✓ A novel approach toward the treatment of glioma was developed in a murine model. The genes for both interleukin-2 (IL-2) and interferon-γ (IFN-γ) were first transfected into a mouse fibroblast cell line that expresses defined major histocompatibility complex (MHC) determinants (H—2k). The double cytokine—secreting cells were then cotransplanted intracerebrally with the Gl261 murine glioma cell line into syngeneic C57BL/6 mice (H—2b) whose cells differed at the MHC from the cellular immunogen. The results indicate that the survival of mice with glioma injected with the cytokine-secreting allogeneic cells was significantly prolonged, relative to the survival of mice receiving equivalent numbers of glioma cells alone. Using a standard 51Cr-release assay, the specific release of isotope from labeled Gl261 cells coincubated with spleen cells from mice injected intracerebrally with the glioma cells and the cytokine-secreting fibroblasts was significantly higher than the release of isotope from glioma cells coincubated with spleen cells from nonimmunized mice. The cellular antiglioma response was mediated by natural killer/lymphokine-activated killer and Lyt-2.2+ (CD8+) cells. The increased survival of mice with glioma and the specific immunocytotoxic responses after immunization with fibroblasts modified to secrete both IL-2 and IFN-γ indicate the potential of an immunotherapeutic approach to gliomas with cytokine-secreting cells.
Terry Lichtor, Roberta P. Glick, Tae Sung Kim, Roger Hand and Edward P. Cohen
Tae Sung Park
Vaninder Chhabra, Edward Sung, Klaus Mewes, Roy A. E. Bakay, Aviva Abosch and Robert E. Gross
With the expanding indications and increasing number of patients undergoing deep brain stimulation (DBS), postoperative MR imaging is becoming even more important in guiding clinical care and practice-based learning; important safety concerns have recently emerged, however. Although phantom model studies have driven conservative recommendations regarding imaging parameters, highlighted by 2 recent reports describing adverse neurological events associated with MR imaging in patients with implanted DBS systems, the risks of MR imaging in such patients in clinical practice has not been well addressed. In this study, the authors capitalized on their large experience with serial MR imaging (3 times per patient) to use MR imaging itself and clinical outcomes to examine the safety of MR imaging in patients who underwent staged implantation of DBS electrodes for Parkinson disease, tremor, and dystonia.
Sixty-four patients underwent staged bilateral lead implantations between 1997 and 2006, and each patient underwent 3 separate MR imaging sessions subsequent to DBS placement. The first of these was performed after the first DBS placement, the second occurred prior to the second DBS placement, and third was after the second DBS placement. Follow-up was conducted to examine adverse events related either to MR imaging or to DBS-induced injury.
One hundred and ninety-two MR images were obtained, and the mean follow-up time was 3.67 years. The average time between the first and second, and second and third MR imaging sessions was 19.4 months and 14.7 hours, respectively. Twenty-two MR imaging–detected new findings of hemorrhage were documented. However, all new findings were related to acute DBS insertion, whereas there were no new findings after imaging of the chronically implanted electrode.
Although potential risks of MR imaging in patients undergoing DBS may be linked to excessive heating, induced electrical currents, disruption of the normal operation of the device, and/or magnetic field interactions, MR imaging can be performed safely in these patients and provides useful information on DBS lead location to inform patient-specific programming and practice-based learning.
Robert E. Gross, Edward K. Sung, Patrick Mulligan, Nealen G. Laxpati, Darlene A. Mayo and John D. Rolston
Various techniques are available for stereotactic implantation of depth electrodes for intracranial epilepsy monitoring. The goal of this study was to evaluate the accuracy and effectiveness of frameless MRI-guided depth electrode implantation.
Using a frameless MRI-guided stereotactic approach (Stealth), depth electrodes were implanted in patients via burr holes or craniotomy, mostly into the medial temporal lobe. In all cases in which it was possible, postoperative MR images were coregistered to planning MR images containing the marked targets for quantitative analysis of intended versus actual location of each electrode tip. In the subset of MR images done with sufficient resolution, qualitative assessment of anatomical accuracy was performed. Finally, the effectiveness of implanted electrodes for identifying seizure onset was retrospectively examined.
Sixty-eight patients underwent frameless implantation of 413 depth electrodes (96% to mesial temporal structures) via burr holes by one surgeon at 2 institutions. In 36 patients (203 electrodes) planning and postoperative MR images were available for quantitative analysis; an additional 8 procedures with 19 electrodes implanted via craniotomy for grid were also available for quantitative analysis. The median distance between intended target and actual tip location was 5.19 mm (mean 6.19 ± 4.13 mm, range < 2 mm–29.4 mm). Inaccuracy for transtemporal depths was greater along the electrode (i.e., deep), and posterior, whereas electrodes inserted via an occipital entry deviated radially. Failure to localize seizure onset did not result from implantation inaccuracy, although 2 of 62 patients (3.2%)—both with electrodes inserted occipitally—required reoperation. Complications were mostly transient, but resulted in long-term deficit in 2 of 68 patients (3%).
Despite modest accuracy, frameless depth electrode implantation was sufficient for seizure localization in the medial temporal lobe when using the orthogonal approach, but may not be adequate for occipital trajectories.
Tung T. Nguyen, Yashdip S. Pannu, Cynthia Sung, Robert L. Dedrick, Stuart Walbridge, Martin W. Brechbiel, Kayhan Garmestani, Markus Beitzel, Alexander T. Yordanov and Edward H. Oldfield
Object. Convection-enhanced delivery (CED), the delivery and distribution of drugs by the slow bulk movement of fluid in the extracellular space, allows delivery of therapeutic agents to large volumes of the brain at relatively uniform concentrations. This mode of drug delivery offers great potential for the treatment of many neurological disorders, including brain tumors, neurodegenerative diseases, and seizure disorders. An analysis of the treatment efficacy and toxicity of this approach requires confirmation that the infusion is distributed to the targeted region and that the drug concentrations are in the therapeutic range.
Methods. To confirm accurate delivery of therapeutic agents during CED and to monitor the extent of infusion in real time, albumin-linked surrogate tracers that are visible on images obtained using noninvasive techniques (iopanoic acid [IPA] for computerized tomography [CT] and Gd—diethylenetriamine pentaacetic acid for magnetic resonance [MR] imaging) were developed and investigated for their usefulness as surrogate tracers during convective distribution of a macromolecule. The authors infused albumin-linked tracers into the cerebral hemispheres of monkeys and measured the volumes of distribution by using CT and MR imaging. The distribution volumes measured by imaging were compared with tissue volumes measured using quantitative autoradiography with [14C]bovine serum albumin coinfused with the surrogate tracer. For in vivo determination of tracer concentration, the authors examined the correlation between the concentration of the tracer in brain homogenate standards and CT Hounsfield units. They also investigated the long-term effects of the surrogate tracer for CT scanning, IPA-albumin, on animal behavior, the histological characteristics of the tissue, and parenchymal toxicity after cerebral infusion.
Conclusions. Distribution of a macromolecule to clinically significant volumes in the brain is possible using convection. The spatial dimensions of the tissue distribution can be accurately defined in vivo during infusion by using surrogate tracers and conventional imaging techniques, and it is expected that it will be possible to determine local concentrations of surrogate tracers in voxels of tissue in vivo by using CT scanning. Use of imaging surrogate tracers is a practical, safe, and essential tool for establishing treatment volumes during high-flow interstitial microinfusion of the central nervous system.
Douglas W. Laske, Paul F. Morrison, Daniel M. Lieberman, Mark E. Corthesy, James C. Reynolds, Patricia A. Stewart-Henney, Sung-Soo Koong, Alex Cummins, Chang H. Paik and Edward H. Oldfield
✓ High-flow interstitial infusion into the brain, which uses bulk fluid flow to achieve a relatively homogeneous drug distribution in the extracellular space of the brain, has the potential to perfuse large volumes of brain. The authors report reproducible long-term delivery of 111In—diethylenetriamine pentaacetic acid—apotransferrin (111In-DTPA-Tf) (molecular mass 81 kD) to Macaca mulatta brain and monitoring with single-photon emission computerized tomography (SPECT). The 111In-DTPA-Tf was infused at 1.9 µl/minute over 87 hours into the frontal portion of the centrum semiovale using a telemetry-controlled, fully implanted pump. On Days 1, 3, 4, 8, 11, and 15 after beginning the infusion, planar and SPECT scans of 111In-DTPA-Tf were obtained. Spread of protein in the brain ranged from 2 to 3 cm and infusion volumes ranged from 3.9 to 6.7 cm3. Perfusion of over one-third of the white matter of the infused hemisphere was achieved. From brain SPECT images of 99mTc—hexamethylpropyleneamine oxime, which was administered intravenously before each 111In scan, the authors also found that blood perfusion in the infused region was reduced by less than 5% relative to corresponding noninfused regions. Histological examination at 30 days revealed only mild gliosis limited to the area immediately surrounding the needle tract. These findings indicate that long-term interstitial brain infusion is effective for the delivery of drugs on a multicentimeter scale in the primate brain. The results also indicate that it should be possible to perfuse targeted regions of the brain for extended intervals to investigate the potential utility of neurotrophic factors, antitumor agents, and other materials for the treatment of central nervous system disorders.
J. Douglas Miller, John F. Butterworth, Steven K. Gudeman, J. Edward Faulkner, Sung C. Choi, John B. Selhorst, John W. Harbison, Harry A. Lutz, Harold F. Young and Donald P. Becker
✓ A prospective and consecutive series of 225 patients with severe head injury who were managed in a uniform way was analyzed to relate outcome to several clinical variables. Good recovery or moderate disability were achieved by 56% of the patients, 10% remained severely disabled or vegetative, and 34% died. Factors important in predicting a poor outcome included the presence of an intracranial hematoma, increasing age, abnormal motor responses, impaired or absent eye movements or pupil light reflexes, early hypotension, hypoxemia or hypercarbia, and elevation of intracranial pressure over 20 mm Hg despite artificial ventilation. Most of these predictive factors were assessed on admission, but a subset of 158 patients was identified in whom coma was present on admission and was known to have persisted at least until the following day. Although the mortality in this subset (40%) was higher than in the total series, it was lower than in several comparable reported series of patients with severe head injury. Predictive correlations were equally strong in the entire series and in the subset of 158 patients with coma. A plea is made for inclusion in the definition of “severe head injury” of all patients who do not obey commands or utter recognizable words on admission to the hospital after early resuscitation.