Primary intracranial extraosseous Ewing's sarcoma of the skull base in an elderly adult: illustrative case.

BACKGROUND: Primary extraosseous intracranial Ewing's sarcoma, also known as a peripheral primitive neuroectodermal tumor or "small round blue cell tumor," is an extremely rare entity with limited representation in the literature beyond the pediatric population. OBSERVATIONS: A 67-year-old male suffering occipital headache, nausea, and gait disturbance was found to have a large, avidly contrast-enhancing cerebellopontine angle mass extending into the cervical spinal canal with associated mass effect on medulla, cerebellum, fourth ventricle, and cervical spinal cord. This mass was not present on the imaging from 8 years prior. He underwent surgical debulking and pathology results demonstrated a malignant small round cell tumor showing diffuse immunopositivity for cytokeratins, CD99 and NKX2.2 with EWRS1-FLI1 rearrangement in 84% of the nuclei confirmatory of Ewing's sarcoma. After 14 cycles of chemotherapy and 6 weeks of radiotherapy, 22 months after discovery, the patient remains in clinical and radiographic remission with complete return to his baseline functioning. LESSONS: Primary skull base extraosseous Ewing's sarcoma should be considered in the differential diagnosis even in the elderly population when imaging studies demonstrate aggressive tumor growth patterns. Tumor debulking to establish a diagnosis followed by adjuvant chemoradiation therapy can result in clinical improvement with remission.

Soft Robotic Deployable Origami Actuators for Neurosurgical Brain Retraction.

Metallic tools such as graspers, forceps, spatulas, and clamps have been used in proximity to delicate neurological tissue and the risk of damage to this tissue is a primary concern for neurosurgeons. Novel soft robotic technologies have the opportunity to shift the design paradigm for these tools towards safer and more compliant, minimally invasive methods. Here, we present a pneumatically actuated, origami-inspired deployable brain retractor aimed at atraumatic surgical workspace generation inside the cranial cavity. We discuss clinical requirements, design, fabrication, analytical modeling, experimental characterization, and in-vitro validation of the proposed device on a brain model.

Syndrome of the trephined: A rare challenge in head & neck reconstruction.

BACKGROUND: Syndrome of the trephined (ST) refers to the rare, reversible event of neurological deterioration following craniectomy. ST is also known as "sinking skin flap syndrome" and typically occurs in the weeks to months following operation. The mechanism underlying syndromic onset is poorly understood. Changes to cerebrospinal fluid flow, alteration of temperature-related perfusion, and scarring at the intracranial surgical site have all been proposed. Patients present with a variety of symptoms related to paradoxical increased intracranial pressure. Sometimes falsely attributed as a consequence of the initial cranial insult, ST is more specifically a symptomatic process resulting as direct consequence of the craniectomy procedure. With timely identification and subsequent cranioplasty, the associated neurological dysfunction can be corrected - this rectification being the primary confirmatory feature of the syndrome. CASE: A 59-year-old female was seen with regards to a wound of the temporoparietal scalp, with exposed cranial implant. She had suffered a traumatic brain injury and underwent craniectomy after a motor vehicle accident 10 years prior. Her injury was complicated by necrosis of her cranial bone flap after reimplantation and at least 10 subsequent attempts to reconstruct her wound. When delayed cranial reconstruction was attempted on two separate occasions, the patient suffered severe syndrome of the trephined and required hospitalization for symptoms of impending herniation. Ultimately, she required revision and replacement of titanium mesh and latissimus dorsi free flap for soft tissue coverage of the titanium mesh. CONCLUSION: This case presents a unique surgical challenge in that chronic infection was perpetuated by the replacement of implant material in the wound. Soft tissue reconstruction alone was not possible given the patient's severe ST. Free tissue transfer was required in order to bring vascularized myofascial tissue to prevent recolonization of the newly implanted mesh and allow the cranial wound to heal.

Multi-modality management of craniopharyngioma: a review of various treatments and their outcomes.

Craniopharyngioma is a rare tumor that is expected to occur in ∼400 patients/year in the United States. While surgical resection is considered to be the primary treatment when a patient presents with a craniopharyngioma, only 30% of such tumors present in locations that permit complete resection. Radiotherapy has been used as both primary and adjuvant therapy in the treatment of craniopharyngiomas for over 50 years. Modern radiotherapeutic techniques, via the use of CT-based treatment planning and MRI fusion, have permitted tighter treatment volumes that allow for better tumor control while limiting complications. Modern radiotherapeutic series have shown high control rates with lower doses than traditionally used in the two-dimensional treatment era. Intracavitary radiotherapy with radio-isotopes and stereotactic radiosurgery may have a role in the treatment of recurrent cystic and solid recurrences, respectively. Recently, due to the exclusive expression of the Beta-catenin clonal mutations and the exclusive expression of BRAF V600E clonal mutations in the overwhelming majority of adamantinomatous and papillary tumors respectively, it is felt that inhibitors of each pathway may play a role in the future treatment of these rare tumors.

Distinguishing grade I meningioma from higher grade meningiomas without biopsy.

BACKGROUND: Many meningiomas are identified by imaging and followed, with an assumption that they are WHO Grade I tumors. The purpose of our investigation is to find clinical or imaging predictors of WHO Grade II/III tumors to distinguish them from Grade I meningiomas. METHODS: Patients with a pathologic diagnosis of meningioma from 2002-2009 were included if they had pre-operative MRI studies and pathology for review. A Neuro-Pathologist reviewed and classified all tumors by WHO 2007. All Brain MRI imaging was reviewed by a Neuro-radiologist. Pathology and Radiology reviews were blinded from each other and clinical course. Recursive partitioning was used to create predictive models for identifying meningioma grades. RESULTS: Factors significantly correlating with a diagnosis of WHO Grade II-III tumors in univariate analysis: prior CVA (p = 0.005), CABG (p = 0.010), paresis (p = 0.008), vascularity index = 4/4: (p = 0.009), convexity vs other (p = 0.014), metabolic syndrome (p = 0.025), non-skull base (p = 0.041) and non-postmenopausal female (p = 0.045). Recursive partitioning analysis identified four categories: 1. prior CVA, 2. vascular index (vi) = 4 (no CVA), 3. premenopausal or male, vi < 4, no CVA. 4. Postmenopausal, vi < 4, no CVA with corresponding rates of 73, 54, 35 and 10% of being Grade II-III meningiomas. CONCLUSIONS: Meningioma patients with prior CVA and those grade 4/4 vascularity are the most likely to have WHO Grade II-III tumors while post-menopausal women without these features are the most likely to have Grade I meningiomas. Further study of the associations of clinical and imaging factors with grade and clinical behavior are needed to better predict behavior of these tumors without biopsy.

Predictors of functional outcome following treatment of posterior fossa arteriovenous malformations.

Posterior fossa arteriovenous malformations (AVM) present particular therapeutic challenges. Studies aimed at clarifying risk of hemorrhage focus on obliteration rates, but few have addressed functional outcomes in these patients. In this study, we aim to explore the predictors of good functional outcome for posterior fossa AVM after treatment. A retrospective review of patients diagnosed with posterior fossa AVM at our institution from 1990 to 2013 was performed, and 61 patients met the inclusion criteria. Functional outcomes were assessed using the modified Rankin Scale (mRS), and mRS ⩽ 1 was defined as good outcome. Within our cohort, 39 patients presented with hemorrhage (64.0%). Spetzler-Martin grades were I (n = 9, 14.8%), II (n = 20, 32.8%), III (n = 22, 36.1%), IV (n = 8, 13.1%), and V (n = 2, 3.3%). Patients were treated with surgery (n = 8), radiosurgery (n = 34), embolization (n = 2) or multimodal therapies (n = 8). Nine patients did not undergo treatment. Average follow-up was 41.9 months. Obliteration of AVM was confirmed in 44.3% of patients (n = 27). Forty-three patients (70.5%) achieved good functional outcomes (mRS ⩽ 1). The absence of pre-treatment symptoms (p < 0.01) and AVM obliteration (p = 0.04) were predictive of good functional outcomes. In contrast, non-hemorrhagic presentation was not a significant predictor (p = 0.60). Asymptomatic presentation and AVM obliteration are associated with good functional outcomes in patients with posterior fossa AVM. Non-hemorrhagic presentation does not necessarily predict good functional outcome. Therefore treatment should not be considered only for those who present with hemorrhage. Posterior fossa AVM should be considered for definitive treatment in order to prevent future hemorrhages and subsequent poor functional outcomes.

Intracranial microcapsule chemotherapy delivery for the localized treatment of rodent metastatic breast adenocarcinoma in the brain.

Metastases represent the most common brain tumors in adults. Surgical resection alone results in 45% recurrence and is usually accompanied by radiation and chemotherapy. Adequate chemotherapy delivery to the CNS is hindered by the blood-brain barrier. Efforts at delivering chemotherapy locally to gliomas have shown modest increases in survival, likely limited by the infiltrative nature of the tumor. Temozolomide (TMZ) is first-line treatment for gliomas and recurrent brain metastases. Doxorubicin (DOX) is used in treating many types of breast cancer, although its use is limited by severe cardiac toxicity. Intracranially implanted DOX and TMZ microcapsules are compared with systemic administration of the same treatments in a rodent model of breast adenocarcinoma brain metastases. Outcomes were animal survival, quantified drug exposure, and distribution of cleaved caspase 3. Intracranial delivery of TMZ and systemic DOX administration prolong survival more than intracranial DOX or systemic TMZ. Intracranial TMZ generates the more robust induction of apoptotic pathways. We postulate that these differences may be explained by distribution profiles of each drug when administered intracranially: TMZ displays a broader distribution profile than DOX. These microcapsule devices provide a safe, reliable vehicle for intracranial chemotherapy delivery and have the capacity to be efficacious and superior to systemic delivery of chemotherapy. Future work should include strategies to improve the distribution profile. These findings also have broader implications in localized drug delivery to all tissue, because the efficacy of a drug will always be limited by its ability to diffuse into surrounding tissue past its delivery source.

Pharmacogenomics-based RNA interference nanodelivery: focus on solid malignant tumors.

INTRODUCTION: RNA interference represents one of the most promising strategies in fighting disease. However, small RNA interference faces substantial challenges for in vivo application due to the inherent instability of the RNA interference molecule. Among the nonviral gene delivery carriers, nanoparticles have attracted interest due to their success in various model systems. Nanomaterials have unique properties compared to conventional bulk materials that may be applicable in this setting. The nanoparticle complex carrying small interference RNA can undergo surface modification to achieve targeted modification for tissue-specific delivery. However, toxicity issues of the delivery systems need to be addressed and they require a pharmacogenomic profile of their own. AREAS COVERED: The authors review pharmacogenomics, toxicogenomics, nanoparticle-based drug delivery, and small interference RNA, with a focus on how logically engineered nanoparticle delivery systems can be used for personalized medicine in malignant tumors. EXPERT OPINION: Pharmacogenomics may be helpful in addressing possible individualized drug response for both the gene silencing capability of the delivered siRNA and the nanoparticle drug delivery system as both complete and distinct units. This may be done by assessing variations in gene expressions and single nucleotide polymorphisms. Patient profiling may be key as patient noncompliance due to toxicity plays a major role in treatment failure.

Etiology and management of hyponatremia in neurosurgical patients.

Hyponatremia is the most common electrolyte disorder encountered in neurosurgical patients. The aggressive treatment of hyponatremia in this group is critical, as hyponatremia can lead to mental status changes, seizures, vasospasm, cerebral edema, and even death. When it occurs, it represents a failure of one of several homeostatic mechanisms that tightly regulate serum sodium. In these patients, hyponatremia is most commonly due to the syndrome of inappropriate antidiuretic hormone (SIADH) or cerebral salt wasting (CSW). It can be problematic to differentiate between these 2 as they share key features, including low serum sodium, low serum osmolality, a higher urine osmolality than serum osmolality, and an elevated urinary sodium concentration. Furthermore, distinctions between CSW and SIADH, namely extracellular fluid (ECF) volume and total sodium balance, are often difficult to establish. Syndrome of inappropriate antidiuretic hormone is characterized by a volume-expanded state, whereas CSW is characterized by a volume-contracted state. Determining the exact cause remains a clinical imperative as the treatment for each is different. The rate at which serum sodium is corrected must be attended to, as rapid shifts in serum sodium pose potential risk of cerebral pontine myelinolysis.

Intracranial microcapsule drug delivery device for the treatment of an experimental gliosarcoma model.

Controlled-release drug delivery systems are capable of treating debilitating diseases, including cancer. Brain cancer, in particular glioblastoma multiforme (GBM), is an extremely invasive cancer with a dismal prognosis. The use of drugs capable of crossing the blood-brain barrier has shown modest prolongation in patient survival, but not without unsatisfactory systemic, dose-limiting toxicity. Among the reasons for this improvement include a better understanding of the challenges of delivery of effective agents directly to the brain tumor site. The combination of carmustine delivered by biodegradable polyanhydride wafers (Gliadel(®)), with the systemic alkylating agent, temozolomide, allows much higher effective doses of the drug while minimizing the systemic toxicity. We have previously shown that locally delivering these two drugs leads to further improvement in survival in experimental models. We postulated that microcapsule devices capable of releasing temozolomide would increase the therapeutic capability of this approach. A biocompatible drug delivery microcapsule device for the intracranial delivery of temozolomide is described. Drug release profiles from these microcapsules can be modulated based on the physical chemistry of the drug and the dimensions of the release orifices in these devices. The drug released from the microcapsules in these experiments was the clinically utilized chemotherapeutic agent, temozolomide. In vitro studies were performed in order to test the function, reliability, and drug release kinetics of the devices. The efficacy of the temozolomide-filled microcapsules was tested in an intracranial experimental rodent gliosarcoma model. Immunohistochemical analysis of tissue for evidence of DNA strand breaks via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed. The experimental release curves showed mass flow rates of 36 µg/h for single-orifice devices and an 88 µg/h mass flow rate for multiple-orifice devices loaded with temozolomide. In vivo efficacy results showed that localized intracranial delivery of temozolomide from microcapsule devices was capable of prolonging animal survival and may offer a novel form of treatment for brain tumors.

Role of pre- and intraoperative imaging and neuronavigation in neurosurgery.

Advances in neuroimaging acquisition, computing and image processing have enabled neurosurgeons to use radiological imaging to guide both preoperative planning and intraoperative guidance. In preoperative planning, imaging may be used to evaluate surgical risks, choose the best method of intervention and select the safest surgical approach. Neuronavigation may be useful in designing the surgical flap and alerting the surgeon of surrounding anatomy. Finally, intraoperative imaging may be used to define brain shift associated with the resection of intracranial lesions, assist in more complete lesion resection, and monitor for certain intraoperative complications. In the following review, we briefly examine the history of neuroradiology for neurosurgery, neuronavigation and intraoperative imaging and trace their advances to current systems in use. We will also highlight new experimental applications of neuroimaging that are currently being refined.

Inflammation in stroke and focal cerebral ischemia.

BACKGROUND: A growing number of recent investigations have established a critical role for leukocytes in propagating tissue damage after ischemia and reperfusion in stroke. Experimental data obtained from animal models of middle cerebral artery occlusion implicate inflammatory cell adhesion molecules, chemokines, and cytokines in the pathogenesis of this ischemic damage. METHODS: Data from recent animal and human studies were reviewed to demonstrate that inflammatory events occurring at the blood-endothelium interface of the cerebral capillaries underlie the resultant ischemic tissue damage. RESULTS: After arterial occlusion, the up-regulated expression of cytokines including IL-1, and IL-6 act upon the vascular endothelium to increase the expression of intercellular adhesion molecule-1, P-selectin, and E-selectin, which promote leukocyte adherence and accumulation. Integrins then serve to structurally modify the basal lamina and extracellular matrix. These inflammatory signals then promote leukocyte transmigration across the endothelium and mediate inflammatory cascades leading to further cerebral infarction. CONCLUSIONS: Inflammatory interactions that occur at the blood-endothelium interface, involving cytokines, adhesion molecules, chemokines and leukocytes, are critical to the pathogenesis of tissue damage in cerebral infarction. Exploring these pathophysiological mechanisms underlying ischemic tissue damage may direct rational drug design in the therapeutic treatment of stroke.

Local delivery of doxorubicin for the treatment of malignant brain tumors in rats.

BACKGROUND: Local delivery of carmustine (BCNU) via biodegradable polymers has been shown to improve survival in patients with glioblastoma multiforme (GBM). In the current study, we hypothesized that local delivery of an anthracycline antibiotic, doxorubicin (DOX), might act to improve the survival of animals bearing experimental intracranial glioma. MATERIALS AND METHODS: Polyanhydride polymers (PCPP-SA), containing either 3% or 5% ADR by weight, were prepared using the mix-melt method. Forty male Fisher 344 rats received an intracranial challenge with a lethal dose of 9L gliosarcoma cells. Five days later, they received DOX or blank polymer. There were a total of four treatment groups: (1) blank polymer; (2) 3% DOX polymer; (3) 5% DOX polymer, and (4) control group with no polymer. RESULTS: Compared to control animals treated with no polymers or blank polymer, animals receiving DOX had significantly extended survival. The median survival for the control group was 21 days vs. 34 days (p < 0.01) for the 3% DOX group and 45 days (p < 0.0001) for the 5% DOX group. CONCLUSION: Doxorubicin, when delivered locally, is an effective monotherapeutic agent against experimental intracranial glioma.

Effects of hypocaloric diet on sleep in young and old rats.

Aging produces a loss in a number of behavioral and cognitive functions, including sleep. Hypocaloric diet is one of the few methods that have been shown to retard the effects due to age. However, the effects of such a diet on sleep have never been investigated. In the present study, 21 months old male F344 rats fed a 60% calorie-reduced diet continued to have a significant reduction in delta power (0.3-4 Hz EEG), less sleep following 12 h total sleep deprivation (TSD) and increased sensitivity to caffeine compared to young rats (3 months) fed a similar diet. These results indicate that caloric restriction is unable to prevent the decline in sleep that occurs with aging.