Seong Hwan Moon

Modulation of the biologic activity of the rabbit intervertebral disc by gene therapy: an in vivo study of adenovirus-mediated transfer of the human transforming growth factor beta 1 encoding gene.

Study Design. In vivo studies using a rabbit model to determine the biologic effects of direct, adenovirus-mediated transfer of a therapeutic gene to the intervertebral disc.Objectives.1) To deliver an exogenous therapeutic gene to rabbit lumbar intervertebral discs in vivo, 2) to quantify the resulSTUDY DESIGNnIn vivo studies using a rabbit model to determine the biologic effects of direct, adenovirus-mediated transfer of a therapeutic gene to the intervertebral disc.nnnOBJECTIVESn1) To deliver an exogenous therapeutic gene to rabbit lumbar intervertebral discs in vivo, 2) to quantify the resulting amount of gene expression, and 3) to determine the effect on the biologic activity of the discs.nnnSUMMARY OF BACKGROUND DATAnAlthough growth factors such as transforming growth factor beta 1 appear to have promising therapeutic properties, there currently is no practical method for sustained delivery of exogenous growth factors to the disc for the management of certain chronic types of disease (e.g., disc degeneration). A possible solution is to modify the disc cells genetically through gene transfer such that the cells manufacture the desired growth factors endogenously on a continuous basis.nnnMETHODSnSaline, with or without virus, was injected directly into lumbar discs of 22 skeletally mature female New Zealand white rabbits. Group 1 (n = 11) received the adenovirus construct Ad/CMV-hTGF beta 1 containing the therapeutic human transforming growth factor beta 1-encoding gene. Group 2 (n = 6) received adenovirus containing the luciferase marker gene. Group 3 (n = 5) received saline only. The rabbits were killed 1 week after injection. Immunohistochemical staining for human transforming growth factor beta 1 was performed on the disc tissues of one rabbit from Group 1. Nucleus pulposus tissues from the remaining rabbits were cultured in serumless medium. Bioassays were performed to determine human transforming growth factor beta 1 production and proteoglycan synthesis.nnnRESULTSnDiscs injected with Ad/CMV-hTGF beta 1 exhibited extensive and intense positive immunostaining for transforming growth factor beta 1. The nucleus pulposus tissues from the discs injected with Ad/CMV-hTGF beta 1 exhibited a 30-fold increase in active transforming growth factor beta 1 production, and a 5-fold increase in total (active + latent) transforming growth factor beta 1 production over that from intact control discs (P < 0.05). Furthermore, these tissues exhibited a 100% increase in proteoglycan synthesis compared with intact control tissue, which was statistically significant (P < 0.05).nnnCONCLUSIONSnThe results of this study suggest that the intervertebral disc is an appropriate site for adenovirus-mediated transfer of exogenous genes and subsequent production of therapeutic growth factors. Gene therapy therefore may have useful applications for study of the basic science of the intervertebral disc and for clinical management of degenerative disc disease.

Human intervertebral disc cells are genetically modifiable by adenovirus-mediated gene transfer: Implications for the clinical management of intervertebral disc disorders

Study Design. Human intervertebral disc cells were cultured in monolayer and treated with adenovirus-containing marker genes to determine the susceptibility of the cells to adenovirus-mediated gene transfer. Objectives. To test the efficacy of the adenovirus-mediated gene transfer technique for transferring exogenous genes to human intervertebral disc cells in vitro. Summary of Background Data. Upregulated proteoglycan synthesis after direct in vivo adenovirus-mediated transfer of growth factor genes to the rabbit intervertebral disc has previously been reported. Before contemplating extending this approach to the treatment of human disc disease, it is necessary to demonstrate that human intervertebral disc cells are indeed susceptible to adenovirus-mediated gene transduction. Methods. Human intervertebral disc cells were isolated from disc tissue obtained from 15 patients during surgical disc procedures. The cells were cultured in monolayer and treated with saline containing five different doses of adenovirus carrying the lacZ gene (Ad/CMV-lacZ), saline containing adenovirus carrying the luciferase gene (Ad/CMV-luciferase), or saline alone. Transgene expression was analyzed by 5-bromo-4-chloro-3-indolyl-&bgr;-galactosidase (X-Gal) staining and luciferase assay. Results. Adenovirus efficiently transferred lacZ and luciferase marker genes to cells from degenerated discs as well as to cells from nondegenerated discs. A minimum dose of 150 MOI Ad/CMV-lacZ was found to be sufficient to achieve transduction of approximately 100% of disc cells—regardless of patient age, sex, surgical indication, disc level, and degeneration grade. No statistically significant difference in the luciferase activities could be detected in disc cell cultures from degenerated and nondegenerated discs treated with Ad/CMV-luciferase. Conclusions. In vitro transducibility of human intervertebral disc cells by adenovirus is relatively insensitive to disc degeneration grade. Because the rate-limiting step for successful gene therapy is the ability to transfer genesefficiently to the target tissue, the achievement of efficient gene transfer to human intervertebral disc cells(using a direct, adenovirus-mediated approach) is an important and necessary step in the development of gene therapy strategies for the management of human intervertebral disc disorders.

Deep vein thrombosis after major spinal surgery: incidence in an East Asian population.

STUDY DESIGNnA prospective study of 313 patients who underwent major spinal surgery.nnnOBJECTIVESnTo determine the incidence of deep vein thrombosis after major spinal surgery in an east Asian population without antithrombotic prophylaxis.nnnSUMMARY OF BACKGROUND DATAnSpinal surgery has been associated with few thrombotic complications (2-14%) compared with other reconstructive surgeries (20-70%). It has also been well documented that the incidence of deep vein thrombosis in east Asians (10%) is lower than in westerners (20-70%) in total joint replacements. There has been no previous report on the incidence of deep vein thrombosis after reconstructive spinal surgery in east Asians.nnnMETHODSnThree hundred thirteen patients who underwent major spinal surgery were evaluated prospectively. All patients were examined with duplex ultrasonography assessments of both lower extremities. No specific antithrombotic prophylaxis were used in any patients before or after surgery.nnnRESULTSnThere were four patients with positive findings of deep vein thrombosis on duplex ultrasonography, and there was only one with clinically symptomatic deep vein thrombosis. The overall incidence of thrombotic complications was 1.3%, and the incidence of symptomatic deep vein thrombosis was 0.3%.nnnCONCLUSIONnConsidering the low rate of deep vein thrombosis, routine screening and prophylaxis for deep vein thrombosis appears unwarranted in east Asians before or after major spinal surgery.

Facet joint degeneration of the cervical spine: a computed tomographic analysis of 320 patients.

Study Design. Retrospective study. Objective. To determine the frequency of facet arthrosis according to age, sex, and cervical level. In addition, we propose and evaluate a new grading system for cervical facet degeneration. Summary of Background Data. Cervical facets can play an important role in symptomatology. However, there is only one computed tomographic grading system for cervical facet joints. Methods. From January 2003 to January 2012, 1944 patients underwent computed tomography of the cervical spine in our institution. We randomly selected 40 males and 40 females from each of the following age groups: 40 to 49, 50 to 59, 60 to 69, and 70 to 79, such that we had a total of 320 patients. We then graded the degree of arthrosis of the facet joints from C2 to C7 on the axial, sagittal, or coronal images according to 4 grades. These categories were: grade I, normal; grade II, degenerative changes including joint space narrowing, cyst formation, small osteophytes without joint hypertrophy seen; grade III, facet joint hypertrophy from large osteophytes without fusion; and grade IV, bony fusion of the facet joint. The intra- and interobserver reliabilities for the grading system were calculated using reliability statistics by intraclass correlation. Results. Facet arthrosis is common with older patients and at C2–C3, C3–C4, and C4–C5. Facet arthrosis was more common on the left side and in males. Greater than grade III facet joint arthrosis was common in patients older than 60 and at C2–C3, C3–C4, and C4–C5. The reliability statistics by intraclass correlation for the grading system was 0.878 for the intraobserver reliability and 0.869 for the interobserver reliability. Conclusion. It seems that upper cervical levels are more likely to degenerate and to have more advanced degrees of degeneration than the lower cervical levels. As expected, age correlates with worsening degeneration. The proposed computed tomographic grading system for cervical facet arthrosis seemed to be reliable. Level of Evidence: 4

Pelvic obliquity in neuromuscular scoliosis: radiologic comparative results of single-stage posterior versus two-stage anterior and posterior approach.

Study Design. Retrospective comparative study (Level III). Objective. To compare the operative results of posterior fusion and a 2-stage anterior L5-S1 fusion followed by posterior fusion in neuromuscular scoliosis patients with significant pelvic obliquity (PO). Summary of Background Data. PO in neuromuscular scoliosis is common and a challenging problem that affects proper sitting balance, necessarily addressing the deformity and proper maintenance of the correction. Methods. A total of 54 patients with neuromuscular scoliosis and significant PO (>10°) were divided into 2 groups. Group 1 (n = 24) was operated on for posterior fusion and pelvic fixation. Group 2 (n = 30) included patients who were subjected to a first-stage procedure consisting of a lumbosacral junction release and fusion through a midline retroperitoneal approach and then a second-stage procedure of posterior fusion and pelvic fixation. Parameters measured included length of the follow-up, number of fusion levels, age at operation, forced vital capacity, operative time, estimated blood loss, and postoperative complications. Radiologic parameters measured before surgery, after surgery at the time of discharge, and at a final follow-up included Cobb angle, T1 translation, sitting pelvic obliquity (PO) in the frontal plane, C7 plumb line, thoracic kyphosis, lumbar lordosis, and sacral inclination angle in the sagittal plane. Results. The correction of scoliosis was similar in both groups. The preoperative PO averaged 19.5° in Group I and 22.9° in Group II (P = 0.22), which corrected after surgery to 9.7° versus 7.4° (P = 0.23), respectively. Group II correction progressively improved significantly compared to Group I (7.0° vs. 11.6° at P = 0.046) at the latest follow-up. A 40.6% correction (mean correction = 7.9) in sitting PO in Group I compared to 70.7% correction (mean correction = 5.9°) in Group II was observed (P = 0.004). The average loss of correction of PO at the final follow-up was lesser in group II, but not statistically significant (P = 0.07). Conclusion. Anterior fusion of the lumbosacral junction followed by posterior fusion provides superior correction and maintenance of PO in patients with neuromuscular scoliosis.

Functional outcomes in Duchenne muscular dystrophy scoliosis: comparison of the differences between surgical and nonsurgical treatment.

BACKGROUNDnWhile most studies of Duchenne muscular dystrophy scoliosis focus on technical and radiographic indices, functional status is a more important factor to consider in the management of Duchenne muscular dystrophy. The objectives of the current study were to compare the pulmonary function, radiographic outcome, and functional recovery, with use of validated questionnaires, in surgically and nonsurgically treated patients with Duchenne muscular dystrophy who have scoliosis.nnnMETHODSnSixty-six patients (forty treated surgically and twenty-six treated nonsurgically) with a minimum follow-up of two years were included in this study. Forced vital capacity, radiographic parameters (the Cobb angle, lordosis, and pelvic obliquity), and functional status, according to the modified Rancho scale and manual muscle test, were measured preoperatively and at the time of the final follow-up. The Muscular Dystrophy Spine Questionnaire (MDSQ) was completed at the final follow-up evaluation.nnnRESULTSnPulmonary function, functional scores (manual muscle test and modified Rancho scale), and radiographic measurements, except for lordosis, were similar for both groups at the time of the initial consultation (p > 0.05). At the time of the final follow-up, all radiographic parameters were significantly improved in the surgical group compared with the nonsurgical group. The mean score (and standard deviation) on the manual muscle test was not significantly different between the surgical and nonsurgical groups (23.2 ± 8.3 versus 22.8 ± 6.3; p = 0.828). The mean score on the modified Rancho scale also showed similar results in the groups (3.9 ± 0.3 and 4.04 ± 0.3, respectively; p = 0.088). The surgical group had higher mean MDSQ scores than the nonsurgical group (35.1 ± 14.7 and 26.9 ± 9.9, respectively; p = 0.008). Both groups showed a decrease in forced vital capacity at the time of the final follow-up, but the deterioration of forced vital capacity was significantly slower (p = 0.035) in the surgical group (268 ± 361 mL) than in the nonsurgical group (536 ± 323 mL).nnnCONCLUSIONSnSurgery in patients who had Duchenne muscular dystrophy with scoliosis improved function and decreased the rate of deterioration of forced vital capacity compared with patients treated conservatively. However, the muscle power and forced vital capacity decreased in both groups.

Safety evaluation of freehand lateral mass screw fixation in the subaxial cervical spine: evaluation of 1256 screws.

Study Design. Prospective study. Objective. To evaluate the safety of the lateral mass screw (LMS) fixation. Summary of Background Data. LMS fixation has been known to have risk of injury to vertebral artery, nerve root, or facet joints. Methods. A consecutive series of 178 patients undergoing planned LMS fixation were studied. Screw fixation was performed using the freehand technique. Entry point of screws was 2-mm medial from the center of the lateral mass. Planned divergent angle of the screw was 30º. Bicortical fixation was tried in all cases. After the surgery, all patients underwent 3-dimensional computed tomographic scan of the cervical spine. We checked the number of screws in each level, divergent angle of the screws, and violation of foramen transversarium (FT), intervertebral foramen, or facet joint by screws. A reliability test was performed. Results. Total 1256 screws were fixed with 269 at C3, 318 at C4, 331 at C5, and 338 screws at C6. Mean divergent angle of the screws were 34.7º/33.1º at C3, 33.9 º/32.1º at C4, 34.7º/32.7º at C5, and 33.6º/30.7º at C6. Incidence of FT violation was 0.876%. FT violation was most common at C6 (6/11 violations). Mean divergent angle in cases of FT violation was 15.0º and was significantly smaller than that of safe cases. There was no injury to vertebral artery. There was no violation of intervertebral foramen. Incidence of facet violation was 1.433%. Seventeen facet violations were within fusion segment. Only 1 screw violated healthy facet. Facet violation was most common at C3 (12/18 violations). Conclusion. LMS fixation is a safe stabilizing technique with very low incidence of violation of FT, intervertebral foramen, and facet. There is a possibility of FT violation if the divergent angle was small. FT violation was most common at C6. Facet violation was most common at C3. Level of Evidence: 2

Clinical Outcome and Changes of Foraminal Dimension in Patients With Foraminal Stenosis After ACDF.

Study Design: Prospective study. Objective: To determine the clinical outcome and change in foraminal dimension after anterior cervical discectomy and fusion (ACDF) and to investigate the correlation between clinical outcome and foraminal dimension. Summary of Background Data: No previous studies have evaluated the correlation between clinical outcome and foraminal dimension after ACDF in foraminal stenosis. Methods: A consecutive series of 44 patients (114 foramina) undergoing planned ACDF due to foraminal stenosis were studied. Clinical outcomes included the neck pain visual analogue scale (VAS), arm pain VAS, neck disability index (NDI), subjective improvement rate, dysphasia, and donor site pain. Radiologic outcomes included anterior and posterior disk height, height of foramen and anterior-posterior diameter of the foramen, and the Cobb angle of the fusion segment. Foraminal dimension was calculated. Results: The neck pain VAS decreased from 3.7 preoperatively to 2.3 postoperatively. Likewise, arm pain VAS decreased from 7.2 to 2.2, and NDI decreased from 31.0% to 17.2%. Mild dysphasia occurred in 3 patients. There was no donor site pain. Subjective improvement rate was 79.3%. The anterior disk height increased from 4.75 mm preoperatively to 7.01 mm postoperatively. Likewise, posterior disk height increased from 4.11 to 5.74 mm, height of foramen increased from 7.30 to 9.25 mm, anterior-posterior diameter of foramen increased from 3.56 to 4.92 mm, dimension of foramen increased from 20.50 to 35.58 mm2, and segmental angle of fusion segment increased from 2.87 to 4.95 degrees. Posterior disk height was positively correlated with foraminal dimension. An increased segmental angle was negatively correlated with foraminal dimension. The foraminal dimension was negatively correlated with the arm pain VAS. Conclusions: ACDF in cervical foraminal stenosis was a useful surgical option to improve clinical outcomes and widen the foraminal dimension. The foraminal dimension was negatively correlated with the arm pain. Restoration of posterior disk height was necessary to widen the foraminal dimension, whereas increased lordosis of the fusion segment did not help to widen the foraminal dimension.

Prognostic factors for surgical outcomes including preoperative total knee replacement and knee osteoarthritis status in female patients with lumbar spinal stenosis

Study Design: A retrospective clinical case series. Objective: To investigate knee osteoarthritis (KOA) and total knee replacement (TKR) status as prognostic factors for surgical outcomes in female patients with lumbar spinal stenosis (LSS). Summary of Background Data: There have been many reports on numerous prognostic factors for surgical outcomes in patients with degenerative lumbar conditions; however, there has been no report on the surgical outcome in patients who underwent spinal surgery with coexisting KOA and TKR. Methods: This study included 141 female patients (mean age, 67.6 y) who underwent spinal surgery for LSS between January 2006 and December 2010. At 1 year postoperatively, surgical outcomes were measured using the Oswestry disability index (ODI). Various clinical factors including KOA and TKR were analyzed as prognostic factors for surgical outcomes. Results: Mean average scores at preoperative evaluation were 26.1±6.6 in the no KOA group, 23.6±7.9 in the KOA group, and 30.4±6.7 in the TKR group (P<0.05). Mean average scores at postoperative 1 year were 13.8±8.5 in the no KOA group, 16.8±9.5 in the KOA group, and 21.4±5.7 in the TKR group (P<0.05, Mann-Whitney U test). Preoperative ODI scores were shown to be significantly affected by the TKR status only (P<0.05), and were significantly higher in the TKR patient group. ODI scores at postoperative 3 months were significantly correlated with the preoperative ODI and the operational level (P<0.05). At postoperative 1 year, ODI scores were shown to be affected by the operational level, the preoperative ODI, and the presence of advanced radiographic KOA (Kellgren/Lawrence grades III and IV) (P<0.05). Conclusions: A poor preoperative functional score, the presence of preoperative KOA, and longer operational levels were shown to be poor prognostic factors for the 1-year surgical outcome of LSS. Also, patients in the TKR group showed the worst ODI scores at preoperative and postoperative 1-year evaluations. Consideration of these factors when planning for spine surgery could be helpful in predicting the surgical outcomes of lumbar spinal surgery.

The thoracic lordosis correction improves sacral slope and walking ability in neuromuscular scoliosis

Study Design:Retrospective study. Objective:To report on neuromuscular patients with preserved walking ability, but forward bending of the body due to thoracic lordosis, and to suggest thoracic lordosis correction as the surgical treatment. Summary of Background Data:It is an established fact that lumbar lordosis or pelvic parameter is directly related to thoracic sagittal balance. However, the reverse relationship has not been fully defined yet. Loss of thoracic kyphosis results in positive sagittal balance, which causes walking difficulty. Neuromuscular patients with thoracic lordosis have not been reported yet, and there have been no reports on their surgical treatments. Methods:This study analyzed 8 patients treated with thoracic lordosis correction surgery. Every patient was diagnosed with muscular dystrophy. In thoracic lordosis correction surgery, anterior release was performed in the first stage and posterior segmental instrumentation was performed in the second stage. Radiographic parameters were compared and walking ability was evaluated with gait analysis. All patients were classified according to the modified Rancho Los Amigos Hospital system preoperatively and 2 years postoperatively to evaluate functional ability. The average follow-up period was 2.9 years. Results:Before surgery, the mean thoracic sagittal alignment was −2.1-degree lordosis, the mean Cobb angle and sacral slope increased to 36.3 and 56.6 degrees, respectively. The anterior pelvic tilt in gait analysis was 29.3 degrees. At last follow-up after surgery, the mean thoracic sagittal alignment changed to 12.6-degree kyphosis, and the Cobb angle and sacral slope decreased to 18.9 and 39.5 degrees, respectively. Lumbar lordosis and the sacral slope showed significant positive correlation (P<0.001). The improvement in thoracic lordosis showed a significant correlation to the preoperative flexibility of the major curve (P=0.028). The anterior pelvic tilt in gait analysis improved to 15.4 degrees. The functional ability improved in 2 (50%) of 4 patients in class 2 and maintained in remaining 6 patients 2 years after surgery. Conclusions:Thoracic lordosis correction surgery in neuromuscular scoliosis patients with thoracic lordosis improved the sacral slope in the standing position and the anterior pelvic tilt in gait. Sagittal imbalance was compensated by the spinopelvic mechanism, and back and hip extensor muscles seem to play a major role in this compensation.