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Prospective multicenter studies in pediatric hydrocephalus

JNSPG 75th Anniversary Invited Review Article

John R. W. Kestle and Jay Riva-Cambrin

Prospective multicenter clinical research studies in pediatric hydrocephalus are relatively rare. They cover a broad spectrum of hydrocephalus topics, including management of intraventricular hemorrhage in premature infants, shunt techniques and equipment, shunt outcomes, endoscopic treatment of hydrocephalus, and prevention and treatment of infection. The research methodologies include randomized trials, cohort studies, and registry-based studies. This review describes prospective multicenter studies in pediatric hydrocephalus since 1990. Many studies have included all forms of hydrocephalus and used device or procedure failure as the primary outcome. Although such studies have yielded useful findings, they might miss important treatment effects in specific subgroups. As multicenter study networks grow, larger patient numbers will allow studies with more focused entry criteria based on known and evolving prognostic factors. In addition, increased use of patient-centered outcomes such as neurodevelopmental assessment and quality of life should be measured and emphasized in study results. Well-planned multicenter clinical studies can significantly affect the care of children with hydrocephalus and will continue to have an important role in improving care for these children and their families.

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Kristine Ravina, Ben A. Strickland, Robert C. Rennert, Joseph N. Carey and Jonathan J. Russin

Graft stenosis and occlusion remain formidable complications in cerebral revascularization procedures, which can lead to significant morbidity and mortality. Graft vasospasm can result in early postoperative graft stenosis and occlusion and is believed to be at least partially mediated through adrenergic pathways. Despite various published treatment protocols, there is no single effective spasmolytic agent. Multiple factors, including anatomical and physiological variability in revascularization conduits, patient age, and comorbidities, have been associated with graft vasospasm pathogenesis and response to spasmolytics. The ideal spasmolytic agent thus likely needs to target multiple pathways to exert a generalizable therapeutic effect. Botulinum toxin (BTX)–A is a powerful neurotoxin widely used in clinical practice for the treatment of a variety of spastic conditions. Although its commonly described paradigm of cholinergic neural transmission blockade has been widely accepted, evidence for other mechanisms of action including inhibition of adrenergic transmission have been described in animal studies. Recently, the first pilot study demonstrating clinical use of BTX-A for cerebral revascularization graft spasm prevention has been reported. In this review, the mechanistic basis and potential future clinical role of BTX-A in graft vasospasm prevention is discussed.

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Danielle Golub, Lizbeth Hu, Siddhant Dogra, Jose Torres and Maksim Shapiro

Spontaneous cervical artery dissection (sCAD) is a major cause of stroke in young adults. Multiple sCAD is a rarer, more poorly understood presentation of sCAD that has been increasingly attributed to cervical trauma such as spinal manipulation or genetic polymorphisms in extracellular matrix components. The authors present the case of a 49-year-old, otherwise healthy woman, who over the course of 2 weeks developed progressive, hemodynamically significant, bilateral internal carotid artery and vertebral artery dissections. Collateral response involved extensive external carotid artery–internal carotid artery anastomoses via the ophthalmic artery, which were instrumental in maintaining perfusion because circle of Willis and leptomeningeal anastomotic responses were hampered by the dissection burden in the corresponding collateral vessels. Endovascular intervention by placement of Pipeline embolization devices and Atlas stents in bilateral internal carotid arteries was successfully performed. No syndromic or systemic etiology was discovered during a thorough workup.

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Soichi Oya, Masahiro Indo, Masabumi Nagashima and Toru Matsui

Aneurysms at the distal portion of the superior cerebellar artery (SCA) are very rare. Because of the deep location and a propensity for nonsaccular morphology, aneurysm trapping or endovascular occlusion of the parent artery are the usual treatment options, which are associated with varying risks of ischemic complications. The authors report on a 60-year-old woman who had a 3.5-mm unruptured aneurysm in the lateral pontomesencephalic segment of the SCA with a significant interval growth to 8 mm. Direct surgical intervention comprising trapping of the aneurysm through a subtemporal approach and intradural anterior petrosectomy combined with revascularization of the distal SCA using the superficial temporal artery (STA) was performed. This approach provided sufficient space for the bypass instruments to be introduced into the deep surgical field at a more favorable angle to enhance microscopic visualization of the anastomosis with minimal retraction of the temporal lobe. The patient was discharged with no neurological deficit. Preservation of the blood flow in the distal SCA should be attempted to minimize the risk of ischemic injury, particularly when the aneurysms arise in the anterior or lateral segment of the SCA. The authors demonstrate the safety and effectiveness of the intradural anterior petrosectomy for STA-SCA bypass along with a relevant anatomical study.

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Güliz Acker, Nicolas Schlinkmann, Lucius Fekonja, Lukas Grünwald, Juliane Hardt, Marcus Czabanka and Peter Vajkoczy

OBJECTIVE

Moyamoya vasculopathy (MMV) is a steno-occlusive cerebrovascular disease that can be treated by a surgical revascularization. All the revascularization techniques influence the blood supply of the scalp, with a risk for wound healing disorders. The authors’ aim was to analyze the wound healing process in the patients who underwent a direct or combined bypass surgery with a focus on different skin incisions.

METHODS

The authors retrospectively identified all the patients with MMV who were treated surgically in their institution. Subsequently, they analyzed demographic data, clinical symptoms, surgical treatment, and detailed history of complications. Based on the evolution of their surgical techniques and the revascularization strategy to be used, the authors applied the following skin incisions: linear incision, curved incision, incomplete Y incision, and complete Y incision. Group comparisons regarding wound healing disorders were performed with significance testing using Fisher’s exact test.

RESULTS

The authors identified 172 patients with MMV (61.6% moyamoya disease, 7% unilateral moyamoya disease, 29.7% moyamoya syndrome, and 1.7% unilateral moyamoya syndrome), of whom 124 underwent bilateral operations. One-quarter of the patients were juveniles. A total of 236 hemispheres were included in the analysis, of which 27.9% were treated by a combined procedure with encephalomyosynangiosis. Overall, 5.1% major and 1.7% minor wound complications occurred. The overall wound complication rate was lower in direct revascularization compared to combined revascularization (3% vs 15.2%). The lowest incidence of wound healing disorders was found in the linear incision group for the parietal superficial temporal artery branch (1.6%), followed by the incomplete Y incision group for the frontal branch of the superficial temporal artery (3.8%) in the direct bypass group. In the combined revascularization cohort, major or minor wound disorders appeared in 14.3% and 4.8%, respectively, in the complete Y incision group and in 4.2% (for both major and minor) in the curved incision group. The complete Y incision caused significantly more wound healing disorders compared to the remaining incision types (17.1% vs 3.1%, p = 0.007).

CONCLUSIONS

Wound healing disorders are one of the major complications of revascularization surgery. Their incidence depends on the revascularization strategy and skin incision applied, with a complete Y incision giving the worst results.

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Kelly Russell, Erin Selci, Brian Black and Michael J. Ellis

OBJECTIVE

The longitudinal effects of sports-related concussion (SRC) in adolescents on health-related quality of life (HRQOL) remain poorly understood. Hence, the authors established two objectives of this study: 1) compare HRQOL outcomes among adolescents with an acute SRC or a sports-related extremity fracture (SREF) who were followed up until physician-documented clinical recovery; and 2) identify the clinical variables associated with worse HRQOL among adolescent SRC patients.

METHODS

The authors conducted a prospective cohort study of adolescents with acute SRC and those with acute SREF who underwent clinical assessment and follow-up at tertiary subspecialty clinics. Longitudinal patient-reported HRQOL was measured at the time of initial assessment and at each follow-up appointment by using the adolescent version (age 13–18 years) of the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale and Cognitive Functioning Scale.

RESULTS

A total of 135 patients with SRC (60.0% male; mean age 14.7 years; time from injury to initial assessment 6 days) and 96 patients with SREF (59.4% male; mean age 14.1 years; time from injury to initial assessment 8 days) participated in the study. At the initial assessment, the SRC patients demonstrated significantly worse cognitive HRQOL and clinically meaningful impairments in school and overall HRQOL compared to the SREF patients. Clinical variables associated with a worse HRQOL among SRC patients differed by domain but were significantly affected by the patients’ initial symptom burden and the development of delayed physician-documented clinical recovery (> 28 days postinjury). No persistent impairments in HRQOL were observed among SRC patients who were followed up until physician-documented clinical recovery.

CONCLUSIONS

Adolescent SRC is associated with temporary impairments in HRQOL that have been shown to resolve in patients who are followed up until physician-documented clinical recovery. Future studies are needed to identify the clinicopathological features that are associated with impaired HRQOL and to assess whether the initiation of multidisciplinary, targeted rehabilitation strategies would lead to an improvement in HRQOL.

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James R. Bean

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Chia-Hua Chen, Pin-Yuan Chen, You-Yu Lin, Li-Ying Feng, Shin-Han Chen, Chia-Yuan Chen, Yin-Cheng Huang, Chiung-Yin Huang, Shih-Ming Jung, Leslie Y. Chen and Kuo-Chen Wei

OBJECTIVE

Despite intensive medical treatment, patients with glioblastoma (grade IV glioma [GBM]) have a low 5-year survival rate of 5.5%. In this study, the authors tried to improve currently used therapies by identification of a therapeutic target, IGFBP3, for glioma treatment.

METHODS

IGFBP3 RNA expression in 135 patients newly diagnosed with glioma was correlated with clinicopathological factors. Immunohistochemical analysis was performed to determine IGFBP3 protein expression in glioma specimens. The effect of IGFBP3 depletion on cell proliferation was examined using IGFBP3 knockdown glioma cells. Intracranial infusion of IGFBP3 siRNAs was performed to evaluate the effect of IGFBP3 depletion in mouse intracranial xenograft models.

RESULTS

We demonstrated higher IGFBP3 expression in GBM than in tumor margin and grade II glioma. IGFBP3 expression was not only positively correlated with tumor grades but also associated with tumor histology and IDH1/2 mutation status. Additionally, higher IGFBP3 expression predicted shorter overall survival in glioma and GBM proneural subgroup patients. In vitro cell culture studies suggested IGFBP3 knockdown suppressed cell proliferation and induced cell cycle G2/M arrest as well as apoptosis in glioma cells. Also, accumulation of DNA double-strand breaks and γH2AX was observed in IGFBP3 knockdown cells. IGFBP3 knockdown delayed in vivo tumor growth in mouse subcutaneous xenograft models. Furthermore, convection-enhanced delivery of IGFBP3 siRNA to mouse brain suppressed intracranial tumor growth and prolonged survival of tumor-bearing mice.

CONCLUSIONS

Our findings suggest IGFBP3 predicts poor outcome of glioma patients and is a potential therapeutic target for which depletion of its expression suppresses tumor growth through inducing apoptosis and accumulation of DNA damage in glioma cells.

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Emerson Magno de Andrade, Raquel C. R. Martinez, Rosana L. Pagano, Patricia S. S. Lopes, Aline V. V. Auada, Flavia V. Gouveia, Geiza F. Antunes, Danielle V. Assis, Ivo Lebrun and Erich T. Fonoff

OBJECTIVE

Motor cortex stimulation (MCS) is a neurosurgical technique used to treat patients with refractory neuropathic pain syndromes. MCS activates the periaqueductal gray (PAG) matter, which is one of the major centers of the descending pain inhibitory system. However, the neurochemical mechanisms in the PAG that underlie the analgesic effect of MCS have not yet been described. The main goal of this study was to investigate the neurochemical mechanisms involved in the analgesic effect induced by MCS in neuropathic pain. Specifically, we investigated the release of γ-aminobutyric acid (GABA), glycine, and glutamate in the PAG and performed pharmacological antagonism experiments to validate of our findings.

METHODS

Male Wistar rats with surgically induced chronic constriction of the sciatic nerve, along with sham-operated rats and naive rats, were implanted with both unilateral transdural electrodes in the motor cortex and a microdialysis guide cannula in the PAG and subjected to MCS. The MCS was delivered in single 15-minute sessions. Neurotransmitter release was evaluated in the PAG before, during, and after MCS. Quantification of the neurotransmitters GABA, glycine, and glutamate was performed using a high-performance liquid chromatography system. The mechanical nociceptive threshold was evaluated initially, on the 14th day following the surgery, and during the MCS. In another group of neuropathic rats, once the analgesic effect after MCS was confirmed by the mechanical nociceptive test, rats were microinjected with saline or a glycine antagonist (strychnine), a GABA antagonist (bicuculline), or a combination of glycine and GABA antagonists (strychnine+bicuculline) and reevaluated for the mechanical nociceptive threshold during MCS.

RESULTS

MCS reversed the hyperalgesia induced by peripheral neuropathy in the rats with chronic sciatic nerve constriction and induced a significant increase in the glycine and GABA levels in the PAG in comparison with the naive and sham-treated rats. The glutamate levels remained stable under all conditions. The antagonism of glycine, GABA, and the combination of glycine and GABA reversed the MCS-induced analgesia.

CONCLUSIONS

These results suggest that the neurotransmitters glycine and GABA released in the PAG may be involved in the analgesia induced by cortical stimulation in animals with neuropathic pain. Further investigation of the mechanisms involved in MCS-induced analgesia may contribute to clinical improvements for the treatment of persistent neuropathic pain syndromes.