Valproic acid ameliorates cauda equina injury by suppressing HDAC2-mediated ferroptosis.

INTRODUCTION: Persistent neuroinflammatory response after cauda equina injury (CEI) lowers nociceptor firing thresholds, accompanied by pathological pain and decreasing extremity dysfunction. Histone deacetylation has been considered a key regulator of immunity, inflammation, and neurological dysfunction. Our previous study suggested that valproic acid (VPA), a histone deacetylase inhibitor, exhibited neuroprotective effects in rat models of CEI, although the underlying mechanism remains elusive. METHODS: The cauda equina compression surgery was performed to establish the CEI model. The Basso, Beattie, Bresnahan score, and the von Frey filament test were carried out to measure the animal behavior. Immunofluorescence staining of myelin basic protein and GPX4 was carried out. In addition, transmission electron microscope analysis was used to assess the effect of VPA on the morphological changes of mitochondria. RNA-sequencing was conducted to clarify the underlying mechanism of VPA on CEI protection. RESULTS: In this current study, we revealed that the expression level of HDAC1 and HDAC2 was elevated after cauda equina compression model but was reversed by VPA treatment. Meanwhile, HDAC2 knockdown resulted in the improvement of motor functions and pathologic pain, similar to treatment with VPA. Histology analysis also showed that knockdown of histone deacetylase (HDAC)-2, but not HDAC1, remarkably alleviated cauda equina injury and demyelinating lesions. The potential mechanism may be related to lowering oxidative stress and inflammatory response in the injured region. Notably, the transcriptome sequencing indicated that the therapeutic effect of VPA may depend on HDAC2-mediated ferroptosis. Ferroptosis-related genes were analyzed in vivo and DRG cells further validated the reliability of RNA-sequencing results, suggesting HDAC2-H4K12ac axis participated in epigenetic modulation of ferroptosis-related genes. CONCLUSION: HDAC2 is critically involved in the ferroptosis and neuroinflammation in cauda equina injury, and VPA ameliorated cauda equina injury by suppressing HDAC2-mediated ferroptosis.

Evaluation of neurotoxicity and long-term function and behavior following intrathecal 1 % 2-chloroprocaine in juvenile rats.

Spinally-administered local anesthetics provide effective perioperative anesthesia and/or analgesia for children of all ages. New preparations and drugs require preclinical safety testing in developmental models. We evaluated age-dependent efficacy and safety following 1 % preservative-free 2-chloroprocaine (2-CP) in juvenile Sprague-Dawley rats. Percutaneous lumbar intrathecal 2-CP was administered at postnatal day (P)7, 14 or 21. Mechanical withdrawal threshold pre- and post-injection evaluated the degree and duration of sensory block, compared to intrathecal saline and naive controls. Tissue analyses one- or seven-days following injection included histopathology of spinal cord, cauda equina and brain sections, and quantification of neuronal apoptosis and glial reactivity in lumbar spinal cord. Following intrathecal 2-CP or saline at P7, outcomes assessed between P30 and P72 included: spinal reflex sensitivity (hindlimb thermal latency, mechanical threshold); social approach (novel rat versus object); locomotor activity and anxiety (open field with brightly-lit center); exploratory behavior (rearings, holepoking); sensorimotor gating (acoustic startle, prepulse inhibition); and learning (Morris Water Maze). Maximum tolerated doses of intrathecal 2-CP varied with age (1.0 µL/g at P7, 0.75 µL/g at P14, 0.5 µL/g at P21) and produced motor and sensory block for 10-15 min. Tissue analyses found no significant differences across intrathecal 2-CP, saline or naïve groups. Adult behavioral measures showed expected sex-dependent differences, that did not differ between 2-CP and saline groups. Single maximum tolerated in vivo doses of intrathecal 2-CP produced reversible spinal anesthesia in juvenile rodents without detectable evidence of developmental neurotoxicity. Current results cannot be extrapolated to repeated dosing or prolonged infusion.

A rare case of isolated cauda equina Nocardia farcinica infection.

Nocardia is a Gram-positive, partially acid-fast, catalase-positive, and urease-positive bacterium that grows aerobically. We present an extremely rare case of cauda equina syndrome due to isolated intramedullary Nocardia farcinica infection. A 44-year-old male presented with low backache and gradually progressive weakness in bilateral lower limbs followed by paraplegia. He was found to have a well-defined, sharply demarcated ring-enhancing lesion located from T11-T12 to L3 vertebral body. He underwent laminectomy and decompression. The histopathological examination revealed a Gram-positive filamentous organism that looks like Nocardia. The culture report was suggestive of Nocardia farcinica. He was then treated with antibiotics and had a remarkable clinical and radiological improvement.

Expression of Nogo-A in dorsal root ganglion in rats with cauda equina injury.

OBJECTIVE: To investigate the expression of Nogo-A in dorsal root ganglion (DRG) in rats with cauda equina injury and the therapeutic effects of blocking Nogo-A and its receptor. METHODS AND MATERIALS: Fifty-eight male Sprague-Dawley rats were divided randomly into either the sham operation group (n = 24) or the cauda equina compression (CEC) control group (n = 34). Behavioral, histological, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses were conducted to assess the establishment of the model. The dynamic expression change of Nogo-A was evaluated using real time-qPCR. Immunofluorescence was used to evaluate the expression of Nogo-A in the DRG and cauda equina. Furthermore, 20 male Sprague-Dawley rats were equally divided into 4 groups, including the sham group, the CEC group, the NEP1-40 (the NgR antagonist peptide) treatment group, and the JTE-013 (the S1PR2 antagonist) treatment group. Behavioral assessments and western blotting were used to evaluate the therapeutic effect of cauda equina injury via blocking Nogo-A and its receptor. RESULTS: Tactile allodynia and heat hyperalgesia in the CEC model developed as soon as 1 day after surgery and recovered to normal at 7 days, which was followed by the downregulation of Nogo-A in DRG neurons. However, the locomotor function impairment in the CEC model showed a different prognosis from the sensory function, which was consistent with the expression change of Nogo-A in the spinal cord. Immunofluorescence results also demonstrated that Nogo A-positive/NF200-negative neurons and axons increased in the DRG and cauda equina 7 days after surgery. Surprisingly, Schwann cells, which myelinate axons in the PNS, also expressed considerable amounts of Nogo-A. Then, after blocking the Nogo-A/NgR signaling pathway by NEP1-40, significant improvement of mechanical allodynia was identified in the first 2 days after the surgery. Western blotting suggested the NEP1-40 treatment group had lower expression of cleaved caspase-3 than the CEC and JTE-013 treatment group. CONCLUSION: Neuronal Nogo-A in the DRG may be involved in regeneration and play a protective role in the CEC model. Whereas Nogo-A, released from the injured axons or expressed by Schwann cells, may act as an inhibiting factor in the process of CEC repairment. Thus, blocking the Nogo-A/NgR signaling pathway can alleviate mechanical allodynia by apoptosis inhibition.

Neuroprotective effect of hydrogen sulfide on acute cauda equina injury in rats.

BACKGROUND: Hydrogen sulfide (H2S), as a novel gaseous messenger molecule, plays an important role in signal transduction and biological modulation. PURPOSE: In the present study the effect of H2S after compression injury of cauda equina was studied. STUDY DESIGN: The setting of this study is the laboratory investigation. METHODS: A total of 162 rats were randomly allocated into three groups: sham group, compression group, and H2S group. Cauda equina compression (CEC) injury in rats was induced by implanting silicone gels (10×1×1 mm) into the epidural spaces L5 and L6; laminectomy was performed at the L4 level of the vertebra in the sham-operated group. The experimental group was treated with sodium hydrosulfide intraperitoneally (20 µmol/kg body weight), whereas the compression and sham groups received equal volumes of physiological saline. Levels of malonaldehyde (MDA) and glutathione (GSH) were determined immediately before CEC surgery, 12 h, 24 h, 48 h, and 72 h after CEC surgery. Furthermore, hematoxylin and eosin (H&E) staining and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling (TUNEL) assay were performed 48 h after CEC. RESULTS: Hematoxylin and eosin staining showed that myelin sheath and the cauda equina fibers in the compression group were less compact and highly degenerated compared with the sham group, and that H2S treatment could improve the status. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling staining exhibited that decreased number of TUNEL positive cells was found in the H2S group than in the compression group. The level of MDA was increased in the sham and H2S groups compared with the compression group (p<.05, p<.01), whereas the level of GSH was decreased (p<.05, p<.01). CONCLUSIONS: With the above data, we conclude that H2S could reduce the oxidative stress and has neuroprotective effect in acute cauda equina syndrome.

Neurophysiologic monitoring in neurosurgery.

This article focuses on the application of neurophysiologic monitoring in uniquely neurosurgical procedures. Neurophysiologic monitoring provides functional testing and mapping to identify neural structures. Once identified, the functionality of the central and peripheral nervous system areas at risk for neurosurgical injury can be monitored. It discusses the use of motor-evoked potentials, sensory evoked potentials, electromyography and electroencephalography to assess neurologic change.

Chronic intrathecal infusion of gabapentin prevents nerve ligation-induced pain in rats.

BACKGROUND: Gabapentin is an anticonvulsant and adjuvant analgesic. It is effective in several pain studies. Neuropathic pain is the most difficult type of pain to treat. In this study, we examined if intrathecal gabapentin could prevent nerve injury-induced pain. METHODS: Under isoflurane anaesthesia, male Sprague-Dawley rats (200-250 g) underwent right L5/6 spinal nerve ligation and placement of an intrathecal catheter connected to an infusion pump. After surgery, intrathecal saline or gabapentin (20 µg h(-1)) was given for 7 days (n=8 per group). The right hind paw withdrawal threshold to von Frey filament stimuli and withdrawal latency to radiant heat were determined before (baseline) and once daily for 7 days after surgery. Haematoxylin and eosin and toluidine blue staining were used to evaluate the neurotoxicity of gabapentin (40 µg h(-1)). RESULTS: Seven days after nerve ligation, the affected paw withdrawal threshold and latency of saline-treated rats decreased from the baseline 11.7 (11.7-22.2) [median (inter-quartile range)] to 1.6 (0.9-3.2) g and 10.8 (10.5-11.2) to 4.3 (4.2-7) s, respectively. Rats receiving gabapentin (20 µg h(-1)) had higher withdrawal threshold [9.9 (9.9-19.3) g] and latency [11.5 (9.7-11.9) s] on day 7 after ligation. No obvious histopathological change or growth retardation was detected after intrathecal gabapentin (40 µg h(-1)) infusion. CONCLUSIONS: We showed a preventative effect of intrathecal gabapentin on the development of nerve injury-induced mechanical allodynia and thermal hyperalgesia. Our data suggest that continuous intrathecal gabapentin may be considered as an alternative for the prevention of nerve injury-induced pain.

Cauda equina compression by hydrogel dural sealant after a laminotomy and discectomy: case report.

STUDY DESIGN: The authors present a case of cauda equina compression after laminotomy and discectomy where incidental durotomy was managed with the application of hydrogel sealant. The patient reported return of radicular symptoms on the first postoperative day, and deterioration to early cauda equina syndrome after bending on the sixth day. OBJECTIVE: To demonstrate that in addition to its recognized volume expansion properties, that the product has the ability to migrate and produce symptoms remote from where it was inserted. SUMMARY OF BACKGROUND DATA: The physical properties of DuraSeal (Confluent Surgical, Waltham, MA), a hydrogel dural sealant, make it an effective adjunct to dural closure. Its volume expansion has been associated with neural compression after posterior fossa decompression. We have found no reported migration of this product. METHODS: Sequential postoperative imaging shows swelling and migration of the hydrogel into spinal canal with resultant compression. Exploration on postoperative day 10 revealed sealant causing cauda equina compression proximal to the site of the durotomy. CONCLUSION: The authors recommend that in addition to caution regarding its potential mass effect, that cognizance be taken of the product's potential to migrate and result in symptoms at a distant site.

The effects of cilostazol on nerve conduction velocity and blood flow: acute and chronic cauda equina compression in a canine model.

STUDY DESIGN: Analyses of improvements in nerve conduction velocity (NCV) and blood flow after administering cilostazol in a dog model of experimental acute and chronic cauda equina compression. OBJECTIVE: To determine whether cilostazol improves NCV and blood flow, and cilostazol inhibits blood clots in capillaries of nerve roots after cauda equina compression. SUMMARY AND BACKGROUND DATA: Reduction in blood flow is an important factor in neurogenic intermittent claudication for lumbar spinal stenosis. Prostaglandin E1 (PGE1) and calcitonin have been reported to improve blood flow and neurogenic intermittent claudication in clinical and experimental studies. Cilostazol affects vasodilator and antiplatelet activity, and protects endothelial cells in blood vessels. METHODS: Experimental groups in the acute compression study (n = 40) were divided into 4 treatment groups. Low-dose (3 microg/kg/min), medium-dose (10 microg/kg/min), or high-dose (30 microg/kg/min) cilostazol or a control vehicle were administered intravenously after cauda equina compression. NCV and blood flow were measured during the observation period (n = 20 measurements for each). Another 12 animals were used to evaluate chronic compression. Cilostazol was administered for 6 days orally 1 day after compression treatment group (n = 6); the nontreatment group (n = 6) did not receive any drug. NCV was measured immediately after and 7 days after compression. Blood flow was measured 7 days after compression. RESULTS: In the acute compression study, NCV in the medium-dose group was significantly higher than that in the other groups during the compression period (P < 0.05). During the recovery period, there was no significant difference in NCV among groups. In the chronic compression study, NCV and blood flow in the cilostazol group were significantly higher than those in the control group (P < 0.05). CONCLUSION: Cilostazol improved NCV and blood flow to the cauda equina in this dog model. Cilostazol might be a potential agent to improve symptoms due to compression of cauda equina and/or cauda equina dysfunction.

Rho kinase inhibitor improves motor dysfunction and hypoalgesia in a rat model of lumbar spinal canal stenosis.

STUDY DESIGN: Immunohistochemical and behavioral study using a rat cauda equina compression model. OBJECTIVE: To investigate, after cauda equina compression by spinal canal stenosis (SCS), Rho activation in the spinal cord and cauda equina, and the effect of intrathecal administration of a Rho kinase inhibitor on hypoalgesia and motor dysfunction. SUMMARY OF BACKGROUND DATA: Compression of the cauda equina caused by SCS is a common clinical disorder associated with sensory disturbance and intermittent claudication. Cauda equina compression is thought to reduce blood flow and result in nerve degeneration caused by various cytokines. Rho, a member of the small GTPases, is a signal transmitter. It promotes Wallerian degeneration, decreases blood flow in the spinal cord and brain, and increases expression of several cytokines. Currently, Rho kinase inhibitor is used clinically to treat progressive nerve damage due to cerebrovascular disorders. However, its effect for SCS has not been evaluated. METHODS: Forty-two 6-week-old male Sprague-Dawley rats (200-250 g) were used. For the SCS model (n = 27), a small piece of silicon was placed under the lamina of the fourth lumbar vertebra. In the sham-operated group, laminectomies were performed at L5 only (n = 15). We examined mechanical sensitivity and motor function using von Frey hairs and a treadmill, and immunohistochemically localized Rho in the spinal ventral neurons, axons, and Schwann cells in the cauda equina. We also examined the effects of intrathecally administered Rho kinase inhibitor for hypoalgesia or motor dysfunction caused by SCS. RESULTS: We observed motor dysfunction and hypoalgesia and activated Rho-immunoreactive cells in spinal ventral neuroreported to induce neurite and axonal outgrowth in the spinal cord and brain after nervous system injury. In addition, 1 report showed that Rho kinase was involved in Wallerian degeneration that was rescued by Rho kinase inhibitor. Furthermore, it is thought that Rho is involved in TNF-alpha and interleukin (IL) production in the central nervous system, and the production was inhibited by administering Rho kinase inhibitor in the central nervous system. Regardns, axons, and Schwann cells in the cauda equina. Intrathecal administration of Rho kinase inhibitor improved mechanical hypoalgesia and motor dysfunction caused by SCS. CONCLUSION: Activated Rho may play an important role in nerve damage in the cauda equina in SCS. Rho kinase inhibitor may be a useful tool in determining the pathomechanism of cauda equina syndrome caused by SCS.

Characterization and restoration of altered inhibitory and excitatory control of micturition reflex in experimental autoimmune encephalomyelitis in rats.

Multiple sclerosis (MS) is characterized by inflammatory lesions throughout the central nervous system. Spinal cord inflammation correlates with many neurological defecits. Most MS patients suffer from micturition dysfunction with urinary incontinence and difficulty in emptying the bladder. In experimental autoimmune encephalomyelitis (EAE) induced in female Lewis rats, a model of MS, we investigated at distinct clinical severity scores the micturition reflex by cystometrograms. All rats presenting symptomatic EAE suffered from micturition reflex alterations with either detrusor areflexia or hyperactivity. During pre-symptomatic EAE, a majority of rats presented with detrusor areflexia, whereas at onset of clinical EAE, detrusor hyperactivity was predominant. During progression of EAE, detrusor areflexia and hyperactivity were equally expressed. Bladder hyperactivity was suppressed by activation of glycine and GABA receptors in the lumbosacral spinal cord with an order of potency: glycine > GABA(B) > GABA(A). Detrusor areflexia was transformed into detrusor hyperactivity by blocking glycine and GABA receptors. Spinalization abolished bladder activity in rats presenting detrusor hyperactivity and failed to induce activity in detrusor areflexia. Altogether, the results reveal an exaggerated descending excitatory control in both detrusor reflex alterations. In detrusor areflexia, a strong segmental inhibition dominates this excitatory control. As in treatment of MS, electrical stimulation of sacral roots reduced detrusor hyperactivity in EAE. Blockade of glycine receptors in the lumbosacral spinal cord suppressed the stimulation-induced inhibitory effect. Our data help to better understand bladder dysfunction and treatment mechanisms to suppress detrusor hyperactivity in MS.

Epidural lidocaine induces dose-dependent neurologic injury in rats.

Although epidural lidocaine administered as a bolus has been shown to cause little neurotoxicity, local anesthetics are often administered repetitively or continuously into the epidural space, and in high doses may induce neurologic injury. We investigated whether epidural lidocaine is neurotoxic when a large dose is continuously administered in rats, and whether the functional impairment and histologic damage is dose dependent. In Experiment 1, 13 rats received a 120-min epidural infusion (at 5 microL/min) of saline or 2% lidocaine. Four days after infusion, rats given 2% lidocaine developed significantly more prolonged tail-flick latencies and showed more apparent morphologic damage than those given saline. In Experiment 2, 41 rats were randomly divided into 5 groups to receive an epidural infusion of saline for 120 min or 5% lidocaine for 15, 30, 60, or 120 min at a rate of 5 muL/min. Rats given 5% lidocaine for 120 min developed a significant increase in tail-flick latency. Paw pressure thresholds did not change in any group. Nerve injury scores for rats given 5% lidocaine for 30, 60, and 120 min were significantly higher than those for rats given saline. Significant difference in damage in nerve roots was also observed among rats given the anesthetic for different durations of time; nerve injury scores with 120-min infusion were higher than with 15- and 30-min infusions, and injury with 60-min infusion was greater than with 15-min infusion. In conclusion, these results suggest that epidural lidocaine causes dose-dependent neurotoxicity after continuous infusion in rats.

Caudal 0.2% ropivacaine is less effective during surgery than 0.2% levobupivacaine and 0.2% bupivacaine: a double-blind, randomized, controlled trial.

BACKGROUND: We hypothesized that without the analgesic effects of volatile anesthetics, caudal 0.20% ropivacaine would be less effective during surgical stimulation than 0.20% bupivacaine or 0.20% levobupivacaine. This trial was designed to examine whether the combination of a caudal block with 0.20% ropivacaine and i.v. anesthesia resulted in reduced analgesic efficacy during surgery compared with caudal 0.20% levobupivacaine or 0.20% bupivacaine in children. METHODS: Ninety ASA I-II children between 1 and 7 years old, scheduled for inguinal hernia repair or orchidopexy under propofol anesthesia were randomized to receive a caudal block with 1 ml x kg(-1) of 0.2% bupivacaine, 0.2% ropivacaine or 0.2% levobupivacaine. The primary outcome measure of the study was the clinical efficacy of the caudal block during surgery. Secondary outcome measures were postoperative pain relief and residual motor blockade. RESULTS: Four children were excluded and 86 were analyzed. The proportion of children with effective caudal block during surgery was significantly higher in children receiving levobupivacaine (26/28) or bupivacaine (27/29) compared with patients receiving ropivacaine (21/29) (P = 0.03). There were no significant differences among groups in the analgesic onset time (P = 0.1), incidence of residual motor blockade (P = 0.4), number of patients requiring analgesia after operation or in the time from caudal injection to the first administration of analgesic medication (P = 0.3). CONCLUSIONS: Combined with propofol anesthesia, 0.2% levobupivacaine and 0.2% bupivacaine are more effective than 0.2% ropivacaine for caudal use in children undergoing inguinal hernia repair or orchidopexy.

Effects on improvement of blood flow in the chronically compressed cauda equina: comparison between a selective prostaglandin E receptor (EP4) agonist and a prostaglandin E1 derivate.

STUDY DESIGN: Vasodilatation was studied in a model of experimental chronic cauda equina compression using measurements of vessel diameter on video recordings. OBJECTIVE: The vasodilative effect was compared between a prostaglandin E2 receptor (EP) subtype agonists (EP4 agonist) and a prostaglandin E1 (PGE1) derivate. SUMMARY AND BACKGROUND DATA: Reduction of blood flow is one important pathogenic factor of neurogenic intermittent claudication (NIC) for lumbar spinal canal stenosis. It is known that PGE1 improves the mean walking distance in patients with cauda equina compression type of NIC. There are four subtypes of EP: EP1, EP2, EP3, and EP4. EP4 is located in vessels of pigs and rabbits. A highly selective EP4 agonist, which has effects on dilatation of pig and rabbit vessels, has recently been developed. One may therefore assume that this agonist may improve blood flow in the chronically compressed cauda equina. METHODS: A total of 25 dogs were used. A plastic balloon inflated to 10 mm Hg was placed under the lamina of the seventh lumbar vertebra for 1 week. OP-1206 cyclodextrin clathrate (OP-1206 CD: prostaglandin E1 derivate) and ONO-4819 CD (a highly selective EP4 agonist) were intravenously administrated. The following 5 experimental groups were assigned: animals in group OP (3) (n = 5) and Group OP (10) (n = 5) received 3 eta g/kg per minute and 10 eta g/kg per minute of OP-1206 CD, respectively; those in Group EP (3) (n = 5) and Group EP (10) (n = 5) received 3 eta g/kg per minute and 10 eta g/kg per minute of ONO-4819 CD, respectively; and those in the control group (n = 5) received saline. After 7 days, the cauda equina was exposed and blood vessels of the second or third sacral nerve root were identified using a specially designed operation microscope equipped with a video camera. The diameters of the observed blood vessels were measured on video-recordings every 10 minutes until 60 minutes after administrating OP-1206 CD or ONO-4819CD. RESULTS: In the Groups OP (3), OP (10), and EP (10), the blood vessels were dilated and blood flow increased after injection of the agents. In the Group EP (10), the vessel diameter and blood flow increased significantly compared with that in the other four groups. In contrast, the blood vessels contracted and the blood flow was reduced in the Group EP (3). CONCLUSIONS: Our results suggested that the EP4 agonist at high concentrations might be a potential therapeutic agent since it is expected to increase blood flow in nerve roots in patients with spinal canal stenosis.

Neurotoxicity of intrathecally administered bupivacaine involves the posterior roots/posterior white matter and is milder than lidocaine in rats.

BACKGROUND AND OBJECTIVES: Clinical and laboratory studies suggest that lidocaine is more neurotoxic than bupivacaine. However, histological evidence of their comparative neurotoxicity is sparse. We thus pathologically and functionally compared the intrathecal neurotoxicity of these agents. METHODS: Rats received 0.12 microL/g body weight lidocaine (0%, 2%, 10%, or 20%) or bupivacaine (0%, 0.5%, 2.5%, or 5%) in distilled water via an intrathecal catheter. The influence of high osmolarity was also examined using 5% bupivacaine in 20% glucose solution (5% BG) and a control 25% glucose solution. The L3 spinal cord, the posterior and anterior roots, and the cauda equina were examined by light and electron microscopy. Walking behavior and sensory threshold were investigated as neurofunctional tests. RESULTS: The posterior root and posterior white matter showed axonal degeneration in rats treated with 10% and 20% lidocaine and 5% bupivacaine in distilled water (5% BDW) and in 5% BG, but not in rats treated with 2% lidocaine, 0.5% and 2.5% bupivacaine, distilled water, or 25% glucose solution. The histological damages were more severe in 20% lidocaine-treated rats than in 5% bupivacaine-treated rats. The damage of posterior white matter was observed only when the posterior root was severely injured. No significant difference of histological findings was observed between 5% BDW and 5% BG. Functional abnormalities were found only in rats treated with 20% lidocaine. CONCLUSIONS: The neurotoxic lesions caused by bupivacaine and lidocaine were indistinguishable in the primary site and the extending pattern, such as axonal degeneration originating from the posterior roots and extending to the posterior white matter. The intrathecal neurotoxicity is greater in lidocaine than in bupivacaine.

The nerve root entry zone is highly vulnerable to intrathecal tetracaine in rabbits.

It has been speculated that the nerve root entry zone in the spinal cord, known as the Obersteiner-Redlich zone, may be more sensitive to large concentrations of local anesthetics administered intrathecally. However, there has been no morphological evidence for this. In the present study, we examined morphological changes of nerve fibers at the nerve root entry zone after administration of intrathecal tetracaine in rabbits. Rabbits were assigned to 4 groups (n = 6 in each) and received intrathecal 0.3 mL saline (control), or 1%, 2%, or 4% tetracaine. Neurological and histopathological assessments were performed 1 wk after the administration. Tetracaine 1% selectively injured the myelin sheaths made by oligodendrocytes at the nerve root entry zones of both ventral and dorsal roots, although neurological dysfunction could not be detected. With tetracaine 2% and 4%, histopathological damage extended to the dorsal funiculus, distal part of roots, and cauda equina and neurological dysfunction became apparent. These results demonstrate that the myelin sheaths made by oligodendrocytes at the nerve root entry zone are highly vulnerable to large concentrations of tetracaine given intrathecally.

Efficacy of leukemia inhibitory factor in experimental autoimmune neuritis.

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine that exerts neurotrophic and myotrophic actions. We have investigated the effect of LIF in experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome (GBS). Treatment with LIF at the onset of the disease showed a slight, but not significant, improvement in the clinical course but no effect on nerve histology.

Nerve vasculature changes induced by serotonin under chronic cauda equina compression.

STUDY DESIGN: An analysis of nerve vascular changes in nerve roots induced by serotonin in chronically compressed nerve roots. OBJECTIVES: To assess the hypotheses that serotonin might have a vasoconstrictive effect in chronically compressed nerve roots. SUMMARY OF BACKGROUND DATA: The 5-hydroxytryptamine 2A receptor is involved in serotonin-induced activation or sensitization of sensory nerve terminals. Serotonin exerts complex effects on pain and hyperalgesia through various receptor subtypes located at various levels of the pain transmission system. Serotonin induces endothelium-dependent contraction in vascular diseases. However, there is no knowledge regarding a response of nerve vasculature induced by serotonin in chronically compressed nerve roots. METHODS: A total of 45 dogs were used. A plastic balloon was placed under the lamina L7 and inflated to 10 mm Hg and left for 1 week. Four experimental groups were used: no operation (Group A, n = 15), the balloon was placed under the lamina but not inflated (Group B, n = 10), the balloon was inflated to 10 mm Hg for 1 week and the pressure was released just before the measurement (Group C, n = 10), and the balloon was inflated to 10 mm Hg for 1 week and inflation was maintained during the measurements (Group D, n = 10). The blood vessels of the second or third sacral nerve were defined after an intra-arterial injection of 0.5 micromol/L or 1.0 micromol/L serotonin using a specially designed operation microscope equipped with a video camera. In all groups 0.5 micromol/L serotonin (each group, n = 5) or 1.0 micromol/L serotonin (each group, n = 5) was injected. In Group A (n = 5) saline was injected. The measurements of diameter of observed blood vessels and blood flow index were performed on video recordings. All statistical assessments were performed by Wilcoxon signed-ranks test and Fisher's PLSD. RESULTS: In Group A, the diameter of blood vessels and blood flow did not change after administration of saline. In the noncompression groups (Groups A and B) the diameter of blood vessels and blood flow increased after injection of 0.5 micromol/L serotonin. In compression groups (Groups C and D) the blood vessels contracted after injecting 0.5 micromol/L serotonin and blood flow decreased. There was a significant difference in the diameter of blood vessels and blood flow between noncompression and compression groups (P < 0.01). There was no difference regarding diameter of blood vessels between released compression (Group C) and maintained compression during measurement group (Group D). In all groups blood vessels contracted and blood flow decreased after injecting 1.0 micromol/L. In electron microscopic observation tight junction of endothelial cells was destroyed in chronically compression nerve roots. DISCUSSION: The present study demonstrated that serotonin had a vasodilative effect on the intact nerve roots, whereas there was a vasoconstrictive effect to the chronically compressed nerve roots. There was no difference in the diameter of blood vessels between released compression and maintained compression during measurement group. Results suggested that dysfunction of endothelial cells induced by serotonin rather than mechanical compression itself might lead to contraction of blood vessels under chronic compression. CONCLUSION: Serotonin had a vasoconstrictive effect on the chronically compressed nerve roots.

[Cauda equina syndrome after intradural anesthesia with bupivacaine]. / Síndrome de cola de caballo tras anestesia subaracnoidea con bupivacaína.

A 70-year-old man developed pain and functional weakness in the lower limbs with dysesthesia and urinary retention after subarachnoid anesthesia with 0.5% hyperbaric bupivacaine. Neurological and electrophysiological tests and follow-up, as well as diagnostic images (CAT and MR), ruled out spinal cord lesions. The diagnosis was cauda equina syndrome. Cauda equina syndrome is a neurological complication of subarachnoid anesthesia. Associated with use of microcatheters for continuous subarachnoid anesthesia and 5% hyperbaric lidocaine, cauda equina syndrome is rare after a single injection of bupivacaine. Although the pathogenesis of cauda equina syndrome is poorly understood, there is agreement on the neurotoxicity of local anesthetics, particularly of 5% hyperbaric lidocaine.

[Neurotoxicity of intrathecal lidocaine]. / Síntomas neurológicos transitorios tras anestesia subaracnoidea con lidocaína.

Lidocaine is a local anesthetic belonging to the amide group and has been administered intrathecally for over 40 years. Although no serious complications had been attributed to lidocaine before the 1990s, subarachnoid administration is now the subject of controversy following its implication in numerous cases of neurological complication. The clinical pictures described in the literature are cauda equina syndrome, which is mainly associated with continuous subarachnoid anesthesia through microcatheters, and transitory neurological symptoms, also termed radicular irritation syndrome and associated with single injections. The literature reveals a clearly higher incidence of transitory neurological symptoms with lidocaine than with other local anesthetics. Although the underlying mechanism remains unclear, the main hypotheses being the neurotoxicity of lidocaine itself or the malpositioning of the paravertebral musculature due to extreme relaxation. The various factors that can lead to neuropathy have been widely described in the many articles reporting complications. Arthroscopy and lithotomy positions are significantly related to the appearance of symptoms, as are early ambulation or the use of small-gauge needles or pencil-point needles. Further clinical studies should be undertaken. No consensus on subarachnoid administration of lidocaine has emerged, yet no alternative has been demonstrated to be safe and to offer similar pharmacological features (short latency, short duration of action and good muscle relaxation). Prilocaine, mepivacaine, articaine and bupivacaine at low doses have been suggested as alternatives.