Direct interstitial infusion of NK1-targeted neurotoxin into the spinal cord: a computational model.

Convection-enhanced delivery of substance P (SP) nocitoxins to the spinal cord interstitium is under consideration for the treatment of chronic pain. To characterize treatment protocols, a three-dimensional finite-element model of infusion into the human dorsal column was developed to predict the distribution of SP-diphtheria toxin fusion protein (SP-DT') within normal and target tissue. The model incorporated anisotropic convective and diffusive transport through the interstitial space, hydrolysis by peptidases, and intracellular trafficking.

A computational model of direct interstitial infusion of macromolecules into the spinal cord.

Convection-enhanced interstitial infusion can deliver macromolecular drugs to large tissue volumes of the central nervous system. To characterize infusion into the spinal cord, an image-based three-dimensional finite element model of the rat spinal cord was developed. The model incorporated convection and diffusion through white and gray matter, including anisotropic transport due to alignment of white matter tracts.

Surgical management of spinal cord hemangioblastomas in patients with von Hippel-Lindau disease.

Object: Von Hippel-Lindau (VHL) disease is an autosomal-dominant disorder frequently associated with hemangioblastomas of the spinal cord. Because of the slow progression, protean nature, and high frequency of multiple spinal hemangioblastomas associated with VHL disease, the surgical management of these lesions is complex. Because prior reports have not identified the factors that predict which patients with spinal cord hemangioblastomas need surgery or what outcomes of this procedure should be expected, the authors have reviewed a series of patients with VHL disease who underwent resection of spinal hemangioblastomas at a single institution to identify features that might guide surgical management of these patients.

Surgical management of brainstem hemangioblastomas in patients with von Hippel-Lindau disease.

Object: Hemangioblastomas of the brainstem constitute 5 to 10% of central nervous system (CNS) tumors in patients with von Hippel-Lindau (VHL) disease. At present, optimal management of brainstem hemangioblastomas associated with VHL disease is incompletely defined. In an attempt to clarify some of the uncertainty about the operative treatment of these lesions and its outcome, the authors reviewed all cases of VHL disease in which resection of brainstem hemangioblastomas was performed at the National Institutes of Health during a 10-year period.

The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease.

Object: The goals of this study were to define the natural history and growth pattern of hemangioblastomas of the central nervous system (CNS) that are associated with von Hippel-Lindau (VHL) disease and to correlate features of hemangioblastomas that are associated with the development of symptoms and the need for treatment.

Methods: The authors reviewed serial magnetic resonance images and clinical histories of 160 consecutive patients with VHL disease who harbored CNS hemangioblastomas and serially measured the volumes of tumors and associated cysts Six hundred fifty-five hemangioblastomas were identified in the cerebellum (250 tumors), brainstem (64 tumors, all of which were located in the posterior medulla oblongata), spinal cord (331 tumors, 96% of which were located in the posterior half of spinal cord), and the supratentorial brain (10 tumors). The symptoms were related to a mass effect.

Induction of glioblastoma multiforme in nonhuman primates after therapeutic doses of fractionated whole-brain radiation therapy.

Object: To determine the acute and long-term effects of a therapeutic dose of brain radiation in a primate model, the authors studied the clinical, laboratory, neuroimaging, molecular, and histological outcomes in rhesus monkeys that had received fractionated whole-brain radiation therapy (WBRT).

Methods: Twelve 3-year-old male primates (Macaca mulatta) underwent fractionated WBRT (350 cGy for 5 days/week for 2 weeks, total dose 3500 cGy). Animals were followed clinically and with laboratory studies and serial magnetic resonance (MR) imaging.

Successful and safe perfusion of the primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during infusion.

Object: Intrinsic disease processes of the brainstem (gliomas, neurodegenerative disease, and others) have remained difficult or impossible to treat effectively because of limited drug penetration across the blood-brainstem barrier with conventional delivery methods. The authors used convection-enhanced delivery (CED) of a macromolecular tracer visible on magnetic resonance (MR) imaging to examine the utility of CED for safe perfusion of the brainstem.

Methods: Three primates (Macaca mulatta) underwent CED of various volumes of infusion ([Vis]; 85, 110, and 120 microl) of Gd-bound albumin (72 kD) in the pontine region of the brainstem during serial MR imaging.

Epileptiform activity extinguished by amygdala infusion of the neurotoxin ibotenate in a rat model of temporal lobe epilepsy.

Object: The long-term antiseizure effects of local convection-enhanced infusion of the excitotoxin ibotenate were examined in a rat model of temporal lobe epilepsy.

Methods: A single injection of kainate, an epileptogenic excitatory amino acid, into the left amygdala elicited chronic spontaneous recurrent seizure activity for at least 36 days after the injection. Two weeks after the injection, infusion of ibotenate, a nonepileptogenic excitatory amino acid that is an axon-sparing neuronal cell toxin, into the left amygdala and piriform lobe induced immediate and permanent extinction of electrical and behavioral seizure activity.

Vertebral osteomyelitis secondary to Pseudallescheria boydii.

Because Pseudallescheria boydii vertebral osteomyelitis is rare and frequently resistant to available antifungal agents, the proper treatment of this lesion has not been defined. To better determine the best treatment of this lesion, the authors evaluated a case P. boydii vertebral osteomyelitis and reviewed the literature.

Direct anterior screw fixation for recent and remote odontoid fractures.

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.

Adult tethered cord syndrome.

Although often overlooked, the diagnosis of adult "tethered cord syndrome" (TCS) is important because the manifestations of this syndrome are readily reversible by untethering. Too often, adult patients with TCS are misdiagnosed as having "failed back syndrome" or other unrelated spinal problems. As a result, many patients are treated with modalities which fail to improve neurological function.

Focal delivery during direct infusion to brain: role of flow rate, catheter diameter, and tissue mechanics.

Direct interstitial infusion is a technique capable of delivering agents over both small and large dimensions of brain tissue. However, at a sufficiently high volumetric inflow rate, backflow along the catheter shaft may occur and compromise delivery. A scaling relationship for the finite backflow distance along this catheter in pure gray matter (x(m)) has been determined from a mathematical model based on Stokes flow, Darcy flow in porous media, and elastic deformation of the brain tissue: x(m) = constant Q(o)(3)R(4)r(c)(4)G(-3)mu(-1) 1/5 [corrected] = volumetric inflow rate, R = tissue hydraulic resistance, r(c) = catheter radius, G = shear modulus, and mu = viscosity).

Scanning electron microscopy of arteriovenous malformations.

Although arteriovenous malformations (AVMs) have been known to have direct communications between arteries and veins without interposing capillaries, the exact location of arterial and venous junctions have not been defined. Utilizing microscopic and endoscopic observations, Yamada and associates identified shunting arterioles (50 mu-250 mu) directly connected to the AVM core vessels. While dissecting the AVMs in functional areas of the brain, shunting arterioles were sectioned to interrupt the arterial blood supply.

Convection-enhanced selective excitotoxic ablation of the neurons of the globus pallidus internus for treatment of parkinsonism in nonhuman primates.

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.

Convective delivery of macromolecules into the naive and traumatized spinal cords of rats.

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 microl) of 14C-albumin were infused into the dorsal columns of 13 naive and five traumatized rat spinal cords.

Endoscopic procedures for resection of arteriovenous malformations.

Background: Resection of arteriovenous malformations (AVMs), particularly those located in functional areas, requires precision. To enhance that precision, endoscope-assisted microsurgery has been employed at Loma Linda University.

Methods: Twenty-five consecutive cases of AVM were treated microsurgically with endoscopic assistance.

Variables affecting convection-enhanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue-cannula sealing time.

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 microl of 14C-albumin to the striatum of 40 rats.

Telomerase activity in microdissected human gliomas.

Future improvements in the diagnosis and treatment of human gliomas might rely on obtaining more specific information concerning the biologic characteristics of individual tumor cells. Telomerase, a ribonucleoprotein that synthesizes telomeres, has been reported to be expressed in a majority of human tumors, including several subtypes of brain tumor. We hypothesized that a quantitative assay for telomerase activity, combined with selective microdissection of tumor or normal brain cells, might reveal telomerase gain-of-function to be important in the pathogenesis of gliomas and that telomerase levels might have prognostic significance.

Direct convective delivery of macromolecules to the spinal cord.

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 microm, outer diameter 170 microm) that provides for constant volumetric inflow to the spinal cord.

Direct convective delivery of macromolecules to peripheral nerves.

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 microm, outer diameter 170 microm) inserted into a peripheral nerve.

The safety of intraoperative autologous blood collection and autotransfusion during cesarean section.

Objective: We evaluated the safety of intraoperative autologous blood collection and autotransfusion during cesarean section.

Study Design: A multicenter historical cohort study identified 139 patients in whom autologous blood collection autotransfusion during cesarean section was performed. We also identified 87 control patients who underwent similar surgical procedures at the same centers without autotransfusion.

Tumor devascularization by intratumoral ethanol injection during surgery. Technical note.

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.

Bypass coaptation procedures for cervical nerve root avulsion.

In the past, patients with cervical spinal nerve root avulsions were resigned to accept a natural crippling from upper extremity neurological deficits. Recently, bypass coaptation procedures have resulted in functional return of denervated muscles after such avulsions, much to the appreciation of patients. Presented are 12 patients with avulsion of cervical spinal nerve roots that form either the brachial plexus upper trunk (n = 7), lower trunk (n = 1), or all three trunks (n = 4).