Erik Curtis

172 A Phase I, Open-Label, Single-Site, Safety Study of Human Spinal Cord-Derived Neural Stem Cell Transplantation for the Treatment of Chronic Spinal Cord Injury.

INTRODUCTION Spinal cord injury (SCI) resulting in paraplegia or quadriplegia is a significant burden in the world. It is estimated that there are approximately 250 000 people living with SCI in the United States alone. Our study offered the direct implantation of human-derived stem cells into the spinal cord of subjects who have chronic SCI. The primary objective of the study is to determine the safety and toxicity of human spinal stem cell transplantation for the treatment of paralysis. The secondary objectives of the study are to evaluate (1) graft survival in the transplant site, (2) effectiveness of transient immunosuppression as determined by absence of donor-specific HLA antibodies, and (3) potential therapeutic role of implantation on motor and sensory function in SCI. METHODS This is a phase I, open-label, single-site, study of human spinal cord-derived neural stem cell (HSSC) transplantation for the treatment of chronic SCI. Four subjects with chronic SCI with ASIA A SCI who met eligibility criteria were enrolled. All subjects received spinal cord injections of HSSC. The treatment consisted of removal of spinal instrumentation followed by direct injections into spinal parenchyma. Six HSSC injections were administered in each subject. Each injection consisted of 2 × 10 cells in 10 µL. RESULTS Four subjects have been implanted to date. All subjects tolerated the procedure well and there have been no major adverse events to date. Prospective data has been collected including ISNCSCI scores, ASIA level, functional and pain surveys, SCIM scores, Sensory and Motor Evoked potentials, EMG, and MRI including a novel sequence of MR spinal diffusion tensor imaging (DTI). These metrics are continuing to be collected and evaluated. CONCLUSION We can conclude that (1) HSSC transplanted into the injury site of a spinal cord in chronic spinal cord injury patients can be done safely. (2) The HSSC graft has been shown to have no major adverse events to date.

Potent spinal parenchymal AAV9-mediated gene delivery by subpial injection in adult rats and pigs

Effective in vivo use of adeno-associated virus (AAV)-based vectors to achieve gene-specific silencing or upregulation in the central nervous system has been limited by the inability to provide more than limited deep parenchymal expression in adult animals using delivery routes with the most clinical relevance (intravenous or intrathecal). Here, we demonstrate that the spinal pia membrane represents the primary barrier limiting effective AAV9 penetration into the spinal parenchyma after intrathecal AAV9 delivery. We develop a novel subpial AAV9 delivery technique and AAV9-dextran formulation. We use these in adult rats and pigs to show (i) potent spinal parenchymal transgene expression in white and gray matter including neurons, glial and endothelial cells after single bolus subpial AAV9 delivery; (ii) delivery to almost all apparent descending motor axons throughout the length of the spinal cord after cervical or thoracic subpial AAV9 injection; (iii) potent retrograde transgene expression in brain motor centers (motor cortex and brain stem); and (iv) the relative safety of this approach by defining normal neurological function for up to 6 months after AAV9 delivery. Thus, subpial delivery of AAV9 enables gene-based therapies with a wide range of potential experimental and clinical utilizations in adult animals and human patients.

A Review of Stem Cell Therapy for Spinal Cord Injury: Large Animal Models and the Frontier in Humans.

OBJECTIVE To review the literature of spinal cord injury and stem cell therapy for large animal models and incorporate those results into an understanding of stem cell therapy for human cord injury. METHODS Review of the literature. RESULTS Eleven canine studies were identified and 3 sub-human primate studies were identified showing variable results. CONCLUSIONS Stem cell therapy is a promising therapeutic option for patients with spinal cord injury; however, the technology has many un-answered questions and further research is needed.

A matched cohort comparison of cervical disc arthroplasty versus anterior cervical discectomy and fusion: Evaluating perioperative outcomes

OBJECTIVE Cervical disc arthroplasty (CDA) is a recent alternative to anterior cervical discectomy and fusion (ACDF) in patients suffering cervical disc herniation and degeneration. To date, a systematic analysis of their comparative advantages and risks following elective surgery remains elusive. METHODS Adult patients undergoing elective CDA or ACDF were extracted from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database years 2011-2014. A total of 19,369 patients were matched 1:1 by age, sex, functional status, charlson comorbidity index, ASA classification, BMI classification, and number of vertebral levels operated on during surgery. This matching process led to a final sample of 588 subjects (294 CDA, 294 ACDF). Multivariable regression was performed for five outcome measures: operation time, early complications, reoperation rates, hospital length of stay (HLOS), and discharge destination. Mean differences (B), odds ratios (OR) and associated 95% confidence intervals (CI) are reported. RESULTS Compared to ACDF, CDA was associated with decreased mean operation time (B=-18.78-min, 95% CI [-29.13, -8.42]; p<0.001), decreased HLOS (B=-0.44-days [-0.77, -0.11]; p=0.009), and increased likelihood of discharge to home (OR=5.39 [1.14-25.43]; p=0.033). No differences in reoperation rates and complications were found. CONCLUSION In a matched cohort analysis, CDA performs comparably to ACDF and is associated with decreased operation time and HLOS, and increased likelihood of discharge to home, without differences in 30-day complications or reoperation rates. Future prospective studies are warranted.

345 Elective Anterior Cervical Discectomy and Fusion vs Cervical Artificial Disc Replacement: A Comparison of Perioperative Morbidity and Early Outcomes.

INTRODUCTION We conducted a retrospective cohort analysis of early outcomes after elective anterior cervical discectomy and fusion (ACDF) vs cervical artificial disc replacement (C-ADR) using the National Surgical Quality Improvement Program database. Risk factors associated with operation time, hospital length of stay, early complications, and discharge destination were studied. METHODS Adult patients undergoing elective ACDF or C-ADR were abstracted from American College of Surgeons National Surgical Quality Improvement Program years 2011 to 2014. Univariate analyses were performed by surgery cohort for each outcome, and corrected for demographic/clinical variables (age = 65, sex, race, body mass index (BMI), ASA score, functional status, inpatient/outpatient status, smoking, hypertension, Charlson Comorbidity Index) using multivariable regression. Means, standard errors, odds ratio (OR), and 95% confidence intervals (CIs) are reported. Significance was assessed at P < .05. RESULTS Of 18 067 subjects (ACDF = 17 296, C-ADR = 771), C-ADR subjects were on average younger (<65 years: 97.4% vs 84.2%; P < .001), less obese (nonobese: 6.10% vs 49.1%; P < .001), less physically burdened (ASA 1: 13.1% vs 4.3%; ASA 3-4: 17.9% vs 38.3%; P < .001), less functionally dependent (0.5% vs 2.2%; P < .001), and presented with fewer overall comorbidities (3.9% vs 6.4%; P < .001). Overall, 31 (0.17%) patients died. Univariate analyses showed that C-ADR had shorter operation time (111.27 ± 1.89-minutes vs 125.59 ± 0.53-minutes; P < .001), shorter hospital length of stay (HLOS) (1.06 ± 0.03 days vs 1.64 ± 0.04 days; P = .003), and higher likelihood of being discharged to home (99.5% vs 96.9%, P < .001). Multivariable analysis confirmed C-ADR association with shorter operation time (B = -9.37; 95% CI, -14.34 to -4.01) and with greater likelihood of returning home (OR, 2.74 [1.01, 7.41]), while a nonsignificant statistical trend was demonstrated for HLOS (B = -0.35; 95% CI, -0.73 to 0.03). Incidences of early complications did not differ between C-ADR and ACDF (1.4% vs 2.5%, P = .620). CONCLUSION Patients selected for elective C-ADR demonstrate lower comorbidity profiles than ACDF. Compared with ACDF, C-ADR is associated with decreased operative times and increased likelihood of being discharged home. Future studies are needed to confirm these findings.

Traumatic L5 Posterolateral Spondyloptosis: A Case Report and Review of the Literature

Traumatic retrolisthesis of the lumbar spine is a rare clinical entity. Only a few case reports have shown retrolisthesis of the fractured fragment over the inferior vertebral body. Fracture dislocations of the spine are unstable injuries that require operative fixation to restore alignment and prevent progressive deformity. We present the case of a traumatic L5-S1 fracture dislocation with retrolisthesis of the L5 vertebral body over the superior aspect of S1 managed with anterior, middle, and posterior column reconstruction. The patient presented with paraplegia and bowel and bladder incontinence. Retrolisthesis fracture dislocations injuries are rare, and as such, there are no guidelines regarding their management. In our case, we performed an L5 vertebrectomy with anterior, middle, and posterior column reconstruction via a posterior approach using a lumbosacral-pelvic construct. The patient did not regain function in his distal lower extremities postoperatively.

Anterior Versus Transforaminal Lumbar Interbody Fusion: Perioperative Risk Factors and 30-Day Outcomes

ABSTRACT Background: Operative management of lower back pain often necessitates anterior lumbar interbody fusion (ALIF) or transforaminal lumbar interbody fusion (TLIF). Specific pathoanatomic advantages and indications exist for both approaches, and few studies to date have characterized comparative early outcomes. Methods: Adult patients undergoing elective ALIF or TLIF operations were abstracted from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) years 2011–2014. Univariate analyses were performed by surgery cohort for each outcome and adjusted for demographic/clinical variables (age ≥ 65, sex, race, body mass index, American Society of Anesthesiologists physical classification score, functional status, inpatient/outpatient status, smoking, hypertension, Charlson Comorbidity Index) using multivariable regression. Means, standard errors, mean differences (B), odds ratios (ORs), and associated 95% confidence intervals (CIs) are reported. Significance was assessed at P < .05. Results: Of 8263 subjects (ALIF: 4325, TLIF: 3938), ALIF subjects were younger, less obese, less physically impaired, and had significantly lower rates of hypertension, diabetes, coagulopathy, and previous cardiac surgery. On multivariable analysis, ALIF associated with shorter operative time (B = −11.80 minutes, 95% CI [−16.48, −7.12]; P < .001). Transforaminal lumbar interbody fusion was associated with increased incidence of urinary tract infections (UTIs; OR = 1.57, 95% CI [1.10, 2.26]; P = .013) and of blood transfusions (OR = 1.19, 95% CI [1.04, 1.37]; P = .012). Multivariate analysis also demonstrated TLIF associated with shorter hospital length of stay (B = −0.27 days, 95% CI [−0.54, −0.01]; P = .041), and fewer cases of pneumonia (OR = 0.55, 95% CI [0.32, 0.94]; P = .029) and prolonged ventilator dependency (OR = 0.33, 95% CI [0.12, 0.84]; P = .021). Conclusions: Comparatively, ALIF patients experienced decreased operative time and decreased incidence of postoperative UTIs and blood transfusions. Anterior lumbar interbody fusion patients were more likely to suffer postoperative pulmonary complications and longer hospital stays. Our data support the notion that both anterior and transforaminal surgical approaches perform comparably in context of 30-day perioperative outcomes.

Subpial Adeno-associated Virus 9 (AAV9) Vector Delivery in Adult Mice.

The successful development of a subpial adeno-associated virus 9 (AAV9) vector delivery technique in adult rats and pigs has been reported on previously. Using subpially-placed polyethylene catheters (PE-10 or PE-5) for AAV9 delivery, potent transgene expression through the spinal parenchyma (white and gray matter) in subpially-injected spinal segments has been demonstrated. Because of the wide range of transgenic mouse models of neurodegenerative diseases, there is a strong desire for the development of a potent central nervous system (CNS)-targeted vector delivery technique in adult mice. Accordingly, the present study describes the development of a spinal subpial vector delivery device and technique to permit safe and effective spinal AAV9 delivery in adult C57BL/6J mice. In spinally immobilized and anesthetized mice, the pia mater (cervical 1 and lumbar 1-2 spinal segmental level) was incised with a sharp 34 G needle using an XYZ manipulator. A second XYZ manipulator was then used to advance a blunt 36G needle into the lumbar and/or cervical subpial space. The AAV9 vector (3-5 µL; 1.2 x 1013 genome copies (gc)) encoding green fluorescent protein (GFP) was then injected subpially. After injections, neurological function (motor and sensory) was assessed periodically, and animals were perfusion-fixed 14 days after AAV9 delivery with 4% paraformaldehyde. Analysis of horizontal or transverse spinal cord sections showed transgene expression throughout the entire spinal cord, in both gray and white matter. In addition, intense retrogradely-mediated GFP expression was seen in the descending motor axons and neurons in the motor cortex, nucleus ruber, and formatio reticularis. No neurological dysfunction was noted in any animals. These data show that the subpial vector delivery technique can successfully be used in adult mice, without causing procedure-related spinal cord injury, and is associated with highly potent transgene expression throughout the spinal neuraxis.