Musculoskeletal Pain Outcomes Pre- and Post Intrathecal Baclofen Pump Implant in Children With Cerebral Palsy: A Prospective Cohort Study.

OBJECTIVE: To characterize musculoskeletal pain intensity, duration, frequency, and interference with activities of daily living in children with cerebral palsy (CP) before and after intrathecal baclofen pump placement. DESIGN: Prospective cohort study. SETTING: Children's tertiary hospital. PARTICIPANTS: Participants were children with CP (N=32; 53% male; mean age, 9.9y; age range, 4-17y). The majority of participants had a CP diagnosis of quadriplegia (76%) and relied on wheeled mobility (91%). INTERVENTIONS: Assessments were completed pre- and post intrathecal baclofen pump implant. MAIN OUTCOME MEASURES: Because of considerable patient heterogeneity, both pain measures (Brief Pain Inventory, Dalhousie Pain Interview) were completed by proxy (parent) report at the time of the procedure and approximately 6 months after intrathecal baclofen (ITB) pump placement. RESULTS: Prior to implant, 31% of participants were living with constant pain, which reduced to 6% post ITB implant (P<.001). Based on Wilcoxon signed rank tests, pain duration significantly decreased post ITB pump implant (P<.01). CONCLUSIONS: This prospective analysis supports the anecdotal and retrospective evidence that musculoskeletal pain decreases in CP following ITB pump implant. The greatest effect appears to be on the duration of pain experience. Pain did not decrease for all individuals, and it would be worth further investigation to better understand the relation between patient characteristics and pain outcomes.

Primary closure of inadvertent durotomies utilizing the U-Clip in minimally invasive spinal surgery.

STUDY DESIGN: Retrospective clinical cohort study. OBJECTIVE: To examine performance of the U-Clip for the closure of inadvertent durotomy occurring during minimally invasive spinal surgery. SUMMARY OF BACKGROUND DATA: Primary closure of inadvertent durotomies that occur during minimally invasive spinal surgery can be technically difficult to accomplish when using standard knot-tying and suture management techniques, owing to the narrow and deep surgical corridor afforded by tubular retraction systems. The U-Clip is a novel device that can achieve tight tissue approximation without the need for knot-tying and excessive suture manipulation, making it ideally suited for use in minimally invasive spinal surgeries. METHODS: We performed a retrospective review of patients who underwent minimally invasive decompressive procedures complicated by durotomy and repaired using U-Clips for the period January 2008 to January 2010. A total of seven patients were identified. RESULTS: Four of the seven patients were male. Six patients underwent lumbar laminectomy or discectomy. One patient underwent resection of a cervical synovial cyst. In each patient, the durotomy was repaired primarily using U-Clips. All six lumbar patients were discharged home on the same day, and the remaining patient was discharged the following morning. Mean follow-up was 6.3 months. No patient experienced symptoms related to persistent cerebrospinal fluid leakage. CONCLUSION: Primary closure of an inadvertent durotomy occurring during minimally invasive spinal surgery can be effectively achieved using the self-closing U-Clip device.

Surgical management of melanoma brain metastases in patients treated with immunotherapy.

OBJECT: Despite the increasing use of immunotherapy in the treatment of metastatic melanoma, the effects of this therapy on the management of patients with associated brain metastases are not completely defined. The authors undertook this study to determine the effectiveness of resection and the effects of immunotherapy on brain metastasis management. METHODS: The authors analyzed data pertaining to consecutive patients with metastatic melanoma treated with immunotherapy within 3 months of discovery of brain metastases that were surgically resected. RESULTS: Forty-one patients (median age 44.4 years, range 19.2-63.1 years) underwent resection of 53 brain metastases (median number of metastases 1, range 1-4). The median metastasis volume was 2.5 cm(3). Fifteen patients underwent whole-brain radiation therapy (WBRT) and 26 patients did not. Duration of survival from brain metastasis diagnosis was not significantly different between patients who received WBRT (mean 24.9 months) and those who did not (mean 23.3 months) (p > 0.05). Local and distant brain recurrence rates were not statistically different between the WBRT (7.1% and 28.6%, respectively) and non-WBRT (7.7% and 41.0%) groups for the duration of follow-up (p > 0.05). An objective systemic response to immunotherapy was associated with increased duration of survival (p < 0.05). CONCLUSIONS: Resection of melanoma brain metastases in patients treated with immunotherapy provides excellent local control with low morbidity. An objective response to systemic immunotherapy is associated with a prolonged survival in patients who have undergone resection of melanoma brain metastases. Moreover, adjuvant WBRT in melanoma immunotherapy patients with limited metastatic disease to the brain does not appear to provide a significant survival benefit.

Spinal cord vascular malformations in children.

Spinal vascular malformations comprise a diverse group of abnormalities, including arteriovenous malformations (AVMs), cavernous malformations, dural arteriovenous fistulas (AVFs), and capillary telangiectasias. These conditions each have distinct causes, presentations, radiologic appearances, and natural histories. This article explores the presentation, natural history, investigation, and treatment of spinal AVMs, spinal AVFs, and spinal cavernous malformations.

The effect of a PP2A inhibitor on the nuclear receptor corepressor pathway in glioma.

OBJECT: Nuclear receptor corepressor (N-CoR) forms a complex that maintains neural stem cells in an undifferentiated state through transcriptional repression. Recently, it has been shown that N-CoR is overexpressed in glioblastoma multiforme (GBM) tumor stem cells and has a putative role in maintaining these cells in an undifferentiated immortal state. To determine the effects of disruption of N-CoR complex function by serine/threonine protein phosphatase 2A (PP2A) inhibition on GBM tumor cell differentiation and proliferation, the authors developed and investigated a competitive small molecule inhibitor (LB1) of PP2A in GBM. METHODS: The authors investigated the effects of LB1 on GBM proliferation and molecular differentiation pathways using in vitro and in vivo studies. RESULTS: The LB1 inhibited PP2A, leading to increased levels of phosphorylated Akt kinase and decreased NCoR expression, as well as dose-dependent antiproliferative activity in cultured U87 and U251 malignant glioma cells (dose range 1-10 microM). Systemic LB1 treatment (1.5 mg/kg/day for 21 days) had significant tumor antiproliferative effects in mice harboring U87 glioma xenografts (73% mean reduction in tumor volume compared with controls; p < 0.001). Moreover, a reduction in PP2A expression and activity after LB1 treatment in vivo correlated with increased Akt phosphorylation, reduced nuclear N-CoR expression and N-CoR cytoplasmic translocation, and increased accumulation of acetylated core histones, which coincided with the appearance of glial fibrillary acidic protein-expressing tumor cells. CONCLUSIONS: These findings indicate that PP2A inhibition effectively disrupts N-CoR complex function/expression and leads to cytoplasmic translocation of N-CoR with subsequent tumor cell differentiation and/or death. Therapeutic paradigms that target N-CoR function in the cancer stem cell component of malignant gliomas may have treatment utility.

Pituitary stalk hemangioblastomas in von Hippel-Lindau disease.

OBJECT: Pituitary stalk hemangioblastomas are rare, and information on them is limited to a small number of case reports. To gain insight into the incidence, clinical effects, and management of pituitary stalk hemangioblastomas, the authors analyzed a series of patients with von Hippel-Lindau (VHL) disease. METHODS: Patients with VHL disease who were enrolled in a prospective National Institutes of Health natural history study were included. Clinical, imaging, and laboratory findings were analyzed. RESULTS: Two hundred fifty patients were included in the study (120 male and 130 female patients). In 8 patients (3%), 8 pituitary stalk hemangioblastomas were identified on MR imaging. This anatomical location was the most common supratentorial site for these lesions; 29% of all supratentorial hemangioblastomas were found there. The mean (+/- standard deviation) pituitary stalk hemangioblastoma volume was 0.5 +/- 0.9 cm(3) (range 0.08-2.8 cm(3)). Results of endocrine laboratory profiles were normal in all patients. All patients remained asymptomatic and none required treatment during the follow-up period (mean duration 41.4 +/- 14.4 months). CONCLUSIONS: The pituitary stalk is the most common site for the development of supratentorial hemangioblastomas in patients with VHL disease. Pituitary stalk hemangioblastomas often remain asymptomatic and do not require treatment. These findings indicate that pituitary stalk hemangioblastomas in patients with VHL disease may be managed with observation and that surgery for them can be reserved until associated signs or symptoms occur.

Pathological satiety caused by brainstem hemangioblastoma.

Because of the multiplicity and saltatory growth pattern associated with central nervous system hemangioblastomas in von Hippel-Lindau (VHL) disease, resection of individual tumors is usually reserved until symptoms occur, to avoid unnecessary surgery over the lifetime of a patient. Brainstem hemangioblastomas in VHL typically cause lower cranial nerve dysfunction, long-tract signs, sensory impairment, and gait abnormalities. The authors report on a 16-year-old girl with VHL who presented with abnormal early satiety resulting in growth and developmental arrest associated with a growing obex hemangioblastoma. Tumor resection resulted in restoration of appetite, with rapid weight gain, growth in stature, and onset of menses. These findings indicate that caudal brainstem-mediated mechanisms have a profound effect on satiety. Moreover, brainstem hemangioblastomas may present with abnormalities in satiety and feeding that can be effectively reversed with resection.

Convection-enhanced delivery for the treatment of pediatric neurologic disorders.

Direct perfusion of specific regions of the central nervous system by convection-enhanced delivery is becoming more widely used for the delivery of compounds in the research and treatment of various neural disorders. In contrast to other currently available central nervous system delivery techniques, convection-enhanced delivery relies on bulk flow for distribution of solute. This allows for safe, targeted, reliable, and homogeneous delivery of small-molecular-weight and large-molecular-weight substances over clinically relevant volumes in a manner that bypasses the blood-central nervous system barrier. Recent studies have also shown that coinfused imaging surrogate tracers can be used to monitor and control the convective distribution of therapeutic agents in vivo. The unique features of convection-enhanced delivery, including the ability to monitor distribution in realtime, provide an opportunity to develop new research and treatment paradigms for pediatric patients with a variety of intrinsic central nervous system disorders.

Training in pediatric neurosurgery.

Pediatric neurosurgery is now a well-established subspecialty within neurosurgery with distinct training requirements and its own certification process. Currently there are over 180 diplomates of the American Board of Pediatric Neurological Surgery (ABPNS). Neurosurgeons in training get a limited and variable experience in pediatric neurosurgery over the course of their residency program. For those who decide to specialize in pediatric neurosurgery, a one year clinical fellowship following the completion of a general neurosurgical residency is recommended. The American Board of Pediatric Neurological Surgeons oversees the certification process for pediatric neurosurgeons. Board certification extends for 10 years, after which time recertification is required. The Board is not under the auspices of the Accreditation Council of Graduate Medical Education (ACGME) but is widely recognized as the pediatric neurosurgery accrediting group.

Spinal disorders associated with skeletal dysplasias and syndromes.

Skeletal dysplasias are a heterogeneous group of disorders in which there is abnormal cartilage and bone formation, growth, and remodeling. There are more than 200 described skeletal dysplasias. Skeletal dysplasias can affect the spine in various ways, with attendant neurosurgical implications for diagnosis and treatment. Craniocervical junction abnormalities, atlantoaxial subluxation, and kyphoscoliotic deformity are among the common spinal problems that are found in certain skeletal dysplasias.

Adeno-associated viral-mediated insulin-like growth factor delivery protects motor neurons in vitro.

Recent work has demonstrated that adeno-associated viral (AAV) vector-mediated delivery of the insulin-like growth factor (IGF-I) gene through retrograde axonal transport can prolong survival and delay disease onset in the superoxide dismutase mutant mouse model of motor neuron (MN) disease. The present experiment examines IGF-I gene transfer in vitro. Adenoviral and AAV vectors for IGF-I infect neurons triggering expression and secretion of biologically active IGF-I. AAV-mediated IGF-I expression in SH-SY5Y neurons protects both cells expressing the transgene, and bystanders without transgene expression from glutamate-induced apoptosis. Similarly, AAV-mediated IGF-I delivery in primary E15 MN culture provides a titer-dependent neuroprotection from glutamate-induced DNA fragmentation. Both infected and noninfected neurons are equally protected. These observations argue that vector-mediated IGF-I gene transfer induces secretion of active IGF-I that acts through direct effects on spinal cord MNs. This mechanism may explain the therapeutic effects observed in vivo despite relatively low affinity AAV spinal cord uptake.

Adeno-associated viral vector gene expression in the adult rat spinal cord following remote vector delivery.

The current investigation tests whether adeno-associated viral vectors (rAAV) undergo remote delivery to the spinal cord via peripheral nerve injection as previously demonstrated with adenoviral vectors. The sciatic nerves of adult rats (n = 10) were injected with either an rAAV (rAAVCMV-lacZ) or adenoviral (AdCMV-lacZ) vector (1.4 x 10(7) particles/ml). After 21 days, the rAAV group demonstrated significantly higher spinal cord viral expression than the adenoviral group (P < 0.024). A second group of rats was injected with rAAV expressing the green fluorescence protein (GFP) reporter gene. GFP was detected 21 days after unilateral sciatic nerve injection in the neurons of the dorsal root ganglion and spinal cord. The codistribution of the viral genome and transgene in CNS neurons was confirmed with in situ hybridization. In summary, rAAV genes are expressed in CNS neurons following peripheral nerve injection at levels exceeding those seen following remote adenovirus injection.

Intraneural colchicine inhibition of adenoviral and adeno-associated viral vector remote spinal cord gene delivery.

OBJECTIVE: The mechanism of remote viral gene delivery to the spinal cord is unknown. The present experiment demonstrates that intraneural injection of colchicine is capable of inhibiting remote delivery of both adenoviral and adeno-associated viral (AAV) vectors, implicating axonal transport in this process. METHODS: The right sciatic nerves of adult Sprague-Dawley rats were injected with phosphate-buffered saline (PBS) (n = 5) or 10 (n = 7) or 100 (n = 4) microg colchicine. Two days later, the nerves of all animals were initially injected with 1.2 x 10(7) plaque-forming units of Ad5RSVntLac-Z. Two separate groups were injected concurrently with vector and PBS (n = 5) or 10 microg colchicine (n = 5). In a second experiment, the right sciatic nerves of CD1 mice were preinjected with PBS (n = 6) or 10 microg colchicine (n = 5). Two days later, the nerves were injected with rAAVCAG-EGFPwpre (an adeno-associated vector carrying the green fluorescent protein gene). In both experiments, sciatic nerves and spinal cords were removed and analyzed for gene expression. RESULTS: Sciatic nerve vector injection resulted in expression in both the nerve injection site and neuronal cell bodies located predominantly in the ipsilateral ventral horn. Analysis of variance revealed a significant treatment effect for 10 and 100 microg intraneural colchicine with inhibition of remote adenoviral delivery at 10 microg and blockade of remote delivery at 100 microg (P < 0.001). Colchicine injection concurrent with and before vector injection had similar inhibitory effects. Two-way analysis of variance revealed significant colchicine inhibition of remote delivery in both adenovirus- and AAV-injected animals (P < 0.003) but no dose-by-vector interaction, suggesting that both vectors are equally inhibited by colchicine. CONCLUSION: Colchicine inhibits remote spinal cord delivery of adeno-associated and adenoviral vectors in a dose-dependent manner, suggesting that remote delivery is dependent on retrograde axonal transport.

Angiotropic large cell lymphoma with imaging characteristics of CNS vasculitis.

This report documents a case of angiotropic large cell lymphoma (ALCL) with imaging characteristics of CNS vasculitis. A 47-year-old man was unresponsive after a 5-month progression of neurologic deterioration and intermittent fevers. MR imaging revealed multiple areas of abnormally increased T2 signal intensity in the cerebral cortex and subcortical white matter. Despite corticosteroid treatment for presumed CNS vasculitis, the patient died. Necropsy revealed a diffuse intravascular malignant mononuclear proliferation consistent with ALCL.