Clinical Outcomes of Cervical Laminoplasty: Results at Two Years.

BACKGROUND: Laminoplasty is an established treatment for cervical myelopathy. Multiple variations have emerged, many advocating the use of allograft, but controversy persists. OBJECTIVE: To assess medium-term clinical outcomes in patients who underwent laminoplasty with autograft at our institution. METHODS: Thirty-two consecutive patients (19 male, 13 female, average age 66 yr) from our prospective outcome registry that underwent cervical laminoplasty between 2009 and 2013 were reviewed. Computed tomography (CT) scan was performed immediately postoperatively and at 6-mo follow-up. Parameters included patient perception of outcome, Nurick score, Neck Disability Index (NDI), visual analog scale for neck pain, and SF-36. RESULTS: On retrospective analysis, all patients felt improved at 3 mo postoperatively; at 2 yr, this rate was 91%. Improvements were seen in Nurick scores, from 3.16 ± 0.9 preoperatively to 1.94 ± 0.8 at 2 yr; NDI score from 28.7% ± 9% preoperatively to 20.8% ± 9.6% at 2 yr; visual analog scale from 2.8 ± 1.2 preoperatively to 1.7 ± 0.9 at 2 yr; and SF-36 physical component summary from 27.9 ± 10 preoperatively to 37.8 ± 11.9 at 2 yr. All values reached significance at all follow-up points ( P < .05) with the exception of 6-mo NDI values ( P = .062). No C5 palsy, graft complications, or reclosure was observed in any patient during the follow-up period. CONCLUSION: Laminoplasty with autograft is a safe and effective method to treat cervical myelopathy, with good medium-term clinical outcome. No reclosures were observed. Bony fusion was seen in all cases on CT scan. Our study found good outcomes in the performance of open-door laminoplasty without hardware, in the treatment of cervical stenosis.

Evaluation of Sensory and Motor Skills in Neurosurgery Applicants Using a Virtual Reality Neurosurgical Simulator: The Sensory-Motor Quotient.

OBJECTIVE: Manual skill is an important attribute for any surgeon. Current methods to evaluate sensory-motor skills in neurosurgical residency applicants are limited. We aim to develop an objective multifaceted measure of sensory-motor skills using a virtual reality surgical simulator. DESIGN: A set of 3 tests of sensory-motor function was performed using a 3-dimensional surgical simulator with head and arm tracking, collocalization, and haptic feedback. (1) Trajectory planning: virtual reality drilling of a pedicle. Entry point, target point, and trajectory were scored-evaluating spatial memory and orientation. (2) Motor planning: sequence, timing, and precision: hemostasis in a postresection cavity in the brain. (3) Haptic perception: touching virtual spheres to determine which is softest of the group, with progressive difficulty. Results were analyzed individually and for a combined score of all the tasks. SETTING: The University of Chicago Hospital's tertiary care academic center. PARTICIPANTS: A total of 95 consecutive applicants interviewed at a neurosurgery residency program over 2 years were offered anonymous participation in the study; in 2 cohorts, 36 participants in year 1 and 27 participants in year 2 (validation cohort) agreed and completed all the tasks. We also tested 10 first-year medical students and 4 first- and second-year neurosurgery residents. RESULTS: A cumulative score was generated from the 3 tests. The mean score was 14.47 (standard deviation = 4.37), median score was 13.42, best score was 8.41, and worst score was 30.26. Separate analysis of applicants from each of 2 years yielded nearly identical results. Residents tended to cluster on the better performance side, and first-year students were not different from applicants. CONCLUSIONS: (1) Our cumulative score measures sensory-motor skills in an objective and reproducible way. (2) Better performance by residents hints at validity for neurosurgery. (3) We were able to demonstrate good psychometric qualities and generate a proposed sensory-motor quotient distribution in our tested population.

Usefulness of a Virtual Reality Percutaneous Trigeminal Rhizotomy Simulator in Neurosurgical Training.

BACKGROUND: Simulation-based training may be incorporated into neurosurgery in the future. OBJECTIVE: To assess the usefulness of a novel haptics-based virtual reality percutaneous trigeminal rhizotomy simulator. METHODS: A real-time augmented reality simulator for percutaneous trigeminal rhizotomy was developed using the ImmersiveTouch platform. Ninety-two neurosurgery residents tested the simulator at American Association of Neurological Surgeons Top Gun 2014. Postgraduate year (PGY), number of fluoroscopy shots, the distance from the ideal entry point, and the distance from the ideal target were recorded by the system during each simulation session. Final performance score was calculated considering the number of fluoroscopy shots and distances from entry and target points (a lower score is better). The impact of PGY level on residents' performance was analyzed. RESULTS: Seventy-one residents provided their PGY-level and simulator performance data; 38% were senior residents and 62% were junior residents. The mean distance from the entry point (9.4 mm vs 12.6 mm, P = .01), the distance from the target (12.0 mm vs 15.2 mm, P = .16), and final score (31.1 vs 37.7, P = .02) were lower in senior than in junior residents. The mean number of fluoroscopy shots (9.8 vs 10.0, P = .88) was similar in these 2 groups. Linear regression analysis showed that increasing PGY level is significantly associated with a decreased distance from the ideal entry point (P = .001), a shorter distance from target (P = .05), a better final score (P = .007), but not number of fluoroscopy shots (P = .52). CONCLUSION: Because technical performance of percutaneous rhizotomy increases with training, we proposed that the skills in performing the procedure in our virtual reality model would also increase with PGY level, if our simulator models the actual procedure. Our results confirm this hypothesis and demonstrate construct validity.

Virtual reality cerebral aneurysm clipping simulation with real-time haptic feedback.

BACKGROUND: With the decrease in the number of cerebral aneurysms treated surgically and the increase of complexity of those treated surgically, there is a need for simulation-based tools to teach future neurosurgeons the operative techniques of aneurysm clipping. OBJECTIVE: To develop and evaluate the usefulness of a new haptic-based virtual reality simulator in the training of neurosurgical residents. METHODS: A real-time sensory haptic feedback virtual reality aneurysm clipping simulator was developed using the ImmersiveTouch platform. A prototype middle cerebral artery aneurysm simulation was created from a computed tomographic angiogram. Aneurysm and vessel volume deformation and haptic feedback are provided in a 3-dimensional immersive virtual reality environment. Intraoperative aneurysm rupture was also simulated. Seventeen neurosurgery residents from 3 residency programs tested the simulator and provided feedback on its usefulness and resemblance to real aneurysm clipping surgery. RESULTS: Residents thought that the simulation would be useful in preparing for real-life surgery. About two-thirds of the residents thought that the 3-dimensional immersive anatomic details provided a close resemblance to real operative anatomy and accurate guidance for deciding surgical approaches. They thought the simulation was useful for preoperative surgical rehearsal and neurosurgical training. A third of the residents thought that the technology in its current form provided realistic haptic feedback for aneurysm surgery. CONCLUSION: Neurosurgical residents thought that the novel immersive VR simulator is helpful in their training, especially because they do not get a chance to perform aneurysm clippings until late in their residency programs.

Virtual reality spine surgery simulation: an empirical study of its usefulness.

OBJECTIVE: This study explores the usefulness of virtual simulation training for learning to place pedicle screws in the lumbar spine. METHODS: Twenty-six senior medical students anonymously participated and were randomized into two groups (A = no simulation; B = simulation). Both groups were given 15 minutes to place two pedicle screws in a sawbones model. Students in Group A underwent traditional visual/verbal instruction whereas students in Group B underwent training on pedicle screw placement in the ImmersiveTouch simulator. The students in both groups then placed two pedicle screws each in a lumbar sawbones models that underwent triplanar thin slice computerized tomography and subsequent analysis based on coronal entry point, axial and sagittal deviations, length error, and pedicle breach. The average number of errors per screw was calculated for each group. Semi-parametric regression analysis for clustered data was used with generalized estimating equations accommodating a negative binomial distribution to determine any statistical difference of significance. RESULTS: A total of 52 pedicle screws were analyzed. The reduction in the average number of errors per screw after a single session of simulation training was 53.7% (P  =  0.0067). The average number of errors per screw in the simulation group was 0.96 versus 2.08 in the non-simulation group. The simulation group outperformed the non-simulation group in all variables measured. The three most benefited measured variables were length error (86.7%), coronal error (71.4%), and pedicle breach (66.7%). CONCLUSIONS: Computer-based simulation appears to be a valuable teaching tool for non-experts in a highly technical procedural task such as pedicle screw placement that involves sequential learning, depth perception, and understanding triplanar anatomy.

Measuring surgical outcomes in subaxial degenerative cervical spine disease patients: minimum clinically important difference as a tool for determining meaningful clinical improvement.

BACKGROUND: Although the concept of minimum clinically important difference (MCID) as a measurement of surgical outcome has been extensively studied, there is lack of consensus on the most valid or clinically relevant MCID calculation approach. OBJECTIVE: To compare the range of MCID threshold values obtained by different anchor-based and distribution-based approaches to determine the best clinically meaningful and statistically significant MCID for our studied group. METHODS: Eighty-eight consecutive patients undergoing surgery for subaxial degenerative cervical spine disease were analyzed from a prospective blinded database. Preoperative, 3-, and 6-month postoperative patient reported outcome (PRO) scores and blinded surgeon ratings were collected. Four calculation methods were used to calculate MCID threshold values: average change, change difference, minimum detectable change, and receiver operating characteristic (ROC) curve. Three anchors were used to evaluate meaningful improvement postsurgery: health transition item, patient overall status, and surgeon ratings. RESULTS: On average, all patients had a statistically significant improvement (P < .001) postoperatively for neck disability index (score 27.42 preoperatively to 19.42 postoperatively), physical component of the Short Form of the Medical Outcomes Study (SF-36) (33.02-42.23), mental component of the SF-36 (44-50.74), and visual analog scale (2.85-1.93). The 4 MCID approaches yielded a range of values for each PRO: 2.23 to 16.59 for physical component of the SF-36, 0.11 to 16.27 for mental component of the SF-36, and 2.72 to 12.08 for neck disability index. In comparison with health transition item and patient overall status anchors, the area under the ROC curve was consistently greater for surgeon ratings for all 4 PROs. CONCLUSION: Minimum detectable change together with surgeon ratings anchor appears to be the most appropriate MCID method. Based on our findings, this combination offers the greatest area under the ROC curve (threshold above the 95% confidence interval). The choice of the anchor did not significantly affect this result.

The impact of obesity on surgeon ratings and patient-reported outcome measures after degenerative cervical spine disease surgery.

OBJECTIVE: Obesity is a growing public health problem. A considerable number of patients undergoing cervical spine surgery are obese, but the correlation between obesity and surgical outcome is still unclear. In this study, we investigated the impact of body mass index (BMI) on patients' and surgeons' perception of spine surgery outcomes. METHODS: We analyzed a prospectively collected spine surgery registry with patient-reported outcome measures and surgeon ratings. Mixed-effects linear models and linear regression models were applied to investigate the relationship between different World Health Organization obesity classifications and surgical outcome. RESULTS: A total of 88 patients had surgery for degenerative cervical spine disease, with 97.72% follow-up at 3 months and 94.31% at 6 months postoperatively. Mean BMI was 27.92 ± 7.9 kg/m(2); 28.57% were overweight (BMI 25-29.9), and 31.57% were obese (Class I obesity, BMI 30-34.9). We found a positive correlation between BMI and VAS at 6 months (R = 0.298, P < 0.05) and between BMI and change in Neck Disability Index (R = 0.385, P < 0.01), suggesting that obese patients had less improvement and more pain 6 months postoperatively than nonobese patients. Overweight patients had worse MCS values (R = -0.275, P < 0.05) and obese patients had worse visual analog scale values 6 months after surgery (R = 0.284, P < 0.03). Interestingly, surgeon ratings matched the aforementioned results. Patients with greater BMI had worse surgeon ratings 3 and 6 months postoperatively (R = 0.555, P < 0.05), whereas normal-weight patients had better outcomes when rated from the surgeon's perspective (R = -0.536, P < 0.05). CONCLUSION: Obese patients had worse postoperative patient-reported outcome scores and less overall patient-rated improvement compared with nonobese patients. Patients with BMI >25 reported less improvement after surgery both in the patients' and in the surgeons' perspectives.

Usefulness of minimum clinically important difference for assessing patients with subaxial degenerative cervical spine disease: statistical versus substantial clinical benefit.

BACKGROUND: The measurement of the therapeutic outcome of cervical spine surgeries commonly relies on four main patient reported outcomes (PROs): Neck Disability Index (NDI), Visual Analog Scale (VAS) for pain, and Short Form-36 (SF-36) Physical (PCS) and Mental (MCS) Component Summary. However, the clinical impact of such scores and how they could effectively measure therapeutic efficacy remains unclear. In this context, the concept of minimum clinically important difference (MCID) is developing into the standard by which to evaluate treatments, patient satisfaction and cost-effectiveness. METHODS: Eighty-eight consecutive patients undergoing surgery for subaxial degenerative cervical spine disease were selected from a prospective blinded database. PROs (NDI, PCS, MCS and VAS) were collected preoperatively, and together with blinded Surgeon Ratings (SR) at 3 months and 6 months post-surgery. Four anchor-based approaches were used to calculate different MCIDs. Three anchors (VAS, HTI (Health Transition Item of the SF-36) and SR) were used to evaluate surgery outcome. The best clinically and statistically relevant MCID was chosen. RESULTS: On average, all patients presented with a statistically significant improvement (p < 0.001) postoperatively for NDI (27.42 to 19.42), PCS (33.02 to 42.03), MCS (44 to 50.74) and VAS (2.85 to 1.93). The four MCID anchor-based approaches yielded a range of values for each PRO: 2.23-16.59 for PCS, 0.11-16.27 for MCS and 2.72-12.08 for NDI. When compared to the VAS and HTI anchors, the area under the ROC curve was greater for SR. This finding suggests that SR may be a more reliable anchor for MCID calculation. CONCLUSION: The MDC (minimum detectable change) approach together with the SR anchor appears to be the most appropriate MCID method. It offers the greatest area under the ROC curve (threshold above the 95 % CI), and the choice of the anchor did not significantly affect this result. MCID values for this dataset were 5.6 for PCS, 5.12 for MCS and 2.41 for NDI.

A novel virtual reality simulation for hemostasis in a brain surgical cavity: perceived utility for visuomotor skills in current and aspiring neurosurgery residents.

OBJECTIVE: To understand the perceived utility of a novel simulator to improve operative skill, eye-hand coordination, and depth perception. METHODS: We used the ImmersiveTouch simulation platform (ImmersiveTouch, Inc., Chicago, Illinois, USA) in two U.S. Accreditation Council for Graduate Medical Education-accredited neurosurgical training programs: the University of Chicago and the University of Texas Medical Branch. A total of 54 trainees participated in the study, which consisted of 14 residents (group A), 20 senior medical students who were neurosurgery candidates (group B), and 20 junior medical students (group C). The participants performed a simulation task that established bipolar hemostasis in a virtual brain cavity and provided qualitative feedback regarding perceived benefits in eye-hand coordination, depth perception, and potential to assist in improving operating skills. RESULTS: The perceived ability of the simulator to positively influence skills judged by the three groups: group A, residents; group B, senior medical students; and group C, junior medical students was, respectively, 86%, 100%, and 100% for eye-hand coordination; 86%, 100%, and 95% for depth perception; and 79%, 100%, and 100% for surgical skills in the operating room. From all groups, 96.2% found the simulation somewhat or very useful to improve eye-hand coordination, and 94% considered it beneficial to improve depth perception and operating room skills. CONCLUSION: This simulation module may be suitable for resident training, as well as for the development of career interest and skill acquisition; however, validation for this type of simulation needs to be further developed.

Comparison between patient and surgeon perception of degenerative spine disease outcomes--a prospective blinded database study.

BACKGROUND: Few have studied the correlation between patients' and spine surgeons' perception on outcomes, or compared these with patient-reported outcome scores. Outcomes studies are increasingly important in evaluating costs and benefits to patients and surgeons, and in developing metrics for payer evaluation and health care policy-making. OBJECTIVE: To compare patients' and surgeons' assessment of spine treatment outcome in a prospective blinded patient-driven spine surgery outcomes registry, and to correlate perceived outcomes ratings to validated outcomes scores. METHODS: Patients filled out surveys at baseline, 3 months and 6 months postoperatively, including Visual Analog Scale (VAS), and Neck Disability Index (NDI) or Oswestry Disability Index (ODI). Outcome was rated independently by patients and surgeons on a 7-point Likert-type scale. RESULTS: Two-hundred and sixty-five consecutive adult patients were surgical candidates. Of these, 154 (58.1 %) opted for surgery, with 69 (44.8 %) cervical and 85 (55.2 %) lumbar patients. One hundred and thirty-five (87.7 %) had both patient and surgeon postoperative ratings. Surgeons' and patients' ratings correlated strongly (Spearman rho = 0.53, p < 0.0001, 45.9 % identical, 88.2 % +/- 1 grade). The surgeon rated outcomes were better than patients in 29.8 % and worse in 21.15 %. Patient rating correlated better with the most recent NDI/ODI and pain scores than with incremental change from baseline. In multivariate analysis, age, location (cervical vs lumbar), pain ratings, and functional scores (NDI, ODI) did not have significant impact on the discrepancy between patient and surgeon ratings. CONCLUSIONS: Patients' and surgeons' global outcome ratings for spinal disease correlate highly. Patients' ratings correlate better with most recent functional scores, rather than incremental change from baseline.

Percutaneous spinal fixation simulation with virtual reality and haptics.

BACKGROUND: In this study, we evaluated the use of a part-task simulator with 3-dimensional and haptic feedback as a training tool for percutaneous spinal needle placement. OBJECTIVE: To evaluate the learning effectiveness in terms of entry point/target point accuracy of percutaneous spinal needle placement on a high-performance augmented-reality and haptic technology workstation with the ability to control the duration of computer-simulated fluoroscopic exposure, thereby simulating an actual situation. METHODS: Sixty-three fellows and residents performed needle placement on the simulator. A virtual needle was percutaneously inserted into a virtual patient's thoracic spine derived from an actual patient computed tomography data set. RESULTS: Ten of 126 needle placement attempts by 63 participants ended in failure for a failure rate of 7.93%. From all 126 needle insertions, the average error (15.69 vs 13.91), average fluoroscopy exposure (4.6 vs 3.92), and average individual performance score (32.39 vs 30.71) improved from the first to the second attempt. Performance accuracy yielded P = .04 from a 2-sample t test in which the rejected null hypothesis assumes no improvement in performance accuracy from the first to second attempt in the test session. CONCLUSION: The experiments showed evidence (P = .04) of performance accuracy improvement from the first to the second percutaneous needle placement attempt. This result, combined with previous learning retention and/or face validity results of using the simulator for open thoracic pedicle screw placement and ventriculostomy catheter placement, supports the efficacy of augmented reality and haptics simulation as a learning tool.

Ocular melanoma metastasis to the cervical spine.

Ocular melanoma is a rare type of malignant melanoma. Melanoma metastatic to the spine typically arises within the vertebral column, presents with back pain, and has a poor prognosis. We present a patient with a unique disease course: ocular melanoma metastasis occurred after an extended latency period of 14 years, attained a large size within the spinal intradural space, presented with severe neurological deficits without additional central nervous system disease, and the tumor was amenable to surgical intervention. We also review the literature on melanoma spine metastasis.

Permanent cerebrospinal fluid diversion in subarachnoid hemorrhage: Influence of physician practice style.

BACKGROUND: Acute hydrocephalus (HCP) after aneurysmal subarachnoid hemorrhage (SAH) often persists. Our previous study described factors that singly and combined in a formula correlate with permanent CSF diversion. We now aimed to determine whether the same parameters are applicable at an institution with different HCP management practice. METHODS: We reviewed records of 181 consecutive patients who presented with SAH and received an external ventricular drain (EVD) for acute HCP. After exclusion and inclusion criteria were met, 71 patients were analyzed. Data included admission Fisher and Hunt and Hess grades, aneurysm location, treatment modality, ventricle size, CSF cell counts and protein levels, length of stay (LOS) in the hospital, and the presence of craniectomy. Outcome measures were: (1) initial EVD challenge outcome; (2) shunting within 3 months; and (3) LOS. RESULTS: Shunting correlated with Hunt and Hess grade, CSF protein, and the presence of craniectomy. The formula derived in our previous study demonstrated a weaker correlation with initial EVD challenge failure. Several parameters that correlated with shunting in the previous study were instead associated with LOS in this study. CONCLUSIONS: The decision to shunt depends on management choices in the context of a disease process that may improve over time. Based on the treatment strategy, the shunting rate may be lowered but LOS increased. Markers of disease severity in patients with HCP after SAH correlate with both shunt placement and LOS. This is the first study to directly evaluate the effect of different practice styles on the shunting rate. Differences in HCP management practices should inform the design of prospective studies.

A review of lumbar spinal instrumentation: evidence and controversy.

Disability secondary to disorders of the spine is a significant problem worldwide. In the USA, there has been a recent surge in the costs associated with caring for spinal pathology; from 1997 to 2005, there was a growth of 65% in healthcare expenditures on spinal disease, totalling $86 billion in 2005. Increasingly, there has been media and public scrutiny over the rapid rise in the volume of procedures with spinal instrumentation; some have suggested that this rise has been fuelled by non-medical drivers such as the financial incentives involved with the use of instrumentation; others suggest that innovation in spine technology and devices has led to improved options for the treatment of spine pathology.In this context, we conducted a review of the literature to assess the use of instrumentation in lumbar procedures and its relationship to successful fusion and patient outcome. Our review suggests that there is data supporting the thesis that lumbar instrumentation improves rates of fusion. However, there is no consistent correlation between increased rates of fusion and improved patient outcomes.

Clinical and functional outcomes of laminoplasty and laminectomy.

OBJECTIVE: Laminoplasty has become a common alternative to laminectomy for cervical spondylotic myelopathy or radiculopathy. The procedures have been compared before, but data on functional recovery are limited. We aim to compare the safety and short-term clinical and functional outcomes of cervical laminoplasty and cervical laminectomy. METHODS: We performed a retrospective analysis of the outcome of 72 patients who had laminoplasty and 49 patients who had laminectomy at our hospital from 1999 to 2005. Patients had cervical spondylotic myelopathy or radiculopathy. All of the patients were similar in age and pre-operative functional status. All patients were assessed pre-operatively and 4 months post-operatively with the Rankin disability score, Glasgow outcome scale and Karnofsky and Nurick scales. RESULTS: Laminoplasty resulted in greater improvement than laminectomy on the Rankin scale (p<0.0001, chi-square test), GOS (p<0.0027, chi-square test) and Karnofsky scores (p<0.01, Wilcoxon test). Nurick scores improved in both groups without a significant difference (p<0.62, Wilcoxon test). The proportion of patients who improved on all scales tended to be greater in the laminoplasty group. Patients spent 1.8 fewer days in the hospital after laminoplasty (p=0.04, Wilcoxon rank-sum test). There was no mortality or permanent morbidity for either procedure. CONCLUSION: Both cervical laminectomy and laminoplasty are safe and effective for the treatment of cervical myelopathy or radiculopathy. Cervical laminoplasty results in a shorter hospital stay and greater functional improvement at 4 months follow-up.

Prospective randomized comparison of safety and efficacy of nicardipine and nitroprusside drip for control of hypertension in the neurosurgical intensive care unit.

OBJECTIVE: The calcium channel blocker nicardipine (NC) is effective for acute control of hypertension. However, efficacy and safety in neurosurgical patients have not been evaluated. We sought to compare NC with the most commonly used agent, sodium nitroprusside (SNP), in patients with subarachnoid or intracerebral hemorrhage. METHODS: We performed a prospective randomized comparison of the safety and efficacy of NC and SNP in patients with subarachnoid or intracerebral hemorrhage. We assessed the number of dose adjustments per patient day, proportion of time within set blood pressure parameters, use of additional medications for blood pressure control, clinical outcome, and drug-related complications. RESULTS: Two hundred patients were screened and 163 patients were randomized, including 89 in the SNP group and 74 in the NC group. In 107 patients, intravenous blood pressure control was started; 60 of these patients received SNP and 47 received NC. When analyzed by intent to treat, patients randomized to NC had fewer dose adjustments per day: 5.7 versus 8.8 in the nitroprusside group (P = 0.0012, Wilcoxon rank-sum test). There were fewer additional medications per day to maintain blood pressure control in the NC group: 1.4 versus 1.9 for SNP (P = 0.043, Wilcoxon rank-sum test). Blood pressure control was similar (NC, 66% of the time within parameters; SNP, 69%). "As-treated" analysis maintained the apparent advantage of NC. CONCLUSION: When used for control of hypertension in patients with subarachnoid or intracerebral hemorrhage, NC and SNP were both safe and effective, but patients on an NC drip required fewer dose adjustments and fewer additional medications.

GDNF-secreting human neural progenitor cells increase tyrosine hydroxylase and VMAT2 expression in MPTP-treated cynomolgus monkeys.

Human neural progenitor cells (hNPCs) have been proposed as a potential source of cells for ex vivo gene therapy. In this pilot study, three 5-year-old female cynomolgus monkeys received a single intracarotid infusion of MPTP, followed 1 week later by MRI-guided stereotaxic intrastriatal and intranigral injections of male hNPCs transgenic for GDNF. Immunosupression with oral cyclosporine (30-40 mg/kg) began 48 h before hNPC transplants and continued throughout the study. We monitored the animals using a clinical rating scale (CRS). Three months postsurgery, we euthanized the animals by transcardiac perfusion, then retrieved and processed their brains for morphological analysis. Our findings include the following. 1) hNPCs survived and produced GDNF in all animals 3 months postsurgery. 2) hNPCs remained in the areas of injection as observed by GDNF immunostaining and in situ hybridization for the human Y chromosome. 3) A "halo" of GDNF expression was observed diffusing from the center of the graft out into the surrounding area. 4) We observed increased TH- and VMAT2-positive fibers in areas of GDNF delivery in two of the three animals. The two animals with TH- and VMAT2-positive fibers also showed reductions in their CRS scores. 5) Some GFAP-positive perivascular cuffing was found in transplanted areas. 6) General blood chemistry and necropsies did not reveal any abnormalities. Therefore, we conclude that hNPCs releasing GDNF may be a possible alternative for intracerebral trophic factor delivery in Parkinson's disease.

Subthalamic glutamic acid decarboxylase gene therapy: changes in motor function and cortical metabolism.

Parkinson's disease (PD) is associated with increased excitatory activity within the subthalamic nucleus (STN). We sought to inhibit STN output in hemiparkinsonian macaques by transfection with adeno-associated virus (AAV) containing the gene for glutamic acid decarboxylase (GAD). In total, 13 macaques were rendered hemiparkinsonian by right intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection. Seven animals were injected with AAV-GAD into the right STN, and six received an AAV gene for green fluorescent protein (GFP). Videotaped motor ratings were performed in a masked fashion on a weekly basis over a 55-week period. At 56 weeks, the animals were scanned with (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Histological examination was performed at the end of the study. No adverse events were observed after STN gene therapy. We found that the clinical rating scores for the two treatment groups had different patterns of change over time (group x time interaction, P<0.001). On FDG PET, the GAD animals exhibited an increase in glucose utilization in the right motor cortex relative to GFP controls (P<0.001). Metabolism in this region correlated with clinical ratings at end point (P<0.01). Histology confirmed GAD expression in treated animals. These findings suggest that STN AAV-GAD is well tolerated and potentially effective in a primate model of PD. The changes in motor cortical glucose utilization observed after gene therapy are consistent with the modulation of metabolic brain networks associated with this disorder.

Survival and early differentiation of human neural stem cells transplanted in a nonhuman primate model of stroke.

OBJECT: Neural cell transplantation has been proposed as a treatment after stroke. The purpose of this study was to establish if human neural stem cells (HNSCs) could survive in the nonhuman primate brain after an ischemic event. METHODS: Three adult cynomolgus monkeys received a unilateral occlusion of the M, segment of the right middle cerebral artery (MCA). One week later each animal received five magnetic resonance (MR) image-guided stereotactic intracerebral injections of HNSC neurospheres labeled with bromodeoxyuridine (BrdU) in the areas surrounding the ischemic lesion as defined in T1- and T2-weighted images. On the day of transplantation and throughout the study the monkeys received oral cyclosporine (10 mg/kg twice a day), and plasma levels were monitored routinely. The animals were killed at 45, 75, or 105 days after transplantation. Magnetic resonance images revealed a cortical and subcortical infarction in the MCA distribution area. Postmortem morphological brain analyses confirmed the distribution of the infarcted area seen in the MR images, with loss of tissue and necrosis in the ischemic region. Cells that were positive for BrdU were present in the three experimental monkeys, mainly along injection tracks. Double-label immunofluorescence for BrdU and betaIII-tubulin (a marker of young neurons) revealed colocalization of few HNSCs, most of which were observed outside the immediate injection site. Colocalization with nestin was also observed, indicating an early neural/glial fate. CONCLUSIONS: In a model of stroke in nonhuman primates, HNSCs can survive up to 105 days when transplanted 1 week after an ischemic event and can partly undergo neuronal differentiation.