Brian J. Dlouhy

Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy, with an estimated 35% lifetime risk in this patient population. There is a surprising lack of awareness among patients and physicians of this increased risk of sudden death: in a recent survey, only 33% of Canadian paediatricians who treated patients with epilepsy knew the term SUDEP. Controversy prevails over whether cardiac arrhythmia or respiratory arrest is more important as the primary cause of death. Effective preventive strategies in high-risk patients will rely on definition of the mechanisms that lead from seizures to death. Here, we summarize evidence for the mechanisms that cause cardiac, respiratory and arousal abnormalities during the ictal and postictal period. We highlight potential cellular mechanisms underlying these abnormalities, such as a defect in the serotonergic system, ictal adenosine release, and changes in autonomic output. We discuss genetic mutations that cause Dravet and long QT syndromes, both of which are linked with increased risk of sudden death. We then highlight possible preventive interventions that are likely to decrease SUDEP incidence, including respiratory monitoring in epilepsy monitoring units and overnight supervision. Finally, we discuss treatments, such as selective serotonin reuptake inhibitors, that might be personalized to a specific genetic or pathological defect.

Detecting activity-evoked pH changes in human brain

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, T1 relaxation in the rotating frame (T1ρ), is sufficiently sensitive to detect widespread pH changes in the mouse and human brain evoked by systemically manipulating carbon dioxide or bicarbonate. Moreover, T1ρ detected a localized acidosis in the human visual cortex induced by a flashing checkerboard. Lactate measurements and pH-sensitive 31P spectroscopy at the same site also identified a localized acidosis. Consistent with the established role for pH in blood flow recruitment, T1ρ correlated with blood oxygenation level-dependent contrast commonly used in functional MRI. However, T1ρ 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.

Autograft-derived spinal cord mass following olfactory mucosal cell transplantation in a spinal cord injury patient

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.

Role of Membrane Association and Atg14-Dependent Phosphorylation in Beclin-1-Mediated Autophagy

ABSTRACT 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.

Flexion-distraction injuries of the thoracolumbar spine: open fusion versus percutaneous pedicle screw fixation

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.

Elevated body mass index and risk of postoperative CSF leak following transsphenoidal surgery

OBJECT Postoperative 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. METHODS The 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. RESULTS In 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/m(2), p = 0.006). Multivariate analyses indicate that for every 5-kg/m(2) increase 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. CONCLUSIONS Elevated 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/m(2) have meticulous sellar reconstruction at surgery and close monitoring postoperatively.

Breathing Inhibited When Seizures Spread to the Amygdala and upon Amygdala Stimulation

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 O2 desaturation occurred when seizures spread to the amygdala. In the same patient, localized electrical stimulation of the amygdala reproduced the apnea and O2 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. SIGNIFICANCE STATEMENT Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with chronic refractory epilepsy. Impaired breathing during and after seizures is common and suspected to play a role in SUDEP. Understanding the cause of this peri-ictal hypoventilation may lead to preventative strategies. In epilepsy patients, we found that seizure invasion of the amygdala co-occurred with apnea and oxygen desaturation, and electrical stimulation of the amygdala reproduced these respiratory findings. Strikingly, the subjects were unaware of the apnea. These findings indicate a functional connection between the amygdala and brainstem respiratory network in humans and suggest that amygdala seizures may cause loss of spontaneous breathing of which patients are unaware—a combination that could be deadly.

Anatomy and biomechanics of the craniovertebral junction

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.

Evolution of transoral approaches, endoscopic endonasal approaches, and reduction strategies for treatment of craniovertebral junction pathology: a treatment algorithm update.

The craniovertebral junction (CVJ), or the craniocervical junction (CCJ) as it is otherwise known, houses the crossroads of the CNS and is composed of the occipital bone that surrounds the foramen magnum, the atlas vertebrae, the axis vertebrae, and their associated ligaments and musculature. The musculoskeletal organization of the CVJ is unique and complex, resulting in a wide range of congenital, developmental, and acquired pathology. The refinements of the transoral approach to the CVJ by the senior author (A.H.M.) in the late 1970s revolutionized the treatment of CVJ pathology. At the same time, a physiological approach to CVJ management was adopted at the University of Iowa Hospitals and Clinics in 1977 based on the stability and motion dynamics of the CVJ and the site of encroachment, incorporating the transoral approach for irreducible ventral CVJ pathology. Since then, approaches and techniques to treat ventral CVJ lesions have evolved. In the last 40 years at University of Iowa Hospitals and Clinics, multiple approaches to the CVJ have evolved and a better understanding of CVJ pathology has been established. In addition, new reduction strategies that have diminished the need to perform ventral decompressive approaches have been developed and implemented. In this era of surgical subspecialization, to properly treat complex CVJ pathology, the CVJ specialist must be trained in skull base transoral and endoscopic endonasal approaches, pediatric and adult CVJ spine surgery, and must understand and be able to treat the complex CSF dynamics present in CVJ pathology to provide the appropriate, optimal, and tailored treatment strategy for each individual patient, both child and adult. This is a comprehensive review of the history and evolution of the transoral approaches, extended transoral approaches, endoscopie assisted transoral approaches, endoscopie endonasal approaches, and CVJ reduction strategies. Incorporating these advancements, the authors update the initial algorithm for the treatment of CVJ abnormalities first published in 1980 by the senior author.

Emerging technology in intracranial neuroendoscopy: application of the NICO Myriad

Improvement in fiber optics and imaging paved the way for tremendous advancements in neuroendoscopy. These advancements have led to increasingly widespread use of the endoscope in neurosurgical procedures, which in turn incited a technological revolution leading to new approaches, instruments, techniques, and a diverse armamentarium for the treatment of a variety of neurosurgical disorders. Soft-tissue removal is often a rate-limiting aspect to endoscopic procedures, especially when the soft tissue is dense or fibrous. The authors review a series of cases involving patients treated between August 2009 and October 2010 with a new device (the NICO Myriad), a non-heat-generating, oscillating, cutting, and tissue removal instrument that can be used through the working channel of the endoscope as well as in open neurosurgical procedures. They used this device in 14 purely endoscopic intracranial procedures and 1 endoscope-assisted keyhole craniotomy. They report that the device was easy to use and found that tissue resection was more efficient than with other available endoscopic instruments, especially in the resection of fibrotic tissue. There were no observed device-related complications. The authors discuss the technical aspects of using this device in endoscopic resection of pituitary tumors, craniopharyngiomas, and colloid cysts. They also demonstrate its use in hydrocephalus and intraventricular clot removal and discuss its potential use in other neurosurgical disorders.