Convection-enhanced delivery into the rat brainstem

2002 ◽  
Vol 96 (5) ◽  
pp. 885-891 ◽  
Author(s):  
David I. Sandberg ◽  
Mark A. Edgar ◽  
Mark M. Souweidane
Keyword(s):  
Fluorescein Isothiocyanate ◽  
Volume Of Distribution ◽  
Convection Enhanced Delivery ◽  
Cross Sectional ◽  
Pontine Nucleus ◽  
Content Type ◽  
Distribution Parameters ◽  
Rat Brainstem ◽  
Cannula Placement ◽  
Fine Print

Object. Convection-enhanced delivery (CED) can be used safely to achieve high local infusate concentrations within the brain and spinal cord. The use of CED in the brainstem has not been previously reported and may offer an alternative method for treating diffuse pontine gliomas. In the present study the authors tested CED within the rat brainstem to assess its safety and establish distribution parameters. Methods. Eighteen rats underwent stereotactic cannula placement into the pontine nucleus oralis without subsequent infusions. Twenty rats underwent stereotactic cannula placement followed by infusion of fluorescein isothiocyanate (FITC)—dextran at a constant rate (0.1 µl/minute) until various total volumes of infusion (Vis) were reached: 0.5, 1, 2, and 4 µl. Additional rats underwent FITC—dextran infusion (Vi 4 µl) and were observed for 48 hours (five animals) or 14 days (five animals). Serial (20-µm thick) brain sections were imaged using confocal microscopy with ultraviolet illumination, and the volume of distribution (Vd) was calculated using computer image analysis. Histological analysis was performed on adjacent sections. No animal exhibited a postoperative neurological deficit, and there was no histological evidence of tissue disruption. The Vd increased linearly (range 15.4–55.8 mm3) along with increasing Vi, with statistically significant correlations for all groups that were compared (p < 0.022). The Vd/Vi ratio ranged from 14 to 30.9. The maximum cross-sectional area of fluorescence (range 9.8–20.9 mm2) and the craniocaudal extent of fluorescence (range 2.8–5.1 mm) increased with increasing Vi. Conclusions. Convection-enhanced delivery can be safely applied to the rat brainstem with substantial and predictable Vds. This study provides the basis for investigating delivery of various candidate agents for the treatment of diffuse pontine gliomas.

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

1999 ◽  
Vol 90 (2) ◽  
pp. 315-320 ◽  
Author(s):  
Michael Y. Chen ◽  
Russell R. Lonser ◽  
Paul F. Morrison ◽  
Lance S. Governale ◽  
Edward H. Oldfield
Keyword(s):  
Target Location ◽  
Regional Distribution ◽  
Small Animal ◽  
Volume Of Distribution ◽  
National Institutes Of Health ◽  
Convection Enhanced Delivery ◽  
Content Type ◽  
The Central Nervous System ◽  
Clinically Significant ◽  
Fine Print

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.

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.

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.

Application of magnetic resonance neurography in the evaluation of patients with peripheral nerve pathology

1996 ◽  
Vol 85 (2) ◽  
pp. 299-309 ◽  
Author(s):  
Aaron G. Filler ◽  
Michel Kliot ◽  
Franklyn A. Howe ◽  
Cecil E. Hayes ◽  
Dawn E. Saunders ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Time Course ◽  
Spin Echo ◽  
Fast Spin Echo ◽  
Mr Neurography ◽  
Magnetic Resonance Neurography ◽  
Cross Sectional ◽  
Content Type ◽  
Direct Nerve ◽  
Fine Print

✓ Currently, diagnosis and management of disorders involving nerves are generally undertaken without images of the nerves themselves. The authors evaluated whether direct nerve images obtained using the new technique of magnetic resonance (MR) neurography could be used to make clinically important diagnostic distinctions that cannot be readily accomplished using existing methods. The authors obtained T2-weighted fast spin—echo fat-suppressed (chemical shift selection or inversion recovery) and T1-weighted images with planes parallel or transverse to the long axis of nerves using standard or phased-array coils in healthy volunteers and referred patients in 242 sessions. Longitudinal and cross-sectional fascicular images readily distinguished perineural from intraneural masses, thus predicting both resectability and requirement for intraoperative electrophysiological monitoring. Fascicle pattern and longitudinal anatomy firmly identified nerves and thus improved the safety of image-guided procedures. In severe trauma, MR neurography identified nerve discontinuity at the fascicular level preoperatively, thus verifying the need for surgical repair. Direct images readily demonstrated increased diameter in injured nerves and showed the linear extent and time course of image hyperintensity associated with nerve injury. These findings confirm and precisely localize focal nerve compressions, thus avoiding some exploratory surgery and allowing for smaller targeted exposures when surgery is indicated. Direct nerve imaging can demonstrate nerve continuity, distinguish intraneural from perineural masses, and localize nerve compressions prior to surgical exploration. Magnetic resonance neurography can add clinically useful diagnostic information in many situations in which physical examinations, electrodiagnostic tests, and existing image techniques are inconclusive.

En bloc laminoplasty without dissection of paraspinal muscles

2005 ◽  
Vol 3 (1) ◽  
pp. 29-33 ◽  
Author(s):  
Noboru Hosono ◽  
Hironobu Sakaura ◽  
Yoshihiro Mukai ◽  
Takahiro Ishii ◽  
Hideki Yoshikawa
Keyword(s):  
Ct Scanning ◽  
Cord Compression ◽  
Neck Muscle ◽  
Open Door ◽  
En Bloc ◽  
Cross Sectional ◽  
Content Type ◽  
Spinous Processes ◽  
Significant Difference ◽  
Fine Print

Object. Although conducting cervical laminoplasty in patients with multisegmental cord compression provides good neurological results, it is not without shortcomings, including C-5 palsy, axial neck pain, and undesirable radiologically detectable changes. Postoperative kyphosis and segmental instability can cause neurological problems and are believed mainly to result from neck muscle disruption. The authors developed a new laminoplasty technique, with the aim of preserving optimal muscle function. Methods. The present technique is a modification of unilateral open-door laminoplasty. By using an ultrasonic osteotome in small gaps of muscle bellies, a gutter is made without disrupting muscles, spinous processes, or their connections on the hinged side. Ceramic spacers are then positioned between elevated laminae and lateral masses at C-3, C-5, and C-7 on the opened side, which is exposed in a conventional manner. This new procedure was used to treat 37 consecutive patients with compression myelopathy. Postoperative computerized tomography (CT) scanning revealed a significant difference in a cross-sectional area of muscles between the hinged and opened side. The mean follow-up period was 40.2 months (range 24–54 months). Changes in alignment were observed in only one patient, and vertebral slippage developed in two. Performed at regular intervals, CT scanning demonstrated that the elevated laminae remained in situ throughout the study period. Conclusions. In using the present unilateral open-door laminoplasty technique, deep extensor muscles are left intact along with their junctions to spinous processes on the hinged side. Radiologically documented changes were minimal because the preserved muscles functioned normally immediately after the operation.

A comparison of radiographic methods of diagnosing constrictive lesions of the spinal canal

1978 ◽  
Vol 48 (3) ◽  
pp. 360-368 ◽  
Author(s):  
M. Judith Donovan Post ◽  
Fredie P. Gargano ◽  
Donald Q. Vining ◽  
Hubert L. Rosomoff
Keyword(s):  
Computerized Tomography ◽  
Cross Section ◽  
Spinal Canal ◽  
Relative Effectiveness ◽  
Ct Scanning ◽  
New Method ◽  
Cross Sectional ◽  
Content Type ◽  
Sectional Anatomy ◽  
Fine Print

✓ With the advent of computerized tomography (CT), a new method of visualizing the spinal canal in cross-section has been created. Before the introduction of CT scanning, evaluation of the cross-sectional anatomy of the spinal canal was accomplished chiefly by the Toshiba unit. This study compares these two forms of tomography and discusses their relative effectiveness in diagnosing constrictive lesions of the spinal canal.

Stretching and breaking characteristics of cerebrospinal fluid shunt tubing

2003 ◽  
Vol 98 (3) ◽  
pp. 578-583 ◽  
Author(s):  
Daniel J. Tomes ◽  
Leslie C. Hellbusch ◽  
L. Russell Alberts
Keyword(s):  
Cerebrospinal Fluid ◽  
Applied Stress ◽  
Revision Surgery ◽  
Csf Shunt ◽  
Stress And Strain ◽  
Sectional Area ◽  
Cross Sectional ◽  
Content Type ◽  
Shunt Tubing ◽  
Fine Print

Object. Cerebrospinal fluid (CSF) shunt system malfunction due to silastic tubing fracture necessitates revision surgery in shunt-dependent individuals. The goal of this study was to examine the mechanical stretching and breaking characteristics of new and used CSF shunt tubing catheters to determine if any inherent physical properties predispose the tubing to fracture. Methods. Fifty-millimeter segments of new and retrieved (used) CSF shunt tubing were stretched to 120 mm in a hydraulic press to determine modulus values (modulus = stress/strain) and to measure permanent tubing deformation imparted by the applied stress and strain. Similar 50-mm tubing segments were also stretched in an electromechanical material testing system until fracture occurred; the force and strain needed to break the tubing was recorded at the time of failure. The results demonstrate that shunt tubing with a greater cross-sectional area requires greater force to fracture, and that catheters become weaker the longer they are implanted. Barium-impregnated shunt tubing, compared with translucent tubing, appears to require less applied stress and strain to break and may fracture more easily in vivo. The variety of modulus values obtained for the new catheters tested indicates that the various companies may be using materials of different quality in tubing manufacture. Conclusions. A CSF shunt catheter design that incorporates tubing with a greater cross-sectional area may lead to fewer fractures of indwelling catheters and a reduction in shunt revision surgery.

The suboccipital cavernous sinus

1997 ◽  
Vol 86 (2) ◽  
pp. 252-262 ◽  
Author(s):  
Kenan I. Arnautović ◽  
Ossama Al-Mefty ◽  
T. Glenn Pait ◽  
Ali F. Krisht ◽  
Muhammad M. Husain
Keyword(s):  
Cavernous Sinus ◽  
Internal Carotid ◽  
Microsurgical Anatomy ◽  
Transverse Foramen ◽  
Cross Sectional ◽  
Anatomical Structures ◽  
Content Type ◽  
Arterial Walls ◽  
Pathological Conditions ◽  
Fine Print

✓ The authors studied the microsurgical anatomy of the suboccipital region, concentrating on the third segment (V3) of the vertebral artery (VA), which extends from the transverse foramen of the axis to the dural penetration of the VA, paying particular attention to its loops, branches, supporting fibrous rings, adjacent nerves, and surrounding venous structures. Ten cadaver heads (20 sides) were fixed in formalin, their blood vessels were perfused with colored silicone rubber, and they were dissected under magnification. The authors subdivided the V3 into two parts, the horizontal (V3h) and the vertical (V3v), and studied the anatomical structures topographically, from the superficial to the deep tissues. In two additional specimens, serial histological sections were acquired through the V3 and its encircling elements to elucidate their cross-sectional anatomy. Measurements of surgically and clinically important features were obtained with the aid of an operating microscope. This study reveals an astonishing anatomical resemblance between the suboccipital complex and the cavernous sinus, as follows: venous cushioning; anatomical properties of the V3 and those of the petrous—cavernous internal carotid artery (ICA), namely their loops, branches, supporting fibrous rings, and periarterial autonomic neural plexus; adjacent nerves; and skull base locations. Likewise, a review of the literature showed a related embryological development and functional and pathological features, as well as similar transitional patterns in the arterial walls of the V3 and the petrous-cavernous ICA. Hence, due to its similarity to the cavernous sinus, this suboccipital complex is here named the “suboccipital cavernous sinus.” Its role in physiological and pathological conditions as they pertain to various clinical and surgical implications is also discussed.

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.

Safety and efficacy of convection-enhanced delivery of gemcitabine or carboplatin in a malignant glioma model in rats

2003 ◽  
Vol 99 (5) ◽  
pp. 893-898 ◽  
Author(s):  
Jeffrey W. Degen ◽  
Stuart Walbridge ◽  
Alexander O. Vortmeyer ◽  
Edward H. Oldfield ◽  
Russell R. Lonser
Keyword(s):  
Chemotherapeutic Agents ◽  
Saline Control ◽  
Convection Enhanced Delivery ◽  
Term Survival ◽  
Similar Treatment ◽  
Safety And Efficacy ◽  
Content Type ◽  
Glioma Model ◽  
9L Glioma ◽  
Fine Print

Object. Convection-enhanced delivery (CED) can be used safely to perfuse regions of the central nervous system (CNS) with therapeutic agents in a manner that bypasses the blood—brain barrier (BBB). These features make CED a potentially ideal method for the distribution of potent chemotherapeutic agents with certain pharmacokinetic properties to tumors of the CNS. To determine the safety and efficacy of the CED of two chemotherapeutic agents (with properties ideal for this method of delivery) into the CNS, the authors perfused naive rats and those harboring 9L gliomas with carboplatin or gemcitabine. Methods. Dose-escalation toxicity studies were performed by perfusing the striatum (10 µl, 24 rats) and brainstem (10 µl, 16 rats) of naive rats with carboplatin (0.1, 1, and 10 mg/ml) or gemcitabine (0.4, 4, and 40 mg/ml) via CED. Efficacy trials involved the intracranial implantation of 9L tumor cells in 20 Fischer 344 rats. The tumor and surrounding regions were perfused with 40 µl of saline (control group, four rats), 1 mg/ml of carboplatin (four rats), or 4 mg/ml of gemcitabine (four rats) 7 days after implantation. Eight rats harboring the 9L glioma were treated with the systemic administration of 60 mg/kg of carboplatin (four rats) or 150 mg/kg of gemcitabine (four rats) 7 days postimplantation. Clinical, gross, and histological analyses were used to determine toxicity and efficacy. Toxicity occurred in rats that had received only the highest dose of the CED of carboplatin or gemcitabine. Among rats with 9L gliomas, all control and systemically treated animals died within 26 days of tumor implantation. Long-term survival (120 days) and eradication of the tumor occurred in both CED-treated groups (75% of rats in the carboplatin group and 50% of rats in the gemcitabine group). Furthermore, animals harboring the 9L glioma and treated with intratumoral CED of carboplatin or gemcitabine survived significantly longer than controls treated with intratumoral saline (p < 0.01) or systemic chemotherapy (p < 0.01). Conclusions. The perfusion of sensitive regions of the rat brain can be accomplished without toxicity by using therapeutic concentrations of carboplatin or gemcitabine. In addition, CED of carboplatin or gemcitabine to tumors in this glioma model is safe and has potent antitumor effects. These findings indicate that similar treatment paradigms may be useful in the treatment of glial neoplasms in humans.

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