Inhibition of glial D-serine release rescues synaptic damage after brain injury.

Synaptic damage is one of the most prevalent pathophysiological responses to traumatic CNS injury and underlies much of the associated cognitive dysfunction; however, it is poorly understood. The D-amino acid, D-serine, serves as the primary co-agonist at synaptic NMDA receptors (NDMARs) and is a critical mediator of NMDAR-dependent transmission and synaptic plasticity. In physiological conditions, D-serine is produced and released by neurons from the enzymatic conversion of L-serine by serine racemase (SRR). However, under inflammatory conditions, glial cells become a major source of D-serine. Here, we report that D-serine synthesized by reactive glia plays a critical role in synaptic damage after traumatic brain injury (TBI) and identify the therapeutic potential of inhibiting glial D-serine release though the transporter Slc1a4 (ASCT1). Furthermore, using cell-specific genetic strategies and pharmacology, we demonstrate that TBI-induced synaptic damage and memory impairment requires D-serine synthesis and release from both reactive astrocytes and microglia. Analysis of the murine cortex and acutely resected human TBI brain also show increased SRR and Slc1a4 levels. Together, these findings support a novel role for glial D-serine in acute pathological dysfunction following brain trauma, whereby these reactive cells provide the excess co-agonist levels necessary to initiate NMDAR-mediated synaptic damage.

Cortical spreading depression as a site of origin for migraine: Role of CGRP.

PREMISE: Migraine is a complex neurologic disorder that leads to significant disability, yet remains poorly understood. PROBLEM: One potential triggering mechanism in migraine with aura is cortical spreading depression, which can activate the trigeminal nociceptive system both peripherally and centrally in animal models. A primary neuropeptide of the trigeminal system is calcitonin gene-related peptide, which is a potent vasodilatory peptide and is currently a major therapeutic target for migraine treatment. Despite the importance of both cortical spreading depression and calcitonin gene-related peptide in migraine, the relationship between these two players has been relatively unexplored. However, recent data suggest several potential vascular and neural connections between calcitonin gene-related peptide and cortical spreading depression. CONCLUSION: This review will outline calcitonin gene-related peptide-cortical spreading depression connections and propose a model in which cortical spreading depression and calcitonin gene-related peptide act at the intersection of the vasculature and cortical neurons, and thus contribute to migraine pathophysiology.

Genome-wide DNA methylation investigation of glucocorticoid exposure within buccal samples.

AIM: Glucocorticoids play a major role in regulating the stress response, and an imbalance of glucocorticoids has been implicated in stress-related disorders. Within mouse models, CpGs across the genome have been shown to be differentially methylated in response to glucocorticoid treatment, and using the Infinium 27K array, it was shown that humans given synthetic glucocorticoids had DNA methylation (DNAm) changes in blood. However, further investigation of the extent to which glucocorticoids affect DNAm across a larger proportion of the genome is needed. METHODS: Buccal samples were collected before and after synthetic glucocorticoid treatment in the context of a dental procedure. This included 30 tooth extraction surgery patients who received 10 mg of dexamethasone. Genome-wide DNAm was assessed with the Infinium HumanMethylationEPIC array. RESULTS: Five CpGs showed genome-wide significant DNAm changes that were >10%. These differentially methylated CpGs were in or nearest the following genes: ZNF438, KLHDC10, miR-544 or CRABP1, DPH5, and WDFY2. Using previously published datasets of human blood gene expression changes following dexamethasone exposure, a significant proportion of genes with false-discovery-rate-adjusted significant CpGs were also differentially expressed. A pathway analysis of the genes with false-discovery-rate-adjusted significant CpGs revealed significant enrichment of olfactory transduction, pentose and glucuronate interconversions, ascorbate and aldarate metabolism, and steroid hormone biosynthesis pathways. CONCLUSION: High-dose synthetic glucocorticoid administration in the setting of a dental procedure was significantly associated with DNAm changes within buccal samples. These findings are consistent with prior findings of an influence of glucocorticoids on DNAm in humans.

Deep Brain Stimulation for Obsessive-Compulsive Disorder: A Long Term Naturalistic Follow Up Study in a Single Institution.

INTRODUCTION: Deep brain stimulation (DBS) is a proven, effective tool in the treatment of movement disorders. Expansion of indications for DBS into the realm of neuropsychiatric disorders, especially obsessive-compulsive disorder (OCD), has gained fervent interest, although data on appropriate clinical utilization remains limited. METHODS: A retrospective, naturalistic study followed nine severely affected OCD patients (average YBOCs score before implantation 34.2 ± 2.5) treated with DBS of ventral capsule/ventral striatum, with average follow up of 54.8 months. RESULTS: With chronic stimulation (years), a majority of the patients achieved significant benefits in obsessive-compulsive and depressive symptoms. Six patients experienced periods of OCD remission following implantation. Four of the six responders required more than 12 months to achieve response. Relief of major depressive symptoms occurred in four out of six patients with documented co-morbid depression. Settings required to achieve efficacy were higher than those typically utilized for movement disorders, necessitating increased impulse generator (IPG) battery demand. We found patients benefited from conversion to a rechargeable IPG to prevent serial operations for IPG replacement. For patients with rechargeable IPGs, the repetitive habit of recharging did not appear to aggravate or trigger new obsessive-compulsive behaviors or anxiety symptoms. CONCLUSIONS: Our study supports and builds upon other research suggesting that DBS for OCD in a real-world setting can be implemented successfully and provide long-term benefit for severely affected OCD patients. Optimal patient selection and DBS programming criteria are discussed. The use of rechargeable IPGs appears to be both cost effective and well-tolerated in this population.

Impact of the Inclusion of C2 in Posterior Cervical Fusions for Cervical Myelopathy on Sagittal Cervical Alignment.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To determine the impact of including C2 in posterior fusions on radiographic parameters of cervical alignment in cervical spondylotic myelopathy. SUMMARY OF BACKGROUND DATA: Despite the use of posterior instrumentation and arthrodesis after cervical laminectomy, loss of lordosis and the development of kyphosis are prevalent. Inadequate cervical lordosis and other measures of sagittal cervical alignment have been shown to correlate with disability, general health scores, and severity of myelopathy. The role of C2 in the posterior tension band, which maintains sagittal alignment, differs from the subaxial spine, as it is the insertion point for erector spinae muscles that play a critical role in maintaining posture. PATIENTS AND METHODS: This study compares the radiographic outcomes of sagittal balance between 2 cohorts of patients who underwent posterior cervical decompression and fusion for cervical myelopathy over a 12-year period at a single institution. Demographic and surgical characteristics were collected using the electronic medical record of patients undergoing posterior cervical fusions (PCF) which included the axis [axial fusion (AF)] and those that were subaxial fusions (SAF). Radiographic measurements included preopertaive and postoperative C2-C7 lordosis (CL), C2-C7 sagittal vertical axis (SVA), and T1 slope (T1S). RESULTS: After review of the electronic medical records, 229 patients were identified as having PCF and decompression for treatment of myelopathy. One hundred sixty-seven patients had AF, whereas 62 had SAF. PCF resulted in loss of CL in both cohorts. Although there was no statistical difference in postoperative CL, there was a significant increase in SVA (P<0.001) and T1S (P<0.001) with AF. CONCLUSIONS: PCF often result in loss of lordosis. When compared with SAF, inclusion of C2 into the fusion construct may result in worsened sagittal balance, increasing the SVA and T1S.

Acute Hydrocephalus Resulting from Neuromyelitis Optica: A Case Report and Review of the Literature.

BACKGROUND: Neuromyelitis optica is an autoimmune disorder of the central nervous system that predominantly affects the optic nerves and spinal cord. The neuropathologic hallmark of the disease is deposits of antibodies and complement, loss of astrocytes, secondary degeneration of oligodendrocytes and neurons, and necrotic lesions with infiltration of neutrophilic and eosinophilic granulocytes. It can rarely be associated with hydrocephalus, but the cause and mechanisms that result in hydrocephalus are not clear. CASE DESCRIPTION: A 35-year-old woman with a history of neuromyelitis optica presented with a 5-day history of progressively worsening lethargy, fatigue, somnolence, and headaches. Imaging demonstrated new hydrocephalus without evidence of obstruction, and extensive periventricular enhancement concerning for active demyelination. She underwent placement of a ventriculostomy, and subsequently underwent endoscopic biopsy and ventriculoperitoneal shunt placement. Pathology confirmed demyelination secondary to neuromyelitis optica. CONCLUSIONS: This case provides evidence of the rapid development of hydrocephalus in association with periventricular inflammation, without aqueductal stenosis. In a state of aquaporin-4 dysfunction such as in neuromyelitis optica, altered cerebrospinal fluid resorption could lead to acute hydrocephalus by a nonobstructive mechanism.

Thoracic Meningocele and Cervical Syringomyelia Treated with Ventriculoperitoneal Shunt.

BACKGROUND: Spinal meningocele is the herniation of dura mater and cerebrospinal fluid through a spinal defect, be it congenital, iatrogenic, or traumatic. Intrathoracic meningoceles are rare and are most commonly associated with neurofibromatosis. When indicated, surgical management of symptomatic thoracic meningocele is aimed at decreasing the size of the meningocele, which can be accomplished by a variety of procedures. CASE DESCRIPTION: A 59-year-old woman with neurofibromatosis type 1 and a known thoracic meningocele was initially managed conservatively. However, she developed syringomyelia and subsequently became symptomatic from the syrinx. She was ultimately treated successfully with ventriculoperitoneal shunt. Shunting resulted in complete resolution of the syrinx, while the thoracic meningocele remained stable in size. CONCLUSIONS: Ventriculoperitoneal shunt can be used to successfully treat a symptomatic syrinx in a patient with an asymptomatic thoracic meningocele. Alterations in normal cerebrospinal fluid flow dynamics from the thoracic meningocele likely contributed to the development of syringomyelia in this patient.

Volume of Brain Herniation After Decompressive Craniectomy in Patients with Traumatic Brain Injury.

BACKGROUND: The decompressive hemicraniectomy operation is highly effective in relieving refractory intracranial hypertension. However, one limitation of this treatment strategy is the requirement to perform a subsequent cranioplasty operation to reconstruct the skull defect-an expensive procedure with high complication rates. An implant that is capable of accommodated post-hemicraniectomy brain swelling, but also provides acceptable skull defect coverage after brain swelling abates, would theoretically eliminate the need for the cranioplasty operation. In an earlier report, the concept of using a thin, moveable plate implant for this purpose was introduced. METHODS: Measurements were obtained in a series of stroke patients to determine whether a plate offset from the skull by 5 mm would accommodate the observed post-hemicraniectomy brain swelling. The volume of brain swelling measured in all patients in the stroke series would be accommodated by a 5-mm offset plate. In the current report, we expanded our analysis to study brain swelling patterns in a different population of patients requiring a hemicraniectomy operation: those with traumatic brain injuries (TBI). RESULTS: We identified 56 patients with TBI and measured their postoperative brain herniation volumes. A moveable plate offset by 5 mm would create sufficient additional volume to accommodate the brain swelling measured in all but one patient. That patient had malignant intraoperative brain swelling and died the following day. CONCLUSIONS: These data suggest that a 5 mm offset plate will provide sufficient volume for brain expansion for almost all hemicraniectomy operations.

A Unique Case of Primary Ewing's Sarcoma of the Cervical Spine in a 53-Year-Old Male: A Case Report and Review of the Literature.

Extraskeletal Ewing's sarcoma (EES) is a rare presentation, representing only 15% of all primary Ewing's sarcoma cases. Even more uncommon is EES presenting as a primary focus in the spinal canal. These rapidly growing tumors often present with focal neurological symptoms of myelopathy or radiculopathy. There are no classic characteristic imaging findings and thus the physician must keep a high index of clinical suspicion. Diagnosis can only be definitively made by histopathological studies. In this report, we discuss a primary cervical spine EES in a 53-year-old man who presented with a two-month history of left upper extremity pain and acute onset of weakness. Imaging revealed a cervical spinal canal mass. After undergoing cervical decompression, histopathological examination confirmed a diagnosis of Ewing's sarcoma. A literature search revealed fewer than 25 reported cases of primary cervical spine EES published in the past 15 years and only one report demonstrating this pathology in a patient older than 30 years of age (age = 38). Given the low incidence of this pathology presenting in this age group and the lack of treatment guidelines, each patient's plan should be considered on a case-by-case basis until further studies are performed to determine optimal evidence based treatment.

A novel role for P450 eicosanoids in the neurogenic control of cerebral blood flow in the rat.

The P450 eicosanoids epoxyeicosatrienoic acids (EETs) are endogenous lipid mediators produced in the brain by P450 epoxygenases and metabolized through multiple pathways, including soluble epoxide hydrolase (sEH). Epoxyeicosatrienoic acids play important functions in the brain, including regulation of cerebral blood flow and protection from ischaemic brain injury. We previously demonstrated that ischaemic preconditioning induces cytochrome P450 2C11 epoxygenase (CYP2C11) expression in the brain, and that pharmacological inhibition and genetic deletion of sEH increases EETs and protects against stroke-induced brain damage. However, the expression profiles of CYP2C11 and sEH in normal brain remain unknown. In agreement with previous reports in peripheral vessels, we here demonstrate by immunofluorescence double-labelling that within cerebral parenchymal microvessels, sEH-immunoreactivity (IR) is localized to the vascular smooth muscle layer. Unexpectedly, however, analysis of large cerebral conduit arteries such as the middle cerebral artery revealed CYP2C11 and sEH expression in extrinsic perivascular nerves. Double-labelling studies revealed that CYP2C11- and sEH-IR predominantly colocalized with neuronal nitric oxide synthase-IR within perivascular nerve fibres. Significant colocalization for CYP2C11 and sEH was also observed with the parasympathetic markers vasoactive intestinal peptide and choline actetyltransferase, in addition to the sensory fibre markers calcitonin gene-related peptide and substance P. No colocalization was observed for either CYP2C11 or sEH with the sympathetic nerve markers dopamine beta-hydroxylase or neuropeptide Y. The presence of enzymes involved in production and inactivation of EETs within extrinsic parasympathetic and sensory vasodilator fibres suggests a novel role for EETs in the neurogenic control of cerebral arteries.