Pallidal stimulation-induced psychosis and suicidality in Parkinson's disease.

Neuropsychiatric adverse events have been previously reported following deep brain stimulation (DBS) for Parkinson's disease (PD). Most cases described have involved DBS of the subthalamic nucleus (STN). We report a unique case of acute-onset and reversible psychosis, suicidality, and depressive symptoms following DBS of the globus pallidus internus (GPi) and review the relevant literature.

Bilateral Thalamic Glioma: A Case Report.

Bilateral thalamic primary gliomas are an exceedingly rare entity. Symptomology heralding a workup and diagnosis of bithalamic gliomas is diverse and varies between the pediatric and adult populations. Herein, we present a case of a 63-year-old female patient who presented with progressive gait imbalance and fatigue, prompting an outpatient brain MRI, remarkable for marked expansion of the bilateral thalami secondary to non-enhancing, T2-weighted-fluid-attenuated inversion recovery (T2-FLAIR) bright bithalamic lesions. The patient underwent a right frontal frameless stereotactic biopsy of the right thalamic lesion, with immuno-histology indicating a high-grade anaplastic astrocytoma with molecular features of glioblastoma (GBM). The patient's functional status declined precipitously in the month following her diagnostic biopsy, precluding any therapy, and the patient ultimately pursued home hospice care without further treatment. This case details the clinical management of a very rare tumor, supplementing the available literature on the progression and treatment of this rare disease.

Chiari malformation and spinal interdural cyst: A proposed association and review of the literature.

Background: Interdural cysts are rare meningeal cysts with an unclear etiology. They are often mistaken for other mass lesions, including arachnoid cysts and tumors. Correctly identifying and classifying these cysts, as well as how they have formed in individual patients, are crucial to providing effective treatment options for patients. Case Description: We report a case of a patient with shunted idiopathic intracranial hypertension who developed a symptomatic Chiari malformation and was subsequently discovered to have a spinal interdural cyst. The Chiari malformation was likely due to intracranial hypotension secondary to lumbar cerebrospinal fluid (CSF) diversion. Once the shunt was removed, a spinal interdural cyst became clinically and radiographically evident, and the Chiari resolved, suggesting that both entities were effects of shared CSF flow dynamics. Conclusion: This cyst likely originated due to the trauma from remote repeated lumbar punctures and lumboperitoneal shunt placement, allowing CSF to enter the interdural space after the catheter was removed.

Differential Patterns of Referral to Neurosurgery: A Comparison of Allopathic Physicians, Osteopathic Physicians, Nurse Practitioners, Physician Assistants, and Chiropractors.

BACKGROUND: Rising cost and limited resources remain major challenges to U.S. health care and neurosurgery in particular. To ensure an efficient and cost-effective health care system, it is important that referrals to neurosurgery clinics are appropriate, and that referred patients have a reasonably high probability of requiring surgical intervention or, at a minimum, ongoing neurosurgical follow-up. This retrospective study tests the null hypothesis that the probability of a referred patient requiring surgery is independent of referring provider credentials and referring service specialty. METHODS: A database of all patients referred to the neurosurgery clinic from 2015 through 2018 (n = 5677) was reviewed; the database included referring provider, referring provider specialty, number of subsequent clinic visits, and outcome of surgery or no surgery. Associations between categorical variables were tested using a χ2 analysis with post hoc relative risk (RR) calculations and binary logistical regression. RESULTS: Compared with patients referred by allopathic physicians, patients referred by osteopathic physicians (RR, 0.63; 95% confidence interval [CI], 0.48-0.84) and those referred by nurse practitioners (RR, 0.66; 95% CI, 0.51-0.86) were significantly less likely to require surgery. Probability of surgical intervention also varied by referrer specialty. Patients referred by neurologists required surgery 35% of the time, whereas patients referred by family practitioners required surgery 19% of the time, and patients referred by pediatricians required surgery only 7% of the time (P < 0.01). Binary logistic regression revealed that referrals from nurse practitioners and osteopathic physicians were independently associated with a decreased probability of surgical intervention. CONCLUSIONS: Our data strengthen the concept of having interdisciplinary teams led by physicians at the primary care level to ensure appropriate referrals. Training and adherence to guidelines must continually be reinforced to ensure proper referrals.

Triacetin-based acetate supplementation as a chemotherapeutic adjuvant therapy in glioma.

Cancer is associated with epigenetic (i.e., histone hypoacetylation) and metabolic (i.e., aerobic glycolysis) alterations. Levels of N-acetyl-L-aspartate (NAA), the primary storage form of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis to generate acetate, are reduced in glioma; yet, few studies have investigated acetate as a potential therapeutic agent. This preclinical study sought to test the efficacy of the food additive Triacetin (glyceryl triacetate, GTA) as a novel therapy to increase acetate bioavailability in glioma cells. The growth-inhibitory effects of GTA, compared to the histone deacetylase inhibitor Vorinostat (SAHA), were assessed in established human glioma cell lines (HOG and Hs683 oligodendroglioma, U87 and U251 glioblastoma) and primary tumor-derived glioma stem-like cells (GSCs), relative to an oligodendrocyte progenitor line (Oli-Neu), normal astrocytes, and neural stem cells (NSCs) in vitro. GTA was also tested as a chemotherapeutic adjuvant with temozolomide (TMZ) in orthotopically grafted GSCs. GTA-induced cytostatic growth arrest in vitro comparable to Vorinostat, but, unlike Vorinostat, GTA did not alter astrocyte growth and promoted NSC expansion. GTA alone increased survival of mice engrafted with glioblastoma GSCs and potentiated TMZ to extend survival longer than TMZ alone. GTA was most effective on GSCs with a mesenchymal cell phenotype. Given that GTA has been chronically administered safely to infants with Canavan disease, a leukodystrophy due to ASPA mutation, GTA-mediated acetate supplementation may provide a novel, safe chemotherapeutic adjuvant to reduce the growth of glioma tumors, most notably the more rapidly proliferating, glycolytic and hypoacetylated mesenchymal glioma tumors.

Treatment of indolent, nonencapsulated cryptococcal meningitis associated with hydrocephalus.

Infection with cryptococcal meningitis is uncommon in immunocompetent patients. The major virulence factor is the polysaccharide capsule, while nonencapsulated mutants are generally considered nonpathogenic. The authors present a case of hydrocephalus caused by meningitis from an indolent, nonencapsulated Cryptococcus sp. requiring placement and multiple revisions of a ventriculoperitoneal shunt (VPS). The patient presented with progressively worsening occipital headaches. Computed tomography and magnetic resonance imaging showed significant hydrocephalus with no apparent cause. Her symptoms initially resolved after placement of a VPS, but returned four months later. Cultures of the shunt tubing and cerebrospinal fluid (CSF) showed no bacterial infection. When the symptoms failed to resolve, CSF fungal culture revealed Cryptococcus-like yeast, although the organisms were nonencapsulated, and the cryptococcal antigen was negative. After antibiotic therapy, the symptoms resolved. The unusual clinical presentation delayed the diagnosis, highlighting the importance of understanding the detection, diagnosis, and treatment of meningeal infections caused by C. neoformans.

Increased rate of complications on a neurological surgery service after implementation of the Accreditation Council for Graduate Medical Education work-hour restriction.

OBJECT: The Accreditation Council for Graduate Medical Education instituted mandatory 80-hour work-week limitations in July 2003. The work-hour restriction was met with skepticism among the academic neurosurgery community and is thought to represent a barrier to teaching, ultimately compromising patient care. The authors hypothesize that the introduction of the mandatory resident work-hour restriction corresponds with an overall increase in morbidity rate. METHODS: This study compares the morbidity and mortality rates on an academic neurological surgery service before and after institution of the work-hour restriction. Complications are individually assessed at a monthly divisional conference by neurosurgical faculty and residents. A prospective database was commenced in July 2000 recording all complications, complications that were deemed to be potentially avoidable ("possibly preventable"), and complications that were deemed unavoidable. The incidence of morbidity and mortality from July 2000 to June 2003 is compared with the incidence from July 2003 to June 2006. RESULTS: The overall rate of morbidity and mortality increased from 103 to 114 per 1000 patients treated after institution of the work-hour restriction, although this increase was not statistically significant (χ(2)(1, N = 8546) = 2.6, p = 0.106). The morbidity rate increased from 70 to 89 per 1000 patients treated after institution of the work-hour restriction (χ(2)(1, N = 8546) = 10, p = 0.001). The overall mortality rate was diminished from 32 to 27 per 1000 patients treated after institution of the work-hour restriction (χ(2)(1, N = 8546) = 3.2, p = 0.075). Morbidities considered avoidable or possibly preventable were seen to increase from 56 to 66 per 1000 patients treated (χ(2)(1, N = 8546) = 5.7, p = 0.017). Avoidable or possibly preventable mortalities numbered 3 per 1000 patients treated, and this rate did not change after introduction of the work-hour restriction (χ(2)(1, N = 8546) = 0.08, p = 0.777). CONCLUSIONS: The morbidity rate on a neurological surgery service is increased after implementation of the work-hour restriction. Mortality rates remain unchanged.

Cortical evoked potentials used for placement of a laminotomy lead array: a case report.

OBJECTIVE: We describe a technique for placement of a cervical spinal cord electrode under general anesthesia using the contacts as cortical evoked potential stimulating electrodes. METHODS: A 37-year-old man required revision of the percutaneous lead of a spinal cord stimulator system placed for right upper extremity pain. A Resume-TL laminotomy lead was inserted at the C5-6 interspace in the prone position under general anesthesia. The contacts were functionally over the right dorsal column by evoked potential recording, despite the apparent midline position of the lead. RESULTS: Postoperatively, the patient had excellent coverage and pain relief at the right shoulder and extremity. There was no stimulation perceived on the left side of the body. CONCLUSION: This technique allows for intraoperative testing under general anesthesia in laminotomy lead placement to localize the optimal position of the lead.

Radiographically distinct variant of pilocytic astrocytoma: a case series.

The imaging findings of pilocytic astrocytomas are classically described as a cyst with an enhancing mural nodule. We report 2 unusual cases of multicystic cerebellar midline masses that were proven to be pilocytic astrocytomas. The uniqueness of the imaging features in these cases may represent an important variant of pilocytic astrocytomas. Recognition of this variant may prevent an unnecessary workup to exclude other etiologies such as parasitic infection (ie, cysticercosis) or cystic metastatic disease.

Use of an artificial neural network to predict head injury outcome.

OBJECT: The authors describe the artificial neural network (ANN) as an innovative and powerful modeling tool that can be increasingly applied to develop predictive models in neurosurgery. They aimed to demonstrate the utility of an ANN in predicting survival following traumatic brain injury and compare its predictive ability with that of regression models and clinicians. METHODS: The authors designed an ANN to predict in-hospital survival following traumatic brain injury. The model was generated with 11 clinical inputs and a single output. Using a subset of the National Trauma Database, the authors "trained" the model to predict outcome by providing the model with patients for whom 11 clinical inputs were paired with known outcomes, which allowed the ANN to "learn" the relevant relationships that predict outcome. The model was tested against actual outcomes in a novel subset of 100 patients derived from the same database. For comparison with traditional forms of modeling, 2 regression models were developed using the same training set and were evaluated on the same testing set. Lastly, the authors used the same 100-patient testing set to evaluate 5 neurosurgery residents and 4 neurosurgery staff physicians on their ability to predict survival on the basis of the same 11 data points that were provided to the ANN. The ANN was compared with the clinicians and the regression models in terms of accuracy, sensitivity, specificity, and discrimination. RESULTS: Compared with regression models, the ANN was more accurate (p < 0.001), more sensitive (p < 0.001), as specific (p = 0.260), and more discriminating (p < 0.001). There was no difference between the neurosurgery residents and staff physicians, and all clinicians were pooled to compare with the 5 best neural networks. The ANNs were more accurate (p < 0.0001), more sensitive (p < 0.0001), as specific (p = 0.743), and more discriminating (p < 0.0001) than the clinicians. CONCLUSIONS: When given the same limited clinical information, the ANN significantly outperformed regression models and clinicians on multiple performance measures. While this paradigm certainly does not adequately reflect a real clinical scenario, this form of modeling could ultimately serve as a useful clinical decision support tool. As the model evolves to include more complex clinical variables, the performance gap over clinicians and logistic regression models will persist or, ideally, further increase.

A case-comparison study of the subdural evacuating port system in treating chronic subdural hematomas.

OBJECT: The Subdural Evacuating Port System (SEPS) was recently introduced as a novel method of treating chronic subdural hematomas (SDHs). This system is a variation of the existing twist-drill craniostomy methods for treating chronic SDH. Compared with craniotomy or bur hole treatment of chronic SDH, this system offers the possibility of treatment at bedside without general anesthesia. In comparison with existing twist-drill methods, the system theoretically offers the advantage of a hermetically closed system that can evacuate a hematoma without an intracranial catheter. METHODS: The authors performed a case-control study of all chronic SDHs treated at a single institution over a 5-year period and compared the efficacy and safety of the SEPS to bur hole evacuation. Patients were matched for age, injury mechanism, medical comorbidities, use of anticoagulation, and radiographic appearance of the SDH. The primary outcome of interest was the recurrence rate in each group, which was evaluated by radiographic evidence as well as the number of patients requiring a second procedure. Secondary outcomes examined were mortality, infection, acute hematoma formation, seizure, length of hospital stay, length of intensive care unit stay, and discharge location. RESULTS: The authors found that there were no appreciable differences in symptoms on presentation, existing comorbidities, home medications, or laboratory values between the treatment groups. The average Hounsfield units of preoperative CT scanning was similar in both groups. Radiographic recurrence was statistically similar between the SEPS group (25.9%) and the bur hole group (18.5%; p = 0.37). Although there was a trend toward higher reoperation rates in the SEPS group, the need for a subsequent procedure was also statistically similar between the SEPS group (25.9%) and the bur hole group (14.8%; p = 0.25). The mortality rate was not significantly different between the SEPS group (9.5%) and the bur hole group (4.8%; p = 0.50). The SEPS procedure provided a mean reduction in SDH thickness of 27.3% compared with 37.9% with bur hole (p = 0.05) when comparing the preoperative CT scan with the first postoperative CT scan. The percentage of reduction in SDH thickness when comparing the preoperative CT scan with the most recent postoperative CT scan was 40.5% in the SEPS group and 45.4% in the bur hole group (p = 0.31). CONCLUSIONS: The SEPS offers an alternative type of twist-drill craniostomy for the treatment of chronic SDH with a trend toward higher recurrence in our experience. The efficacy and safety of SEPS is similar to that of other twist-drill methods reported in the literature. In the authors' experience, the efficacy of this treatment as measured by radiographic worsening or the need for a subsequent procedure is statistically similar to that of bur hole treatment. There was no difference in mortality or other adverse outcomes associated with SEPS.

Ca(v)1.2 splice variant with exon 9* is critical for regulation of cerebral artery diameter.

L-type voltage-dependent Ca(2+) channels (VDCCs) are essential for numerous processes in the cardiovascular and nervous systems. Alternative splicing modulates proteomic composition of Ca(v)1.2 to generate functional variation between channel isoforms. Here, we describe expression and function of Ca(v)1.2 channels containing alternatively spliced exon 9* in cerebral artery myocytes. RT-PCR showed expression of Ca(v)1.2 splice variants both containing (alpha(1)C(9/9*/10)) and lacking (alpha(1)C(9/10)) exon 9* in intact rabbit and human cerebral arteries. With the use of laser capture microdissection and RT-PCR, expression of mRNA for both alpha(1)C(9/9*/10) and alpha(1)C(9/10) was demonstrated in isolated cerebral artery myocytes. Quantitative real-time PCR revealed significantly greater alpha(1)C(9/9*/10) expression relative to alpha(1)C(9/10) in intact rabbit cerebral arteries compared with cardiac tissue and cerebral cortex. To demonstrate a functional role for alpha(1)C(9/9*/10), smooth muscle of intact cerebral arteries was treated with antisense oligonucleotides targeting alpha(1)C(9/9*/10) (alpha(1)C(9/9*/10)-AS) or exon 9 (alpha(1)C-AS), expressed in all Ca(v)1.2 splice variants, by reversible permeabilization and organ cultured for 1-4 days. Treatment with alpha(1)C(9/9*/10)-AS reduced maximal constriction induced by elevated extracellular K(+) ([K(+)](o)) by approximately 75% compared with alpha(1)C(9/9*/10-)sense-treated arteries. Maximal constriction in response to the Ca(2+) ionophore ionomycin and [K(+)](o) EC(50) values were not altered by antisense treatment. Decreases in maximal [K(+)](o)-induced constriction were similar between alpha(1)C(9/9*/10)-AS and alpha(1)C-AS groups (22.7 + or - 9% and 25.6 + or - 4% constriction, respectively). We conclude that although cerebral artery myocytes express both alpha(1)C(9/9*/10) and alpha(1)C(9/10) VDCC splice variants, alpha(1)C(9/9*/10) is functionally dominant in the control of cerebral artery diameter.

A novel association between a chronic subdural hematoma and a fibrinolytic pathway defect: case report.

OBJECTIVE: Chronic subdural hematoma (CSDH) is a common form of intracranial hemorrhage that is known to recur in up to one-fifth of treated patients. We present a patient with recurrent CSDH who was found to have a defect in the fibrinolytic pathway, which may be a novel explanation for recurrent CSDH. This defect, deficiency of plasminogen activator inhibitor type I (PAI-1), should be recognized as a possible cause of CSDH. CLINICAL PRESENTATION: A 49-year-old man presented with a CSDH, which recurred each time after 2 initially-effective craniotomies. INTERVENTION: A deficiency of PAI-1 was diagnosed after the second recurrence. We hypothesize that this defect in the fibrinolytic system contributed to the recurrent hematoma. Treatment with aminocaproic acid led to resolution of the CSDH. CONCLUSION: PAI-1 deficiency should be considered in patients with recurrent CSDH that lack another compelling explanation, particularly in patients with a family history of bleeding diatheses. PAI-1 deficiency can be identified by measuring plasma levels and can be treated with an oral course of aminocaproic acid.

A model for idiopathic intracranial hypertension and associated pathological ICP wave-forms.

Idiopathic intracranial hypertension (IIH) is a syndrome of unknown cause characterized by elevated intracranial pressure (ICP). While imaging often reveals a stenosis of the transverse sinuses, the role of this feature in IIH has been in dispute. Many patients with chronic daily headache have been found to actually be suffering from a milder form of IIH without papilledema (IIHWOP). These patients often demonstrate hypertensive B-waves and plateau-like waves upon continuous ICP monitoring. Recently, we presented modeling studies which suggest that the sinus stenosis and hypertension of IIH are physiological manifestations of a stable state of elevated pressures that exists when the transverse sinus is sufficiently collapsible. Many of the features of IIH were explained by this model but the prevalence of pathological ICP wave-forms observed in IIHWOP remained unresolved. The model presented here is a modified version of a previous model with a semi-collapsible sinus represented by a refined downstream Starling-like resistor based on experimental data. The qualitative behavior of this model is presented in terms of the collapsibility of the transverse sinus. For a sufficiently rigid sinus, there is a unique stable state of normal pressures. As the degree of collapsibility increases, there is a Hopf bifurcation, the normal state becomes unstable, low-frequency, high-amplitude ICP waves prevail, and small perturbations can lead to hypertensive ICP spikes. As the collapsibility increases further, so does the duration of the waves, until they are replaced by two stable states: one of normal pressures and one of elevated pressures. In this parameter domain, temporary perturbations can now cause permanent transitions between states. The model presented here retains the capability of our previous model to elucidate many features of IIH and additionally provides insight into the prevalence of the low-frequency, high-amplitude waves observed in IIHWOP.

Modeling intracranial pressures in microgravity: the influence of the blood-brain barrier.

INTRODUCTION: A majority of astronauts experience symptoms of headache, vomiting, nausea, lethargy, and gastric discomfort during the first few hours or days after entering a microgravity environment. Due to similarities in symptoms and their time evolution, it has been hypothesized that some of these conflicts are related to the development of benign intracranial hypertension in these individuals in microgravity. METHODS: This hypothesis was tested using a validated mathematical model that embeds the intracranial system in whole-body physiology. This model was used to predict steady-state intracranial pressures in response to various cardiovascular stimuli associated with microgravity, including changes in arterial pressure, central venous pressure, and blood colloid osmotic pressure. The model also allowed alterations of the blood-brain barrier due to factors such as gravitational unloading and increased exposure to radiation in space to be considered. RESULTS: Simulations predicted that intracranial pressure will increase significantly if, combined with a drop in blood colloid osmotic pressure, there is a reduction in the integrity of the blood-brain barrier in microgravity. DISCUSSION: These results suggest that in some otherwise healthy individuals microgravity environments may elevate intracranial pressure to levels associated with benign intracranial hypertension, producing symptoms that can adversely affect crew health and performance.

Treatment of single brain metastasis with resection, intracavity carmustine polymer wafers, and radiation therapy is safe and provides excellent local control.

PURPOSE: To define the safety and efficacy of carmustine polymer wafers when added to a regimen of surgery and external beam radiotherapy for treatment of a single brain metastasis. EXPERIMENTAL DESIGN: Adult patients underwent craniotomy for a single brain metastasis, and carmustine polymer wafers were placed in the tumor resection cavity. Patients then received whole-brain radiotherapy and were followed for patterns of recurrence in the central nervous system, toxicity, and survival. RESULTS: We enrolled 25 patients with solitary brain metastases from lung (13 patients), melanoma (4 patients), breast (3 patients), and renal carcinoma (3 patients). Two patients had severe adverse events thought to be related to wafer placement, one with seizures alone, and one with seizures and subsequent respiratory compromise. Both responded to medical therapy. There were no wound infections. The local recurrence rate was surprisingly low (0%). Four patients (16%) relapsed elsewhere in the brain, and two patients (8%) relapsed in the spinal cord. Median survival was 33 weeks; 33% of patients survived 1 year, and 25% survived 2 years. CONCLUSIONS: The addition of local chemotherapy delivered via carmustine polymer wafers to a regimen of surgical resection and external beam radiotherapy was well tolerated by patients undergoing surgery for a single brain metastasis. There were no local recurrences, suggesting that this treatment further reduced the risk of local relapse.

Heparin-binding EGF-like growth factor mediates oxyhemoglobin-induced suppression of voltage-dependent potassium channels in rabbit cerebral artery myocytes.

Oxyhemoglobin (OxyHb) can suppress voltage-dependent K(+) channel (K(V)) currents through protein tyrosine kinase activation, which may contribute to cerebral vasospasm following subarachnoid hemorrhage. Here we have tested the hypothesis that shedding of heparin-binding EGF-like growth factor (HB-EGF) and the resulting activation of the tyrosine kinase EGF receptor (EGFR) underlie OxyHb-induced K(V) channel suppression in the cerebral vasculature. With the use of the conventional whole cell patch-clamp technique, two EGFR ligands, EGF and HB-EGF, were found to mimic OxyHb-induced K(V) suppression in rabbit cerebral artery myocytes. K(V) current suppression by OxyHb or EGF ligands was eliminated by a specific EGFR inhibitor, AG-1478, but was unaffected by PKC inhibition. Compounds (heparin and CRM-197) that specifically interfere with HB-EGF signaling eliminated OxyHb-induced K(V) suppression, suggesting that HB-EGF is the EGFR ligand involved in this pathway. HB-EGF exists as a precursor protein that, when cleaved by matrix metalloproteases (MMPs), causes EGFR activation. MMP activation was detected in OxyHb-treated arteries by gelatin zymography. Furthermore, the MMP inhibitor (GM-6001) abolished OxyHb-induced K(V) current suppression. We also observed K(V) current suppression due to EGFR activation in human cerebral artery myocytes. In conclusion, these data demonstrate that OxyHb induces MMP activation, causing HB-EGF shedding and enhanced EGFR activity, ultimately leading to K(V) channel suppression. We propose that EGFR-mediated K(V) suppression contributes to vascular pathologies, such as cerebral vasospasm, and may play a more widespread role in the regulation of regional blood flow and peripheral resistance.

A modeling study of idiopathic intracranial hypertension: etiology and diagnosis.

OBJECTIVE: To investigate the relationship between idiopathic intracranial hypertension (IIH) and transverse sinus stenosis through experiments performed on a validated mathematical model. METHODS: A mathematical model of intracranial pressure (ICP) dynamics has been extended to accommodate venous sinus compression through the introduction of a Starling-like resistor between the sagittal and transverse sinuses. RESULTS: In the absence of this type of resistor, the sinuses are rigid, and the model has only a unique, stable steady state with normal pressures. With resistance a function of the external pressure on the sinus, a second stable steady state may exist. This state is characterized by elevated ICP concurrent with a compressed transverse sinus. Simulations predict that a temporary perturbation that causes a transient elevation of ICP can induce a permanent transition from the normal to the higher steady state. Comparisons to clinical data from IIH patients provide supporting evidence for the validity of the model's predictions. Simulations suggest a possible clinical diagnostic technique to determine if an individual has a compressible transverse sinus and is at risk for developing IIH. CONCLUSIONS: Results of the model experiments suggest that the primary cause of IIH may be a compressible, as opposed to rigid, transverse sinus, and that the observed stenosis is a necessary characteristic of the elevated pressure state.

Idiopathic intracranial hypertension and transverse sinus stenosis: a modelling study.

Idiopathic intracranial hypertension (IIH) is a syndrome of unknown etiology characterized by elevated intracranial pressure (ICP). Although a stenosis of the transverse sinus has been observed in many IIH patients, the role this feature plays in IIH is in dispute. In this paper, a lumped-parameter model is developed for the purpose of analytically investigating the elevated pressures associated with IIH and a collapsible transverse sinus. This analysis yields practical predictions regarding the degree of elevated ICPs and the effectiveness of various treatment methods. Results suggest that IIH may be caused by a sufficiently collapsible transverse sinus, but it is also possible that a stenosed sinus may persist following resolution of significant intracranial hypertension.

Oxyhemoglobin-induced suppression of voltage-dependent K+ channels in cerebral arteries by enhanced tyrosine kinase activity.

Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) has devastating consequences. Oxyhemoglobin (oxyhb) has been implicated in SAH-induced cerebral vasospasm as it causes cerebral artery constriction and increases tyrosine kinase activity. Voltage-dependent, Ca(2+)-selective and K(+)-selective ion channels play an important role in the regulation of cerebral artery diameter and represent potential targets of oxyhb. Here we provide novel evidence that oxyhb selectively decreases 4-aminopyridine sensitive, voltage-dependent K(+) channel (K(v)) currents by approximately 30% in myocytes isolated from rabbit cerebral arteries but did not directly alter the activity of voltage-dependent Ca(2+) channels or large conductance Ca(2+)-activated (BK) channels. A combination of tyrosine kinase inhibitors (tyrphostin AG1478, tyrphostin A23, tyrphostin A25, genistein) abolished both oxyhb-induced suppression of K(v) channel currents and oxyhb-induced constriction of isolated cerebral arteries. The K(v) channel blocker 4-aminopyridine also inhibited oxyhb-induced cerebral artery constriction. The observed oxyhb-induced decrease in K(v) channel activity could represent either channel block, or a decrease in K(v) channel density on the plasma membrane. To explore whether oxyhb altered trafficking of K(v) channels to the plasma membrane, we used an antibody generated against an extracellular epitope of K(v)1.5 channels. In the presence of oxyhb, staining of K(v)1.5 on the plasma membrane surface was markedly reduced. Furthermore, oxyhb caused a loss of spatial distinction between staining with K(v)1.5 and the general anti-phosphotyrosine antibody PY-102. We propose that oxyhb-induced suppression of K(v) currents occurs via a mechanism involving enhanced tyrosine kinase activity and channel endocytosis. This novel mechanism may contribute to oxyhb-induced cerebral artery constriction following SAH.