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Background Glossopharyngeal neuralgia/neuropathy is rare, and less than 3% of cases involve cardiac arrhythmias of syncope due to activated vagal reflex pathways. Most of these cases are successfully treated with medical management with or without pacemaker placement. We present the first reported case of glossopharyngeal neuralgia/neuropathy with cardiac symptoms refractory to medical management including pacemaker placement but successfully treated with Gamma Knife Radiosurgery. Case Description A 70-year-old Caucasian man with recurrent squamous cell carcinoma of the tongue base treated with multiple surgeries, lymph node excision, chemotherapy, and external beam radiation, developed episodes of severe right ear and throat pain. These episodes would be followed by syncopal episodes associated with hypotension and bradycardia. Aggressive medical management including pacemaker could not stabilize the patient’s hemodynamic instability. After extensive workup, the patient was diagnosed with glossopharyngeal neuralgia/neuropathy with associated carotid sinus instability. The patient was not a strong surgical candidate, thus the patient underwent Gamma Knife Radiosurgery. The target was set as the glossopharyngeal meatus. Within days of treatment, the patient had no further clinically significant syncope or hemodynamic instability for the remaining 6 months of his life. Conclusions To our knowledge, we present the first case of glossopharyngeal neuralgia/neuropathy with medically refractory cardiac dysfunction successfully treated with Gamma Knife Radiosurgery. We advocate that Gamma Knife be considered for similar subsets of patients.

Background Extracranial metastasis, mainly a feature of World Health Organization (WHO) grade III meningiomas, is only rarely reported in grade II meningiomas. Case Description We report a case of a 48-year-old man who was initially diagnosed in 2010 with an occipital convexity meningioma based on computed tomography scan/magnetic resonance imaging (MRI) and treated with surgical therapy and gamma knife. The first operation achieved a macroscopically complete resection. The tumor was histologically classified as an atypical meningioma. The patient had a recurrence in 2014 on the left tentorial leaflet as noted on postcontrast MRI. The patient was asymptomatic, without focal neurologic deficits. In 2016, the patient reported new-onset pain in the neck and left upper extremity. MRI indicated complete replacement of the C7 vertebral marrow, with a soft tissue component extending posteriorly into the epidural space that appeared to be flattening the thecal sac but without evidence of abnormal cord signal. Histopathology of resection confirmed atypical meningioma. Conclusions This case represents a rare instance of intraosseous spine as the first site of metastasis of WHO grade II atypical meningioma and is the first reported case of extracranial metastasis of a meningioma to the C7 vertebral body.

Decompressive craniectomy (DC) improves functional outcomes in selected patients with malignant hemispheric infarction (MHI), but variability in the surgical technique and occasional complications may be limiting the effectiveness of this procedure. Our aim was to evaluate predefined perioperative CT measurements for association with post-DC midline brain shift in patients with MHI.At two medical centers we identified 87 consecutive patients with MHI and DC between January 2007 and December 2019. We used our previously tested methods to measure the craniectomy surface area, extent of transcalvarial brain herniation, thickness of tissues overlying the craniectomy, diameter of the cerebral ventricle atrium contralateral to the stroke, extension of infarction beyond the craniectomy edges, and the pre and post-DC midline brain shifts. To avoid potential confounding from medical treatments and additional surgical procedures, we excluded patients with the first CT delayed30 hours post-DC, resection of infarcted brain, or insertion of an external ventricular drain during DC. The primary outcome in multiple linear regression analysis was the postoperative midline brain shift.We analyzed 72 qualified patients. The average midline brain shift decreased from 8.7 mm pre-DC to 5.4 post-DC. The only factors significantly associated with post-DC midline brain shift at the p0.01 level were preoperative midline shift (coefficient 0.32, standard error 0.10, p=0.002) and extent of transcalvarial brain herniation (coefficient -0.20, standard error 0.05, p0.001).In patients with MHI and DC, smaller post-DC midline shift is associated with smaller pre-DC midline brain shift and greater transcalvarial brain herniation. This knowledge may prove helpful in assessing DC candidacy and surgical success. Additional studies to enhance the surgical success of DC are warranted.

Studying the complex molecular mechanisms involved in traumatic brain injury (TBI) is crucial for developing new therapies for TBI. Current treatments for TBI are primarily focused on patient stabilization and symptom mitigation. However, the field lacks defined therapies to prevent cell death, oxidative stress, and inflammatory cascades which lead to chronic pathology. Little can be done to treat the mechanical damage that occurs during the primary insult of a TBI; however, secondary injury mechanisms, such as inflammation, blood-brain barrier (BBB) breakdown, edema formation, excitotoxicity, oxidative stress, and cell death, can be targeted by therapeutic interventions. Elucidating the many mechanisms underlying secondary injury and studying targets of neuroprotective therapeutic agents is critical for developing new treatments. Therefore, we present a review on the molecular events following TBI from inflammation to programmed cell death and discuss current research and the latest therapeutic strategies to help understand TBI-mediated secondary injury.

Background Pseudomeningocele is an uncommon but widely recognized complication of spinal surgery that can be challenging to correct. When conservative measures fail, patients frequently require reoperation to attempt primary closure of the durotomy, yet attempts at true watertight closures of the dura or fascia sometimes fall short. We describe a technique of lumbosacral pseudomeningocele repair involving a 2-layer pants-over-vest closure of the pseudomeningocele coupled with mobilization of bilateral paraspinal musculature to create a Z-plasty, or a Z-shaped flap. We have demonstrated a high success rate with our small series. Methods The technique used meticulous manipulation of the pseudomeningocele to make a 2-layer pants-over-vest closure. This closure coupled with wide mobilization and importation of paraspinous muscle into the wound effectively obliterated dead space with simultaneous tamponade of the dural tear. The lateral row perforators were left intact, providing excellent vascularity with adequate mobility to the patient. Results This technique was incorporated into the care of 10 patients between 2004 and July 2019. All wounds were closed in a single stage after careful flap section based on the wound's needs. We demonstrated successful pseudomeningocele resolution in all 10 patients with no observed clinical recurrence of symptomatic pseudomeningocele after at least 6 months of follow-up. Conclusions This technique provides a straightforward option for the spine surgeon to manage these challenging spinal wounds with minimal, if any, need for further laminectomy as well as a high fistula control rate with minimal morbidity.

Formation of neutrophil extracellular traps worsens cerebrovascular outcomes after traumatic brain injury., Traumatic brain injury (TBI) is a major cause of mortality and morbidity. Preventative measures reduce injury incidence and/or severity, yet one-third of hospitalized patients with TBI die from secondary pathological processes that develop during supervised care. Neutrophils, which orchestrate innate immune responses, worsen TBI outcomes via undefined mechanisms. We hypothesized that formation of neutrophil extracellular traps (NETs), a purported mechanism of microbial trapping, exacerbates acute neurological injury after TBI. NET formation coincided with cerebral hypoperfusion and tissue hypoxia after experimental TBI, while elevated circulating NETs correlated with reduced serum deoxyribonuclease-1 (DNase-I) activity in patients with TBI. Functionally, Toll-like receptor 4 (TLR4) and the downstream kinase peptidylarginine deiminase 4 (PAD4) mediated NET formation and cerebrovascular dysfunction after TBI. Last, recombinant human DNase-I degraded NETs and improved neurological function. Thus, therapeutically targeting NETs may provide a mechanistically innovative approach to improve TBI outcomes without the associated risks of global neutrophil depletion.

Intracerebral hemorrhage is a devastating neurological injury that produces poor patient outcomes. In this report, Vaibhav et al. demonstrate that remote ischemic post-conditioning noninvasively accelerates hematoma resolution by enhancing AMPK-dependent alternative macrophage activation., Spontaneous intracerebral hemorrhage (ICH) produces the highest acute mortality and worst outcomes of all stroke subtypes. Hematoma volume is an independent determinant of ICH patient outcomes, making clot resolution a primary goal of clinical management. Herein, remote-limb ischemic post-conditioning (RIC), the repetitive inflation–deflation of a blood pressure cuff on a limb, accelerated hematoma resolution and improved neurological outcomes after ICH in mice. Parabiosis studies revealed RIC accelerated clot resolution via a humoral-mediated mechanism. Whereas RIC increased anti-inflammatory macrophage activation, myeloid cell depletion eliminated the beneficial effects of RIC after ICH. Myeloid-specific inactivation of the metabolic regulator, AMPKα1, attenuated RIC-induced anti-inflammatory macrophage polarization and delayed hematoma resolution, providing a molecular link between RIC and immune activation. Finally, chimera studies implicated myeloid CD36 expression in RIC-mediated neurological recovery after ICH. Thus, RIC, a clinically well-tolerated therapy, noninvasively modulates innate immune responses to improve ICH outcomes. Moreover, immunometabolic changes may provide pharmacodynamic blood biomarkers to clinically monitor the therapeutic efficacy of RIC., Graphical Abstract

Mitochondria are dynamic organelles responsible for cellular energy production. Besides, regulating energy homeostasis, mitochondria are responsible for calcium homeostasis, signal transmission, and the fate of cellular survival in case of injury and pathologies. Accumulating reports have suggested multiple roles of mitochondria in neuropathologies, neurodegeneration, and immune activation under physiological and pathological conditions. Mitochondrial dysfunction, which occurs at the initial phase of brain injury, involves oxidative stress, inflammation, deficits in mitochondrial bioenergetics, biogenesis, transport, and autophagy. Thus, development of targeted therapeutics to protect mitochondria may improve functional outcomes following traumatic brain injury (TBI) and intracerebral hemorrhages (ICH). In this review, we summarize mitochondrial dysfunction related to TBI and ICH, including the mechanisms involved, and discuss therapeutic approaches with special emphasis on past and current clinical trials.

Traumatic brain injury (TBI) is a major public health issue, producing significant patient mortality and poor long-term outcomes. Increasing evidence suggests an important, yet poorly defined, role for the immune system in the development of secondary neurologic injury over the days and weeks following a TBI. In this study, we tested the hypothesis that peripheral macrophage infiltration initiates long-lasting adaptive immune responses after TBI. Using a murine controlled cortical impact model, we used adoptive transfer, transgenic, and bone marrow chimera approaches to show increased infiltration and proinflammatory (classically activated [M1]) polarization of macrophages for up to 3 wk post-TBI. Monocytes purified from the injured brain stimulated the proliferation of naive T lymphocytes, enhanced the polarization of T effector cells (TH1/TH17), and decreased the production of regulatory T cells in an MLR. Similarly, elevated T effector cell polarization within blood and brain tissue was attenuated by myeloid cell depletion after TBI. Functionally, C3H/HeJ (TLR4 mutant) mice reversed M1 macrophage and TH1/TH17 polarization after TBI compared with C3H/OuJ (wild-type) mice. Moreover, brain monocytes isolated from C3H/HeJ mice were less potent stimulators of T lymphocyte proliferation and TH1/TH17 polarization compared with C3H/OuJ monocytes. Taken together, our data implicate TLR4-dependent, M1 macrophage trafficking/polarization into the CNS as a key mechanistic link between acute TBI and long-term, adaptive immune responses.

The CNS is regarded as an immunoprivileged organ, evading routine immune surveillance; however, the coordinated development of immune responses profoundly influences outcomes after brain injury. Innate lymphoid cells (ILCs) are cytokine-producing cells that are critical for the initiation, modulation, and resolution of inflammation, but the functional relevance and mechanistic regulation of ILCs are unexplored after acute brain injury. We demonstrate increased proliferation of all ILC subtypes within the meninges for up to 1 year after experimental traumatic brain injury (TBI) while ILCs were present within resected dura and elevated within cerebrospinal fluid (CSF) of moderate-to-severe TBI patients. In line with energetic derangements after TBI, inhibition of the metabolic regulator, AMPK, increased meningeal ILC expansion, whereas AMPK activation suppressed proinflammatory ILC1/ILC3 and increased the frequency of IL-10-expressing ILC2 after TBI. Moreover, intracisternal administration of IL-33 activated AMPK, expanded ILC2, and suppressed ILC1 and ILC3 within the meninges of WT and Rag1-/- mice, but not Rag1-/- IL2rg-/- mice. Taken together, we identify AMPK as a brake on the expansion of proinflammatory, CNS-resident ILCs after brain injury. These findings establish a mechanistic framework whereby immunometabolic modulation of ILCs may direct the specificity, timing, and magnitude of cerebral immunity.

A gonadotroph secreting pituitary adenoma, a rare endocrinopathy, is often overlooked due to ambiguous symptoms leading to other diagnoses, such as ovarian hyperstimulation syndrome (OHSS). A 53 year old African American woman presented for evaluation of a 4 month history of right hemianopsia. Her past medical history included a total hysterectomy and bilateral oophorosalpingectomy for recurrent ovarian cysts 11 years prior. Initial MRI:4.1x3.6x3.9 cm pituitary macroadenoma with prechiasmtic optic nerve compression. Initial laboratory studies: follicular stimulating hormone (FSH) level 186.83 mIU/mL (RR:23.0-116.3 mIU/mL) and luteinizing hormone (LH) 14.44 mIU/mL (RR:15.9-54.0 mIU/mL). Other pituitary labs were unremarkable. Debulking surgery was performed to relieve mass effect; pathology showed an FSH immunoreactive adenoma. Postoperatively, FSH was 2.55 mIU/mL and LH was 0.75 mIU/mL. The prevalence of pituitary adenomas is 80-100 per 100,000 persons; 15-30% are non-functional. The majority of gonadotroph adenomas are difficult to identify because they may not produce biologically active hormones. Clinically functioning gonadotroph adenomas are very rare, often macroadenomas when found, most often found in reproductive age women, and preferentially secrete FSH. In reproductive age women, a FSH secreting adenomas may present clinically with OHSS, with multiple large ovarian cysts found on ultrasound for menstrual or pelvic complaints as seen in our patient. While OHSS is a known complication of assisted reproductive procedures, spontaneous OHSS is atypical and suggests need for evaluation of a FSH-secreting adenoma. Men may present with macroorchidism. Children may present with precocious puberty. The treatment of choice is surgical removal of the adenoma, normalizing FSH to an age appropriate level. When OHSS is present, this results in a rapid decline in estradiol level and regression of ovarian cysts. Medical treatment, if surgery is contraindicated, is limited to cabergoline, which can initially decrease FSH and estradiol levels. In patients with normal pituitary function, gonadotropin-releasing hormone agonists acutely stimulate LH and FSH, thereby desensitizing GnRH receptors and decreasing gonadotropin secretion. In patients with FSH-secreting adenomas, they may have a persistent stimulatory effect, and in rare cases, result in pituitary apoplexy. Tumors that cannot be completely surgically removed may be treated by adjuvant radiotherapy or radiosurgery.

Meningiomas are the most common primary intracranial tumor accounting for almost 37% of all CNS tumors. Malignant meningiomas are uncommon, accounting for 0.5% of all meningiomas. Malignant meningioma that is metastatic outside the cranium/skull is even rarer, with only a few case reports. Metastases to the lung and abdomen have been reported and thought to travel via venous drainage. WHO Grading suggest that Grade III meningiomas have the greatest potential to metastasize extra-cranially. We present the case for the 47-year-old Senegalese American man with biopsy proven Grade II meningioma metastatic to his lungs with resultant hypercapnic respiratory failure.

Background The management of brain arteriovenous malformations (AVMs) remains a controversial topic. Given the relatively low incidence, high heterogeneity, and high morbidity and mortality of these lesions, consensus on treatment strategies is an issue of concern to organized neurosurgery. The present retrospective analysis examined and quantified the outcomes of patients with an initial presentation of intracranial hemorrhage from a Spetzler-Martin grade III or IV AVM, later ruled out as surgical candidates. Methods A total of 16 patients (5 females; 11 males) had presented with symptomatic hemorrhage confirmed by non–contrast-enhanced computed tomography and were deemed to not be surgical candidates owing to AVM location and/or architecture. The patients underwent combined endovascular embolization and gamma knife stereotactic radiosurgery (SRS). The modified Rankin scale was used to measure the clinical outcomes, comparing the scores at presentation, gamma knife treatment, and the last known follow-up examination. A radiographic evaluation was used to determine the level of AVM nidus involution after the procedure. Results The present study identified 16 patients with ruptured high-grade AVMs of high surgical risk. All the patients had undergone immediate embolization with delayed SRS for treatment of the hemorrhage and nidus of the AVM. A statistically significant proportion of patients showed marked improvement in the modified Rankin scale scores. No subsequent repeat hemorrhage or any associated complications after embolization occurred in any patient. Conclusion These findings warrant consideration of endovascular embolization with adjuvant SRS as a powerful treatment option for cases with high surgical morbidity due to AVM characteristics.

Traumatic brain injury (TBI) is a leading cause of mortality and long-term morbidity worldwide. Despite decades of pre-clinical investigation, therapeutic strategies focused on acute neuroprotection failed to improve TBI outcomes. This lack of translational success has necessitated a reassessment of the optimal targets for intervention, including a heightened focus on secondary injury mechanisms. Chronic immune activation correlates with progressive neurodegeneration for decades after TBI; however, significant challenges remain in functionally and mechanistically defining immune activation after TBI. In this review, we explore the burgeoning evidence implicating the acute release of damage associated molecular patterns (DAMPs), such as adenosine 5'-triphosphate (ATP), high mobility group box protein 1 (HMGB1), S100 proteins, and hyaluronic acid in the initiation of progressive neurological injury, including white matter loss after TBI. The role that pattern recognition receptors, including toll-like receptor and purinergic receptors, play in progressive neurological injury after TBI is detailed. Finally, we provide support for the notion that resident and infiltrating macrophages are critical cellular targets linking acute DAMP release with adaptive immune responses and chronic injury after TBI. The therapeutic potential of targeting DAMPs and barriers to clinical translational, in the context of TBI patient management, are discussed.

The clivus is centrally located in the skull base surrounded by critical neurovascular structures making surgical access difficult. Several approaches to this region have been described. Herein we discuss the transfacial approaches to the clivus with emphasis on endoscopic approaches.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Cerebral edema, a life-threatening medical complication, contributes to elevated intracranial pressure (ICP) and a poor clinical prognosis after TBI. Unfortunately, treatment options to reduce post-traumatic edema remain suboptimal, due in part, to a dearth of viable therapeutic targets. Herein, we tested the hypothesis that cerebral innate immune responses contribute to edema development after TBI. Our results demonstrate that high-mobility group box protein 1 (HMGB1) was released from necrotic neurons via a NR2B-mediated mechanism. HMGB1 was clinically associated with elevated ICP in patients and functionally promoted cerebral edema after TBI in mice. The detrimental effects of HMGB1 were mediated, at least in part, via activation of microglial toll-like receptor 4 (TLR4) and the subsequent expression of the astrocytic water channel, aquaporin-4 (AQP4). Genetic or pharmacological (VGX-1027) TLR4 inhibition attenuated the neuroinflammatory response and limited post-traumatic edema with a delayed, clinically implementable therapeutic window. Human and rodent tissue culture studies further defined the cellular mechanisms demonstrating neuronal HMGB1 initiates the microglial release of interleukin-6 (IL-6) in a TLR4 dependent mechanism. In turn, microglial IL-6 increased the astrocytic expression of AQP4. Taken together, these data implicate microglia as key mediators of post-traumatic brain edema and suggest HMGB1-TLR4 signaling promotes neurovascular dysfunction after TBI.

Object Intrathecal baclofen therapy has been used successfully for intractable spasticity in children with cerebral palsy. Infections are rare, but they are potentially life threatening if complicated by bacteremia or meningitis. Treatment without removal of the system is desirable if it can be done safely and effectively. Methods The authors reviewed the records of 207 patients ranging from 3 to 18 years of age with cerebral palsy who underwent placement or revision of a baclofen pump. They identified 38 patients with suspected or documented infectious complications. Initial attempts were made to eradicate infection with the devices in situ in all patients. Methods and effectiveness of pump salvage were evaluated. Results Of the 38 patients identified, 13 (34.2%) had documented infections; 11 had deep wound/pocket empyemas and 2 had meningitis. Eight patients with deep wound infections received intravenous antibiotics alone. All required pump explantation. The remaining 3 patients underwent a washout procedure as well; the infection was cured in 1 patient. Both patients with meningitis received intravenous and intrathecal antibiotics, and both required device explantation. In addition, 25 patients (65.8%) had excessive or increasing wound erythema. No objective criteria to document a superficial infection were present. The wounds were considered suspicious and were managed with serial examinations and oral antibiotics. The erythema resolved in 24 of the 25 patients. Conclusions In general, observation, wound care, and oral antibiotics are sufficient for wounds that are suspicious for superficial infection. For deep-seated infection, antibiotic therapy alone is generally insufficient and explantation is required. Washout procedures can be considered, but failures are common.

Background Intrathecal drug-delivery systems have become widely used tools in the management of refractory chronic pain and spasticity. Because increasing numbers of patients are using these systems, rehabilitation specialists frequently are the initial care providers who identify clinical signs and symptoms indicating possible complications relating to the implanted system. Identification of a pump malfunction often presents a diagnostic challenge. Distinguishing among progression of disease, new organic problems, and/or drug-device complications is critical. The use of nuclear medicine indium 111 diethylenetriamine pentaacetic acid (DTPA) studies represents a highly effective, straightforward, minimally invasive way to assess implant function and drug distribution. Objective To identify patients with suspected intrathecal pump malfunction and to determine whether the use of indium 111 DTPA is effective in identifying the source of failure. Design A retrospective review was performed from 2011 to 2012. Setting The study was performed at Georgia Health Sciences University. Patients The 23 selected patients had implanted devices for either spasticity or pain and were experiencing symptoms of a possible pump malfunction despite normal radiographic imaging. Twenty-four scintigraphic studies were performed, with malfunction documented in 19 patients. Methods A standard refill technique was used to inject 0.3 mL of indium 111 DTPA into the pump reservoir. Radionuclide images were reviewed at varying time points up to 48 hours after injection. The extent of radionuclide progression from the pump reservoir to the intrathecal space was evaluated. In cases in which a problem with the implant was identified, correlation with operative findings is described. Results Normal results of studies ultimately correlated with other clinical issues and confirmed an alternative etiology for the clinical changes noted. In studies with abnormal results, several patterns of failure were identified: restriction of the radionuclide to the pump reservoir, extravasations of tracer into the pump subcutaneous pocket, failure of the tracer to migrate from the subcutaneous catheter to the intrathecal space, and pooling of the tracer in the subcutaneous tissues. In all cases, surgical findings confirmed the suspected mechanism of malfunction as determined by the study. Conclusions Indium 111 DTPA scintigraphy is a safe, straightforward way to identify and characterize clinical changes associated with intrathecal drug-delivery systems and to guide appropriate and clinical surgical management.

This article discusses the epidemiology, diagnosis, and management of traumatic cerebrospinal fluid (CSF) leaks. An overview of traumatic CSF leaks is presented, and both conservative and operative therapies are reviewed. Management decisions are discussed based on the current literature. Controversial clinical topics are addressed, including the use of prophylactic antibiotics and the timing of surgical repair.

Neuroblastoma (NB) is the most prevalent pediatric solid tumor and a leading cause of cancer-related death in children. In the present study, a novel cytotoxic role for the dietary compounds, curcumin, andrographolide, wedelolactone, dibenzoylmethane, and tanshinone IIA was identified in human S-type NB cells, SK-N-AS and SK-N-BE(2). Mechanistically, cell death appeared apoptotic by flow cytometry; however, these effects proceeded independently from both caspase-3 and p53 activation, as assessed by both genetic (shRNA) and pharmacological approaches. Notably, cell death induced by both curcumin and andrographolide was associated with decreased NFκB activity and a reduction in Bcl-2 and Bcl-xL expression. Finally, curcumin and andrographolide increased cytotoxicity following co-treatment with either cisplatin or doxorubicin, two chemotherapeutic agents widely used in the clinical management of NB. Coupled with the documented safety in humans, dietary compounds may represent a potential adjunct therapy for NB.

Object Pituitary adenomas, which are common intracranial tumors, are associated with significant patient morbidity due to hormone secretion or mass effect or as a complication of therapy. Epigenetic regulation has emerged as an important component of malignant tumor pathogenesis, although the contribution in the progression of benign pituitary tumors remains largely unexplored. The present study evaluates the effect of anacardic acid (6-pentadecyl salicylic acid), a natural histone acetyltransferase inhibitor, on pituitary adenoma cells. Methods The concentration- and time-dependent effects of anacardic acid on the viability of GH3 and MMQ pituitary adenoma cells were determined by 3-(4,5-dimethylthiazoyl-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle phase distribution, protein expression, and percentage of apoptotic cells were assessed by flow cytometry and Western blotting. Colony forming assays were used to study the radiosensitizing effect of anacardic acid. Results The present study identifies a novel antiproliferative and cytotoxic effect of anacardic acid on pituitary adenoma cells. These effects were associated with an increase in poly([adenosine diphosphate]-ribose) polymerase cleavage, sub-G1 arrest, and annexin V staining, consistent with apoptotic cell death; however, the pancaspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-(O-methyl)-fluoromethylketone failed to reverse anacardic acid–induced cell death, suggesting a possible nonclassical apoptotic mechanism. Anacardic acid also reduced the expression of survivin and X-linked inhibitor of apoptosis protein, antiapoptotic proteins associated with cellular survival and radioresistance, and radiosensitized pituitary adenoma cells. Conclusions These findings warrant further exploration of anacardic acid as a single agent or as an adjunct to radiation therapy for the treatment of pituitary tumors.

Object Traumatic brain injury (TBI) induces significant neurological damage, including deficits in learning and memory, which contribute to a poor clinical prognosis. Treatment options to limit cognitive decline and promote neurological recovery are lacking, in part due to a poor understanding of the secondary or delayed processes that contribute to brain injury. In the present study, the authors characterized the temporal and spatial changes in the expression of postsynaptic density protein-95 (PSD-95), a key scaffolding protein implicated in excitatory synaptic signaling, after controlled cortical impacts in mice. Neurological injury, as assessed by the open-field activity test and the novel object recognition test, was compared with changes in PSD-95 expression. Methods Adult male CD-1 mice were subjected to controlled cortical impacts to simulate moderate TBI in humans. The spatial and temporal expression of PSD-95 was analyzed in the cerebral cortex and hippocampus at various time points following injury and sham operations. Neurological assessments were performed to compare changes in PSD-95 with cognitive deficits. Results A significant decrease in PSD-95 expression was observed in the ipsilateral hippocampus beginning on Day 7 postinjury. The loss of PSD-95 corresponded with a concomitant reduction in immunoreactivity for NeuN (neuronal nuclei), a neuron-specific marker. Aside from the contused cortex, a significant loss of PSD-95 immunoreactivity was not observed in the cerebral cortex. The delayed loss of hippocampal PSD-95 directly correlated with the onset of behavioral deficits, suggesting a possible causative role for PSD-95 in behavioral abnormalities following head trauma. Conclusions A delayed loss of hippocampal synapses was observed following head trauma in mice. These data may suggest a cellular mechanism to explain the delayed learning and memory deficits in humans after TBI and provide a potential framework for further testing to implicate PSD-95 as a clinically relevant therapeutic target.

Traumatic brain injury is a devastating neurological injury associated with significant morbidity and mortality. Medical therapies to limit cerebral edema, a cause of increased intracranial hypertension and poor clinical outcome, are largely ineffective, emphasizing the need for novel therapeutic approaches. In the present study, pre-treatment with curcumin (75, 150 mg/kg) or 30 min post-treatment with 300 mg/kg significantly reduced brain water content and improved neurological outcome following a moderate controlled cortical impact in mice. The protective effect of curcumin was associated with a significant attenuation in the acute pericontusional expression of interleukin-1beta, a pro-inflammatory cytokine, after injury. Curcumin also reversed the induction of aquaporin-4, an astrocytic water channel implicated in the development of cellular edema following head trauma. Notably, curcumin blocked IL-1beta-induced aquaporin-4 expression in cultured astrocytes, an effect mediated, at least in part, by reduced activation of the p50 and p65 subunits of nuclear factor kappaB. Consistent with this notion, curcumin preferentially attenuated phosphorylated p65 immunoreactivity in pericontusional astrocytes and decreased the expression of glial fibrillary acidic protein, a reactive astrocyte marker. As a whole, these data suggest clinically achievable concentrations of curcumin reduce glial activation and cerebral edema following neurotrauma, a finding which warrants further investigation.

Object Patients undergoing craniotomies have traditionally received opiates with acetaminophen for the management of their postoperative pain. The use of narcotic pain medications can be costly, decrease rates of early postoperative ambulation, lengthen hospital stays, and alter a patient's neurological examination. The use of alternative pain medications such as tramadol may benefit patients by resolving many of these issues. Methods The authors conducted a randomized, blinded prospective study to evaluate the efficacy of alternative pain management strategies for patients following craniotomies. Fifty patients were randomly assigned either to a control group who received narcotics and acetaminophen alone or an experimental group who received tramadol in addition to narcotic pain medications (25 patients assigned to each group). Results The control group was noted to have statistically significant higher visual analog scale pain scores, an increased length of hospital stay, and increased narcotic use compared with the tramadol group. The narcotics and acetaminophen group also had increased hospitalization costs when compared with the tramadol group. Conclusions The use of scheduled atypical analgesics such as tramadol in addition to narcotics with acetaminophen for the management of postoperative pain after craniotomy may provide better pain control, decrease the side effects associated with narcotic pain medications, encourage earlier postoperative ambulation, and reduce total hospitalization costs.

The current WHO 2007 classification divides meningiomas into a 3-grade prognostic hierarchy. Recent literature evokes two pathways to disease progression in meningiomas akin to a comparable paradigm in gliomas, but without similar prognostic connotation: de novo anaplastic meningioma (better prognosis), and transformed meningioma (worse prognosis). We present two adult cases of transformed meningiomas that display a spectrum of morphologic progression. Case 1 at presentation showed a random admixture of meningothelial, atypical and anaplastic meningioma. The tumor recurred as anaplastic meningioma. Case 2 presented as a chordoid meningioma, but recurred as anaplastic meningioma mainly at the invasive front in transition with residual chordoid pattern. Of interest, portions of tumor also showed papillary configuration. In accordance with the dire prognosis for anaplastic meningioma, both patients succumbed to their disease within 2 months of recurrence. The present study highlights two main points: First, that proper recognition of focal high-grade areas in a heterogeneous low-grade meningioma (case 1) provides critical morphologic clues to spatial histologic progression and predicts aggressive biologic behavior, as evidenced by progression to frankly anaplastic meningioma at recurrence. Second, the presence of papillary in addition to anaplastic areas, in the recurrence of a previously diagnosed chordoid meningioma supports the ostensibly heightened transforming potential of grade II meningiomas, but also reflects on the morphologic heterogeneity of high-grade meningiomas, and their potentially diverse pathways of progression. We propose that grading of meningiomas as outlined by WHO is of more critical prognostic import than histologic sub-typing, and must include a thorough survey of the tumor-brain interface. Future molecular genetic correlates, akin to those characterized in gliomas, could help stratify prognostic subcategories to refine meningioma grading, and govern optimal therapeutic strategies.

Objective Adenomas of the pituitary gland are among the most common types of tumors of the adult brain. Although adenomas are histologically benign, they may be associated with significant morbidity and mortality, mostly because of their invasive growth pattern and hormone hypersecretion. Current medical therapies are suppressive, acting at a receptor level. Thus, there is a need to identify novel cellular and molecular targets for pituitary tumors. We investigated the possible role of the NFkappaB transcription factor in pituitary tumor cell growth. Methods The effect of NFkappaB pathway inhibition on cellular viability was studied in the GH3 pituitary adenoma cell line, a well-characterized rat cell line that secretes growth hormone and prolactin. Cells were treated with mechanistically diverse pharmacological NFkappaB pathway inhibitors or with molecular inhibitors that were overexpressed in tumor cells before the assessment of cellular viability. NFkappaB activity was also assessed in GH3 cells using deoxyribonucleic acid binding assays. Results GH3 cells exhibited constitutive NFkappaB activity, which contributed to increased cellular proliferation. Treatment with wedelolactone, an IkappaB kinase inhibitor, or overexpression of an IkappaB super-repressor reduced cell viability, further implicating NFkappaB in pituitary tumor cell growth. Pharmacological or molecular inhibition of Akt similarly reduced GH3 viability and NFkappaB binding, suggesting that constitutive activation of NFkappaB may be, at least in part, mediated by Akt. Conclusion Directed targeting of the Akt and NFkappaB signaling pathways may be a useful adjunct in the clinical management of pituitary tumors. Further elucidation of this pathway may yield novel information regarding the behavior of pituitary tumors in humans.

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Current medical therapies exhibit limited efficacy in reducing neurological injury and the prognosis for patients remains poor. While most research is focused on the direct protection of neuronal cells, non-neuronal cells, such as astrocytes, may exert an active role in the pathogenesis of TBI. Astrocytes, the predominant cell type in the human brain, are traditionally associated with providing only structural support within the CNS. However, recent work suggests astrocytes may regulate brain homeostasis and limit brain injury. In contrast, reactive astrocytes may also contribute to increased neuroinflammation, the development of cerebral edema, and elevated intracranial pressure, suggesting possible roles in exacerbating secondary brain injury following neurotrauma. The multiple, opposing roles for astrocytes following neurotrauma may have important implications for the design of directed therapeutics to limit neurological injury. As such, a primary focus of this review is to summarize the emerging evidence suggesting reactive astrocytes influence the response of the brain to TBI.

✓Modern neurological and spinal surgical techniques have been developed on the foundations established by predecessors. Modern 21st century neurosurgery begins in the Babylonian period, with the Edwin Smith papyrus. Throughout history, periods of enlightenment have resulted in advances in knowledge and understanding that have served as stepping stones for generations to come. As in other fields, in neurosurgery these periods of “enlightenment” have occurred in a variety of civilizations and time periods.

Objective Patients undergoing craniotomies have traditionally received opiates for the management of their postoperative pain. The use of narcotic pain medications can be costly, can decrease early walking, can lengthen hospital stay, and can alter a patient's neurological examination results. The use of alternative pain medications such as cyclooxygenase-2 (COX-2) inhibitors may benefit patients by resolving many of these issues. Compared with traditional nonsteroidal anti-inflammatory drugs, these anti-inflammatory medications may be used safely in neurosurgical patients because of their selective inhibition of the COX-2 enzyme, which avoids the platelet dysfunction caused by other nonsteroidal anti-inflammatory drugs. Methods A randomized, single-blinded prospective study was used to evaluate the efficacy of alternative pain management strategies for patients who have undergone craniotomy. Twenty-seven patients were randomly assigned to a control group (n = 13) receiving narcotics alone or an experimental group (n = 14) receiving a COX-2 inhibitor in addition to narcotic pain medications. Results The narcotics group was noted to have statistically significantly higher visual analog scale scores, increased length of stay, and increased narcotic use compared with the COX-2 group. The narcotics group also had increased hospitalization costs when compared with the COX-2 group. Conclusion The use of scheduled atypical analgesics, such as COX-2 inhibitors, in addition to narcotics for the management of postoperative pain after craniotomy may provide better pain control, may decrease side effects associated with narcotic pain medications, may encourage earlier walking, and may reduce total hospitalization costs.

Depressed skull fractures overlying the major venous sinus are often managed nonoperatively because of the high associated risks of surgery in these locations. In the presence of clinical and radiographic evidence of sinus occlusion, however, surgical therapy may be necessary. The authors present the case of a 9-year-old boy with a depressed skull fracture overlying the posterior third of the superior sagittal sinus. After initial conservative treatment, delayed signs of intracranial hypertension and a symptomatic tonsillar herniation with tonsillar necrosis developed. Possible causes as well as diagnostic and treatment options are reviewed.

Hemostatic options available to the surgeon in the late 19th and early 20th centuries were limited. The surgical ligature was limited in value to the neurological surgeon because of the unique structural composition of brain tissue as well as the approaches and operating angles used in this type of surgery. In this manuscript the authors review the options available and the evolution of surgical hemostatic techniques and electrosurgery in the late 19th and early 20th centuries and the impact of these methods on the surgical management of tumors of the brain and its coverings.

Background context: The management of lesions at the craniocervical junction presents unique difficulties for the spine surgeon. The complexity of this region creates a variety of mechanical forces that challenge any fusion construct. An understanding of the ligamentous, bone and vascular structures in this region is critical. Purpose: To describe a method of occipital–cervical fusion with long-term follow-up. Study design/setting: Retrospective case series. Patient sample: Twenty-one consecutive patients with craniocervical compression and/or instability who were treated using the Locksley intersegmental tie bar technique. Outcome measures: Neurologic function, fusion, postoperative complications. Methods: Patients with craniocervical instability underwent occipital–cervical fusion using the Locksley intersegmental tie bar technique. The pathologic processes causing compression and/or instability at the craniocervical junction, as well as the patients' pre- and postoperative neurologic status, are reported. Results: Solid fusion was attained in all 19 patients surviving at 2 years. Two patient deaths were reported in this series in the early postoperative period because of systemic disease. Conclusions: This approach allows for rigid, immediate stabilization of this region. An external orthosis is most often not required. This technique has unique applicability to patients where the normal ligamentous and bone structures are weakened because of underlying disease or injury.

Objective: Intrathecal drug delivery systems (IT-DDSs) have gained more widespread use in patients with non-cancer-related pain, notably failed back surgery syndrome and spinal arachnoiditis. Secondary to the longer life spans of these patients, more complications have been discovered with IT-DDSs. With an estimated incidence of 1% to 3%, an uncommon but serious complication is that of granuloma formation. Case Report: We describe a case of a 38-year-old woman with a malfunctioning IT-DDS containing morphine and bupivacaine. The device had stopped providing relief for several months because of presumed leakage from the connection site between the pump and the proximal catheter. The IT-DDS spontaneously resumed functioning. The IT-DDS was explanted for low battery life, upon which we discovered that the leakage site had been encapsulated by drug concretion and granuloma formation, thus providing a sealed conduit that reestablished drug flow between the pump and the catheter. Conclusions: This case report reinforces the view that the infusate is the causal agent of this lesion.

Background Malignant glioma is one of the most devastating tumors in adults with poor patient prognosis. Notably, glioma often exhibits resistance to conventional chemotherapeutic approaches, complicating patient treatments. However, the molecular mediators involved in tumor chemoresistance remain poorly defined, creating a barrier to the successful management of glioma. In the present study, we hypothesized that the antioxidant transcription factor, Nrf2 (nuclear factor erythroid-derived 2 like 2), attenuates glioma cytotoxicity to Carmustine (BCNU), a widely used chemotherapeutic agent known to modulate cellular oxidative balance. Methods To test the hypothesis, we employed human malignant glioma cell line, U87MG and overexpression of Nrf2 in glioma cells was achieved using both pharmacological and genetic approaches. Results Notably, induction of Nrf2 was associated with increased expression of heme oxygenase-1 (HO-1), a stress inducible enzyme involved in anti-oxidant defense. In addition, over expression of Nrf2 in U87MG cells significantly attenuated the cytotoxicity of Carmustine as evidenced by both cellular viability assay and flow cytometry analysis. Consistent with this, antioxidants such as glutathione and N-acetyl cysteine significantly reduced Carmustine mediated glioma cytotoxicity. Conclusions Taken together, these data strongly implicate an unexplored role of Nrf2 in glioma resistance to Carmustine and raise the possible use of Nrf2 inhibitors as adjunct to Carmustine for the treatment of malignant glioma. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1134-z) contains supplementary material, which is available to authorized users.

This study presents a MLC-based, 3D grid-therapy technique with characteristics of both 3D-conformal-radiotherapy and grid-therapy. It generates a brachytherapy-like dose distribution, with D50% of 20, 9.8, 5.4 and 2.9-Gy, for the spheres, target, 1 cm-outershell and 2 cm-outershell, respectively. It may provide a strategy to deliver ablative doses to large tumors safely.

Objective The diversion of cerebrospinal fluid (CSF) has been widely used in the prevention and treatment of CSF fistulae. A common method is the use of a lumbar drainage system. Although it is effective, several serious complications can develop, which can be avoided by regulating the flow of CSF with a standard intravenous infusion pump. Technique We present a simple, inexpensive, and accurate method of flow-controlled lumbar subarachnoid drainage that minimizes patient discomfort and the unpredictability of a gravity-dependent system. This system uses a standard lumbar drain connected to an intravenous infusion pump to provide drainage of CSF in a constant and predictable manner. Results A total of 42 patients from two institutions were treated with this method. CSF fistulae occurred secondary to trauma in 9 patients, after spinal surgery in 11 patients, after transsphenoidal surgery in 10 patients, and after cranial base surgery in 12 patients. Resolution of the fistula was attained in 36 of 42 patients. There were no deaths, no cases of deep venous thrombosis, and no incidence of meningitis. One patient developed tension pneumocephalus, and two patients developed headache with nausea and vomiting. All patients were ambulatory, and only three patients required narcotic analgesia for headaches. Conclusion Pump-regulated lumbar subarachnoid drainage is safe and effective in the treatment of CSF fistulae, as reported elsewhere in the literature. The advantage of this method is that the drainage of CSF can be carefully controlled and titrated in a predictable fashion. Because the system is independent of gravity to produce drainage of CSF, patients are not confined to bed and serious complications of overdrainage can be avoided.

Previous work in our laboratory has shown a correspondence between the chemosensitivity of C6 rat glioma and that of human glioblastoma (GBM) to a panel of chemotherapeutic agents in vitro, as determined by the MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide] colorimetric assay. In the present study, an in vivo model of intracerebral C6 glioma in Sprague-Dawley rats was used to determine if a correlation exists between in vitro chemosensitivity and in vivo survival of the animals, and post-mortem histopathological changes in the tumor. Cisplatin (CDDP) and methotrexate (MTX), agents previously shown to demonstrate high and low in vitro cytotoxicity, respectively, against C6, were administered by intra-carotid infusion over the course of two days. In a separate series of animals, LTC4 was administered prior to infusion of CDDP or MTX; LTC4 was used in view of its known, selective, vasogenic effect on the permeability of brain tumor capillaries. It was found that survival of animals treated with CDDP alone was increased, although this did not reach statistical significance; histopathologically, CDDP-treated animals showed significant tumor necrosis. However, in CDDP-treated animals, pre-treatment with LTC4 increased survival to a statistically significant degree. When administered alone, LTC4 (not followed by CDDP) had no effect on either survival or histology. The survival-enhancing effect of CDDP, when combined with LTC4, was probably not due to any cytotoxic effect of LTC4; this is based on our finding that, on the in vitro MTT colorimetric assay, LTC4 showed low cytotoxicity for C6 glioma cells. By contrast with CDDP, MTX – with or without pretreatment with LTC4 – affected neither survival nor tumor histology. With respect to the question of correspondence between the MTT colorimetric in vitro assay and in vivo effect, MTX showed a clear correlation: low cytotoxicity in vitro and poor in vivo response. In the case of CDDP, the correspondence was not clear-cut: there was a high level of in vitro chemosensitivity of the C6 cell line to CDDP as well as post-mortem tumor necrosis, but in vivo testing showed no significant prolongation of survival. However, pre-treatment with LTC4 did significantly extend survival in animals treated with CDDP.