Arun Paul Amar

Pathogenesis and pharmacological strategies for mitigating secondary damage in acute spinal cord injury.

OBJECTIVE Experimental models and clinical observations of acute spinal cord injury (SCI) support the concepts of primary and secondary injury, in which the initial mechanical insult is succeeded by a series of deleterious events that promote progressive tissue damage and ischemia. Whereas the primary injury is fated by the circumstances of the trauma, the outcome of the secondary injury may be amenable to therapeutic modulation. This article reviews the pathogenetic determinants of these two phases of injury and summarizes the pharmacological manipulations that may restore neurological function after SCI. METHODS Experimental models of SCI and their inherent limitations in simulating human SCI are surveyed. The pathogenesis of primary and secondary injury, as well as the theoretical bases of neurological recovery, are examined in detail. The effects of glucocorticoids, lazeroids, gangliosides, opiate antagonists, calcium channel blockers, glutamate receptor antagonists, antioxidants, free radical scavengers, and other pharmacological agents in both animal models and human trials are summarized. Practical limitations to inducing neural regeneration are also addressed. RESULTS The molecular events that mediate the pathogenesis of SCI are logical targets for pharmacological manipulation and include glutamate accumulation, aberrant calcium fluxes, free radical formation, lipid peroxidation, and generation of arachidonic acid metabolites. Enhancement of neural regeneration and plasticity comprise other possible strategies. CONCLUSION Pharmacological agents must be given within a narrow window of opportunity to be effective. Although many therapeutic agents show potential promise in animal models, only methylprednisolone has been shown in large, randomized, double-blinded human studies to enhance the functional recovery of neural elements after acute SCI. Future therapy is likely to involve various combinations of these agents.

Percutaneous transpedicular polymethylmethacrylate vertebroplasty for the treatment of spinal compression fractures.

OBJECTIVETo assess the safety, feasibility, and clinical outcome of percutaneous transpedicular polymethylmethacrylate vertebroplasty (PTPV) for the treatment of spinal compression fractures causing refractory pain. METHODSWe retrospectively reviewed a consecutive group of patients undergoing PTPV at our institution between April 1998 and January 2001. Outcome measures included analgesic requirements, ambulatory status, sleep comfort, and overall quality of life 2 weeks after the procedure. RESULTSA total of 97 patients (73 women and 24 men) underwent 258 PTPV procedures during 133 treatment sessions. The mean age was 76 years (range, 42–99 yr). The mean duration of follow-up was 14.7 months (range, 2–35 mo). Most of the patients had osteoporotic compression fractures, although some had osteolytic malignancies. Complete follow-up was obtained in 81 patients (84%). Narcotic and analgesic usage decreased in 63% of patients, increased in 7%, and remained the same in 30%. Ambulation and mobility were improved in 51%, worse in 1% and the same in 48%. One-half of the patients were able to sleep more comfortably after the procedure, whereas the other half remained the same. Most patients who reported no change in sleep or ambulation had experienced no impairment of these activities before PTPV. Overall, 74% of patients believed that PTPV significantly enhanced their quality of life and 26% reported no change. No patient was worse after PTPV. One patient with preexisting pneumonia died of respiratory failure after the procedure; another died of an acute stroke weeks later. One patient developed symptomatic pulmonary embolism of cement, and another developed transient quadriceps weakness from radiculopathy. Other complications were minor and infrequent. There were no infections. CONCLUSIONPTPV provided significant relief in a high percentage of patients with refractory pain. PTPV is a safe and feasible treatment for patients with spinal compression fractures.

Anti-Inflammatory, Antithrombotic, and Neuroprotective Effects of Activated Protein C in a Murine Model of Focal Ischemic Stroke

BackgroundActivated protein C (APC) contributes to systemic anticoagulant and anti-inflammatory activities. APC may reduce organ damage by inhibiting thrombin generation and leukocyte activation. Neutrophils and cerebrovascular thrombosis contribute to ischemic neuronal injury, suggesting that APC may be a potential protective agent for stroke. Methods and ResultsWe examined the effects of APC in a murine model of focal ischemia. After middle cerebral artery occlusion/reperfusion, the average survival time in controls was 13.6 hours. Animals that received purified human plasma–derived APC 2 mg/kg IV either 15 minutes before or 10 minutes after stroke induction survived 24 hours and were killed for neuropathological analysis. APC 2 mg/kg given before or after onset of ischemia restored cerebral blood flow, reduced brain infarct volume (59% to 69%;P <0.003) and brain edema (50% to 61%;P <0.05), eliminated brain infiltration with neutrophils, and reduced the number of fibrin-positive cerebral vessels by 57% (P <0.05) and 25% (nonsignificant), respectively. The neuroprotective effect of APC was dose-dependent and associated with significant inhibition of ICAM-1 expression on ischemic cerebral blood vessels (eg, 61% inhibition with 2 mg/kg APC). Intracerebral bleeding was not observed with APC. ConclusionsAPC exerts anti-inflammatory, antithrombotic, and neuroprotective effects in stroke. Central effects of APC are likely to be related to improved maintenance of the blood-brain barrier to neutrophils and to reduced microvascular obstructions and fibrin deposition.

An institutional experience with cervical vagus nerve trunk stimulation for medically refractory epilepsy: rationale, technique, and outcome.

OBJECTIVE Intermittent stimulation of the left cervical vagus nerve trunk is emerging as a novel adjunct in the treatment of medically refractory seizures. We sought to evaluate theoretical and practical issues attendant to this concept. We review the anatomic and physiological background arguing for clinical application of vagus nerve stimulation, discuss salient aspects of patient selection and the nuances of surgical technique, and present our observations of and results from application of the method. METHODS Each of 18 patients with medically refractory epilepsy and at least six complex partial or secondarily generalized seizures per month underwent placement of a NeuroCybernetic Prosthesis pulse generator (Cyberonics, Webster, TX) in the chest, connected to helical platinum leads applied to the left cervical vagus nerve trunk. The patients were then randomized in a double-blinded fashion to receive either high (presumably therapeutic) or low (presumably less therapeutic) levels of vagus nerve stimulation. Reduction in seizure frequency, global assessments of quality of life, physiological measurements, and adverse events were recorded during a 3-month period. Patients in the low group were then crossed over to high-stimulation paradigms during a 15-month extension trial. RESULTS All operations were successful, uneventful, and without adverse postoperative sequelae. One patient was excluded from analysis because of inadequate seizure calendars. Of the seven patients initially assigned to high stimulation, the mean reduction in seizure frequency was 71% at 3 months and 81% at 18 months. Five (72%) of these patients had a greater than 75% reduction in seizure frequency, and one (14%) remained seizure-free after more than 1.5 years of follow-up. The mean reduction in seizure frequency among the low-stimulation group was only 6% at 3 months. No serious complications, device failures, or physiological perturbations occurred. CONCLUSION In our experience, vagus nerve stimulation has proven to be a safe, feasible, and potentially effective method of reducing seizures in select patient populations. However, the elements of strict definition for the application of the method require further study.

Hypertension, Age, and Location Predict Rupture of Small Intracranial Aneurysms

BACKGROUND:Although current guidelines for the management of unruptured intracranial aneurysms (IAs) suggest aneurysms larger than 7 mm should be considered for treatment, a significant number of subarachnoid hemorrhages are caused by IAs 7 mm or smaller. Thus, we sought to identify risk factors associated with the rupture of IAs 7 mm or smaller. METHODS:We identified 100 patients with subarachnoid hemorrhage resulting from IAs 7 mm or smaller between January 2001 and 2004. Patients were compared with controls (n = 51) with unruptured IAs 7 mm or smaller, diagnosed by conventional angiography or three-dimensional computerized angiography, with respect to aneurysm characteristics (size, location, and age of presentation) and risk factors (hypertension, smoking, cocaine use, and family history). RESULTS:Hypertensive patients with IAs 7 mm or smaller were 2.6 times more likely to experience rupture (P = 0.01; 95% confidence interval, 1.21–5.53) than patients with normal blood pressure. Posterior circulation aneurysms were 3.5 times more likely to rupture than anterior circulation aneurysms (P = 0.048; 95% confidence interval, 0.95–19.4). After adjustment for location and hypertension, the age of patient on presentation was associated with a trend toward inverse correlation with aneurysmal rupture risk (P = 0.07). Hypertension and posterior location remained significant independent predictors in the logistic regression model. CONCLUSION:Among patients with small aneurysms (≤7 mm), hypertension, relatively young age, and posterior circulation were significant risk factors for rupture. Given the minimal long-term morbidity and mortality of treatment of unruptured aneurysms in large, tertiary medical centers, management of unruptured aneurysms 7 mm or smaller should be governed by factors other than size, specifically age, history of hypertension, and location.

Vagus nerve stimulation therapy after failed cranial surgery for intractable epilepsy: results from the vagus nerve stimulation therapy patient outcome registry.

OBJECTIVE To determine the effectiveness of vagus nerve stimulation (VNS) therapy among patients with persistent or recurrent seizures after lobar resection, callosotomy, and other cranial operations for intractable epilepsy. METHODS Data were obtained from the VNS therapy patient outcome registry, which was established after United States Food and Drug Administration approval of the VNS device in 1997 as a means of capturing open-label clinical data outside of protocol. The integrity of the systems for collecting and processing registry data was authenticated by an independent auditing agency. The effect of potential selection bias, however, remains uncertain. RESULTS Two nonconsecutive cohorts were compared: patients tracked in the registry who had previously undergone cranial surgery for epilepsy (CS group, n=921) and those who had not (non-CS group, n = 3822). For the CS group, the median reduction in seizure frequency was 42.5% after 3 months of VNS therapy, 42.9% at 6 months, 45.7% at 12 months, 52.0% at 18 months, and 50.5% at 24 months. For the non-CS group, analogous rates were 47.0%, 52.9%, 60.0%, 62.7%, and 66.7%, respectively. In the CS group, seizures were reduced by at least 50% in 55.1% of patients, at least 75% in 31.4% of patients, at least 90% in 17.3% of patients, and 100% in 5.1% of patients after 24 months of VNS therapy. Response rates were more pronounced in the non-CS group: at least 50% in 62.2% of patients, at least 75% in 43.7% of patients, at least 90% in 26.8% of patients, and 100% in 8.3% of patients. Patients in both groups experienced marked improvements in quality of life parameters. CONCLUSION The effectiveness of VNS is maintained during prolonged stimulation, and overall seizure control continues to improve with time. Patients in whom prior cranial surgery had failed did not respond as favorably as all other patients receiving VNS therapy. Nonetheless, many of the former group improved substantially. Thus, on the basis of these open-label data, VNS therapy represents a potentially palliative treatment option for patients with refractory seizures after failed cranial surgery.

Surgery of the mind and mood: a mosaic of issues in time and evolution.

The prevalence and economic burden of neuropsychiatric disease are enormous. The surgical treatment of these psychiatric disorders, although potentially valuable, remains one of the most controversial subjects in medicine, as its concept and potential reality raises thorny issues of moral, ethical, and socioeconomic consequence.This article traces the roots of concept and surgical efforts in this turbulent area from prehistory to the 21st century. The details of the late 19th and 20th century evolution of approaches to the problem of intractable psychiatric diseases with scrutiny of the persona and contributions of the key individuals Gottlieb Burckhardt, John Fulton, Egas Moniz, Walter Freeman, James Watts, and William Scoville are presented as a foundation for the later, more logically refined approaches of Lars Leksell, Peter Lindstrom, Geoffrey Knight, Jean Talaraich, and Desmond Kelly. These refinements, characterized by progressive minimalism and founded on a better comprehension of underlying pathways of normal function and disease states, have been further explored with recent advances in imaging, which have allowed the emergence of less invasive and technology driven non-ablative surgical directives toward these problematical disorders of mind and mood.The application of therapies based on imaging comprehension of pathway and relay abnormalities, along with explorations of the notion of surgical minimalism, promise to serve as an impetus for revival of an active surgical effort in this key global health and socioeconomic problem.Eventual coupling of cellular and molecular biology and nanotechnology with surgical enterprise is on the horizon.

Pituitary anatomy and physiology

The pituitary has been called the master gland of the body because of its central role in governing homeostasis, maintaining the reproductive cycle, and directing the activity of other glands. Housed in the sella turcica of the sphenoid bone at the base of the skull, it has important anatomic relations with the hypothalamus, visual pathways, cavernous sinus, carotid artery, and cranial nerves. The gland originates from two discrete parts of the developing embryo. Rathkes pouch, a dorsal evagination of the stomodeum, forms the anterior and intermediate lobes. The infundibulum, a ventral extension of the diencephalon, forms the posterior lobe. The anterior, intermediate, and posterior lobes of the pituitary gland function as three separate endocrine organs, each characterized by distinct cell populations, secretory products, and regulatory mechanisms. The anterior lobe secretes thyroid stimulating hormone, corticotropin, luteinizing hormone, follicle stimulating hormone, growth hormone, and prolactin. It is regulated by the hypothalamus via the portal vascular system. The posterior lobe releases oxytocin and vasopressin from axon terminals that originate in cell bodies located in the hypothalamus. The intermediate lobe is rudimentary in human beings but produces several hormones whose physiologic significance is only now being established.

Complications of endovascular treatment for acute stroke in the SWIFT trial with solitaire and Merci devices.

The safety of 2 devices to treat acute ischemic stroke was evaluated in 144 patients with special attention paid to complications such as cerebral hemorrhage, SAH, air emboli, vessel dissections, major groin complications, and emboli in new territories. Fewer endovascular complications occurred after treatment with the Solitaire device when compared with the Merci, particularly with respect to symptomatic cerebral hemorrhage. BACKGROUND AND PURPOSE: Treatment of patients with ischemic stroke after endovascular treatment requires in-depth knowledge of complications. The goal of this study was to make endovascular treatment for acute ischemic stroke safer through an in-depth review of the major periprocedural complications observed in the Solitaire FR With Intention for Thrombectomy (SWIFT) trial. MATERIALS AND METHODS: The SWIFT data base was searched for major peri-procedural complications defined as symptomatic intracranial hemorrhage within 36 hours, SAH, air emboli, vessel dissection, major groin complications, and emboli to new vascular territories. RESULTS: Major peri-procedural complications occurred in 18 of 144 patients (12.5%) as follows: symptomatic intracranial hemorrhage, 4.9%; air emboli, 1.4%; vessel dissection, 4.2%; major groin complications, 2.8%; and emboli to new vascular territories, 0.7%. Rates of symptomatic intracranial bleeding by subtype were PH1, 0.7%; PH2, 0.7% (PH1 indicates hematoma within ischemic field with some mild space-occupying effect but involving ≤30% of the infarcted area; PH2, hematoma within ischemic field with space-occupying effect involving >30% of the infarcted area); intracranial hemorrhage remote from ischemic zone, 0%; intraventricular hemorrhage, 0.7%; and SAH, 3.5%. We did not observe any statistically significant associations of peri-procedural complications with age; type of treatment center; duration of stroke symptoms; NIHSS score, IV thrombolytics, atrial fibrillation, site of vessel occlusion; rescue therapy administered after endovascular treatment; or device. Comparing the Merci with the Solitaire FR retrieval device, we observed symptomatic cerebral hemorrhage (10.9% versus 1.1%; P = .013); symptomatic SAH (7.3% versus 1.1%; P = .07), air emboli (1.8% versus 1.1%; P = 1.0), emboli to new vascular territories (1.8% versus 0%; P = .38), vessel dissection (1.8% versus 4.5%; P = .65), and major groin complications (3.6% versus 7.9%; P = .48). Angiographic vasospasm was common but without clinical sequelae. CONCLUSIONS: Understanding of procedural complications is important for treatment of patients with stroke after endovascular treatment. We observed fewer endovascular complications with the Solitaire FR device treatment compared with Merci device treatment, particularly symptomatic cerebral hemorrhage.

Molecular Genetic Analysis of Two Large Kindreds With Intracranial Aneurysms Demonstrates Linkage to 11q24-25 and 14q23-31

Background and Purpose— Both environmental and genetic factors contribute to the formation, growth, and rupture of intracranial aneurysms (IAs). To search for IA susceptibility genes, we took an outlier approach, using parametric genome-wide linkage analysis in extended IA kindreds in which IA is inherited as a simple Mendelian trait. We hereby present the molecular genetic analysis of 2 such families. Methods— For genome-wide linkage analysis, we used a 2-stage approach. First, using gene chips in affected-only analysis, we identified genomic regions that provide maximum theoretical logarithm of odds (lod) scores. Next, to confirm or exclude these candidate loci, we genotyped all available family members, both affected and unaffected, using polymorphic microsatellite markers located within these regions. Results— We obtained significant lod scores of 4.3 and 3.00 for linkage to chromosomes 11q24-25 and 14q23-31, respectively. Conclusions— Molecular genetic analysis of 2 large IA kindreds confirms linkage to chromosome 11q and 14q, which were suggested to contain IA susceptibility genes in a previous study of Japanese sib pairs. Independent identification of these 2 loci strongly suggests that IA susceptibility genes lie within these regions. While demonstrating the genetic heterogeneity of IA, these results are also an important step toward cloning IA genes and ultimately understanding its pathophysiology.