Dilantha B. Ellegala

Acute spinal cord injury, part I: pathophysiologic mechanisms.

Spinal cord injury (SCI) is a devastating and common neurologic disorder that has profound influences on modern society from physical, psychosocial, and socioeconomic perspectives. Accordingly, the present decade has been labeled the Decade of the Spine to emphasize the importance of SCI and other spinal disorders. Spinal cord injury may be divided into both primary and secondary mechanisms of injury. The primary injury, in large part, determines a given patients neurologic grade on admission and thereby is the strongest prognostic indicator. However, secondary mechanisms of injury can exacerbate damage and limit restorative processes, and hence, contribute to overall morbidity and mortality. A burgeoning body of evidence has facilitated our understanding of these secondary mechanisms of injury that are amenable to pharmacological interventions, unlike the primary injury itself. Secondary mechanisms of injury encompass an array of perturbances and include neurogenic shock, vascular insults such as hemorrhage and ischemia–reperfusion, excitotoxicity, calcium-mediated secondary injury and fluid–electrolyte disturbances, immunologic injury, apoptosis, disturbances in mitochondrion function, and other miscellaneous processes. Comprehension of secondary mechanisms of injury serves as a basis for the development and application of targeted pharmacological strategies to confer neuroprotection and restoration while mitigating ongoing neural injury. The first article in this series will comprehensively review the pathophysiology of SCI while emphasizing those mechanisms for which pharmacologic therapy has been developed, and the second article reviews the pharmacologic interventions for SCI.

Imaging Tumor Angiogenesis With Contrast Ultrasound and Microbubbles Targeted to αvβ3

Background Angiogenesis is a critical determinant of tumor growth and metastasis. We hypothesized that contrastenhanced ultrasound (CEU) with microbubbles targeted to &agr;v‐integrins expressed on the neovascular endothelium could be used to image angiogenesis. Methods and Results Malignant gliomas were produced in 14 athymic rats by intracerebral implantation of U87MG human glioma cells. On day 14 or day 28 after implantation, CEU was performed with microbubbles targeted to &agr;v&bgr;33 by surface conjugation of echistatin. CEU perfusion imaging with nontargeted microbubbles was used to derive tumor microvascular blood volume and blood velocity. Vascular &agr;v‐integrin expression was assessed by immunohistochemistry, and microbubble adhesion was characterized by confocal microscopy. Mean tumor size increased markedly from 14 to 28 days (2±1 versus 35±14 mm2, P<0.001). Tumor blood volume increased by ≈35% from day 14 to day 28, whereas microvascular blood velocity decreased, especially at the central portions of the tumors. On confocal microscopy, &agr;v&bgr;3‐targeted but not control microbubbles were retained preferentially within the tumor microcirculation. CEU signal from &agr;v&bgr;3‐targeted microbubbles in tumors increased significantly from 14 to 28 days (1.7±0.4 versus 3.3±1.0 relative units, P<0.05). CEU signal from &agr;v&bgr;3‐targeted microbubbles was greatest at the periphery of tumors, where &agr;v‐integrin expression was most prominent, and correlated well with tumor microvascular blood volume (r=0.86). Conclusions CEU with microbubbles targeted to &agr;v&bgr;3 can noninvasively detect early tumor angiogenesis. This technique, when coupled with changes in blood volume and velocity, may provide insights into the biology of tumor angiogenesis and be used for diagnostic applications. (Circulation. 2003;108:336‐341.)

Differential Macrophage Responses in the Peripheral and Central Nervous System during Wallerian Degeneration of Axons

We characterized quantitatively the macrophage response following axonal injury in both the peripheral (PNS) and central nervous system (CNS) of adult mammals. A monoclonal antibody (ED-1) which stains monocytes, macrophages, and activated microglia was employed. In one model, Wallerian degeneration of the sciatic nerve was studied. An increase in the number of macrophages was seen as early as 1 day following nerve transection. Macrophage number increased synchronously along the length of degenerating nerve over a 21-day period. In a second model, transection of a spinal dorsal sensory root allowed us to compare and contrast the macrophage response along the PNS and CNS portions of a single axonal pathway. An increased number of macrophages restricted to the PNS portion of this pathway was seen by 3 days and continued to increase over a 14-day period. Myelin breakdown occurred in association with an increase in the number of macrophages by 3 days in the PNS but not the CNS portion of the degenerating dorsal root axon pathway. Low-affinity nerve growth factor receptor immunohistochemical staining increased by Day 1 in the PNS but not the CNS portion of this pathway, occurring prior to the invasion of macrophages. In both models, the morphology of infiltrating macrophages changed over time from small slender ramified cells to large elongated multivacuolated cells. In conclusion, our results demonstrate that the macrophage response during Wallerian degeneration of axons in adult mammals is much more rapid and robust in the PNS, where axonal regeneration occurs, than in the CNS, where axonal regeneration is far more limited.

Acute spinal cord injury, part II: contemporary pharmacotherapy.

Spinal cord injury (SCI) remains a common and devastating problem of modern society. Through an understanding of underlying pathophysiologic mechanisms involved in the evolution of SCI, treatments aimed at ameliorating neural damage may be developed. The possible pharmacologic treatments for acute spinal cord injury are herein reviewed. Myriad treatment modalities, including corticosteroids, 21-aminosteroids, opioid receptor antagonists, gangliosides, thyrotropin-releasing hormone (TRH) and TRH analogs, antioxidants and free radical scavengers, calcium channel blockers, magnesium replacement therapy, sodium channel blockers, N-methyl-D-aspartate receptor antagonists, &agr;-amino-3-hydroxy-5-methylisoxazole-4-propionic acid–kainate receptor antagonists, modulators of arachadonic acid metabolism, neurotrophic growth factors, serotonin antagonists, antibodies against inhibitors of axonal regeneration, potassium channel blockers (4-aminopyridine), paclitaxel, clenbuterol, progesterone, gabexate mesylate, activated protein C, caspase inhibitors, tacrolimus, antibodies against adhesion molecules, and other immunomodulatory therapy have been studied to date. Although most of these agents have shown promise, only one agent, methylprednisolone, has been shown to provide benefit in large clinical trials. Given these data, many individuals consider methylprednisolone to be the standard of care for the treatment of acute SCI. However, this has not been established definitively, and questions pertaining to methodology have emerged regarding the National Acute Spinal Cord Injury Study trials that provided these conclusions. Additionally, the clinical significance (in contrast to statistical significance) of recovery after methylprednisolone treatment is unclear and must be considered in light of the potential adverse effects of such treatment. This first decade of the new millennium, now touted as the Decade of the Spine, will hopefully witness the emergence of universal and efficacious pharmacologic therapy and ultimately a cure for SCI.

Use of FloSeal hemostatic sealant in transsphenoidal pituitary surgery: Technical note

OBJECTIVE Bleeding during transsphenoidal pituitary surgery can lead to a variety of operative difficulties. When the endonasal transsphenoidal approach is used, even mild intraoperative hemorrhage can lessen visibility in the confined operative field of view. This technical note describes the use of a hemostatic agent we have found of benefit in obtaining prompt hemostasis during this operation. METHODS Operative records were reviewed for an 18-month period for all patients who underwent transsphenoidal surgery since we began using FloSeal hemostatic sealant in January 2000. RESULTS During the study period, 293 transsphenoidal operations were performed for pituitary lesions. Of these, 20 procedures involved vigorous or persistent bleeding. When the standard techniques for hemostasis failed or were inadequate, FloSeal, a sterile mixture of a gelatin matrix and thrombin component mixed at the time of use, was applied to the site of hemorrhage by use of a 14-gauge angiocatheter to reach the sella. We observed complete hemostasis immediately on application of FloSeal in all cases except one, which required a second application. Hemostasis was obtained immediately after the second application. No operations were aborted during this period as a consequence of undue bleeding. CONCLUSION We detail the method in which we use FloSeal in transsphenoidal surgery and report our impression of its effectiveness. FloSeal has been demonstrated to be safe and biocompatible as compared with hemostatic agents currently in use.

Results of transsphenoidal surgery for Cushing's disease in patients with no histologically confirmed tumor.

OBJECTIVE Pathological confirmation of surgical resection of an adenoma for Cushings disease is not always achieved. We reviewed our experience to determine the prognostic significance of this lack of confirmation regarding outcome, and we evaluate explanations for this situation. METHODS The records of all patients undergoing transsphenoidal surgery for Cushings disease from 1992 to 1998 were reviewed, and those with no histological confirmation of tumor were identified. Information regarding preoperative and postoperative hormonal levels and clinical symptoms, preoperative magnetic resonance imaging data, intraoperative findings, and the number of reoperations were recorded. RESULTS There were 29 patients with no confirmation of tumor. Nineteen (66%) of these patients were cured with surgery and only one had a recurrence of disease, with an average follow-up of 38 months. An abnormality thought to represent an adenoma at the time of surgery was removed in 26 patients (90%). Preoperative magnetic resonance imaging suggested a discrete lesion in 21 patients (72%). Neither intraoperative impression nor magnetic resonance imaging appearance was correlated with outcome. CONCLUSION Patients with no histological confirmation of tumor after transsphenoidal surgery for Cushings disease are likely to have a good outcome. The results do not differ significantly from reported cure rates in patients with confirmed adenomas. Possible explanations for this situation are discussed.

Neurosurgical capacity building in the developing world through focused training

OBJECT In Tanzania, there are 4 neurosurgeons for a population of 46 million. To address this critical shortage of neurosurgical care, the authors worked with local Tanzanian health care workers, neurosurgeons, the Ministry of Health and Social Welfare, and the Office of the President of Tanzania to develop a train-forward method for sustainable, self-propagating basic and emergency neurosurgery in resource-poor settings. The goal of this study was to assess the safety and effectiveness of this method over a 6-year period. METHODS The training method utilizes a hands-on bedside teaching technique and was introduced in 2006 at a remote rural hospital in northern Tanzania. Local health care workers were trained to perform basic and emergency neurosurgical procedures independently and then were taught to train others. Outcome information was retrospectively collected from hospital records for the period from 2005 (1 year before method implementation) through 2010. Analysis of de-identified data included descriptive statistics and multivariable assessment of independent predictors of complications following a patients first neurosurgical procedure. RESULTS By 2010, the initial Tanzanian trainee had trained a second Tanzanian health care worker, who in turn had trained a third. The number of neurosurgical procedures performed increased from 18 in 2005 to an average of 92 per year in the last 3 years of the study period. Additionally, the number of neurosurgical cases performed independently by Tanzanian health care providers increased significantly from 44% in 2005 to 86% in 2010 (p < 0.001), with the number of complex cases independently performed also increasing over the same time period from 34% to 83% (p < 0.001). Multivariable analysis of clinical patient outcome information to assess safety indicated that postoperative complications decreased significantly from 2005 through 2010, with patients who had been admitted as training progressed being 29% less likely to have postoperative complications (OR 0.71, 95% CI 0.52-0.96, p = 0.03). CONCLUSIONS The Madaktari Africa train-forward method is a reasonable and sustainable approach to improving specialized care in a resource-poor setting.

The Baromodulatory Effect of Gamma Knife Irradiation of the Hypothalamus in the Obese Zucker Rat

Objective: The aim of this study was to evaluate the effect on body weight set point over time of focused, subnecrotic doses of radiation via gamma knife (GK) to the hypothalamus of the genetically obese Zucker rat. Methods: A total of 36 adolescent animals were used in this experiment and placed in 6 groups of 6. The genetically obese homozygous Zucker rat was used in 4 groups (n = 24) and received GK, subcutaneous cobalt protoporphyrin (CoPP), both treatments combined or sham treatment. The heterozygous lean Zucker rat was used in 2 control groups (n = 12) and received either GK or sham treatment. All animals were weighed at the beginning of the experiment and at weekly intervals for 34 weeks. GK irradiation was accomplished using a specially designed stereotactic frame and a total dose of 40 Gy was given to 2 nearby targets in the medial hypothalamus. The drug subgroups received weekly subcutaneous injections. All animals were housed in the same environment with unlimited access to food. Results: There were no significant differences in weight between the lean GK and sham groups. For the obese cohort, beginning at week 7 and throughout the remainder of the experiment, there were significant and sustained reductions in weight set point for animals that received GK (p < 0.05) and CoPP (p < 0.05) compared to sham-treated animals. Curiously, there was no statistical difference between the combined treatment and sham subgroups, though there was a trend toward weight reduction (p < 0.10). With the exception of one animal in the obese GK cohort in which there was a small area of necrosis lateral to the target area, histopathological analysis failed to reveal any abnormalities. There were no gross behavioral abnormalities noted. Conclusion: Our experimental results suggest that a single dose of GK irradiation to the hypothalamus can produce sustained reduction in the weight set point without emaciation in adolescent animals. The effect of this treatment is comparable to a well-studied drug therapy with a metalloporphyrin. We hypothesize that this involves a resetting of the hypothalamic set point for body weight through an as yet uncharacterized neuromodulatory effect.

Site-specific imaging of tumor angiogenesis using contrast-enhanced ultrasound imaging with microbubbles targeted to alpha-V beta-3

flow, was mildly increased at 1 hr (2.0+2.3), then increased over the first week peaking at day 4 (5.6+2.6), then declined rapidly (0.950.7 at day 26). The MB, Signal peak preceded increases in normalized blood flow and blood volume, were not detected until after day 14 (0.52+0.11 and 0.87*0.09, for blood flow and volume at 28 days). MB, Signal peak also preceded an increase in ischemic muscle tissue PO, (normalized values Of 0.24+0.06 and 0.47+0.10, at 1 hr and 28 days, respectively). We conclude that CEU with microbubbles targeted for endothelial a,-in&grins can be used to non-invasively assess anglogenic responses in skeletal muscle. These results suggest that targeted CEU imaging of endothelial markers of angiogenesis may potentially be used for assessing intrinsic and therapeutic angiogenesis prior to changes tn perfusion. IO:00 a.m.