David B. Pettigrew

Spinal deformity: a new classification derived from neutral upright spinal alignment measurements in asymptomatic juvenile, adolescent, adult, and geriatric individuals.

OBJECTIVE: To evaluate the role of stereotactic radiosurgery (SRS) in the management of recurrent or residual intracranial hemangioblastomas, we assessed tumor control, survival, and complications in 32 consecutive patients. METHODS: We retrospectively reviewed records of 32 consecutive hemangioblastoma patients (74 intracranial tumors) who underwent gamma knife SRS. The median patient age was 43.8 years (range, 21.3-79.4 yr). Thirty-one patients had undergone previous surgical resections. Nineteen patients had sporadic lesions (22 tumors), and 13 patients had von Hippel-Lindau disease-associated hemangioblastomas (52 tumors). The median SRS target volume was 0.72 mL (range, 0.08-16.6 mL), and the median marginal dose was 16.0 Gy (range, 11-20 Gy). RESULTS: At a median of 50.1 months (range, 6.0-165.4 mo), seven patients had died from disease progression, and one patient had died secondary to heart failure. The overall survival after radiosurgery was 100%, 94.4%, and 68.7% at 1, 3, and 7 years, respectively. Follow-up imaging studies demonstrated tumor control in 68 tumors (91.9%). The progression-free survival after SRS at 1, 3, and 5 years was 96.9%, 95.0%, and 89.9%, respectively. Factors associated with an improved progression-free survival included von Hippel-Lindau disease-associated hemangioblastoma, solid tumor, lower tumor volume, and greater marginal dose. CONCLUSION: SRS is an important tool in the management of hemangioblastomas and is associated with a high tumor control rate and a low risk of adverse radiation effects.OBJECTIVEIn this literature review, the authors analyze data from previously published studies that evaluated neutral upright spinal alignment (NUSA) from the occiput to the pelvis in asymptomatic individuals. Based on the data for NUSA in asymptomatic volunteers, a new classification is proposed for spinal deformity. METHODSA review of the English literature was conducted to identify studies evaluating NUSA from the occiput to the pelvis in asymptomatic juvenile, adolescent, adult, and geriatric volunteers. From the literature review, 17 angles and displacements were selected to depict neutral upright coronal and axial spinal alignment, and 21 angles and displacements were selected to depict neutral upright sagittal spinal alignment. Pooled estimates of the mean and variance were calculated for the angles and displacements from the articles that met inclusion criteria. A new classification of spinal deformity was then developed based on age-dependent NUSA; spinal abnormality; deformity curve location, pattern, magnitude, and flexibility; and global spinal alignment. RESULTSDespite a wide variation in the regional curves from the occiput to the pelvis in asymptomatic volunteers, global spinal alignment is maintained in a narrow range for preservation of horizontal gaze and balance of the spine over the pelvis and femoral heads. CONCLUSIONA new classification of spinal deformity is proposed that provides a structure for defining deformity of all patient ages and spinal abnormalities.

Major Neurologic Deficit Immediately After Adult Spinal Surgery: Incidence and Etiology Over 10 Years at a Single Training Institution

Study Design Retrospective study of adult patients who underwent spinal surgery over a 10-year period at a single institution. Objective New onset postoperative paralysis remains one of the most feared complications of spinal surgery. The goal of this study was to determine the incidence and etiology of new onset major neurologic deficit immediately after adult spinal surgery. Summary of Background Data Previous studies, focusing on specific disease entities, have shown incidence rates of significant spinal cord or cauda equina injury after spinal surgery ranging from approximately 0% to 2%. Methods The authors reviewed the quality assurance records for adult patients who underwent spinal surgery over a 10-year period (July 1, 1996 to June 30, 2006) by surgeons in the Department of Neurosurgery, University of Cincinnati College of Medicine at hospitals affiliated with the neurologic surgery residency program. Patients with new onset major neurologic deficit immediately after spinal surgery were identified. Results Of 11,817 adult spinal operations, 21 patients experienced new onset major neurologic deficit immediately after spinal surgery, yielding an overall incidence of 0.178%; in the cervical spine 0.293%, thoracic spine 0.488%, and lumbar/sacral spine 0.0745%. The difference in incidence between spinal regions was statistically significant (P=0.00343). The etiology of the neurologic deficits was confirmed with reoperation and/or postoperative imaging studies: epidural hematoma in 8 patients, inadequate decompression in 5 patients, presumed vascular compromise in 4 patients, graft/cage dislodgement in 2 patients, and presumed surgical trauma in 2 patients. Placement of spinal instrumentation was performed in 12 of 21 patients (57.1%) and was associated with a significantly higher risk of new onset major neurologic deficit immediately after spinal surgery (P=0.022). Conclusions The incidence of new onset major neurologic deficit immediately after adult spinal surgery is low. Epidural hematoma and inadequate decompression were the most common etiologies in this series of patients.

Spinal cord intramedullary pressure in cervical kyphotic deformity: a cadaveric study.

Study Design. In vitro cadaveric study of cervical spinal cord intramedullary pressure (IMP) in kyphotic deformity. Objective. To define the relationship between cervical spinal kyphotic deformity and spinal cord IMP. Summary of Background Data. Previous studies of asymptomatic volunteers have revealed that the greatest variation in regional sagittal neutral upright spinal alignment occurs in the cervical spine with “normal” alignment ranging up to +15 to +20° kyphosis. We sought to determine whether IMP changes in response to increasing cervical kyphosis. Methods. In eight fresh-frozen cadavers, a progressive kyphotic deformity was created. Cadavers were positioned sitting with cervical lordosis, with head stabilized using a skull clamp. The C1 posterior arch was removed, dura was opened, and three pressure sensors were advanced caudally to C7, C4–C5, and C2 within the cord parenchyma. A stepwise kyphotic deformity was then induced by sequentially releasing and retightening the skull clamp while distracting posterior short segment rods and closing anterior segmental osteotomies. After each step, fluoroscopic images and pressure measurements were obtained. The C2–C7 Gore angle and horizontal displacement of the odontoid plumb line relative to C7 (C2–C7 sagittal vertical axis [SVA]) were measured. Results. Minor IMP increases of 2 to 5 mm Hg were observed at one or more spinal cord levels in one of eight cadavers when the Gore angle was <+7.5° and in three of eight cadavers when the Gore angle was >+7.5° and <+21°. At Gore angles exceeding +21°, change in pressure (&Dgr;IMP) progressively increased at one or more spinal cord levels in eight of eight cadavers. Gore angles ranging from +21° to +78° resulted in statistically significant increases in IMP ranging to >50 mm Hg, as did C2–C7 SVA >+75 mm. &Dgr;IMP did not correlate with segmental spinal canal diameter (stenosis). Conclusion. Cervical lordosis and kyphosis less than +7.5° resulted in no meaningful increase in IMP. Minor cervical kyphosis measuring +7.5° to +21° resulted in 2 to 5 mm Hg increases in IMP. As the cervical kyphotic deformity exceeded +21°, IMP increased significantly. &Dgr;IMP with spinal alignment may help to explain the wide range of “normal” cervical neutral upright sagittal alignment in studies of asymptomatic individuals and may help further define cervical kyphotic deformity.

Dynamic properties of regulatory motifs associated with induction of three temporal domains of memory in aplysia.

A model was developed to examine dynamical properties of regulatory motifs correlated with different temporal domains of memory. The model represents short-, intermediate-, and long-term phases of protein kinase A (PKA) activation, which appear related to corresponding phases of facilitation of the Aplysia sensorimotor synapse. The model also represents phosphorylation of the transcription factor CREB1 by PKA and consequent induction of the immediate-early gene Aplysia ubiquitin hydrolase (Ap-uch), which is essential for long-term synaptic facilitation (LTF). Simulations suggest mechanisms responsible for differing profiles of synaptic facilitation following massed vs. spaced exposures to 5-HT, and suggest a novel regulatory motif (gated positive feedback) is important for LTF. Simulations suggest zero-order ultrasensitivity may underlie a requirement of a threshold number of exposures to 5-HT for LTF induction. The model makes predictions for the dynamics of PKA activation and Ap-uch induction when MAP kinase is activated, or when repression of Ap-uch is relieved by inhibiting the transcription factor CREB2. This model may therefore be useful for understanding processes underlying memory formation in Aplysia and other systems.

A simple, efficient tool for assessment of mice after unilateral cortex injury

A refined battery of neurological tests, SNAP (Simple Neuroassessment of Asymmetric Impairment), was developed and validated to efficiently assess neurological deficits induced in a mouse model of traumatic brain injury. Four to 7-month old mice were subjected to unilateral controlled cortical impact or sham injury (craniectomy only). Several behavioral tests (SNAP, beam walk, foot fault, and water maze) were used to assess functional deficits. SNAP was unique among these in that it required no expensive equipment and was performed in less than 5 min per mouse. SNAP demonstrated a high level of sensitivity and specificity as determined by receiver-operator characteristics curve analysis. Interrater reliability was good, as determined by Cohens Kappa method and by comparing the sensitivity and specificity across various raters. SNAP detected deficits in proprioception, visual fields, and motor strength in brain-injured mice at 3 days, and was sensitive enough to detect magnitude and recovery of injury. The contribution of individual battery components changed as a function of time after injury, however, each was important to the overall SNAP score. SNAP provided a sensitive, reliable, time-efficient and cost-effective means of assessing neurological deficits in mice after unilateral brain injury.

Laminectomy, durotomy, and piotomy effects on spinal cord intramedullary pressure in severe cervical and thoracic kyphotic deformity: a cadaveric study.

OBJECT Previous studies have shown that cervical and thoracic kyphotic deformity increases spinal cord intramedullary pressure (IMP). Using a cadaveric model, the authors investigated whether posterior decompression can adequately decrease elevated IMP in severe cervical and thoracic kyphotic deformities. METHODS Using an established cadaveric model, a kyphotic deformity was created in 16 fresh human cadavers (8 cervical and 8 thoracic). A single-level rostral laminotomy and durotomy were performed to place intraparenchymal pressure monitors in the spinal cord at C-2, C4-5, and C-7 in the cervical study group and at T4-5, T7-8, and T11-12 in the thoracic study group. Intramedullary pressure was recorded at maximal kyphosis. Posterior laminar, dural, and pial decompressions were performed while IMP was monitored. In 2 additional cadavers (1 cervical and 1 thoracic), a kyphotic deformity was created and then corrected. RESULTS The creation of the cervical and thoracic kyphotic deformities resulted in significant increases in IMP. The mean increase in cervical and thoracic IMP (change in IMP [ΔIMP]) for all monitored levels was 37.8 ± 7.9 and 46.4 ± 6.4 mm Hg, respectively. After laminectomies were performed, the mean cervical and thoracic IMP was reduced by 22.5% and 18.5%, respectively. After midsagittal durotomies were performed, the mean cervical and thoracic IMP was reduced by 62.8% and 69.9%, respectively. After midsagittal piotomies were performed, the mean cervical and thoracic IMP was reduced by 91.3% and 105.9%, respectively. In 2 cadavers in which a kyphotic deformity was created and then corrected, the ΔIMP increased with the creation of the deformity and returned to zero at all levels when the deformity was corrected. CONCLUSIONS In this cadaveric study, laminar decompression reduced ΔIMP by approximately 15%-25%, while correction of the kyphotic deformity returned ΔIMP to zero. This study helps explain the pathophysiology of myelopathy in kyphotic deformity and the failure of laminectomy alone for cervical and thoracic kyphotic deformities with myelopathy. In addition, the study emphasizes the need for correction of deformity during operative treatment of kyphotic deformity, the need for maintaining adequate intraoperative blood pressure during operative treatment, and the higher risk of spinal cord injury associated with operative treatment of kyphotic deformity.

Global expression of NGF promotes sympathetic axonal growth in CNS white matter but does not alter its parallel orientation.

Axonal regeneration is normally limited after injuries to CNS white matter. Infusion of neurotrophins has been successful in promoting regenerative growth through injured white matter but this growth generally fails to extend beyond the infusion site. These observations are consistent with a chemotropic effect of these factors on axonal growth and support the prevailing view that neurotrophin-induced axonal regeneration requires the use of gradients, i.e., gradually increasing neurotrophin levels along the target fiber tract. To examine the potential of global overexpression of neurotrophins to promote, and/or modify the orientation of, regenerative axonal growth within white matter, we grafted nerve growth factor (NGF) responsive neurons into the corpus callosum of transgenic mice overexpressing NGF throughout the CNS under control of the promoter for glial fibrillary acidic protein. One week later, glial fibrillary acidic protein and chondroitin sulfate proteoglycan immunoreactivity increased within injured white matter around the grafts. NGF levels were significantly higher in the brains of transgenic compared with non-transgenic mice and further elevated within injury sites compared with the homotypic region of the non-injured side. Although there was minimal outgrowth from neurons grafted into non-transgenic mice, extensive parallel axonal regeneration had occurred within the corpus callosum up to 1.5 mm beyond the astrogliotic scar (the site of maximum NGF expression) in transgenic mice. These results demonstrate that global overexpression of neurotrophins does not override the constraints limiting regenerative growth to parallel orientations and suggest that such factors need not be presented as positive gradients to promote axonal regeneration within white matter.

Pia Mater Significantly Contributes to Spinal Cord Intraparenchymal Pressure in a Simulated Model of Edema.

Study Design. Intraparenchymal pressure (IPP) measurements in an in vitro cadaveric model of CNS edema. Objective. To assess the contribution of pia mater to IPP and the effect of piotomy. Summary of Background Data. Multicenter randomized control trials have shown that decompression with durotomy/duroplasty significantly decreases intracranial pressure (ICP). There is a paucity of evidence regarding the effectiveness of decompression of the spinal cord by piotomy. Methods. The supratentorial brain and spinal cord were removed from six fresh cadavers. Dura and arachnoid mater were removed. ICP monitors were placed bilaterally in the frontal and parietal lobes, and centrally in the cervical and thoracic spinal cord. To simulate edema, specimens were submerged in hypotonic solution. IPP was recorded for 5 days. A complete dorsal midline piotomy was performed on the spinal cord and resulting IPP was recorded. Results. Brain and spinal cord both increased in weight. IPP significantly increased in both brain and spinal cord. The IPP increase within the spinal cord was substantially greater (averages: all four lobes = 4.0 mm Hg; cervical = 73.7 mm Hg; thoracic = 49.3 mm Hg). After piotomy, cervical and thoracic spinal cord IPP decreased immediately (avg. postpiotomy IPP = 9.7 and 10.3, respectively). Conclusion. There were differential effects on brain and spinal cord IPP. Brain IPP increased only slightly, possibly because of the absence of the cranium and dura mater. In contrast, spinal cord IPP increased substantially even in the absence of the laminae, dura, and arachnoid mater. Piotomy immediately and dramatically reduced spinal cord IPP. These data are consistent with the hypothesis that spinal cord IPP is primarily dependent on constraints imposed by the pia mater. Conversely, in the absence of the cranium and dura mater, the sulci may permit the pia-invested brain to better accommodate edema without significant increases in IPP. Level of Evidence: N/A

Sympathetic neurite growth on central nervous system sections is region-specific and unaltered by aging.

Several lines of evidence suggest that the brain exhibits reduced plasticity with aging. However, a variety of soluble neurite outgrowth-promoting factors, such as neurotrophins, are not decreased in the aged brain, and aged neurons do not possess dramatically reduced growth potential. The possibility that aging results in reduced baseline substrate-bound neurite outgrowth-promoting activity in the central nervous system (CNS) was evaluated using tissue section culture. There were clear differences between brain regions in the extent of neurite outgrowth on both young and aged brain sections. However, no differences in the extent of neurite outgrowth were observed as a function of age. These results suggest that aging of the rat CNS is not accompanied by major alterations in the baseline neurite outgrowth-promoting substrate properties of the tissue.

Virtual preoperative measurement and surgical manipulation of sagittal spinal alignment using a novel research and educational software program.

Understanding regional as well as global spinal alignment is increasingly recognized as important for the spine surgeon. A novel software program for virtual preoperative measurement and surgical manipulation of sagittal spinal alignment was developed to provide a research and educational tool for spine surgeons. This first-generation software program provides tools to measure sagittal spinal alignment from the occiput to the pelvis, and to allow for virtual surgical manipulation of sagittal spinal alignment. The software was developed in conjunction with Clifton Labs, Inc. Photographs and radiographs were imported into the software program, and a 2D virtual spine was constructed from the images. The software then measured regional and global sagittal spinal alignment from the virtual spine construct, showing the user how to perform the measurements. After measuring alignment, the program allowed for virtual surgical manipulation, simulating surgical procedures such as interbody fusion, facet osteotomy, pedicle subtraction osteotomy, and reduction of spondylolisthesis, as well as allowing for rotation of the pelvis on the hip axis. Following virtual manipulation, the program remeasured regional and global sagittal spinal alignment. Computer software can be used to measure and manipulate sagittal spinal alignment virtually, providing a new research and educational tool. In the future, more comprehensive programs may allow for measurement and interaction in the coronal, axial, and sagittal planes.