Traumatic brain injury (TBI) remains a significant public health problem and is a leading cause of death and disability in many countries. Durable treatments for neurological function deficits following TBI have been elusive, as there are currently no FDA-approved therapeutic modalities for mitigating the consequences of TBI. Neurostimulation strategies using various forms of electrical stimulation have recently been applied to treat functional deficits in animal models and clinical stroke trials. The results from these studies suggest that neurostimulation may augment improvements in both motor and cognitive deficits after brain injury. Several studies have taken this approach in animal models of TBI, showing both behavioral enhancement and biological evidence of recovery. There have been only a few studies using deep brain stimulation (DBS) in human TBI patients, and future studies are warranted to validate the feasibility of this technique in the clinical treatment of TBI. In this review, the authors summarize insights from studies employing neurostimulation techniques in the setting of brain injury. Moreover, they relate these findings to the future prospect of using DBS to ameliorate motor and cognitive deficits following TBI.
Samuel S. Shin, C. Edward Dixon, David O. Okonkwo and R. Mark Richardson
R. Mark Richardson, Nicholas M. Barbaro, Arturo Alvarez-Buylla and Scott C. Baraban
✓ Mesial temporal lobe epilepsy (MTLE) is presumed to develop progressively as a consequence of synaptic reorganization and neuronal loss, although the exact etiology of seizure development is unknown. Nearly 30% of patients with MTLE have disabling seizures despite pharmacological treatment, and the majority of these patients are recommended for resection. The authors review cell transplantation as an alternative approach to the treatment of epilepsy. Recent work in animal models shows that grafted neuronal precursors that differentiate into inhibitory interneurons can increase the level of local inhibition. Grafts of these inhibitory neurons could help restore equilibrium in MTLE. Developing a sound transplantation strategy involves careful consideration of the etiology of MTLE and the expected functional role of transplanted cells. These issues are reviewed, with a focus on those factors most likely to influence clinically applicable results.
R. Mark Richardson, Helen L. Fillmore, Kathryn L. Holloway and William C. Broaddus
Object. Given the success and limitations of human fetal primary neural tissue transplantation, neuronal stem cells (NSCs) that can be adequately expanded in culture have been the focus of numerous attempts to develop a superior source of replacement cells for restorative neurosurgery. To clarify recent progress toward this goal, the transplantation into the adult brain of NSCs, expanded in vitro before grafting, was reviewed.
Methods. Neuronal stem cells can be expanded from a variety of sources, including embryos, fetuses, adult bone marrow, and adult brain tissue. Recent investigations of each of these expanded stem cell types have generated a large body of information along with a great number of unanswered questions regarding the ability of these cells to replace damaged neurons. Expanded NSCs offer many advantages over their primary tissue predecessors, but also may exhibit different functional abilities as grafted cells. Because expanded NSCs will most likely ultimately replace primary tissue grafting in clinical trials, this review was undertaken to focus solely on this distinct body of work and to summarize clearly the existing preclinical data regarding the in vivo successes, limits, and unknowns of using each expanded NSC type when transplanted into the adult brain.
Conclusions. Embryonic stem cell—derived cells have demonstrated appropriate neuronal phenotypes after transplantation into nonneurogenic areas of the adult brain. Understanding the mechanisms responsible for this may lead to similar success with less studied adult neuronal progenitor cells, which offer the potential for autologous NSC transplantation with less risk of tumorigenesis.
Jason S. Cheng, R. Mark Richardson, Alisa D. Gean and Shirley I. Stiver
The authors report the case of a patient who presented with a hoarse voice and left hemiparesis following a gunshot injury with trajectory entering the left scapula, traversing the suboccipital bone, and coming to rest in the right lateral medullary cistern. Following recovery from the hemiparesis, abrupt quadriparesis occurred coincident with fall of the bullet into the anterior spinal canal. The bullet was retrieved following a C-2 and C-3 laminectomy, and postoperative MR imaging confirmed signal change in the cord at the level where the bullet had lodged. The patient then made a good neurological recovery. Bullets can fall from the posterior fossa with sufficient momentum to cause an acute spinal cord injury. Consideration for craniotomy and bullet retrieval should be given to large bullets lying in the CSF spaces of the posterior fossa as they pose risk for acute spinal cord injury.
Kalil G. Abdullah, Mark A. Attiah, Andrew S. Olsen, Andrew Richardson and Timothy H. Lucas
Although the use of topical vancomycin has been shown to be safe and effective for reducing postoperative infection rates in patients after spine surgery, its use in cranial wounds has not been studied systematically. The authors hypothesized that topical vancomycin, applied in powder form directly to the subgaleal space during closure, would reduce cranial wound infection rates.
A cohort of 150 consecutive patients who underwent craniotomy was studied retrospectively. Seventy-five patients received 1 g of vancomycin powder applied in the subgaleal space at the time of closure. This group was compared with 75 matched-control patients who were accrued over the same time interval and did not receive vancomycin. The primary outcome measure was the presence of surgical site infection within 3 months. Secondary outcome measures included tissue pH from a subgaleal drain and vancomycin levels from the subgaleal space and serum.
Vancomycin was associated with significantly fewer surgical site infections (1 of 75) than was standard antibiotic prophylaxis alone (5 of 75; p < 0.05). Cultures were positive for typical skin flora species. As expected, local measured vancomycin concentrations peaked immediately after surgery (mean ± SD 499 ± 37 μg/ml) and gradually decreased over 12 hours. Vancomycin in the circulating serum remained undetectable. Subgaleal topical vancomycin was associated with a lower incidence of surgical site infections after craniotomy. The authors attribute this reduction in the infection rate to local vancomycin concentrations well above the minimum inhibitory concentration for antimicrobial efficacy.
Topical vancomycin is safe and effective for reducing surgical site infections after craniotomy. These data support the need for a prospective randomized examination of topical vancomycin in the setting of cranial surgery.
Dali Yin, R. Mark Richardson, Massimo S. Fiandaca, John Bringas, John Forsayeth, Mitchel S. Berger and Krystof S. Bankiewicz
The purpose of this study was to optimize stereotactic coordinates for delivery of therapeutic agents into the thalamus and brainstem, using convection-enhanced delivery (CED) to avoid leakage into surrounding anatomical structures while maximizing CED of therapeutics within the target volume.
The authors recently published targeting data for the nonhuman primate putamen in which they defined infusion parameters, referred to as “red,” “blue,” and “green” zones, that describe cannula placements resulting in poor, suboptimal, and optimal volumes of distribution, respectively. In the present study, the authors retrospectively analyzed 22 MR images with gadoteridol as a contrast reagent, which were obtained during CED infusions into the thalamus (14 cases) and brainstem (8 cases) of nonhuman primates.
Excellent distribution of gadoteridol within the thalamus was obtained in 8 cases and these were used to define an optimal target locus (or green zone). Good distribution in the thalamus, with variable leakage into adjacent anatomical structures, was noted in 6 cases, defining a blue zone. Quantitative containment (99.7 ± 0.2%) of gadoteridol within the thalamus was obtained when the cannula was placed in the green zone, and less containment (85.4 ± 3.8%) was achieved with cannula placement in the blue zone. Similarly, a green zone was also defined in the brainstem, and quantitative containment of infused gadoteridol within the brainstem was 99.4 ± 0.6% when the cannula was placed in the green zone. These results were used to determine a set of 3D stereotactic coordinates that define an optimal site for infusions intended to cover the thalamus and brainstem of nonhuman primates.
The present study provides quantitative analysis of cannula placement and infusate distribution using real-time MR imaging and defines an optimal zone for infusion in the nonhuman primate thalamus and brainstem. Cannula placement recommendations developed from such translational nonhuman primate studies have significant implications for the design of anticipated clinical trials featuring CED therapy into the thalamus and brainstem for CNS diseases.
R. Mark Richardson, Amanpreet Singh, Dong Sun, Helen L. Fillmore, Dalton W. Dietrich III and M. Ross Bullock
Approximately 350,000 individuals in the US are affected annually by severe and moderate traumatic brain injuries (TBI) that may result in long-term disability. This rate of injury has produced ~ 3.3 million disabled survivors in the US alone. There is currently no specific treatment available for TBI other than supportive care, but aggressive prehospital resuscitation, rapid triage, and intensive care have reduced mortality rates. With the recent demonstration that neurogenesis occurs in all mammals (including man) throughout adult life, albeit at a low rate, the concept of replacing neurons lost after TBI is now becoming a reality. Experimental rodent models have shown that neurogenesis is accelerated after TBI, especially in juveniles. Two approaches have been followed in these rodent models to test possible therapeutic approaches that could enhance neuronal replacement in humans after TBI. The first has been to define and quantify the phenomenon of de novo hippocampal and cortical neurogenesis after TBI and find ways to enhance this (for example by exogenous trophic factor administration). A second approach has been the transplantation of different types of neural progenitor cells after TBI. In this review the authors discuss some of the processes that follow after acute TBI including the changes in the brain microenvironment and the role of trophic factor dynamics with regard to the effects on endogenous neurogenesis and gliagenesis. The authors also discuss strategies to clinically harness the factors influencing these processes and repair strategies using exogenous neural progenitor cell transplantation. Each strategy is discussed with an emphasis on highlighting the progress and limiting factors relevant to the development of clinical trials of cellular replacement therapy for severe TBI in humans.