✓ The use of intracerebroventricular bethanechol chloride infusion in patients with Alzheimer's disease was first reported in 1984. An initial trial in four patients demonstrated the feasibility of this approach for cholinergic drug delivery to the brain, but objective improvement in cognitive function was not documented. A collaborative placebo-controlled double-blind crossover study has now been carried out in 49 patients with biopsy-documented Alzheimer's disease. The results demonstrate a statistical improvement in Mini-Mental State scores and significantly slower performance on Trails A testing during drug infusion. Other neuropsychological test scores were not similarly affected. The degree of improvement was not sufficient to justify further treatment of Alzheimer's disease patients by intracerebroventricular infusion of bethanechol chloride. The drug delivery system used in the study was well tolerated, with two irreversible complications in more than 50,000 patient days.
Results of a collaborative double-blind study
Robert E. Harbaugh, Teddi M. Reeder, Howard J. Senter, David S. Knopman, David S. Baskin, Francis Pirozzolo, Helena Chang Chui, Andrew G. Shetter, Roy A. E. Bakay, Richard Leblanc, Robert T. Watson, Steven T. DeKosky, Frederick A. Schmitt, Stephen L. Read and Jimmie T. Johnston
Gary K. Steinberg, Steven D. Chang, Richard P. Levy, Michael P. Marks, Ken Frankel and Mary Marcellus
✓ Although radiosurgery is effective in obliterating small arteriovenous malformations (AVMs), it has a lower success rate for thrombosing larger AVMs. The authors surgically resected AVMs from 33 patients ranging in age from 7 to 64 years (mean 30.4 years) 1 to 11 years after radiosurgery. Initial AVM volumes were 0.8 to 117 cm3 (mean 21.6 cm3), and doses ranged from 4.6 to 45 GyE (mean 21.2 GyE). Of 27 AVMs in eloquent or critical areas, 10 were located in language, motor, sensory, or visual cortex, 11 in the basal ganglia/thalamus, one each in the brainstem, hypothalamus, and cerebellum, and three in the corpus callosum. Venous drainage was deep in 13, superficial in 12, or both in eight lesions. Spetzler—Martin grades were II in one, III in 12, IV in 16, and V in four patients. Eight patients experienced rebleeding after radiosurgery but prior to surgery. Three patients developed radiation necrosis and 25 underwent endovascular embolization prior to surgery.
At surgery the AVMs were found to be markedly less vascular, partially thrombosed, and more easily resected, compared to those seen in patients who had not undergone radiosurgery. Pathological investigation showed endothelial proliferation with hyaline and calcium in vessel walls. There was partial or complete thrombosis of some AVM vessels and evidence of vessel and brain necrosis in many cases. Complete resection was achieved in 28 patients and partial resection in five. Clinical outcome was excellent or good in 31 cases, and two patients died of rebleeding from residual AVM. Four patients' conditions worsened following microsurgical resection. Final clinical outcome was largely related to the pretreatment grade. Radiosurgery several years prior to open microsurgery may prove to be a useful adjunct in treating unusually large and complex AVMs.
Steven D. Chang, Gary K. Steinberg, Marshal Rosario, Rebecca S. Crowley and Robert F. Hevner
✓ In this report, the authors discuss the case of a patient with a mixed cerebrovascular malformation in which an arteriovenous malformation (AVM) was associated with a capillary telangiectasia. Recent reports have contained reviews of various subsets of mixed malformations. To the authors' knowledge, however, this is the first report of a mixed vascular malformation with both arterial and capillary components. The patient underwent complete resection of the AVM after presenting with a clinical hemorrhage. She required a second operation to resect the capillary telangiectasia after new symptoms developed several months following the first procedure. The authors conclude that a mixed AVM—capillary telangiectasia is a rare but distinct entity.
Lawrence L. Wald, Sarah J. Nelson, Mark R. Day, Susan E. Noworolski, Roland G. Henry, Steven L. Huhn, Susan Chang, Michael D. Prados, Penny K. Sneed, David A. Larson, William M. Wara, Michael McDermott, William P. Dillon, Phillip H. Gutin and Daniel B. Vigneron
✓ The utility of three-dimensional (3-D) proton magnetic resonance spectroscopy (1H-MRS) imaging for detecting metabolic changes after brain tumor therapy was assessed in a serial study of 58 total examinations of 12 patients with glioblastoma multiforme (GBM) who received brachytherapy.
Individual proton spectra from the 3-D array of spectra encompassing the lesion showed dramatic differences in spectral patterns indicative of radiation necrosis, recurrent or residual tumor, or normal brain. The 1H-MRS imaging data demonstrated significant differences between suspected residual or recurrent tumor and contrast-enhancing radiation-induced necrosis. Regions of abnormally high choline (Cho) levels, consistent with viable tumor, were detected beyond the regions of contrast enhancement for all 12 gliomas.
Changes in the serial 1H-MRS imaging data were observed, reflecting an altered metabolism following treatment. These changes included the significant reduction in Cho levels after therapy, indicating the transformation of tumor to necrotic tissue. For patients who demonstrated subsequent clinical progression, an increase in Cho levels was observed in regions that previously appeared either normal or necrotic. Several patients showed regional variations in response to brachytherapy as evaluated by 1H-MRS imaging.
This study demonstrates the potential of noninvasive 3-D 1H-MRS imaging to discriminate between the formation of contrast-enhancing radiation necrosis and residual or recurrent tumor following brachytherapy. This modality may also allow better definition of tumor extent prior to brachytherapy by detecting the presence of abnormal metabolite levels in nonenhancing regions of solid tumor.
Steven D. Chang, Joseph Poen, Steven L. Hancock, David P. Martin and John R. Adler Jr.
✓ Two cases of acute hearing loss are reported following fractionated stereotactic radiosurgery for acoustic neuroma. Both patients had neurofibromatosis type 2 and were treated with a peripheral tumor dose of 21 Gy delivered in three fractions (7 Gy each) with a minimum interfraction interval of 10 hours. One patient who had previously undergone surgical resection of the treated tumor presented with only rudimentary hearing in the treated ear secondary to an abrupt decrease in hearing prior to treatment. That patient reported total loss of hearing before complete delivery of the third fraction. The second patient had moderately impaired hearing prior to treatment; however, within 10 hours after delivery of the final fraction, he lost all hearing. Both patients showed no improvement in response to glucocorticoid therapy. Possible explanations for this phenomenon are presented.
Steven D. Chang and John R. Adler Jr.
The management of patients with multiple brain metastases remains a difficult challenge for neurosurgeons. This patient population has a poor prognosis when compared with those harboring a solitary brain metastasis, and historically treatment has generally consisted of administering whole-brain radiotherapy once the diagnosis of multiple brain metastases is made. Resection can be useful in a subset of patients with multiple metastases in whom one or two of the lesions are symptomatic, as this may provide rapid reduction of mass effect and edema. Furthermore, the authors of recent studies have shown that stereotactic radiosurgery can be used in certain patients with multiple brain metastases as part of the treatment regimen. In this review the authors outline the treatment options and indications as well as a management strategy for the treatment of patients with multiple brain metastases.
Steven D. Chang, Elizabeth Lee, Gordon T. Sakamoto, Nalani P. Brown and John R. Adler Jr.
Patients with multiple brain metastases are often treated primarily with fractionated whole-brain radiation therapy (WBRT). In previous reports the authors have shown that patients with four or fewer brain metastases can benefit from stereotactic radiosurgery in addition to fractionated WBRT. In this paper the authors review their experience using linear accelerator stereotactic radiosurgery to treat patients with multiple brain metastases.
Fifty-three patients with 149 brain metastases underwent stereotactic radiosurgery. The mean age of patients was 53.1 years (range 20–78 years). There were 23 men and 30 women. The primary tumor location was lung (27 patients), melanoma (10), breast (six), ovary (six), and other (four). All patients harbored at least two metastatic tumors treated with radiosurgery; 27 patients (51%) harbored two lesions, 17 (32%) three lesions, eight (15%) four lesions, and one patient (2%) harbored five lesions. The mean radiation dose administered was 19.6 Gy (range 14–30 Gy), and the mean secondary collimator size was 15.7 mm (range 7.5–40 mm). One hundred thirty-two (89%) of the 149 treated tumors were available for review on magnetic resonance (MR) imaging at 3 months posttreatment. Fifty-two percent were smaller in size, 31% were stable, 9% had increased in size, and 8% had disappeared. New metastatic tumors appeared in 12 (23%) of the 53 patients on MR imaging within 6 months posttreatment. Radiation-induced necrosis occurred at the site of eight (5.4%) of the 149 tumors at 6 months. Seven tumors (4.7%) subsequently required surgical resection for either tumor progression (four cases) or worsening edema from radiation-induced necrosis (three cases). Median actuarial survival was 9.6 months.
Stereotactic radiosurgery can be used to treat patients with up to four brain metastases with a 91% rate of either decrease or stabilization in tumor size and a low rate of radiation-induced necrosis. In the authors' study only a small number of patients subsequently required surgical resection of a treated lesion.
Steven D. Chang, David P. Martin, Elizabeth Lee and John R. Adler Jr.
In patients with chordomas the lesions often recur. Furthermore, the location of some chordomas within the base of the skull and the cervical spine can prevent complete resection from being achieved. Previous series have shown that stereotactic radiosurgery can be used as a treatment for residual chordomas with good overall results. The authors review their experience in using linear accelerator (LINAC) stereotactic radiosurgery to treat patients with recurrent and/or residual cranial base and cervical chordomas.
Ten patients with chordomas (eight with cranial base and two with cervical lesions [below C-2]) underwent LINAC stereotactic radiosurgery. The mean patient age was 49 years (range 30–73 years). There were seven men and three women. Three patients had undergone one prior surgery, five had undergone two previous surgeries, and two had undergone three prior operations. The mean radiation dose was 19.4 Gy (range 18–24 Gy), and the maximum intratumoral dose averaged 27 Gy (range 24.1–33.1 Gy). The mean secondary collimator size was 14.4 mm (range 7.5–20 mm). The volume of the tumor treated ranged from 1.1 to 21.5 ml. In five patients a standard frame-based LINAC radiosurgery system was used, whereas in the other five the CyberKnife, a frameless image-guided LINAC radiosurgical system, was used. All patients were available for follow-up review, which averaged 4 years (range 1–9 years). Over the course of follow up, one chordoma (10%) was smaller in size, seven were stable, and two chordomas progressed (one in a patient who underwent reoperation and a second course of stereotactic radiosurgery, and the second in a patient who underwent reoperation alone). There were no new neurological deficits noted following radiosurgery in the eight of 10 patients in whom there was no tumor progression, and no patient developed radiation-induced necrosis.
Stereotactic radiosurgery can be used to treat patients with recurrent or residual chordomas with excellent tumor control rates. Longer follow-up review in larger series is warranted to confirm these findings.
Martin J. Murphy, Steven Chang, Iris Gibbs, Quynh-Tu Le, David Martin and Daniel Kim
The authors describe a new method for treating metastatic spinal tumors in which noninvasive, image-guided, frameless stereotactic radiosurgery is performed. Stereotactic radiosurgery delivers a high dose of radiation in a single or limited number of fractions to a lesion while maintaining delivery of a low dose to adjacent normal structures.
Image-guided radiosurgery was developed by coupling an orthogonal pair of real-time x-ray cameras to a dynamically manipulated robot-mounted linear accelerator that guides the radiation beam to treatment sites associated with radiographic landmarks. This procedure can be conducted in an outpatient setting without the use of frame-based skeletal fixation. The system relies on skeletal landmarks or implanted fiducial markers to locate treatment targets. Four patients with spinal metastases underwent radiosurgery with total prescription doses of 1000 to 1600 cGy in one or two fractions. Alignment of the treatment dose with the target volume was accurate to within 1.5 mm. During the course of each treatment fraction, patient movement was less than 0.5 mm on average. Dosimetry was highly conformal, with a demonstrated ability to deliver 1600 cGy to the perimeter of an irregular target volume while keeping exposure to the cord itself below 800 cGy.
These experiences indicate that frameless radiosurgery is a viable therapeutic option for metastatic spine disease.