Harry S. Goldsmith

Axonal regeneration after spinal cord transection and reconstruction

Following complete transection of the spinal cord, cats were separated into 2 groups to undergo: (i) surgical reconstruction of the disconnected cord using a neuroactive agent mixed into a collagen matrix bridge and omental transposition and (ii) cord transection-only. After 90 days, animals were killed and the brain and spinal cord were removed for immunohistochemistry. Two weeks prior to sacrifice, spinal cord blood flows were measured and the retrograde axonal tracer Fluoro-Gold was injected below the transection site. Gross inspection of the spinal cords at autopsy showed excellent integration and continuity of the collagen matrix bridge with the proximal-distal stumps in the surgical reconstruction group. In the transection-only group, the proximal-distal stumps were connected by a fibrotic, often tapered in the middle, tissue bridge. Results show that omental transposition in the surgical reconstruction group increased spinal cord blood flow by 58% when compared to transection-only animals. Fluoro-Gold was found in mesencephalic and brainstem catecholaminergic and cholinergic neurons known to send axons to the spinal cord. Immunohistochemical staining with antibodies against catecholamine synthesizing enzymes tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) showed that surgical reconstruction treated cat cords but not transection-only, developed dense bundles of dopaminergic and noradrenergic fibers which were present in the collagen matrix bridge and in the distal spinal cord. Extension of these catecholaminergic fibers in surgical reconstruction treated cats showed maximal outgrowth of 90 mm below the transection site when the neuroactive agent 4-aminopyridine was mixed into the collagen matrix. In addition, the synaptogenic marker synaptophysin (SYN) was observed on preganglionic sympathetic neurons in association with dopaminergic- and noradrenergic-containing varicosities distal to the collagen matrix bridge, an indication that neo-synaptic contacts may have been made on these previously denervated neurons. No TH, DBH or SYN was observed below the transection site in transection-only cats. These findings indicate that surgical reconstruction treated cords can develop dense supraspinal fiber outgrowth across a treated collagen matrix bridge fed by an omental blood supply and that these fibers may have made neo-synaptic contacts with appropriate distal spinal cord target tissue.

Brain and spinal cord revascularization by omental transposition

It has been learned over the years that placement of the pedicled omentum onto the brain and the spinal cord results in the rapid development of blood vessels that penetrate directly, vertically and deeply into the underlying CNS structure. Rapid clinical changes in some patients following omental transposition to the CNS raised the question as to whether the changes might be due not only to increased vascular perfusion, but to neurochemicals within omental tissue. Subsequent studies have shown that the omentum incorporates in its tissue neurotransmitters, nerve growth substances, gangliosides and angiogenic factors of high activity. These neurochemical and angiogenic substances are undoubtedly involved in some manner in the ability of axons in a transected spinal cord to grow at 1 mm/day and apparently make appropriate connections with distal spinal cord target tissue.

Collagen-omental graft in experimental spinal cord transection

SummarySpinal cord transection was induced in 3 groups of cats. The gap was surgically reconstructed using a collagen matrix bridge (Group COL), collagen matrix + pedicled omentum graft (Group COM), or gelfoam (Group GEF). After a variable observation period, animals underwent distal cord horse-radish peroxidase (HRP) injections, somatosensory evoked potentials recordings and polarographic measurement of local spinal cord blood flow (lSCBF) using the hydrogen clearance technique. The cord tissue was removed for histologic and immunohistochemical analysis.Results showed retrograde HRP labelling of proximal segmental cord neurons and somatosensory evoked potentials were present in group COM but not in COL or GEF treated animals. Local SCBF was 66% and 87% higher in COM than COL or GEF animals respectively but this increase could be reversed if flow from the pedicled omentum was clamped-off. Histologic examination of cord tissue after 45 days revealed the presence of catecholaminergic axons distal to the transection site in COM but not COL or GEF groups. Moreover, after 90 days, the rate and density of tyrosine hydroxylase immunoreactive (TH-IR) axons was 10-fold higher in COM than COL group and this was accompanied by a proportionate increase in the vascular density between the two groups. GEF treated animals showed no regeneration of transected fibers and poor blood flow pattern. These findings indicate that the placement of a pedicled omentum on a collagen matrix bridge results in near restoration of normal SCBF to the reconstructed cord region and is associated with marked regeneration of axons below the lesion site.

Regional cerebral blood flow after omental transposition to the ischaemic brain in man. A five year follow-up study.

SummaryRegional cerebral blood flow, recorded by the133Xenon inhalation method, was measured preoperatively and over a five years postoperative period in six patients with completed stroke and stabilized neurological deficits, who had undergone omental transposition for revascularization of the ischaemic brain. Comparisons of the preoperative blood flow values with those recorded following surgery demonstrate a postoperative increase of blood flow in five patients, with a high statistical degree of significance in four of them at the final examination. The flow increase was noted over the infarcted areas of the brain, upon which the omentum had been placed, as well as areas of the ischaemic hemisphere without omental placement and the contralateral hemisphere. Out of the five patients who demonstrated preoperative flow values below the expected norm for age, four showed final postoperative cerebral blood flow within the normal limits for their age. The results are consistent with the assumption that the transposed omentum played a role in postoperative blood flow increase, by adding collateral circulation to the ischaemic brain.

Omental transposition for Alzheimer’s disease

A patient with Alzheimers disease of long standing was treated with omental transposition to his brain. The rational for the procedure was to use the omentum to increase cerebral blood flow and to augment cholinergic neurotransmission activity. The patient improved for a year following surgery but after that time slowly began to decline neurologically and cognitively. However, according to Alzheimers specialists who have followed the patient pre and postoperatively, he still maintains, 2.5 years after surgery, a higher level of performance than expected. There is theoretical and now a clinical suggestion that the omentum might play some role in the treatment of Alzheimers disease. In view of the devastating nature of the disease, it seems reasonable to suggest that a limited controlled study be carried out to support or negate the benefit of the operation.

Vasoactive Neurochemicals Identified in Omentum: A preliminary report

There has been increasing interest in biologic, immunologic, and chemical activity originating from omental tissue. Since clinical improvement has been observed in some patients very shortly after surgically transposing their omentum to the spinal cord or brain, the question arose as to whether neurochemicals might be present in omental tissue; a possible explanation for some of these neurological changes. This paper reports the presence of vasoactive neurochemicals in canine omental tissue. It remains unclear, however, whether the omentum produces or simply concentrates these and other neurochemicals.

Choline Acetyltransferase Activity in Omental Tissue

Choline acetyltransferase (ChAT), the enzyme responsible for the formation of ACh from choline and acetyl-coenzyme A, is a marker of cholinergic function and is significantly depressed in the brains of Alzheimer patients. It has been shown that omental tissue contains several neuroactive substances and causes revascularization when placed upon the brain of stroke patients. In this study, it was demonstrated that omental tissue exhibits specific ChAT activity. This activity was choline-dependent, inhibited by N-ethylmaleimide (a known ChAT inhibitor), and was characterized by kinetic parameters consistent with values for the neuronal enzyme. It is suggested that omental placement to the brain together with oral choline administration might prove to be useful for increasing ACh synthesis in Alzheimers disease.

Increased blood flow enhances axon regeneration after spinal transection.

It is not known whether increasing the amount of blood flow to axotomized fibers in mammalian CNS can result in more robust sprouting. To find out, an intact pedicled omentum was surgically transposed to cover a collagen matrix gel used to bridge the transected cat spinal cord stumps. Control animals were similarly treated but did not receive the pedicled omentum. Twelve weeks after cord transection, animals receiving the pedicled omentum showed a 66% spinal cord blood flow increase over animals that did not. Moreover, treatment with the pedicled omentum increased the density of regenerating adrenergic axons 10-fold over the control group. These findings indicate that boosting flow with an omental graft to the collagen bridge site results in robust axonal outgrowth of spinal transected nerve fibers.

Early application of pedicled omentum to the acutely traumatised spinal cord

Placement of the intact omentum upon a recently traumatised spinal cord was found to be effective in lessening motor and neuroelectrical dysfunction in a group of cats. It was theorised that the beneficial effect of omental transposition was due to the establishment of a dynamic equilibrium between production of vasogenic oedema from the injured cord and its absorption through omental pathways. Removing vasogenic oedema at the omental I spinal cord interface is hypothesised to stabilise a rising tissue pressure within the cord during the acute phase of injury and at a later date to decrease scar formation at the injury site.

Experimental studies of omentum-derived neurotrophic factors

Experimental and clinical evidence continues to accumulate regarding the beneficial effects of omental placement upon the brain and spinal cord for repair of apparently irreversible injuries. Of particular interest have been the rapid neurological changes observed 24 h to several days following omental transposition in some stroke patients with long-standing motor and speech deficits (1). The observation that these changes could occur years after a stroke raised the possibility that omental tissue might contain neurotrophic factors that facilitate regenerative and possibly synaptogenic events in the central nervous system.