Minimally Invasive Subacute to Chronic Subdural Hematoma Evacuation with Angled Matchstick Drill and Repurposed Antibiotic Ventriculostomy Catheter Augmented with Alteplase: A Technical Case Report.

The operative management of subacute subdural hematomas (sSDHs) and chronic subdural hematomas (cSDHs) in the elderly is complicated by age itself, multiple medical comorbidities, and anticoagulant and antiplatelet medications; therefore, the search for less invasive, yet more effective, treatment techniques has become a goal. Here, we present the use of a repurposed ventriculostomy catheter in the minimally invasive drainage of a mixed sSDH with the residual solid clot component subsequently liquefied with local alteplase (tPA) administration in an elderly female producing effective hematoma and symptom resolution.

Copenhagen Head Injury Ciclosporin Study: A Phase IIa Safety, Pharmacokinetics, and Biomarker Study of Ciclosporin in Severe Traumatic Brain Injury Patients.

Traumatic brain injury (TBI) contributes to almost one third of all trauma-related deaths, and those that survive often suffer from long-term physical and cognitive deficits. Ciclosporin (cyclosporine, cyclosporin A) has shown promising neuroprotective properties in pre-clinical TBI models. The Copenhagen Head Injury Ciclosporin (CHIC) study was initiated to establish the safety profile and pharmacokinetics of ciclosporin in patients with severe TBI, using a novel parenteral lipid emulsion formulation. Exploratory pharmacodynamic study measures included microdialysis in brain parenchyma and protein biomarkers of brain injury in the cerebrospinal fluid (CSF). Sixteen adult patients with severe TBI (Glasgow Coma Scale 4-8) were included, and all patients received an initial loading dose of 2.5 mg/kg followed by a continuous infusion for 5 days. The first 10 patients received an infusion dosage of 5 mg/kg/day whereas the subsequent 6 patients received 10 mg/kg/day. No mortality was registered within the study duration, and the distribution of adverse events was similar between the two treatment groups. Pharmacokinetic analysis of CSF confirmed dose-dependent brain exposure. Between- and within-patient variability in blood concentrations was limited, whereas CSF concentrations were more variable. The four biomarkers, glial fibrillary acidic protein, neurofilament light, tau, and ubiquitin carboxy-terminal hydrolase L1, showed consistent trends to decrease during the 5-day treatment period, whereas the samples taken on the days after the treatment period showed higher values in the majority of patients. In conclusion, ciclosporin, as administered in this study, is safe and well tolerated. The study confirmed that ciclosporin is able to pass the blood-brain barrier in a TBI population and provided an initial biomarker-based signal of efficacy.

Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition.

Mitochondrial uptake of calcium in excitotoxicity is associated with subsequent increase in reactive oxygen species (ROS) generation and delayed cellular calcium deregulation in ischemic and neurodegenerative insults. The mechanisms linking mitochondrial calcium uptake and ROS production remain unknown but activation of the mitochondrial permeability transition (mPT) may be one such mechanism. In the present study, calcium increased ROS generation in isolated rodent brain and human liver mitochondria undergoing mPT despite an associated loss of membrane potential, NADH and respiration. Unspecific permeabilization of the inner mitochondrial membrane by alamethicin likewise increased ROS independently of calcium, and the ROS increase was further potentiated if NAD(H) was added to the system. Importantly, calcium per se did not induce a ROS increase unless mPT was triggered. Twenty-one cyclosporin A analogs were evaluated for inhibition of calcium-induced ROS and their efficacy clearly paralleled their potency of inhibiting mPT-mediated mitochondrial swelling. We conclude that while intact respiring mitochondria possess powerful antioxidant capability, mPT induces a dysregulated oxidative state with loss of GSH- and NADPH-dependent ROS detoxification. We propose that mPT is a significant cause of pathological ROS generation in excitotoxic cell death.

Gamma Knife surgery targeting the centromedian nucleus of the thalamus for the palliative management of thalamic pain: durable response in stroke-induced thalamic pain syndrome.

The authors report the neuroimaging features, treatment planning, and outcome in a case of radiosurgical thalamotomy targeting the centromedian nucleus (CMN) for stroke-induced thalamic pain. A 79-year-old man, with embolic occlusion of the left middle cerebral artery and large hemispheric infarction involving the thalamus, suffered a right hemiplegia and expressive aphasia. One year poststroke, severe right-sided facial, scalp, arm, and trunk pain developed and was exacerbated by any tactile contact. Medical treatment had failed. Medical illness, including mandatory anticoagulation therapy for atrial fibrillation, precluded surgical procedures. Minimally invasive radiosurgery was offered as an alternative. Magnetic resonance imaging and computed tomography were used to localize the left CMN. A single shot of 140 Gy was delivered to the 100% isodose line by using the 4-mm collimator helmet. The patient was evaluated at regular intervals. By 12 weeks posttreatment, he had significant improvements in pain control and his ability to tolerate physical contact during activities of daily living. Magnetic resonance imaging demonstrated baseline encephalomalacia from his prior stroke, and signal changes in the left CMN consistent with gamma irradiation-based thalamotomy. Currently, nearly 7 years after radiosurgery, he continues to enjoy a marked reduction in pain without the need of analgesic medications. Thalamic pain syndrome is generally refractory to conventional treatment. Neurosurgical interventions provide modest benefit and carry associated risks of invasive surgery and anesthesia. The CMN is readily localized with neuroimaging and is an approximate target to reduce the suffering aspect of pain. In this case, radiosurgery was a safe and effective treatment, providing durable symptom control and improved quality of life.

Gamma knife surgery for refractory postherpetic trigeminal neuralgia: targeting in one session both the retrogasserian trigeminal nerve and the centromedian nucleus of the thalamus.

OBJECT: The authors tested the hypothesis that two targets are needed to treat postherpetic trigeminal neuralgia (TN): one in the trigeminal nerve for the direct sharp pain and one in the thalamus for the diffuse burning pain. METHODS: Three patients with refractory postherpetic TN were treated with gamma knife surgery (GKS) through a novel two-target approach. In a single treatment session, both the trigeminal nerve and centromedian nucleus were targeted. First, the trigeminal nerve, ipsilateral to the facial pain, was treated with 60 to 80 Gy. Second, the centromedian nucleus was localized using standard coordinates and by comparing magnetic resonance images with a stereotactic atlas. A single dose of 120 to 140 Gy was delivered to the target point with a single 4-mm isocenter. Patients were followed clinically and with neuroimaging studies. Pain relief was scored as excellent (75-100%), good (50-75%), poor (25-50%); or none (0-25%). Follow up ranged from 6 to 53 months. There were no GKS-related complications. Two patients died of unrelated medical illnesses but had good or excellent pain relief until death. One patient continues to survive with 44 months follow up and no decrease in pain intensity, but with a decreased area of pain. CONCLUSIONS: Combined GKS of the centromedian nucleus and trigeminal nerve in a single treatment session is feasible and safe, and the effect was promising. A larger study is required to confirm and expand these results.

Up-regulation and altered distribution of lysyl oxidase in the central nervous system of mutant SOD1 transgenic mouse model of amyotrophic lateral sclerosis.

Mutations of the copper-zinc superoxide dismutase (SOD1) gene can result in the development of amyotrophic lateral sclerosis (ALS). The exact cellular mechanisms causing ALS are not known, but oxidative stress is thought to play a prominent role. Lysyl oxidase (LOX) is one of the genes that are known to be up-regulated in ALS patients. In this study, we examined LOX localization in wild type rat and mouse brain sections using immunohistochemistry coupled with laser-scanning confocal microscope. The results showed that LOX, an extracellular matrix protein, was expressed in the choroid plexus, blood vessel walls, brain matrix, and neurons of normal rat and mice. In neurons, LOX was localized within the cytoplasm. LOX immunoreactivity increased in neurons of the spinal cord, brain stem and cortex, and the Purkinje cells of the cerebellum in transgenic G93A SOD1 (mSOD1) mouse model of ALS. In situ hybridization indicated that LOX gene expression was enhanced in the neurons of the spinal cord, brain stem, cortex, caudoputamen and cerebellum in mSOD1 mice compared with wild type controls. LOX enzyme activity was increased in mSOD1 mice. An increase in the amount of LOX mRNA, protein and enzyme activity was coincidental with late stage ALS, indicating that LOX may be associated with the progression of the neurodegenerative process in the mSOD1 model of ALS.

Powerful cyclosporin inhibition of calcium-induced permeability transition in brain mitochondria.

The mitochondrial permeability transition (mPT) is considered to be an important mediator of apoptosis and necrosis, and is specifically blocked by cyclosporin A (CsA). CsA has been shown to exert a potent neuroprotective action in vivo when allowed to cross the blood-brain barrier in various animal models of acute neurological insults and neurodegenerative disease. The neuroprotective effect of CsA is considered to be mediated through specific inhibition of the mitochondrial permeability transition pore (mPTP) and through inhibition of neuronal calcineurin activity. Characterization of mPT has mainly been performed in liver and heart mitochondria, and some brain studies have reported a decreased inhibitory effect of CsA and questioned the importance of mPT in brain-derived mitochondria. We have used the de-energized model of swelling to examine the mPT in brain-derived non-synaptosomal mitochondria. Ca(2+)-induced swelling was evaluated by electron microscopy and by measurement of spectrophotometric alterations in light scattering. Permeability transition was readily induced in a majority of the mitochondria at a wide range of Ca(2+) levels and was powerfully inhibited by CsA with a half-maximal effect at approximately 23 nM CsA. The swelling kinetics and CsA effects were comparable to previous findings in de-energized liver and heart mitochondria. Careful characterization of mPT and CsA effects in brain-derived mitochondria is the first step in evaluating newly developed CsA analogues capable of crossing the blood-brain barrier and preferentially entering the brain. The importance of CsA causing a shift of the mitochondrial sensitivity to Ca(2+) in neurological disorders is discussed.

Life span extension and reduced neuronal death after weekly intraventricular cyclosporin injections in the G93A transgenic mouse model of amyotrophic lateral sclerosis.

OBJECT: The authors investigated whether cyclosporin A (CsA), a cyclophilin ligand with mitochondrial permeability transition pore-blocking and calcineurin-inhibiting properties, affects motor function, neuronal death, and life span in the G93A transgenic mouse model of familial amyotrophic lateral sclerosis (FALS). METHODS: The G93A mice received weekly intracerebroventricular injections of CsA (20 microg/mouse/week) starting at the age of 65 days, and physical performance on an exercise wheel was monitored beginning at 84 days of age. Mice were allowed to survive for clinical observation of body weight, hindlimb weakness, and life span or until a defined end stage or were killed at 110 days of age for histological analysis. CONCLUSIONS: Treatment with CsA significantly delayed the onset of hindlimb weakness and also extended the time from its onset to paralysis. The overall life span of CsA-treated G93A mice was significantly extended, by 12% compared with vehicle-treated transgenic littermates. The CsA also prolonged physical performance on the exercise wheel and delayed weight loss. Histologically, there was significant preservation of both cervical and lumbar spine motor neurons and also tyrosine hydroxylase-positive dopaminergic substantia nigra neurons in 110-day-old CsA-treated mice compared with their transgenic littermates. The local administration of CsA directly into the brain ventricles is an effective means of central nervous system drug delivery (because CsA does not readily cross the blood-brain barrier), which in this study ameliorated clinical and neuropathological features of FALS in G93A mice. The remarkably low intrathecal CsA dose required for neuroprotection reduces potential adverse effects of systemic immunosuppression or nephrotoxicity seen with chronic systemic delivery of the drug.

Gamma knife subthalamotomy for Parkinson disease: the subthalamic nucleus as a new radiosurgical target. Case report.

The authors present the neuroimaging, treatment planning, and radiosurgical technique for the first reported case of unilateral radiosurgical subthalamotomy, which was performed to control motor symptoms associated with advanced Parkinson disease (PD) in a patient who had undergone previous contralateral radiofrequency (RF) pallidotomy. A 73-year-old woman with end-stage PD had undergone RF pallidotomy of the right globus pallidus with resolution of symptoms. Two years following this procedure, due to the natural progression of her disease, she suffered recurrent motor fluctuations, dyskinesia, and worsening bradykinesia of the right side. Her Parkinson's Disease Disability Rating (PDDR) score was 28. Computerized tomography and magnetic resonance (MR) imaging were used to localize the left subthalamic nucleus (STN). The patient underwent gamma knife radiosurgery-a single shot of 120 Gy was administered using the 4-mm collimator helmet. The patient was evaluated up to 42 months after the procedure. The dyskinesia became minimal. Right-sided motor control improved as did her balance. At 3 months after treatment MR imaging demonstrated the radiosurgical lesion in the left STN. At 3.5 years postradiosurgery, she experienced minimal focal (oral) dyskinesia, no bradykinesia or rigidity, and her PDDR score was 11. Radiosurgery of the STN in this case was safe and effective. The STN is a readily localized anatomical target with neuroimaging. Radiosurgery avoids the risks of open procedures.

Anatomy and the access grid: exploiting plastinated brain sections for use in distributed medical education.

Computerized animation is becoming an increasingly popular method to provide dynamic presentation of anatomical concepts. However, most animations use artistic renderings as the base illustrations that are subsequently altered to depict movement. In most cases, the artistic rendering is a schematic that lacks realism. Plastinated sections provide a useful alternative to artistic renderings to serve as a base image for animation. The purpose of this study is to describe a method for developing animations by using plastinated sections. This application is used in Project TOUCH as a supplemental learning tool for a problem-based learning case distributed over the National Computational Science Alliance's Access Grid. The case involves traumatic head injury that results in an epidural hematoma with transtentorial uncal herniation. In addition, a subdural hematoma is animated permitting the student to contrast the two processes for a better understanding of dural hematomas, in general. The method outlined uses P40 plastinated coronal brain sections that are digitized and to which contiguous anatomical structures are rendered. The base illustration is rendered, interpolated, and viewed while audio narration describes the event. This method demonstrates how realistic anatomical animations can be generated quickly and inexpensively for medical education purposes by using plastinated brain sections.

Integration of advanced technologies to enhance problem-based learning over distance: Project TOUCH.

Distance education delivery has increased dramatically in recent years as a result of the rapid advancement of communication technology. The National Computational Science Alliance's Access Grid represents a significant advancement in communication technology with potential for distance medical education. The purpose of this study is to provide an overview of the TOUCH project (Telehealth Outreach for Unified Community Health; http://hsc.unm.edu/touch) with special emphasis on the process of problem-based learning case development for distribution over the Access Grid. The objective of the TOUCH project is to use emerging Internet-based technology to overcome geographic barriers for delivery of tutorial sessions to medical students pursuing rotations at remote sites. The TOUCH project also is aimed at developing a patient simulation engine and an immersive virtual reality environment to achieve a realistic health care scenario enhancing the learning experience. A traumatic head injury case is developed and distributed over the Access Grid as a demonstration of the TOUCH system. Project TOUCH serves as an example of a computer-based learning system for developing and implementing problem-based learning cases within the medical curriculum, but this system should be easily applied to other educational environments and disciplines involving functional and clinical anatomy. Future phases will explore PC versions of the TOUCH cases for increased distribution.

Virtual patient simulator for distributed collaborative medical education.

Project TOUCH (Telehealth Outreach for Unified Community Health; http://hsc.unm.edu/touch) investigates the feasibility of using advanced technologies to enhance education in an innovative problem-based learning format currently being used in medical school curricula, applying specific clinical case models, and deploying to remote sites/workstations. The University of New Mexico's School of Medicine and the John A. Burns School of Medicine at the University of Hawai'i face similar health care challenges in providing and delivering services and training to remote and rural areas. Recognizing that health care needs are local and require local solutions, both states are committed to improving health care delivery to their unique populations by sharing information and experiences through emerging telehealth technologies by using high-performance computing and communications resources. The purpose of this study is to describe the deployment of a problem-based learning case distributed over the National Computational Science Alliance's Access Grid. Emphasis is placed on the underlying technical components of the TOUCH project, including the virtual reality development tool Flatland, the artificial intelligence-based simulation engine, the Access Grid, high-performance computing platforms, and the software that connects them all. In addition, educational and technical challenges for Project TOUCH are identified.

Distributed interactive virtual environments for collaborative experiential learning and training independent of distance over Internet2.

Medical knowledge and skills essential for tomorrow's healthcare professionals continue to change faster than ever before creating new demands in medical education. Project TOUCH (Telehealth Outreach for Unified Community Health) has been developing methods to enhance learning by coupling innovations in medical education with advanced technology in high performance computing and next generation Internet2 embedded in virtual reality environments (VRE), artificial intelligence and experiential active learning. Simulations have been used in education and training to allow learners to make mistakes safely in lieu of real-life situations, learn from those mistakes and ultimately improve performance by subsequent avoidance of those mistakes. Distributed virtual interactive environments are used over distance to enable learning and participation in dynamic, problem-based, clinical, artificial intelligence rules-based, virtual simulations. The virtual reality patient is programmed to dynamically change over time and respond to the manipulations by the learner. Participants are fully immersed within the VRE platform using a head-mounted display and tracker system. Navigation, locomotion and handling of objects are accomplished using a joy-wand. Distribution is managed via the Internet2 Access Grid using point-to-point or multi-casting connectivity through which the participants can interact. Medical students in Hawaii and New Mexico (NM) participated collaboratively in problem solving and managing of a simulated patient with a closed head injury in VRE; dividing tasks, handing off objects, and functioning as a team. Students stated that opportunities to make mistakes and repeat actions in the VRE were extremely helpful in learning specific principles. VRE created higher performance expectations and some anxiety among VRE users. VRE orientation was adequate but students needed time to adapt and practice in order to improve efficiency. This was also demonstrated successfully between Western Australia and UNM. We successfully demonstrated the ability to fully immerse participants in a distributed virtual environment independent of distance for collaborative team interaction in medical simulation designed for education and training. The ability to make mistakes in a safe environment is well received by students and has a positive impact on their understanding, as well as memory of the principles involved in correcting those mistakes. Bringing people together as virtual teams for interactive experiential learning and collaborative training, independent of distance, provides a platform for distributed "just-in-time" training, performance assessment and credentialing. Further validation is necessary to determine the potential value of the distributed VRE in knowledge transfer, improved future performance and should entail training participants to competence in using these tools.

Large cerebellar hemorrhage during trumpet playing: importance of blood pressure elevation during the valsalva maneuver: case report.

OBJECTIVE: The authors report a case of a large intracerebellar hemorrhage that occurred in a professional musician while playing the trumpet. This is the first report of such a complication. CLINICAL PRESENTATION: A 60-year-old man presented with severe occipital headache accompanied by nausea, vomiting, and dizziness that occurred while he was practicing the trumpet. On presentation, he was hypertensive with a systolic blood pressure of 255 mmHg and was found to have a large left cerebellar hemorrhage. INTERVENTION: Magnetic resonance imaging and magnetic resonance angiography were performed but revealed no tumor or vascular abnormality. The patient was initially stable but, despite maximal medical therapy, deteriorated and was taken to the operating room for suboccipital craniectomy and evacuation of the hematoma. CONCLUSION: This patient likely had chronic hypertension; however, the transient increase in systolic blood pressure associated with intensive trumpet playing and the Valsalva maneuver may have contributed to his risk of hemorrhage. We suggest that hypertensive screening and therapy may be especially important in this population and emphasize the importance for neurosurgeons to understand the physiology involved in the Valsalva maneuver.

Brain-derived respiring mitochondria exhibit homogeneous, complete and cyclosporin-sensitive permeability transition.

The mitochondrial permeability transition (mPT) is increasingly implicated in neuronal cell death. In the present study, isolated respiring brain mitochondria were examined for their ability to undergo calcium-induced mPT and their sensitivity to mPT inhibition by cyclosporin A (CsA). Previous studies have suggested a heterogeneous response to calcium, a limitation of CsA inhibition, and a relative resistance in the ability of respiring brain mitochondria to undergo mPT. Using fluorometric and electron microscopic analyses, we found that virtually the whole population of respiring brain mitochondria readily undergo mPT and swell upon calcium exposure. Further, brain mitochondria were highly sensitive to CsA which potentiated morphological recovery after transient swelling as well as completely blocked mPT induction in the presence of a low concentration of ADP. Using flow cytometry, which allows analysis of individual mitochondria, we demonstrate that both brain and liver mitochondria display homogeneous responses to calcium-induced mPT. We conclude that the mPT is one likely target for the broad in vivo neuroprotective effects displayed by CsA when allowed to penetrate the blood-brain barrier, and that development of compounds inhibiting mPT may prove beneficial for the treatment of severe brain disease.

The nonimmunosuppressive cyclosporin analogs NIM811 and UNIL025 display nanomolar potencies on permeability transition in brain-derived mitochondria.

Cyclosporin A (CsA) is highly neuroprotective in several animal models of acute neurological damage and neurodegenerative disease with inhibition of the mitochondrial permeability transition (mPT) having emerged as a possible mechanism for the observed neuroprotection. In the present study, we have evaluated two new nonimmunosuppressive cyclosporin analogs NIM811 (Novartis) and UNIL025 (Debiopharm) for their ability to inhibit mPT in rat brain-derived mitochondria. Both NIM811 and UNIL025 were found to be powerful inhibitors of calcium-induced mitochondrial swelling under energized and deenergized conditions, and the maximal effects were identical to those of native CsA. The potencies of mPT inhibition by NIM811 and UNIL025 were stronger, with almost one order of magnitude higher potency for UNIL025 compared to CsA, correlating to their respective inhibitory action of cyclophilin activity. These compounds will be instrumental in the evaluation of mPT as a central target for neuroprotection in vivo.