Nitric oxide as a mediator of nucleus pulposus-induced effects on spinal nerve roots.

Nerve root dysfunction and sciatic pain in disc herniation are considered to be caused by mechanical compression and related to the presence of nucleus pulposus in the epidural space. Autologous nucleus pulposus has been shown to induce endoneural edema and to decrease nerve-conduction velocity in spinal nerve roots in experimental disc herniation models, and inflammatory mediators have been suggested to be involved in these mechanisms. Nitric oxide, a potent inflammatory mediator, is implicated in vasoregulation, neurotransmission, and neuropathic pain. Nitric oxide synthesis can be induced by different cytokines, e.g., tumor necrosis factor-alpha, which recently was shown to be of pathophysiological importance in experimental disc herniation. The enzyme nitric oxide synthase mediates the production of nitric oxide. Three series of experiments were performed in rat and pig disc herniation models to (a) investigate nitric oxide synthase activity in spinal nerve roots after exposure to autologous nucleus pulposus and (b) evaluate the effects of systemic treatment with aminoguanidine, a nitric oxide synthase inhibitor, on vascular permeability and nerve-conduction velocity. In a disc herniation model in the rat, calcium-independent nitric oxide synthase activity was measured in nerve roots exposed to nucleus pulposus; however, no nitric oxide synthase activity was detected in nerve roots from animals that underwent a sham operation, reflecting increased inducible nitric oxide synthase activity. In nucleus pulposus-exposed spinal nerve roots in the pig, the edema was less severe after systemic aminoguanidine administration than without aminoguanidine treatment. Aminoguanidine treatment also significantly reduced the negative effect of nucleus pulposus on nerve-conduction velocity in spinal nerve roots in the pig. These results demonstrate that nucleus pulposus increases inducible nitric oxide synthase activity in spinal nerve roots and that nitric oxide synthase inhibition reduces nucleus pulposus-induced edema and prevents reduction of nerve-conduction velocity. Furthermore, the results suggest that nitric oxide is involved in the pathophysiological effects of nucleus pulposus in disc herniation.

Transport of epidurally applied horseradish peroxidase to the endoneurial space of dorsal root ganglia: a light and electron microscopic study.

The route by which an epidurally applied macromolecule might reach the endoneurial space of spinal nerve roots was assessed with light and electron microscopy in a pig model established to explore the pathophysiology of disk herniation. Horseradish peroxidase (HRP) dissolved in saline was infused epidurally. Animals were sacrificed after 5 minutes (n = 5) or 30 minutes (n = 5). Two control animals received only a saline infusion and were sacrificed after 30 minutes. Nerve root specimens were collected, fixed, and exposed to the HRP substrate, 3.3'-di-amino-benzidine (DAB). The distribution of HRP reaction product in the nerve tissue was studied with light and electron microscopy. In 5-minute specimens, HRP was found in epidural and intradural vessel walls. At the nerve root level, HRP was detected in meningeal membranes but was not seen in periaxonal space. In addition to engaging the outer cell layers of the dorsal root ganglion (DRG) capsule, HRP was detected as a gradient among the peripherally located nerve cell bodies and sometimes among the emerging afferent axons. The 30-minute group demonstrated similar findings. The results confirm that HRP can reach the periaxonal spaces of lumbar DRG within 5 minutes after epidural application. Although the transport mechanism is not fully understood, the DRG may constitute an anatomical location allowing epidurally applied macromolecules entrance to the endoneurial space, either by direct diffusion or via vascular transport. The demonstrated transport route may have implications in the pathophysiology of sciatica in conjunction with lumbar disc herniation.

A long-term (4- to 12-year) follow-up study of surgical treatment of lumbar spinal stenosis.

Limited data are available about the long-term outcome of surgical treatment for lumbar spinal stenosis, and there is a wide variation in reported success rates. There is also a controversy regarding differences in long-term outcome between patients undergoing decompressive surgery alone and those undergoing both decompression and fusion. The aim of this study was to evaluate the long-term clinical outcome and possible complications of decompressive surgery, with special reference to possible differences between patients undergoing fusion, with or without instrumentation, and those undergoing decompression alone. All 124 patients undergoing first-time surgery for lumbar spinal stenosis between 1982 and 1991 at our department were included, and their medical records were reviewed retrospectively. Ninety-six of the patients were available for follow-up and were re-examined by an independent investigator and assessed with a questionnaire after a mean follow-up period of 7.1 (range 4.0-12.2) years. Sixty-five percent of all the patients at the follow-up were subjectively satisfied. Eighty-eight percent of the patients reported constant or daily leg pain preoperatively compared to 43% at follow-up. Constant or daily low back pain was reported by 83% of the patients preoperatively compared to 45% at follow-up. Improvement in walking capacity was found in most patients, and only 4% of the patients who had a preoperatively documented maximum walking distance reported a decreased walking capacity. Twenty-four (25%) of all patients used analgesics daily at the time of follow-up, 34 patients (35%) occasionally and 38 patients (40%) never. The patients with fusions, instrumented or non-instrumented, did not differ significantly from the unfused patients regarding any of the above-mentioned parameters. The results of the study showed that most patients demonstrated a considerable improvement in walking capacity at follow-up. This improvement was significant (P < 0.001) and of clinical importance. A significant improvement regarding both low back pain and leg pain was found postoperatively compared to preoperatively (P < 0.001). There were no statistical differences, judged by all the evaluated parameters, regarding the clinical outcome between patients who were fused and those who were not. Neither were any significant differences found between instrumented fusions compared to uninstrumented fusions. In accordance with most other long-term follow-up studies, about two-thirds (65%) of the patients claimed a satisfactory result at follow-up.

Methylprednisolone reduces the early vascular permeability increase in spinal nerve roots induced by epidural nucleus pulposus application.

Autologous nucleus pulposus is known to have injurious effects on spinal nerve roots when applied epidurally. Both inflammatory and immunological mechanisms have been implicated in this regard. Various proinflammatory substances might be released or activated by nucleus pulposus and might affect the endoneural nerve root vessels. The present study assessed nucleus pulposus-induced early vascular reactions and the possibility of blocking these reactions with intravenous, high-dose, methylprednisolone pretreatment. In 25 pigs, the S2 and S3 nerve roots were exposed. In five pigs (control group), retroperitoneal fat was applied epidurally on the nerve roots, and the other 20 pigs had nucleus pulposus applied. This group was sub-divided into the treatment group (n = 8), in which the pigs were pretreated with intravenous high-dose methylprednisolone (30 mg/kg body weight), and the nontreatment group (n = 12), in which the pigs received a corresponding volume of saline solution. After 2 hours, Evans blue labeled albumin was injected intravenously 5 minutes before death. Endoneural extravasation of Evans blue labeled albumin was evaluated with fluorescence microscopy. A marked albumin leakage was found in 67% of the nontreated animals, in 25% of those in the treatment group, and in none of the control animals. These results demonstrate that nucleus pulposus can induce a rapid increase in endoneural vascular permeability in spinal nerve roots after epidural application. This increase can be partially prevented by pretreatment with high-dose methylprednisolone.

Early effects of nucleus pulposus application on spinal nerve root morphology and function.

It is known that 24 h or more after epidural application of autologous nucleus pulposus, functional and structural changes are established in adjacent nerve roots. It is, however, not known how soon after the application these changes appear. The aim of this study was to reduce the exposure duration to 3 h and to evaluate nerve function and histological changes in the nerve tissue during this time period. A total of 12 pigs was used. In ten pigs, autologous nucleus pulposus (NP) was applied epidurally on the cauda equina. Nerve function was then monitored for 3 h by measurements of muscle action potentials (MAP) in the tail muscles, following nerve root stimulation cranial to the exposed zone. In five of the ten pigs with NP application, nerve root compression to 50 mm Hg was added by means of an inflatable balloon. In two control animals, neither NP nor compression was applied. At the end point, nerve root specimens were harvested for histological assessment. No reduction of MAP amplitude was detected in any of the series. However, there was an epidural accumulation of leucocytes and mast cells, as well as minor axonal and Schwann cell changes in both the NP and NP+ compression series, as compared to the control series. Morphological changes in terms of an epidural inflammatory reaction and minor axonal and Schwann cell damage may thus be demonstrated within 3 h of NP application, with or without compression. However, there is no functional deterioration of the nerve roots detectable within this time period.

Intermittent cauda equina compression. An experimental study of the porcine cauda equina with analyses of nerve impulse conduction properties.

STUDY DESIGN: Neurophysiologic reactions of cauda equina nerve roots to intermittently applied compression were assessed for two different modes of compression using a porcine model. OBJECTIVE: To assess the neurophysiologic reactions of cauda equina nerve roots to intermittently applied compression. SUMMARY OF BACKGROUND DATA: A number of experimental studies have been presented recently regarding the reaction pattern of spinal nerve roots to compression. These studies have used a continuous pressure level. For studies of pathophysiologic mechanisms behind neurogenic claudication, however, it would be more relevant to study the effects of intermittently applied compression. METHODS: The cauda equina was exposed and compression was applied by two inflatable balloons. Two different modes of compression were used. Either the two balloons were inflated and deflated simultaneously (intermittent compression), or just the caudal balloon was inflated and deflated while the cranial balloon was kept continuously inflated (continuous/intermittent compression). The experimental series were: intermittent compression at 10 mm Hg (n = 5) and 50 mm Hg (n = 5), and continuous/intermittent compression at 10 mm Hg (n = 5) and 50 mm Hg (n = 5). For both modes of compression the pressure in the balloons with intermittent inflation was maintained for 10 minutes and deflated for 5 minutes. This procedure was repeated in 8 cycles for 2 hours. Muscle action potentials were recorded in the tail muscles. RESULTS: Compression at 10 mm Hg induced similar reductions of muscle action potentials for both compression modes. At 50 mm Hg, the effects were more pronounced at continuous/intermittent compression than at intermittent compression. The reduction of muscle action potentials was slightly more pronounced for 50 than for 10 mm Hg at intermittent compression. However, a statistically significant difference in the results was found only between 10 and 50 mm Hg at the continuous/intermittent compression mode. CONCLUSIONS: The established model allows investigation of the effects of intermittent cauda equina compression, which might be clinically more relevant than continuous compression regarding the pathophysiologic mechanisms behind neurogenic claudication.

A rapid transport route between the epidural space and the intraneural capillaries of the nerve roots.

STUDY DESIGN: The possibility of epidurally applied substances reaching the intraneural capillaries of the spinal nerve roots and cauda equina was assessed in the pig sacrococcygeal spine. METHODS: The presence of Evans blue-labelled albumin in intraneural capillaries after epidural application for 1, 10, or 30 minutes was studied with fluorescence microscopy. Ink angiography was used to determine whether there were any direct communicating vessels between the epidural vein plexus and the intraneural capillaries. RESULTS: Evans blue-labelled albumin was present in the intraneural capillaries 1 minute after epidural application. Microangiography demonstrated small venules that connected the epidural vein plexus and the intraneural capillaries. CONCLUSIONS: The results of this study demonstrated a rapid transport route between the epidural space and the intraneural capillaries. The results suggest that nucleus pulposus material, as well as epidurally applied substances, such as local anesthetic drugs or epidurally injected corticosteroids, may have a rapid, direct transport route to the axons of the spinal nerve roots. The demonstrated transport route also may be related to the mechanisms behind epidural anesthesia and spinal nerve root infiltration.

Effects of methylprednisolone on nucleus pulposus-induced nerve root injury.

STUDY DESIGN: The effects of intervention by intravenous injection of methylprednisolone to reduce the nerve root injury after epidural application of autologous nucleus pulposus was studied in an experimental model on the pig cauda equina in 20 animals. METHODS: Nucleus pulposus was harvested from a lumbar disc. After lowering the pH of the nucleus pulposus to 3.5 it was placed onto the sacrococcygeal cauda equina. Fifteen of the pigs received a single intravenous injection of 30 mg/kg methylprednisolone, 5 minutes, 24 hours, or 48 hours, respectively, after the application. After 7 days, the nerve conduction velocity was determined, and biopsies of the cauda equina was examined by lightmicroscopy. RESULTS: In the five pigs that did not receive any methylprednisolone treatment, nerve conduction velocity was reduced, whereas it was normal in the pigs treated 5 minutes and 24 hours after nucleus pulposus application. In pigs treated after 48 hours, nerve conduction velocity was reduced only slightly. At the light microscopic level, significant changes occurred in all series. CONCLUSIONS: This study indicates that the nucleus pulposus-induced effects on nerve function in an experimental pig model may be reduced dramatically by high-dose methylprednisolone administration within 24-48 hours after epidural application of autologous nucleus pulposus. The light microscopic changes were probably not significant for the nerve function. Instead, a morphologic explanation on a subcellular level should probably be sought.

The European Spine Society AcroMed Prize 1994. Acute thermal nerve root injury.

Bone cement is sometimes used for vertebral body reconstruction following tumor removal. During such procedures, the polymerization of the methyl-metacrylate in the bone cement generates heat. Such temperature increase might cause damage to the nerve roots within the spinal canal. In the present study, pig cauda equina nerve roots were subjected to controlled temperature increases by means of a heat-generating probe. A temperature of 40 degrees C applied for 5 min did not cause any changes in nerve root function. However, 70 degrees C resulted in a complete block of nerve root function within 5 min. Histological nerve fiber damage was seen after exposure to 60 degrees C and 70 degrees C. The present study provides basic knowledge of heat-resistance properties of spinal nerve roots that might be directly applicable as guidelines for safety margins during surgical spine reconstruction procedures using bone cement.