MicroRNA Regulatory Network as Biomarkers of Late Seizure in Patients with Spontaneous Intracerebral Hemorrhage.

Approximately 15% of patients experience seizures after spontaneous intracerebral hemorrhage (ICH). The pathogenesis of seizures post-ICH is not well-known; however, iron deposition-related neuronal injury following hemoglobin breakdown may contribute. Profiling known miRNAs to identify biomarkers for post-ICH late seizures, we found 64 differentially expressed miRNA: 32 upregulated and 32 downregulated in seizure vs. non-seizure. Functional classification of upregulated miRNA for KEGG pathways and biological processes identified enrichment for cell cycle, protein modifications, and FoxO neurotrophin signaling pathways. No significant enrichment was found for downregulated miRNA. Molecular functions Gene Ontology (GO) terms enriched for upregulated miRNA are numerous, while downregulated miRNAs were associated with ion channel activity. RT-PCR confirmed two miRNAs, 4317 and 4325, were differentially expressed in patients who developed seizures at 1 year. MiR-4317 regulates SLC38A1, a glutamine-glutamate transporter. Integrated miRNA-mRNA network analysis identified COMMD6, APOBEC2, and RASSF6-involved in NF-kB regulation. Two miRNAs (miR-4317 and 4325) differentiated post-ICH late seizures vs. non-seizures at 1 year. The results suggest functional and miRNA-mRNA networks as potential biomarkers for post-ICH late seizures.

Single Local Application of TGF-ß Promotes a Proregenerative State Throughout a Chronically Injured Nerve.

BACKGROUND: The lack of nerve regeneration and functional recovery occurs frequently when injuries involve large nerve trunks because insufficient mature axons reach their targets in the distal stump and because of the loss of neurotrophic support, primarily from Schwann cells (SCs). OBJECTIVE: To investigate whether a single application of transforming growth factor-beta (TGF-ß) plus forskolin or forskolin alone can promote and support axonal regeneration through the distal nerve stump. METHODS: Using a delayed repair rat model of nerve injury, we transected the tibial nerve. After 8 wk, end-to-end repair was done and the repair site was treated with saline, forskolin, or TGF- ß plus forskolin. After 6 wk, nerve sections consisting of the proximal stump, distal to the site of repair, and the most distal part of the nerve stump were removed for nerve histology, axon counts, and immunohistochemistry for activated SCs (S100), macrophages (CD68), cell proliferation (Ki67), p75NGFR, and apoptosis (activated caspase-3). RESULTS: TGF-ß plus forskolin significantly increased the numbers of axons regenerated distal to the repair site and the most distal nerve sections. Both treatments significantly increased the numbers of axons regenerated in the most distal nerve sections compared to saline treated. Both treatments exhibited extended expression of regeneration-associated marker proteins. CONCLUSION: TGF-ß plus forskolin treatment of chronically injured nerve improved axonal regeneration and increased expression of regeneration-associated proteins beyond the repair site. This suggests that a single application at the site of repair has mitogenic effects that extended distally and may potentially overcome the decrease in regenerated axon over long distance.

Transforming growth factor beta 1, a cytokine with regenerative functions.

We review the biology and role of transforming growth factor beta 1 (TGF-ß1) in peripheral nerve injury and regeneration, as it relates to injuries to large nerve trunks (i.e., sciatic nerve, brachial plexus), which often leads to suboptimal functional recovery. Experimental studies have suggested that the reason for the lack of functional recovery resides in the lack of sufficient mature axons reaching their targets, which is a result of the loss of the growth-supportive environment provided by the Schwann cells in the distal stump of injured nerves. Using an established chronic nerve injury and delayed repair animal model that accurately mimics chronic nerve injuries in humans, we summarize our key findings as well as others to better understand the pathophysiology of poor functional recovery. We demonstrated that 6 month TGF-ß1 treatment for chronic nerve injury significantly improved Schwann cell capacity to support axonal regeneration. When combined with forskolin, the effect was additive, as evidenced by a near doubling of regenerated axons proximal to the repair site. We showed that in vivo application of TGF-ß1 and forskolin directly onto chronically injured nerves reactivated chronically denervated Schwann cells, induced their proliferation, and upregulated the expression of regeneration-associated proteins. The effect of TGF-ß1 and forskolin on old nerve injuries is quite impressive and the treatment regiment appears to mediate a growth-supportive milieu in the injured peripheral nerves. In summary, TGF-ß1 and forskolin treatment reactivates chronically denervated Schwann cells and could potentially be used to extend and prolong the regenerative responses to promote axonal regeneration.

Transforming Growth Factor-ß Promotes Axonal Regeneration After Chronic Nerve Injury.

When spinal cord injury (SCI) occurs, injured cells must survive and regenerate to close gaps caused by the injury and to create functional motor units. After peripheral nerve injury, Wallerian degeneration in the distal nerve stump creates a neurotrophic and growth-supportive environment for injured neurons and axons via Schwann cells and secreted cytokines/neurotrophins. In both SCI and peripheral nerve injury, injured motor and sensory neurons must regenerate axons, eventually reaching and reinnervating target tissue (SDC Figure 1, http://links.lww.com/BRS/B116). This process is often unsuccessful after SCI, and the highly complex anatomy of branching axons and nerves in the peripheral nervous system leads to slow recovery of function, even with careful and appropriate techniques.

Effect of local application of transforming growth factor-ß at the nerve repair site following chronic axotomy and denervation on the expression of regeneration-associated genes. Laboratory investigation.

OBJECTIVES: Although peripheral nerves can regenerate after traumatic injury, functional recovery is often suboptimal, especially after injuries to large nerve trunks such as the sciatic nerve or brachial plexus. Current research with animal models suggests that the lack of functional recovery resides in the lack of sufficient mature axons reaching their targets due to the loss of neurotrophic support by Schwann cells in the distal stump of injured nerves. This study was designed to investigate the effect of one-time application of transforming growth factor-ß (TGF-ß) at the repair site of chronically injured nerve. METHODS: The authors used the rat tibial nerve injury and repair model to investigate the effects of application of physiological concentrations of TGF-ß plus forskolin or forskolin alone in vivo at the repair site on gene and protein expression and axon regeneration at 6 weeks after nerve repair. They used gene expression profiling and immunohistochemical analysis of indicative activated proteins in Schwann cells to evaluate the effects of treatments on the delayed repair. They also quantified the regenerated axons distal to the repair site by microscopy of paraffin sections. RESULTS: Both treatment with forskolin only and treatment with TGF-ß plus forskolin resulted in increased numbers of axons regenerated compared with saline-only control. There was robust activation and proliferation of both Schwann cells and macrophages reminiscent of the processes during Wallerian degeneration. The treatment also induced upregulation of genes implicated in cellular activation and growth as detected by gene array. CONCLUSIONS: Addition of TGF-ß plus forskolin to the repair after chronic nerve injury improved axonal regeneration, probably via upregulation of required genes, expression of growth-associated protein, and reactivation of Schwann cells and macrophages. Further studies are required to better understand the mechanism of the positive effect of TGF-ß treatment on old nerve injuries.

Minimally invasive versus open transforaminal lumbar interbody fusion for degenerative spondylolisthesis grades 1-2: patient-reported clinical outcomes and cost-utility analysis.

BACKGROUND: Transforaminal lumbar interbody fusion (TLIF) is the standard surgical treatment for patients with lumbar degenerative spondylolisthesis who do not respond to a 6-week course of conservative therapy. A number of morbidities are associated with the conventional open-TLIF method, so minimally invasive surgery (MIS) techniques for TLIF (MIS-TLIF) have been introduced to reduce the trauma to paraspinal muscles and hasten postoperative recovery. Because providing cost-effective medical treatment is a core initiative of healthcare reforms, a comparison of open-TLIF and MIS-TLIF must include a cost-utility analysis in addition to an analysis of clinical effectiveness. METHODS: We compared patient-reported clinical functional outcomes and hospital direct costs in age-matched patients treated surgically with either open-TLIF or MIS-TLIF. Patients were followed for at least 1 year, and patient scores on the Oswestry Disability Index (ODI) and visual analog scale (VAS) were analyzed at 6 weeks, 6 months, and ≥1 year postoperatively in the 2 treatment groups. RESULTS: Compared to their preoperative scores, patients in both the open-TLIF and MIS-TLIF groups had significant improvements in the ODI and VAS scores at each follow-up point, but no significant difference in functional outcome occurred between the open-TLIF and MIS-TLIF groups (P=0.46). However, open-TLIF is significantly more costly compared to MIS-TLIF (P=0.0002). CONCLUSION: MIS-TLIF is a more cost-effective treatment than open-TLIF for patients with degenerative spondylolisthesis and is equally effective as the conventional open-TLIF procedure, although further financial analysis-including an analysis of indirect costs-is needed to better understand the full benefit of MIS-TLIF.

Midline minimally invasive placement of spinal cord stimulators: a technical note.

BACKGROUND: Spinal cord stimulators (SCSs) have conventionally been implanted through open approaches requiring extensive muscle dissection to perform laminectomies and permanently place the paddle lead. This approach could contribute to worsening the pain syndrome in patients who experience chronic pain. In an attempt to reduce operative times, minimize blood loss and postoperative pain, and ease the technical challenges of placing the paddle lead in the midline via a paramedian and off-midline incision, we designed a new minimally invasive surgery (MIS) technique to place the paddle lead using a tubular retractor system through a true midline approach. METHODS: We performed a retrospective review of all MIS paddle lead placements performed by the senior author between October 2010 and June 2013. Patient demographics; clinical indications for placement of paddle lead; location of paddle lead; and perioperative data including blood loss, length of surgery, and surgical and perioperative morbidity were recorded. RESULTS: Between October 2010 and June 2013, 78 patients had MIS placement of paddle lead SCSs. Patient ages ranged from 27 to 87 years old, with a mean age of 59. The most common levels for paddle lead placement were T8 and T9. No minor or major neurologic complications occurred in our patient population. No patient was readmitted after being discharged from the hospital and all surgeries were outpatient procedures. We had a migration rate comparable to open techniques and minimal blood loss. CONCLUSION: Our technique is safe and effective and carries minimal surgical morbidity compared to standard open techniques for placement of SCSs.

Intraoperative neurophysiological monitoring for minimally invasive 1- and 2-level transforaminal lumbar interbody fusion: does it improve patient outcome?

BACKGROUND: Despite the widespread use of intraoperative monitoring (IOM) in many types of spinal surgeries, an absence of data comparing monitored a nd unmonitored postoperative outcomes places IOM's efficacy into question. A lack of consensus among surgeons about when to use monitoring also raises concerns about its overuse in routine and low-risk procedures. METHODS: We performed a retrospective database review of 112 patients undergoing a 1- or 2-level minimally invasive surgery transforaminal lumbar interbody fusion (MIS-TLIF). Our analysis focused on patient demographics, use of IOM, length of surgery, hospital length of stay, the perioperative complication of pedicle screw malposition, and average hospital cost. RESULTS: For the 73 patients who underwent MIS-TLIF with intraoperative neuromonitoring, their hospital length of stay (P=0.8) and need for pedicle screw revisions (P=0.93) were not statistically significant compared to the 39 patients who underwent MIS-TLIF procedures without IOM. The incidence of reoperation was 5.48% and 5.13%, and average length of stay was 3.25 days and 3.13 days, respectively. However, the cost of surgery and the length of surgery were significantly higher in the monitored group compared to the nonmonitored group (P=0.008 and P=0.009, respectively). CONCLUSION: IOM is widely used in spine surgery, but our retrospective review shows that its use does not necessarily decrease the incidence of malpositioning of pedicle screws. In fact, no statistical difference was detected in the incidence of screw malposition in the 2 groups of patients. On the other hand, IOM adds cost and increases the length of surgery. Because the use of IOM did not make a difference in the incidence of pedicle screw malpositioning and because of the comparative cost analysis for both groups of patients, we believe that the use of IOM for MIS-TLIF provides no added benefit.

One-stage resection of giant invasive thoracic schwannoma: case report and review of literature.

BACKGROUND: Schwannomas comprise approximately 25% of all spinal tumors, being the third most frequent soft-tissue tumor after hemangiomas and lipomas. Grade 5 invasive giant schwannomas erode the vertebral bodies, involve 2 or more levels, and invade the myofascial planes. Because 3 compartments are involved, these tumors represent a surgical challenge and frequently require staged surgeries with a multidisciplinary surgical team. CASE REPORT: We report the case of a 62-year-old female who presented with intermittent upper back pain for 3 years. A magnetic resonance imaging scan of the thoracic spine showed a mass invading the vertebral body, pedicle, and lamina of T4 and part of T3 and T5. Needle biopsy confirmed the diagnosis of schwannoma. The patient underwent surgery using a parascapular extracavitary costotransversectomy approach. CONCLUSION: Giant invasive spinal schwannomas are rare in the thoracic spine, and surgical approaches usually have entailed multiple-stage surgeries with the assistance of other surgical specialties. Our 1-stage complete surgical resection of a giant invasive spinal schwannoma used a parascapular costotransversectomy approach that maintained spinal stability and thus avoided the need for instrumentation.

Neurobiology of peripheral nerve injury, regeneration, and functional recovery: from bench top research to bedside application.

OBJECTIVES: We review the state-of-the-art neurobiology of nerve injury and regeneration, especially as it relates to return of useful function in patients who have sustained injuries to large nerve trunks such as the brachial plexus. METHODS: This review focuses on research conducted in our laboratory at Ochsner and at other laboratories related to the neurobiology of nerve injury with emphasis on how some of the key findings from animal research help us understand the pathophysiology of poor functional recovery after nerve injury. CONCLUSIONS: Published research on the neurobiology of nerve injury and regeneration strongly suggests that chronic Schwann cell denervation, chronic neuronal axotomy, and misdirection of regenerating axons into wrong endoneurial tubes are primarily responsible for poor functional recovery. The effect of muscle denervation atrophy is secondary. Experimental therapeutic strategies (which we are currently investigating in our laboratory at Ochsner) to combat these 3 neurobiologic phenomena have the potential to improve the return of function in patients who have sustained nerve injuries.

Resection and nerve grafting of a lipofibrohamartoma of the median nerve: case report.

OBJECTIVE AND IMPORTANCE: Our patient's symptomatology, history, physical examination, diagnosis, management, and functional outcome 1 year after surgical repair is presented and discussed in light of the current literature on lipofibrohamartomas. CLINICAL PRESENTATION: A 3-year-old boy presented to the Louisiana State University Nerve Clinic for evaluation and management because he was experiencing progressive symptoms of left hand swelling, dysesthesia, and impaired motor function. Physical examination demonstrated median nerve distribution motor impairment. Electromyographic/nerve conduction velocity studies also showed severely reduced conduction and amplitude of the median nerve response, and the magnetic resonance imaging findings were highly suggestive of lipofibrohamartoma. Hence, the presumed diagnosis was lipofibrohamartoma on the basis of imaging characteristics, location, and patient's age. INTERVENTION: The patient was brought to the operating room with the objectives of carpal tunnel release and biopsy. However, routine intraoperative nerve action potential recordings showed no or very poor responses, consistent with significant loss of median nerve function. On the basis of the intraoperative nerve action potentials, we opted to resect the tumor back to healthy median nerve fascicles and to perform graft repairs. Surgery proceeded uneventfully, without any complications. Pathology confirmed the diagnosis of lipofibrohamartoma. CONCLUSION: At 18 months postoperatively, the patient had excellent left hand function. On the basis of our experience with this patient, we believe that intraoperative nerve action potentials and the availability of usable proximal and distal nerve fascicles (which may be discernible on diagnostic imaging) are key factors in deciding whether a lipofibrohamartoma needs to be repaired or decompressed/biopsied. As illustrated by our case, we believe that resection and graft repair may be the best treatment option for some of these patients, and perhaps more so for pediatric patients.