Bruce E. Mathern

Spreading depolarisations and outcome after traumatic brain injury: a prospective observational study

BACKGROUND Pathological waves of spreading mass neuronal depolarisation arise repeatedly in injured, but potentially salvageable, grey matter in 50-60% of patients after traumatic brain injury (TBI). We aimed to ascertain whether spreading depolarisations are independently associated with unfavourable neurological outcome. METHODS We did a prospective, observational, multicentre study at seven neurological centres. We enrolled 109 adults who needed neurosurgery for acute TBI. Spreading depolarisations were monitored by electrocorticography during intensive care and were classified as cortical spreading depression (CSD) if they took place in spontaneously active cortex or as isoelectric spreading depolarisation (ISD) if they took place in isoelectric cortex. Investigators who treated patients and assessed outcome were masked to electrocorticographic results. Scores on the extended Glasgow outcome scale at 6 months were fitted to a multivariate model by ordinal regression. Prognostic score (based on variables at admission, as validated by the IMPACT studies) and spreading depolarisation category (none, CSD only, or at least one ISD) were assessed as outcome predictors. FINDINGS Six individuals were excluded because of poor-quality electrocorticography. A total of 1328 spreading depolarisations arose in 58 (56%) patients. In 38 participants, all spreading depolarisations were classified as CSD; 20 patients had at least one ISD. By multivariate analysis, both prognostic score (p=0·0009) and spreading depolarisation category (p=0·0008) were significant predictors of neurological outcome. CSD and ISD were associated with an increased risk of unfavourable outcome (common odds ratios 1·56 [95% CI 0·72-3·37] and 7·58 [2·64-21·8], respectively). Addition of depolarisation category to the regression model increased the proportion of variance in outcome that could be attributed to predictors from 9% to 22%, compared with the prognostic score alone. INTERPRETATION Spreading depolarisations were associated with unfavourable outcome, after controlling for conventional prognostic variables. The possibility that spreading depolarisations have adverse effects on the traumatically injured brain, and therefore might be a target in the treatment of TBI, deserves further research. FUNDING US Army CDMRP PH/TBI research programme.

Two pole air gap electrospinning: Fabrication of highly aligned, three-dimensional scaffolds for nerve reconstruction

We describe the structural and functional properties of three-dimensional (3D) nerve guides fabricated from poly-ε-caprolactone (PCL) using the air gap electrospinning process. This process makes it possible to deposit nano-to-micron diameter fibers into linear bundles that are aligned in parallel with the long axis of a cylindrical construct. By varying starting electrospinning conditions it is possible to modulate scaffold material properties and void space volume. The architecture of these constructs provides thousands of potential channels to direct axon growth. In cell culture functional assays, scaffolds composed of individual PCL fibers ranging from 400 to 1500 nm supported the penetration and growth of axons from rat dorsal root ganglion. To test the efficacy of our guide design we reconstructed 10mm lesions in the rodent sciatic nerve with scaffolds that had fibers 1 μm in average diameter and void volumes >90%. Seven weeks post implantation, microscopic examination of the regenerating tissue revealed dense, parallel arrays of myelinated and non-myelinated axons. Functional blood vessels were scattered throughout the implant. We speculate that end organ targeting might be improved in nerve injuries if axons can be directed to regenerate along specific tissue planes by a guide composed of 3D fiber arrays.

FTY720 Reduces Inflammation and Promotes Functional Recovery after Spinal Cord Injury

A robust and complex inflammatory cascade is known to be a prominent component of secondary injury following spinal cord injury (SCI). Specifically, the concept of trauma-induced autoimmunity has linked the lymphocyte population with neural tissue injury and neurologic deficit. FTY720, a sphingosine receptor modulator that sequesters lymphocytes in secondary lymphoid organs, has been shown to be effective in the treatment of a variety of experimental autoimmune disorders. Accordingly, by reducing lymphocyte infiltration into the spinal cord following SCI, this novel immunomodulator may enhance tissue preservation and functional recovery. In the present study, a moderate to severe contusion SCI was simulated in adult Long-Evans hooded rats. Using flow cytometry we showed that daily FTY720 treatment dramatically reduced T-cell infiltration into the SCI lesion site at 4 and 7 days post-injury, while other inflammatory cell populations were relatively unaltered. To assess functional recovery, three groups of injured animals (treated, vehicle, and injury only) were evaluated weekly for hindlimb recovery. Animals in the treated group consistently exhibited higher functional scores than animals in the control groups after 2 weeks post-injury. This finding was associated with a greater degree of white matter sparing at the lesion epicenter when cords were later sectioned and stained. Furthermore, treated animals were found to exhibit improved bladder function and a reduced incidence of hemorrhagic cystitis compared to control counterparts. Collectively these results demonstrate the neuroprotective potential of FTY720 treatment after experimental SCI.

Surgical management of traumatic brain injury: a comparative-effectiveness study of 2 centers

OBJECT Mass lesions from traumatic brain injury (TBI) often require surgical evacuation as a life-saving measure and to improve outcomes, but optimal timing and surgical technique, including decompressive craniectomy, have not been fully defined. The authors compared neurosurgical approaches in the treatment of TBI at 2 academic medical centers to document variations in real-world practice and evaluate the efficacies of different approaches on postsurgical course and long-term outcome. METHODS Patients 18 years of age or older who required neurosurgical lesion evacuation or decompression for TBI were enrolled in the Co-Operative Studies on Brain Injury Depolarizations (COSBID) at Kings College Hospital (KCH, n = 27) and Virginia Commonwealth University (VCU, n = 24) from July 2004 to March 2010. Subdural electrode strips were placed at the time of surgery for subsequent electrocorticographic monitoring of spreading depolarizations; injury characteristics, physiological monitoring data, and 6-month outcomes were collected prospectively. CT scans and medical records were reviewed retrospectively to determine lesion characteristics, surgical indications, and procedures performed. RESULTS Patients enrolled at KCH were significantly older than those enrolled at VCU (48 vs 34 years, p < 0.01) and falls were more commonly the cause of TBI in the KCH group than in the VCU group. Otherwise, KCH and VCU patients had similar prognoses, lesion types (subdural hematomas: 30%-35%; parenchymal contusions: 48%-52%), signs of mass effect (midline shift ≥ 5 mm: 43%-52%), and preoperative intracranial pressure (ICP). At VCU, however, surgeries were performed earlier (median 0.51 vs 0.83 days posttrauma, p < 0.05), bone flaps were larger (mean 82 vs 53 cm(2), p < 0.001), and craniectomies were more common (performed in 75% vs 44% of cases, p < 0.05). Postoperatively, maximum ICP values were lower at VCU (mean 22.5 vs 31.4 mm Hg, p < 0.01). Differences in incidence of spreading depolarizations (KCH: 63%, VCU: 42%, p = 0.13) and poor outcomes (KCH: 54%, VCU: 33%, p = 0.14) were not significant. In a subgroup analysis of only those patients who underwent early (< 24 hours) lesion evacuation (KCH: n = 14; VCU: n = 16), however, VCU patients fared significantly better. In the VCU patients, bone flaps were larger (mean 85 vs 48 cm(2) at KCH, p < 0.001), spreading depolarizations were less common (31% vs 86% at KCH, p < 0.01), postoperative ICP values were lower (mean: 20.8 vs 30.2 mm Hg at KCH, p < 0.05), and good outcomes were more common (69% vs 29% at KCH, p < 0.05). Spreading depolarizations were the only significant predictor of outcome in multivariate analysis. CONCLUSIONS This comparative-effectiveness study provides evidence for major practice variation in surgical management of severe TBI. Although ages differed between the 2 cohorts, the results suggest that a more aggressive approach, including earlier surgery, larger craniotomy, and removal of bone flap, may reduce ICP, prevent cortical spreading depolarizations, and improve outcomes. In particular, patients requiring evacuation of subdural hematomas and contusions may benefit from decompressive craniectomy in conjunction with lesion evacuation, even when elevated ICP is not a factor in the decision to perform surgery.

Neuroprotective Effects of Perflurocarbon (Oxycyte) after Contusive Spinal Cord Injury

Spinal cord injury (SCI) often results in irreversible and permanent neurological deficits and long-term disability. Vasospasm, hemorrhage, and loss of microvessels create an ischemic environment at the site of contusive or compressive SCI and initiate the secondary injury cascades leading to progressive tissue damage and severely decreased functional outcome. Although the initial mechanical destructive events cannot be reversed, secondary injury damage occurs over several hours to weeks, a time frame during which therapeutic intervention could be achieved. One essential component of secondary injury cascade is the reduction in spinal cord blood flow with resultant decrease in oxygen delivery. Our group has recently shown that administration of fluorocarbon (Oxycyte) significantly increased parenchymal tissue oxygen levels during the usual postinjury hypoxic phase, and fluorocarbon has been shown to be effective in stroke and head injury. In the current study, we assessed the beneficial effects of Oxycyte after a moderate-to-severe contusion SCI was simulated in adult Long-Evans hooded rats. Histopathology and immunohistochemical analysis showed that the administration of 5 mL/kg of Oxycyte perfluorocarbon (60% emulsion) after SCI dramatically reduced destruction of spinal cord anatomy and resulted in a marked decrease of lesion area, less cell death, and greater white matter sparing at 7 and 42 days postinjury. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining showed a significant reduced number of apoptotic cells in Oxycyte-treated animals, compared to the saline group. Collectively, these results demonstrate the potential neuroprotective effect of Oxycyte treatment after SCI, and its beneficial effects may be, in part, a result of reducing apoptotic cell death and tissue sparing. Further studies to determine the most efficacious Oxycyte dose and its mechanisms of protection are warranted.

Reduction of hypoxia by perfluorocarbon emulsion in a traumatic spinal cord injury model

OBJECT Few therapies have consistently demonstrated effectiveness in preserving O2 delivery after spinal cord injury (SCI). Perfluorocarbons (PFCs) offer great promise to carry and deliver O2 more efficiently than conventional measures. The authors investigated the use of Clark-type microelectrodes to monitor spinal cord oxygenation directly (intraparenchymal [IP] recording) and indirectly (cerebrospinal fluid [CSF] recording) in the context of SCI, O2 therapy, and PFC treatment. METHODS After placement of a subdural/CSF Licox probe in rats, incremental increases in the fraction of inspired O2 (FiO2) up to 100% were administered to establish a dose-response curve. The probe was then placed in the parenchyma of the same animals for a second dose-response curve. In a second study, rats with CSF or IP probes underwent SCI with the NYU Impactor and treatment with O2, followed by administration of PFC, or saline in the control group. RESULTS All animals in the first experiment responded to the FiO2 dose increase, with changes in PO2 evident in both CSF and IP levels. The SCI in the second experiment caused a marked drop in PO2 from a mean of 21.4 to 10.4 mm Hg, with most animals dropping to less than half their preinjury value. All animals responded to 100% O2 treatment. Every animal that received PFCs showed significant improvement, with a mean increase in PO2 of 23.3 mm Hg. Only 1 saline-treated animal showed any benefit. Oxygen values in the PFC treatment group reached up to 6 times the normal level. CONCLUSIONS Oxygen levels in SCI show a profound drop almost immediately postinjury. Administration of PFCs combined with 100% O2 therapy can reverse tissue hypoxia and holds promise for reducing ischemic injury.

Evaluation of glycerol-preserved bone allografts in cervical spine fusion: a prospective, randomized controlled trial

OBJECT Bone allografts used for interbody spinal fusion are often preserved through either freeze drying or lowtemperature freezing, each having disadvantages related to graft preparation time and material properties. In response, a glycerol preservation treatment has been developed to maintain the biomechanical properties of allografts at ambient temperatures, requiring no thawing or rehydration and minimal rinsing prior to implantation. The authors conducted a prospective randomized study to compare the clinical results of glycerol-preserved Cloward dowels and those of freezedried Cloward dowels in anterior cervical discectomy and fusion. The primary outcome measures were evidence of fusion and graft subsidence, and the secondary outcome measures included adverse events, pain, and neck disability scores. METHODS Of 106 patients, 53 (113 levels of surgery) were randomly assigned to the glycerol-preserved graft group and 53 (114 levels of surgery) to the freeze-dried graft group. Subsidence was assessed at 3 and 6 months after implantation. Evidence of fusion was evaluated radiographically at 6 months postimplantation. Subsidence was quantitatively assessed based on physical measurements obtained from radiographs by using calibrated comparators, whereas fusion was also evaluated visually. Surgeons were blinded to treatment type during visual and physical assessments of the patients and the radiographs. RESULTS No one in either group had evidence of complete nonunion according to radiographic evaluation at the 6-month follow-up. Average subsidence for all graft-treated levels was 2.11 mm for the glycerol-preserved group and 2.73 mm for the freeze-dried group at the 3-month follow-up and 2.13 and 2.83 mm at the 6-month follow-up, respectively. The 2 treatment groups were statistically equivalent (p = 0.2127 and 0.1705 for the 3- and 6-month follow-up, respectively). No differences were noted between the graft types in terms of adverse event incidence or severity. CONCLUSIONS Glycerol-preserved bone allografts exhibit fusion results and subsidence values similar to those of their freeze-dried counterparts, potentially more favorable biomechanical properties, and significantly shorter preparation times.

The incorporation of growth factor and chondroitinase ABC into an electrospun scaffold to promote axon regrowth following spinal cord injury

Spinal cord injury results in tissue necrosis in and around the lesion site, commonly leading to the formation of a fluid‐filled cyst. This pathological end point represents a physical gap that impedes axonal regeneration. To overcome the obstacle of the cavity, we have explored the extent to which axonal substrates can be bioengineered through electrospinning, a process that uses an electrical field to produce fine fibres of synthetic or biological molecules. Recently, we demonstrated the potential of electrospinning to generate an aligned matrix that can influence the directionality and growth of axons. Here, we show that this matrix can be supplemented with nerve growth factor and chondroitinase ABC to provide trophic support and neutralize glial‐derived inhibitory proteins. Moreover, we show how air‐gap electrospinning can be used to generate a cylindrical matrix that matches the shape of the cord. Upon implantation in a completely transected rat spinal cord, matrices supplemented with NGF and chondroitinase ABC promote significant functional recovery. An examination of these matrices post‐implantation shows that electrospun aligned monofilaments induce a more robust cellular infiltration than unaligned monofilaments. Further, a vascular network is generated in these matrices, with some endothelial cells using the electrospun fibres as a growth substrate. The presence of axons within these implanted matrices demonstrates that they facilitate axon regeneration following spinal cord injury. Collectively, these results demonstrate the potential of electrospinning to generate an aligned substrate that can provide trophic support, directional guidance cues and regeneration‐inhibitory neutralizing compounds to regenerating axons following spinal cord injury. Copyright