Nicholas C. Bambakidis

Intracranial Complications of Frontal Sinusitis in Children: Pott’s Puffy Tumor Revisited

The objective of the present study is to describe the diagnosis and treatment of intracranial complications of frontal sinusitis (Pott’s puffy tumor) in a series of pediatric patients at our institution. A rare entity, Pott’s puffy tumor has been reported in only 21 pediatric cases in the literature of the antibiotic era. The hospital records and radiographic files at Rainbow Babies and Childrens Hospital, Cleveland, Ohio, USA, over the previous 16 years were retrospectively reviewed in a search for patients with the diagnosis of Pott’s puffy tumor, defined as scalp swelling and associated intracranial infection. There were 6 male patients and 1 female patient. Ages ranged from 11 to 18 years (median 14.5 years). Intracranial infections consisted of epidural abscess in 5 patients, subdural empyema in 4 and brain abscess in 1. Intraoperative cultures grew anaerobic organisms in 1 patient, microaerophilic streptococcus in 5 patients, Klebsiella species in 1 patient and Streptococcus pneumoniae in another. All patients presented with frontal scalp swelling, and other common symptoms included headache, fever, nasal drainage and frontal sinus tenderness. Five patients were treated with antibiotics prior to their presentation. Four patients presented with neurologic decompensation characterized by varying degrees of hemiparesis, obtundation, pupillary dilatation or aphasia. All patients underwent craniotomy and evacuation of the intracranial infection. Even severely impaired patients demonstrated full neurologic recovery. Despite the widespread use of antibiotics, neurosurgical complications of sinusitis continue to occur. A high degree of suspicion, along with prompt neurosurgical intervention and the use of appropriate antibiotics, can result in favorable outcomes in even the sickest patients.

Atypical teratoid/rhabdoid tumors of the central nervous system: clinical, radiographic and pathologic features.

Introduction: Atypical teratoid/rhabdoid tumors (ATT/RT) of the central nervous system (CNS) are uncommon malignancies of childhood with an aggressive course and a uniformly fatal outcome. Methods: The medical records, radiographic images and pathologic files at the Rainbow Babies and Childrens Hospital over the previous 6 years were retrospectively reviewed. Results: Eight children underwent surgery for CNS ATT/RT at our institution since 1996. There were 6 boys and 2 girls. Median age at presentation was 21 months. Four tumors had multifocal disease at the time of diagnosis. Six patients received multiagent chemotherapy including 3 patients with autologous bone marrow transplantation, and 6 patients received radiation therapy. Median survival was 9 months from the time of diagnosis. Conclusions: In spite of aggressive therapy, the prognosis for ATT/RT remains dismal. The search for effective treatment strategies will require a better understanding of the biology and molecular genetics of this tumor.

Differential grading of endolymphatic sac tumor extension by virtue of von Hippel-Lindau disease status.

Objective: Endolymphatic sac tumors are aggressive papillary tumors of the temporal bone frequently associated with von Hippel-Lindau disease. The goal of this study was to use a newly devised classification system as a means to analyze differences between endolymphatic sac tumor extension in von Hippel-Lindau disease and non–von Hippel-Lindau disease patients. Methods: Previously reported cases of endolymphatic sac tumor and two new cases were retrospectively reviewed and assigned to a new classification system consisting of four grades based on tumor extent and location. Results: Mean age of 103 patients without von Hippel-Lindau disease was 52.5 years, whereas in 46 patients with VHL the mean age was 31.3 years. Patients with von Hippel-Lindau disease were more likely to be female (female-to male ratio of 2:1 for von Hippel-Lindau disease patients versus 1:1 for non–von Hippel-Lindau disease patients). Symptoms consisted of hearing loss (100% [mean duration, 10 yr] for VHL patients versus 97% [mean duration, 7.8 yr] for non–von Hippel-Lindau disease patients), facial weakness (38% versus 49%), and tinnitus or vertigo (41% versus 60%). Bilateral tumors were common in von Hippel-Lindau disease patients (28% versus 1%). Tumors in von Hippel-Lindau disease patients were significantly more likely to be lower grade than tumors in non–von Hippel-Lindau disease patients (Grade I, 40% versus 25%; Grade II, 50% versus 58%; Grade III, 8% versus 14%; and Grade IV, 2% versus 4%; p < 0.05). Before 1988, there were relatively fewer Grade I (15% versus 33%) and relatively more Grade II (69% versus 47%) endolymphatic sac tumors in non–von Hippel-Lindau disease patients than after 1988. Conclusions: Increased usefulness of intracranial imaging since 1988 has led to the diagnosis of sporadic endolymphatic sac tumors with lower grades. Surveillance imaging in von Hippel-Lindau disease may account for the greater proportion of endolymphatic sac tumors diagnosed with lower grades. Endolymphatic sac tumors associated with a diagnosis of von Hippel-Lindau disease appear to affect a younger population of patients than non–von Hippel-Lindau disease cases and occur in women twice as often as in men when associated with von Hippel-Lindau disease. In addition, tumors are more frequently bilateral and less advanced in the von Hippel-Lindau disease patient as opposed to the non–von Hippel-Lindau disease patient.

Surgical technique and outcomes in the treatment of spinal cord ependymomas, part 1: intramedullary ependymomas.

BACKGROUND: Intramedullary spinal ependymomas are rare tumors. OBJECTIVE: To provide a large retrospective review in the modern neuroimaging era from a tertiary center where aggressive surgical resection is favored. METHODS: Charts of intramedullary spinal ependymomas treated between 1983 and 2006 were reviewed. RESULTS: Sixty-seven cases were reviewed. The mean age was 45.6 years (range, 11-78 years) with a male-to-female ratio of 2:1. The most common location was the cervical spine, followed by the thoracic and lumbar spine. The average duration of symptoms was 33 months, with the most common symptom being pain and/or dysesthesias, followed by weakness, numbness, and urinary or sexual symptoms. Gross total resection was achieved in 55 patients and a subtotal resection was performed in 12 patients; 9 patients were treated with adjuvant radiation therapy. Mean follow-up was 32 months. The mean McCormick neurological grade at last follow-up was 2.0. The preoperative outcome correlated significantly with postoperative outcome (P < .001). A significant number of patients who initially worsened improved at their 3-month follow-up examination. Outcomes were significantly worse in patients undergoing subtotal resection with or without radiation therapy (P < .05). There were 3 recurrences. The overall complication rate was 34%. The primary complications were wound infections or cerebrospinal fluid leaks. CONCLUSION: Spinal cord ependymomas are difficult lesions to treat. Aggressive surgical resection is associated with a high overall complication rate. However, when gross total resection can be achieved, overall outcomes are excellent and the recurrence rate is low.

Improvement of neurological recovery and stimulation of neural progenitor cell proliferation by intrathecal administration of Sonic hedgehog

OBJECT Sonic hedgehog (Shh) is a glycoprotein molecule that has been shown to be associated with the proliferative capacity of endogenous neural precursor cells during embryonic development. It has also been shown to regulate the proliferative capacity of neural stem cells in the adult subventricular zone (SVZ), which are also upregulated in animal models of ischemic stroke. In the present study, the effects of exogenous administration of intrathecal Shh protein were examined in the setting of a rodent model of ischemic stroke, with particular attention given to endogenous neural stem cell proliferation and migration as well as inducible differences in behavioral recovery. METHODS A rodent model of ischemic stroke was created using the intraluminal suture method of reversible middle cerebral artery occlusion. Animals were treated with intrathecal administration of Shh protein at 24 hours after the onset of the stroke. Behavioral testing was performed, and the animals were killed for measurements of infarct volume 7 days after stroke. Immunohistochemical staining was performed and measurements of cellular proliferation were obtained, with a focus on the proportion and distribution of neural progenitor cells in the SVZ. These values were compared across experimental groups. RESULTS Treatment with intrathecal Shh protein resulted in significant improvement in behavioral function compared with the control group, with a significant reduction of ischemic tissue in the cerebral hemisphere. An increase of nestin immunoreactive cells was observed along the SVZ. CONCLUSIONS Intrathecal Shh agonist at doses that upregulate spinal cord GLI1 transcription increases the population of neural precursor cells after spinal cord injury in adult rats. Intrathecal administration of Shh protein appears to have a neuroprotective effect in animal models of ischemic stroke and is associated with improved behavioral recovery, which may be related to its effects on neurogenesis in the SVZ and could be associated with improved functional recovery.

Quantitative comparison of Kawase's approach versus the retrosigmoid approach: implications for tumors involving both middle and posterior fossae.

OBJECTIVE Few quantitative data are available to describe Kawases exposure of the posterior fossa. We used a cadaveric model to compare Kawases and the retrosigmoid approach to the petroclival region. METHODS Eighteen cadaveric specimens were dissected and analyzed (6 retrosigmoid, 6 Kawases, and 6 retrosigmoid intradural suprameatal approaches). Clival and brainstem working areas and surgical freedom were measured. RESULTS The retrosigmoid approach provided a significantly larger clival and brainstem working area than Kawases approach. Surgical freedom at the trigeminal root entry zone, origin of the anterior inferior cerebellar artery, and Dorellos canal was equivalent across approaches. Kawases approach provided the most surgical freedom at the trigeminal porus. However, the addition of a suprameatal extension significantly improved the surgical freedom provided by the retrosigmoid approach. CONCLUSION The retrosigmoid approach is a powerful approach to lesions of the cerebellopontine angle and ventral brainstem. Lesions involving the trigeminal porus and Meckels cave can be approached through Kawases approach or a suprameatal extension of the retrosigmoid approach. Kawases approach is best suited for accessing middle fossa lesions with smaller petroclival components located above the internal auditory canal.

Peritumoral brain edema in intracranial meningiomas: the emergence of vascular endothelial growth factor-directed therapy.

Meningioma is the second most common type of adult intracranial neoplasm. A substantial subset of patients present with peritumoral brain edema (PTBE), which can cause significant morbidity via mass effect, complicate surgical management, and impact the safety of stereotactic radiosurgery. Recent studies suggest a close relationship between vascular endothelial growth factor-A (VEGF-A) expression and PTBE development in meningiomas. The authors performed a systematic review of the literature on the pathogenesis of PTBE in meningiomas, the effectiveness of steroid therapy, the role played by VEGF-A, and the current clinical evidence for antiangiogenic therapy to treat peritumoral brain edema. Mounting evidence suggests VEGF-A is secreted directly by meningioma cells to induce angiogenesis and edemagenesis of tumoral as well as peritumoral brain tissue. The VEGF-A cascade results in recruitment of cerebral-pial vessels and disruption of the tumor-brain barrier, which appear to be requisite for VEGF-A to have an edemagenic effect. Results of preliminary clinical studies suggest VEGF-directed therapy has modest activity against recurrent and progressive meningioma growth but can alleviate PTBE in some patients. A comprehensive understanding of the VEGF-A pathway and its modulators may hold the key to an effective therapeutic approach to treating PTBE associated with meningiomas. Further clinical trials with larger patient cohorts and longer follow-up periods are warranted to confirm the efficacy of VEGF-directed therapy.

Endogenous stem cell proliferation induced by intravenous hedgehog agonist administration after contusion in the adult rat spinal cord: Laboratory investigation

OBJECT Sonic hedgehog (Shh) is a glycoprotein molecule that upregulates the transcription factor Gli1. The Shh protein plays a critical role in the proliferation of endogenous neural precursor cells when directly injected into the spinal cord after a spinal cord injury in adult rodents. Small-molecule agonists of the hedgehog (Hh) pathway were used in an attempt to reproduce these findings through intravenous administration. METHODS The expression of Gli1 was measured in rat spinal cord after the intravenous administration of an Hh agonist. Ten adult rats received a moderate contusion and were treated with either an Hh agonist (10 mg/kg, intravenously) or vehicle (5 rodents per group) 1 hour and 4 days after injury. The rats were killed 5 days postinjury. Tissue samples were immediately placed in fixative. Samples were immunohistochemically stained for neural precursor cells, and these cells were counted. RESULTS Systemic dosing with an Hh agonist significantly upregulated Gli1 expression in the spinal cord (p < 0.005). After spinal contusion, animals treated with the Hh agonist had significantly more nestin-positive neural precursor cells around the rim of the lesion cavity than in vehicle-treated controls (means +/- SDs, 46.9 +/- 12.9 vs 20.9 +/- 8.3 cells/hpf, respectively, p < 0.005). There was no significant difference in the area of white matter injury between the groups. CONCLUSIONS An intravenous Hh agonist at doses that upregulate spinal cord Gli1 transcription also increases the population of neural precursor cells after spinal cord injury in adult rats. These data support previous findings based on injections of Shh protein directly into the spinal cord.

Stereotactic radiosurgery with and without embolization for intracranial arteriovenous malformations: a systematic review and meta-analysis.

OBJECT The effectiveness and risk of stereotactic radiosurgery (SRS) in the management of partially embolized intracranial arteriovenous malformations (AVMs) remain controversial. The aim of this analysis was to assess current evidence regarding the efficiency and safety of SRS for AVM patients with and without prior embolization. METHODS To compare SRS in patients with and without embolization, the authors conducted a meta-analysis of studies by searching the literature via PubMed and EMBASE for the period between January 2000 and December 2013, complemented by a hand search. Primary outcome was the rate of AVM obliteration on a 3-year follow-up angiogram. Secondary outcome was the rate of hemorrhage at 3 years after SRS. Tertiary outcome was permanent neurological deficits related to radiation-induced changes. RESULTS Ten studies eligible for analysis included 1988 patients: 593 had undergone embolization followed by SRS and 1395 had undergone SRS alone. The AVM obliteration rate was significantly lower in patients who had undergone embolization followed by SRS than in those who had undergone SRS alone (41.0% vs 59%, OR 0.46, 95% CI 0.37-0.56, p < 0.00001). However, the rates of hemorrhage (7.3% vs 5.6%, OR 1.17, 95% CI 0.74-1.83, p = 0.50) and permanent neurological deficits related to radiation-induced changes (3.3% vs 3.4%, OR 1.41, 95% CI 0.64-3.11, p = 0.39) were not significantly different between the two groups. CONCLUSIONS Embolization before SRS significantly decreases the AVM obliteration rate. However, there is no significant difference in the risk of hemorrhage and permanent neurological deficits after SRS alone and following embolization. Further validation by well-designed prospective or randomized cohort studies is still needed.

The shh signaling pathway is upregulated in multiple cell types in cortical ischemia and influences the outcome of stroke in an animal model.

Recently the sonic hedgehog (shh) signaling pathway has been shown to play an important role in regulating repair and regenerative responses after brain injury, including ischemia. However, the precise cellular components that express and upregulate the shh gene and the cellular components that respond to shh signaling remain to be identified. In this study, using a distal MCA occlusion model, our data show that the shh signal is upregulated both at the cortical area near the injury site and in the adjacent striatum. Multiple cell types upregulate shh signaling in ischemic brain, including neurons, reactive astrocytes and nestin-expressing cells. The shh signaling pathway genes are also expressed in the neural stem cells (NSCs) niche in the subventricular zone (SVZ). Conditional deletion of the shh gene in nestin-expressing cells both at the SVZ niche and at the ischemic site lead to significantly more severe behavioral deficits in these shh iKO mice after cortical stroke, measured using an automated open field locomotion apparatus (Student’s t-test, p<0.05). In contrast, animals given post-stroke treatment with the shh signaling agonist (SAG) demonstrated less deficits in behavioral function, compared to vehicle-treated mice. At 7 days after stroke, SAG-treated mice showed higher values in multiple horizontal movement parameters compared to vehicle treated mice (Student’s t-test, p<0.05) whereas there were no differences in pre-stroke measurements, (Student’s t-test, p>0.05). In summary, our data demonstrate that shh signaling plays critical and ongoing roles in response to ischemic injury and modulation of shh signaling in vivo alters the functional outcome after cortical ischemic injury.