Charles Kuntz

A Phase I/IIa Clinical Trial of a Recombinant Rho Protein Antagonist in Acute Spinal Cord Injury

Multiple lines of evidence have validated the Rho pathway as important in controlling the neuronal response to growth inhibitory proteins after central nervous system (CNS) injury. A drug called BA-210 (trademarked as Cethrin(®)) blocks activation of Rho and has shown promise in pre-clinical animal studies in being used to treat spinal cord injury (SCI). This is a report of a Phase I/IIa clinical study designed to test the safety and tolerability of the drug, and the neurological status of patients following the administration of a single dose of BA-210 applied during surgery following acute SCI. Patients with thoracic (T2-T12) or cervical (C4-T1) SCI were sequentially recruited for this dose-ranging (0.3 mg to 9 mg Cethrin), multi-center study of 48 patients with complete American Spinal Injury Association assessment (ASIA) A. Vital signs; clinical laboratory tests; computed tomography (CT) scans of the spine, head, and abdomen; magnetic resonance imaging (MRI) of the spine, and ASIA assessment were performed in the pre-study period and in follow-up periods out to 1 year after treatment. The treatment-emergent adverse events that were reported were typical for a population of acute SCI patients, and no serious adverse events were attributed to the drug. The pharmacokinetic analysis showed low levels of systemic exposure to the drug, and there was high inter-patient variability. Changes in ASIA motor scores from baseline were low across all dose groups in thoracic patients (1.8±5.1) and larger in cervical patients (18.6±19.3). The largest change in motor score was observed in the cervical patients treated with 3 mg of Cethrin in whom a 27.3±13.3 point improvement in ASIA motor score at 12 months was observed. Approximately 6% of thoracic patients converted from ASIA A to ASIA C or D compared to 31% of cervical patients and 66% for the 3-mg cervical cohort. Although the patient numbers are small, the observed motor recovery in this open-label trial suggests that BA-210 may increase neurological recovery after complete SCI. Further clinical trials with Cethrin in SCI patients are planned, to establish evidence of efficacy.

Accuracy of Thoracic Vertebral Body Screw Placement Using Standard Fluoroscopy, Fluoroscopic Image Guidance, and Computed Tomographic Image Guidance: A Cadaver Study

Study Design. A surgical simulation study in human cadaver spine specimens was conducted to evaluate the accuracy of thoracic vertebral body screw placement using four different intraoperative imaging techniques. Objective. To compare standard fluoroscopy, fluoroscopy-based image guidance with two different referencing methods, and computed tomography–based image guidance by the measuring the time required for screw placement, the radiation exposure to specimen and surgeon, and the accuracy of screw position in the thoracic spine. Summary of Background Data. Image guidance provides additional anatomic information to the surgeon and may improve safety of technically difficult surgical procedures. The placement of screws in the thoracic spine is a technically demanding procedure in which inaccurate screw positioning places the spinal cord, nerve roots, and paraspinal structures such as the aorta and pleural space at risk for injury. Image-guided surgery may improve the accuracy of thoracic screw placement. Methods. Using four different intraoperative imaging methods, two experienced surgeons placed 337 vertebral body screws through the pedicles of thoracic vertebrae in 20 human cadaver thoracic spine specimens. The specimens then were examined with radiographs, computed tomography, and anatomic dissection to determine screw position. Measurements included procedure setup and screw insertion time, radiation exposure to the specimen, the surgeon’s hand, the surgeon’s body, frequency, direction, and magnitude of screw perforation through the cortical margins of thoracic vertebrae. Results. As compared with surgery using standard fluoroscopy, fluoroscopy-based image guidance that uses multiple reference marks and computed tomography–based image guidance improves the accuracy of thoracic vertebral body screws, but increases the time required for screw placement and the specimen radiation exposure. Exposure to radiation is minimal at the surgeon’s body level and dependent on surgical technique at the surgeon’s hand level. Screw perforation occurs most frequently in the lateral direction. Conclusions. Fluoroscopy-based image guidance that uses only a single reference marker for the entire thoracic spine is highly inaccurate and unsafe. Systems with registration based on the instrumented vertebrae provide more accurate placement of thoracic vertebral body screws than standard fluoroscopy, but expose the patient to more radiation and require more time for screw insertion.

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.

Disruption of the hyaluronan-based extracellular matrix in spinal cord promotes astrocyte proliferation.

Astrocyte proliferation is tightly controlled during development and in the adult nervous system. In the present study, we find that a high‐molecular‐weight (MW) form of the glycosaminoglycan hyaluronan (HA) is found in rat spinal cord tissue and becomes degraded soon after traumatic spinal cord injury. Newly synthesized HA accumulates in injured spinal cord as gliosis proceeds, such that high‐MW HA becomes overabundant in the extracellular matrix surrounding glial scars after 1 month. Injection of hyaluronidase, which degrades HA, into normal spinal cord tissue results in increased numbers of glial fibrillary acidic protein (GFAP)‐positive cells that also express the nuclear proliferation marker Ki‐67, suggesting that HA degradation promotes astrocyte proliferation. In agreement with this observation, adding high‐ but not low‐MW HA to proliferating astrocytes in vitro inhibits cell growth, while treating confluent, quiescent astrocyte cultures with hyaluronidase induces astrocyte proliferation. Collectively, these data indicate that high‐MW HA maintains astrocytes in a state of quiescence, and that degradation of HA following CNS injury relieves growth inhibition, resulting in increased astrocyte proliferation.

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.

Prospective Evaluation of Thoracic Pedicle Screw Placement Using Fluoroscopic Imaging

Background: In this 1 prospective 18-month study, 29 patients underwent posterior thoracic instrumentation with placement of 209 transpedicular screws guided by intraoperative fluoroscopic imaging and anatomic landmarks. We assessed the safety, accuracy, complications, and early stability of this technique. Methods: Pedicle and pedicle-rib units were measured, and screw cortical penetrations were graded on anatomy and depth of penetration. All 29 patients underwent preoperative computed tomographic (CT) imaging, and 28 underwent postoperative CT imaging (199/209 screws). Results: From T2 to T12, screw diameters were ≥5 mm with mean medial screw angulation measuring 20–25°. Of the 209 screws placed from T1 to T12, 111 had diameters greater than or equal to the pedicle width. From T3 to T9, the mean diameter of the pedicle screws exceeded the mean pedicle width. Lateral pedicle wall penetration occurred significantly more often than superior, inferior, and medial pedicle wall penetrations and anterolateral vertebral body penetration. Five of six high-risk screw penetrations occurred in one patient when intraoperative technique was compromised. We observed no new postoperative neurologic deficits, visceral injuries, or pedicle screw instrumentation failures. The three high-risk anterolateral vertebral body penetrations at T1 and T2 were associated with a significantly decreased mean screw transverse angle; the three high-risk medial pedicle wall penetrations occurring from T3 to T9 were associated with a significantly increased mean screw transverse angle. Among all 26 patients available at postoperative follow-up (mean 11.9 months), the mean loss of kyphosis correction was 2.0°. Conclusions: Guided by intraoperative fluoroscopic imaging and anatomic landmarks, thoracic pedicle screws can be placed safely. Early clinical follow-up reveals excellent results with minimal loss of kyphosis correction.

Classification systems for adolescent and adult scoliosis.

OBJECTIVETo review current classification systems for adolescent and adult scoliosis. METHODSThe literature was reviewed in reference to scoliosis classification systems for adolescent and adult scoliosis. RESULTSThere are multiple classification systems for scoliosis. Classification of scoliosis is dependent on patient age, spinal abnormality, scoliotic curve, and global spinal alignment. To date, classification systems have focused predominantly on adolescent idiopathic scoliosis or adult/degenerative scoliosis; a single classification system evaluating scoliotic deformities of different ages and spinal abnormalities has not been identified. CONCLUSIONThe importance of scoliosis classification schemes lies in their ability to standardize communication among health care providers. With regard to the classification of adolescent scoliosis, the Lenke system has addressed many of the significant limitations of the King system and is now the standard classification scheme. Classification schemes for adult scoliosis have been reported only recently, and each offers specific advantages (the simple pathogenesis-based system of Aebi, the strong clinical relevance of the Schwab system, and the richly descriptive Scoliosis Research Society system). This article highlights the salient features of currently used scoliosis classification systems.

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.

Hyaluronate-based extracellular matrix: keeping glia in their place.

Hyaluronate (HA; also called hyaluronic acid; hyaluronan) is a nonsulfated, protein-free polysaccharide found in nearly all extracellular matrices (Fraser et al., 1997; Toole, 2001). A variety of functions have been ascribed to HA, including maintenance of the overall conformation of matrix surrounding cells and the creation of cell-free spaces upon hydration. HA can also activate cell surface receptors, described below, that influence intracellular signaling cascades affecting cell growth, migration, and differentiation. In the nervous system, HA functions in conjunction with a number of HA-binding proteoglycans, including the versican family, aggrecan, neurocan, and brevican (reviewed by Bandtlow and Zimmerman, 2000). These aggregating proteoglycans, collectively referred to as hyalectans (or lecticans) carry predominantly chondroitin sulfate side-chains on core proteins that share structural motifs in their Nand C-termini. HA and the hyalectans have been implicated in regulating neural crest, glial cell and neuronal migration, axonal pathfinding, and synaptic modulation. While there have been numerous studies on the roles of hyalectans and other proteoglycans in the nervous system (for excellent reviews, see Margolis and Margolis, 1993; Oohira et al., 1994; Bandtlow and Zimmerman, 2000; Hartmann and Maurer, 2001), many of the functions of HA are only now being elucidated. In the present study, we discuss current findings on the roles of HA and HA-proteoglycan interactions in the developing, adult, and diseased nervous system, and propose a model for how HA influences glial cell growth, migration, and differentiation.

Long-term follow-up of cervical radiographic sagittal spinal alignment after 1- and 2-level cervical corpectomy for the treatment of spondylosis of the subaxial cervical spine causing radiculomyelopathy or myelopathy: a retrospective study

OBJECT Few data exist regarding long-term outcomes after cervical corpectomy for spondylotic cervical myelopathy and radiculomyelopathy. In this retrospective review, long-term radiographic outcomes are reported for 130 patients after 1- or 2-level cervical corpectomy for spondylotic myelopathy or radiculomyelopathy. METHODS Electronic medical records including clinical data and radiographic images during a 15-year period (1993-2008) were reviewed at the Cincinnati Department of Veterans Affairs Medical Center. All patients underwent radiographic follow-up for at least 12 months (range 12-156, mean 45 ± 39.3 months), as well as clinical follow-up performed by neurosurgery staff for a mean of 29.3 ± 39.6 months (range 4-156 months). Clinical parameters at surgery and last examination included the Chiles modified Japanese Orthopaedic Association (mJOA) Myelopathy Scale. Measurements included cervical spine sagittal alignment on lateral radiographs preoperatively and postoperatively, focal Cobb angles at operated levels, and C2-7 regional alignment. Statistical analysis included the Student t-test and chi-square test. Perioperative complications and additional surgery in the cervical spine were recorded. RESULTS The mJOA scores improved from a mean of 11.91 ± 2.4 preoperatively to 14.9 ± 2.33 postoperatively. The mean sagittal lordosis of the C2-7 spine increased from -16.2° ± 9.2° preoperatively to -18.5° ± 11.9° at last follow-up. Focal Cobb angles averaged a slight kyphotic angulation of 4.1° ± 2.3° at latest radiographic follow-up; of note, 7 patients (5.4%), all who had cylindrical titanium mesh cages (CTMCs), showed severe kyphotic angulation (+8.4° ± 2.4°). Patients with preoperative myelopathy showed clinical improvement at follow-up. The fusion rate was 96.2%; 3 of the 5 patients with radiographic evidence of nonfusion were smokers. Patients with postoperative kyphosis had significantly more chronic neck pain (visual analog scale score >4 lasting more than 6 months) and visits related to pain (p <0.01). Those with CTMCs had higher rates of postoperative kyphosis, chronic neck pain, and visits related to pain, irrespective of the number of levels fused (p <001). At latest follow-up, although a kyphotic increase occurred in the focal cervical sagittal Cobb angles, lordosis increased in C2-7 sagittal Gore angles. Two patients (1.5%) underwent revision of the implanted graft and/or hardware, and 5 patients (3.8%) had another procedure for adjacent-level pathologies 1-9 years later (mean 4.4 ± 2.7 years). CONCLUSIONS Long-term follow-up data in our veteran population support cervical corpectomy as an effective, long-lasting treatment for spondylotic myelopathy of the cervical spine. Use of CTMCs without end caps was associated with statistically significant increased postoperative kyphotic angulation and chronic pain. Despite an increase in focal kyphosis over time, regional cervical sagittal lordotic alignment had increased at the latest follow-up. Further investigation will include the association of chronic neck pain and postoperative kyphosis, and high fusion rates among a veteran population of heavy smokers.