Treatment options for anaplastic or malignant intramedullary spinal cord tumors (IMSCTs) remain limited. Paclitaxel has potent cytotoxicity against experimental intracranial gliomas and could be beneficial in the treatment of IMSCTs, but poor CNS penetration and significant toxicity limit its use. Such limitations could be overcome with local intratumoral delivery. Paclitaxel has been previously incorporated into a biodegradable gel depot delivery system (OncoGel) and in this study the authors evaluated the safety of intramedullary injections of OncoGel in rats and its efficacy against an intramedullary rat gliosarcoma.
Safety of intramedullary OncoGel was tested in 12 Fischer-344 rats using OncoGel concentrations of 1.5 and 6.0 mg/ml (5 μl); median survival and functional motor scores (Basso-Beattie-Bresnahan [BBB] scale) were compared with those obtained with placebo (ReGel) and medium-only injections. Efficacy of OncoGel was tested in 61 Fischer-344 rats implanted with an intramedullary injection of 9L gliosarcoma containing 100,000 cells in 5 μl of medium, and randomized to receive OncoGel administered on the same day (in 32 rats) or 5 days after tumor implantation (in 29 rats) using either 1.5 mg/ml or 3.0 mg/ml doses of paclitaxel. Median survival and BBB scores were compared with those of ReGel-treated and tumor-only rats. Animals were killed after the onset of deficits for histopathological analysis.
OncoGel was safe for intramedullary injection in rats in doses up to 5 μl of 3.0 mg/ml of paclitaxel; a dose of 5 μl of 6.0 mg/ml caused rapid deterioration in BBB scores. OncoGel at concentrations of 1.5 mg/ml and 3.0 mg/ml paclitaxel given on both Day 0 and Day 5 prolonged median survival and preserved BBB scores compared with controls. OncoGel 1.5 mg/ml produced 62.5% long-term survivors when delivered on Day 0. A comparison between the 1.5 mg/ml and the 3.0 mg/ml doses showed higher median survival with the 1.5 mg/ml dose on Day 0, and no differences in median survival or BBB scores after treatment on Day 5.
OncoGel is safe for intramedullary injection in rats in doses up to 5 μl of 3.0 mg/ml, prolongs median survival, and increases functional motor scores in rats challenged with an intramedullary gliosarcoma at the doses tested. This study suggests that locally delivered chemotherapeutic agents could be of temporary benefit in the treatment of malignant IMSCTs under experimental settings.
intramedullary spinal cord tumor; OncoGel chemotherapy; gliosarcoma; rat; paclitaxel; oncology
The pathogenesis of cervical spondylotic myelopathy (CSM) is related to both primary mechanical and secondary biological injury. The authors of this study explored a novel, noninvasive method of promoting neuroprotection in myelopathy by using curcumin to minimize oxidative cellular injury and the capacity of omega-3 fatty acids to support membrane structure and improve neurotransmission.
An animal model of CSM was created using a nonresorbable expandable polymer placed in the thoracic epidural space, which induced delayed myelopathy. Animals that underwent placement of the expandable polymer were exposed to either a diet rich in docosahexaenoic acid and curcumin (DHA-Cur) or a standard Western diet (WD). Twenty-seven animals underwent serial gait testing, and spinal cord molecular assessments were performed after the 6-week study period.
At the conclusion of the study period, gait analysis revealed significantly worse function in the WD group than in the DHA-Cur group. Levels of brain-derived neurotrophic factor (BDNF), syntaxin-3, and 4-hydroxynonenal (4-HNE) were measured in the thoracic region affected by compression and lumbar enlargement. Results showed that BDNF levels in the DHA-Cur group were not significantly different from those in the intact animals but were significantly greater than in the WD group. Significantly higher lumbar enlargement syntaxin-3 in the DHA-Cur animals combined with a reduction in lipid peroxidation (4-HNE) indicated a possible healing effect on the plasma membrane.
Data in this study demonstrated that DHA-Cur can promote spinal cord neuroprotection and neutralize the clinical and biochemical effects of myelopathy.
myelopathy; docosahexaenoic acid; curcumin; membrane; spinal cord injury; rat
There is currently no reproducible animal model of human spinal metastasis that allows for laboratory study of the human disease. Consequently, the authors sought to develop an orthotopic model of spinal metastasis by using a human lung cancer cell line, and to correlate neurological decline with tumor growth.
To establish a model of spinal metastasis, the authors used a transperitoneal surgical approach to implant PC-14 lung tumors into the L-3 vertebral body of nude mice via a drill hole. In 24 animals, motor function was scored daily by using the validated semiquantitative Basso-Beattie-Bresnahan (BBB) scale. A second group of 26 animals (6 or 7 per time point) were sacrificed at specific times, and the spines were removed, sectioned, and stained. Canal compromise was analyzed quantitatively by determining the ratio of the area of the neural elements to the area of the spinal canal on histological sections (neural/canal ratio). Correlations between BBB score and histological evaluation of tumor growth were assessed.
Lung cancer xenografts grew in all animals undergoing functional evaluation (24 mice) according to a reliable and reproducible time course, with paraplegia occurring at a median interval of 30 days following tumor implantation (95% CI 28.1–31.9 days). Importantly, the analysis defined 4 key milestones based on components of the BBB score; these were observed in all animals, were consistent, and correlated with histological progression of tumor. From Days 1 to 14, the mean BBB score declined from 21 to 19. The animals progressed from normal walking with the tail up to walking with the tail constantly touching the ground (milestone 1). The median time to tail dragging was 12 days (95% CI 10.8–13.2). Histological studies on Day 14 demonstrated that tumor had progressed from partial to complete VB infiltration, with initial compression of the neural elements and epidural tumor extension to adjacent levels (mean neural/canal ratio 0.32 ± 0.05, 7 mice). From Days 15 to 20/21 (left/right leg), the mean BBB score declined from 19 to 14. Animals showed gait deterioration, with the development of dorsal stepping (milestone 2). The median time to dorsal stepping was 21 days (95% CI 19.4–22.6) in the left hindlimb and 23 days (95% CI 20.6–25.4) in the right hindlimb. Histological studies on Day 21 demonstrated an increase in the severity of the neural element compression, with tumor extending to adjacent epidural and osseous levels (mean neural/canal ratio 0.19 ± 0.05, 6 mice). From Days 22 to 26/27 (left/right leg), the mean BBB score declined from 14 to 8. Animals had progressive difficulty ambulating, to the point where they showed only sweeping movements of the hindlimb (milestone 3). The median time to hindlimb sweeping was 26 days (95% CI 23.6–28.4) and 28 days (95% CI 27.1–28.9) in the left and right hindlimbs, respectively. Histological studies on Day 28 revealed progressive obliteration of the spinal canal (mean neural/canal ratio 0.09 ± 0.01, 7 mice). From Days 29 to 36, the animals progressed to paralysis (milestone 4). The median time to paralysis was 29 days (95% CI 27.6–30.4) and 30 days (95% CI 28.1–31.9) in the left and right hindlimbs, respectively.
The authors have developed an orthotopic murine model of human spinal metastasis in which neurological decline reproducibly correlates with severity of tumor progression. Although developed for lung cancer, this model can be expanded to study other types of metastatic or primary spinal tumors. Ultimately, this will allow testing of targeted therapies against specific tumor types.
spinal metastasis; nude mouse; spinal cord compression; animal model
Craniocervical decompression for Chiari malformation Type I (CM-I) and syringomyelia has been reported to fail in 10%–40% of patients. The present prospective clinical study was designed to test the hypothesis that in cases in which syringomyelia persists after surgery, craniocervical decompression relieves neither the physiological block at the foramen magnum nor the mechanism of syringomyelia progression.
The authors prospectively evaluated and treated 16 patients with CM-I who had persistent syringomyelia despite previous craniocervical decompression. Testing before surgery included the following: 1) clinical examination; 2) evaluation of the anatomy using T1-weighted MR imaging; 3) assessment of the syrinx and CSF velocity and flow using cine phase-contrast MR imaging; and 4) appraisal of the lumbar and cervical subarachnoid pressures at rest, during a Valsalva maneuver, during jugular compression, and following the removal of CSF (CSF compliance measurement). During surgery, ultrasonography was performed to observe the motion of the cerebellar tonsils and syrinx walls; pressure measurements were obtained from the intracranial and lumbar intrathecal spaces. The surgical procedure involved enlarging the previous craniectomy and performing an expansile duraplasty with autologous pericranium. Three to 6 months after surgery, clinical examination, MR imaging, and CSF pressure recordings were repeated. Clinical examination and MR imaging studies were then repeated annually.
Before reexploration, patients had a decreased size of the CSF pathways and a partial blockage in CSF transmission at the foramen magnum. Cervical subarachnoid pressure and pulse pressure were abnormally elevated. During surgery, ultrasonographic imaging demonstrated active pulsation of the cerebellar tonsils, with the tonsils descending during cardiac systole and concomitant narrowing of the upper pole of the syrinx. Three months after reoperation, patency of the CSF pathways was restored and pressure transmission was improved. The flow of syrinx fluid and the diameter of the syrinx decreased after surgery in 15 of 16 patients.
Persistent blockage of the CSF pathways at the foramen magnum resulted in increased pulsation of the cerebellar tonsils, which acted on a partially enclosed cervical subarachnoid space to create elevated cervical CSF pressure waves, which in turn affected the external surface of the spinal cord to force CSF into the spinal cord through the Virchow-Robin spaces and to propel the syrinx fluid caudally, leading to syrinx progression. A surgical procedure that reestablished the CSF pathways at the foramen magnum reversed this pathophysiological mechanism and resolved syringomyelia. Elucidating the pathophysiology of persistent syringomyelia has implications for its primary and secondary treatment.
syringomyelia; therapeutics; radiography; physiology; Arnold-Chiari malformation, Type I
The pathogenesis of syringomyelia in patients with an associated spinal lesion is incompletely understood. The authors hypothesized that in primary spinal syringomyelia, a subarachnoid block effectively shortens the length of the spinal subarachnoid space (SAS), reducing compliance and the ability of the spinal theca to dampen the subarachnoid CSF pressure waves produced by brain expansion during cardiac systole. This creates exaggerated spinal subarachnoid pressure waves during every heartbeat that act on the spinal cord above the block to drive CSF into the spinal cord and create a syrinx. After a syrinx is formed, enlarged subarachnoid pressure waves compress the external surface of the spinal cord, propel the syrinx fluid, and promote syrinx progression.
To elucidate the pathophysiology, the authors prospectively studied 36 adult patients with spinal lesions obstructing the spinal SAS. Testing before surgery included clinical examination; evaluation of anatomy on T1-weighted MRI; measurement of lumbar and cervical subarachnoid mean and pulse pressures at rest, during Valsalva maneuver, during jugular compression, and after removal of CSF (CSF compliance measurement); and evaluation with CT myelography. During surgery, pressure measurements from the SAS above the level of the lesion and the lumbar intrathecal space below the lesion were obtained, and cardiac-gated ultrasonography was performed. One week after surgery, CT myelography was repeated. Three months after surgery, clinical examination, T1-weighted MRI, and CSF pressure recordings (cervical and lumbar) were repeated. Clinical examination and MRI studies were repeated annually thereafter. Findings in patients were compared with those obtained in a group of 18 healthy individuals who had already undergone T1-weighted MRI, cine MRI, and cervical and lumbar subarachnoid pressure testing.
In syringomyelia patients compared with healthy volunteers, cervical subarachnoid pulse pressure was increased (2.7 ± 1.2 vs 1.6 ± 0.6 mm Hg, respectively; p = 0.004), pressure transmission to the thecal sac below the block was reduced, and spinal CSF compliance was decreased. Intraoperative ultrasonography confirmed that pulse pressure waves compressed the outer surface of the spinal cord superior to regions of obstruction of the subarachnoid space.
These findings are consistent with the theory that a spinal subarachnoid block increases spinal subarachnoid pulse pressure above the block, producing a pressure differential across the obstructed segment of the SAS, which results in syrinx formation and progression. These findings are similar to the results of the authors' previous studies that examined the pathophysiology of syringomyelia associated with obstruction of the SAS at the foramen magnum in the Chiari Type I malformation and indicate that a common mechanism, rather than different, separate mechanisms, underlies syrinx formation in these two entities. Clinical trial registration no.: NCT00011245. (http://thejns.org/doi/abs/10.3171/2012.8.SPINE111059)
syringomyelia; physiology; ultrasonography; surgery; cerebrospinal fluid; magnetic resonance imaging; myelography
Nerve transfers are an effective means of restoring control to paralyzed somatic muscle groups and recently shown to be effective in denervated detrusor muscle in a canine model.
A cadaveric project was performed to examine the anatomic feasibility of transferring femoral muscular nerve branches to vesical branches of the pelvic nerve as a method of potentially restoring innervation to control the detrusor muscle in humans using transfer of somatic nerves.
Twenty cadavers were dissected bilaterally to expose pelvic and femoral muscular nerve branches. Ease of access and ability to transfer the nerves were assessed, as were nerve cross sectional areas.
The pelvic nerve was accessed at the base of the bladder, inferior to the ureter and accompanied by inferior vesical vessels. Muscular branches of the femoral nerve to the vastus medialis and intermedius muscles (L3, 4 origins) were followed distally for 17.4 ± 0.8 cm. Two muscle branches were split from the femoral nerve trunk, and tunneled inferior to the inguinal ligament. One was moved medially towards the base of the bladder and linked to the ipsilateral pelvic nerve. The second was tunneled superior to the bladder and linked to the contralateral pelvic nerve. The cross sectional area of the pelvic nerve vesical branch was 2.60 ± 0.169 mm2 (mean ± SEM), and the femoral nerve branches at the suggested transection site was 4.40 ± 0.41 mm2.
Use of femoral nerve muscular branches from the vastus medialis and intermedius muscles for heterotopic nerve transfer of bilateral pelvic nerves is surgically feasible, based on anatomical location and cross sectional areas.
bladder; femoral nerve; nerve transfer; incontinence
Primary malignant spinal glioma represents a significant clinical challenge due to the devastating effect on patient clinical outcomes seen in the majority of cases. As they are infrequently encountered in any one center, there has been little population-based data analysis on the incidence patterns of these aggressive tumors. The objective of this study was to use publically available Surveillance, Epidemiology and End Results (SEER) program data to examine overall incidence and incidence patterns over time with regard to patient age at diagnosis, gender, race, primary site of tumor and histological subtype for patients diagnosed with primary malignant spinal cord gliomas between 1973 and 2006.
The study population of interest was limited to primary, malignant, pathologically confirmed spinal cord gliomas using data from the SEER 9 standard registries for patients diagnosed between 1973 and 2006. Variables of interest included age at diagnosis, gender, race, primary site of tumor, and histological subtype of tumor. The SEER*Stat 6.5.2. program was used to calculate frequencies, age-adjusted incidence rates with 95% confidence intervals and annual percentage change (APC) statistics with a 2-sided p-values. In addition, linear correlation coefficients (R2) were calculated for the time association stratified by variables of interest.
The overall age-adjusted incidence rate for primary malignant spinal gliomas was 0.12 per 100,000 and increased significantly over the study time period (APC= 1.74; p-value=0.0004; R2=0.36). Incidence was highest for patients diagnosed at ages 35–49 (0.17 per 100,000), males (0.14 per 100,000), Whites (0.13 per 100,000) and those who had epdenymomas (0.07 per 100,000). Over the study period, the incidence of ependymomas increased significantly (APC = 3.17; p-value<0.0001; R2=0.58) as did the incidence of these tumors in Whites (APC = 2.13; p-value=0.001) and for both males (APC=1.90, p-value<0.0001) and females (APC=1.60, p-value<0.0001). No significant changes in incidence over time by age of diagnosis were found.
This study demonstrates an increasing overall incidence of primary, malignant spinal cord glioma over the past three decades. Notably, for ependymoma the incidence has increased, while the incidence of most other glioma subtypes remained stable. This may be due to improved diagnostic and surgical techniques, changes in histological classification criteria, and changes in neuro-pathology diagnostic criteria. Although rare, an improved understanding of the incidence of these rare tumors will assist investigators and clinicians in planning potential studies and preparing for allocation of resources to care for these challenging patients.
Spinal cord glioma; incidence; patterns over time; population-based; SEER
Advocates of minimally invasive discectomy (MID) have promoted this operation as an alternative to open discectomy (OD), arguing that there may be less injury to the paraspinal muscles, decreased postoperative pain, and a faster recovery time. However, a recently published large randomized controlled trial (RCT) comparing these approaches reported inferior relief of leg pain in patients undergoing MID. The authors conducted a meta-analysis to evaluate complications and improvement in leg pain in patients with radiculopathy enrolled in RCTs comparing OD to MID.
The authors performed a literature search using Medline and EMBASE of studies indexed between January 1990 and January 2011. Predetermined RCT eligibility included the usage of tubular retractors during MID, a minimum follow-up duration of 1 year, and quantification of pain with the visual analog scale (VAS). Trials that only evaluated patients with recurrent disc herniation were excluded. Data on operative parameters, complications, and VAS scores of leg pain were extracted by 2 investigators. A meta-analysis was performed assuming random effects to determine the difference in mean change for continuous outcomes and the risk ratio for binary outcomes.
Six trials comprising 837 patients (of whom 388 were randomized to MID and 449 were randomized to OD) were included. The mean operative time was 49 minutes during MID and 44 minutes during OD; this difference was not statistically significant. Incidental durotomies occurred significantly more frequently during MID (5.67% compared with 2.90% for OD; RR 2.05, 95% CI 1.05–3.98). Intraoperative complications (incidental durotomies and nerve root injuries) were also significantly more common in patients undergoing MID (RR 2.01, 95% CI 1.07–3.77). The mean preoperative VAS score for leg pain was 6.9 in patients randomized to MID and 7.2 in those randomized to OD. With long-term follow-up (1–2 years postoperatively), the mean VAS score improved to 1.6 in both the MID and OD cohorts. There was no significant difference in relief of leg pain between the 2 approaches with either short-term follow-up (2–3 months postoperatively, 0.81 points on the VAS, 95% CI −4.71 to 6.32) or long-term follow-up (2.64 on the VAS, 95% CI −2.15 to 7.43). Reoperation for recurrent herniation was more common in patients randomized to the MID group (8.50% compared with 5.35% in patients randomized to the OD group), but this difference was not statistically significant (RR 1.56, 95% CI 0.92–2.66). Total complications did not differ significantly between the operations (RR 1.50, 95% CI 0.97–2.33).
The current evidence suggests that both OD and MID lead to a substantial and equivalent long-term improvement in leg pain. Adequate decompression, regardless of the operative approach used, may be the primary determinant of pain relief—the major complaint of many patients with radiculopathy. Incidental durotomies occurred significantly more frequently during MID, but total complications did not differ between the techniques.
Discectomy; incidental durotomy; lumbar spine; meta-analysis; tubular discectomy; sciatica
Nerve transfers are effective for restoring control to paralyzed somatic muscle groups and, recently, even to denervated detrusor muscle in a canine model. A pilot project was performed in cadavers to examine the feasibility of transferring somatic nerves to vesical branches of the pelvic nerve as a method for potentially restoring innervation to control the detrusor muscle in humans.
Eleven cadavers were dissected bilaterally to expose intercostal, ilioinguinal, and iliohypogastric nerves, along with vesical branches of the pelvic nerve. Ease of access and ability to transfer the former 3 nerves to the pelvic vesical nerves were assessed, as were nerve cross-sectional areas.
The pelvic vesical nerves were accessed at the base of the bladder, inferior to the ureter and accompanied by inferior vesical vessels. The T-11 and T-12 intercostal nerves were too short for transfer to the pelvic vesical nerves without grafting. Ilioinguinal and iliohypogastric nerves (L-1 origin) were identified retroperitoneally and, with full dissection, were easily transferred to the pelvic vesical nerves intraabdominally. The mean cross-sectional area of the dominant pelvic vesical branch was 2.60 ± 0.169 mm2; ilioinguinal and iliohypogastric branches at the suggested transection site were 2.38 ± 0.32 mm2 (the means are expressed ± SEM).
Use of the ilioinguinal or iliohypogastric nerves for heterotopic transfer to pelvic vesical nerves is surgically feasible, based on anatomical location and cross-sectional areas.
intercostal nerve; ilioinguinal nerve; pelvic nerve; bladder; cadaver dissection; anatomy
The authors performed a study to determine if lesion expansion occurs in humans during the early hours after spinal cord injury (SCI), as has been established in rodent models of SCI, and to identify factors that might predict lesion expansion.
The authors studied 42 patients with acute cervical SCI and admission American Spinal Injury Association Impairment Scale Grades A (35 patients) and B (7 patients) in whom 2 consecutive MRI scans were obtained 3-134 hours after trauma. They recorded demographic data, clinical information, Injury Severity Score (ISS), admission MRI-documented spinal canal and cord characteristics, and management strategies.
The characteristics of the cohort were as follows: male/female ratio 37:5; mean age, 34.6 years; and cause of injury, motor vehicle collision, falls, and sport injuries in 40 of 42 cases. The first MRI study was performed 6.8 ± 2.7 hours (mean ± SD) after injury, and the second was performed 54.5 ± 32.3 hours after injury. The rostrocaudal intramedullary length of the lesion on the first MRI scan was 59.2 ± 16.1 mm, whereas its length on the second was 88.5 ± 31.9 mm. The principal factors associated with lesion length on the first MRI study were the time between injury and imaging (p = 0.05) and the time to decompression (p = 0.03). The lesion’s rate of rostrocaudal intramedullary expansion in the interval between the first and second MRI was 0.9 ± 0.8 mm/hour. The principal factors associated with the rate of expansion were the maximum spinal cord compression (p = 0.03) and the mechanism of injury (p = 0.05).
Spinal cord injury in humans is characterized by lesion expansion during the hours following trauma. Lesion expansion has a positive relationship with spinal cord compression and may be mitigated by early surgical decompression. Lesion expansion may be a novel surrogate measure by which to assess therapeutic effects in surgical or drug trials.
trauma; spinal cord injury; magnetic resonance imaging; American Spinal Injury Association Impairment Scale; lesion expansion
Nerve transfers are an effective means of restoring control to paralyzed somatic muscle groups and, recently, even denervated detrusor muscle. The authors performed a cadaveric pilot project to examine the feasibility of restoring control to the urethral and anal sphincters using a femoral motor nerve branch to reinnervate the pudendal nerve through a perineal approach.
Eleven cadavers were dissected bilaterally to expose the pudendal and femoral nerve branches. Pertinent landmarks and distances that could be used to locate these nerves were assessed and measured, as were nerve cross-sectional areas.
A long motor branch of the femoral nerve was followed into the distal vastus medialis muscle for a distance of 17.4 ± 0.8 cm, split off from the main femoral nerve trunk, and transferred medially and superiorly to the pudendal nerve in the Alcock canal, a distance of 13.7 ± 0.71 cm. This was performed via a perineal approach. The cross-sectional area of the pudendal nerve was 5.64 ± 0.49 mm2, and the femoral nerve motor branch at the suggested transection site was 4.40 ± 0.41 mm2.
The use of a femoral nerve motor branch to the vastus medialis muscle for heterotopic nerve transfer to the pudendal nerve is surgically feasible, based on anatomical location and cross-sectional areas.
incontinence; reinnervation; nerve transfer; urethra; anal canal; perineum
The relative rarity of spinal cord tumors has hampered the study of these uncommon nervous system malignancies. Consequently, the understanding of the fundamental biology and optimal treatment of spinal cord tumors is limited, and these cancers continue to inflict considerable morbidity and mortality in children and adults. As a first step to improving the outcome of patients affected with spinal cord tumors, the National Institutes of Health Office of Rare Diseases Research in cooperation with the National Cancer Institute and the National Institute of Neurological Disorders and Stroke convened a workshop to discuss the current status of research and clinical management of these tumors. The overall goal of this meeting was to initiate a process that would eventually translate fundamental basic science research into improved clinical care for this group of patients. Investigational priorities for each of these areas were established, and the opportunities for future multidisciplinary research collaborations were identified.
epidemiology; spinal cord tumor; consortium; outcome; glioma; meningioma; metastasis
Glial scar and cystic formation greatly contribute to the inhibition of axonal regeneration after spinal cord injury (SCI). Attempts to promote axonal regeneration are extremely challenging in this type of hostile environment. The objective of this study was to examine the surgical methods that may be used to assess the factors that influence the level of scar and cystic formation in SCI.
In the first part of this study, a complete transection was performed at vertebral level T9–10 in adult female Sprague-Dawley rats. The dura mater was either left open (control group) or was closed using sutures or hyaluronic acid. In the second part of the study, complete or subpial transection was performed, with the same dural closure technique applied to both groups. Histological analysis of longitudinal sections of the spinal cord was performed, and the percentage of scar and cyst formation was determined.
Dural closure using sutures resulted in significantly less glial scar formation (p = 0.0248), while incorporation of the subpial transection surgical technique was then shown to significantly decrease cyst formation (p < 0.0001).
In this study, the authors demonstrated the importance of the vasculature in cyst formation after spinal cord trauma and confirmed the importance of dural closure in reducing glial scar formation.
traumatic spinal cord injury; vascular injury; glial cell response to injury
A 9 year-old girl with syringomyelia and scoliosis was treated with Echols’ procedure, a surgical technique that employs a metal stent to maintain drainage of fluid from the syrinx into the subarachnoid space. The patient presented to our institution 34 years later with a history of progressive myelopathy and surgically-treated deformities of the thoracic spine, lumbar spine, and right foot. Computer-assisted myelography indicated that the metal wire remained in place and that the syrinx had collapsed. Neurological examination and neurophysiological testing confirmed the presence of thoracic myelopathy, which may be due to the wire tethering the thoracic spinal cord to the dorsal dura. This is believed to be the sole long-term report of the effects of Echols’ procedure. The history of direct treatment of syringomyelia is reviewed and is contrasted with indirect treatment of syringomyelia, which relieves the condition by opening obstructed CSF pathways within the foramen magnum or spine.
Syringomyelia; Arnold Chiari Malformation; Type 1; History; Surgery
Biochemical irritation of the dorsal root ganglion (DRG) after intervertebral disc herniation contributes to radiculopathy through tumor necrosis factor–α (TNFα)–mediated inflammation. Soluble TNF receptor Type II (sTNFRII) sequesters this cytokine, providing clinical benefit. Previous work involving conjugation of sTNFRII with thermally responsive elastin-like polypeptide (ELP) yielded a chimeric protein (ELP–sTNFRII) with in vitro anti-TNFα bioactivity. Furthermore, temperature-triggered ELP aggregation into a “depot” prolongs protein residence time following perineural injection. In this study the authors evaluated the inflammatory phenotype of DRG explants after TNFα stimulation, and assessed the abilities of sTNFRII or ELP–sTNFRII to attenuate these neuroinflammatory changes.
Rat lumbar DRGs (35 animals) were treated in 6 groups, as follows: control; TNFα (25 ng/ml); TNFα with low- (0.2 µg/ml) or high-dose (1 µg/ml) sTNFRII; and TNFα with low- (52.5 µg/ml) or high-dose (262.5 µg/ml) ELP–sTNFRII. After 24 hours, supernatant was evaluated for inflammatory cytokines (interleukin [IL]–1, IL-6, and IL-10); prostaglandin E2; and metabolites (glutamate, lactate, and pyruvate). Single-factor analysis of variance with post hoc Dunn analysis (α = 0.05) was used to assess treatment differences.
Incubation of explants with TNFα caused metabolic stress reflected by an increased lactate/pyruvate ratio (1.8 ± 0.5–fold) and extracellular glutamate (79 ± 8% increase). Inflammatory activation was observed with heightened IL-6 release (5.2 ± 1.4–fold) and prostaglandin E2 production (14 ± 3–fold). An autoregulatory response occurred with an 11.8 ± 0.6–fold increase in sTNFRI shedding. Treatment with high doses of sTNFRII or ELP–sTNFRII reversed all changes. Values are expressed as the mean ± standard deviation.
These results demonstrate that TNFa stimulation of DRG explants yields a phenotype of neurotoxic
metabolite release and inflammatory mediator expression. Coincubation with either sTNFRII or ELP–sTNFRII antagonizes TNFa activity to abrogate these changes, suggesting potential for therapeutic intervention to treat peripheral
nerve inflammatory disease.
dorsal root ganglion; elastin-like polypeptide; inflammation; rat; soluble tumor necrosis factor receptor; tumor necrosis factor–α