Can adjunctive therapies augment the efficacy of endovascular thrombolysis? A potential role for activated protein C.

In the management of acute ischemic stroke, vessel recanalization correlates with functional status, mortality, cost, and other outcome measures. Thrombolysis with intravenous tissue plasminogen activator has many limitations that restrict its applicability, but recent advances in the development of mechanical thrombectomy devices as well as improved systems of stroke care have resulted in greater likelihood of vessel revascularization. Nonetheless, there remains substantial discrepancy between rates of recanalization and rates of favorable outcome. The poor neurological recovery among some stroke patients despite successful recanalization confirms the need for adjuvant pharmacological therapy for neuroprotection and/or neurorestoration. Prior clinical trials of such drugs may have failed due to the inability of the agent to access the ischemic tissue beyond the occluded artery. A protocol that couples revascularization with concurrent delivery of a neuroprotectant drug offers the potential to enhance the benefit of thrombolysis. Analogs of activated protein C (APC) exert pleiotropic anti-inflammatory, anti-apoptotic, antithrombotic, cytoprotective, and neuroregenerative effects in ischemic stroke and thus appear to be promising candidates for this novel approach. A multicenter, prospective, double-blinded, dose-escalation Phase 2 randomized clinical trial has enrolled 110 patients to assess the safety, pharmacokinetics, and efficacy of human recombinant 3K3A-APC following endovascular thrombolysis. This article is part of the Special Issue entitled 'Cerebral Ischemia'.

Increasing awareness with recognition of pulsatile tinnitus for nurse practitioners in the primary care setting: A case study.

BACKGROUND AND PURPOSE: Pulsatile tinnitus is a whooshing sound heard synchronous with the heartbeat. It is an uncommon symptom affecting fewer than 10% of patients with tinnitus. It often goes unrecognized in the primary care setting. Failure to recognize this symptom can result in a missed or delayed diagnosis of a potentially life-threatening condition known as a dural arteriovenous fistula. The purpose of this case study is to provide a structured approach to the identification of pulsatile tinnitus and provide management recommendations. METHOD: A case study and review of pertinent literature. CONCLUSIONS: Pulsatile tinnitus usually has a vascular treatable cause. A comprehensive history and physical examination will alert the nurse practitioner (NP) when pulsatile tinnitus is present. Auscultation in specific areas of the head can detect audible or objective pulsatile tinnitus. Pulsatile tinnitus that is audible to the examiner is an urgent medical condition requiring immediate consultation and referral. IMPLICATIONS FOR PRACTICE: Knowledge of pulsatile tinnitus and awareness of this often treatable condition directs the NP to perform a detailed assessment when patients present with tinnitus, directs appropriate referral for care and treatment, and can reduce the risk of delayed or missed diagnosis.

Theoretical Basis of Vagus Nerve Stimulation.

Despite a myriad of medical and surgical treatments for epilepsy developed over the past few decades, a large subset of patients remains refractory to treatment. Over this time period, vagus nerve stimulation (VNS) has become an accepted and viable treatment modality for this population. Since the earliest report of VNS implantation in 1988, tens of thousands of patients worldwide have received VNS therapy, and >100,000 patient-years of experience have been accrued. The mechanisms underlying the response to VNS therapy continue to be elucidated. As understanding of the VNS mechanisms of action continues to grow, more pathologies will arise as potential treatment indications. Furthermore, current treatment populations with refractory epilepsy, depression, and inflammatory diseases may enjoy improved response to stimulation.

Combined neurothrombectomy or thrombolysis with adjunctive delivery of 3K3A-activated protein C in acute ischemic stroke.

In the treatment of acute ischemic stroke (AIS), vessel recanalization correlates with improved functional status and reduced mortality. Mechanical neurothrombectomy achieves a higher likelihood of revascularization than intravenous thrombolysis (IVT), but there remains significant discrepancy between rates of recanalization and rates of favorable outcome. The poor neurological recovery among some stroke patients despite successful recanalization confirms the need for adjuvant therapy, such as pharmacological neuroprotection. Prior clinical trials of neuroprotectant drugs failed perhaps due to inability of the agent to reach the ischemic tissue beyond the occluded artery. A protocol that couples mechanical neurothrombectomy with concurrent delivery of a neuroprotectant overcomes this pitfall. Activated protein C (APC) exerts pleiotropic anti-inflammatory, anti-apoptotic, antithrombotic, cytoprotective, and neuroregenerative effects in stroke and appears a compelling candidate for this novel approach.

Medical Management of Cerebral Vasospasm following Aneurysmal Subarachnoid Hemorrhage: A Review of Current and Emerging Therapeutic Interventions.

Cerebral vasospasm is a major source of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). Evidence suggests a multifactorial etiology and this concept remains supported by the assortment of therapeutic modalities under investigation. The authors provide an updated review of the literature for previous and recent clinical trials evaluating medical treatments in patients with cerebral vasospasm secondary to aSAH. Currently, the strongest evidence supports use of prophylactic oral nimodipine and initiation of triple-H therapy for patients in cerebral vasospasm. Other agents presented in this report include magnesium, statins, endothelin receptor antagonists, nitric oxide promoters, free radical scavengers, thromboxane inhibitors, thrombolysis, anti-inflammatory agents and neuroprotectants. Although promising data is beginning to emerge for several treatments, few prospective randomized clinical trials are presently available. Additionally, future investigational efforts will need to resolve discrepant definitions and outcome measures for cerebral vasospasm in order to permit adequate study comparisons. Until then, definitive recommendations cannot be made regarding the safety and efficacy for each of these therapeutic strategies and medical management practices will continue to be implemented in a wide-ranging manner.

Mechanical thrombectomy in acute stroke: utilization variances and impact of procedural volume on inpatient mortality.

BACKGROUND: An increasing number of endovascular mechanical thrombectomy procedures are being performed for the treatment of acute ischemic stroke. This study examines variances in the allocation of these procedures in the United States at the hospital level. We investigate operative volume across centers performing mechanical revascularization and establish that procedural volume is independently associated with inpatient mortality. METHODS: Data was collected using the Nationwide Inpatient Sample database in the United States for 2008. Medical centers performing mechanical thrombectomy were identified using International Classification of Diseases, 9th revision codes, and procedural volumes were evaluated according to hospital size, location, control/ownership, geographic characteristics, and teaching status. Inpatient mortality was compared for hospitals performing ≥10 mechanical thrombectomy procedures versus those performing<10 procedures annually. After univariate analysis identified the factors that were significantly related to mortality, multivariable logistic regression was performed to compare mortality outcome by hospital procedure volume independent of covariates. RESULTS: Significant allocation differences existed for mechanical thrombectomy procedures according to hospital size (P<.001), location (P<.0001), control/ownership (P<.0001), geography (P<.05), and teaching status (P<.0001). Substantial procedural volume was independently associated with decreased mortality (P=.0002; odds ratio 0.49) when adjusting for demographic covariates. CONCLUSIONS: The number of mechanical thrombectomy procedures performed nationally remains relatively low, with a disproportionate distribution of neurointerventional centers in high-volume, urban teaching hospitals. Procedural volume is associated with mortality in facilities performing mechanical thrombectomy for acute ischemic stroke patients. These results suggest a potential benefit for treatment centralization to facilities with substantial operative volume.

Recurrence of "cured" dural arteriovenous fistulas after Onyx embolization.

Endovascular embolization with Onyx has been increasingly used to treat intracranial and spinal dural arteriovenous fistulas (DAVFs). Several case series have been published in recent years reporting high DAVF cure rates with this technique. Although it is seldom reported, DAVF recurrence may occur despite initial "cure." The authors present 3 separate cases of a recurrent DAVF after successful transarterial Onyx embolization. Despite adequate Onyx penetration into the fistula and draining vein, these cases demonstrate that DAVF recanalization may reappear with filling from previous or newly recruited arterial feeders. Other published reports of DAVF recurrence are examined, and potential contributory factors are discussed. These cases highlight the need for awareness of this possible phenomenon and suggest that follow-up angiography should be considered in patients treated with catheter embolization.

Controversies in the neurosurgical management of cerebellar hemorrhage and infarction.

Evidence-based guidelines for the management of hemorrhagic and ischemic cerebellar stroke are sparse, and most available data come from Class III studies. As a result, opinions and practices regarding the nature and role of neurosurgical intervention vary widely. A comprehensive literature review was conducted to adjudicate several contentious issues, such as the difference in the management of cerebellar hemorrhage versus infarction, criteria for imaging to exclude an underlying structural lesion, the value of MRI for patient selection, the role of external ventricular drainage, the indications for operative management, the timing of surgical intervention, and various options of surgical technique, among others. Treatment algorithms proposed in several different studies are compared and contrasted. This analysis is concluded by a summary of the recommendations from the American Stroke Association, which advises that patients with cerebellar hemorrhage who experience neurological deterioration or who have brainstem compression and/or hydrocephalus due to ventricular obstruction should undergo surgical evacuation of the hemorrhage as soon as possible, and that initial treatment of such patients with ventricular drainage alone rather than surgical removal of the hemorrhage is not recommended.

Brain and vascular imaging of acute stroke.

Contemporary imaging technologies permit the rapid and accurate assessment of the acute stroke patient. These studies form the underpinning of all therapeutic approaches. Although unenhanced computed tomography remains the principal diagnostic examination to exclude hemorrhagic stroke, multimodal computed tomography and magnetic resonance imaging can be use to assess cerebral perfusion and may reveal the ischemic penumbra, thus leading to better patient selection for intravenous or intra-arterial reperfusion strategies.

Vagus nerve stimulation therapy in patients with autism spectrum disorder and intractable epilepsy: results from the vagus nerve stimulation therapy patient outcome registry.

OBJECT: The purpose of this study was to determine the effectiveness of vagus nerve stimulation (VNS) therapy on quality-of-life (QOL) variables among patients with both autism spectrum disorder (ASD) and persistent or recurrent intractable epilepsy. METHODS: Data were obtained from the VNS therapy patient outcome registry, which was established after US FDA approval of the VNS device in 1997 as a means of capturing open-label clinical data outside of protocol. The integrity of the systems for collecting and processing registry data was authenticated by an independent auditing agency. The effect of potential selection bias, however, remains uncertain. RESULTS: Two cohorts were compared: 1) patients with epilepsy but without ASD (non-ASD [NASD] Group, 315 patients) who were being tracked in the registry (this cohort, which was controlled for age, included patients 20 years of age or younger); and 2) patients with a diagnosis of ASD who underwent implantation of the VNS device (ASD Group, 77 patients). Differences between the ASD and NASD groups were noted in the following categories: sex (male preponderance in ASD); normal imaging results (MR imaging results normal in ASD); depression (less common in ASD); behavioral problems (more common in ASD); neurological deficit (more common in ASD); mental retardation (more common in ASD); and developmental delay. The only QOL difference between the ASD and NASD groups was noted in mood at 12 months postimplant (mood was improved in ASD) (p = 0.04). There were no other differences in the QOL variables. CONCLUSIONS: Patients with ASD and intractable epilepsy respond as favorably as all other patients receiving VNS therapy. In addition, they may experience a number of QOL improvements, some of which exceed those classically observed following placement of a VNS device.

Vagus nerve stimulation therapy after failed cranial surgery for intractable epilepsy: results from the vagus nerve stimulation therapy patient outcome registry.

OBJECTIVE: To determine the effectiveness of vagus nerve stimulation (VNS) therapy among patients with persistent or recurrent seizures after lobar resection, callosotomy, and other cranial operations for intractable epilepsy. METHODS: Data were obtained from the VNS therapy patient outcome registry, which was established after United States Food and Drug Administration approval of the VNS device in 1997 as a means of capturing open-label clinical data outside of protocol. The integrity of the systems for collecting and processing registry data was authenticated by an independent auditing agency. The effect of potential selection bias, however, remains uncertain. RESULTS: Two nonconsecutive cohorts were compared: patients tracked in the registry who had previously undergone cranial surgery for epilepsy (CS group, n=921) and those who had not (non-CS group, n = 3822). For the CS group, the median reduction in seizure frequency was 42.5% after 3 months of VNS therapy, 42.9% at 6 months, 45.7% at 12 months, 52.0% at 18 months, and 50.5% at 24 months. For the non-CS group, analogous rates were 47.0%, 52.9%, 60.0%, 62.7%, and 66.7%, respectively. In the CS group, seizures were reduced by at least 50% in 55.1% of patients, at least 75% in 31.4% of patients, at least 90% in 17.3% of patients, and 100% in 5.1% of patients after 24 months of VNS therapy. Response rates were more pronounced in the non-CS group: at least 50% in 62.2% of patients, at least 75% in 43.7% of patients, at least 90% in 26.8% of patients, and 100% in 8.3% of patients. Patients in both groups experienced marked improvements in quality of life parameters. CONCLUSION: The effectiveness of VNS is maintained during prolonged stimulation, and overall seizure control continues to improve with time. Patients in whom prior cranial surgery had failed did not respond as favorably as all other patients receiving VNS therapy. Nonetheless, many of the former group improved substantially. Thus, on the basis of these open-label data, VNS therapy represents a potentially palliative treatment option for patients with refractory seizures after failed cranial surgery.

Vagus nerve stimulation for the treatment of intractable epilepsy.

Vagus nerve stimulation is a safe and reliable treatment adjunct for patients with medically intractable epilepsy. It is both a preventive and abortive form of therapy, potentially effective against both partial and generalized seizures in adults and children. Vagus nerve stimulation also has a number of serendipitous effects on mood, memory and attention, and has been approved for the treatment of refractory depression. Owing to its pleiotropic effects, it also holds promise for several other diseases. Its principal limitations are its unknown mechanism of action, the low likelihood of complete cure and the inability to predict which patients will derive substantial benefit. This article reviews the theoretical rationale, practical background and clinical applications of vagus nerve stimulation therapy.

Percutaneous spinal interventions.

Interventional neuroradiology procedures of the spine are being performed with increasing frequency. These therapies complement and, in some cases, replace more conventional operations of the vertebral column and its contents. This article surveys the background, present application, and future horizons of several minimally invasive spinal interventions, including vertebroplasty and kyphoplasty, microcatheterization of the cervical epidural space via lumbar puncture for drug delivery, percutaneous intraspinal navigation, and percutaneous spinal fixation.

Vagus nerve stimulation therapy after failed cranial surgery for intractable epilepsy: results from the vagus nerve stimulation therapy patient outcome registry.

OBJECTIVE: To determine the effectiveness of vagus nerve stimulation (VNS) therapy among patients with persistent or recurrent seizures after lobar resection, callosotomy, and other cranial operations for intractable epilepsy. METHODS: Data were obtained from the VNS therapy patient outcome registry, which was established after United States Food and Drug Administration approval of the VNS device in 1997 as a means of capturing open-label clinical data outside of protocol. The integrity of the systems for collecting and processing registry data was authenticated by an independent auditing agency. The effect of potential selection bias, however, remains uncertain. RESULTS: Two nonconsecutive cohorts were compared: patients tracked in the registry who had previously undergone cranial surgery for epilepsy (CS group, n = 921) and those who had not (non-CS group, n = 3822). For the CS group, the median reduction in seizure frequency was 42.5% after 3 months of VNS therapy, 42.9% at 6 months, 45.7% at 12 months, 52.0% at 18 months, and 50.5% at 24 months. For the non-CS group, analogous rates were 47.0%, 52.9%, 60.0%, 62.7%, and 66.7%, respectively. In the CS group, seizures were reduced by at least 50% in 55.1% of patients, at least 75% in 31.4% of patients, at least 90% in 17.3% of patients, and 100% in 5.1% of patients after 24 months of VNS therapy. Response rates were more pronounced in the non-CS group: at least 50% in 62.2% of patients, at least 75% in 43.7% of patients, at least 90% in 26.8% of patients, and 100% in 8.3% of patients. Patients in both groups experienced marked improvements in quality of life parameters. CONCLUSION: The effectiveness of VNS is maintained during prolonged stimulation, and overall seizure control continues to improve with time. Patients in whom prior cranial surgery had failed did not respond as favorably as all other patients receiving VNS therapy. Nonetheless, many of the former group improved substantially. Thus, on the basis of these open-label data, VNS therapy represents a potentially palliative treatment option for patients with refractory seizures after failed cranial surgery.

Hydrocephalus in children with middle fossa arachnoid cysts.

OBJECT: The optimal management of children with middle fossa arachnoid cysts (MFACs) remains controversial. In this study the authors evaluated the relationship between two preoperative variables, hydrocephalus and nonspecific macrocephaly, in children undergoing fenestration of temporal arachnoid cysts and hydrocephalus-related shunt placement. METHODS: During a 16-year period, 40 children (30 boys and 10 girls) underwent treatment of MFACs. All but one patient experienced either worsening symptoms or progressive serial imaging-documented cyst enlargement. Hydrocephalus was present in six patients and nonspecific macrocephaly in another nine. The mean age at surgery was 66 months (range 1-201 months, median 36 months), and the mean follow-up duration was 54 months (range 6-83 months, median 39 months). All patients presenting with hydrocephalus required placement of a ventriculoperitoneal (VP) shunt as well as cyst fenestration, regardless of which procedure was performed first. Five patients with macroencephaly undergoing initial fenestration required subsequent VP shunt insertion. Complications of cerebrospinal fluid (CSF) diversion were typical. CONCLUSIONS: Patients with hydrocephalus or macrocephaly are likely to require VP shunt placement in addition to cyst fenestration. Children with nonspecific macrocephaly may harbor a latent derangement of CSF circulation.

Use of a screw-syringe injector for cement delivery during kyphoplasty: technical report.

OBJECTIVE: Percutaneous kyphoplasty is postulated to have several advantages over percutaneous vertebroplasty for the treatment of vertebral compression fractures and is gaining increased popularity. However, cement delivery with the KyphX kit (Kyphon, Inc., Santa Clara, CA), the only commercially available device for percutaneous kyphoplasty, is relatively problematic. This kit uses a series of "bone filler device" (BFD) tubes. Each BFD must be loaded manually with cement, which is then injected into the kyphoplasty cavity by manually depressing an inner stylet. The high profile of the BFD cannulas and their stylets requires frequent repositioning of the image intensifier tube and table. Because each accommodates only a small volume, the BFDs must be exchanged frequently. This delivery method also places the operator's hands directly in the field of radiation. We sought to overcome these limitations. METHODS: Dissatisfied with the shortcomings of the BFDs, we substituted the EZflow screw-syringe injector (Parallax Medical, Mountain View, CA) we use to deliver cement during conventional percutaneous vertebroplasty. This amalgam of the KyphX kit and the screw-syringe injector has been used for kyphoplasty treatment of 26 thoracolumbar compression fractures in 17 patients. RESULTS: The screw-syringe injector allows controlled volumetric delivery of large boluses of high-viscosity cement without having to refill the reservoir. It minimizes radiation exposure and does not require repositioning of the x-ray tubes. It may theoretically allow decompression should cement extrusion occur. Also, it delivers cement to the interstices of bony trabeculae outside the kyphoplasty cavity, thus combining the mechanical benefits of percutaneous kyphoplasty and percutaneous vertebroplasty. CONCLUSION: The use of a screw-syringe injector has several merits over the customary means of cement delivery during kyphoplasty.

Pituitary anatomy and physiology.

The pituitary has been called the master gland of the body because of its central role in governing homeostasis, maintaining the reproductive cycle, and directing the activity of other glands. Housed in the sella turcica of the sphenoid bone at the base of the skull, it has important anatomic relations with the hypothalamus, visual pathways, cavernous sinus, carotid artery, and cranial nerves. The gland originates from two discrete parts of the developing embryo. Rathke's pouch, a dorsal evagination of the stomodeum, forms the anterior and intermediate lobes. The infundibulum, a ventral extension of the diencephalon, forms the posterior lobe. The anterior, intermediate, and posterior lobes of the pituitary gland function as three separate endocrine organs, each characterized by distinct cell populations, secretory products, and regulatory mechanisms. The anterior lobe secretes thyroid stimulating hormone, corticotropin, luteinizing hormone, follicle stimulating hormone, growth hormone, and prolactin. It is regulated by the hypothalamus via the portal vascular system. The posterior lobe releases oxytocin and vasopressin from axon terminals that originate in cell bodies located in the hypothalamus. The intermediate lobe is rudimentary in human beings but produces several hormones whose physiologic significance is only now being established.

Endovascular restorative neurosurgery: a novel concept for molecular and cellular therapy of the nervous system.

The amalgam of molecular biology and neurosurgery offers immense promise for neurorestoration and the management of neurodegenerative deficiencies, developmental disorders, neoplasms, stroke, and trauma. This article summarizes present strategies for and impediments to gene therapy and stem cell therapy of the central nervous system and advances the concept of a potential new approach, namely endovascular restorative neurosurgery. The objectives of gene transfer to the central nervous system are efficient transfection of host cells, selective sustained expression of the transgene, and lack of toxicity or immune excitation. The requisite elements of this process are the identification of candidate diseases, the construction of vehicles for gene transfer, regulated expression, and physical delivery. In the selection of target disorders, the underlying genetic events to be overcome, as well as their spatial and temporal distributions, must be considered. These factors determine the requirements for the physical dispersal of the transgene, the duration of transgene expression, and the quantity of transgene product needed to abrogate the disease phenotype. Vehicles for conveying the transgene to the central nervous system include viral vectors (retroviruses, lentiviruses, adenoviruses, adeno-associated viruses, and herpes simplex virus), liposomes, and genetically engineered cells, including neural stem cells. Delivery of the transgene into the brain presents several challenges, including limited and potentially risky access through the cranium, sensitivity to volumetric changes, restricted diffusion, and the blood-brain barrier. Genetic or cellular therapeutic agents may be injected directly into the brain parenchyma (via stereotaxy or craniotomy), into the cerebrospinal fluid (in the ventricles or cisterns), or into the bloodstream (intravenously or intra-arterially). The advantages of the endovascular route include the potential for widespread distribution, the ability to deliver large volumes, limited perturbation of neural tissue, and the feasibility of repeated administration.