✓Discovery that the Schwann cell is the primary cell type responsible for both the neurofibroma as well as the schwannoma has proven to represent a crucial milestone in understanding the pathogenesis of peripheral nerve tumor development. This information and related findings have served as a nidus for research aimed at more fully characterizing this family of conditions. Recent discoveries in the laboratory have clarified an understanding of the molecular mechanisms underlying the pathogenesis of benign peripheral nerve tumors. Similarly, the mechanisms whereby idiopathic and syndromic (NF1- and NF2-associated) nerve sheath tumors progress to malignancy are being elucidated. This detailed understanding of the molecular pathogenesis of peripheral nerve tumors provides the information necessary to create a new generation of therapies tailored specifically to the prevention, cessation, or reversal of pathological conditions at the fundamental level of dysfunction. The authors review the data that have helped to elucidate the molecular pathogenesis of this category of conditions, explore the current progress toward exploitation of these findings, and discuss potential therapeutic avenues for future research.
Jonathan Riley, Alejandro Spiotta, and Nicholas Boulis
Jonathan Riley, Walter Sweeney, and Nicholas Boulis
✓ Recent advances in the laboratory have improved the current understanding of neurobiological mechanisms underlying the initiating events and pathological progression observed in amyotrophic lateral sclerosis (ALS). Whereas initial studies have revealed the late-stage intracellular cascades contributing to neuronal dysfunction and cell death, more recently collected data have begun to elucidate the presence and importance of a “non–cell autonomous” component indicating that affected glial cell subtypes may serve distinct and required roles. Pharmacological interventions for ALS have largely been disappointing likely in part because they have failed to address either the proximate events contributing to neuronal dysfunction and death or the deleterious contributions of non-neuronal cells within the local microenvironment. Alternatively, cell-based therapeutics offer the potential of a multifaceted approach oriented toward the dual ends of protecting remaining viable neurons and attempting to restore neuronal function lost as a manifestation of disease progression. The authors review the evolving knowledge of disease initiation and progression, with specific emphasis on the role of affected glia as crucial contributors to the observed ALS phenotype. This basis is used to underscore the potential roles of cell-based therapeutics as modifiers of the ALS-specific microenvironment.
Charles Y. Liu, Brian Lee, Nicholas Boulis, and Ali R. Rezai
Nicholas M. Boulis, Danielle E. Turner, Michael J. Imperiale, and Eva L. Feldman
Object. Virus-mediated central nervous system gene delivery is a promising means of treating traumatized tissue or degenerative diseases. In the present study, the authors examined gene expression and neuronal survival in the spinal cord after sciatic nerve administration of an adenovirus vector expressing a LacZ reporter gene.
Methods. The time course of adenovirus gene expression, DNA fragmentation, and neuronal density were quantified in rat lumbar spinal cord by staining for β-galactosidase (β-Gal), terminal deoxynucleotidyl transferase, and cresyl violet after microinjection of either saline or the reporter virus into rat sciatic nerve. The expression of β-Gal following remote vector delivery peaked at 7 days and declined thereafter but was not accompanied by neuronal cell death, as measured by DNA fragmentation. No significant difference in spinal motor neuron density was detected between virus-treated and control rats at any time point examined. Although the spinal cords removed from rats treated with cyclosporine prior to adenovirus injection contained substantially more neurons staining for β-Gal at 7 days (67% of total neurons), the decay in the number of stained neurons was not paralleled by a decline in motor neuron density.
Conclusions. The authors conclude that remote gene expression is suppressed by a noncytolytic process.
Nicholas M. Boulis, Vikas Bhatia, Theodore I. Brindle, Harland T. Holman, Daniel J. Krauss, Mila Blaivas, and Julian T. Hoff
Object. The present study characterizes the time course and loci of gene expression induced by the administration of adenoviral vectors into spinal cord. Although a marked inflammatory response to these vectors occurred, no effect on spinal cord function was seen in the 1st postoperative week. The expression of transgenic genes delivered by viral vectors is being exploited throughout the nervous system. The present study utilized adenoviral vectors containing the Rous sarcoma virus (RSV) promoter and a nuclear localization signal to achieve transgenic expression in mammalian spinal cord.
Methods. Initial experiments utilizing the vector Ad.RSVlacZ (1012 particles/ml) injected into the region of the central canal resulted in viral gene expression stretching over approximately 1.2 cm of spinal cord. Gene expression was first detected 3 days following viral administration and lasted until postinjection Day 14 with peak expression at Day 7. A variety of cell types in both white and gray matter expressed lacZ. Transgenic expression of the neurotrophin nerve growth factor (NGF) was achieved using injections of Ad.RSVNGF. On histological examination mononuclear inflammatory infiltrate and gliosis were revealed surrounding the injection sites of spinal cords receiving adenovirus but not vehicle. To assess spinal cord function during viral gene expression, animals previously trained in an operant runway task were tested at 7 days postinjection (the peak of viral gene expression) and demonstrated no changes in spinal cord function.
Conclusions. Results of this study using adenoviral neurotrophic gene transfer indicate that it provided an effective tool for the delivery of potentially therapeutic proteins to the injured or diseased spinal cord.
Cervical spinal cord delivery of a rabies G protein pseudotyped lentiviral vector in the SOD-1 transgenic mouse
Invited submission from the Joint Section Meeting on Disorders of the Spine and Peripheral Nerves, March 2004
Kiana Tanase, Qingshan Teng, Ajit A. Krishnaney, James K. Liu, Mary E. Garrity-Moses, and Nicholas M. Boulis
Object. Lentiviral vectors may constitute a vehicle for long-term therapeutic gene expression in the spinal cord. In amyotrophic lateral sclerosis, spinal cord sclerosis and altered axonal transport pose barriers to therapeutic gene distribution. In the present study the authors characterize gene expression distribution and the behavioral impact of the rabies G (RabG) protein pseudotyped lentiviral vector EIAV.LacZ through cervical spinal cord injection in control and Cu/Zn superoxide dismutase—1 (SOD-1) transgenic mice.
Methods. Seven-week-old SOD-1 transgenic mice and their wild-type littermates underwent exposure of the cervicomedullary junction and microinjection of RabG.EIAV.LacZ or vehicle. The Basso-Beattie-Bresnahan locomotor score, grip strength meter, and Rotarod assays were used to assess the effects of disease progression, spinal cord microinjection, and lentiviral gene expression. Spinal cords were removed when the mice were in the terminal stage of the disease. The distribution of LacZ gene expression was histologically evaluated and quantified.
Direct cervical spinal cord microinjection of RabG.EIAV.LacZ results in extensive central nervous system uptake in SOD-1 transgenic mice; these findings were statistically similar to those in wild-type mice (p > 0.05). Gene expression lasts for the duration of the animal's survival (132 days). The SOD-1 mutation does not prevent retrograde axonal transport of the vector. Three behavioral assays were used to demonstrate that long-term gene expression does not alter sensorimotor function. In comparison with normative data, vector injection and transgene expression do not accelerate disease progression.
Conclusions. Direct spinal cord injection of RabG.EIAV vectors represents a feasible method for delivering therapeutic genes to upper cervical spinal cord and brainstem motor neurons. Distribution is not affected by the SOD-1 mutation or disease phenotype.
Vibhash D. Sharma, Yarema B. Bezchlibnyk, Faical Isbaine, Kushal B. Naik, Jennifer Cheng, John T. Gale, Svjetlana Miocinovic, Cathrin Buetefisch, Stewart A. Factor, Jon T. Willie, Nicholas M. Boulis, Thomas Wichmann, Mahlon R. DeLong, and Robert E. Gross
Lead placement for deep brain stimulation (DBS) using intraoperative MRI (iMRI) relies solely on real-time intraoperative neuroimaging to guide electrode placement, without microelectrode recording (MER) or electrical stimulation. There is limited information, however, on outcomes after iMRI-guided DBS for dystonia. The authors evaluated clinical outcomes and targeting accuracy in patients with dystonia who underwent lead placement using an iMRI targeting platform.
Patients with dystonia undergoing iMRI-guided lead placement in the globus pallidus pars internus (GPi) were identified. Patients with a prior ablative or MER-guided procedure were excluded from clinical outcomes analysis. Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores and Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scores were assessed preoperatively and at 6 and 12 months postoperatively. Other measures analyzed include lead accuracy, complications/adverse events, and stimulation parameters.
A total of 60 leads were implanted in 30 patients. Stereotactic lead accuracy in the axial plane was 0.93 ± 0.12 mm from the intended target. Nineteen patients (idiopathic focal, n = 7; idiopathic segmental, n = 5; DYT1, n = 1; tardive, n = 2; other secondary, n = 4) were included in clinical outcomes analysis. The mean improvement in BFMDRS score was 51.9% ± 9.7% at 6 months and 63.4% ± 8.0% at 1 year. TWSTRS scores in patients with predominant cervical dystonia (n = 13) improved by 53.3% ± 10.5% at 6 months and 67.6% ± 9.0% at 1 year. Serious complications occurred in 6 patients (20%), involving 8 of 60 implanted leads (13.3%). The rate of serious complications across all patients undergoing iMRI-guided DBS at the authors’ institution was further reviewed, including an additional 53 patients undergoing GPi-DBS for Parkinson disease. In this expanded cohort, serious complications occurred in 11 patients (13.3%) involving 15 leads (10.1%).
Intraoperative MRI–guided lead placement in patients with dystonia showed improvement in clinical outcomes comparable to previously reported results using awake MER-guided lead placement. The accuracy of lead placement was high, and the procedure was well tolerated in the majority of patients. However, a number of patients experienced serious adverse events that were attributable to the introduction of a novel technique into a busy neurosurgical practice, and which led to the revision of protocols, product inserts, and on-site training.
Yarema B. Bezchlibnyk, Vibhash D. Sharma, Kushal B. Naik, Faical Isbaine, John T. Gale, Jennifer Cheng, Shirley D. Triche, Svjetlana Miocinovic, Cathrin M. Buetefisch, Jon T. Willie, Nicholas M. Boulis, Stewart A. Factor, Thomas Wichmann, Mahlon R. DeLong, and Robert E. Gross
Deep brain stimulation (DBS) lead placement is increasingly performed with the patient under general anesthesia by surgeons using intraoperative MRI (iMRI) guidance without microelectrode recording (MER) or macrostimulation. The authors assessed the accuracy of lead placement, safety, and motor outcomes in patients with Parkinson disease (PD) undergoing DBS lead placement into the globus pallidus internus (GPi) using iMRI or MER guidance.
The authors identified all patients with PD who underwent either MER- or iMRI-guided GPi-DBS lead placement at Emory University between July 2007 and August 2016. Lead placement accuracy and adverse events were determined for all patients. Clinical outcomes were assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) part III motor scores for patients completing 12 months of follow-up. The authors also assessed the levodopa-equivalent daily dose (LEDD) and stimulation parameters.
Seventy-seven patients were identified (MER, n = 28; iMRI, n = 49), in whom 131 leads were placed. The stereotactic accuracy of the surgical procedure with respect to the planned lead location was 1.94 ± 0.21 mm (mean ± SEM) (95% CI 1.54–2.34) with frame-based MER and 0.84 ± 0.007 mm (95% CI 0.69–0.98) with iMRI. The rate of serious complications was similar, at 6.9% for MER-guided DBS lead placement and 9.4% for iMRI-guided DBS lead placement (RR 0.71 [95% CI 0.13%–3.9%]; p = 0.695). Fifty-seven patients were included in clinical outcome analyses (MER, n = 16; iMRI, n = 41). Both groups had similar characteristics at baseline, although patients undergoing MER-guided DBS had a lower response on their baseline levodopa challenge (44.8% ± 5.4% [95% CI 33.2%–56.4%] vs 61.6% ± 2.1% [95% CI 57.4%–65.8%]; t = 3.558, p = 0.001). Greater improvement was seen following iMRI-guided lead placement (43.2% ± 3.5% [95% CI 36.2%–50.3%]) versus MER-guided lead placement (25.5% ± 6.7% [95% CI 11.1%–39.8%]; F = 5.835, p = 0.019). When UPDRS III motor scores were assessed only in the contralateral hemibody (per-lead analyses), the improvements remained significantly different (37.1% ± 7.2% [95% CI 22.2%–51.9%] and 50.0% ± 3.5% [95% CI 43.1%–56.9%] for MER- and iMRI-guided DBS lead placement, respectively). Both groups exhibited similar reductions in LEDDs (21.2% and 20.9%, respectively; F = 0.221, p = 0.640). The locations of all active contacts and the 2D radial distance from these to consensus coordinates for GPi-DBS lead placement (x, ±20; y, +2; and z, −4) did not differ statistically by type of surgery.
iMRI-guided GPi-DBS lead placement in PD patients was associated with significant improvement in clinical outcomes, comparable to those observed following MER-guided DBS lead placement. Furthermore, iMRI-guided DBS implantation produced a similar safety profile to that of the MER-guided procedure. As such, iMRI guidance is an alternative to MER guidance for patients undergoing GPi-DBS implantation for PD.