Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy, and yet many physicians do not know about this high risk of sudden death. It has been widely believed that SUDEP is due to cardiac abnormalities during the post-ictal period. However, recent studies have demonstrated that respiratory depression is common following a seizure, and can be severe enough to cause a substantial decrease in oxygen saturation. In this review we summarize evidence for cardiac, respiratory, and arousal abnormalities during the ictal and post-ictal period and potential mechanisms for these abnormalities. We discuss mouse models of seizure-induced death and how these models are useful for understanding the mechanisms that underlie SUDEP. Some of these are due to genetic mutations that have counterparts in human syndromes. Controversy remains regarding the relative importance of cardiac failure versus respiratory arrest as the primary cause of death. Resolving this controversy will require simultaneous monitoring of cardiac and respiratory parameters during cases of near SUDEP in humans and detailed pathophysiological data from animal models during seizure-induced death. Effective preventive strategies in high-risk patients will rely on defining the mechanisms that initiate the sequence of events that lead from seizures to death.

Sudden unexpected death in epilepsy (SUDEP) is increasingly recognized as a common and devastating problem. Because impaired breathing is thought to play a critical role in these deaths, we sought to identify forebrain sites underlying seizure-evoked hypoventilation in humans. We took advantage of an extraordinary clinical opportunity to study a research participant with medically intractable epilepsy who had extensive bilateral frontotemporal electrode coverage while breathing was monitored during seizures recorded by intracranial electrodes and mapped by high-resolution brain imaging. We found that central apnea and O 2 desaturation occurred when seizures spread to the amygdala. In the same patient, localized electrical stimulation of the amygdala reproduced the apnea and O 2 desaturation. Similar effects of amygdala stimulation were observed in two additional subjects, including one without a seizure disorder. The participants were completely unaware of the apnea evoked by stimulation and expressed no dyspnea, despite being awake and vigilant. In contrast, voluntary breath holding of similar duration caused severe dyspnea. These findings suggest a functional connection between the amygdala and medullary respiratory network in humans. Moreover, they suggest that seizure spread to the amygdala may cause loss of spontaneous breathing of which patients are unaware, and thus has potential to contribute to SUDEP.

Localized pH changes have been suggested to occur in the brain during normal function. However, the existence of such pH changes has also been questioned. Lack of methods for noninvasively measuring pH with high spatial and temporal resolution has limited insight into this issue. Here we report that a magnetic resonance imaging (MRI) strategy, T 1 relaxation in the rotating frame (T 1 ρ), is sufficiently sensitive to detect widespread pH changes in the mouse and human brain evoked by systemically manipulating carbon dioxide or bicarbonate. Moreover, T 1 ρ detected a localized acidosis in the human visual cortex induced by a flashing checkerboard. Lactate measurements and pH-sensitive 31 P spectroscopy at the same site also identified a localized acidosis. Consistent with the established role for pH in blood flow recruitment, T 1 ρ correlated with blood oxygenation level-dependent contrast commonly used in functional MRI. However, T 1 ρ was not directly sensitive to blood oxygen content. These observations indicate that localized pH fluctuations occur in the human brain during normal function. Furthermore, they suggest a unique functional imaging strategy based on pH that is independent of traditional functional MRI contrast mechanisms. T o what degree pH changes during normal brain function is unclear (1). However, neuronal activity could cause transient, localized pH changes via several mechanisms. Increased neuronal activity enhances carbohydrate metabolism producing the pHlowering by-products lactic acid and CO 2 (2). Activity-evoked HCO 3 − transport can alter pH (3). Local field potentials produced by ion fluxes could change pH (4). In addition, acidic synaptic vesicles release protons during neurotransmission (5). Such dynamic pH fluctuations have the potential to dramatically alter physiology and behavior through a number of pH-sensitive receptors and channels (6). Acid-sensing ion channels, for example, play critical roles in synaptic plasticity, learning, memory, pain, and neurodegeneration (7-10). Superimposed on activity-dependent brain pH changes and the potential physiological effects are several buffering systems. Principal among these is the CO 2 /HCO 3 − system. In a reversible reaction, CO 2 combines with water to form carbonic acid, which readily dissociates into HCO 3 − and H + . Raising HCO 3− shifts the equilibrium away from H + and increases pH. Conversely, raising CO 2 shifts the equilibrium toward H + , thereby lowering pH. The ability to measure these pH changes in the functioning brain is key for gaining insight into this poorly understood dimension of CNS physiology and pathophysiology.Routinely measuring pH in the brain would require novel noninvasive methods. Traditionally, 31 P spectroscopy has been used to estimate brain pH (11); however, 31 P is limited by poor spatial resolution (typically 10-to 30-cm 3 volumes), long acquisition times (often 5-10 min for a single measurement), and the need for special hardware not typically available on clinical scanners. Recently, 1 H MRI pulse...

ObjectPostoperative CSF leakage can be a serious complication after a transsphenoidal surgical approach. An elevated body mass index (BMI) is a significant risk factor for spontaneous CSF leaks. However, there is no evidence correlating BMI with postoperative CSF leak after transsphenoidal surgery. The authors hypothesized that patients with elevated BMI would have a higher incidence of CSF leakage complications following transsphenoidal surgery.MethodsThe authors conducted a retrospective review of 121 patients who, between August 2005 and March 2010, underwent endoscopic endonasal transsphenoidal surgeries for resection of primarily sellar masses. Patients requiring extended transsphenoidal approaches were excluded. A multivariate statistical analysis was performed to investigate the association of BMI and other risk factors with postoperative CSF leakage.ResultsIn 92 patients, 96 endonasal endoscopic transsphenoidal surgeries were performed that met inclusion criteria. Thirteen postoperative leaks occurred and required subsequent treatment, including lumbar drainage and/or reoperation. The average BMI of patients with a postoperative CSF leak was significantly greater than that in patients with no postoperative CSF leak (39.2 vs 32.9 kg/m2, p = 0.006). Multivariate analyses indicate that for every 5-kg/m2increase in BMI, patients undergoing a transsphenoidal approach for a primarily sellar mass have 1.61 times the odds (95% CI 1.10–2.29, p = 0.016, by multivariate logistic regression) of having a postoperative CSF leak.ConclusionsElevated BMI is an independent predictor of postoperative CSF leak after an endonasal endoscopic transsphenoidal approach. The authors recommend that patients with BMI greater than 30 kg/m2have meticulous sellar reconstruction at surgery and close monitoring postoperatively.

Over the last decade, human cell transplantation and neural stem cell trials have examined the feasibility and safety of these potential therapies for treatment of a variety of neurological disorders. However, significant safety concerns have surrounded these trials due to the possibility of ectopic, uncontrolled cellular growth and tumor formation. The authors present the case of an 18-year-old woman who sustained a complete spinal cord injury at T10–11. Three years after injury, she remained paraplegic and underwent olfactory mucosal cell implantation at the site of injury. She developed back pain 8 years later, and imaging revealed an intramedullary spinal cord mass at the site of cell implantation, which required resection. Intraoperative findings revealed an expanded spinal cord with a multicystic mass containing large amounts of thick mucus-like material. Histological examination and immunohistochemical staining revealed that the mass was composed mostly of cysts lined by respiratory epithelium, submucosal glands with goblet cells, and intervening nerve twigs. This is the first report of a human spinal cord mass complicating spinal cord cell transplantation and neural stem cell therapy. Given the prolonged time to presentation, safety monitoring of all patients with cell transplantation and neural stem cell implantation should be maintained for many years.

Object Flexion-distraction injuries occur due to distractive forces causing disruption of the posterior and middle spinal columns. These fractures classically consist of a fracture line through the posterior bony elements; involvement of the posterior ligamentous complex is, however, common. Surgical treatment is often required for these unstable injuries to avoid neurological deterioration and posttraumatic kyphosis, and the surgery traditionally consists of an open posterior approach with instrumented fusion. Percutaneous pedicle screw fixation for these injuries, with the goal of minimal tissue disruption and preservation of normal anatomy while achieving adequate stabilization, has recently been reported in the literature, but to date, a direct comparative study comparing open and percutaneous fixation has not been reported. The authors report their experience treating these fractures with both techniques and review the available literature. Methods Patients with flexion-distraction injury who were treated between May 2003 and March 2013 were prospectively followed. American Spinal Injury Association scores and degree of kyphotic angulation were recorded at admission, discharge, and follow-up. Data regarding intraoperative blood loss and operative time were obtained from a chart review. Patients treated with open versus minimally invasive procedures were compared. Results The authors identified 39 patients who suffered flexion-distraction injuries and were treated at their institution during the specified period; one of these patients declined surgery. All had injury to the posterior ligamentous complex. Open surgical procedures with pedicle screw fixation and posterolateral fusion were performed in 27 patients, while 11 patients underwent minimally invasive pedicle screw placement. Overall, there was improvement in kyphotic angulation at the time of discharge as well as most recent follow-up in both the open surgery and minimally invasive surgery (MIS) groups. The authors found no significant difference in American Spinal Injury Association score or the degree of kyphotic angulation between the MIS and open surgery groups. There was a trend toward shorter operative time for the MIS group, and patients who underwent minimally invasive procedures had significantly less blood loss. Conclusions Minimally invasive percutaneous pedicle screw fixation appears to have similar efficacy in the treatment of flexion-distraction injuries and it allows for reduced blood loss and tissue damage compared with open surgical techniques. Therefore it should be considered as an option for the treatment of this type of injury.

During autophagy, a double membrane envelops cellular material for trafficking to the lysosome. Human beclin-1 and its yeast homologue, Atg6/Vps30, are scaffold proteins bound in a lipid kinase complex with multiple cellular functions, including autophagy. Several different Atg6 complexes exist, with an autophagy-specific form containing Atg14. However, the roles of Atg14 and beclin-1 in the activation of this complex remain unclear. We here addressed the mechanism of beclin-1 complex activation and reveal two critical steps in this pathway. First, we identified a unique domain in beclin-1, conserved in the yeast homologue Atg6, which is involved in membrane association and, unexpectedly, controls autophagosome size and number in yeast. Second, we demonstrated that human Atg14 is critical in controlling an autophagy-dependent phosphorylation of beclin-1. We map these novel phosphorylation sites to serines 90 and 93 and demonstrate that phosphorylation at these sites is necessary for maximal autophagy. These results help clarify the mechanism of beclin-1 and Atg14 during autophagy.A utophagy is a catabolic membrane trafficking process that turns over cytosolic material following encapsulation by autophagosomes and subsequent degradation in the lysosome (in higher eukaryotes) or the vacuole (in plants and unicellular eukaryotes). Genetic studies in yeast have identified a battery of conserved proteins that are required for starvation-induced autophagy (1). In both higher eukaryotes and yeast, autophagy also occurs constitutively as a cargo-selective quality control process (2). Consistent with its dual role in metabolism and cellular quality control, autophagy has been shown to play a role in a variety of human pathologies, including cancer and neurodegeneration (3).Many of the proteins identified as essential for autophagy in yeast have homologues in higher eukaryotes that carry out conserved functions. Among these is the tumor suppressor beclin-1, discovered in a two-hybrid screen as a protein that interacts with the antiapoptotic protein Bcl-2 (4, 5). Beclin-1 is a core component of the phosphatidylinositol 3-kinase complex, along with the catalytic subunit Vps34 and the putative protein kinase Vps15 (6). Atg6/Vps30, the yeast homologue of beclin-1, shares 24.4% amino acid homology and functions in selective and nonselective autophagy (7), as well as endosomal trafficking. Similar to beclin-1, additional components bind the core Atg6-lipid kinase complex to direct functions in these different membrane trafficking pathways (8).Localization of the yeast Atg6/Vps15/Vps34 complex to the preautophagosomal structure is largely dictated by the binding of Atg6 to Atg14 (7). Recently, the human homologue of Atg14, hAtg14/Barkor/Atg14L (here referred to as hAtg14), has been identified by several groups. hAtg14 has been shown to be a member of a beclin-1 complex analogous to that in yeast, although the mechanism of action in autophagy may be distinct (6,9,10,11). hAtg14 interacts with beclin-1 through its coiled-coil doma...

The craniovertebral junction (CVJ) has unique anatomical structures that separate it from the subaxial cervical spine. In addition to housing vital neural and vascular structures, the majority of cranial flexion, extension, and axial rotation is accomplished at the CVJ. A complex combination of osseous and ligamentous supports allow for stability despite a large degree of motion. An understanding of anatomy and biomechanics is essential to effectively evaluate and address the various pathological processes that may affect this region. Therefore, the authors present an up-to-date narrative review of CVJ anatomy, normal and pathological biomechanics, and fixation techniques.