Pathophysiology of Spinal Cord Injury

One of the most important factors associated with an SCI is the production of vasogenic edema and extravasated blood that occurs rapidly at the site of the injury. A traumatized SC decreases the amount of localized edema that accumulates at the site of the injured SC by the dynamic movement of the fluid up and down the SC.¹ This compensatory action within the SC, however, usually is inadequate to decrease the high interstitial pressure that is caused by fluid accumulation at the site of the SCI. The swelling of the SC caused by this fluid accumulation continues within the confines of the nonyielding dura mater and the rigid spinal canal. When the interstitial pressure within the SC becomes excessive due to swelling, venous compression results. This action results in an elevated upstream venous pressure, which further enhances the capillary extrusion of blood from the porous blood vessels at the injury site. This situation causes an increase in focal osmotic pressure, which leads to a further increase in fluid accumulation. The high interstitial pressure within the SC also compresses small capillaries in the region of the SCI, which can lead to the progressive loss of capillary perfusion. This eventually can lead to complete blockage of vascular flow, causing the destruction of viable neural tissue in the area of the SC impaction.

Over the years, surgeons dealing with SCIs have appreciated the dangers of a high interstitial pressure occurring in an injured SC. This concern prompted the development of two surgical procedures—laminectomy and myelotomy—to lower the high interstitial pressure at the site of an SCI. Because the results of these attempts were unpredictable, however, they were not often used. A probable cause of these surgical failures was the inability of either operation to absorb the edema and blood accumulation that routinely develop at the site of an SCI.

The inability of edema fluid and blood to be absorbed at the site of an SCI is due to the absence of a lymphatic system in the SC. Without the absorbing mechanisms of a lymphatic system, edema fluid and blood remain at the SCI site, and the fluids eventually result in fibrosis scarring. This scarring is thought to be caused by the fibrinogen that is present in the blood that leaks from injured SC blood vessels. The fibrinogen apparently becomes activated at the SC injury site to make fibrin scar, which causes compression on blood vessels, a decrease in SC blood flow, and the blockage of axons from penetrating through the tissue (Fig. 121-1).

FIGURE 121-1 Spinal cord injury (450 g/cm weight injury) 1 month postoperatively. Note surface and circumferential scarring. Persistence of edema fluid also present.

If healing of an acute SCI is to take place, it would appear that action should be undertaken as early as possible after injury to limit edema and blood accumulation resulting from the SCI. It has been shown that if an intact omentum pedicle is placed directly on an SC shortly after injury, absorption of edema and blood can be accomplished with little, if any, fluid accumulation or scar formation (Fig. 121-2), due to the enormous ability of the omentum to absorb fluids.^2,3 Placing the omentum directly on an injured SC apparently establishes a dynamic equilibrium between the production of blood and edema by the traumatized SC and the absorption of these fluids by the overlying omentum. Such absorption by the omentum not only decreases interstitial pressure in the area of the SCI, but, most importantly, its absorptive capability decreases the amount of blood (fibrinogen) in the injured area, thereby lessening the potential for scar formation at the injury site.

FIGURE 121-2 Omentum placed on injured spinal cord (SC; 450 g/cm weight injury) 3 weeks following injury. Note the complete adherence of the omentum to the SC with no presence of fibrosis or fluid accumulation.

To apply the omentum directly onto an SCI location, a laminectomy is required, followed by opening of the dura mater. These maneuvers alone have a beneficial effect on an SCI, because they allow the injured SC to expand, thereby lowering the high interstitial pressure in the SC, which promotes capillary perfusion to increase in the area of the SC injury. It cannot be overemphasized that in an acute SC it is not sufficient to simply surgically stabilize the vertebral column. It appears to be necessary to open the dura mater and treat the SC directly by applying the omentum onto the injured SC, thus allowing edema absorption. This procedure must be done shortly after injury (within a few days), because a fibrotic process begins within a week of injury.

Spinal Cord Revascularization

As with any type of wound, adequate blood supply to the involved area is essential to optimize healing. Research has shown that when the omentum is laid directly on an injured SC, vascular connections penetrate from the omentum into the SC within hours.⁴ This ability to revascularize the SC by the omentum was clearly proven by injecting India ink into an artery located within an intact omental pedicle that had been placed directly on a normal SC. The injected dye marker was subsequently observed on the surface of the SC, as well as in the deepest positioned capillaries that are located within the SC. It subsequently was observed in laboratory animals that omental blood vessels revascularize the SC rapidly and that a sizeable amount of blood was delivered to an uninjured SC through these omental vessels. The revascularization process was found to be even more rapid when the omentum was placed directly on an injured SC (Fig. 121-3). It is important, however, that the omentum be placed on the SCI as early following the injury as clinically possible.⁵

FIGURE 121-3 Early revascularization of the spinal cord (SC) is already apparent 50 hours following a 450-g/cm weight injury to the SC in a cat. Blood vessels originating from the omentum are clearly seen connecting to the SC.

Spinal Cord Scarring

Clinical SCI research today is aimed primarily at determining how to improve treatment results. This is of critical importance because there has been no significant improvement in the surgical approach to such injuries over the years. It has been found, however, that absorption of blood and edema by the omentum at the site of an SCI in animals has led to functional improvement, suggesting that this approach might have a comparable beneficial effect in humans.

It is known that in animals with an acute SCI, laying an omental pedicle graft on an injured SC facilitates the absorption of blood and edema.⁶ The importance of this absorptive capability is that it impedes the development of scar tissue, a step that appears to be critical in preventing the evolution of scarring in the injured SC. The idea that scar tissue markedly hinders SCI improvement is not new. Ramon y Cajal claimed over 100 years ago that functional regeneration in the SC could be accomplished if physical obstacles to central neuritic outgrowth could be removed.⁷ The critical significance of scar being the physical obstacle preventing axons from penetrating through scar tissue was later brought into clearer focus by the work of Freeman at the University of Indiana in the 1950s. He clearly demonstrated that scar tissue at an SCI site prevented axons from penetrating through and making connections with neural structures in the caudal cord. Freeman wrote “that axons have a relentless compulsion to grow until they participate in return of function. If axonal regrowth is blocked by scar tissue, axons continue to grow in circles to form neuromata.”⁸ Cajal’s and Freeman’s observations strongly indicate that if scar can be eliminated from the healing process within an injured SC, functional and neuroelectrical improvement might well occur.

There appears to be no question that adequate blood supply and prevention of scar formation are crucial if SC healing is to take place. As far as revascularization is concerned, the ability of the omentum to carry out increased angiogenic activity in any area of the body is well known, especially since it has been shown that the highest concentration of vascular endothelial growth factor, the most angiogenic substance in the body, is in omental tissue.⁹ Although revascularization of an injured SC obviously is important, scarring within the SC may well turn out to be the critical issue if SC healing is to occur.

The importance of eliminating SC scarring was clearly shown in a group of cats who had their SCs and dura mater totally transected at the T9 level. The transection resulted in an SC separation of 3 to 6 mm due to the elasticity of the SC. The stumps of the divided SCs were irrigated with iced saline to reduce the axoplasmic extrusion that routinely occurs following an SC transection. The gap between the divided ends of the SC was filled with collagen gel dispensed through a syringe. The collagen gel was allowed to harden for approximately 40 minutes, after which an intact pedicled omentum was placed directly on top of the collagen bridge and on the ends of the rostral and caudal SC stumps.

Blood flow measurements in the SC of animals with the omental-collagen bridge and in control animals were taken just before sacrifice, 90 days after surgery. The SC blood flow in omental-collagen animals demonstrated a 59% increase compared with the SC blood flow in normal (nontransected) control animals.¹⁰ Also noted was a 3-to-1 increase in the blood vessel density counts in the omental-collagen–treated cats as compared with normal controls.¹¹

Of particular importance in the omental-collagen bridge animals was the presence of dopaminergic and noradrenergic fibers that penetrated through the biodegrading collagen bridge with continued growth of the fibers into the distal SC stump¹² (Fig. 121-4). The axons were found to have grown at a rate of 1 mm per day for a maximum distance of 90 mm during the cats’ 12-week recovery period. This penetration of axons occurred because of the absence of scar tissue.

FIGURE 121-4 Axons are seen exiting from the distal end of the biodegrading omental-collagen bridge. Axons continue to grow into the distal spinal cord at the rate of 1 mm/day.

The finding that axons grew through the omental-collagen preparation was considered extremely important, but it was necessary to demonstrate whether these penetrating axons actually made synaptic connections with distal neural elements. Such penetration and connections of these axons were proven to occur by the use of the axonal marker hydroxystilbamidine (Fluoro-Gold; Fluorochrome, LLC, Denver, CO). When this dye marker was injected into the distal SC of a normal cat, the dye followed a retrograde axonal pathway up to the brain and was clearly seen in the cytoplasm and processes of neurons located in the locus coeruleus, subcoeruleus, Kolliker-Fuse nucleus, and substantia nigra. However, when cats simply had their SCs transected, the injection of Fluoro-Gold into their SCs caudal to the transection did not travel retrograde up axonal pathways toward the brain and was never observed in various locations within their brains. In contrast, when Fluoro-Gold was injected into the distal SC of cats in the presence of an omental-collagen bridge created after SC transection, Fluoro-Gold was found in the brain in the same locations as the injected Fluoro-Gold found in the brains of nontransected animals¹³ (Fig. 121-5).

FIGURE 121-5 Retrograde axonal labeling by Fluoro-Gold shows marker in locus coeruleus neurons. Fluoro-Gold was injected in the caudal spinal cord (SC) 2 weeks before the animal’s sacrifice 90 days after omental-collagen bridging of a transected SC.

Histologic studies of the SCs of animals that had undergone omental-collagen reconstruction following SC transection were carefully evaluated. They showed that following the exposure of these SCs to the synaptogenic marker synaptophysin, this marker was found adjacent to preganglionic synaptic neurons located rostral and caudal to the omental-collagen bridge.¹¹ This finding indicated that synaptic remodeling (regeneration) by previously denervated supraspinal axons had occurred. Both the Fluoro-Gold and synaptophysin observations strongly suggested that following complete SC transection in cats, an omental-collagen bridge inserted at an SC transection site allowed disconnected supraspinal fibers to regenerate over long distances and apparently engage in synaptic remodeling with target tissue located at a distant site.

It is uncommon to encounter a patient with a transected SC. Interestingly, however, several years after successful omental-collagen bridging in transected SCs in animals, a 23-year-old woman who had suffered an SCI in a high-speed skiing accident 3 years earlier was treated with this technique. An MRI taken shortly after that injury showed a complete anatomic transection of her SC at the T6-7 level (Fig. 121-6). Over the next 3 years she continued to exhibit complete motor and sensory loss below this level.

FIGURE 121-6 MRI taken shortly after injury reported as complete anatomic transection at the T6-7 level (arrow).

At 39 months after injury, the patient underwent reconstruction of her separated SC using the same operation that had been successfully used in cats, the omental-collagen bridge technique. At operation, a massive block of scar tissue was present between T6 and T8, resulting from the fibrotic reaction that had developed between the separated stumps of the SC. The scar tissue was surgically removed, which left an extremely large SC separation of 1.6 inches (4 cm). This defect was filled with 5 cc of collagen gel, followed by the direct application of an overlying omental pedicle onto the underlying collagen bridge.

Over the next several years, the patient regained extensive motor activity following intensive physical therapy. At the end of 4 years she could walk, but required the use of a walker (Fig. 121-7). Serial MRIs were taken of her SC on a yearly basis, and after 4 years the separated SC on MRI examination was shown to have anatomically reconstructed itself in an incontinuity longitudinal connection (Fig. 121-8). This case has been carefully documented.¹⁴

FIGURE 121-7 The patient was able to walk for long distances but required a walker because her balance did not return.

FIGURE 121-8 MRI study at 4 years after surgery showed healing of the omental-collagen bridge into a longitudinal structure connecting to the proximal and distal ends of the previously transected spinal cord.

Summary

The aim of SCI research and clinical care is to find new approaches that will improve the functional outcome of patients with an SCI.⁶ An adequate blood supply is necessary for healing of an SCI to take place. Such an additional source of blood for a healing SCI can be provided by placing an omental pedicle on an acute SCI. Of even greater importance in improving the treatment of an SCI is finding a way to limit the production of scar tissue within the SC following an SCI. Such scar tissue has been known for many years to be a major physical obstacle that prevents axons from penetrating through the scar. Such action blocks connections of axons to neural tissue in the distal SC. Because the omentum can revascularize the SC and limit scarring within the SC, it seems possible that it would improve the results following surgical treatment of an acute SCI. It seems reasonable to suggest that clinical evaluation of omental transposition be undertaken, because its success could generate the clinical improvement that we continue to seek for patients who sustain an SCI.