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Russell R. Lonser, John D. Heiss and Edward H. Oldfield

✓ Preoperative reduction in tumor vascularity has been accomplished previously by selective catheterization of tumor vessels and delivery of occlusive materials. The results of percutaneous infusion of vertebral hemangiomas and other vascular lesions led the authors to speculate that rapid devascularization of tumors by direct injection of ethanol (ETOH) could be used to reduce bleeding and facilitate resection during surgery. Thus, the use of intratumoral injection of ETOH and its effects on tumor hemostasis and resectability were examined. Four patients received direct injection of ETOH into either a spinal epidural (two renal cell carcinomas and one rhabdomyosarcoma) or a large cerebellar neoplasm (hemangioblastoma). Intraoperative perfusion of the tumors with ETOH produced immediate blanching and devascularization and enhanced visualization and resection.

Incremental tumor devascularization is achieved by careful injection of small amounts of ETOH directly into the lesion, producing immediate and complete regional tumor devascularization. Use of this technique reduces intratumoral bleeding and enhances the ease and effectiveness of resection.

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Russell R. Lonser, Robert J. Weil, Paul F. Morrison, Lance S. Governale and Edward H. Oldfield

Object. Although many macromolecules have treatment potential for peripheral nerve disease, clinical use of these agents has been restricted because of limitations of delivery including systemic toxicity, heterogeneous dispersion, and inadequate distribution. In an effort to overcome these obstacles, the authors examined the use of convection to deliver and distribute macromolecules into peripheral nerves.

Methods. For convective delivery, the authors used a gas-tight, noncompliant system that provided continuous flow through a small silica cannula (inner diameter 100 µm, outer diameter 170 µm) inserted into a peripheral nerve. Increases in the volume of infusion (Vi) (10, 20, 30, 40, and 80 µl) of 14C-labeled (nine nerves) or gadolinium-labeled (two nerves) albumin were infused unilaterally or bilaterally into the tibial nerves of six primates (Macaca mulatta) at 0.5 µl/minute. The volume of distribution (Vd), percentage recovery, and delivery homogeneity were determined using quantitative autoradiography, an imaging program developed by the National Institutes of Health, magnetic resonance (MR) imaging, scintillation counting, and kurtosis (K) analysis. One animal that was infused bilaterally with gadolinium-bound albumin (40 µl to each nerve) underwent MR imaging and was observed for 16 weeks after infusion.

The Vd increased with the Vi in a logarithmic fashion. The mean Vd/Vi ratio over all Vi was 3.7 ± 0.8 (mean ± standard deviation). The concentration across the perfused region was homogeneous (K = −1.07). The infusate, which was limited circumferentially by the epineurium, followed the parallel arrangement of axonal fibers and filled long segments of nerve (up to 6.8 cm). Recovery of radioactivity was 75.8 ± 9%. No neurological deficits arose from infusion.

Conclusions. Convective delivery of macromolecules to peripheral nerves is safe and reliable. It overcomes obstacles associated with current delivery methods and allows selective regional delivery of putative therapeutic agents to long sections of nerve. This technique should permit the development of new treatments for numerous types of peripheral nerve lesions.

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Russell R. Lonser, Nitin Gogate, Paul F. Morrison, J. David Wood and Edward H. Oldfield

Object. Because of the limited penetration of macromolecules across the blood—spinal cord barrier, numerous therapeutic compounds with potential for treating spinal cord disorders cannot be used effectively. The authors have developed a technique to deliver and distribute macromolecules regionally in the spinal cord by using convection in the interstitial space.

Methods. The authors designed a delivery system connected to a “floating” silica cannula (inner diameter 100 µm, outer diameter 170 µm) that provides for constant volumetric inflow to the spinal cord. A solution containing albumin that was either unlabeled or labeled with carbon-14 or gadolinium was infused at various volumes (3, 6, 10, 20, 40, or 50 µl) at a rate of 0.1 µl/minute into the spinal cord dorsal columns of nine swine and into the lateral columns of three primates (Macaca mulatta). Volume of distribution (Vd), concentration homogeneity, and percentage of recovery were determined using scintillation analysis, kurtosis calculation (K), and quantitative autoradiography (six swine), magnetic resonance imaging (one swine and three primates), and histological analysis (all animals). Neurological function was observed for up to 3 days in four of the swine and up to 16 weeks in the three primates.

The Vd of 14C-albumin was linearly proportional (R2 = 0.97) to the volume of infusion (Vi) (Vd/Vi = 4.4 ± 0.5; [mean ± standard deviation]). The increases in Vd resulting from increases in Vi were primarily in the longitudinal dimension (R2 = 0.83 in swine; R2 = 0.98 in primates), allowing large segments of spinal cord (up to 4.3 cm; Vi 50 µl) to be perfused with the macromolecule. The concentration across the area of distribution was homogeneous (K = −1.1). The mean recovery of infused albumin from the spinal cord was 85.5 ± 5.6%. Magnetic resonance imaging and histological analysis combined with quantitative autoradiography revealed the albumin infusate to be preferentially distributed along the white matter tracts. No animal exhibited a neurological deficit as a result of the infusion.

Conclusions. Regional convective delivery provides reproducible, safe, region-specific, and homogeneous distribution of macromolecules over large longitudinal segments of the spinal cord. This delivery method overcomes many of the obstacles associated with current delivery techniques and provides for research into new treatments of various conditions of the spinal cord.

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J. David Wood, Russell R. Lonser, Nitin Gogate, Paul F. Morrison and Edward H. Oldfield

Object. Many macromolecules have the potential to enhance recovery after injury and other lesions of the spinal cord, but because of the limited penetration of these compounds across the blood—spinal cord barrier, they cannot be used effectively. To determine if convective delivery could be used in a common animal model to investigate potential therapeutic macromolecules and to examine the effects of trauma on convective delivery in that model, the authors examined the distribution of a macromolecule in naive and traumatized rat spinal cords.

Methods. Using convection, various infusion volumes ([Vi]; 1, 2, and 4 µl) of 14C-albumin were infused into the dorsal columns of 13 naive and five traumatized rat spinal cords. Volume of distribution (Vd), homogeneity, percentage of recovery, and anatomical location were determined using quantitative autoradiography, scintillation analysis, calculation of kurtosis (K) value, and histological analysis. In the nontraumatized group, Vd was linearly proportional (R2 = 0.98) to Vi (Vd/Vi, 4.3 ± 0.6; mean ± standard deviation), with increases in Vd resulting from linear expansion (R2 = 0.94) primarily in the craniocaudal dimension. In the traumatized spinal cords, the Vd/Vi ratio (3.7 ± 0.5) was smaller (p < 0.02) and distributions were less confined to the craniocaudal dimension, with significantly larger cross-sectional distributions in the region of injury (p < 0.02) compared to the noninjured spinal cords. Histological analysis revealed that after infusion into the dorsal columns, albumin distribution in naive cords was limited to the dorsal white matter, but in the traumatized cords there was penetration into the central gray matter. The distribution of the infusate was homogeneous in the nontraumatized (K = −1.1) and traumatized (K = −1.1) spinal cords. Recovery of radioactivity was not significantly different (p > 0.05) between the nontraumatized (84.8 ± 6.8%) and traumatized (79.7 ± 12.1%) groups.

Conclusions. Direct convective delivery of infusate can be used to distribute macromolecules in a predictable, homogeneous manner over significant volumes of naive and traumatized rat spinal cord. These characteristics make it a valuable tool to investigate the therapeutic potential of various compounds for the treatment of injury and spinal cord disease.

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Russell R. Lonser, John D. Heiss and Edward H. Oldfield

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Michael Y. Chen, Russell R. Lonser, Paul F. Morrison, Lance S. Governale and Edward H. Oldfield

Object. Although recent studies have shown that convection can be used to distribute macromolecules within the central nervous system (CNS) in a homogeneous, targeted fashion over clinically significant volumes and that the volume of infusion and target location (gray as opposed to white matter) influence distribution, little is known about other factors that may influence optimum use of convection-enhanced distribution. To understand the variables that affect convective delivery more fully, we examined the rate of infusion, delivery cannula size, concentration of infusate, and preinfusion sealing time.

Methods. The authors used convection to deliver 4 µl of 14C-albumin to the striatum of 40 rats. The effect of the rate of infusion (0.1, 0.5, 1, and 5 µl/minute), cannula size (32, 28, and 22 gauge), concentration of infusate (100%, 50%, and 25%), and preinfusion sealing time (0 and 70 minutes) on convective delivery was examined using quantitative autoradiography, National Institutes of Health image analysis software, scintillation analysis, and histological analysis.

Higher rates of infusion (1 and 5 µl/minute) caused significantly (p < 0.05) more leakback of infusate (22.7 ± 11.7% and 30.3 ± 7.8% [mean ± standard deviation], respectively) compared with lower rates (0.1 µl/minute [4 ± 3.6%] and 0.5 µl/minute [5.2 µ 3.6%]). Recovery of infusate was significantly (p < 0.05) higher at the infusion rate of 0.1 µl/minute (95.1 ± 2.8%) compared with higher rates (85.2 ± 4%). The use of large cannulae (28 and 22 gauge) produced significantly (p < 0.05) more leakback (35.7 ± 8.1% and 21.1 ± 7.5%, respectively) than the smaller cannula (32 gauge [5.2 ± 3.6%]). Varying the concentration of the infusate and the preinfusion sealing time did not alter the volume of distribution, regional distribution, or infusate recovery.

Conclusions. Rate of infusion and cannula size can significantly affect convective distribution of molecules, whereas preinfusion sealing time and variations in infusate concentration have no effect in this small animal model. Understanding the parameters that influence convective delivery within the CNS can be used to enhance delivery of potentially therapeutic agents in an experimental setting and to indicate the variables that will need to be considered for optimum use of this approach for drug delivery in the clinical setting.

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Russell R. Lonser, Marc-Etienne Corthésy, Paul F. Morrison, Nitin Gogate and Edward H. Oldfield

Object. Selective treatment of central nervous system (CNS) structures holds therapeutic promise for many neurological disorders, including Parkinson's disease (PD). The ability to inhibit or augment specific neuronal populations within the CNS reliably by using present therapeutic techniques is limited. To overcome this problem, the authors modeled and developed a method in which convection was used to deliver compounds to deep brain nuclei in a reproducible, homogeneous, and targeted manner. To determine the feasibility and clinical efficacy of convective drug delivery for treatment of a neurological disorder, the investigators selectively ablated globus pallidus internus (GPi) neurons with quinolinic acid (QA), an excitotoxin, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)—induced model of primate parkinsonism.

Methods. After the parameters of convective distribution to the GPi were confirmed by infusion of biotinylated albumin into the GPi of a primate (Macaca mulatta), seven adult monkeys of this species were rendered either fully parkinsonian by intravenous injections of MPTP (five animals) or hemiparkinsonian by a right-sided intracarotid injection of this agent (two monkeys). Using convection-enhanced delivery to the GPi, animals were infused with either QA (three fully parkinsonian, two hemiparkinsonian) or saline (two fully parkinsonian).

The three fully parkinsonian animals that underwent GPi lesioning with QA had substantial improvement of PD symptoms, manifested by a marked increase in activity (34 ± 2.5%; mean ± standard deviation) and dramatic improvement of parkinsonian clinical scores. In contrast, the control animals did not improve (activity monitor change = −1.5 × 0.5%). The two hemiparkinsonian animals that underwent QA lesioning of the GPi had dramatic recovery of extremity use. Histological examination revealed selective neural ablation of GPi neurons (mean loss 87%) with sparing of surrounding gray and white matter structures. No animal developed worsening signs of PD or neurological deficits after infusion.

Conclusions. Convection-enhanced delivery of QA permits selective, region-specific (GPi), and safe lesioning of neuronal subpopulations, resulting in dramatic improvement in parkinsonian symptomatology. The properties of convection-enhanced delivery indicate that this method could be used for chemical neurosurgery for medically refractory PD and that it may be ideal for cell-specific therapeutic ablation or trophic treatment of other targeted structures associated with CNS disorders.

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Ronald I. Apfelbaum, Russell R. Lonser, Robert Veres and Adrian Casey

Object

The management of odontoid fractures remains controversial. Only direct anterior screw fixation provides immediate stabilization of the spine and may preserve normal C1–2 motion. To determine the indications, optimum timing, and results for direct anterior screw fixation of odontoid fractures, the authors reviewed the surgery-related outcome of patients who underwent this procedure at two institutions.

Methods

One hundred forty-seven consecutive patients (98 males and 49 females) who underwent direct anterior screw fixation for a recent fracture (< 6 months postinjury [129 patients]) or remote (≥ 18 months postinjury [18 patients]) Type II (138 cases) or III (nine cases) odontoid fractures at the University of Utah (94 patients) and National Institute of Traumatology in Budapest, Hungary (53 patients) between 1986 and 1998 are included in this study (mean follow-up period 18.2 months). Data obtained from clinical examination, review of hospital charts, operative findings, and imaging studies were used to analyze the surgery-related results in these patients.

In patients with recent fractures there was an overall bone fusion rate of 88%. The rate of anatomical bone fusion of recent fractures was significantly (p ≤ 0.05) higher in fractures oriented in the horizontal and posterior oblique direction (as compared with anterior oblique), but this finding was independent (p ≥ 0.05) of age, sex, number of screws placed (one or two), and the degree or the direction of odontoid displacement. In patients with remote fractures there was a significantly lower rate of bone fusion (25%). Overall, complications related to hardware failure occurred in 14 patients (10%) and unrelated to hardware in three patients (2%). There was one death (1%) related to surgery.

Conclusions

Direct anterior screw fixation is an effective and safe method for treating recent odontoid fractures (< 6 months postinjury). It confers immediate stability, preserves C1–2 rotatory motion, and achieves a fusion rate that compares favorably with alternative treatment methods. In contradistinction, in patients with remote fractures (≥ 18 months postinjury) a significantly lower rate of fusion is found when using this technique, and these patients are believed to be poor candidates for this procedure.

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