Seizures that occur during the neonatal period do so with a greater frequency than at any other age, have profound consequences for cognitive and motor development, and are difficult to treat with the existing series of antiepileptic drugs. During development, γ-aminobutyric acid (GABA)ergic neurotransmission undergoes a switch from excitatory to inhibitory due to a reversal of neuronal chloride (Cl–) gradients. The intracellular level of chloride ([Cl–]i) in immature neonatal neurons, compared with mature adult neurons, is about 20–40 mM higher due to robust activity of the chloride-importing Na-K-2Cl cotransporter NKCC1, such that the binding of GABA to ligand-gated GABAA receptor-associated Cl– channels triggers Cl– efflux and depolarizing excitation. In adults, NKCC1 expression decreases and the expression of the genetically related chloride-extruding K-Cl cotransporter KCC2 increases, lowering [Cl–]i to a level such that activation of GABAA receptors triggers Cl– influx and inhibitory hyperpolarization. The excitatory action of GABA in neonates, while playing an important role in neuronal development and synaptogenesis, accounts for the decreased seizure threshold, increased seizure propensity, and poor efficacy of GABAergic anticonvulsants in this age group. Bumetanide, a furosemide-related diuretic already used to treat volume overload in neonates, is a specific inhibitor of NKCC1 at low doses, can switch the GABA equilibrium potential of immature neurons from depolarizing to hyperpolarizing, and has recently been shown to inhibit epileptic activity in vitro and in vivo in animal models of neonatal seizures. The fundamental role of NKCC1 in establishing excitatory GABAergic neurotransmission in the neonate makes it a tempting target of a novel mechanism-based anticonvulsant strategy that could utilize the well-known pharmacology of bumetanide to help treat neonatal seizures.
Kristopher T. Kahle and Kevin J. Staley
Brian V. Nahed, Manuel Ferreira Jr., Matthew R. Naunheim, Kristopher T. Kahle, Mark R. Proctor and Edward R. Smith
Clinical and radiographic evidence of subarachnoid hemorrhage (SAH)-related vasospasm is rare in children and has not been reported in infants. In this report the authors present the case of a 22-month-old child who developed clinically symptomatic, radiographically identifiable vasospasm after traumatic SAH. To the authors' knowledge, this is the first report of vasospasm associated with SAH in a child this young. This 22-month-old boy fell and had a dense SAH. He had a history of surgically corrected craniosynostosis and nonsymptomatic ventriculomegaly. The boy was evaluated for occult vascular lesions using imaging; none were found and normal vessel caliber was noted. Ten days later, the child developed left-sided weakness and a right middle cerebral artery infarct was identified. Evaluation disclosed significant intracranial vasospasm. This diagnosis was supported by findings on CT angiography, transcranial Doppler ultrasonography, MR imaging, and conventional angiography. The child was treated using intraarterial verapamil with a good result, as well as with conventional intensive care measures to reduce vasospasm. This report documents the first known case of intracranial vasospasm with stroke after SAH in a patient under the age of 2 years. This finding is important because it demonstrates that the entity of SAH-associated vasospasm can affect the very young, widening the spectrum of ages susceptible to this condition. This case is also important because it demonstrates that even very young children can respond to conventional therapeutic interventions such as intraarterial verapamil. Thus, clinicians need to be alert to the possibility of vasospasm as a potential diagnosis when evaluating young children with SAH.
Kristopher T. Kahle, David Kozono, Kimberly Ng, Grace Hsieh, Pascal O. Zinn, Masayuki Nitta and Clark C. Chen
Our understanding of glioblastoma multiforme (GBM), the most common form of primary brain cancer, has been significantly advanced by recent efforts to characterize the cancer genome using unbiased high-throughput sequencing analyses. While these studies have documented hundreds of mutations, gene copy alterations, and chromosomal abnormalities, only a subset of these alterations are likely to impact tumor initiation or maintenance. Furthermore, genes that are not altered at the genomic level may play essential roles in tumor initiation and maintenance. Identification of these genes is critical for therapeutic development and investigative methodologies that afford insight into biological function. This requirement has largely been fulfilled with the emergence of RNA interference (RNAi) and high-throughput screening technology. In this article, the authors discuss the application of genome-wide, high-throughput RNAi-based genetic screening as a powerful tool for the rapid and cost-effective identification of genes essential for cancer proliferation and survival. They describe how these technologies have been used to identify genes that are themselves selectively lethal to cancer cells, or synthetically lethal with other oncogenic mutations. The article is intended to provide a platform for how RNAi libraries might contribute to uncovering glioma cell vulnerabilities and provide information that is highly complementary to the structural characterization of the glioblastoma genome. The authors emphasize that unbiased, systems-level structural and functional genetic approaches are complementary efforts that should facilitate the identification of genes involved in the pathogenesis of GBM and permit the identification of novel drug targets.
J. Marc Simard, Kristopher T. Kahle and Volodymyr Gerzanich
Microvascular failure largely underlies the damaging secondary events that accompany traumatic brain injury (TBI). Changes in capillary permeability result in the extravasation of extracellular fluid, inflammatory cells, and blood, thereby producing cerebral edema, inflammation, and progressive secondary hemorrhage (PSH). Recent work in rat models of TBI and stroke have implicated 2 ion transport proteins expressed in brain endothelial cells as critical mediators of edema formation: the constitutively expressed Na+-K+-2Cl– cotransporter, NKCC1, and the trauma/ischemia-induced SUR1-regulated NCCa-ATP (SUR1/TRPM4) channel. Whereas NKCC1 function requires adenosine 5′-triphosphate (ATP), activation of SUR1/TRPM4 occurs only after ATP depletion. This opposite dependence on intracellular ATP levels implies that one or the other mechanism will activate/deactivate as ATP concentrations rise and fall during periods of ischemia/reperfusion, resulting in continuous edema formation regardless of cellular energy status. Moreover, with critical ATP depletion, sustained opening of SUR1/TRPM4 channels results in the oncotic death of endothelial cells, leading to capillary fragmentation and PSH. Bumetanide and glibenclamide are 2 well-characterized, safe, FDA-approved drugs that inhibit NKCC1 and the SUR1/TRPM4 channel, respectively. When used alone, these drugs have provided documented beneficial effects in animal models of TBI- and ischemiaassociated cerebral edema and PSH. Given the mechanistic and temporal differences by which NKCC1 and the SUR1/TRPM4 channel contribute to the pathophysiological mechanisms of these events, combination therapy with bumetanide and glibenclamide may yield critical synergy in preventing injury-associated capillary failure.
Brian P. Walcott, Brian V. Nahed, Kristopher T. Kahle, Navid Redjal and Jean-Valery Coumans
Previous methods to determine stroke prevalence, such as nationwide surveys, are labor-intensive endeavors. Recent advances in search engine query analytics have led to a new metric for disease surveillance to evaluate symptomatic phenomenon, such as influenza. The authors hypothesized that the use of search engine query data can determine the prevalence of stroke.
The Google Insights for Search database was accessed to analyze anonymized search engine query data. The authors' search strategy utilized common search queries used when attempting either to identify the signs and symptoms of a stroke or to perform stroke education. The search logic was as follows: (stroke signs + stroke symptoms + mini stroke − heat) from January 1, 2005, to December 31, 2010.
The relative number of searches performed (the interest level) for this search logic was established for all 50 states and the District of Columbia. A Pearson product-moment correlation coefficient was calculated from the statespecific stroke prevalence data previously reported.
Web search engine interest level was available for all 50 states and the District of Columbia over the time period for January 1, 2005–December 31, 2010. The interest level was highest in Alabama and Tennessee (100 and 96, respectively) and lowest in California and Virginia (58 and 53, respectively). The Pearson correlation coefficient (r) was calculated to be 0.47 (p = 0.0005, 2-tailed).
Search engine query data analysis allows for the determination of relative stroke prevalence. Further investigation will reveal the reliability of this metric to determine temporal pattern analysis and prevalence in this and other symptomatic diseases.
Benjamin D. Schanker, Brian P. Walcott, Brian V. Nahed, Kristopher T. Kahle, Yan Michael Li and Jean-Valery C. E. Coumans
Chiari malformations (Types I–IV) are abnormalities of the posterior fossa that affect the cerebellum, brainstem, and the spinal cord with prevalence rates of 0.1%–0.5%. Case reports of familial aggregation of Chiari malformation, twin studies, cosegregation of Chiari malformation with known genetic conditions, and recent gene and genome-wide association studies provide strong evidence of the genetic underpinnings of familial Chiari malformation. The authors report on a series of 3 family pairs with Chiari malformation Type I: 2 mother-daughter pairs and 1 father-daughter pair. The specific genetic causes of familial Chiari malformation have yet to be fully elucidated. The authors review the literature and discuss several candidate genes. Recent advances in the understanding of the genetic influences and pathogenesis of familial Chiari malformation are expected to improve management of affected patients and monitoring of at-risk family members.
Jean-Valery Coumans, Brian P. Walcott, William E. Butler, Brian V. Nahed and Kristopher T. Kahle
Resolution of syringomyelia is common following hindbrain decompression for Chiari malformation, yet little is known about the kinetics governing this process. The authors sought to establish the volumetric rate of syringomyelia resolution.
A retrospective cohort of patients undergoing hindbrain decompression for a Chiari malformation Type I with preoperative cervical or thoracic syringomyelia was identified. Patients were included in the study if they had at least 3 neuroimaging studies that detailed the entirety of their preoperative syringomyelia over a minimum of 6 months postoperatively. The authors reconstructed the MR images in 3 dimensions and calculated the volume of the syringomyelia. They plotted the syringomyelia volume over time and constructed regression models using the method of least squares. The Akaike information criterion and Bayesian information criterion were used to calculate the relative goodness of fit. The coefficients of determination R 2 (unadjusted and adjusted) were calculated to describe the proportion of variability in each individual data set accounted for by the statistical model.
Two patients were identified as meeting inclusion criteria. Plots of the least-squares best fit were identified as 4.01459e −0.0180804 x and 13.2556e −0.00615859 x. Decay of the syringomyelia followed an exponential model in both patients (R2 = 0.989582 and 0.948864).
Three-dimensional analysis of syringomyelia resolution over time enables the kinetics to be estimated. This technique is yet to be validated in a large cohort. Because syringomyelia is the final common pathway for a number of different pathological processes, it is possible that this exponential only applies to syringomyelia related to treatment of Chiari malformation Type I.
Brian P. Walcott, Jean-Valery C. E. Coumans and Kristopher T. Kahle
Disorders of the spine are common in clinical medicine, and spine surgery is being performed with increasing frequency in the US. Although many patients with an established diagnosis of a true surgically treatable lesion are referred to a neurosurgeon, the evaluation of patients with spinal disorders can be complex and fraught with diagnostic pitfalls. While “common conditions are common,” astute clinical acumen and vigilance are necessary to identify lesions that masquerade as surgically treatable spine disease that can lead to erroneous diagnosis and treatment. In this review, the authors discuss musculoskeletal, peripheral nerve, metabolic, infectious, inflammatory, and vascular conditions that mimic the syndromes produced by surgical lesions. It is possible that nonsurgical and surgical conditions coexist at times, complicating treatment plans and natural histories. Awareness of these diagnoses can help reduce diagnostic error, thereby avoiding the morbidity and expense associated with an unnecessary operation.
Brian P. Walcott, Brian V. Nahed, Kristopher T. Kahle, Ann-Christine Duhaime, Nutan Sharma and Emad N. Eskandar
Generalized dystonic syndromes may escalate into persistent episodes of generalized dystonia known as status dystonicus that can be life-threatening due to dystonia-induced rhabdomyolysis and/or respiratory compromise. Treatment of these conditions usually entails parenteral infusion of antispasmodic agents and sedatives and occasionally necessitates a medically induced coma for symptom control. The authors report a series of 3 children who presented with medically intractable, life-threatening status dystonicus and were successfully treated with bilateral pallidal deep brain stimulation. Bilateral globus pallidus internus stimulation appears to be effective in the urgent treatment of medically refractory and life-threatening movement disorders.
Arjun Khanna, Brian P. Walcott, Kristopher T. Kahle and J. Marc Simard
Cerebral edema and hemorrhagic conversion are common, potentially devastating complications of ischemic stroke and are associated with high rates of mortality and poor functional outcomes. Recent work exploring the molecular pathophysiology of the neurogliovascular unit in ischemic stroke suggests that deranged cellular ion homeostasis due to altered function and regulation of ion pumps, channels, and secondary active transporters plays an integral role in the development of cytotoxic and vasogenic edema and hemorrhagic conversion. Among these proteins involved in ion homeostasis, the ischemia-induced, nonselective cation conductance formed by the SUR1-TRPM4 protein complex appears to play a prominent role and is potently inhibited by glibenclamide, an FDA-approved drug commonly used in patients with Type 2 diabetes. Several robust preclinical studies have demonstrated the efficacy of glibenclamide blockade of SUR1-TRPM4 activity in reducing edema and hemorrhagic conversion in rodent models of ischemic stroke, prompting the study of the potential protective effects of glibenclamide in humans in an ongoing prospective phase II clinical trial. Preliminary data suggest glibenclamide significantly reduces cerebral edema and lowers the rate of hemorrhagic conversion following ischemic stroke, suggesting the potential use of glibenclamide to improve outcomes in humans.