Background: The spinal cord often responds to injury with profound loss of neural tissue and functional capacity. The incidence of spinal cord injury is approximately 12,000 new cases per year with a prevalence of 240,000 chronic cases in the United States, ~22% of which are currently veterans. Veterans represent a high proportion of these chronic spinal cord injury cases relative to the general population due to the hazardous nature of combat-related activities. The condition is particularly devastating because young soldiers are predominantly affected and irreversible paralysis may last for many decades of life. Therefore, an important goal of rehabilitation following spinal cord injury is to increase neuromuscular strength and function and reduce healthcare dependence. At present, only methylprednisolone has been shown to have efficacy in humans for spinal cord injury. Although methylprednisolone can improve locomotor function, recovery is modest and treatment must begin within, but not after, 8 hours following injury. A high dosage regimen is recommended, which may cause myopathy as well as suppression of immunological function and consequent infection. Because of these limitations, additional or alternative countermeasures that can be used to treat spinal cord injuries due to combat-related activities are needed.

Potentially superior countermeasures are available, but they require a demonstration of efficacy in an appropriate animal model of spinal cord injury before use in patient trials. The proposed studies are based on preliminary data in which x-irradiation of the injury site increased locomotor function following spinal cord injury. Targeted x-irradiation can now be delivered with precision by stereotactic irradiation procedures that shape the radiation beam to the target. This allows avoidance of radiation injury to surrounding tissues and uninjured portions of the spinal cord, so that irradiation of the minimum volume of injured spinal cord necessary for optimal therapeutic benefit can be achieved. Because of the precision of stereotactic x-irradiation compared to conventional x-irradiation, the optimal dimensions of the spinal cord target volume with respect to the contusion epicenter, e.g., rostral vs. causdal, can be investigated. Although other agents have been demonstrated to have some benefit in various studies of spinal cord injury, only x-irradiation ensures complete penetration of the therapeutic agent into injured spinal cord tissue.

Objective: The purpose of these studies is to demonstrate the efficacy of treatment with stereotactic x-irradiation of the injury site for improving recovery from contusion of the spinal cord in an established model of spinal cord injury. Stereotactic x-irradiation also will be used in combination with methylprednisolone, the only approved treatment for spinal cord injury, to determine whether there is greater benefit. The results from these studies will be used to design clinical trials with combined stereotactic x-irradiation and methylprednisolone treatment. In addition, the role of angiogenesis and tissue perfusion in improved recovery by stereotactic x-irradiation will be investigated.

Specific Aims: (1) To determine the optimum conditions for opposing loss of locomotor function following contusion injury in rats with stereotactic x-irradiation used alone and in combination with methylprednisolone. A model of graded contusion injury used in the Multicenter Animal Spinal Cord Injury Study (MASCIS) will be examined. Locomotor function will be evaluated at weekly intervals for 6 weeks with the 21-point BBB scale (MASCIS). The dimensions of the minimum target volume with respect to the contusion epicenter and the therapeutic time-window for improving locomotor function with stereotactic x-irradiation will be examined. Finally, the combined effectiveness of the optimized treatment with both stereotactic x-irradiation and methylprednisolone will be determined. (2) To determine the extent to which treatment with stereotactic x-irradiation alone and in combination with methylprednisolone spares spinal cord white matter following contusion. Quantitative histomorphometric measurements of sparing of white matter at the lesion site will be determined and correlated with the extent of recovery of locomotor function (BBB score), as well as hindlimb muscle atrophy. (3) To investigate the mechanisms by which stereotactic x-irradiation improves recovery of locomotor function following contusion injury. The ability of stereotactic x-irradiation to stimulate angiogenesis and improve tissue perfusion following spinal cord injury will be examined.

Study Design: A model of graded contusion injury used in the MASCIS will be examined. Locomotor function will be evaluated at weekly intervals for 6 weeks with the 21-point BBB scale (MASCIS). Because of the precision of stereotactic x-irradiation compared to conventional x-irradiation, the optimal dimensions of the spinal cord target volume with respect to the contusion epicenter, e.g., rostral vs. causdal, will be investigated. Quantitative histomorphometric measurements of sparing of white matter and angiogenesis, tissue oxygenation, and permeability of the blood spinal cord barrier at the lesion site will be determined and correlated with the extent of recovery of locomotor function (BBB score), as well as hindlimb muscle atrophy as the injury progresses.

Relevance: Optimization of stereotactic x-irradiation treatment may lead to a therapeutic modality for spinal cord injury suitable for use in battlefield conditions.