Targeting of nanoparticles to the cerebral vasculature after traumatic brain injury.

Traumatic brain injury has faced numerous challenges in drug development, primarily due to the difficulty of effectively delivering drugs to the brain. However, there is a potential solution in targeted drug delivery methods involving antibody-drug conjugates or nanocarriers conjugated with targeting antibodies. Following a TBI, the blood-brain barrier (BBB) becomes permeable, which can last for years and allow the leakage of harmful plasma proteins. Consequently, an appealing approach for TBI treatment involves using drug delivery systems that utilize targeting antibodies and nanocarriers to help restore BBB integrity. In our investigation of this strategy, we examined the efficacy of free antibodies and nanocarriers targeting a specific endothelial surface marker called vascular cell adhesion molecule-1 (VCAM-1), which is known to be upregulated during inflammation. In a mouse model of TBI utilizing central fluid percussion injury, free VCAM-1 antibody did not demonstrate superior targeting when comparing sham vs. TBI brain. However, the administration of VCAM-1-targeted nanocarriers (liposomes) exhibited a 10-fold higher targeting specificity in TBI brain than in sham control. Flow cytometry and confocal microscopy analysis confirmed that VCAM-1 liposomes were primarily taken up by brain endothelial cells post-TBI. Consequently, VCAM-1 liposomes represent a promising platform for the targeted delivery of therapeutics to the brain following traumatic brain injury.

Temporary occipital fixation in young children with severe cervical-thoracic spinal deformity.

OBJECTIVE The long-term effects of instrumentation and fusion of the occipital-cervical-thoracic spine on spinal growth in young children are poorly understood. To mitigate the effects of this surgery on the growing pediatric spine, the authors report a novel technique used in 4 children with severe cervical-thoracic instability. These patients underwent instrumentation from the occiput to the upper thoracic region for stabilization, but without bone graft at the craniovertebral junction (CVJ). Subsequent surgery was then performed to remove the occipital instrumentation, thereby allowing further growth and increased motion across the CVJ. METHODS Three very young children (15, 30, and 30 months old) underwent occipital to thoracic posterior segmental instrumentation due to cervical or upper thoracic dislocation, progressive kyphosis, and myelopathy. The fourth child (10 years old) underwent similar instrumentation for progressive cervical-thoracic scoliosis. Bone graft was placed at and distal to C-2 only. After follow-up CT scans demonstrated posterior arthrodesis without unintended fusion from the occiput to C-2, 3 patients underwent removal of the occipital instrumentation. RESULTS Follow-up cervical spine flexion/extension radiographs demonstrated partial restoration of motion at the CVJ. One patient has not had the occipital instrumentation removed yet, because only 4 months have elapsed since her operation. CONCLUSIONS Temporary fixation to the occiput provides increased biomechanical stability for spinal stabilization in young children, without permanently eliminating motion and growth at the CVJ. This technique can be considered in children who require longer instrumentation constructs for temporary stabilization, but who only need fusion in more limited areas where spinal instability exists.

Craniopharyngioma arising in a Rathke's cleft cyst: case report.

Craniopharyngioma is one of the most common non-glial intracranial tumors of childhood. Its relation to Rathke's cleft cyst (RCC) is controversial, and both lesions have been hypothesized to lie on a continuum of cystic ectodermal lesions of the sellar region. The authors report on a 7-year-old boy who presented with decreased visual acuity, presumably of at least 2 years' duration, and was found to have a 5.2-cm sellar lesion with rim enhancement. Histological examination of the resected lesion showed a mixture of areas with simple RCC morphology with focal squamous metaplasia and areas with typical craniopharyngioma morphology. Immunohistochemical staining with CK20 and Ki 67 differentially highlighted the 2 morphological components. Testing for beta-catenin and BRAF mutations was negative in the craniopharyngioma component, precluding definitive molecular classification. Follow-up imaging showed minimal residual enhancement and the patient will be closely followed up with serial MRI. Given the clinical and histological findings in the case, a progressive transformation of the RCC to craniopharyngioma seems to be the most plausible explanation for the co-occurrence of the 2 lesion types in this patient. An extensive review of previously proposed theories of the relationship between craniopharyngioma and RCC is also presented.

Diffusion tensor imaging as a predictor of locomotor function after experimental spinal cord injury and recovery.

Traumatic spinal cord injury (SCI) causes long-term disability with limited functional recovery linked to the extent of axonal connectivity. Quantitative diffusion tensor imaging (DTI) of axonal integrity has been suggested as a potential biomarker for prognostic and therapeutic evaluation after trauma, but its correlation with functional outcomes has not been clearly defined. To examine this application, female Sprague-Dawley rats underwent midthoracic laminectomy followed by traumatic spinal cord contusion of differing severities or laminectomy without contusion. Locomotor scores and hindlimb kinematic data were collected for 4 weeks post-injury. Ex vivo DTI was then performed to assess axonal integrity using tractography and fractional anisotropy (FA), a numerical measure of relative white matter integrity, at the injury epicenter and at specific intervals rostral and caudal to the injury site. Immunohistochemistry for tissue sparing was also performed. Statistical correlation between imaging data and functional performance was assessed as the primary outcome. All injured animals showed some recovery of locomotor function, while hindlimb kinematics revealed graded deficits consistent with injury severity. Standard T2 magnetic resonance sequences illustrated conventional spinal cord morphology adjacent to contusions while corresponding FA maps indicated graded white matter pathology within these adjacent regions. Positive correlations between locomotor (Basso, Beattie, and Bresnahan score and gait kinematics) and imaging (FA values) parameters were also observed within these adjacent regions, most strongly within caudal segments beyond the lesion. Evaluation of axonal injury by DTI provides a mechanism for functional recovery assessment in a rodent SCI model. These findings suggest that focused DTI analysis of caudal spinal cord should be studied in human cases in relationship to motor outcome to augment outcome biomarkers for clinical cases.

Two-level thoracic pedicle subtraction osteotomy for progressive post-laminectomy kyphotic deformity following resection of an unusual thoracolumbar intradural extramedullary tumor.

The authors report a case in which multilevel thoracic pedicle subtraction osteotomy (PSO) was performed to correct post-laminectomy kyphotic deformity in a 9-year-old boy presenting with worsening lower-extremity neurological deficits. Five years prior to presentation, the patient underwent multilevel thoracolumbar laminectomies for resection of an atypical teratoid/rhabdoid tumor (AT/RT), a rare lesion that typically occurs intracranially and has a poor prognosis, making this particular presentation unusual and the patient's subsequent postoperative course remarkable. No fusion was undertaken at the time of resection, given the patient's age and presumptive poor prognosis. Over the next 5 years, the patient developed progressive thoracolumbar kyphotic deformity, with a Cobb angle greater than 110°, despite bracing, and bilateral lower-extremity weakness requiring ankle-foot orthotics for continued ambulation due to progressive foot drop. Worsening gait and the onset of respiratory issues prompted surgical intervention. Multilevel thoracic PSO and thoracolumbar fusion were performed, resulting in improved lower-extremity function and correction of the kyphotic deformity to approximately 65°. This report outlines an unusual AT/RT presentation and postoperative course and also discusses literature related to PSO within the context of pediatric kyphotic deformity. The authors' experience supports the use of multilevel PSO with fusion as a potential treatment option for significant pediatric thoracolumbar kyphotic deformity requiring surgical correction.

Biochemical, structural, and biomarker evidence for calpain-mediated cytoskeletal change after diffuse brain injury uncomplicated by contusion.

Calpain-mediated degradation of the cytoskeletal protein alpha-II-spectrin has been implicated in the pathobiology of experimental and human traumatic brain injury (TBI). Spectrin proteolysis after diffuse/widespread TBI uncomplicated by either subtle or overt contusion and/or mass lesions, (i.e. mild to moderate TBI), has not been previously evaluated. To determine the spatiotemporal pattern and cellular localization of calpain-mediated spectrin proteolysis after diffuse/widespread TBI and the extent to which parenchymal changes in calpain-mediated spectrin proteolysis are reflected in the cerebrospinal fluid, adult rats were subjected to a moderate midline fluid percussion injury and allowed to survive for 3 hours to 7 days postinjury. Light and electron microscopic immunocytochemical and Western blot analyses were performed to identify the calpain-specific 145-kDa breakdown product of alpha-II-spectrin (SBDP145). After diffuse TBI, enhanced levels of SBDP145 immunoreactivity were observed in the neocortex, subcortical white matter, thalamus, and hippocampus, peaking between 24 and 48 hours postinjury. Immunoreactivity was localized almost exclusively to damaged axons and axonal terminal debris. Heightened levels of SBDP145 were also observed in the cerebrospinal fluid at 24 hours postinjury. These results confirm the widespread occurrence of calpain-mediated spectrin proteolysis after diffuse TBI without contusion and support the potential utility of SBDPs as biomarkers of a diffusely injured brain.

Traumatic axonal injury in the perisomatic domain triggers ultrarapid secondary axotomy and Wallerian degeneration.

Traumatic axonal injury (TAI) arising from diffuse brain injury (DBI) results in focally impaired axonal transport with progressive swelling and delayed disconnection over several hours within brainstem axons. Neocortical DBI-mediated perisomatic axotomy does not result in neuronal death, suggesting that a comparably delayed axotomy progression was responsible for this unanticipated response. To evaluate delayed perisomatic axotomy, the current study was initiated. Rats received intracerebroventricular 10-kDa dextran followed by moderate midline/central fluid percussion injury (FPI) or FPI alone. At 15, 30, 60, and 180 min post-injury, light and transmission electron microscopy identified impaired axonal transport via antibodies targeting amyloid precursor protein (APP), while double-label fluorescent microscopy explored concomitant focal axolemmal alterations via dextran-APP co-localization. At 15 min post-injury, perisomatic TAI was identified with LM within dorsolateral and ventral posterior thalamic nuclei. Using TEM, many sustaining somata and related proximal/distal axonal segments revealed normal ultrastructural detail that was continuous with focal axonal swellings characterized by cytoskeletal and organelle pathology. In other cases, axotomy was confirmed by loss of axonal continuity distal to the swelling. By 30 min post-injury, perisomatic axotomy predominated. By 60-180 min, somatic, proximal axonal segment, and swelling ultrastructure were comparable to earlier time points although swelling diameter increased. Distal axonal segment ultrastructure now revealed the initial stages of Wallerian degeneration. The site of perisomatic axotomy did not internalize dextran, suggesting that its pathogenesis occurred independent of altered axolemmal permeability. Collectively, this DBI-mediated ultrarapid perisomatic axotomy and its sequelae further illustrate the varied axonal responses to trauma.