study was to evaluate the safety and efficacy of radiosurgery in the management of patients with oligodendrogliomas (ODGs) or mixed oligoastrocytomas (OGAs).

Methods. A retrospective chart review of patients treated between May 1990 and January 2000 identified 18 patients (21 tumors) with either an ODG (10) or a mixed OGA (11) who had undergone radiosurgery. The median patient age was 43 years (range 23–67 years). Sixteen patients had undergone one or more tumor resections before radiosurgery; in two patients biopsy sampling alone had been performed. Tumor grades at the most recent operation were Grade 1 (one), Grade 2 (one), Grade 3 (12), and Grade 4 (seven patients). Seventeen patients had undergone prior radiotherapy; 11 were treated with chemotherapy before radiosurgery, and one had undergone a prior linear accelerator—based radiosurgery treatment. The median tumor volume was 8.2 cm3 (range 1.9–47.7 cm3); the median margin dose was 15 Gy (range 12–20 Gy); and the median maximum dose was 32 Gy (range 24–50 Gy).

In this heterogeneous group, 12 patients died whereas six remain alive. Survival after radiosurgery was 78%, 61%, and 44% at 12, 24, and 48 months, respectively. Factors associated with an improved survival rate included younger age and smaller tumors.

Conclusions. For patients with oligoastroglial tumors that have failed to respond to conventional therapies, radiosurgery may provide some survival benefit. Further study is needed to determine which subpopulation of these patients will have the best chances of enhanced survival from this treatment.

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Edward D. Wirth III, Daniel P. Theele, Thomas H. Mareci, Douglas K. Anderson, Stacey A. Brown and Paul J. Reier

✓ Magnetic resonance (MR) imaging was evaluated for its possible diagnostic application in determining the survival of fetal central nervous system tissue grafts in the injured spinal cord. Hemisection cavities were made at the T11—L1 level of eight adult female cats. Immediately thereafter, several pieces of tissue, either obtained from the fetal cat brain stem on embryonic Day 37 (E-37), from the fetal neocortex on E-37, or from the fetal spinal cord on E-23, were implanted into the cavities made in seven cats. The eighth cat served as a control for the effect of the lesion only. In another group of four animals, a static-load compression injury was made at the L-2 level. Seven weeks later, the lesion was resected in three cases and fragments of either fetal brainstem or spinal cord tissue were introduced. A small cyst was observed in a fourth cat in the compression injury group and a suspension of dissociated E-23 brain-stem cells was injected into this region of cavitation without disturbing the surrounding leptomeninges. Five months to 2 years posttransplantation, MR imaging was performed with a 2.0-tesla VIS imaging spectrometer by acquiring multislice spin-echo images (TR 1000 msec, TE 30 msec) in both the transverse and sagittal planes.

Collectively, these intermediate-weighted images revealed homogeneous, slightly hyperintense signals at the graft site relative to the neighboring host tissue in seven of the 11 graft recipients. Two of the remaining four cats exhibited signals from the graft site that were approximately isointense with the adjacent host spinal cord, and the final two cats and the lesion-only control presented with very hypointense transplant/resection regions. The hyperintense and isointense images were tentatively interpreted as representing viable graft tissue, whereas the hypointense transplant/resection sites were considered to be indicative of a lack of transplant survival or the absence of tissue in the lesion-only control animal.

Postmortem gross inspection of fixed specimens and light microscopy verified the MR findings in the control animal in 10 of the 11 graft recipients by showing either transplants and/or cysts corresponding to the MR images obtained. In one cat in the hemisection group, histological analysis revealed a very small piece of graft tissue that was not detected on the MR images. Therefore, it is suggested that within certain spatial- and contrast-resolution limits, MR imaging can reliably detect the presence of transplanted neural tissue in both the hemisected and compression-injured spinal cord of living animals. Thus, MR imaging can serve as an important adjunct to histological, electrophysiological, and long-term behavioral analyses of graft-mediated anatomical and functional repair of the injured spinal cord. It is further suggested that this noninvasive diagnostic approach offers many advantages in terms of the judicious and optimum use of valuable animal models, and that these findings address an important prerequisite (in situ verification of transplant survival) for any future clinical trials involving these or equivalent neural tissue grafting approaches, when such are warranted.

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Thomas L. Babb, Henry V. Soper, Jeffrey P. Lieb, W. Jann Brown, Carlos A. Ottino and Paul H. Crandall

✓ Six rhesus monkeys were stimulated on the paravermal cortex for 205 hours (18 days) with different charge densities in order to determine the electrode performance and neural damage that may result from long-term cerebellar stimulation comparable to that being used in man. The electrode-tissue interface was relatively stable and no neural damage was found when the charge/phase (0.5 µC/ph) or charge density (7.4 µC/sq cm/ph) was very low. At all higher charge levels tested (2.4, 4.8, 10, and 22 µC/ph), changes in the electrode-tissue interface, meningeal encapsulation, and neural damage were directly related to the charge density delivered. Unstimulated electrodes on the opposite paravermal cortex exhibited mild tissue reactivity and cell damage, probably due to mechanical compression of the molecular layer and pial vessels. Motor cortex field potentials could be evoked by charges as low as 0.1 µC/ph delivered to paravermal cortex; for a given charge/phase longer pulses were more effective than short pulses. After neural damage resulting from 205 hours of 4.8 µC pulses at 10 per second (total charge 14.76 C), the threshold for the motor cortex evoked potential increased by a factor of four or more. With the charge held constant to different-sized electrodes placed bilaterally in the same monkey, damage was greater under the smaller electrode. This finding suggests that the charge density to cerebellar cortex must be controlled to avoid neural damage.

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W. Jann Brown, Thomas L. Babb, Henry V. Soper, Jeffrey P. Lieb, Carlos A. Ottino and Paul H. Crandall

✓ Light and electron microscopic analyses were carried out on the stimulated and unstimulated paravermal cortices of six rhesus monkeys that had electrodes implanted on their cerebella for 2 months. The electrodes and the stimulation regime (10 p.p.s.: 8 min on, 8 min off) were similar to those used to stimulate the human cerebellum for treatment of certain neurological disorders. Mere presence of the electrode array in the posterior fossa for 2 months resulted in some meningeal thickening, attenuation of the molecular layer, and loss of Purkinje cells immediately beneath the electrode array. There was no evidence of scarring. After 205 hours of stimulation (7.38 × 106 pulses) over 18 days, a charge of 0.5 µC/ph or estimated charge density of 7.4 µC/sq cm/ph resulted in no damage to the cerebellum attributable to electrical stimulation per se. Such a charge/phase is about five times the threshold for evocation of cerebellar efferent activity, and might be considered “safe” for stimulation of human cerebellum. Charge density/phase and charge/phase were directly related to increased cerebellar injury in the six other cerebellar cortices stimulated. Leptomeningeal thickening increased with increased charge density. Injury included severe molecular layer attenuation, ongoing destruction of Purkinje cells, gliosis, ongoing degeneration of myelinated axons, collagen intrusion, and increased levels of local polysaccharides. In all cases, even with damage that destroyed all conducting elements beneath the electrodes, there was no damage further than 1 to 2 mm from the edges of the electrode arrays.

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Edward G. Shaw, Brian Berkey, Stephen W. Coons, Dennis Bullard, David Brachman, Jan C. Buckner, Keith J. Stelzer, Geoffrey R. Barger, Paul D. Brown, Mark R. Gilbert and Minesh Mehta

Object

In 1998, the Radiation Therapy Oncology Group initiated a Phase II study of observation for adults < 40 years old with cerebral low-grade glioma who underwent a neurosurgeon-determined gross-total resection (GTR).

Methods

Patient eligibility criteria included the presence of a World Health Organization Grade II astrocytoma, oligodendroglioma, or mixed oligoastrocytoma confirmed histologically; age 18–39 years; Karnofsky Performance Scale score ≥ 60; Neurologic Function Scale score ≤ 3; supratentorial tumor location; neurosurgeon-determined GTR; and pre- and postoperative MR imaging with contrast enhancement available for central review by the principal investigator. Patients were observed following GTR and underwent MR imaging every 6 months. Prognostic factors analyzed for their contribution to patient overall survival, progression-free survival (PFS), and tumor recurrence included age, sex, Karnofsky Performance Scale score, Neurologic Function Scale score, histological type, contrast enhancement on preoperative MR imaging, preoperative tumor diameter, residual disease based on postoperative MR imaging, and baseline Mini-Mental State Examination score.

Results

Between 1998 and 2002, 111 eligible patients were entered into the study. In these 111 patients, the overall survival rates at 2 and 5 years were 99 and 93%, respectively. The PFS rates in these 111 patients at 2 and 5 years were 82 and 48%, respectively. Three prognostic factors predicted significantly poorer PFS in univariate and multivariate analyses: 1) preoperative tumor diameter ≥ 4 cm; 2) astrocytoma/oligoastrocytoma histological type; and 3) residual tumor ≥ 1 cm according to MR imaging. Review of the postoperative MR imaging results revealed that 59% of patients had < 1 cm residual disease (with a subsequent 26% recurrence rate), 32% had 1–2 cm residual disease (with a subsequent 68% recurrence rate), and 9% had > 2 cm residual disease (with a subsequent 89% recurrence rate).

Conclusions

These data suggest that young adult patients with low-grade glioma who undergo a neurosurgeondetermined GTR have a > 50% risk of tumor progression 5-years postoperatively, warranting close follow-up and consideration for adjuvant treatment.

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Claudio E. Tatsui, R. Jason Stafford, Jing Li, Jonathan N. Sellin, Behrang Amini, Ganesh Rao, Dima Suki, Amol J. Ghia, Paul Brown, Sun-Ho Lee, Charles E. Cowles, Jeffrey S. Weinberg and Laurence D. Rhines

OBJECT

High-grade malignant spinal cord compression is commonly managed with a combination of surgery aimed at removing the epidural tumor, followed by spinal stereotactic radiosurgery (SSRS) aimed at local tumor control. The authors here introduce the use of spinal laser interstitial thermotherapy (SLITT) as an alternative to surgery prior to SSRS.

METHODS

Patients with a high degree of epidural malignant compression due to radioresistant tumors were selected for study. Visual analog scale (VAS) scores for pain and quality of life were obtained before and within 30 and 60 days after treatment. A laser probe was percutaneously placed in the epidural space. Real-time thermal MRI was used to monitor tissue damage in the region of interest. All patients received postoperative SSRS. The maximum thickness of the epidural tumor was measured, and the degree of epidural spinal cord compression (ESCC) was scored in pre- and postprocedure MRI.

RESULTS

In the 11 patients eligible for study, the mean VAS score for pain decreased from 6.18 in the preoperative period to 4.27 within 30 days and 2.8 within 60 days after the procedure. A similar VAS interrogating the percentage of quality of life demonstrated improvement from 60% preoperatively to 70% within both 30 and 60 days after treatment. Imaging follow-up 2 months after the procedure demonstrated a significant reduction in the mean thickness of the epidural tumor from 8.82 mm (95% CI 7.38–10.25) before treatment to 6.36 mm (95% CI 4.65–8.07) after SLITT and SSRS (p = 0.0001). The median preoperative ESCC Grade 2 was scored as 4, which was significantly higher than the score of 2 for Grade 1b (p = 0.04) on imaging follow-up 2 months after the procedure.

CONCLUTIONS

The authors present the first report on an innovative minimally invasive alternative to surgery in the management of spinal metastasis. In their early experience, SLITT has provided local control with low morbidity and improvement in both pain and the quality of life of patients.