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

2002 ◽  
Vol 97 (4) ◽  
pp. 905-913 ◽  
Author(s):  
Russell R. Lonser ◽  
Stuart Walbridge ◽  
Kayhan Garmestani ◽  
John A. Butman ◽  
Hugh A. Walters ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Magnetic Resonance ◽  
Mr Imaging ◽  
Histological Analysis ◽  
Volume Of Distribution ◽  
Convection Enhanced Delivery ◽  
Content Type ◽  
Large Molecular Weight ◽  
Fine Print

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 µl) of Gd-bound albumin (72 kD) in the pontine region of the brainstem during serial MR imaging. Infusate volume of distribution (Vd), homogeneity, and anatomical distribution were visualized and quantified using MR imaging. Neurological function was observed and recorded up to 35 days postinfusion. Histological analysis was performed in all animals. Large regions of the pons and midbrain were successfully and safely perfused with the macromolecular protein. The Vd was linearly proportional to the Vi (R2 = 0.94), with a Vd/Vi ratio of 8.7 ± 1.2 (mean ± standard deviation). Furthermore, the concentration across the perfused region was homogeneous. The Vd increased slightly at 24 hours after completion of the infusion, and remained larger until the intensity of infusion faded (by Day 7). No animal exhibited a neurological deficit after infusion. Histological analysis revealed normal tissue architecture and minimal gliosis that was limited to the region immediately surrounding the cannula track. Conclusions. First, CED can be used to perfuse the brainstem safely and effectively with macromolecules. Second, a large-molecular-weight imaging tracer can be used successfully to deliver, monitor in vivo, and control the distribution of small- and large-molecular-weight putative therapeutic agents for treatment of intrinsic brainstem processes.

Real-time in vivo imaging of the convective distribution of a low-molecular-weight tracer

2005 ◽  
Vol 102 (1) ◽  
pp. 90-97 ◽  
Author(s):  
David Croteau ◽  
Stuart Walbridge ◽  
Paul F. Morrison ◽  
John A. Butman ◽  
Alexander O. Vortmeyer ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Real Time ◽  
Ct Scanning ◽  
Quantitative Autoradiography ◽  
Cerebral White Matter ◽  
Low Molecular Weight ◽  
Convection Enhanced Delivery ◽  
Content Type ◽  
Fine Print

Object. Convection-enhanced delivery (CED) is increasingly used to distribute therapeutic agents to locations in the central nervous system. The optimal application of convective distribution of various agents requires the development of imaging tracers to monitor CED in vivo in real time. The authors examined the safety and utility of an iodine-based low-molecular-weight surrogate tracer for computerized tomography (CT) scanning during CED. Methods. Various volumes (total volume range 90–150 µ1) of iopamidol (MW 777 D) were delivered to the cerebral white matter of four primates (Macaca mulatta) by using CED. The distribution of this imaging tracer was determined by in vivo real-time and postinfusion CT scanning (≤ 5 days after infusion [one animal]) as well as by quantitative autoradiography (14C-sucrose [all animals] and 14C-dextran [one animal]), and compared with a mathematical model. Clinical observation (≤ 5 months) and histopathological analyses were used to evaluate the safety and toxicity of the tracer delivery. Real-time CT scanning of the tracer during infusion revealed a clearly definable region of perfusion. The volume of distribution (Vd) increased linearly (r2 = 0.97) with an increasing volume of infusion (Vi). The overall Vd/Vi ratio was 4.1 ± 0.7 (mean ± standard deviation) and the distribution of infusate was homogeneous. Quantitative autoradiography confirmed the accuracy of the imaged distribution for a small (sucrose, MW 359 D) and a large (dextran, MW 70 kD) molecule. The distribution of the infusate was identifiable up to 72 hours after infusion. There was no clinical or histopathological evidence of toxicity in any animal. Conclusions. Real-time in vivo CT scanning of CED of iopamidol appears to be safe, feasible, and suitable for monitoring convective delivery of drugs with certain features and low infusion volumes.

A realistic brain tissue phantom for intraparenchymal infusion studies

2004 ◽  
Vol 101 (2) ◽  
pp. 314-322 ◽  
Author(s):  
Zhi-Jian Chen ◽  
George T. Gillies ◽  
William C. Broaddus ◽  
Sujit S. Prabhu ◽  
Helen Fillmore ◽  
...  
Keyword(s):  
Mr Imaging ◽  
Bromophenol Blue ◽  
Agarose Gel ◽  
Convection Enhanced Delivery ◽  
Content Type ◽  
Force Profile ◽  
The Brain ◽  
Fine Print

Object. The goal of this study was to validate a simple, inexpensive, and robust model system to be used as an in vitro surrogate for in vivo brain tissues in preclinical and exploratory studies of infusion-based intraparenchymal drug and cell delivery. Methods. Agarose gels of varying concentrations and porcine brain were tested to determine the infusion characteristics of several different catheters at flow rates of 0.5 and 1 µl per minute by using bromophenol blue (BPB) dye (molecular weight [MW] ∼690) and gadodiamide (MW ∼573). Magnetic resonance (MR) imaging and videomicroscopy were used to measure the distribution of these infusates, with a simultaneous measurement of infusion pressures. In addition, the forces of catheter penetration and movement through gel and brain were measured. Agarose gel at a 0.6% concentration closely resembles in vivo brain with respect to several critical physical characteristics. The ratio of distribution volume to infusion volume of agarose was 10 compared with 7.1 for brain. The infusion pressure of the gel demonstrated profiles similar in configuration and magnitude to those of the brain (plateau pressures 10–20 mm Hg). Gadodiamide infusion in agarose closely resembled that in the brain, as documented using T1-weighted MR imaging. Gadodiamide distribution in agarose gel was virtually identical to that of BPB dye, as documented by MR imaging and videomicroscopy. The force profile for insertion of a silastic catheter into agarose gel was similar in magnitude and configuration to the force profile for insertion into the brain. Careful insertion of the cannula using a stereotactic guide is critical to minimize irregularity and backflow of infusate distribution. Conclusions. Agarose gel (0.6%) is a useful surrogate for in vivo brain in exploratory studies of convection-enhanced delivery.

Magnetic resonance appearance of multiple intracranial epidermoid cysts: intrathecal seeding of the cysts?

2000 ◽  
Vol 92 (4) ◽  
pp. 711-714 ◽  
Author(s):  
Yasushi Miyagi ◽  
Satoshi O. Suzuki ◽  
Toru Iwaki ◽  
Katsuya Ishido ◽  
Takehisa Araki ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Mr Imaging ◽  
Histological Analysis ◽  
Clinical Manifestations ◽  
Content Type ◽  
Epidermoid Cysts ◽  
Chronic Headaches ◽  
Cyst Rupture ◽  
Intracranial Epidermoid ◽  
Fine Print

✓ A 44-year-old man presented to the hospital with multiple intracranial epidermoid cysts. The clinical manifestations of his disease included chronic headaches and one seizurelike episode. Findings determined by magnetic resonance (MR) imaging, surgery, and histological analysis indicated intrathecal and intraventricular seeding of the cysts. Spontaneous (nontraumatic) seeding of multiple daughter cysts from intracranial epidermoid cysts is still very rare and their multiple appearances on MR imaging should be distinguished from the simple scattering of oily contents due to cyst rupture.

Convective distribution of macromolecules in the primate brain demonstrated using computerized tomography and magnetic resonance imaging

2003 ◽  
Vol 98 (3) ◽  
pp. 584-590 ◽  
Author(s):  
Tung T. Nguyen ◽  
Yashdip S. Pannu ◽  
Cynthia Sung ◽  
Robert L. Dedrick ◽  
Stuart Walbridge ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Mr Imaging ◽  
Computerized Tomography ◽  
Ct Scanning ◽  
Therapeutic Agents ◽  
Content Type ◽  
Drug Concentrations ◽  
The Brain ◽  
Fine Print

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.

Image-guided convection-enhanced delivery of gemcitabine to the brainstem

2007 ◽  
Vol 106 (2) ◽  
pp. 351-356 ◽  
Author(s):  
Gregory J. A. Murad ◽  
Stuart Walbridge ◽  
Paul F. Morrison ◽  
Nicholas Szerlip ◽  
John A. Butman ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Mr Imaging ◽  
Histological Analysis ◽  
Chemotherapeutic Agent ◽  
Volume Of Distribution ◽  
Magnetic Resonance Images ◽  
Quantitative Autoradiography ◽  
Therapeutic Application ◽  
Convection Enhanced Delivery ◽  
Therapeutic Doses

Object To determine if the potent antiglioma chemotherapeutic agent gemcitabine could be delivered to the brainstem safely at therapeutic doses while monitoring its distribution using a surrogate magnetic resonance (MR) imaging tracer, the authors used convection-enhanced delivery to perfuse the primate brainstem with gemcitabine and Gd–diethylenetriamine pentaacetic acid (DTPA). Methods Six primates underwent convective brainstem perfusion with gemcitabine (0.4 mg/ml; two animals), Gd-DTPA (5 mM; two animals), or a coinfusion of gemcitabine (0.4 mg/ml) and Gd-DTPA (5 mM; two animals), and were killed 28 days afterward. These primates were observed over time clinically (six animals), and with MR imaging (five animals), quantitative autoradiography (one animal), and histological analysis (all animals). In an additional primate, 3H-gemcitabine and Gd-DTPA were coinfused and the animal was killed immediately afterward. In the primates there was no histological evidence of infusate-related tissue toxicity. Magnetic resonance images obtained during infusate delivery demonstrated that the anatomical region infused with Gd-DTPA was clearly distinguishable from surrounding noninfused tissue. Quantitative autoradiography confirmed that Gd-DTPA tracked the distribution of 3H-gemcitabine and closely approximated its volume of distribution (mean volume of distribution difference 13.5%). Conclusions Gemcitabine can be delivered safely and effectively to the primate brainstem at therapeutic concentrations and at volumes that are higher than those considered clinically relevant. Moreover, MR imaging can be used to track the distribution of gemcitabine by adding Gd-DTPA to the infusate. This delivery paradigm should allow for direct therapeutic application of gemcitabine to brainstem gliomas while monitoring its distribution to ensure effective tumor coverage and to maximize safety.

scholarly journals Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents

2005 ◽  
Vol 103 (5) ◽  
pp. 923-929 ◽  
Author(s):  
Michal T. Krauze ◽  
Ryuta Saito ◽  
Charles Noble ◽  
Matyas Tamas ◽  
John Bringas ◽  
...  
Keyword(s):  
Trypan Blue ◽  
High Speed ◽  
Volume Of Distribution ◽  
Blue Dye ◽  
Agarose Gel ◽  
Convection Enhanced Delivery ◽  
Flow Rates ◽  
Content Type ◽  
Fine Print

Object. Clinical application of the convection-enhanced delivery (CED) technique is currently limited by low infusion speed and reflux of the delivered agent. The authors developed and evaluated a new step-design cannula to overcome present limitations and to introduce a rapid, reflux-free CED method for future clinical trials. Methods. The CED of 0.4% trypan blue dye was performed in agarose gel to test cannula needles for distribution and reflux. Infusion rates ranging from 0.5 to 50 µl/minute were used. Agarose gel findings were translated into a study in rats and then in cynomolgus monkeys (Macaca fascicularis) by using trypan blue and liposomes to confirm the efficacy of the reflux-free step-design cannula in vivo. Results of agarose gel studies showed reflux-free infusion with high flow rates using the step-design cannula. Data from the study in rats confirmed the agarose gel findings and also revealed increasing tissue damage at a flow rate above 5-µl/minute. Robust reflux-free delivery and distribution of liposomes was achieved using the step-design cannula in brains in both rats and nonhuman primates. Conclusions. The authors developed a new step-design cannula for CED that effectively prevents reflux in vivo and maximizes the distribution of agents delivered in the brain. Data in the present study show reflux-free infusion with a constant volume of distribution in the rat brain over a broad range of flow rates. Reflux-free delivery of liposomes into nonhuman primate brain was also established using the cannula. This step-design cannula may allow reflux-free distribution and shorten the duration of infusion in future clinical applications of CED in humans.

Use of magnetic resonance imaging for in vivo measurements of water content in human brain: method and normal values

1999 ◽  
Vol 90 (1) ◽  
pp. 109-115 ◽  
Author(s):  
Panos P. Fatouros ◽  
Anthony Marmarou
Keyword(s):  
Magnetic Resonance ◽  
Mr Imaging ◽  
Water Content ◽  
Pure Water ◽  
Anatomical Location ◽  
Imaging Method ◽  
Content Type ◽  
Brain Water ◽  
Fine Print

Object. The authors present a quantitative in vivo magnetic resonance (MR) imaging method and propose its use for the accurate assessment of brain water in humans.Methods. With this technique, a pure T1-weighted image of a selected brain slice in a patient is generated, and the image is subsequently converted to a pure water image by means of an equation derived from a tissue relaxation model. The image intensity in the resulting water map directly yields absolute measures of water expressed in grams of water per gram of tissue at a given anatomical location. The method has been validated previously in a series of phantom experiments and in an infusion model of brain edema in cats. In this report, the authors evaluate the method by using samples of tissue harvested from patients who underwent surgery for brain tumor removal and apply the technique to a series of normal volunteers, providing average regional brain water content (fw) values for a range of tissues. Application of the method in pathological conditions such as head trauma, tumor, and hydrocephalus allows quantification of regional or global increases in fw that result from edema.Conclusions. It is now possible to obtain accurate brain water measurements with the anatomical resolution of MR imaging. This permits monitoring of the development and resolution of edema in a variety of clinical circumstances, thus enhancing understanding of the underlying pathophysiological processes.

Early changes measured by magnetic resonance imaging in cerebral blood flow, blood volume, and blood-brain barrier permeability following dexamethasone treatment in patients with brain tumors

1999 ◽  
Vol 90 (2) ◽  
pp. 300-305 ◽  
Author(s):  
Leif Østergaard ◽  
Fred H. Hochberg ◽  
James D. Rabinov ◽  
A. Gregory Sorensen ◽  
Michael Lev ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Magnetic Resonance ◽  
Brain Tumors ◽  
Mr Imaging ◽  
Blood Volume ◽  
Cerebral Blood Volume ◽  
Clinical Effects ◽  
Content Type ◽  
Fine Print

Object. In this study the authors assessed the early changes in brain tumor physiology associated with glucocorticoid administration. Glucocorticoids have a dramatic effect on symptoms in patients with brain tumors over a time scale ranging from minutes to a few hours. Previous studies have indicated that glucocorticoids may act either by decreasing cerebral blood volume (CBV) or blood-tumor barrier (BTB) permeability and thereby the degree of vasogenic edema.Methods. Using magnetic resonance (MR) imaging, the authors examined the acute changes in CBV, cerebral blood flow (CBF), and BTB permeability to gadolinium-diethylenetriamine pentaacetic acid after administration of dexamethasone in six patients with brain tumors. In patients with acute decreases in BTB permeability after dexamethasone administration, changes in the degree of edema were assessed using the apparent diffusion coefficient of water.Conclusions. Dexamethasone was found to cause a dramatic decrease in BTB permeability and regional CBV but no significant changes in CBF or the degree of edema. The authors found that MR imaging provides a powerful tool for investigating the pathophysiological changes associated with the clinical effects of glucocorticoids.

Accelerated spondylotic changes adjacent to the fused segment following central cervical corpectomy: magnetic resonance imaging study evidence

2004 ◽  
Vol 100 (1) ◽  
pp. 2-6 ◽  
Author(s):  
Vaijayantee Kulkarni ◽  
Vedantam Rajshekhar ◽  
Lakshminarayan Raghuram
Keyword(s):  
Magnetic Resonance ◽  
Mr Imaging ◽  
Imaging Study ◽  
Degenerative Changes ◽  
Adjacent Segment ◽  
Mr Images ◽  
Short Term ◽  
Content Type ◽  
Fine Print

Object. The authors studied whether cervical spine motion segments adjacent to a fused segment exhibit accelerated degenerative changes on short-term follow-up magnetic resonance (MR) imaging. Methods. Preoperative and short-term follow-up (mean duration 17.5 months, range 10–48 months) cervical MR images obtained in 44 patients who had undergone one- or two-level corpectomy for cervical spondylotic myelopathy were evaluated qualitatively and quantitatively. The motion segment adjacent to the fused segment and a segment remote from the fused segment were evaluated for indentation of the thecal sac, disc height, and sagittal functional diameter of the spinal canal on midsagittal T2-weighted MR images. Thecal sac indentations were classifed as mild, moderate, and severe. New indentations of the thecal sac of varying severity (mild in 17 patients [38.6%], moderate in 10 [22.7%], and severe in six [13.6%]) had developed at the adjacent segments in 33 (75%) of 44 patients. The degenerative changes were seen at the superior level in 11 patients, inferior level in 10 patients, and at both levels in 12 patients and resulted from both anterior and posterior element degeneration in the majority (23 [69.6%]) of patients. The remote segments showed mild thecal sac indentations in seven patients and moderate indentations in two patients (nine [20.5%] of 44). Compared with the changes at the remote segment, the canal size was significantly decreased at the superior adjacent segment by 0.9 mm (p = 0.007). No patient sustained a new neurological deficit due to adjacent-segment changes. Conclusions. On short-term follow-up MR imaging, levels adjacent to the fused segment exhibited more pronounced degenerative changes (compared with remote levels) in 75% of patients who had undergone one- or two-level central corpectomy.

Lack of agreement between direct magnetic resonance imaging and statistical determination of a subthalamic target: the role of electrophysiological guidance

2002 ◽  
Vol 97 (3) ◽  
pp. 591-597 ◽  
Author(s):  
Emmanuel Cuny ◽  
Dominique Guehl ◽  
Pierre Burbaud ◽  
Christian Gross ◽  
Vincent Dousset ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Mr Imaging ◽  
Functional Response ◽  
Anterior Commissure ◽  
Surgical Techniques ◽  
High Frequency Stimulation ◽  
Mr Images ◽  
Posterior Commissure ◽  
Content Type ◽  
Fine Print

Object. The goal of this study was to determine the most suitable procedure(s) to localize the optimal site for high-frequency stimulation of the subthalamic nucleus (STN) for the treatment of advanced Parkinson disease. Methods. Stereotactic coordinates of the STN were determined in 14 patients by using three different methods: direct identification of the STN on coronal and axial T2-weighted magnetic resonance (MR) images and indirect targeting in which the STN coordinates are referred to the anterior commissure—posterior commissure (AC—PC) line, which, itself, is determined either by using stereotactic ventriculography or reconstruction from three-dimensional (3D) MR images. During the surgical procedure, electrode implantation was guided by single-unit microrecordings on multiple parallel trajectories and by clinical assessment of stimulations. The site where the optimal functional response was obtained was considered to be the best target. Computerized tomography scanning was performed 3 days later and the scans were combined with preoperative 3D MR images to transfer the position of the best target to the same system of stereotactic coordinates. An algorithm was designed to convert individual stereotactic coordinates into an all-purpose PC-referenced system for comparing the respective accuracy of each method of targeting, according to the position of the best target. Conclusions. The target that is directly identified by MR imaging is more remote (mainly in the lateral axis) from the site of the optimal functional response than targets obtained using other procedures, and the variability of this method in the lateral and superoinferior axes is greater. In contrast, the target defined by 3D MR imaging is closest to the target of optimal functional response and the variability of this method is the least great. Thus, 3D reconstruction adjusted to the AC—PC line is the most accurate technique for STN targeting, whereas direct visualization of the STN on MR images is the least effective. Electrophysiological guidance makes it possible to correct the inherent inaccuracy of the imaging and surgical techniques and is not designed to modify the initial targeting.

Sign in / Sign up

Export Citation Format

Share Document