COMPONENT MECHANISMS IN SPINAL CORD INJURY
- AN ANIMAL MODEL FOR DRUG TREATMENT PROTOCOLS -

G.M. McNeice (1), W.A. Lee (1), K.C. Lennon (1), C.D. Riddle (1), R.L. Ferguson (1), M. LaBerge (2)
(1) Greenville Hospital System Medical Education & Research,
(2) GHS/Clemson University
Biomedical Cooperative, Greenville, S.C. 29605, USA

Presented at the 20th Annual Meeting of the American Society of Biomechanics
Atlanta, Georgia. October 17-19, 1996

INTRODUCTION

Spinal cord injury models continue to be used to study the pathophysiology of injury and the potential of various therapeutic treatments. Recent NIH (Young et. al., 1995) supported studies have aimed at standardizing the impact trauma to the cord in the rat model. The present authors have discussed some potential errors inherent in the NYU proposed model (McNeice et. al., 1994, 1995) and introduced a refined rat model using a miniature accelerometer that allows the biomechanics of the impact to be established. The NYU model excludes the effect of cord compression on the neurologic deficit, a factor often seen in human injuries. The present study demonstrates the successful application of this refined model to drug therapy of the impacted cord as well as introduces an extension of the model to include the effects of cord compression. Compression levels of 65% and 85% are demonstrated.

REVIEW AND THEORY

Clinical and animal studies have indicated that early treatment using glucocorticoids may lessen the degree of neurologic deficit. This has led to a current national emergency treatment protocol that requires the administration of methlyprednisolone (MP) within eight hours of the trauma. Although MP has been shown to reduce neurologic deficit in laboratory animals, it has only been marginally effective in clinical studies. There are many contributing factors including dosage, time of administration and the degree of injury to the cord. In attempts to study these factors, many researchers continue to use animal models to establish drug type and dosage. These models use various methods to traumatize the cord such as direct impact, clip compression or static compression. In all cases, the cord is free to return to its original anatomical shape following the trauma. In the case of human injuries, this seldom happens. In addition to the impact force, permanent cord compression caused by bony fragments (burst), canal compromise (bilateral facet dislocation) or other residual deformation effects contribute to the degree of injury. With regard to the selection of drug type and treatment protocols, how do these factors affect the ultimate performance and efficacy of the drug selected? The animal model should be capable of addressing each factor separate as well as in combination.

MODEL AND PROCEDURES

In this ongoing study the authors have established an animal model that will address the following component mechanisms of spinal cord injury:

A. Instantaneous Impact without Compression

B. Compression followed by Decompression

C. Permanent Compression

D. Combined Impact and Compression

The model makes use of the rat with cannulation of the jugular for placebo and drug delivery, and a refined drop mass impact trauma device with a miniature accelerometer that allows full biomechanical impact analysis at the cord interface. To provide cord compression, cylindrical metal rod implants of different diameters (1.6 & 2 mm dia., referenced as R1.6 & R2.0) were designed and placed extradurally to span the partial laminectomy at the T9 vertebra. Neurological deficit was assessed using an extended Tarlov hind limb motor response scale. Sequential video records were kept of each animal and its ability to ambulate, up to six weeks post injury. These tapes allowed multiple trained personnel, blinded to the study, to evaluate the output from the model.

APPLICATION

Application has been made to mechanism A using methylprednisolone (MP) with trauma levels between 40 and 60 gm. cms. of absorbed energy (McNeice et al.,1994). Twenty seven (27) Long Evan hooded rats were studied. Thirteen (13) received placebo (sterile saline) and fourteen (14) MP. Total drug/placebo dosage of 150 mg/kg was administered to each of the 27 animals. This dosage is similar to the approved ER protocol used in most states. A bolus of 60 ml/kg was delivered over a one minute time interval and within two minutes of the trauma. Additional injections of 30 mg/kg were derived at 2, 4, and 6 hours post-trauma. Application was made to Category B without drug treatment. Both immediate (10 R1.6 & 3 R2.0) and subsequent decompression (4 R1.6 & 0 R2.0) were studied on seventeen (17) animals. Application was made to mechanism C without drug treatment. Permanent compression was studied on 24 animals (14 R1.6 & 10 R2.0). Studies of mechanism D are ongoing.

RESULTS AND DISCUSSION

Results from mechanism A indicate that early (5 min. post injury) administration of MP does have a positive effect (recovery to 70% normal compared to 50% normal without MP using the Wilcoxon rank sum test, p=.04). Preliminary results from mechanisms B and C, in the form of mean and standard deviation, are presented in Figure 1. Results from mechanism B (see Figures 1 & 2) indicate that for 65% cord compression, immediate or subsequent total decompression does result in hind limb functional recovery up to as much as 80% of normal. However, immediate decompression of an 85% compressed cord as seen in Figure 1 showed no recovery above 30% of normal. Preliminary results from mechanism C indicate that permanent 65% cord compression caused 50% deficit levels (Figures 1 & 2) while 85% cord compression (Figure 1) causes severe deficit (30% normal). Additional studies involving MP in mechanisms A through D are ongoing.

Figure 1: Effect of Cord Compression on Motor Responses.

Figure 2: 65% Spinal Cord Compression (Typical).

REFERENCES

McNeice G.M. et al. A refined spinal cord contusion device with measurement at the impact interface. Twelfth Annual Neurotrauma Symposium, Miami Beach, Florida, November 12-13, 1994

McNeice G.M. et al. Example of the "Trauma Window" for SCI Research with Application to a Refined Impact Interface Spinal Cord Contusion Device, 3rd International Neurotrauma Symposium, Toronto, Ontario, July 1995.

Young W et al. Phamacological Treatment of spinal Cord Injury - Experimental and Clinical Studies, 3rd International Neurotrauma Symposium, Toronto, Ontario, July 1995.

ACKNOWLEDGMENTS

Appreciation is expressed to Clemson University faculty and staff at the Godley Snell Research Center and the GHS/CU Biomedical Cooperative for their continuing assistance and support of this study.